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Diabetes in Pregnancy
Abstract
This Clinical Practice Guideline has been prepared by the
Maternal Fetal Medicine Committee; reviewed by the Family Objective: This guideline reviews the evidence relating to the
Physicians Advisory, Aboriginal Health Initiative, and Clinical diagnosis and obstetrical management of diabetes in pregnancy.
Practice e Obstetrics Guideline Committees and the
Canadian Diabetes Association; endorsed by the Canadian Outcomes: The outcomes evaluated were short- and long-term
Diabetes Association; and approved by the Board of the maternal outcomes, including preeclampsia, Caesarean section,
Society of Obstetricians and Gynaecologists of Canada. future diabetes, and other cardiovascular complications, and fetal
outcomes, including congenital anomalies, stillbirth, macrosomia,
PRINCIPAL AUTHORS birth trauma, hypoglycemia, and long-term effects.
Howard Berger, MD, Toronto ON Evidence: Published literature was retrieved through searches of
PubMed and the Cochrane Library using appropriate controlled
Robert Gagnon, MD, Montreal QC
vocabulary (MeSH terms “diabetes” and “pregnancy”). Where
Mathew Sermer, MD, Toronto ON appropriate, results were restricted to systematic reviews,
randomized control trials/controlled clinical trials, and observational
MATERNAL FETAL MEDICINE COMMITTEE
studies. There were no date limits, but results were limited to
Melanie Basso, RN, Vancouver BC English or French language materials.
Hayley Bos, MD, Victoria BC Values: The quality of evidence was rated using the criteria described
in the Report of the Canadian Task Force on Preventive Health
Richard N. Brown, MD, Beaconsfield QC
Care (Table 1).
Emmanuel Bujold, MD, Quebec QC
Summary Statements
Stephanie L. Cooper, MD, Calgary AB
1. The adverse outcomes associated with diabetes in pregnancy are
Robert Gagnon, MD, Montreal QC substantially associated with hyperglycemia and the coexisting
Katy Gouin, MD, Quebec QC metabolic environment. Women with preexisting diabetes should
receive preconception care to optimize blood sugar control and
N. Lynne McLeod, MD, Halifax NS other comorbidities. Outcomes for the fetus/neonate and the mother
Savas M. Menticoglou, MD, Winnipeg MB in both pre-gestational diabetes mellitus and gestational diabetes
mellitus pregnancies are improved by multidisciplinary management
William R. Mundle, MD, Windsor ON in which the goal is achieving optimal blood sugar control and
Anne Roggensack, MD, Calgary AB appropriate fetal surveillance. (II-2)
Frank L. Sanderson, MD, Saint John NL 2. Retrospective studies indicate that women with pre-gestational
diabetes mellitus have an increased risk of stillbirth before 40
Jennifer D. Walsh, MD, Rothesay NB
weeks’ gestation compared with the general obstetrical population.
Disclosure statements have been received from all members of Similarly, large recent cohort and simulation studies of women with
the committee(s). gestational diabetes mellitus pregnancies also indicate a higher risk
of stillbirth between 36 to 39 weeks’ gestation. (II-2)
3. Women with gestational diabetes mellitus have a higher risk of
Key Words: Diabetes, pregnancy, stillbirth preeclampsia, shoulder dystocia, Caesarean section, and large for
http://dx.doi.org/10.1016/j.jogc.2016.04.002 gestational age infants. (II-2)
4. Treatment of women with gestational diabetes mellitus and optimi-
zation of glycemic control reduce the risk of preeclampsia, shoulder
J Obstet Gynaecol Can 2016;-(-):1e13 dystocia, and large for gestational age infants. (I)
Copyright ª 2016 by the The Society of Obstetricians and 5. The occurrence of gestational diabetes mellitus increases the risk of
Gynaecologists of Canada/La Société des obstétriciens developing type 2 diabetes in the future for the mother. (II-2)
et gynécologues du Canada
This document reflects emerging clinical and scientific advances on the date issued and is subject to change. The information should not be
construed as dictating an exclusive course of treatment or procedure to be followed. Local institutions can dictate amendments to these opinions.
They should be well documented if modified at the local level. None of these contents may be reproduced in any form without prior written
permission of the SOGC.
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CLINICAL PRACTICE GUIDELINE
Table 1. Key to evidence statements and grading of recommendations, using the ranking of the Canadian Task Force on
Preventative Health Care
Quality of evidence assessment* Classification of recommendations†
I Evidence obtained from at least one properly randomized A. There is good evidence to recommend the clinical preventive
controlled trial action
II-1 Evidence from well-designed controlled trials without B. There is fair evidence to recommend the clinical preventive
randomization action
II-2 Evidence from well-designed cohort (prospective or C. The existing evidence is conflicting and does not allow to make a
retrospective) or case-control studies, preferably from more recommendation for or against use of the clinical preventive
than one centre or research group action; however, other factors may influence decision-making
II-3 Evidence obtained from comparisons between times or places D. There is fair evidence to recommend against the clinical pre-
with or without the intervention. Dramatic results in uncontrolled ventive action
experiments (such as the results of treatment with penicillin in E. There is good evidence to recommend against the clinical pre-
the 1940s) could also be included in the category ventive action
III Opinions of respected authorities, based on clinical experience, F. There is insufficient evidence (in quantity or quality) to make a
descriptive studies, or reports of expert committees recommendation; however, other factors may influence decision-
making
*The quality of evidence reported in these guidelines has been adapted from The Evaluation of Evidence criteria described in the Canadian Task Force on Preventive
Health Care.
†Recommendations included in these guidelines have been adapted from the Classification of Recommendations criteria described in The Canadian Task Force on
Preventive Health Care.
Woolf SH, Battista RN, Angerson GM, Logan AG, Eel W. Canadian Task Force on Preventive Health Care. New grades for recommendations from the Canadian Task
Force on Preventive Health Care. CMAJ 2003;169:207e8.
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Diabetes in Pregnancy
5. For patients with pre-gestational diabetes mellitus or gestational indicated. When administered, close maternal glycemic surveil-
diabetes mellitus, starting at 28 weeks as a baseline, with subse- lance is recommended. (I-A)
quent serial assessment of fetal growth, every 3 to 4 weeks is 10. If not previously done, in women with threatened preterm labour
suggested to assess the effect of maternal glycemic control on fetal requiring betamethasone, a screening for gestational diabetes
growth rate and amniotic fluid volume. (II-2B) mellitus should be performed either before or at least 7 days after
6. Initiation of weekly assessment of fetal well-being at 36 weeks is the administration of betamethasone. (III-B)
recommended in pre-gestational diabetes mellitus and gestational 11. Women with gestational diabetes mellitus should be offered testing
diabetes mellitus. It is also reasonable to consider weekly fetal with a 75-g oral glucose tolerance test between 6 weeks and 6
assessment for women with diet controlled gestational diabetes months postpartum to detect prediabetes and diabetes.1 (II-2A)
mellitus beginning at 36 weeks. Acceptable methods of assess-
ment of fetal well-being near term can include the non-stress test, 11.1. Normal
non-stress test þ amniotic fluid index, biophysical profile, or a i. Fasting plasma glucose < 6.1 mmol/L
combination of these. (III-A)
ii. 2-hour plasma glucose < 7.8 mmol/L
7. If comorbid factors are present, such as obesity, evidence
iii. Glycated hemoglobin < 6.0%
of suboptimal glycemic control, large for gestational age
(> 90%), previous stillbirth, hypertension, or small for gesta- 11.2. Pre-diabetic
tional age (< 10%), earlier onset and/or more frequent fetal i. Fasting plasma glucose 6.1 to 6.9 mmol/L or
health surveillance is recommended. In specific cases in which
fetal growth restriction is suspected, the addition of umbilical ii. 2-hour plasma glucose 7.8 to 11.0 mmol/L or
artery and fetal middle cerebral artery Doppler assessment may iii. Glycated hemoglobin 6.0% to 6.4%
be helpful. (II-2A)
11.3. Type 2 diabetes mellitus
8. Pregnant women with gestational diabetes mellitus or pre-
i. FPG 7.0 mmol/L
gestational diabetes mellitus should be offered induction between
38 to 40 weeks’ gestation depending on their glycemic control and ii. Random plasma glucose or 2-hour plasma glucose
other comorbidity factors. (II-2B) 11.1 mmol/L
9. The administration of betamethasone to pregnant women with iii. Glycated hemoglobin 6.5%
gestational diabetes mellitus should be restricted to the routine 12. Breastfeeding is strongly recommended after delivery for all
obstetric indications related to the risk of preterm and late preterm women with pre-gestational diabetes mellitus or gestational dia-
delivery between 24 to 36 weeks’ gestation, when clinically betes mellitus. (II-2A)
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CLINICAL PRACTICE GUIDELINE
type 2 DM, doubled from 2.7% to 5.6% for GDM and IMPACT OF DIABETES MELLITUS ON PERINATAL
from 0.7% to 1.5% for PGDM.2 When compared with MORTALITY
non-diabetic pregnant women, the risk of both congenital Table 2 summarizes the RR or OR for stillbirth in preg-
anomalies (OR 1.86, 95% CI 1.49 to 2.33) and perinatal nancies with GDM in different populations studied
mortality (OR 2.33 [1.59 to 3.43]) remained higher in compared with non-GDM pregnancies. A wide range of
PGDM pregnant women.2 Similarly, in a Swedish absolute stillbirth rate (per 1000 pregnancies) has been re-
population-based cohort of over 1.2 million pregnancies ported, from as low as 0.32 to 4.2 per 1000 pregnancies,
with singleton gestations, women with GDM had a higher depending on the population studied and the gestational age
risk of adverse maternal outcomes (OR 1.81 [1.64 to 2.00]; cutoff used to define stillbirth (see Table 2). Some studies11
for shoulder dystocia of (OR 2.74 [2.04 to 3.68]); and for have confirmed that GDM may be diagnosed before 24
Caesarean section (OR 1.46 [1.38 to 1.54]).3 In addition, weeks’ gestation approximately 22% to 27% of the time.
with GDM, a higher risk of adverse neonatal outcomes has Almost one third (or 8% of the total diagnosed with GDM)
been reported, including LGA (OR 3.43 [3.21 to 3.67]), of these patients will have type 2 diabetes when tested
Erb’s palsy (OR 2.56 [1.96 to 3.32]), prematurity (OR 1.71 postpartum.12 This is particularly true in the presence of the
[1.58 to 1.86]), and major malformations (OR 1.19 [1.02 to following risk factors: maternal age > 35 years; obesity (BMI
1.39]).3 It is of interest that no statistically significant > 30); ethnicity (Aboriginal, African, Asian, Hispanic, South
improvement in maternal and neonatal outcome was seen Asian); family history of diabetes; polycystic ovary syn-
over time in either study, with the exception of a decline in drome; acanthosis nigricans; corticosteroid use; previous
the rate of congenital anomalies by 23%.2,3 pregnancy complicated with GDM; or previous macrosomic
Even though the benefits of specialized management of infant.1 Hutcheon et al.6 have suggested that only stillbirths
pregnancies complicated by PGDM is well-known, we now greater than 28 weeks’ gestation should be included to
have data from RCTs that document a reduction in certain determine the risk of stillbirth associated with GDM.
perinatal morbidities after diagnosis and management of Including women with an earlier diagnosis may not represent
GDM.4,5 The primary goal of this management is to attain the risk associated with GDM but rather a mix of GDM and
and then maintain euglycemia. This is best done by a other causes of stillbirths, leading to the introduction of a
multidisciplinary team with attention to diet and exercise; bias by including a period of follow-up during which, by
glucose monitoring; and, as appropriate, medical manage- design, death or the study outcome cannot occur. Because
ment with insulin and/or oral hypoglycemic agents. GDM is usually diagnosed after 24 to 28 weeks’ gestation, it
would be more appropriate to include only late stillbirth
The purpose of these guidelines is to review the diagnostic occurring after 28 weeks. Table 2 illustrates this phenome-
criteria and issues related to the obstetrical management of non. When defining stillbirth occurring at > 20 weeks, the
GDM and PGDM. Specific recommendations regarding risk of stillbirth attributable to GDM is reduced or insig-
glycemic control are beyond the scope of this document nificant.6e9 This is because more than 30% of stillbirths
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Diabetes in Pregnancy
occur at 20 to 23 weeks, before GDM is usually diagnosed.13 delivery in both GDM and PGDM pregnancies with
When including only stillbirths occurring after 28 weeks, specific attention to stratification by adequacy of glycemic
many studies to date have shown a trend or a statistically control; the impact on maternal, fetal and neonatal out-
significant increased risk of stillbirth attributable to comes; and economic analysis of different management
GDM.3,6,10 The specific excess risk of stillbirth in relation to strategies.
week of gestation has recently been shown in a cohort10 and
Summary Statements
simulation study derived from this cohort.14 This retro-
spective analysis14 of population-based data from California
showed that the overall risk of stillbirth from 36 to 42 weeks’ 1. The adverse outcomes associated with diabetes in
gestation was higher in women with GDM compared with pregnancy are substantially associated with
women without GDM (17.1 vs. 12.7/10 000 deliveries; RR hyperglycemia and the coexisting metabolic
1.34; 95% CI 1.2 to 1.5). Stillbirth rates were also examined at environment. Women with preexisting diabetes
each gestational age, and from 36 to 39 weeks, women with should receive preconception care to optimize blood
GDM had a statistically significant elevated RR of stillbirth sugar control and other comorbidities. Outcomes for
compared with women without GDM, ranging from RR the fetus/neonate and the mother in both pre-
1.45 (95% CI 1.1 to 1.9) at 36 weeks to RR 1.84 (95% CI 1.5 gestational diabetes mellitus and gestational diabetes
to 2.3) at 37 weeks.14 This increased risk of stillbirth mellitus pregnancies are improved by multidisci-
remained statistically significant at 39 weeks with a RR of plinary management in which the goal is achieving
1.56 (95% CI 1.2 to 2.0) but not at 40 and 41 weeks’ gesta- optimal blood sugar control and appropriate fetal
tion. The loss of significance at 40 to 41 weeks’ gestation was surveillance. (II-2)
either due to the increase in stillbirths in non-GDM preg- 2. Retrospective studies indicate that women with pre-
nancies15 or due to the relatively low number of patients after gestational diabetes mellitus have an increased risk of
39 weeks’ gestation in GDM pregnancies compared with stillbirth before 40 weeks’ gestation compared with the
non-GDM pregnancies. In addition, the risk of expectant general obstetrical population. Similarly, large recent
management in women with GDM carried a higher risk of cohort and simulation studies of women with gesta-
perinatal mortality than the risk of delivery at 39 and 40 tional diabetes mellitus pregnancies also indicate a
weeks’ gestation.10,14 The number of women with GDM higher risk of stillbirth between 36 to 39 weeks’
needed to be delivered at 39 and 40 weeks to prevent 1 gestation. (II-2)
excess death was 1518 and 1311, respectively.13 This is
comparable with the number needed to be delivered of 1299
Screening for GDM (Appendix A)
at 40 weeks for women without GDM and 40 years at the
time of delivery.15 The retrospective nature of this study and Despite not meeting many of the criteria for a program of
the inability to control for glycemic control and insulin population-based screening,18 screening for GDM has
treatment presented limitations. A retrospective cohort been accepted widely and is almost universally practiced
study from a center with a policy of induction by 40 weeks’ among health care professionals in North America.19,20
gestation for all pregnant women with diet-controlled GDM Methods for screening for GDM include the following:
suggested that it is protective against stillbirth compared with 1. Screening with a 1-hour 50-g glucose load (or
the general obstetrical population (OR 0.5 [0.4 to 0.7]).8 The alternative)
impact of this policy of induction on Caesarean section rates 2. Risk factor based screening
and neonatal morbidity is controversial. However, a small
3. One-step testing with a diagnostic 2-hour 75-g OGTT
RCT in mainly non-diabetic women by Nicholson et al.16
(this does not in fact constitute a screening test but
demonstrated a lower neonatal intensive care unit admis-
rather universal testing)
sion rate, a higher uncomplicated vaginal birth rate, and a
lower mean adverse outcome index score (better pregnancy 4. Screening with alternative biochemical tests: FPG, gly-
outcomes) among women who were actively managed using cated hemoglobin, random plasma glucose
elective labour induction based on a unique management of
risk scoring system. There have been no RCTs comparing screening for GDM
with no screening,20 thus the decision to perform screening
There is good evidence that PGDM is associated with a is based on the recent RCTs that have shown certain health
3- to 5-fold increased risk in stillbirths compared with benefits for treatment of GDM.4,5 Because GDM is an
non-diabetic pregnant women.17 Further prospective asymptomatic condition, logic dictates that some form of
research is needed on the optimization of timing of screening would need to be performed to diagnose cases
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CLINICAL PRACTICE GUIDELINE
that might benefit from treatment and management. The The CDA guidelines, in which SOGC was represented in
Toronto Tri Hospital study established that adverse out- an attempt to achieve consensus between obstetricians and
comes associated with GDM increase along a continuum endocrinologists, were updated in 2013.1 Guiding the de-
of increasing glucose thresholds.21 More recently, the Hy- cisions of the committee were the realization that: (1)
perglycemia and Adverse Pregnancy Outcome study22 women with 1 abnormal value on the OGTT (previously
confirmed these findings in a large, prospective, observa- classified as intolerance to glucose of pregnancy) have
tional study but was unable to define outcome-based similar outcomes of women with 2 abnormal values and
thresholds for the diagnosis of GDM. Despite this, the are routinely managed in the same manner12,29e33; (2) the
International Association of Diabetes and Pregnancy Study HAPO trial22 provided data that could be used to help
Group published recommendations for new thresholds for formulate outcome-based diagnostic thresholds for GDM;
the diagnosis of GDM based on statistical re-analysis of the and (3) there is a need to achieve some degree of unifor-
HAPO data.23 The thresholds for the 2-hour 75-g OGTT mity with regard to screening methodology and diagnostic
used were calculated by defining glucose concentrations at criteria in Canada. The CDA 2013 guidelines recommend a
which the OR of the 4 HAPO primary outcomes (birth- universal screening for GDM for all pregnant women be-
weight > 90%, primary Caesarean section rate, neonatal tween 24 and 28 weeks’ gestation followed by a 2-hour
hypoglycemia, and cord C-peptide levels > 90%) reached 75-g OGTT if the 1-hour PG after a 50-g glucose load
1.75. These thresholds, when applied to the HAPO cohort, value is 7.8 mmol.1 This is referred to as the “preferred
led to an average GDM incidence of 17% across all HAPO 2-step” approach, with diagnostic criteria thresholds cor-
sites. In addition the IADPSG recommended abandoning responding to an OR of 2.0 for the 4 main HAPO out-
the 1-hour 50-g glucose load in favour of a 1-step testing comes.22 An “alternative 1-step” approach with diagnostic
strategy. Table 3 provides a summary of the glucose criteria thresholds with an OR of 1.7522 for adverse peri-
thresholds, screening, and diagnostic strategies used natal outcome is also acceptable.1 The 2014 American
worldwide. In North America, either a 2-step or a 1-step Diabetes Association guidelines25 endorsed an approach
approach is believed to be acceptable because there is no similar to those of the CDA 2013 guidelines, although the
demonstrated difference in outcome using either second step differs with the diagnostic test remaining the
strategy.1,24,25 100-g OGTT.25 These guidelines are also more in line with
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Diabetes in Pregnancy
the ACOG 2013 guidelines.25 It is of note that the Aus- (Aboriginal, African, Asian, Hispanic, South Asian); family
tralasian Diabetes in Pregnancy Society and the World history of diabetes; polycystic ovary syndrome; acanthosis
Health Organization have both adopted the IADPSG nigricans; corticosteroid use; previous pregnancy compli-
criteria in their 2013 guidelines.27,28 The incidence of cated with GDM; or previous macrosomic infantdeither a
GDM varies between 3.2% and 16.1%, depending of the 1-hour 50-g GCT or a diagnostic 75-g OGTT can be
thresholds used and the composition of the screened offered in the first half of the pregnancy and repeated at 24
population. Table 3 summarizes the different screening and to 28 weeks’ gestation if the result is negative.1 Until there
diagnostic criteria used for GDM. is evidence to support alternative thresholds for the early
50-g GCT or 75-g OGTT, we suggest using the same
THE 1-HOUR 50-G GCT criteria that is used for the standard 24 to 28 weeks’
gestation test.
It is recognized that there is controversy regarding the use
of a 1-hour 50-g non-fasting GCT as a screening test for Pregnancy after bariatric surgery is becoming more com-
GDM. Criticism is focused on the following issues: (1) the mon. GDM diagnostic testing, when applied to women
inability to identify women with isolated elevated FPG, (2) who have undergone Roux-en-Y gastric bypass, increases
limited reproducibility, (3) incomplete uptake of the diag- the GDM diagnosis without changing pregnancy
nostic test in those whose screening result is positive, (4) outcome.37 In addition, a high incidence of 58% of reactive
delay in diagnosis of GDM, and (5) test sensitivity of only hypoglycemia is encountered during OGTT. Therefore,
76.6%.34 In contrast, this test is widely practiced in North studies are needed to provide alternative screening and
America and has high acceptance in both patients and diagnostic criteria for GDM in women who have under-
caregivers. Until data emerge that support significant su- gone bariatric surgery. Due to a lack of evidence sup-
perior outcomes with a 1-step diagnostic test, the SOGC porting different thresholds for screening for GDM, it is
has decided to recommend the continued use of the 50-g not possible to define alternative thresholds. Until then, it
OGTT as the primary screening tool in women without is reasonable to order fasting and 1-hour postprandial
high-risk characteristics. blood glucose in addition to the glycated hemoglobin level
in these women to rule out abnormalities in carbohydrate
There are no established criteria for the diagnosis of GDM metabolism (see Appendix A).
based on the 1-hour 50-g post-load value, but it is recog-
Recommendations
nized that there are results of this test that indicate a very
high chance of diagnosing GDM on the confirmatory test.
Cheng et al.,35 in a cohort of 14 771 pregnancies with 1. The “preferred screening and diagnostic 2-step”
GDM, showed that there is an increase in Caesarean sec- approach for gestational diabetes mellitus of the Ca-
tion (OR 4.18 [1.15 to 15.2]) and an increase in shoulder nadian Diabetes Association 2013 guidelines is
dystocia (OR 15.14 [1.64 to 140]) in women who had a endorsed. All pregnant women should be offered
screening 1-hour 50-g glucose post-load value above 11.1 screening between 24 to 28 weeks using a standardized
mmol/L. When the outcome 1-hour 50-g glucose non-fasting 50-g glucose challenge screening test with
post-load is defined by an abnormal OGTT only, the plasma glucose measured 1 hour later. (III-B)
cutoff value that can reliably diagnose GDM is probably 1.1. If the value is < 7.8 mmol/L, no further testing
> 12.2 mmol/L.35,36 is required.
1.2. If the value of the glucose challenge screening
For these reasons, the joint CDA-SOGC 2013 committee test is 7.8 to 11.0, a 2-hour 75-g oral glucose
on diabetes in pregnancy decided that if a value of 11.1 tolerance test with fasting plasma glucose,
mmol/L after a 1-hour 50-g glucose post-load is obtained, 1-hour plasma glucose, and 2-hour plasma
a 2-hour 75-g OGTT is unnecessary. glucose should be performed.
When the a priori risk of diagnosing GDM or overt DM is Gestational diabetes mellitus is diagnosed if 1 value is
high based on clinical, demographic, or historical risk met or exceeded:
factors, it will be prudent to offer either screening or i. Fasting plasma glucose 5.3 mmol/L
testing earlier in gestation. This is mainly to facilitate the ii. 1-hour plasma glucose 10.6 mmol/L
diagnosis of unrecognized type 2 DM that will benefit from iii. 2-hour plasma glucose 9.0 mmol/L
earlier interventions to ensure adequate glycemic control. 1.3. If the value of the glucose challenge screening
In the presence of the following risk factorsdmaternal age test is 11.1 mmol/L, gestational diabetes
> 35 years; obesity (pre-pregnancy BMI > 30); ethnicity mellitus is diagnosed.
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CLINICAL PRACTICE GUIDELINE
2. The “alternative 1-step diagnostic” approach of the 4. Treatment of women with gestational diabetes
Canadian Diabetes Association 2013 guidelines is mellitus and optimization of glycemic control reduce
acceptable. In this strategy pregnant women should be the risk of preeclampsia, shoulder dystocia, and large-
offered testing between 24 to 28 weeks using a stan- for-gestational-age infants. (I)
dardized 2-hour 75-g oral glucose tolerance test with 5. The occurrence of gestational diabetes mellitus
fasting plasma glucose, 1-hour plasma glucose, and 2- increases the risk of developing type 2 diabetes in the
hour plasma glucose. (III-B) future for the mother. (II-2)
Gestational diabetes mellitus is diagnosed if 1 value is
met or exceeded:
i. Fasting plasma glucose 5.1 mmol/L Optimizing Fetal Growth and Preventing
ii. 1-hour plasma glucose 10.0 mmol/L Macrosomia
iii. 2-hour plasma glucose 8.5 mmol/L Fetal macrosomia may occur without gestational diabetes.
However, the incidence of macrosomia in pregnancies
It is recognized that the use of different diagnostic
complicated with maternal hyperglycemia is a function of
thresholds for the “preferred” and “alternative” strate-
maternal glycemic control.22,32,33,38,40e42 There is an
gies could cause confusion in certain settings. Despite
association between excessive fetal weight and certain
this, the committee has identified the importance of
perinatal complications, including shoulder dystocia and
remaining aligned with the current Canadian Diabetes
birth trauma,43,44 perinatal mortality,45 and Caesarean
Association 2013 guidelines as being a priority. It is thus
delivery.21,46e49 Landon et al.5 have shown that the treat-
recommended that each care centre strategically align
ment of mild gestational diabetes results in a significant
with 1 of the 2 strategies and implement protocols to
reduction compared with usual care in several prespecified
ensure consistent and uniform reporting of test results.
secondary outcomes, including mean birth weight (3302 vs.
3. If there is a high risk of gestational diabetes mellitus
3408 g), neonatal fat mass (427 vs. 464 g), the frequency of
based on multiple risk factors, screening or testing
LGA infants (7.1% vs. 14.5%), birth weight greater than
should be offered during the first half of the pregnancy
4000 g (5.9% vs. 14.3%), shoulder dystocia (1.5% vs.
and repeated at 24 to 28 weeks’ gestation if initially
4.0%), and Caesarean delivery (26.9% vs. 33.8%). In a
normal. If for any reason it was missed or if there is a
secondary analysis the Maternal Fetal Medicine Network
clinical suspicion of later onset of gestational diabetes,
RCT for the treatment of mild GDM demonstrated that
a screening or diagnostic test should be performed.
induction of labour between 37 to 40 weeks’ gestation in
(II-2B)
women did not increase the rate of Caesarean delivery.50
Treatment of GDM compared with usual care was also
associated with reduced rates of preeclampsia and gesta-
tional hypertension (combined rates for the 2 conditions,
ANTEPARTUM MANAGEMENT OF GDM 8.6% vs. 13.6%; P ¼ 0.01).
The benefits of treating GDM are now generally Current CDA 2013 guidelines for maternal glycemic con-
accepted.4,5 There is also an association between the trol suggest striving for the following targets on self-
presence of GDM and hypertensive disorders of preg- monitored blood glucose: fasting SMBG < 5.3 mmol/L;
nancy.22,38 The goals of treatment are: (1) optimizing 1-hour postprandial < 7.8 mmol/L; or 2 hours post-
fetal growth and preventing macrosomia, (2) reducing the prandial < 6.7 mmol/L. This often can be achieved with
risk of intrauterine fetal death, (3) reducing the risk of nutritional counselling and modification of physical activity
preeclampsia,39 (4) reducing the risk of Caesarean section, level. When treatment with non-medical interventions is
and (5) reducing the risk of neonatal complications, unsuccessful after 1 to 2 weeks, medical therapy should be
including shoulder dystocia, birth trauma, and neonatal initiated.1 Optimizing maternal glycemic control in women
hypoglycemia. with GDM decreases the risk of preeclampsia, fetal mac-
Summary Statements rosomia, shoulder dystocia, and Caesarean section.5
An SGA fetus can also be a complication of overtreatment
3. Women with gestational diabetes mellitus have a of GDM or a complication of associated risk factors.50 An
higher risk of preeclampsia, shoulder dystocia, RCT comparing insulin therapy based on “tight” maternal
Caesarean section, and large for gestational age glycemic control (keeping fasting SMBG < 5.0 mmol/L
infants. (II-2) and 2-hour postprandial at < 6.7 mmol/L) alone versus
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Diabetes in Pregnancy
ultrasound-based measurement of fetal abdominal known value of the biophysical profile in non-diabetic
circumference percentile and more “relaxed” maternal pregnancies59,60 to a diabetic pregnancy surveillance
glycemic control (fasting SMBG < 6.6 mmol/L and 2- protocol.
hour postprandial < 11.1 mmol/L) demonstrated that
both methods resulted in an equivalent perinatal The use of pre-delivery weight estimation to detect the
outcome.51 The addition of measuring the abdominal presence of fetal macrosomia is problematic due to the
circumference every 3 to 4 weeks helped guide the decision poor performance of all methods of pre-delivery fetal
to treat some pregnant women more aggressively with weight estimation.61e63 Previous evidence has suggested
tighter glycemic control to prevent macrosomia but using a that in the context of suspected fetal macrosomia there is
more “relaxed” control if the abdominal circumference was no proven benefit of induction of labour compared with
low to prevent the development of an SGA fetus.51e53 If a expectant management.64 However, more recently, Boul-
SGA fetus is suspected, umbilical artery and middle cere- vain et al.65 demonstrated in a large randomized clinical
bral artery Doppler (if available) should be performed as trial that induction of labour for suspected large-for-date
part of the assessment of placental function and fetal fetuses is associated with a reduced risk of shoulder
well-being. In the presence of fetal macrosomia or poor dystocia and associated morbidity compared with expec-
glycemic control, polyhydramnios may also develop. tant management. Induction of labour did not increase the
Therefore, the measurement of the amniotic fluid volume risk of Caesarean delivery and improved the likelihood of
can be another tool used to assess maternal glycemic spontaneous vaginal delivery. There is only 1 randomized
control in the context of GDM.54 clinical trial comparing elective induction with expectant
management in GDM pregnancies.66 In a mixed group of
Reducing the Risk of Intrauterine Fetal Death women with uncomplicated insulin-requiring GDM or
The most important factor to minimize fetal death is PGDM, expectant management of pregnancy after 38
optimizing maternal glycemic control to optimize fetal weeks’ gestation did not reduce or increase the incidence of
growth. The 2007 SOGC guidelines on antenatal fetal Caesarean delivery. However, there was an increased
surveillance55 lists pre-pregnancy diabetes and insulin- prevalence of LGA infants (23% vs. 10%) and shoulder
requiring GDM as conditions associated with increased dystocia (3% vs. 0% [not significant]) in the expectant
perinatal morbidity/mortality and conditions in which group.
antenatal fetal surveillance may be beneficial. In the light of
more recent evidence that diet-controlled GDM might also Recommendations
be associated with an increase in perinatal mortality,6,10,14
particularly after 38 weeks’ gestation, these patients 4. Women with preexisting or gestational diabetes
should not be excluded from a protocol for antenatal fetal mellitus should be provided with care by a
surveillance applicable to high-risk pregnancies. Landon multidisciplinary team aimed at attaining and then
and Vickers56 previously questioned whether patients with maintaining euglycemia. (II-2B)
diet-controlled GDM should have any fetal health sur- 5. For patients with pre-gestational diabetes mellitus or
veillance prior to 40 weeks’ gestation because the risk of gestational diabetes mellitus, starting at 28 weeks as a
fetal death is low. In contrast, they advocated twice per baseline, with subsequent serial assessment of fetal
week fetal health surveillance starting at 32 weeks for all growth, every 3 to 4 weeks is suggested to assess the
insulin-treated GDM patients. Most published protocols effect of maternal glycemic control on fetal growth
for antenatal fetal surveillance for diet-controlled GDM rate and amniotic fluid volume. (II-2B)
include ultrasound for fetal growth every 3 to 4 weeks 6. Initiation of weekly assessment of fetal well-being at
starting at 28 weeks’ gestation and delivery no later than 40 36 weeks is recommended in pre-gestational diabetes
weeks’ gestation.8,51,53,57 The ACOG 2013 guidelines24 mellitus and gestational diabetes mellitus. It is also
state that for women with GDM and poor glycemic con- reasonable to consider weekly fetal assessment for
trol, fetal surveillance may be beneficial. A retrospective women with diet controlled gestational diabetes mel-
study of 2134 women with pregnancies complicated by litus beginning at 36 weeks. Acceptable methods of
diabetes reported that an antepartum fetal surveillance assessment of fetal well-being near term can include
program using a twice-weekly non-stress test and fluid the non-stress test, non-stress test þ amniotic fluid
index assessment was successful in preventing stillbirth.58 index, biophysical profile, or a combination of these.
The role of the biophysical profile in antenatal surveil- (III-A)
lance of diabetic pregnancies has not been studied in a 7. If comorbid factors are present, such as obesity,
large population, but one can logically extrapolate from the evidence of suboptimal glycemic control, large for
- JOGC - 2016 l 9
CLINICAL PRACTICE GUIDELINE
10 l - JOGC - 2016
Diabetes in Pregnancy
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CLINICAL PRACTICE GUIDELINE
Yvonne M. Cargill, MD, Ottawa ON 2. Accuracy and improved safety in the diagnosis of ectopic
pregnancy.
Nanette Denis, RDMS, Saskatoon SK
Johanne Dubé, MD, Mont-Royal QC Evidence: A MEDLINE search and review of bibliographies identified
articles was conducted.
Phyllis Glanc, MD, Toronto ON
Values: The evidence collected was reviewed by the Diagnostic
Kenneth I. Lim (Co-chair), MD, Vancouver BC
Imaging Committee of the Society of Obstetricians and
Lucie Morin (Co-chair), MD, Outremont QC Gynaecologists of Canada. The recommendations were made
Kentia Naud, MD, Edmonton AB according to the guidelines developed by The Canadian Task Force
on Preventive Health Care (Table 1).
Mila Smithies, MD, Halifax ON
Benefits, Harms, and Costs: Women presenting with first trimester
Disclosure statements have been received from all members of bleeding may be incorrectly diagnosed with a missed abortion, may
the committee. have an ectopic pregnancy overlooked, or may be inappropriately
reassured about viability. Improvement in the identification of the
sonographic landmarks of normal embryonic development and
awareness of the sonographic risk factors of pregnancy failure may
lead to more case-specific management strategies. Diagnosis of
suspected ectopic pregnancy often involves an assessment of both
hormonal markers and sonographic features. Maternal morbidity
and mortality can be reduced with an early diagnosis of ectopic
Key Words: Missed abortion, anembryonic pregnancy, ectopic pregnancy.
pregnancy, ultrasound, threatened abortion
Recommendations
http://dx.doi.org/10.1016/j.jogc.2016.06.001
1. Embryonic demise can be diagnosed when ultrasound imag-
ing documents the following features: intrauterine gestational
sac, embryonic crown-rump length 7 mm, no cardiac activity.
J Obstet Gynaecol Can 2016;38(10):982e988 (II-2A)
Copyright ª 2016 The Society of Obstetricians and Gynaecologists of 2. Anembryonic pregnancy can be diagnosed when ultrasound imag-
Canada/La Société des obstétriciens et gynécologues du Canada. ing documents the following features: no embryo and mean sac
Published by Elsevier Inc. All rights reserved. diameter 25 mm. (II-2A)
This document reflects emerging clinical and scientific advances on the date issued, and is subject to change. The information should not be
construed as dictating an exclusive course of treatment or procedure to be followed. Local institutions can dictate amendments to these opinions.
They should be well documented if modified at the local level. None of these contents may be reproduced in any form without prior written
permission of the publisher.
Table 1. Key to evidence statements and grading of recommendations, using the ranking of the Canadian Task Force on
Preventative Health Care
Quality of evidence assessment* Classification of recommendations†
I: Evidence obtained from at least one properly randomized A. There is good evidence to recommend the clinical preventive action
controlled trial B. There is fair evidence to recommend the clinical preventive action
II-1: Evidence from well-designed controlled trials without C. The existing evidence is conflicting and does not allow to make a
randomization recommendation for or against use of the clinical preventive action;
II-2: Evidence from well-designed cohort (prospective or however, other factors may influence decision-making
retrospective) or case-control studies, preferably from more than D. There is fair evidence to recommend against the clinical preventive
one centre or research group action
II-3: Evidence obtained from comparisons between times or places E. There is good evidence to recommend against the clinical preven-
with or without the intervention. Dramatic results in uncontrolled tive action
experiments (such as the results of treatment with penicillin in the L. There is insufficient evidence (in quantity or quality) to make a
1940s) could also be included in the category recommendation; however, other factors may influence
III: Opinions of respected authorities, based on clinical experience, decision-making
descriptive studies, or reports of expert committees
*The quality of evidence reported in these guidelines has been adapted from The Evaluation of Evidence criteria described in the Canadian Task Force on Preventive
Health Care.
†Recommendations included in these guidelines have been adapted from the Classification of recommendations criteria described in The Canadian Task Force on
Preventive Health Care.
3. In clinically stable or asymptomatic patients, when a suspicion of nancy. With a complex adnexal mass, a tubal ring, or complex fluid in
early pregnancy loss is being considered, a follow-up ultrasound the pelvis the probability of tubal ectopic pregnancy is high, while a
scan should be booked after an additional 7e10 days. (III-A) live extrauterine embryo is diagnostic of an ectopic pregnancy. (II-2A)
4. Failure to detect an intrauterine gestational sac, by transvaginal 5. b-hCG values in a viable pregnancy rise at least 55% over 48 hours.
ultrasound, when the b-hCG value exceeds a discriminatory level of Deviation from this before 7 weeks is indicative of a nonviable
2000e3000 mIU/mL indicates an increased risk for ectopic preg- pregnancy, intrauterine or ectopic. (II-2A)
ABBREVIATIONS
b-hCG beta human chorionic gonadotropin
CRL crown-rump length
CS Caesarean section
In the second study using 359 women from the first study Table 2. Typical embryonic chronological landmarks in
group, the authors concluded that growth rates for the the development of the embryo, as seen on transvaginal
gestational sac and the embryo could not predict viability ultrasound examination (conception to 8 weeks
accurately. They demonstrated that the absence of a visible development)
yolk sac or embryo on second scan performed 7 days or 5 þ 0 weeks Empty gestational sac (mean diameter 10 mm)
more after the first scan was always associated with preg- 5 þ 4 weeks Gestational sac with yolk sac visible
nancy loss.4 6 þ 0 weeks Gestational sac (mean diameter 16 mm) and yolk
sac with adjacent heart beat but small embryo
Based on these studies, the Multispecialty Panel on Early (3mm)
First Trimester Diagnosis of Miscarriage and Exclusion 8 þ 0 weeks Embryo with CRL of 16 mm with separate amniotic
sac and celomic cavity with yolk sac
of a Viable Intrauterine Pregnancy from the Society of
Embryo body movements visible, heart rate 175 bpm
Radiologists in Ultrasound published guidelines that were
Table 3. Diagnosis of asymptomatic tubal ectopic If the viability and location of a pregnancy needs to be
pregnancy decided at a single point in time, such as an emergency visit
Possible ectopic Serum b-hCG level > 2000 mIU/mL by a pregnant woman with symptoms of bleeding and pain,
pregnancy Absence of intrauterine pregnancy on the most useful single test to differentiate a viable from a
transvaginal ultrasound nonviable pregnancy is a progesterone level. Progesterone
Probable ectopic Serum b-hCG level > 2000 mIU/mL less than 20 nmol/L have a sensitivity of 75% and speci-
pregnancy Absence of intrauterine pregnancy on
transvaginal ultrasound ficity of 98% in predicting nonviable pregnancy.20 The
Adnexal mass on transvaginal ultrasound most useful single test to differentiate an intrauterine from
Diagnosis of Gestational sac inside fallopian tube on an ectopic pregnancy is an ultrasound.
ectopic pregnancy transvaginal ultrasound
An ultrasound diagnosis of an embryonic demise can be
made when there is no cardiac activity in an embryo with a
CRL greater than or equal to 7 mm.1 Ultrasound diagnosis
The amnion is a thin, rounded membrane surrounding the of an anembryonic pregnancy can be made when the mean
embryo and is completely enveloped by the thick echogenic gestational sac diameter is greater than or equal to 25 mm
chorion. The yolk sac is situated between the amnion and but without a yolk sac or an embryo. Transvaginal ultra-
the chorion. The amnion is thin, difficult to visualize, and sound is the method of choice for early first trimester
best seen when the amnion membrane is perpendicular to pregnancy complications although transabdominal or
the ultrasound beam. The amnion grows rapidly during transvaginal ultrasound may be used for patients with first
pregnancy and fuses with the chorion between 12 and 16 trimester bleeding.
weeks of gestation.8,10
In the absence of cardiac activity, if the gestational sac or
The embryo can be visualized when as small as 1e2 mm in the embryo is smaller than expected by menstrual dating,
CRL length. Cardiac activity immediately adjacent to the the possibility of incorrect dates should always be consid-
yolk sac indicates a live embryo but may not be seen until ered, especially when there is no pain or bleeding. Under
the embryo CRL measures 7 mm. From 5.5e6.5 weeks, these circumstances, a repeat ultrasound scan should be
an embryonic heart rate of less than 100 beats per minute arranged after an additional 7e10 days.1,5 Single or serial
is normal. During the following 3 weeks, there is a b-hCG values may be used to add support to a diagnosis
rapid increase up to 180 beats per minute.11,12 Table 2 of a nonviable pregnancy. b-hCG values that are falling or
summarizes the sonographic features of normal early not rising appropriately would confirm a nonviable
pregnancy. pregnancy.
No intrauterine pregnancy
and β-hCG available
(1) empty uterus, (2) simple adnexal cyst, (3) complex adnexal mass, (4)
Ultrasound signs of an solid adnexal mass, (5) tubal ring,( 6) free fluid in the adnexa-cul de sac
ectopic? area, or (7) complex fluid in the pelvis .
No
Yes
18. Ferrazzi E, Brambati B, Lanzani A, Oldrini A, Stripparo L, Guerneri S, et al. 25. Doubilet PM, Benson CB. First, do no harm.to early. J Ultrasound Med
The yolk sac in early pregnancy failure. Am J Obstet Gynecol 2010;29:685e9.
1988;158:137e42.
26. Fleischer AC, Pennell RG, McKee MS, Worrell JA, Keefe B, Herbert CM,
19. Mantoni M, Pedersen JF. Intrauterine haematoma an ultrasonic study of et al. Ectopic pregnancy: features transvaginal sonography. Radiology
threatened abortion. British J Obstet Gynecol 1981;88:47e51. 1990;174:375e8.
20. Verhaegen J, Gallos ID, van Mello NM, Abdel-Aziz M, Takwoingi Y, et al. 27. Richardson A, Gallos I, Dobson S, Campbell BK, Coomarasam A, Raine-
Accuracy of single progesterone test to predict early pregnancy outcome in Fenning N. Accuracy of first trimester ultrasound diagnosis of tubal
women with pain or bleeding: meta-analysis of cohort studies. BMJ pregnancy in the absence of an obvious extrauterine embryo: systematic
2012;345:e6077. review and meta analysis. Ultrasound Obstet Gynecol 2016;477:28e37.
21. DeVoe RW, Pratt JH. Simultaneous intra- and extrauterine pregnancy. Am J 28. De Crespigny LC. Demonstration of ectopic pregnancy by transvaginal
Obstet Gynecol 1948;56:1119. ultrasound. British J Obstet Gynaecol 1988;95:1253e6.
22. Dimitry ES, Subak-Sharpe R, Mills M, Maragara R, Winston R. Nine cases 29. Jurkovic D, Bourne TH, Jauniaux E. Transvaginal colour Doppler study of
of heterotopic pregnancies in 4 years of in vitro fertilization. Fertil Steril blood flows in ectopic pregnancies. Fertil Steril 1992;57:68e72.
1990;53:107e10.
30. Kadar N, DeVore G, Romero R. Discriminatory hCG zone: its use in the
23. Gamberdella FR, Marrs RP. Heterotopic pregnancy associated with assisted sonographic evaluation for ectopic pregnancy. Obstet Gynecol
reproductive technology. Am J Obstet Gynecol 1989;160:1520e4. 1981;58:156e61.
24. Nyberg DA, Laing FC, Filly RA, Uri-Simmons M, Jeffrey RB. 31. Condous G, Kirk E, Lu C, Van Huffel S, Gevaert O, de Moor B, et al.
Ultrasonographic differentiation of the gestational sac of early intrauterine Diagnostic accuracy of varying discriminatory zones for the prediction of
pregnancy from the pseudogestational sac of ectopic pregnancy. Radiology ectopic pregnancy in women with a pregnancy of unknown location.
1983;146:755e9. Ultrasound Obstet Gynecol 2005;26:770e5.
Julie Hakim, MD, Ottawa ON Benefits/Harms/Costs: These guidelines are designed to help
practitioners caring for adolescent women during pregnancy
Deanna Murphy, MD, St. John’s NL in Canada and allow them to take the best care of these
Rachel Spitzer, MD, Toronto ON young women in a manner appropriate for their age, cultural
backgrounds, and risk profiles.
Disclosure statements have been received from all contributors.
The literature searches and bibliographic support for this Recommendations
guideline were undertaken by Becky Skidmore, Medical 1. Health care providers should adapt their prenatal care for
Research Analyst, Society of Obstetricians and Gynaecologists adolescents and offer multidisciplinary care that is easily
of Canada. accessible to the adolescent early in the pregnancy, recognizing
that adolescents often present to care later than their adult
counterparts. A model that provides an opportunity to address all
of these needs at one site may be the preferred model of care for
pregnant adolescents. (II-1A)
2. Health care providers should be sensitive to the unique
Key Words: Pregnancy, adolescent, teen, teenager, youth developmental needs of adolescents through all stages of
pregnancy and during intrapartum and postpartum care. (III-B)
3. Adolescents have high-risk pregnancies and should be managed
accordingly within programs that have the capacity to manage their
care. The unique physical risks of adolescent pregnancy should be
J Obstet Gynaecol Can 2015;37(8):740–756 recognized and the care provided must address these. (II-1A)
This document reflects emerging clinical and scientific advances on the date issued and is subject to change. The information
should not be construed as dictating an exclusive course of treatment or procedure to be followed. Local institutions can dictate
amendments to these opinions. They should be well documented if modified at the local level. None of these contents may be
reproduced in any form without prior written permission of the SOGC.
Table 1. Key to evidence statements and grading of recommendations, using the ranking of the Canadian Task Force
on Preventive Health Care
Quality of evidence assessment* Classification of recommendations†
I: Evidence obtained from at least one properly randomized A. There is good evidence to recommend the clinical preventive action
controlled trial
II-1: Evidence from well-designed controlled trials without B. There is fair evidence to recommend the clinical preventive action
randomization
II-2: Evidence from well-designed cohort (prospective or C. The existing evidence is conflicting and does not allow to make a
retrospective) or case–control studies, preferably from recommendation for or against use of the clinical preventive action;
more than one centre or research group however, other factors may influence decision-making
II-3: Evidence obtained from comparisons between times or D. There is fair evidence to recommend against the clinical preventive action
places with or without the intervention. Dramatic results in
uncontrolled experiments (such as the results of treatment with E. There is good evidence to recommend against the clinical preventive
penicillin in the 1940s) could also be included in this category action
III: Opinions of respected authorities, based on clinical experience, L. There is insufficient evidence (in quantity or quality) to make
descriptive studies, or reports of expert committees a recommendation; however, other factors may influence
decision-making
*The quality of evidence reported in these guidelines has been adapted from The Evaluation of Evidence criteria described in the Canadian Task Force on
Preventive Health Care.119
†Recommendations included in these guidelines have been adapted from the Classification of Recommendations criteria described in the Canadian Task Force
on Preventive Health Care.119
4. Fathers and partners should be included as much as possible in the care usual for adult populations is supported for pregnant
pregnancy care and prenatal/infant care education. (III-B) adolescents at this time. (II-2A)
5. A first-trimester ultrasound is recommended not only for the usual 12. Practitioners should consult gestational diabetes mellitus (GDM)
reasons for properly dating the pregnancy, but also for assessing guidelines. In theory, testing all patients is appropriate, although
the increased risks of preterm birth. (I-A) rates of GDM are generally lower in adolescent populations.
Practitioners should be aware, however, that certain ethnic groups
6. Counselling about all available pregnancy outcome options
including Aboriginal populations are at high risk of GDM. (II-2A)
(abortion, adoption, and parenting) should be provided to any
adolescent with a confirmed intrauterine gestation. (III-A) 13. An ultrasound anatomical assessment at 16 to 20 weeks
is recommended because of increased rates of congenital
7. Testing for sexually transmitted infections (STI) (II-2A) and
anomalies in this population. (II-2A)
bacterial vaginosis (III-B) should be performed routinely upon
presentation for pregnancy care and again in the third trimester; 14. As in other populations at risk of intrauterine growth restriction
STI testing should also be performed postpartum and when (IUGR) and low birth weight, an ultrasound to assess fetal well-
needed symptomatically. being and estimated fetal weight at 32 to 34 weeks gestational
age is suggested to screen for IUGR. (III-A)
a. Because pregnant adolescents are inherently at increased
risk for preterm labour, preterm birth, and preterm pre-labour 15. Visits in the second or third trimester should be more frequent to
rupture of membranes, screening and management of address the increased risk of preterm labour and preterm birth
bacterial vaginosis is recommended. (III-B) and to assess fetal well-being. All caregivers should be aware of
the signs and symptoms of preterm labour and should educate
b. After treatment for a positive test, a test of cure is needed 3 their patients to recognize them. (III-A)
to 4 weeks after completion of treatment. Refer partner for
screening and treatment. Take the opportunity to discuss 16. It should be recognized that adolescents have improved vaginal
condom use. (III-A) delivery rates and a concomitantly lower Caesarean section
rate than their adult counterparts. (II-2A) As with antenatal care,
8. Routine and repeated screening for alcohol use, substance peripartum care in hospital should be multidisciplinary, involving
abuse, and violence in pregnancy is recommended because of social care, support for breastfeeding and lactation, and the
their increased rates in this population. (II-2A) involvement of children’s aid services when warranted. (III-B)
9. Routine and repeated screening for and treatment of mood 17. Postpartum care should include a focus on contraceptive
disorders in pregnancy is recommended because of their methods, especially long-acting reversible contraception
increased rates in this population. The Edinburgh Postnatal methods, as a means to decrease the high rates of repeat
Depression Scale administered in each trimester and postpartum, pregnancy in this population; discussion of contraception should
and more frequently if deemed necessary, is one option for such begin before delivery. (III-A)
screening. (II-2A)
18. Breastfeeding should be recommended and sufficient support
10. Pregnant adolescents should have a nutritional assessment, given to this population at high risk for discontinuation. (II-2A)
vitamins and food supplementation if needed, and access to a
19. Postpartum care programs should be available to support
strategy to reduce anemia and low birth weight and to optimize
adolescent parents and their children, to improve the mothers’
weight gain in pregnancy. (II-2A)
knowledge of parenting, to increase breastfeeding rates, to screen
11. Conflicting evidence supports and refutes differences in for and manage postpartum depression, to increase birth intervals,
gestational hypertension in the adolescent population; therefore, and to decrease repeated unintended pregnancy rates. (III-B)
20. Adolescent women in rural, remote, northern, and Aboriginal births worldwide, but 23% of maternal morbidity and
communities should be supported to give birth as close to home
as possible. (II-2A)
mortality.1 Adolescent pregnancy is the leading cause of
mortality in girls aged 15 to 19 worldwide; 90% of these
21. Adolescent pregnant women who need to be evacuated from
a remote community should be able to have a family member deaths occur in resource-poor countries and most of them
or other person accompany them to provide support and are preventable.1,2 Adolescent pregnancy is also a cause
encouragement. (II-2A) for concern worldwide because of high rates of unsafe
22. Culturally safe prenatal care including emotional, educational, abortion and poor knowledge-seeking behaviours, prenatal
and clinical support to assist adolescent parents in leading
healthier lives should be available, especially in northern and
care, and support.1
Aboriginal communities. (II-3A)
In Canada, the fertility rate for adolescents aged 15 to 19 in
23. Cultural beliefs around miscarriage and pregnancy issues, and
special considerations in the handling of fetal remains, placental
2009 was 14.2 births per 1000 women; 15 638 babies were
tissue, and the umbilical cord, must be respected. (III) born to women under 20 that year, up slightly from the all-
time low reached in 2005 (13.4), though still significantly
INTRODUCTION lower than the rates seen in the 1980s.3 Across the country,
adolescent pregnancy rates are highest in Nunavut and the
age-related exceptions for adolescents aged 12 to 16 with postpartum issues such as breastfeeding, contraception,
partners ranging from up to 2 years older to 5 years older and school return.23
depending on their own age. For exploitive sexual activity,
the age of consent is 18. See Appendix A for a detailed Multidisciplinary adolescent-focused prenatal care
outline of consent for different ages and the definition of leads to better outcomes than standard prenatal care in
exploitive sex.11 adolescents,8,10,24 including reductions in PTB,8,10 LBW,10,25
and NICU admissions,26 increased SVD,10,26 and reduction
Respecting the autonomy and confidentiality of the in operative delivery.8,10 Major cost savings related to infant
adolescent patient may at times be complicated by the and paediatric health could be realized by preventing
care setting and the surrounding environment. Issues of preterm births.
confidentiality are likely to arise with care of very young
adolescents, care in a small community, and care of other Adolescent-centred multidisciplinary comprehensive care
family members in the clinic and potentially even within with a goal to improving outcomes for mothers and their
team care. Child protection agencies, although not actively infants is considered the gold standard for management
involved and part of the circle of care until after the birth of the myriad problems that present in an adolescent
of the baby in cases of newborn apprehension, may be pregnancy (Appendix B).8 Elements of care are aimed at
able to provide support for counselling, parenting, and reducing adverse maternal and neonatal outcomes. Teaching
financial assistance. strategies and topics are important considerations when
providing health information for pregnant adolescents.
When considering options for pregnant adolescents in The adolescent should have easy access to care based on a
our country, it is important to remember that there is no philosophy of providing care in a welcoming environment
specific age of consent for medical treatment in Canada. with multidisciplinary teams to meet the many health care
As long as individuals are deemed to have the capacity needs of the adolescent. It is also important to encourage
to provide consent (i.e. to understand the nature of the early enrollment into prenatal care and participation in
procedure as well as its risks and alternatives), they do not community support programs.8
need to have reached a particular age in order to provide
consent. (By law in Quebec, however, parents have the Two cohort studies demonstrated a significant reduction
right to access the medical records of children under the in PTB and LBW when adolescents attended specialized
age of 14).12 multidisciplinary antenatal care. An Australian cohort
showed that screening for and treating STIs resulted
in a significant reduction in PTB in a general antenatal
ANTEPARTUM CARE
clinic (OR 0.4; 95% CI 0.25 to 0.62),27 and the Canadian
Prenatal Care and Multidisciplinary Care Programs cohort demonstrated that dedicated multidisciplinary
Unfortunately, adolescents have a significantly lower care provided in an adolescent-friendly community
attendance of prenatal classes (aRR 0.87, 95% CI 0.85 to outreach program led to a 53% reduction in PTB (OR
0.91) and first-trimester antenatal visits (aRR 0.53, 95% CI 0.47, 95% CI 0.22 to 1.00).10 This Canadian study
0.51 to 0.55) than adult women.6,13,14 Reasons for delay in observed a 59% reduction in LBW babies (95% CI
seeking care are multifactorial: lack of knowledge about 0.18 to 0.95).10 It is important to address nutritional
the importance of prenatal care and lack of understanding requirements and maternal weight gain when caring for
of the consequences of its absence; history as a victim pregnant adolescents; useful strategies may include dietary
of violence, desire to hide pregnancy, fear of potential assessments, a comprehensive prenatal nutrition program,
apprehension of the baby, contemplation of abortion and a community food donation program in addition to
services; concerns about lack of privacy or judgemental access to prenatal care.10 Multidisciplinary adolescent-
attitudes from health care providers or adults; and financial focused antenatal care therefore has tremendous potential
barriers.14 Lack of, or delayed, adolescent prenatal care is to reduce the significant health care costs associated with
associated with adverse maternal, obstetrical, and neonatal PTB and LBW infants.
outcomes.9,13,15–17
A number of models of multidisciplinary care have been
Standard prenatal care improves outcomes in adolescent described that achieve the aforementioned desired objectives.
pregnancy18–21; adequate prenatal care has been shown Successful models have been implemented in hospitals,
to be protective against fetal and infant mortality in this schools, clinics, and community facilities.10 Multidisciplinary
population.9 However, studies suggest that standard care care is usually provided in one place at one time,10 and
misses psychosocial vulnerabilities, STI screening,22 and further study should continue to evaluate this mode of
care. Where possible “one-stop shopping” and easy visits 4. Fathers and partners should be included as much as
work best for the adolescent.10 Home visiting programs by possible in pregnancy care and prenatal/infant care
health care professionals and trained lay visitors have also education. (III-B)
been assessed; though this model may impact a particular 5. A first-trimester ultrasound is recommended not
outcome, it does not appear to contribute to the overall only for the usual reasons for properly dating the
desired outcomes.28–31 Helping the pregnant adolescent to pregnancy, but also for assessing the increased risks
navigate the system is an important function for all team of preterm birth. (III-A)
members to be aware of and participate in, including being
aware of the roles of other team members, the services Choice in Pregnancy
available, and in particular client-centred issues, to assist Upon diagnosis of intrauterine pregnancy, adolescents can
patients to access needed services.32 and should be counselled, without specific consideration
of their age, about their options for continuation with the
Antenatal opportunities to develop parenting skills that intent to parent, adoption, or termination. They should
continue in the postpartum period are likely to improve be offered support with the participation of the support
birth outcomes, increase maternal school attendance, and person(s) of their choice. Canada has no abortion law, and
reduce rapid repeat pregnancy.33 Assistance with varied
thus abortion remains an option for the patient so long as
parenting structures to reduce parenting stress and child
access permits. Access to abortion, however, varies greatly
dysfunction can also be helpful. The family system and the
in different jurisdictions and provinces across the country.36
intergenerational dynamics within a multigenerational care-
giving structure are critical to the health and well-being Recommendation
of both mothers and their children.34 Decisions about 6. Counselling about all available pregnancy outcome
including families of origin and fathers when appropriate in options (abortion, adoption, and parenting) should
the parenting process are often complex and require special be provided to any adolescent with a confirmed
consideration of their risks and benefits. Many fathers intrauterine gestation. (III-A)
struggle to stay involved in the lives of their children, and
prenatal and young family support programs seek to find Sexually Transmitted Infections
opportunities to engage young fathers in the programs Adolescents are at greater risk for STIs because they
and ultimately in their children’s lives.35 Adolescents who frequently have multiple partners, have unprotected
participate in such support and education in adolescent- intercourse, are biologically more vulnerable to sexually
centred care models are more likely to continue their acquired infections and face multiple obstacles to
education during the pregnancy and the postpartum year utilization of health care.37 Pregnant adolescents may be
than peers who do not participate in such programs. at further risk because they are less likely to use condoms
with intercourse during their pregnancy than non-pregnant
Recommendations
adolescents.21,38 In pregnancy, STIs have been associated
1. Health care professionals should adapt with preterm delivery, chorioamnionitis, and postpartum
their prenatal care for adolescents and offer infections.39 Adolescents with an STI have a higher risk
multidisciplinary care that is easily accessible to of PPROM leading to PTB.10,27,40 Vertical transmission
the adolescent early in the pregnancy, recognizing of chlamydia during vaginal delivery ranges from 30%
that adolescents often present to care later than
to 50% and may result in pneumonia and ophthalmia
their adult counterparts. A model that provides an
neonatorum.39 Screening and treatment is associated with
opportunity to address all of these needs at one site
a significant decrease in the incidence of newborn febrile
may be the preferred model of care for pregnant
morbidity (10% vs. 25%, P = 0.02).41 These infections can
adolescents. (II-1A)
2. Health care providers should be sensitive to also increase the risk of HIV acquisition and transmission.41
the unique developmental needs of adolescents Adolescent women are at heightened risk because of the
through all stages of pregnancy and during physiologic immaturity of their cervix and the consequent
intrapartum and postpartum care. (III-B) susceptibility of the tissues to infection.42
3. Adolescents are high-risk pregnancies and should Prevalence of chlamydia in adolescent pregnancy is high.
be managed accordingly within programs that
At initial prenatal visit, infection rates range from 11.8%
have the capacity to manage their care. The unique
to 31%.41,43–47
physical risks of adolescent pregnancy should be
recognized and the care provided must address The recurrence rate throughout the pregnancy is also high
these. (II-1A) among adolescents. A Canadian retrospective study reported
an infection rate of 22.1% in routine third trimester screening.44 alcohol. For general recommendations concerning alcohol
A prospective cohort of 125 adolescents with chlamydia or and substance use in pregnancy, see the SOGC Alcohol
gonorrhoea in pregnancy who were retested in third trimester Use and Pregnancy Consensus Clinical Guidelines50 and
reported a reinfection rate of 11%; 7% had a new infection, Substance Use in Pregnancy.51
while 3% had recurrent gonorrhoea.45 Repeated testing
between 3 and 4 weeks later to ensure treatment success and Violence and Coercion
lack of reinfection is recommended in this population.48 Violence in adolescent pregnancy is unfortunately quite
common, with an odds ratio of 1.8 in one study.52 Violence
BV in pregnancy has also been associated with adverse in pregnancy is associated with late engagement in prenatal
outcomes including PPROM, PTL, PTB, and postpartum care and an increased risk of adverse perinatal outcomes
endometritis. There is evidence to support screening such as LBW, PTB, and fetal death,53 and postpartum
and treatment at 12 to 16 weeks in high-risk (those depression.54,55 Rates of IPV in pregnant adolescents, at
with previous PTL, PTB, or PPROM) or symptomatic 26% to 31%, are higher than in their adult counterparts.
pregnancies, although it is not recommended in low-risk Violence often begins in the first trimester and is usually
or asymptomatic pregnancies.48 Because of their inherently committed by the partner. A history of abuse within
increased risks of PPROM, PTL, and PTB, adolescent the last year is predictive of violence in pregnancy.56 In
pregnancies are all considered to be high-risk. addition, 26% of pregnant adolescents known to be
victims of IPV also reported sexual coercion from their
Recommendation partner.57 A history of past physical abuse at any point is
7. Testing for sexually transmitted infection (II-2A) strongly associated with adolescent pregnancy.58 See the
and bacterial vaginosis (III-B) should be performed SOGC Intimate Partner Violence Consensus Statement59
routinely upon presentation for pregnancy care for recommendations concerning IPV in pregnancy and
and again in the third trimester; testing for sexually Appendix C60 for a short screening tool for IPV.
transmitted infection should also be performed
postpartum and when needed symptomatically. Exploring pregnancy intentions and the behaviours of
a. Because pregnant adolescents are inherently at partners of sexually active adolescents may help to identify
increased risk for preterm labour, preterm birth, youth experiencing IPV57; questions about all types of
and preterm pre-labour rupture of membranes, abuse should routinely be asked of adolescent patients.59
they are a high-risk group and therefore
Recommendation
screening and management of bacterial
vaginosis is recommended. (III-B) 8. Routine and repeated screening for alcohol use,
b. After treatment for a positive test, a test of substance abuse, and violence in pregnancy is
cure is needed 3 to 4 weeks after completion recommended because of their increased rates in
of treatment. Refer partner for screening and this population. (II-2A)
treatment. Take the opportunity to discuss Mood Disorders
condom use. (III-A) Depression is diagnosed in 4% to 8% of adolescents.
Smoking, Substance Abuse, and Alcohol Abuse In pregnancy, the rate varies from 16% to 44%, almost
Adolescents who are pregnant have higher rates of twice as high as among adult pregnant women and non-
smoking (38.8% vs. 11.9%, P < 0.001) and substance pregnant adolescents. Depressive symptoms among
abuse (11.7% vs. 5.1%, P < 0.0001) than their adult pregnant adolescents become more severe between the
counterparts.13 An Australian retrospective study revealed second and third trimesters,61 and half of adolescent
20.3% of adolescents used marijuana during pregnancy, of mothers experience symptoms of depression in the early
which 33.5% were multidrug users. Of adolescents who postpartum period.62 Adolescent mothers are twice as
were non-users, 50% were previous users who ceased drug likely to experience depression than adult mothers.16
use immediately before or early during pregnancy. Illegal Factors significantly associated with depressive symptoms
drug use was associated with concomitant cigarette and in pregnancy include antenatal depressive symptoms and
alcohol use.49 However, pregnancy is a powerful incentive IPV.55,63
for many adolescents to reduce tobacco, alcohol, and drug
use; previous studies have shown cessation rates of up to Untreated maternal depression is associated with adverse
60% to 75%.49 A critical component of the care of this maternal, neonatal, and childhood outcomes, as well as
pregnant population should therefore be aimed at reducing with postpartum depression16,61 and increased frequency
the effects of smoking and substance abuse, including of subsequent pregnancies. Untreated maternal depression
is also associated with preterm delivery and SGA Some studies demonstrate a higher rate of hypertensive
infants. Finally, untreated depression is associated with disorders in adolescent pregnancies than in adults.70,71
unresponsive mothering and behavioural and cognitive Other studies, however, do not demonstrate a difference
problems in children.64 in gestational hypertension between adolescents and adults
of the same parity.6,13 While the methodologies of the
The risk of postpartum depression is significant in studies differ, it is also important to control for potential
adolescent mothers. Indeed, 47% of adolescent mothers confounders such as parity, smoking, and substance use.
had significant symptoms of depression at 4 to 6 weeks When adjusted for these factors, a decreased risk of
postpartum, and the depressive symptoms continued at 12 gestational hypertension was seen in a Canadian cohort
months postpartum.62 Of particular concern, by 12 months (aRR 0.73, 95% CI 0.68 to 0.79).13
postpartum, none of the adolescent mothers in this study
with symptoms of depression had pursued referrals for Recommendation
mental health evaluation and treatment.62 11. Conflicting evidence supports and refutes
differences in gestational hypertension in the
It is therefore crucial to promote improved maternal
adolescent population; therefore, the care usual
mental health in the adolescent population including early
for adult populations is supported for pregnant
recognition and management of psychiatric disorders
adolescents at this time. (II-2A)
and treatment of depression and suicidal ideation and
intent.61,62,64 The Edinburgh Postnatal Depression Scale is Gestational Diabetes
one option for routine screening.65 In Canada, the prevalence of GDM in all pregnancies is
Recommendation
higher than previously thought, varying from 3.7% in the
non-Aboriginal population to 8% to 18% in Aboriginal
9. Routine and repeated screening for and treatment
populations.72 However, recent retrospective studies
of mood disorders in pregnancy is recommended
indicate that non-Aboriginal adolescents have lower rates
because of their increased rates in this population.
of GDM (OR 0.04; 95% CI 0.01 to 0.29),73 (aRR 0.34;
The Edinburgh Postnatal Depression Scale
95% CI 0.30 to 0.39)13 than adult women. However, at this
administered in each trimester and postpartum, and
time, screening of pregnant adolescents should follow the
more frequently if deemed necessary, is one option
same guidelines and management for GDM as for adult
for such screening. (II-2A)
women.71
Anemia and Nutritional Care
Recommendation
Anemia (hemoglobin < 105 g/L) is a very common
complication in pregnant adolescents, with a reported 12. Practitioners should consult gestational diabetes
mellitus (GDM) guidelines. In theory, testing all
prevalence of from 50% to 66%27,66 and an increased
patients is appropriate, although rates of GDM
relative risk of 1.27 (95% CI 1.15 to 1.4),67 usually
are generally lower in adolescent populations.
attributed to inadequate replacement or nutrition. In
Practitioners should be aware, however, that certain
addition, a prospective study demonstrated that low
ethnic groups including Aboriginal populations are
body iron stores and low ferritin were significantly more
at high risk of GDM. (II-2A)
common in pregnant adolescents than in pregnant adults.68
Smoking status was an important risk factor for LBW and Prevention of Adverse Maternal and Neonatal
anemia.69 Care for the pregnant adolescent should therefore Outcomes: PTB, LBW, and IUGR
incorporate nutritional care to both optimize weight gain Adolescent pregnancies have a higher risk of adverse
and manage potential nutritional deficiencies. outcomes such as PTB (< 37 weeks),9,15,18,66,74,75 very PTB,
Recommendation (< 32 weeks),9,13,18,74,75 and extremely PTB (< 28 weeks),9,76
10. Pregnant adolescents should have a nutritional LBW (< 2500 g),9,15,66,74,75 very LBW (< 1500 g),9,74 IUGR
assessment, vitamin and food supplementation if (< 3rd centile for GA) and stillbirths,9,67,70,76 and NICU
needed, and access to a strategy to reduce anemia admissions and neonatal deaths.9,13,17,74–77 In addition,
and low birth weight and to optimize weight gain in congenital anomalies are more common in adolescent
pregnancy. (II-2A) pregnancies. These include central nervous system
anomalies (anencephaly, spina bifida, hydrocephaly,
Hypertensive Disorders of Pregnancy microcephaly), gastrointestinal anomalies (gastroschisis,
There is conflicting evidence regarding the risk of omphalocele), and musculoskeletal anomalies (cleft lip,
preeclampsia and gestational hypertension in adolescents. cleft palate, polydactaly, syndactaly).74,75,78
Since a significant proportion of pregnant adolescents 14. As in other populations at risk of intrauterine
have a low socioeconomic status, it has been assumed that growth restriction (IUGR) and low birth weight, an
the high risk nature of these pregnancies is due to their ultrasound to assess fetal well-being and estimated
environment.79,80 However, 2 large retrospective cohort fetal weight at 32 to 34 weeks’ gestational age is
studies challenge this assumption. suggested to screen for IUGR. (III-A)
The first is a retrospective cohort study of almost 2 million 15. Visits in the second or third trimester should be
adolescent births in the United States adjusted for potential more frequent to address the increased risks of
confounders such as state, race, marital status, smoking, preterm labour and preterm birth and to assess fetal
alcohol use, and prenatal care.74 In this cohort, even after well-being. All caregivers should be aware of the
adjusting for those confounders, adolescent pregnancy signs and symptoms of preterm labour and should
was independently associated with increased risk of PTB educate their patients to recognize them. (III-A)
(RR = 1.2), very PTB (RR = 1.26), LBW (RR = 1.14), very
LBW (RR = 1.11), SGA (RR = 1.07), and neonatal mortality INTRAPARTUM CARE
(RR = 1.15). The effect of adolescent pregnancy on neonatal
mortality disappeared after adjustment of birth weight and Many retrospective studies in high income countries
gestational age; this suggests that neonatal mortality may have demonstrated a higher rate of vaginal deliveries in
be explained by the higher rate of PTB and LBW infants adolescents than in adults, along with a shorter active phase
in adolescent mothers.74 Other studies have found similar of labour, similar length of second stage, and a lower rate
results, proposing that increased NICU admission rates are of assisted vaginal delivery and CS varying from 2% to
likely a result of increased preterm deliveries.9,17,75 14%.6,10,18,67,74,84,85
The second study is a recent retrospective cohort study Two large retrospective studies found a higher rate of
with data adjusted for race, twins, and number of prior vaginal deliveries in adolescents than in adult women (aRR
births in 37 million births in the United States, of which 1.76; 95% CI 1.70 to 1.82),13 while their rates of assisted
over 300 000 were to adolescent mothers ≤ 15 years of age. vaginal deliveries (aRR = 0.62 to 0.76) and CS (aRR 0.57 to
These young adolescents were at significantly increased risk 0.79) were lower.13,18,84 The adolescent group also had lower
of PTB (OR = 1.76), very PTB (OR = 2.4), extremely PTB epidural use.13,86 However, when adolescents required a CS,
(OR = 2.48), LBW (OR = 1.37), very LBW (OR = 1.47), unlike adult women, it was most often in an emergency.13,84
SGA (OR = 1.14), IUGR (OR = 1.21), stillbirth (OR = 1.31), The most common indications for emergency CS in the
and infant death (OR = 1.87). Adequate prenatal care was adolescent group in one study were non-reassuring fetal
protective against fetal and infant mortality.9 status and labour dystocia.13
Recommendation
When reviewing the fetal and infant outcomes of Canadian
adolescent pregnancies, similar adverse outcomes are seen. 16. It should be recognized that adolescents
A recent retrospective study comparing almost 24 000 have improved vaginal delivery rates and a
adolescents with adults in Ontario revealed that neonates concomitantly lower Caesarean section rate than
born to adolescent mothers have a significantly higher their adult counterparts. (II-2A). As with antenatal
risk of admission to NICU (aRR = 1.08) and very PTB care, peripartum care in hospital should be
(aRR = 1.16). The risk of having a large for gestational multidisciplinary, involving social care, support for
age infant was significantly lower in the adolescent group breastfeeding and lactation, and the involvement of
(aRR = 0.92). There were no significant differences in children’s aid services when warranted. (III-B)
SGA (aRR = 1.00), LBW (aRR = 1.05), PTB (aRR = 1.04),
and fetal death (aRR = 1.02).13 In another study, Canadian POSTPARTUM CARE
adolescents had a 3-fold increase in the risk of delivery
before 34 weeks, with a subsequent increase in NICU Contraception
admissions.75 This is a concerning finding, because preterm Adolescent mothers are at significant risk for repeat
birth is an important indicator of neonatal well-being that pregnancy, with 25% becoming pregnant again within
has been associated with severe morbidity and mortality.80–83 2 years of delivery.87 However, not all adolescent pregnancies
are undesired, and a significant number of them are in fact
Recommendation
planned. A prospective cohort study of adolescents in a
13. An ultrasound anatomical assessment at 16 to 20 multidisciplinary care setting demonstrated that over 50% of
weeks is recommended because of increased rates adolescents idealized pregnancy as the “single most exciting
of congenital anomalies in this population. (II-2A) and positive event to have occurred.”30 In a Canadian
retrospective study, one third desired their pregnancy. Canada, and the Breastfeeding Committee for Canada also
Efforts to promote awareness and the availability of states that exclusive breastfeeding for the first 6 months
contraception would not have prevented these pregnancies.88 is important for the nutrition, immunologic protection,
Protective factors against repeat pregnancy include use of growth, and development of infants and toddlers.101
LARC, school attendance, and living alone or with a parent
as opposed to with a partner.89 Postpartum care and the In Canada, breastfeeding initiation rates have increased
provision of options for contraception are therefore crucial significantly in the last decades. In 1965, fewer than 25%
elements of pregnancy care for the adolescent. Evidence in of mothers breastfed compared with 88.4% in 2011.101
the postpartum adolescent population specifically suggests However, in 2011 only 27.8% continued to breastfeed their
that LARCs such as DMPA and IUDs are far better at infants to 6 months.2,3 Adolescent mothers have an even
preventing repeat pregnancies than are shorter-term methods lower initiation and continuation rate of breastfeeding
such as oral contraception, contraceptive patch, or barrier than adult women.102–105 Published data for breastfeeding
rates among adolescent mothers is sparse.102 An American
methods.90 In one study, 14.2% of adolescents on DMPA
study indicated that 42.8% of adolescent women initiated
were pregnant again one year later compared with 29.7%
breastfeeding, but only 9.1% continued to breastfeed to 6
and 31.8% of oral contraception and patch users.91 LARCs
months compared with 15% to 34% of mothers from all
are specifically endorsed for adolescents by the American
other age groups.102
Congress of Obstetricians and Gynecologists.92 Educational
encounters with health care providers and education + Adolescent mothers and their infants are at greater risk
contraception programs have shown protective outcomes,93 for many health and socioeconomic issues such as anemia
while behavioural interventions alone have not shown and depressive disorders in the mother; LBW, PTB,
consistent results.94 Provision of emergency contraception developmental problems, and learning difficulties in the
in addition to the usual contraceptive methods has been infants, and rapid repeat pregnancy. Breastfeeding could
associated with a higher likelihood of its use, although these greatly benefit these young mothers and their infants by
adolescents may also be more likely to engage in unprotected ameliorating some of these outcomes.
intercourse.95 Immediate postpartum contraception, with
initiation of DMPA postpartum, placement of IUD at the Studies in the adolescent population have suggested
time of delivery, or placement of contraceptive implant multiple sociodemographic factors are associated
before hospital discharge have also shown significantly with lower rates of breastfeeding including age, race,
decreased repeat pregnancy rates.96 However, expulsion educational level, marital status, and socioeconomic
rates of IUDs are noted to be higher with immediate status.102,103,105 Other studies have suggested that lack of
postpartum placement.97 Other novel techniques to decrease knowledge, a negative opinion about pregnancy, and lack
repeat pregnancy rates include peer-led educational models, of breastfeeding support from family, friends, and partner
varied educational modalities, and the use of cell phones could affect breastfeeding rates.102,103
and social media to promote participation and follow-up.
Programs should be available during pregnancy and
More investigation of such options is required. Pregnancy
postpartum to support breastfeeding, enhance parenting
prevention and contraception counselling in this population skills, reduce rapid repeat pregnancies and improve
require extra time and energy to improve knowledge,33,98,99 continuation of maternal education. These may be
uptake, and management of sociodemographic risk factors. continuations of an adolescent pregnancy program
Recommendation or specific early-years parenting programs provided
17. Postpartum care should include a focus on through public health agencies and other locally available
contraceptive methods, especially long-acting supports. Increased breastfeeding rates can be achieved
reversible contraception methods, as a means to and supported by adolescent mothers’ involvement in
decrease the high rates of repeat pregnancy in this antenatal classes and proactive breastfeeding support from
population; discussion of contraception should a lactation consultant, physician, midwife, or nurse with
begin before delivery. consideration of specific adolescent concerns such as
privacy, body image, and pumping.
Breastfeeding and Postpartum Support
Recommendation
The joint WHO/UNICEF global recommendations for
optimal infant feeding is exclusive breastfeeding during the 18. Breastfeeding should be recommended and
first 6 months.100 In Canada, a joint statement by Health sufficient support given to this population at high
Canada, the Canadian Paediatric Society, Dieticians of risk for discontinuation. (II-2A)
19. Postpartum care programs should be available to northern communities. Young mothers and fathers require
support adolescent parents and their children, to emotional, educational, medical, and potentially financial
improve the mothers’ knowledge of parenting, support to lead healthier lives without drugs and alcohol
to increase breastfeeding rates, to screen for and and to become positive role models for their children,
manage postpartum depression, to increase birth younger siblings, and the community.
intervals, and to decrease repeated unintended
Management of diabetes, including GDM, in Aboriginal
pregnancy rates. (III-B)
people should follow the same clinical practice guidelines
as those for the general population with recognition of,
SPECIAL CONSIDERATIONS IN ABORIGINAL respect for, and sensitivity to the unique language, cultural,
ADOLESCENT POPULATIONS
and geographic issues relating to diabetes care and
Culturally, adolescent pregnancies have been accepted education in Aboriginal communities across Canada and
in most Aboriginal communities. By tradition, babies the increased rates of diabetes mellitus in this population.72
are regarded as a gift from the Creator and children are
Aboriginal adolescent mothers in remote northern
welcomed into the families regardless of the mother’s
communities face additional challenges around birthplace
age. Most of the young mothers keep their babies and are
choices and locations. Local maternity care programs do not
well supported by their own mothers, extended families,
exist in many communities and frequently young mothers
and communities.106 At the same time it appears that
are required to travel weeks in advance to a regional centre
there is some stigma attached to adolescent childbearing
to give birth. This practice leads to separation and isolation
in Aboriginal communities, especially when the mother is
from family members and the home community and has
very young.107
an even greater impact on adolescent mothers who require
Currently, concerns about adolescent pregnancies in additional support during the labour and birth process.112
Aboriginal communities are growing for a number of
reasons. While recent Canadian statistics show a steady The loss of indigenous knowledge and medicine in
decline in adolescent pregnancy and birth rates since Aboriginal cultures has been described by many leaders
the 1990s, adolescent pregnancy rates in Aboriginal and and Elders as the root of many contemporary health and
northern communities continue to be up to 4 times higher well-being issues faced by Aboriginal peoples today.113
than the national average.108 Among women who reported Supporting existing traditional practices (such as the
an Aboriginal background, 24% were adolescent mothers inclusion of Elders in prenatal care, the use of herbal
compared with just 10% of non-Aboriginal women. medicines, specific diet recommendations, the young
woman’s desire to give birth on traditional territory) and
The prevalence of current smoking among Aboriginal the use of traditional birthing practices (such as Aboriginal
youth is more than double that among non-Aboriginal midwifery, smudging, naming ceremony, and retention
youth (24.9% vs. 10.4%).109 Aboriginal youth also had a of placental tissue, and umbilical cord remnants) are
higher prevalence of regular exposure to second-hand important when caring for adolescent pregnant women in
smoke at home (37.3% vs. 19.7%) and in cars (51.0% northern and Aboriginal communities.113,114 Recognizing
vs. 30.3%). Aboriginal youth were more likely than non- and acknowledging the importance and the wide variety of
Aboriginal youth to have tried marijuana and other illicit community-specific practices both across the country and
drugs and to engage in binge drinking; it is also suggested within a region are important, as is the acceptance of those
that fetal alcohol spectrum disorder rates are higher in practices by the pregnant adolescent.115,116
this population than in other populations in Canada.110
Aboriginal youth were less likely than non-Aboriginal Custom adoption, the cultural practices of Aboriginal
youth to have tried to quit smoking.109 Although alcohol peoples to raise a child by a person who is not the child’s
and substance abuse have been frequently reported parent, according to the custom of the First Nations and/
as influencing factors in becoming pregnant, they are or Aboriginal community of the child, is a common form
generally not an ongoing lifestyle choice for most of adoption in Aboriginal communities; it is recognized
Aboriginal adolescents. The responsibility of motherhood in the Indian Act of 1985117 and in most Canadian
is a powerful motivator for many of the young women to jurisdictions, for example in the 1990 Aboriginal Custom
stop harmful behaviours and to start planning for their Adoption Recognition Act of the Northwest Territories.118
futures.111 Access to culturally safe maternity care for Custom adoption ensures that Aboriginal children maintain
adolescents may not always be available in Aboriginal and their cultural, linguistic, and spiritual identity.
Aboriginal custom adoption takes place usually between 2 Care; 2009. Available at: http://www.health.gov.on.ca/en/public/
publications/pubhealth/init_report. Accessed on June 7, 2012.
families who know each other or have connected with one
4. McKay A. Trends in Canadian national and provincial/territorial teen
another through word of mouth in the community and
pregnancy rates 2001-2010. Can J Hum Sex 2012;21:3–4.
often includes a custom adoption ceremony. Statistics on
5. United Nations Population Fund. State of the world population 2011.
custom adoptions are difficult to obtain. New York (NY): UNFPA; 2011. Available at http://foweb.unfpa.org/
SWP2011/reports/EN-SWOP2011-FINAL.pdf. Accessed May 30, 2014.
Recommendations
6. World Health Organization (WHO). Issues in adolescent health and
20. Adolescent women in rural, remote, northern, development: adolescent pregnancy. Geneva (CH): WHO, Department of
and Aboriginal communities should be supported Child and Adolescent Health and Development; 2004.
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preterm birth: a prospective study. BJOG 2004;111:57–8.
give birth as close to home as possible. (II-2A)
21. Adolescent pregnant women who need to be 9. Malabarey OT, Balayla J, Klam SL, Shrim A, Abenhaim HA. Pregnancies
in young adolescent mothers: a population-based study on 37 million
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able to have a family member or other person
10. Fleming NA, Tu X, Black AY. Improved obstetrical outcomes for
accompany them to provide support and adolescents in a community-based outreach program: a matched cohort
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22. Culturally safe prenatal care including emotional, 11. Department of Justice. Age of consent to sexual activity. Frequently
educational, and clinical support to assist asked questions. Ottawa (ON): Government of Canada; 2015.
Available at: http://www.justice.gc.ca/eng/rp-pr/other-autre/clp/
adolescent parents in leading healthier lives should
faq.html. Accessed on June 7, 2015.
be available, especially in northern and Aboriginal
12. Canadian Medical Protective Association. Age of consent for sexual
communities. (II-3A) activity and duty to report. Ottawa (ON): CMPA; 2010. Available at:
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APPENDIX A
APPENDIX B
Risks Interventions/solutions
Socioeconomic
Financial/housing Consult social work
Smoking Smoking cessation program: Kick Butt for 2; harm reduction strategies
Substance use/alcohol Addiction counselling
Violence Screen for violence (see validated questionnaire)
Mood Screen for depression, ± referral to psychiatry
Compliance with appointment Adolescent-focused multidisciplinary care
Provide assistance with transportation
School curriculum, prenatal class
Maternal
Anemia Dietician, food donation, vitamins
Inadequate nutrition Prenatal nutrition program, Buns in the Oven
STI Screen/treat STI initial visit; each trimester, if symptomatic
Neonatal
Prematurity Accurate dating scan
Screen/treat STI initial visit; each trimester, if symptomatic
Frequent visits in 2nd and 3rd trimester
Screen for substance use and violence in pregnancy
LBW, very LBW, IUGR, stillbirth Frequent visits in 2nd and 3rd trimester
32 week ultrasound for growth
Assessment of fetal well-being
Nutritional assessment/support
Postnatal
Repeat pregnancy Assess desire
Contraception counselling during pregnancy
Follow-up at 1 to 2 weeks and 6 weeks postpartum and beyond
Provide free contraception (CCAP)
Breastfeeding Lactation consultant (pre- and post pregnancy)
Breastfeeding class
Postpartum depression Assess risk in pregnancy, refer to psychiatry if necessary
Follow-up at 2 and 6 weeks postpartum
CCAP: Compassionate Contraceptive Assistance Program (available through Society of Obstetricians and Gynaecologists of Canada)
APPENDIX C
Screening questions relating to domestic violence
2. Are there situations in the past 6 months when you have felt afraid of
your partner or a family member?
Code: Yes by partner by family member
No
Unsure/declined to answer
3. In the past 6 months, have you ever been a victim of domestic violence
from your partner or a family member?
Code: Yes If yes, by Family member Yes/No
Partner, current Yes/No
Partner, previous Yes/No
Other Yes/No
No
Unsure/declined to answer
4. In the past 6 months, have you ever been hit, kicked, punched,
or physically hurt by a partner or family member?
Code: Yes If yes, by Family member Yes/No
Partner, current Yes/No
Partner, previous Yes/No
Other Yes/No
No
Unsure/declined to answer
5. In the past 6 months, have you ever been forced to have sex or
do sexual things that you did not want to do by a partner or family
member?
Code: Yes If yes, by Family member Yes/No
Partner, current Yes/No
Partner, previous Yes/No
Other Yes/No
No
Unsecure/declined to answer
Note: “Fig. 1. Screening questions on domestic violence and the coding of answers.” Journal
of Pediatric and Adolescent Gynecology.60 Reproduced with permission of Elsevier Inc.
Disclosure statements have been received from all contributors. Values: The quality of evidence in this document was rated using the
criteria described in the Report of the Canadian Task Force on
The literature searches and bibliographic support for this Preventive Health Care (Table 1).
guideline were undertaken by Becky Skidmore, Medical
Research Analyst, Society of Obstetricians and Gynaecologists Results: This document reviews the evidence regarding the
of Canada. available techniques and technologies for EA, preoperative and
postoperative care, operative set-up, anaesthesia, and practical
considerations for practice.
Keywords: Endometrial ablation, hysteroscopy, menorrhagia,
heavy menstrual bleeding, abnormal uterine bleeding,
hysterectomy.
J Obstet Gynaecol Can 2015;37(4):362–376
This document reflects emerging clinical and scientific advances on the date issued and is subject to change. The information
should not be construed as dictating an exclusive course of treatment or procedure to be followed. Local institutions can dictate
amendments to these opinions. They should be well documented if modified at the local level. None of these contents may be
reproduced in any form without prior written permission of the SOGC.
Table 1. Key to evidence statements and grading of recommendations, using the ranking of the Canadian Task Force
on Preventive Health Care
Quality of evidence assessment* Classification of recommendations†
I: Evidence obtained from at least one properly randomized A. There is good evidence to recommend the clinical preventive action
controlled trial
II-1: Evidence from well-designed controlled trials without B. There is fair evidence to recommend the clinical preventive action
randomization
II-2: Evidence from well-designed cohort (prospective or C. The existing evidence is conflicting and does not allow to make a
retrospective) or case–control studies, preferably from recommendation for or against use of the clinical preventive action;
more than one centre or research group however, other factors may influence decision-making
II-3: Evidence obtained from comparisons between times or D. There is fair evidence to recommend against the clinical preventive action
places with or without the intervention. Dramatic results in
uncontrolled experiments (such as the results of treatment with E. There is good evidence to recommend against the clinical preventive
penicillin in the 1940s) could also be included in this category action
III: Opinions of respected authorities, based on clinical experience, L. There is insufficient evidence (in quantity or quality) to make
descriptive studies, or reports of expert committees a recommendation; however, other factors may influence
decision-making
*The quality of evidence reported in here has been adapted from The Evaluation of Evidence criteria described in the Canadian Task Force on Preventive Health
Care.51
†Recommendations included in these guidelines have been adapted from the Classification of Recommendations criteria described in the Canadian Task Force
on Preventive Health Care.51
Benefits, harms, and costs: Implementation of the guideline allow the use of local rather than general anaesthesia. However,
recommendations will improve the provision of EA as an effective both techniques have comparable patient satisfaction and
treatment of AUB. Following these recommendations would allow reduction of heavy menstrual bleeding. (I)
the surgical procedure to be performed safely and maximize
4. Both resectoscopic and non-resectoscopic endometrial ablation
success for patients.
(EA) have low complication rates. Uterine perforation, fluid
Conclusions: EA is a safe and effective minimally invasive option for overload, hematometra, and cervical lacerations are more
the treatment of AUB of benign etiology. common with resectoscopic EA; perioperative nausea/vomiting,
uterine cramping, and pain are more common with non-
Summary Statements resectoscopic EA. (I)
1. Endometrial ablation is a safe and effective minimally invasive 5. All non-resectoscopic endometrial ablation devices available in
surgical procedure that has become a well-established alternative Canada have demonstrated effectiveness in decreasing menstrual
to medical treatment or hysterectomy to treat abnormal uterine flow and result in high patient satisfaction. The choice of which
bleeding in select cases. (I) device to use depends primarily on surgical judgement and the
2. Endometrial preparation can be used to facilitate resectoscopic availability of resources. (I)
endometrial ablation (EA) and can be considered for some non- 6. The use of local anaesthetic and blocks, oral analgesia, and
resectoscopic techniques. For resectoscopic EA, preoperative conscious sedation allows for the provision of non-resectoscopic
endometrial thinning results in higher short-term amenorrhea EA in lower resource-intense environments including regulated
rates, decreased irrigant fluid absorption, and shorter operative non-hospital settings. (II-2)
time than no treatment. (I)
7. Low-risk patients with satisfactory pain tolerance are good
3. Non-resectoscopic techniques are technically easier to perform candidates to undergo endometrial ablation in settings outside the
than resectoscopic techniques, have shorter operative times, and operating room or in free-standing surgical centres. (II-2)
8. Both resectoscopic and non-resectoscopic endometrial ablation
are relatively safe procedures with low complication rates. The
ABBREVIATIONS complications perforation with potential injury to contiguous
AUB abnormal uterine bleeding structures, hemorrhage, and infection. (II-2)
GnRH gonadotropin releasing hormone 1. Preoperative assessment should be comprehensive to rule out
any contraindication to endometrial ablation. (II-2A)
HSG hysterosalpingogram
2. Patients should be counselled about the need for permanent
LNG-IUS levonorgestrel intrauterine system contraception following endometrial ablation. (II-2B)
NSAIDS non-steroidal anti-inflammatories
3. Recommended evaluations for abnormal uterine bleeding,
RCT randomized control trial including but not limited to endometrial sampling and an
costs of EA are about half that of hysterectomy, it seems Table 2. Indications and contraindications to EA
that the costs of the 2 procedures become equivalent at 4 Indications
years because some women with EA will need additional • AUB of benign origin
treatment. Age < 40 years, prior tubal ligation, and • EA may be considered as a primary intervention in
preoperative dysmenorrhea are independent predictors of circumstances such as intolerance to or failure of medical
EA failure and subsequent re-intervention.9,10 therapy, or patient preference
• EA may be considered for patients who refuse or are poor
Summary Statement surgical candidates for hysterectomy
1. Endometrial ablation is a safe and effective Absolute contraindications
minimally invasive surgical procedure that has • Pregnancy
become a well-established alternative to medical • Desire to preserve fertility
treatment or hysterectomy to treat abnormal uterine • Known or suspected endometrial hyperplasia or cancer
bleeding in select cases. (I) • Cervical cancer
• Active pelvic infection
Recommendation • Specific contraindications related to non-resectoscopic
1. Preoperative assessment should be comprehensive techniques*
to rule out any contraindication to endometrial *See “Special Considerations”
ablation. (II-2A)
amenorrhea rates at 12-month follow-up were 39% for
PREOPERATIVE AND POSTOPERATIVE CARE endometrial preparation with GnRH agonists compared
with 34% for danazol, 26% for medroxyprogesterone
Preoperative Care acetate, and 18% for D&C.14
The work-up of patients with AUB and the algorithm for
decision-making have been previously described.11 The use of endometrial preparation prior to non-resectoscopic
EA will depend on the product monograph for each individual
Patients must not desire future fertility as serious maternal– device. Meta-analysis of a few randomized trials on second-
fetal complications have been reported in pregnancies generation devices (radiofrequency ablation and balloon
following EA (uterine rupture causing maternal death, devices) suggest that preoperative endometrial thinning does
limb defects, premature labour).12 Therefore, women must not improve postoperative rates of amenorrhea.13
be counselled that EA is not considered a sterilization
method. Women must also be appropriately counselled No RCTs have yet supported or refuted the role of
about realistic expectations of ablation outcomes. The antibiotic prophylaxis before EA by any technique.15
goal of EA is to reduce bleeding symptoms; amenorrhea,
although possible, cannot be guaranteed. Postoperative Care
Patients can usually be discharged within 1 to 3 hours
Endometrial preparation can be considered preoperatively of EA depending on the type of anaesthesia used. They
as a thin endometrium can improve visualization for the can resume their normal activities progressively, but are
resectoscopic techniques and improve patient outcomes. advised to abstain from sexual intercourse for one week.
A thin endometrium can be achieved by scheduling Pain can be managed with NSAIDS or opiates, and will
the procedure in the immediate post-menstrual phase, usually resolve within 24 hours. Light vaginal bleeding or
performing curettage prior to the procedure or administering pinkish discharge is usual and can last up to several weeks
of preoperative hormonal therapy. A systematic review following the procedure. Patients are counselled to seek
suggested that preoperative endometrial thinning with GnRH medical care if they have fever, intense pain, or profuse
agonists and danazol resulted in higher rates of amenorrhea vaginal bleeding.
at 12 and 24 months than placebo/no treatment.13 Whether
or not this difference is maintained beyond 24 months is Summary Statement
uncertain. GnRH agonists and danazol also had a beneficial 2. Endometrial preparation can be used to facilitate
effect on the intrauterine operating environment with resectoscopic endometrial ablation (EA) and can be
respect to shorter operating time and reduced absorption of considered for some non-resectoscopic techniques.
distention media. The disadvantages of these agents include For resectoscopic EA, preoperative endometrial
the costs and side effects. Randomized data assessing the thinning results in higher short-term amenorrhea
value of progestins in preoperative endometrial thinning rates, decreased irrigant fluid absorption, and
prior to EA are scarce. In a study of resectoscopic EA, shorter operative time than no treatment. (I)
Efficacy of Resectoscopic EA serum sodium, it is less likely to cause cerebral edema than
Early studies reported high rates of improvement in heavy the absorption of hypotonic media.
menstrual bleeding and high rates of patient satisfaction.
O’Connor and Magos reported a 20% repeat surgery rate Fluid absorption increases significantly when intrauterine
including a 9% hysterectomy rate over 5 years follow-up in a pressure exceeds mean arterial pressure. For every 100 mL
group of 525 patients undergoing endometrial resection.21 of non-electrolyte solution absorbed, serum sodium falls
Martyn and Allan reported similar results with a repeat by 1 meq. Electronic fluid management systems provide an
surgery rate of 19.2% including an 11.6% hysterectomy accurate measurement of fluid deficits and can safeguard
rate at 5 years of follow-up.22 The presence of fibroids and against complications of excess absorption. Excess absorption
dysmenorrhea did not increase the risk of failure. of isotonic solutions may be less dangerous than absorption
of hypotonic solutions because there is a smaller chance of
A meta-analysis of 21 randomized trials comparing cerebral edema. Excessive fluid absorption may be prevented
different resectoscopic techniques of endometrial by pre-treatment of the endometrium,14 intracervical
destruction showed no difference in rates of amenorrhea injection of pressor agents (vasopressin, epinephrine) and the
and subsequent hysterectomy.16 First-generation techniques use of distension pressure less than that of the patient’s mean
showed improvement in bleeding in 72.5% to 79.5% at arterial pressure. Electronic fluid monitoring systems, which
1-year follow-up and high patient satisfaction rates. allow regulation of the flow rate, infusion pressure, outflow
suction, and fluid deficit may be more accurate in calculating
Advantages and Disadvantages of Resectoscopic EA fluid deficits than traditional gravity infusion systems and
Compared with the non-resectoscopic techniques, the manual estimation of fluid deficit.
resectoscopic EA offers certain advantages. It allows for
accurate assessment of uterine pathology with directed Non-resectoscopic EA
biopsies, documentation with photography, and concurrent Currently various energy sources are used in 6 non-
treatment of intracavitary pathology. It can also be used resectoscopic EA devices approved by Health Canada:
in patients who have had previous EA or transmyometrial bipolar radiofrequency ablation(NovaSure), cryotherapy
surgery. However, resectoscopic EA is a skill-dependent (Her Option),23 heated fluid freely circulated in the uterine
procedure that requires an operative room environment cavity (Hydro ThermAblator), and fluid contained in a
and has a higher complication rate than non-resectoscopic balloon (Thermachoice, Thermablate EAS, and Cavaterm).
methods. Specifications of each of these devices are compared in
Table 3. Future technologies such as the Aurora ablation
Distending Media for Resectoscopic EA system (radiofrequency energy and heated Argon gas
Distending media provide uterine distension and irrigate forming plasma energy) have promising preliminary results.24
blood and tissue fragments from the surgical field. A non-
electrolyte solution is required for monopolar resectoscopic In the absence of large differences in effectiveness and
surgery, but normal saline can be used with bipolar systems. with low complication rates for each of the devices, the
The following are common distending media: choice of which to use depends primarily on the following
practical issues and patient factors:
Conductive solutions (electrolytic/crystalloids)
•• availability of scientific evidence
•• Normal saline (290 mOsm/L): isotonic/isonatremic
•• cost effectiveness
Non-conductive (non-ionic, non-electolytic) •• surgeon preference
•• mannitol (275 mOsm/L): isotonic/hyponatremic, •• ease of use in outpatient/clinic setting
induces diuresis
•• requirement of endometrial preparation
•• glycine 1.5% (200 mOsm/L): hypotonic/hyponatremic;
acidic with a pH of 6.1 •• uterine cavity characteristics (size, cavitary pathology)
•• sorbitol 3.3% (165 mOsm/L): hypotonic/
CLINICAL TIP
hyponatremic
• For safety and appropriate intracavitary device placement,
•• cystosol (mannitol 0.54% and sorbitol 2.7%): pre- and post -procedural diagnostic hysteroscopy or
isotonic/hyponatremic intraprocedural ultrasound guidance may be considered.
Comparing the Efficacy of Non-resectoscopic Devices compared resectoscopic and non-resectoscopic techniques
Patient satisfaction and re-intervention rates may be and reported similar amenorrhea rates at 1 year (37% vs.
more clinically meaningful than absolute amenorrhea 28%) and at 2 to 5 years (53% vs. 48%).16 Because women
rates in comparing outcomes of procedures using non- who suffer from menorraghia are likely to be satisfied with
resectoscopic devices. All of these devices work well and either hypomenorrhea or normal menses, satisfaction rates
lead to high levels of patient satisfaction, as demonstrated for both types of ablations are high.32 In the Cochrane
by the FDA’s pivotal trials that showed satisfaction rates of meta-analysis, satisfaction rates were also comparable at 1
86% to 99% at 1 year.25 year (91% vs. 88%) and at 2 to 5 years (93% vs. 87%).16 In
an updated analysis of 25 RCTs with over 4000 patients,
Direct comparisons of non-resectoscopic devices are the rates of amenorrhea and patient satisfaction were not
scarce, and differences between trials with respect to significantly different, even up to 10 years after surgery.33
outcome measures, preoperative endometrial preparation, The surgical re-intervention rate (repeat ablation and/or
practice settings, and follow-up times make it challenging hysterectomy) for AUB has been reported to be similar
to compare outcomes accurately. NovaSure radiofrequency between techniques (21% vs. 25% at 2 to 5 years).16
ablation has been the most studied in randomized trials However, analysis of studies with longer follow-up shows
comparing it with Hydro ThermAblator and the hot liquid that non-resectoscopic EA has a lower re-intervention rate
balloons Thermachoice and Cavaterm. (RR 0.6, 95% CI 0.38 to 0.96) than resectoscopic EA.33
NovaSure versus Hydro ThermAblator Although clinical outcomes between techniques were
At 12 months’ follow-up, NovaSure had significantly higher comparable, non-resectoscopic procedures required
rates of patient satisfaction (87% vs. 68%) and amenorrhea shorter surgical time, were more likely to be performed
(47% vs 24%) than Hydro ThermAblator.26 This benefit under local anaesthesia, and resulted in patients’ quicker
persisted at 5 years, with NovaSure having significantly return to normal activity.32,33 The overall perioperative
higher satisfaction rates (81% vs. 48%), higher amenorrhea complication rate was low with both techniques (< 2.5%
rates (55% vs. 37%), and fewer surgical re-interventions each), but the non-resectoscopic procedures had a
(15% vs. 35%).27 lower incidence of uterine perforation, fluid overload,
hematometra and cervical laceration.32,33 These advantages
NovaSure versus Thermachoice were offset by increased nausea/vomiting and uterine
At the 5-year follow-up, both groups had similar cramping in the perioperative period.33 A higher incidence
improvements in health-related quality of life measures of equipment failure of second-generation devices was
and no significant differences in amenorrhea rates (48% reported in earlier trials, but this is becoming less of a
vs. 32%) and surgical re-interventions (10% vs. 13%).28 concern with updated models.
Resectoscopic ablation is frequently performed under The most common adverse events following EA are
general or regional anaesthesia in the operating room. pelvic pain, cramping, and nausea/vomiting. These will
However, in the appropriate setting, it can also be safely and generally resolve within 12 to 24 hours of the procedure.
effectively performed using a local paracervical block with Other problems that can develop post-procedure are
intravenous sedation. hematometrium, pyometrium, or endometritis. More
severe complications are rare with both techniques of
Local, regional, or general anaesthesia can be used for non-
EA, but can include injury to contiguous pelvic structures
resectoscopic EA. A main advantage of non-resectoscopic
procedures is that they may be conducted under local such as pelvic blood vessels, the bowel, and urinary tract
anaesthesia in a lower resource-intense environment than the anatomic components. Procedural complications such as
operating room. Performing such procedures in the operating severe pain, bleeding, uterine perforation, and infection
room rather than through a hysteroscopic procedure in may require emergent surgical management.16
another setting adds significant instrumentation costs but no The FDA has a reporting system for non-resectoscopic
value to the patient. ablation complications, and bowel injury is the most
In addition to local anaesthesia by paracervical block, oral common complication reported to its Manufacturer and
or intravenous conscious sedation may be used depending User Facility Device (MAUDE) database.36 Other major
on patient pain tolerance and surgeon preference. NSAIDS complications reported more infrequently are urinary
can be administered preoperatively and are moderately tract injuries, immediate hysterectomy, gas embolism,
effective in diminishing uterine contractions during and necrotizing fasciitis, and death. The incidence of such
after the procedure.34 complications is unavailable from such databases as
the denominator (total number of cases) is not known.
Procedure Room Versus Operating Room Setting However, the majority of these adverse events were
In the United States non-resectoscopic EA is frequently an associated with non-compliance with the manufacturers’
office-based procedure, and provider payment processes instructions for use. To mitigate the risk of injury with
promote these less resource-intense environments.35 non-resectoscopic procedures, surgeons may consider
Currently no mechanisms in the Canadian health care system post-dilatation hysteroscopy or concurrent ultrasound
compensate providers for non-resectoscopic EA in such a surveillance during the procedure.
setting. EA performed in a hospital-based procedure room or
a free-standing surgical centre rather than an operating room Serious Complications of EA
offers the advantages of a patient-centred environment, Uterine perforation has been reported in 0.3% of non-
easier scheduling, and reduced costs per case. Appropriate resectoscopic EA procedures and 1.3% of resectoscopic
low-risk patient selection and a satisfactory pain management ablations or resections.16 If uterine perforation is suspected
strategy are critical in this environment. Procedure rooms to have occurred during cervical dilatation or with the
must have appropriate emergency equipment available and resectoscope (without electrosurgery), the procedure should
all personnel must be trained in appropriate adverse event be abandoned and the patient should be closely monitored
protocols. A systematic review comparing non-resectoscopic for signs of intraperitoneal hemorrhage or visceral injury.
EA performed in the outpatient setting to resectoscopic EA If the perforation occurs while using electrosurgery or if
in the operating room, showed varying amounts of cost- the mechanism of perforation is uncertain, abdominal
savings.31 In the Canadian setting, an estimated savings of exploration is warranted to obtain hemostasis and rule out
$562 per patient receiving EA has been attributed to the visceral injury.
introduction of balloon devices in the outpatient setting.31
Perioperative hemorrhage has been reported in 1.2% of women
Summary Statements
undergoing non-resectoscopic ablation and 3.0% of those
6. The use of local anaesthetic and blocks, oral undergoing resectoscopic ablation.16
analgesia, and conscious sedation allows for the
provision of non-resectoscopic EA in lower Hematometra have been reported in 0.9% of women
resource-intense environments including regulated undergoing non-resectoscopic ablation and in 2.4 of
non-hospital settings. (II-2) those undergoing in resectoscopic ablation.16 Although
7. Low-risk patients with satisfactory pain tolerance intrauterine scarring is an expected result of EA,
are good candidates to undergo endometrial hematometra will occur when areas of the endometrium
ablation in settings outside the operating room or are adherent and there is endometrial bleeding behind
free-standing surgical centres. (II-2) the occlusion. Hematometra and cervical stenosis may be
often non-resectoscopic procedures such as NovaSure, < 4 cm reported an amenorrhea rate of 39% with the
Thermachoice, Thermablate, HydroThermAblator.45 HydroThermAblator treatment. However, amenorrhea rates
In most cases, both procedures were reported to be were significantly higher for patients with normal cavities
successful for the ablation and placement of the implants (62% at 30 months’ follow-up).48 Rates of re-intervention
at rate of 83% to 89%. The NovaSure requires placement were also significantly higher in patients with distorted
of implants after the procedure, while balloon thermal cavities.48 Women with types 1 and 2 submucosal fibroids
transfer and circulating saline could be performed before < 3 cm who were followed prospectively following treatment
or after hysteroscopic tubal sterilization. with NovaSure had amenorrhea rates of 69% at 1 year.49
Thermachoice also demonstrated a decrease in menstrual
Problems with combined Essure placement arise from the flow in 4 women with submucosal myomas < 3 cm.50
FDA’s mandatory requirement of confirming postoperative
tubal occlusion by HSG at 3 months. Obliteration of the Despite encouraging results showing that non-
uterine cavity following EA may make confirmation of tubal resectoscopic EA may be beneficial in treating AUB in
occlusions by HSG difficult. However, in other countries women with small (< 3 cm) submucosal fibroids, further
including Canada, HSG is not mandatory following research is still required. Where possible, hysteroscopic
hysteroscopic sterilization and many articles advocate myomectomy/polypectomy combined with resectoscopic
using three-dimensional US and X-ray to confirm bilateral EA should be used to treat women with symptomatic
placement and the non-migration of the tubal inserts.46 intracavitary pathology.
non-resectoscopic EA techniques. These procedures 3. Cooper K, Lee A, Chien P, Raja E, Timmaraju V, Bhattacharya S.
Outcomes following hysterectomy or endometrial ablation for heavy
were originally designed to treat normal uterine cavities. menstrual bleeding: retrospective analysis of hospital episode statistics in
Subsequently, various attempts have been made to examine Scotland. BJOG. 2011;118(10):1171–9.
the utility of these technologies in distorted cavities with 4. Kaunitz AM, Meredith S, Inki P, Kubba A, Sanchez-Ramos L.
submucosal fibroids. The HydroThermAblator, which relies Levonorgestrel-releasing intrauterine system and endometrial ablation in
heavy menstrual bleeding: a systematic review and meta-analysis. Obstet
on freely circulating heated fluid under direct visualization, Gynecol 2009;113:1104–16.
may be suited to treat distorted cavities as it does not rely
5. Lethaby AE, Cooke I, Rees M. Progesterone or progestogen-releasing
on the fixed shape of a mesh or balloon. A prospective intrauterine systems for heavy menstrual bleeding. Cochrane Database
study of patients with type 0 or type 1 submucosal fibroids Syst Rev 2005;(4):CD002126.
6. Matteson KA, Abed H, Wheeler TL, Sung VW, Rahn DD, Schaffer JI, et al. 25. Sharp HT. Assessment of new technology in the treatment of
A systematic review comparing hysterectomy with less-invasive treatments idiopathic menorrhagia and uterine leiomyomata. Obstet Gynecol
for abnormal uterine bleeding. J Minim Invasive Gynecol 2012;19:13–28. 2006;108:990–1003.
7. Munro MG, Dickersin K, Clark MA, Langenberg P, Scherer RW, Frick KD, 26. Penninx JPM, Mol BW, Engels R, van Rumste MME, Kleijn C,
et al. The Surgical Treatments Outcomes Project for Dysfunctional Uterine Koks CAM, et al. Bipolar radiofrequency endometrial ablation compared
Bleeding: summary of an Agency for Health Research and Quality- with hydrothermablation for dysfunctional uterine bleeding: a randomized
sponsored randomized trial of endometrial ablation versus hysterectomy for controlled trial. Obstet Gynecol 2010;116:819–26.
women with heavy menstrual bleeding. Menopause 2011;18:445–52. 27. Penninx JPM, Herman MC, Mol BW, Bongers MY. Five-year follow-up
8. Bhattacharya S, Middleton LJ, Tsourapas A, Lee AJ, Champaneria R, after comparing bipolar endometrial ablation with hydrothermablation for
Daniels JP, et al. Hysterectomy, endometrial ablation and Mirena® for heavy menorrhagia. Obstet Gynecol 2011;118:1287–92.
menstrual bleeding: a systematic review of clinical effectiveness and cost- 28. Kleijn JH, Engels R, Bourdrez P, Mol BWJ, Bongers MY. Five-year
effectiveness analysis. Health Technol Assess. 2011;15(19):iii–xvi–1–252. follow up of a randomised controlled trial comparing NovaSure and
9. Longinotti MK, Jacobson GF, Hung Y-Y, Learman LA. Probability ThermaChoice endometrial ablation. BJOG. 2008;115:193–8.
of hysterectomy after endometrial ablation. Obstet Gynecol 29. Abbott J, Hawe J, Hunter D, Garry R. A double-blind randomized
2008;112:1214–20. trial comparing the Cavaterm and the NovaSure endometrial ablation
10. El-Nashar SA, Hopkins MR, Creedon DJ, St Sauver JL, Weaver AL, systems for the treatment of dysfunctional uterine bleeding. Fertil Steril
McGree ME, et al. Prediction of treatment outcomes after global 2003;80:203–8.
endometrial ablation. Obstet Gynecol 2009;113:97–106. 30. Daniels JP, Middleton LJ, Champaneria R, Khan KS, Cooper K,
11. Singh S, Best C, Dunn S, Leyland N, Wolfman WL; SOGC Clinical Mol BWJ, et al. Second generation endometrial ablation techniques for
Practice–Gynaecology Committee. Abnormal uterine bleeding in heavy menstrual bleeding: network meta-analysis. BMJ 2012;344:e2564.
pre-menopausal women. SOGC Clinical Practice Guideline, No. 292, 31. Kroft J, Liu G. First- versus second-generation endometrial ablation
May 2013. J Obstet Gynaecol Can 2013;35:473–9. devices for treatment of menorrhagia: a systematic review, meta-
12. Laberge PY. Serious and deadly complications from pregnancy after analysis and appraisal of economic evaluations. J Obstet Gynaecol Can.
endometrial ablation: two case reports and review of the literature. 2013;35:1010–9.
J Gynecol Obstet Biol Reprod (Paris) 2008;37:609–13. 32. Middleton LJ, Champaneria R, Daniels JP, Bhattacharya S, Cooper KG,
13. Tan YH, Lethaby A. Pre-operative endometrial thinning agents before Hilken NH, et al. Hysterectomy, endometrial destruction, and
endometrial destruction for heavy menstrual bleeding. Cochrane Database levonorgestrel releasing intrauterine system (Mirena) for heavy menstrual
Syst Rev 2013;11:CD010241. bleeding: systematic review and meta-analysis of data from individual
patients. BMJ 2010;341:c3929.
14. Shawki O, Peters A, Abraham-Hebert S. Hysteroscopic endometrial
destruction, optimum method for preoperative endometrial preparation: 33. Lethaby A, Penninx J, Hickey M, Garry R, Marjoribanks J. Endometrial
a prospective, randomized, multicenter evaluation. JSLS 2002;6:23–7. resection and ablation techniques for heavy menstrual bleeding. Cochrane
Database Syst Rev. 2013;8:CD001501.
15. Thinkhamrop J, Laopaiboon M, Lumbiganon P. Prophylactic antibiotics
for transcervical intrauterine procedures. Cochrane Database Syst Rev 34. Ahmad G, O’Flynn H, Attarbashi S, Duffy JM, Watson A. Pain relief for
2007;(3):CD005637. outpatient hysteroscopy. Cochrane Database Syst Rev. 2010;(11):CD007710.
16. Lethaby A, Hickey M, Garry R, Penninx J. Endometrial resection/ 35. Glasser MH. Practical tips for office hysteroscopy and second-generation
ablation techniques for heavy menstrual bleeding. Cochrane Database “global” endometrial ablation. J Minim Invasive Gynecol 2009;16:384–99.
Syst Rev 2009;(4):CD001501. 36. Gardner S, Schultz DG. Complications associated with global
17. Deb S, Flora K, Atiomo W. A survey of preferences and practices of endometrial ablation: the utility of the MAUDE database. Obstet
endometrial ablation/resection for menorrhagia in the United Kingdom. Gynecol 2004;103(5 Pt 1):995–6.
Fertil Steril 2008;90:1812–7. 37. McCausland A, McCausland V. Frequency of symptomatic cornual
18. Neuwirth RS, Amin HK. Excision of submucus fibroids with hematometra and postablation tubal sterilization syndrome after total
hysteroscopic control. Am J Obstetr Gynecol 1976;126:95–9. rollerball endometrial ablation: a 10-year follow-up. Am J Obstet Gynecol
2002;186:1274–80; discussion 1280–3.
19. Goldrath MH, Fuller TA, Segal S. Laser photovaporization of
38. Gadzinski JA, Sheran J, Garbe G, Fitzgerald G, Mueller E, Wagner S.
endometrium for the treatment of menorrhagia. Am J Obstet Gynecol
Obstet Gynecol 2014;123(Suppl 1):124S. doi: 10.1097/01.
1981;140:14–9.
AOG.0000447083.64986.03.
20. Vilos GA. Hysteroscopic and nonhysteroscopic endometrial ablation.
39. McCausland A, McCausland V. Long-term complications of endometrial
Obstet Gynecol Clin North Am 2004;31:687–704, xi.
ablation: cause, diagnosis, treatment, and prevention. J Minim Invasive
21. O’Connor H, Magos A. Endometrial resection for the treatment of Gynecol 2007;14:399–406.
menorrhagia. N Engl J Med 1996;335:151–6.
40. Glasser MH, Heinlein PK, Hung Y-Y. Office endometrial ablation with
22. Martyn P, Allan B. Long-term follow-up of endometrial ablation. local anaesthesia using the HydroThermAblator system: comparison of
J Am Assoc Gynecol Laparosc 1998;5:115–8. outcomes in patients with submucous myomas with those with normal
23. Townsend DE, Duleba AJ, Wilkes MM. Durability of treatment effects cavities in 246 cases performed over 5(1/2) years. J Minim Invasive
after endometrial cryoablation versus rollerball electroablation for Gynecol 2009;16:700–7.
abnormal uterine bleeding: two-year results of a multicenter randomized 41. Munro MG. Mechanisms of thermal injury to the lower genital tract
trial. Am J Obstet Gynecol 2003;188:699–701. with radiofrequency resectoscopic surgery. J Minim Invasive Gynecol
2006;13:36–42.
24. Sabbah R, Laberge P, Fortin C, Thiel J, Garza-Leal J, Fullop T, et al.
A multi-center, single-arm, international clinical study of the safety and 42. MacLean-Fraser E, Penava D, Vilos GA. Perioperative complication rates
efficacy of the AURORA endometrial ablation system. Preliminary clinical of primary and repeat hysteroscopic endometrial ablations. J Am Assoc
results. J Minim Invasive Gynecol 2011;18:S82. Gynecol Laparosc 2002;9:175–7.
43. Hansen BB, Dreisler E, Stampe Sørensen S. Outcome of repeated 48. Glasser MH, Heinlein PK, Hung Y-Y. Office endometrial ablation with
hysteroscopic resection of the endometrium. J Minim Invasive Gynecol local anaesthesia using the HydroThermAblator system: comparison of
2008;15:704–6. outcomes in patients with submucous myomas with those with normal
cavities in 246 cases performed over 5(1/2) years. J Minim Invasive
44. Connor VF. Essure: a review six years later. J Minim Invasive Gynecol Gynecol 2009;16:700–7.
2009;16:282–90.
49. Sabbah R, Desaulniers G. Use of the NovaSure impedance controlled
45. Donnadieu AC, Deffieux X, Gervaise A, Faivre E, Frydman R, endometrial ablation system in patients with intracavitary disease:
Fernandez H. Essure sterilization associated with endometrial 12-month follow-up results of a prospective, single-arm clinical study.
ablation. Int J Gynaecol Obstet 2007;97:139–42. J Minim Invasive Gynecol 2006;13:467–71.
46. Mircea CN, Goojha C, Thiel JA. Concomitant NovaSure endometrial 50. Soysal ME, Soysal SK, Vicdan K. Thermal balloon ablation in
ablation and Essure tubal sterilization: a review of 100 cases. J Obstet myoma-induced menorrhagia under local anaesthesia. Gynecol
Gynaecol Can 2011;33:361–6. Obstet Invest 2001;51:128–33.
47. Khan Z, El-Nashar SA, Hopkins MR, Famuyide AO. Efficacy and safety 51. Woolf SH, Battista RN, Angerson GM, Logan AG, Eel W. Canadian Task
of global endometrial ablation after cesarean delivery: a cohort study. Am Force on Preventive Health Care. New grades for recommendations from the
J Obstet Gynecol2011;205:450.e1–4. Canadian Task Force on Preventive Health Care. CMAJ 2003;169:207–8.
APPENDIX
ENDOMETRIAL ABLATION PATIENT INFORMATION SHEET
Endometrial ablation is an alternative surgical procedure for heavy menstrual bleeding. It attempts to destroy or remove the
endometrium—the lining of your uterus. This can replace hysterectomy in many cases.
This is a day surgery procedure. The technique varies depending on the method used to destroy the endometrium.
Most EA procedures can be done in an outpatient surgical centre while others must be performed in an operating room. Factors such
as the size of your uterus, presence of fibroid tumours, and experience of the surgeon will help determine which endometrial ablation
method is best for you.
While medications are typically recommended as first line treatment for heavy menstrual bleeding, endometrial ablation may be an
option if medications don’t help or you decline to try them.
Endometrial ablation is not recommended for women who: Endometrial ablation risks may include:
• wish to become pregnant in the future, • perforation of the uterine wall,
• have cancer of the uterus, • damage to nearby organs, and/or
• have large fibroid tumours in the uterus, and/or • pain, bleeding, or infection.
• have had recent pelvic infection.
Future pregnancy
Many women stop having periods after endometrial ablation, but pregnancy is still possible in some women. Most of these pregnancies
will have an abnormal outcome. Women who wish to become pregnant in the future should not consider endometrial ablation.
Some women may choose to undergo a sterilization procedure at the time of endometrial ablation or consider other forms of reliable
contraception to prevent pregnancy. Concomitant laparoscopic tubal ligation would usually require general anaesthetic.
The procedure
Endometrial ablation can be performed in your doctor’s office, but some types of endometrial ablation are performed in a hospital
operating room, especially if you will need general anaesthesia.
The cervix is dilated to allow for the passage of the instruments used in endometrial ablation. Endometrial ablation procedures vary by
the method used to destroy your endometrium.
• Electrosurgery. This method uses a small hysteroscope to view the uterine cavity during the procedure. An electrode is used to
resect or destroy the lining of the uterus.
• Free-flowing hot fluid. Saline fluid heated to 80°C to 90°C is circulated within the uterus for about 10 minutes.
• Heated balloon. A balloon device is inserted through your cervix and then inflated with fluid heated to 87°C for about 2 to
10 minutes.
• Bipolar radiofrequency. This uses a bipolar wire mesh electrode that contacts the uterine cavity. The instrument transmits high
frequency electrical energy that vaporizes the endometrial tissue in about 90 seconds.
This document reflects emerging clinical and scientific advances on the date issued and is subject to change. The information
should not be construed as dictating an exclusive course of treatment or procedure to be followed. Local institutions can dictate
amendments to these opinions. They should be well documented if modified at the local level. None of these contents may be
reproduced in any form without prior written permission of the SOGC.
monitored by the Clinical Practice Obstetrics Committee 2. Leduc D, Biringer A, Lee L, Dy J; Clinical Practice Obstetrics
Committee, Society of Obsetricians and Gynaecologists of
for potential change of practice implications. Canada. Induction of labour. SOGC Clinical Practice Guideline
No. 296, September 2013. J Obstet Gynaecol Can 2013;36:248–52.
It is to be noted that, to ensure the best quality of care, the
3. Eunice Kennedy Shriver National Institute of Child Health and
SOGC is currently developing a standard of practice under Human Development (NICHD). A Randomized Trial of Induction
which evidence will be reviewed on a regular basis to decide Versus Expectant Management (ARRIVE). Bethesda, MD: US National
whether all or part of a guideline should be updated based Institute of Health; 2014. Available at: http://clinicaltrials.gov/ct2/show/
on new robust (Canadian Task Force on Preventive Health NCT01990612?term=ARRIVE&rank=2. Accessed on December 10, 2014.
Care5 level I) evidence. 4. Nottingham Clinical Trials Unit. Induction of labour versus
expectant management for women over 35 years of age. Nothingham, GB:
NCTU; 2013. Available at: http://www.35-39trial.org.
REFERENCES Accessed on December 10, 2014.
5. Woolf SH, Battista RN, Angerson GM, Logan AG, Eel W;
1. Mishanina E, Rogozinska E, Thatthi T, Uddin-Khan R, Khan KS, Canadian Task Force on Preventive Health Care. New grades for
et al. Use of labour induction and risk of cesarean delivery: a systematic recommendations from the Canadian Task Force on Preventive
review and meta-analysis. CMAJ 2014;186:665–73. Health Care. CMAJ 2003;169:207–8.
This document reflects emerging clinical and scientific advances on the date issued and is subject to change. The information
should not be construed as dictating an exclusive course of treatment or procedure to be followed. Local institutions can dictate
amendments to these opinions. They should be well documented if modified at the local level. None of these contents may be
reproduced in any form without prior written permission of the SOGC.
Key to evidence statements and grading of recommendations, using the ranking of the Canadian Task Force on
Preventive Health Care
Quality of evidence assessment* Classification of recommendations†
I: Evidence obtained from at least one properly randomized A. There is good evidence to recommend the clinical preventive action
controlled trial
II-1: Evidence from well-designed controlled trials without B. There is fair evidence to recommend the clinical preventive action
randomization
II-2: Evidence from well-designed cohort (prospective or C. The existing evidence is conflicting and does not allow to make a
retrospective) or case–control studies, preferably from recommendation for or against use of the clinical preventive action;
more than one centre or research group however, other factors may influence decision-making
II-3: Evidence obtained from comparisons between times or D. There is fair evidence to recommend against the clinical preventive action
places with or without the intervention. Dramatic results in
uncontrolled experiments (such as the results of treatment with E. There is good evidence to recommend against the clinical preventive
penicillin in the 1940s) could also be included in this category action
III: Opinions of respected authorities, based on clinical experience, L. There is insufficient evidence (in quantity or quality) to make
descriptive studies, or reports of expert committees a recommendation; however, other factors may influence
decision-making
*The quality of evidence reported in here has been adapted from The Evaluation of Evidence criteria described in the Canadian Task Force on Preventive Health
Care.52
†Recommendations included in these guidelines have been adapted from the Classification of Recommendations criteria described in the Canadian Task Force
on Preventive Health Care.52
8. If fibroids are removed abdominally, efforts should be made pathological examination).9 The main drawbacks of MRI
to use an anterior uterine incision to minimize the formation of
evaluation are lack of accessibility and high cost.8
postoperative adhesions. (II-2A)
9. Widespread use of the laparoscopic approach to myomectomy Hysterosalpingography is often performed to assess
may be limited by the technical difficulty of this procedure. Patient
selection should be individualized based on the number, size, and
tubal patency in women with infertility and to exclude
location of uterine fibroids and the skill of the surgeon. (III-A) intrauterine pathology. However, the sensitivity and
10. Women, fertile or infertile, seeking future pregnancy should not positive predictive value of this test for the identification
generally be offered uterine artery embolization as a treatment of intrauterine lesions can be as low as 50% and 28.6%
option for uterine fibroids. (II-3E) respectively.12 Hysterosalpingography cannot therefore
be considered reliable to exclude endometrial distortion
secondary to submucosal myomas.
INTRODUCTION
U
Hysterosonography, which has the advantages of
terine fibroids, myomas, or leiomyomata are smooth
pelvic ultrasound, has been advocated as superior to
muscle cell tumours and are the most common benign
transvaginal ultrasound alone13 and equal to hysteroscopy
gynaecologic tumour in women of reproductive age.1 They are
in the evaluation of endometrial impingement.14 It has
often found as part of the investigation of a couple presenting
been shown to be highly sensitive and specific in the
with infertility, and their origin is monoclonal.2 They are rarely
identification of submucosal myomas. Its main drawbacks
found before menarche and usually regress after menopause.3
are the risk of infection (approximately 1%) and the
They are hormonally responsive, and estrogens appear to
discomfort associated with the injection of sterile saline.13
promote their growth.4,5 Local estrogen concentrations have
been shown to be higher in myomas than in the surrounding No studies to date have evaluated the optimal mode of
myometrium, possibly because of a higher concentration of evaluating uterine myoma in women presenting with
aromatase.6 Hormonal responsiveness appears to be greater infertility. It is also unclear whether all women with
in submucosal than subserosal myomas.7 infertility should have the integrity of their endometrial
cavity evaluated. However, it seems clear that part of the
EVALUATION AND CLASSIFICATION OF FIBROIDS heterogeneity in the results of studies attempting to clarify
the relationships between fibroids and infertility and the
Submucosal fibroids have a negative impact on rates of impact of treatment on conception is due to inadequate
implantation, clinical pregnancy, ongoing pregnancy, classification of fibroids, and in particular their impact on
miscarriage, and live birth. An important feature of fibroid the endometrial cavity.
classification systems is the evaluation of the uterine cavity
in order to define a fibroid as submucosal. Many studies Recommendations
have not included proper evaluation of the cavity, and 1. In women with infertility, an effort should be
therefore potential biases can be expected in their results. made to adequately evaluate and classify fibroids,
Imaging is now recognized as a necessary tool in the particularly those impinging on the endometrial
preoperative evaluation of myomas, especially for uterus- cavity, using transvaginal ultrasound, hysteroscopy,
sparing procedures.8 hysterosonography, or magnetic resonance
imaging. (III-A)
Ultrasound has been shown to be an adequate, rapid, safe,
2. Preoperative assessment of submucosal fibroids
and cost-effective means of evaluating the size, number, and
should include, in addition to an assessment of
location of fibroids.9 Transvaginal ultrasound may identify
fibroid size and location within the uterine cavity,
fibroids of up to 4 to 5 mm in diameter.10 Ultrasound evaluation of the degree of invasion of the cavity
may, however, be suboptimal for multiple fibroids, because and thickness of residual myometrium to the serosa.
of acoustic shadowing, and for the proper evaluation of A combination of hysteroscopy and transvaginal
endometrial impingement. Interobserver variation has also ultrasound or hysterosonography are the modalities
been found to be greater with this technique than with MRI.11 of choice. (III-B)
MRI has been well studied in the evaluation of fibroid 3. Submucosal fibroids are managed hysteroscopically.
uteruses, especially for fibroid mapping and submucosal The fibroid size should be < 5 cm, although larger
penetration. It was shown to be the most reliable fibroids have been managed hysteroscopically, but
method of evaluation when compared with vaginal repeat procedures are often necessary. (III-B)
ultrasound, hysterosonography, and hysteroscopy, with 4. A hysterosalpingogram is not an appropriate exam to
100% sensitivity and 91% specificity (gold standard was evaluate and classify fibroids. (III-D)
IMPACT OF FIBROIDS ON The greatest debate remains on the impact and treatment of
REPRODUCTIVE FUNCTION intramural fibroids. Part of the disagreement between studies
may result from inappropriate evaluation of the endometrial
The prevalence of fibroids in the infertile population cavity causing the erroneous inclusion of submucosal fibroids
of women is controversial. According to Donnez,15 in the group of intramural fibroids. Considering only the
approximately 5% to 10% of women presenting with most recent good quality meta-analysis, intramural fibroids do
infertility are found to have one or multiple fibroids.
seem to have an impact on both IR and CPR (RR 0.684; 95%
However, when all other causes of infertility are excluded,
CI 0.587 to 0.796, P < 0.001 and RR 0.810; 0.696 to 0.941,
fibroids are found in only 1% to 2% of the remaining
P = 0.006, respectively) but less than that of submucosal
women.16 Both infertility and age have been associated
fibroids. Although the number of studies reporting this
with the presence of myomas and may therefore confound
outcome was small, there was no impact found on LBR/
results of studies attempting to clarify the relationship
OPR.25 This finding remained significant regardless of study
between fibroids and infertility.17 There have been no
design and when looking exclusively at studies on IVF, except
appropriately designed studies to demonstrate a direct
that Sunkara et al.27 found a reduction in LBR in women
causal relationship between the presence of fibroids and
undergoing IVF in the presence of intramural fibroids (RR
infertility.
0.79; 95% CI 0.70 to 0.88, P < 0.001). This discrepancy in
Many hypotheses have been generated to explain how IVF studies could be explained by the authors’ not controlling
fibroids might cause infertility. Perfusion studies have for age and number of IVF cycles. Considering only studies
shown that blood flow to uterine fibroids is less than that that included an adequate hysteroscopic evaluation of the
to the adjacent myometrium.18–20 Blood flow to the uterine uterine cavity, implantation remains the only rate significantly
arteries is also different in fibroid uteruses than non-fibroid affected by the presence of intramural fibroids.25 Fibroid size
uteruses.21 This and the fact that there may be endometrial did not seem to have an impact on these results, although
inflammation and an altered local hormonal environment large intramural fibroids would presumably have been
may impede embryo implantation. Myomas also seem to treated surgically and hence not included in such studies.
alter uterine contractility possibly interfering with sperm Most studies included intramural fibroids < 5 cm. No
and ovum interaction or embryo migration.4,15 This may studies have examined the distance between fibroid edge
especially be true in uteruses with multiple large fibroids and endometrium. Only one retrospective study evaluated
with important cavity distortion. the impact of a single intramural fibroid on IVF outcomes
for severe male factor. Endometrial cavity was assessed using
Six systematic reviews or meta-analyses published between hysteroscopy in all patients. Fibroid sizes ranged from 5 to
2001 and 201015,22–26 assessed whether fibroids have an 43 mm. IR and CPR were similar between cases (n = 61)
impact on fertility. On the whole, it appears that women and controls (n = 444).28 Miscarriage rates were found to be
with fibroids have decreased fertility. The presence of increased in women with intramural fibroids (RR 1.747; 95%
fibroids, regardless of location, significantly decreases CI 1.22 to 2.489, P = 0.002), but this effect was lost when
both implantation and clinical pregnancy rates (RR 0.821; only studies with adequate cavity involvement evaluation
95% CI 0.722 to 0.932, P = 0.002 and RR 0.849; 95% CI were included.25
0.734 to 0.982, P < 0.03 respectively).25 The impact of
fibroid number and size on fertility has not been clearly Another way of assessing whether a uterine pathology
elucidated.17 Reproductive success does, however, seem to has an impact on conception rates is to evaluate whether
be related to fibroid location. pregnancy rates increase more after removal than after
expectant management. It is equally important to ensure
Subserosal fibroids do not appear to have an impact on that treatment does not have an intrinsically negative
fertility; all systematic reviews and meta-analyses agreed on impact on fertility, particularly in surgical treatments that
this point. Submucosal fibroids (fibroids with endometrial can result in the formation of scar tissue and adhesions
impingement), however, have been shown uniformly known to have deleterious effects on conception rates.
to have a negative impact on rates of implantation, Studies on treatment for leiomyomas in women with
clinical pregnancy, miscarriage, and live birth/ongoing infertility have been few and small. Two types of control
pregnancy, although available studies are few and small groups have been used: women with fibroids left in situ
(IR: RR 0.283; 95% CI 0.123 to 0.649, P = 0.003; CPR: and women with unexplained infertility without fibroids.
RR 0.363; 95% CI 0.179 to 0.737, P = 0.005; MR:
RR 1.678; 95% CI 1.373 to 2.051, P = 0.022; LBR/OPR: No large trials have evaluated the impact of myomectomy
RR 0.318; 95% CI 0.119 to 0.850, P < 0.001).25 in women with submucosal fibroids. A meta-analysis of
the small studies available found an apparent benefit of A recent meta-analysis demonstrated similar findings, with
hysteroscopic myomectomy over fibroids left in situ an improvement in pregnancy rates in infertile patients
on CPR (RR 2.034, 95% CI 1.081 to 3.826, P = 0.028). undergoing surgical removal of submucosal fibroids, but
Pregnancy rates after myomectomy become statistically not in those undergoing surgical removal of intramural
similar to those in women with infertility without fibroids.25 fibroids.25
In the matter of the surgical removal of intramural fibroids
to improve fertility, data fail to show a clear benefit of Surgical treatment of fibroids can be associated with
myomectomy over myomas left in situ. morbidity. It has been associated with both pelvic and
intrauterine adhesions, so any potential benefit from the
Summary Statement removal of the fibroids may be negated by the detrimental
1. Subserosal fibroids do not appear to have an impact effect of the surgery on uterine integrity. In addition, the
on fertility; the effect of intramural fibroids remains consequences of myomectomy on pregnancy outcomes
unclear. If intramural fibroids do have an impact on are not negligible. It is therefore imperative that surgical
fertility, it appears to be small and to be even less signifi- management of fibroids for infertility be undertaken
cant when the endometrium is not involved. (II-3) only when there is evidence to support improvement
in pregnancy outcomes through surgical intervention.
MEDICAL MANAGEMENT There may, however, be instances when surgical removal
of fibroids in an infertile patient may be undertaken for
Contemporary medical management of uterine fibroids reasons other than fertility enhancement, such as relief of
exploits the estrogen- and progesterone-responsiveness pressure symptoms or surgical management of menstrual
of uterine fibroids; however, no pharmacological agent is disturbances secondary to fibroids.
curative of fibroids. As a result, medical therapy is essentially
a treatment option for the control of symptoms. Several Recommendations
agents exist for the management of uterine fibroids through 5. In women with otherwise unexplained infertility,
symptom control, reduction in fibroid volume, and reduction submucosal fibroids should be removed in order to
in menstrual blood loss. Most commonly used agents have improve conception and pregnancy rates. (II-2)
been GnRH analogues. Newer, novel therapies including 6. Removal of subserosal fibroids is not
aromatase inhibitors, mifepristone, selective estrogen recommended. (III-D)
receptor modulators, and selective progesterone receptor 7. There is fair evidence to recommend against
modulators have shown promise in symptom improvement myomectomy in women with intramural fibroids
and fibroid regression without the hypoestrogenic symptoms (hysteroscopically confirmed intact endometrium)
associated with GnRH analogues. and otherwise unexplained infertility, regardless of
the size of the fibroids. (II-2D) If the patient has no
Summary Statement
other options, the benefits of myomectomy should
2. Because current medical therapy for fibroids is be weighed against the risks, and management of
associated with suppression of ovulation, reduction intramural fibroids should be individualized. (III-C)
of estrogen production, or disruption of target
action of estrogen or progesterone at the receptor Surgical approach to fibroids can be either vaginal or
level, and it has the potential to interfere in abdominal. The abdominal approach may be either by
endometrial development and implantation, there is laparotomy or laparoscopy. The specific approach will
no role for medical therapy as stand-alone treatment depend on fibroid size and location and on skill of the
for fibroids in the infertile population. (III) practitioner. The decision to proceed with myomectomy
for improvement in fertility outcomes, especially when
SURGICAL MANAGEMENT laparotomy is recommended, should be weighed against
the patient’s clinical fertility history, subsequent plans for
Well-designed surgical intervention trials for myomectomy fertility treatment, and estimated fecundability with or
and infertility are sparse, with a single RCT published without myomectomy.
to date.28 This study demonstrated an improvement in
spontaneous conception rates after the surgical removal Hysteroscopic Myomectomy
of submucosal fibroids, but pregnancy rates following Hysteroscopic myomectomy is the least invasive surgical
the removal of intramural or subserosal fibroids were no approach to fibroid removal. It is most effective for
more improved than in the expectant management group patients with submucosal fibroids completely within the
of women with intramural-subserosal fibroids in situ. uterine cavity (Type 0) or with at least 50% of the fibroid
volume within the uterine cavity (Type I). Fibroids with Postoperative formation of adhesions after myomectomy is
less than 50% of the fibroid volume in the cavity (Type II) extremely high: in one study it was 94% with uterine incisions
are much more difficult to resect completely and are more on the posterior wall and 55% when the incision occurred
often associated with the need for repeated procedures.29,30 on the anterior uterine wall. Obviously these adhesions may
Additionally, it has generally been recommended that have a negative impact on fertility in women where this is
hysteroscopic myomectomy be undertaken with fibroids already a concern. These adhesions were lysed at second-
under 5 cm; however fibroids greater than 5 cm and look laparoscopy 6 weeks post myomectomy, with a 67%
Type II fibroids have been resected hysteroscopically.31 cumulative pregnancy rate 12 months post myomectomy.35
Summary Statement Recommendation
3. Preoperative assessment of submucosal fibroids is 8. If fibroids are removed abdominally, efforts should be
essential to the decision on the best approach for made to use an anterior uterine incision to minimize
treatment. (III) the formation of postoperative adhesions. (II-2A)
Of late, complications that may further impair fertility Best practice for adhesion prevention in gynaecologic
after hysteroscopic myomectomy, intrauterine adhesions surgery has been thoroughly described elsewhere.36
are the most concerning. The incidence of intrauterine
adhesions after hysteroscopic myomectomy was shown Two RCTs with a combined 267 patients compared
in one study to be 7.5%.32 Postoperative adjuvant therapy, reproductive outcomes of laparoscopic myomectomy
including estrogen therapy for 4 to 8 weeks or insertion and myomectomy by laparotomy. In the first study of
of an intrauterine device, pediatric Foley catheter, or other patients undergoing myomectomy for infertility and
balloon for 1 week postoperatively, have all been used to at least 1 fibroid > 5 cm, pregnancy rates were similar
prevent further adhesion development. However, there is following in the laparoscopy and laparotomy groups
scant evidence to support the use of these postoperative (53.6% vs. 55.9%).37 There was lower febrile morbidity in
therapies.33,34 the laparoscopy group (26.2% vs. 12.1%), shorter hospital
stay, and a lower postoperative drop in hemoglobin. In
Summary Statement the second study, 12 months postoperatively, cumulative
4. There is little evidence on the use of Foley catheters, pregnancy rates were similar in the laparoscopy and
estrogen, or intrauterine devices for the prevention laparotomy groups (52.9% vs. 38.2%).38 Miscarriage rates
of intrauterine adhesions following hysteroscopic and preterm delivery rates were also similar between
myomectomy. (II-3) groups and similar to expected rates in the general
population. Interestingly, in the subgroup of patients
Abdominal Myomectomy undergoing myomectomy for non-fertility indications the
Abdominal myomectomy is an effective surgical procedure cumulative pregnancy rate was greater in the laparoscopy
for women wishing to preserve their fertility and who have subgroup (73.7% vs. 50%). In this study, it appears
pressure symptoms due to the mass effect of large fibroids. myomectomy was not considered a contraindication to
It may also be performed in women wishing to preserve vaginal delivery, and 31% of all patients who delivered
their fertility with symptomatic menorrhagia that is neither underwent a successful vaginal delivery.
controlled by medical management nor effectively managed
by hysteroscopic myomectomy. With improvements Summary Statement
in hysteroscopic myomectomy techniques, the use of 5. In the infertile population, cumulative pregnancy
abdominal myomectomy to improve fecundity has narrowed rates by the laparoscopic and minilaparotomy
to a small subgroup of infertile patients with fibroids. The approaches are similar, but the laparoscopic
current indication for abdominal myomectomy is for infertile approach is associated with a quicker recovery, less
patients with large (> 5 cm) Type II submucosal fibroids or postoperative pain, and less febrile morbidity. (II-2)
Type II fibroids with < 1 cm between the external surface of
the fibroid and the uterine serosa. The goal, similar to that Recommendation
of hysteroscopic myomectomy for infertility, is to remove 9. Widespread use of the laparoscopic approach
the fibroid in its entirety and to restore normal uterine cavity to myomectomy may be limited by the technical
size and architecture. Abdominal myomectomy may be difficulty of this procedure. Patient selection should
conducted through a subumbilical vertical incision for large be individualized based on the number, size, and
fibroids, as a mini-laparotomy through a Pfannenstiel incision location of uterine fibroids and the skill of the
for smaller fibroids (typically < 10 cm), or laparoscopically. surgeon. (III-A)
13. Dueholm M, Forman A, Jensen ML, Laursen H, Kracht P. Transvaginal 34. Tonguc EA, Var T, Yilmaz N, Batioglu S. Intrauterine device or estrogen
sonography combined with saline contrast sonohysterography in treatment after hysteroscopic septum resection. Int J Gynaecol Obstet
evaluating the uterine cavity in premenopausal patients with abnormal 2010;109:226–9.
uterine bleeding. Ultrasound Obstet Gynecol 2001;18:54–61.
35. Tulandi T, Murray C, Guralnick M. Adhesion formation and reproductive
14. Dueholm M, Lundorf E, Hansen ES, Ledertoug S, Olesen F. Evaluation outcome after myomectomy and second-look laparoscopy. Obstet
of the uterine cavity with magnetic resonance imaging, transvaginal Gynecol 1983;82:213–5.
sonography, hysterosonographic examination, and diagnostic
36. Robertson D, Lefebvre G; Society of Obstetricians and Gynaecologists of
hysteroscopy. Fertil Steril 2001;76:350–7.
Canada Clinical Practice Gynaecology Committee. Adhesion prevention in
15. Donnez J, Jadoul P. What are the implications of myomas on fertility? gynaecological surgery. SOGC Clinical Practice Guideline, No. 243, June
A need for a debate? Hum Reprod 2002;17:1424–30. 2010. J Obstet Gynaecol Can 2010;32:598–608.
16. Cook H, Ezzati M, Segars JH, McCarthy K. The impact of uterine 37. Seracchioli R, Rossi S, Govoni F, Rossi E, Venturoli S, Bulletti C, et al.
leiomyomas on reproductive outcomes. Minerva Ginecol 2010;62:225–36. Fertility and obstetric outcome after laparoscopic myomectomy of large
17. Olive DL, Pritts EA. Fibroids and reproduction. Semin Reprod Med myomata: a randomized comparison with abdominal myomectomy. Hum
2010;28:218–27. Reprod 2000;15:2663–8.
18. de Souza NM, Brosens JJ, Schwieso JE, Paraschos T, Winston RM. The 38. Palomba S, Zupi E, Falbo A, Russo T, Marconi D, Tolino A, et al.
potential value of magnetic resonance imaging in infertility. Clin Radiol A multicenter randomized, controlled study comparing laparoscopic
1995;50:75–9. versus minilaparotomic myomectomy: reproductive outcomes. Fertil Steril
2007;88:933–41.
19. Forssman L. Blood flow in myomatous uteri as measured by intra-arterial
133Xenon. Acta Obstet Gynecol Scand 1976;55:21–4. 39. Ravina JH, Herbreteau D, Ciraru-Vigneron N, Bouret JM, Houdart E,
Aymard A, et al. Arterial embolisation to treat uterine myomata. Lancet
20. Forssman, L. Distribution of blood flow in myomatous uteri as measured 1995;346:671–2.
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40. Radeleff B, Eiers M, Bellemann N, Ramsauer S, Rimbach S, Kauczor HU,
21. Kurjak A, Kupesic-Urek S, Miric D. The assessment of benign uterine et al. Expulsion of dominant submucosal fibroids after uterine artery
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1992;18:645–9.
41. Scheurig-Muenkler C, Wagner M, Franiel T, Hamm B, Kroencke TJ.
22. Griffiths AN, D’Angelo A, Amso NN. Surgical treatment of fibroids for Effect of uterine artery embolization on uterine and leiomyoma
subfertility. Cochrane Database Syst Rev 2006;(3):CD003857 11. perfusion: evidence of transient myometrial ischemia on magnetic
23. Klatsky PC, Tran ND, Caughey AB, Fujimoto VY. Fibroids and resonance imaging. J Vasc Interv Radiol 2010;21:1347–53.
reproductive outcomes: a systematic literature review from conception to 42. Agdi M, Tulandi T. Endoscopic management of uterine fibroids. Best
delivery. Am J Obstet Gynecol 2008;198:357–66. Pract Res Clin Obstet Gynaecol 2008;22:707–16.
24. Pritts EA. Fibroids and infertility: a systematic review of the evidence. 43. Agdi M, Valenti D, Tulandi T. Intraabdominal adhesions after uterine
Obstet Gynecol Surv 2001;56:483–91. artery embolization. Am J Obstet Gynecol 2008;199:482.e1–482.e3.
25. Pritts EA, Parker WH, Olive DL. Fibroids and infertility: an updated 44. Mara M, Maskova J, Fucikova Z, Kuzel D, Belsan T, Sosna O. Midterm
systematic review of the evidence. Fertil Steril 2009;91:1215–23. clinical and first reproductive results of a randomized controlled trial
26. Somigliana E, Vercellini P, Daguati R, Pasin R, De Giorgi O, Crosignani comparing uterine fibroid embolization and myomectomy. Cardiovasc
PG. Fibroids and female reproduction: a critical analysis of the evidence. Intervent Radiol 2008;31:73–85.
Hum Reprod Update 2007;13:465–76. 45. Goodwin SC, McLucas B, Lee M, Chen G, Perrella R, Vedantham S, et al.
27. Sunkara SK, Khairy M, El-Toukhy T, Khalaf Y, Coomarasamy A. The Uterine artery embolization for the treatment of uterine leiomyomata
effect of intramural fibroids without uterine cavity involvement on the midterm results. J Vasc Intervent Radiol 1999;10:1159–65.
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28. Bozdag G, Esinler I, Boynukalin K, Aksu T, Gunalp S, Gurgan T. Single embolization, myomectomy, and hysterectomy on ovarian function.
intramural leiomyoma with normal hysteroscopic findings does not J Vasc Intervent Radiol 2006;17:1111–5.
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AP, Birnie E, et al. Loss of ovarian reserve after uterine artery
28. Casini ML, Rossi F, Agostini R, Unfer V. Effects of position of fibroids embolization: a randomized comparison with hysterectomy. Hum Reprod
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29. Wamsteker K, Emanuel MH, de Kruif JH. Transcervical hysteroscopic 48. Homer H, Saridogan E. Uterine artery embolization for fibroids
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This document reflects emerging clinical and scientific advances on the date issued and is subject to change. The information
should not be construed as dictating an exclusive course of treatment or procedure to be followed. Local institutions can dictate
amendments to these opinions. They should be well documented if modified at the local level. None of these contents may be
reproduced in any form without prior written permission of the SOGC.
Table 1. Key to evidence statements and grading of recommendations, using the ranking of the Canadian Task Force
on Preventive Health Care
Quality of evidence assessment* Classification of recommendations†
I: Evidence obtained from at least one properly randomized A. There is good evidence to recommend the clinical preventive action
controlled trial
II-1: Evidence from well-designed controlled trials without B. There is fair evidence to recommend the clinical preventive action
randomization
II-2: Evidence from well-designed cohort (prospective or C. The existing evidence is conflicting and does not allow to make a
retrospective) or case–control studies, preferably from recommendation for or against use of the clinical preventive action;
more than one centre or research group however, other factors may influence decision-making
II-3: Evidence obtained from comparisons between times or D. There is fair evidence to recommend against the clinical preventive action
places with or without the intervention. Dramatic results in
uncontrolled experiments (such as the results of treatment with E. There is good evidence to recommend against the clinical preventive
penicillin in the 1940s) could also be included in this category action
III: Opinions of respected authorities, based on clinical experience, L. There is insufficient evidence (in quantity or quality) to make
descriptive studies, or reports of expert committees a recommendation; however, other factors may influence
decision-making
*The quality of evidence reported in here has been adapted from The Evaluation of Evidence criteria described in the Canadian Task Force on Preventive Health
Care.204
†Recommendations included in these guidelines have been adapted from the Classification of Recommendations criteria described in the Canadian Task Force
on Preventive Health Care.204
10. In women who present with acute uterine bleeding associated impact on women’s quality of life as well as their productivity:
with uterine fibroids, conservative management with estrogens,
in one survey of more than 21 000 women from 8 different
selective progesterone receptor modulators, antifibrinolytics,
Foley catheter tamponade, and/or operative hysteroscopic countries, including 2500 from Canada, these symptoms had
intervention may be considered, but hysterectomy may a negative impact on sexual life (43%), performance at work
become necessary in some cases. In centres where (28%), and relationship, and family (27%).4–6
available, intervention by uterine artery embolization may
be considered. (III-B)
Of 11 880 screened Canadian women, aged 20 to 49 years,
12.0% indicated they had been diagnosed with uterine
INTRODUCTION fibroids, including 3.2% reporting current fibroids. Those
with moderate to severe fibroid symptoms experienced a
Clinical Importance of Uterine Fibroids significantly heavier burden of illness, with lost productivity
Pathophysiology of Myomas
ABBREVIATIONS Uterine fibroids are monoclonal tumours that arise from
AAGL American Association of Gynecologic Laparoscopists the uterine smooth muscle tissue (i.e. the myometrium).
AUB abnormal uterine bleeding They are benign neoplasms composed of disordered
EA endometrial ablation “myofibroblasts” buried in abundant quantities of
ER α estrogen receptor alpha extracellular matrix that accounts for a substantial portion
FDA United States Food and Drug Administration of tumour volume. The initiating events for fibroid genesis
FIGO International Federation of Gynecology and Obstetrics remain speculative.
GnRH gonadotropin-releasing hormone
The cells proliferate at a modest rate and their growth
HRT hormone replacement therapy
is dependant on the ovarian steroids estrogen and
LNG-IUS levonorgestrel intrauterine system progesterone and therefore most fibroids shrink after
MRg-FUS magnetic resonance-guided focused ultrasound menopause. The biologically potent estrogen estradiol
MRI magnetic resonance imaging induces the production of PR by means of ER-α.
NETA norethindrone acetate PR is essential for the response of fibroid tissue to
PR progesterone receptor progesterone secreted by the ovaries. Progesterone and
QoL quality of life PR are indispensable to tumour growth, increasing cell
RF radio frequency proliferation and survival and enhancing extracellular
RFVTA radio frequency volumetric thermal ablation matrix formation. In the absence of progesterone and PR,
SERM selective estrogen receptor modulator
estrogen and ER-α are not sufficient for fibroid growth.11
SPRM selective progesterone receptor modulator Myomas can be single or multiple and can vary in size,
UAE uterine artery embolization location, and perfusion. Myomas are commonly classified
UAO uterine artery occlusion into 3 subgroups based on their location: subserosal
UPA ulipristal acetate (projecting outside the uterus), intramural (within the
myometrium), and or submucosal (projecting into the cavity management of fibroids to exclude other possible causes.15
of the uterus). A newer, more detailed classification system In the postmenopausal woman presenting with new
has been devised and advocated by FIGO (Figure 1).12 onset of pain and/or bleeding in new or existing fibroids,
leiomyosarcoma should be considered.18
Recognized risk factors for development of uterine fibroids
include nulliparity, early menarche, increased frequency of Fibroids and Fertility
menses, history of dysmenorrhea, family history of uterine A new SOGC guideline on the management of uterine
fibroids, African descent, obesity, and age (peak incidence fibroids in women with otherwise unexplained infertility
at 40 to 50). Clinical conditions that seem to increase risk will be published in the spring of 2015.19
of fibroids include hypertension and diabetes.13
Fibroids in Pregnancy
Clinical Presentation Estimates of the prevalence of fibroids in pregnancy vary
The presence of uterine fibroids can lead to various clinical depending on the quality of the ultrasound study and
challenges. The need for and choice of intervention must the race and age of the women being studied. A recent
be individualized to the clinical situation. ultrasound study found the prevalence to be 18% in
African-American women, 8% in white women, and 10%
The most common symptom of uterine leiomyoma is in Hispanic women.20
AUB. In a published series of myomectomies, 30% of
women suffered from heavy menstrual bleeding.14–15 The Most ultrasound studies found that fibroids remain the
mechanism of leiomyoma-associated AUB is unknown. same size or become smaller during pregnancy.21–23 In a
Increased endometrial surface area, vascular dysregulation, 2011 report, 171 pregnant women with fibroids were
and interference with endometrial hemostasis have been followed by serial ultrasound. Postpartum, 36% of women
offered as possible explanations.16 Clinicians with patients had no identifiable fibroid and 79% of remaining fibroids
presenting with AUB should refer to the SOGC clinical had decreased in size.24 One study reported an increase in
practice guideline on the management of AUB.17 myoma size during pregnancy.25
Pelvic pain is rare with fibroids and usually signifies Several large retrospective studies of ultrasounds and
degeneration, torsion, or possibly associated adenomyosis medical records of pregnant women have reported on
and/or endometriosis. Pelvic pressure, bowel dysfunction, the impact of fibroids on pregnancy outcomes.26–30 A
and bladder symptoms such as urinary frequency and 2008 meta-analysis found an overall increased risk of
urgency may be present with larger fibroids. Urinary malpresentation (OR 2.9; 95% CI 2.6 to 3.2), Caesarean
symptoms should be investigated prior to surgical delivery (OR 3.7; 95% CI 3.5 to 3.9), and preterm delivery
(OR 1.5; 95% CI 1.3 to 1.7).31
In 2010, a study including the 2 extremes, leiomyomas and leiomyosarcomas. The
72 000 pregnancies reported significant differences in odds spectrum includes several variants with unusual features
ratios for placenta previa, abruption, premature rupture of showing various combinations and permutations of 3
membranes, preterm birth < 34 weeks, and intrauterine histologic criteria including nuclear atypia, mitotic index,
fetal death, but the differences were all < 2%, which would and zonal necrosis that may indicate malignancy.
not be considered clinically relevant.32 It would seem that
women with fibroids, especially large ones, merit close Frequently, these variants pose diagnostic challenges because
obstetrical follow-up but are likely to have a good outcome. they exhibit some features of malignancy but do not meet
full criteria and therefore cannot be clearly interpreted and
Traditional teaching has been that myomectomy, other classified as either benign or malignant. Furthermore, the
than for symptomatic pedunculated fibroids, should not be behavioural and clinical outcomes associated with some of
performed in pregnant women because of the increased risk these variants have not yet been elucidated. This uncertainty
of uncontrolled bleeding. However, a number of case series frequently leads to therapeutic dilemmas, especially when
report good outcomes after myomectomy performed during the diagnosis is made in myomectomy specimens from
pregnancy or at the time of Caesarian section, therefore it women who wish to maintain or enhance their fertility.
can be considered as an option if clinically necessary.33–36 In 2003, the World Health Organization labelled these
tumours “smooth muscle tumours of uncertain malignant
Concerns about Malignancy potential” (STUMP).42,43
Leiomyosarcomas
In clinical practice, the mere finding of pelvic tumours in Other malignancies
symptomatic or asymptomatic women may raise the concern Other uterine malignancies such as cervical cancer and
of malignancy in both patients and health care providers. endometrial cancer may be present and contribute to AUB;
In a review of 6815 patients who underwent myomectomy these should be ruled out by appropriate evaluation and
between 1950 and 1993, only 18 patients (0.26%) had screening.
leiomyosarcomas. In the subpopulation of women whose
Summary Statements
masses had grown rapidly, the prevalence was the same at
0.27%.37 Based on this evidence, rapid growth of a fibroid 2. The presence of uterine fibroids can lead to a variety
does not seem to be a predictor of leiomyosarcoma. of clinical challenges. (III)
However postmenopausal growth or onset of symptoms 3. Concern about possible complications related
should carry a higher index of suspicion for malignancy. to fibroids in pregnancy is not an indication for
myomectomy except in women who have had a
Other case series have estimated the incidence of previous pregnancy with complications related to
leiomyosarcoma at 0.22% to 0.49%, although in women these fibroids. (III)
in their 6th decade it may rise to 1% of hysterectomy 4. Women who have fibroids detected in pregnancy
specimens.37,38 Most recent reviews are consistent with may require additional maternal and fetal
older studies and estimate that in women undergoing surveillance. (II-2)
surgery for fibroids approximately 1 in 400 (0.25%) is at
risk of having a leiomyosarcoma.39 Recommendation
1. Women with asymptomatic fibroids should be
Although incidental uterine leiomyosarcomas have been reassured that there is no evidence to substantiate
encountered during routine resectoscopic myomectomy,40 major concern about malignancy and that
their incidence appears to be lower than that reported hysterectomy is not indicated. (III-D)
following hysterectomy (0.13%).41 Whether leiomyosarcomas
develop from leiomyomas or arise independently is not Evaluation
known. The challenge lies in the fact that leiomyomas and On physical examination, an enlarged, mobile uterus
leiomyosarcomas cannot reliably be distinguished clinically (correlating to a weight of approximately 300 g or 12
or by any imaging technique. weeks of pregnancy) with irregular contour is consistent
with fibroids.
Smooth muscle tumours of uncertain
malignant potential Ultrasonography (transabdominal, transvaginal, contrast
Morphologically, there exists a spectrum of uterine sonohysterorography) is the most widely used modality
smooth muscle tumours with conventionally well-defined because of its availability, ease of use, and cost-effectiveness.
histologic criteria and predictable clinical outcomes at It is particularly helpful to assess myoma growth and the
adnexae if these cannot be palpated separately with Because estrogen upregulation of both ERs and PRs
confidence.44 Contrast infusion saline or gel sonography and during the follicular phase is followed by progesterone-
2D and 3D sonohysterography are very accurate diagnostic induced mitogenesis during the luteal phase, all hormonal
procedures to detect submucosal lesions, all with sensitivity therapies to control uterine bleeding aim to regulate the
and specificity of 98% to 100%.45,46 In women with large effect of these 2 gonadal steroids.
fibroids, diagnostic imaging occasionally demonstrates
hydronephrosis, the clinical significance of which is Oral Contraceptives
unknown. Complete ureteric obstruction is extremely rare.47 There is no evidence that low-dose oral contraceptives
cause benign fibroids to grow, thus uterine fibroids are
CT is of limited value in delineating the location of myomas not a contraindication to their use. Oral contraceptives are
relative to the endometrium or myometrium.48 MRI is the effective in reducing menstrual bleeding in the short-term
most accurate modality in assessing the adnexae49 and and may prevent the development of uterine fibroids.59
the uterus because it provides information on the size,
location, number, and perfusion of leiomyomas as well Progestins/Levonorgestrel Intrauterine System
as the presence of other uterine pathology including Progestogens are natural or synthetic progestational
adenomyosis and/or adenomyoma.50–52 hormones which may potentially have dual actions on
fibroid growth. While the natural hormone progesterone
Treatment augments epidermal growth factor, which stimulates fibroid
The majority of uterine leiomyomas are asymptomatic and growth, it also inhibits insulin-like growth factor-1, which
will not require therapy. However, 20% to 50% are clinically may inhibit growth.60 Progestogens also down-regulate both
symptomatic, causing AUB, iron deficiency anemia, bulk estrogen and progesterone receptors in fibroids, which may
effects, and/or reproductive issues,53 and may require act as another mechanism in modulating fibroid biology and
treatment. Treatment of women with uterine leiomyomas growth.61 Both natural progesterone and synthetic progestins
must be individualized, based on symptomatology, the cause endometrial atrophy, which has the potential to
size and location of fibroids, age, the needs and desires of decrease menstrual blood loss in women with fibroids.
the patient for preservation of fertility or the uterus, the
availability of therapy, and the experience of the therapist. One study concluded that the LNG-IUS significantly
reduces menstrual blood loss and uterine volume in
Symptomatic uterine fibroids may be treated medically, women with menorrhagia, with and without fibroids,
surgically, or with a combination of both (Figure 2). while it does not significantly reduce fibroid volume.62
Another RCT found that although the rate of treatment
Expectant Management
failure was similar in both groups, the LNG-IUS was more
Prospective imaging studies indicate that 3% to 7% of
effective in reducing menstrual blood loss than combined
untreated fibroids in premenopausal women regress over
oral contraceptives in women with fibroid-related
6 months to 3 years.54,55 Most women experience shrinkage
menorrhagia.59
of fibroids and relief of symptoms at menopause;
therefore, depending on the severity of their symptoms, A systematic review reported on both oral progestogens
women who are approaching menopause may choose and the LNG-IUS for the treatment of leiomyomas. The
to wait for the onset of menopause before deciding on authors found that the oral progestogen lynestrenol was
treatment. Postmenopausal hormone replacement therapy not as effective as leuprolin in reducing uterine fibroid
is not contraindicated in the presence of fibroids and does size at 16 weeks,63 and they concluded that evidence was
not lead to the development of new fibroids, although it lacking to support the use of progestogens for treating
may be associated with some myoma growth, which may in premenopausal women with uterine fibroids.64
turn lead to clinical symptoms.56,57
Gonadotropin-Releasing Hormone Agonists
MEDICAL MANAGEMENT GnRH agonists are available in nasal spray, subcutaneous
injections, and slow-release injections. In general, fibroids
Until recently, medical management options for uterine may be expected to shrink by up to 50% of their initial
leiomyomas have been of limited value because of their volume within 3 months of therapy. However, GnRH
moderate efficacy and/or associated adverse effects. Novel agonist treatment is restricted to a 3- to 6-month interval,
therapies at the receptor and gene levels have emerged following which regrowth of fibroids usually occurs within
or are undergoing investigation and may eventually offer 12 weeks. Prolonged use of GnRH agonists with estrogen
better long-term management options.58 add-back therapy requires investigation. However, there is
Uterine myomas
Asymptomatic Symptomatic
BSO: bilateral salpingo-oophorectomy; MRg-FUS: Magnetic resonance-guided focused ultrasound; OC: oral contraceptives
evidence that progestin add-back negatively impacts the glucocorticoids in receptor binding and acts at different
effectiveness of GnRH agonists on fibroid size.65,66 levels of the hypothalamic-pituitary-ovarian-uterine
axis. Aside from its androgenic effects, it also lowers
GnRH agonists are useful preoperatively to shrink fibroids estrogen levels by suppressing gonadotropin secretion
and to reduce anemia related to uterine bleeding.47,67 at the levels of the hypothalamus and inhibits ovarian
steroidogenesis.70
Gonadotropin-Releasing Hormone Antagonists
While GnRH agonists work by down-regulation and Danazol has been associated with a reduction in volume
desensitization of the GnRH receptors, GnRH antagonists of fibroids in the order of 20% to 25%.71 Although the
work via the classical competitive blockage mechanism. use of danazol for the shrinkage of uterine fibroids has
The main advantage of using GnRH antagonists is their been described in cohort studies, a systematic review did
lack of the initial “flare” effect seen with GnRH agonist not find any randomized trials comparing its efficacy with
stimulation and supraphysiological amounts of follicle placebo or other treatments.72
stimulating hormone, luteinizing hormone, and estradiol,
and hence have a much shorter onset of action and Although the long-term response to danazol is modest,
treatment period.68,69 it may offer an advantage in reducing myoma associated
heavy menstrual bleeding.71
The use of GnRH antagonists as a treatment for fibroids
requires further evaluation. Aromatase Inhibitors (Letrozole)
Myometrial cultured cells overexpress aromatase P450
Androgens (Danazol) and synthesize sufficient estradiol to accelerate their own
Danazol is chemically related to 17-α ethinyl testosterone. cell growth. Aromatase inhibitors may serve to block the
It competes with natural androgens, progesterone, and aromatase activity and growth of leiomyomata.73
Letrozole, an aromatase inhibitor, inhibits the conversion While mifepristone is thought to have almost pure antagonistic
of androgen into estrogen. In a systematic review, only one properties, other SPRMs such as ulipristal acetate exhibit
trial involving 70 participants was included. Significantly mixed agonist and antagonist properties. Though the exact
fewer women reported hot flushes in the letrozole mechanisms of this new class of medications are still being
group than in the GnRH agonist group (0/33 vs. 26/27, studied, several studies have evaluated their effectiveness in
P < 0.05). Use of letrozole reduced fibroid volume by the shrinkage of fibroids and control of menstrual bleeding
46% and use of a GnRH agonist by 32% after 12 weeks symptoms. While several other SPRMs are currently under
of treatment, although these results were not statistically investigation, here we present the evidence for SPRMs that
significant. The authors concluded that the evidence is have been studied in randomized controlled trials.
currently insufficient to support the use of aromatase
inhibitor drugs in the treatment of women with uterine Mifepristone
fibroids.74 Mifepristone (RU-486) is a progesterone receptor modulator
that has almost pure antagonistic properties and may directly
Estrogen Receptor Antagonists (Fulvestrant) decrease the PR in the myometrium and leiomyoma. Though
The estrogen receptor antagonist fulvestrant promotes the exact mechanism for myoma size reduction is unclear, a
degradation and down-regulation of estrogen receptors.75 2013 meta-analysis of 11 RCTs involving 780 premenopausal
However, fulvestrant was not as effective as the GnRH women with symptomatic leiomyomas concluded that
agonist goserelin in reducing fibroid and uterine volume mifepristone significantly reduced uterine and leiomyoma
and in inducing amenorrhea.76 volume and alleviated leioma-related symptoms. The authors
recommended 2.5 mg daily for 3 to 6 months as the optimum
Selective Estrogen Receptor Modulators treatment. There is insufficient evidence that mifepristone
SERMs are nonsteroidal drugs that bind to estrogen treatment led to atypical endometrial hyperplasia.86
receptors and may act as agonists or antagonists to
produce tissue-specific effects. They are generally used for Ulipristal acetate
treating and preventing recurrence of estrogen receptor UPA is an SPRM that also exhibits antiproliferative effects
positive breast cancers. Tamoxifen has agonist properties on leiomyoma cells and the endometrium.87 One RCT that
on the uterus, but raloxifene is the most studied SERM investigated the effects of UPA versus placebo before
surgical treatment of symptomatic fibroids showed a
for treatment of leiomyomata.77,78 Given the conflicted
reduction in myoma volume with 13 weeks of 5 mg and
and limited data regarding the use of raloxifene alone, it
10 mg of UPA of 21.2% and 12.3%, respectively, while
is difficult to ascertain its true effect on uterine fibroids,
the placebo group had a median 3% growth of myoma
though it may be a useful adjunct to a GnRH agonist in
volume (P < 0.01).88 Patients also experienced significant
inducing fibroid shrinkage.
decreased uterine bleeding symptoms with treatment.
Selective Progesterone Receptor Modulators In a parallel RCT, UPA appeared to be no less effective than
Compared with the myometrium, fibroids overexpress leuprolide acetate in controlling heavy menstrual bleeding:
estrogen and progesterone receptors,79 and there is “cross- 90% of the 5 mg group and 98% of the 10 mg group
talk” between ER and PR.80 It has been shown that experienced controlled bleeding symptoms versus 89% of
fibroids grow primarily during the secretory phase of the the leuprolide acetate group. Median time to amenorrhea
menstrual cycle,81,82 and exogenous progesterone increases was 7 days, 5 days, and 21 days for the 5 mg, 10 mg, and
mitotic activity and cellularity in fibroids.83 leuprolide acetate groups, respectively (P < 0.001 for
10 mg vs. leuprolide acetate). However, in terms of uterine
In a randomized trial of a GnRH analogue plus add-
volumes, the 47% reduction in the leuprolide acetate group
back therapy with progestin alone versus progestin plus
was significantly greater than the reductions of 20% in the
estrogen, the authors reported that, in most instances,
5 mg group and 22% in the 10 mg group. No differences
the add-back progestin alone (but not the progestin plus
were seen in hemoglobin at the end of the treatment
estrogen) negated the effects of the GnRH analogue on period. Vasomotor symptoms were experienced in 11% of
fibroid volume reduction.84 Progesterone is therefore the 5 mg and 10% of the 10 mg groups versus 40% of the
essential for fibroid growth, and these observations have leuprolide acetate group (P < 0.001).89
stimulated research for the development of progesterone
antagonist and/or SPRM drugs. SPRMs are progesterone Novel PRM-associated endometrial changes have been
receptor ligands that have agonist, antagonist, partial, or noticed with the SPRM class of drugs and appear to
mixed effects on progesterone target tissues.85 be benign and fully reversible.89 These changes may be
confused with endometrial hyperplasia by a pathologist against increased operative morbidity associated with
who is not informed that the patient received UPA future growth.93
treatment or who has not been updated on the potential
effect of UPA on the endometrium. It is important that Type of hysterectomy
the pathologist be aware of the use and effects of UPA. The choice and type of hysterectomy, whether it is
performed by abdominal, laparoscopic, or vaginal route,
A recent study investigated the efficacy and safety of UPA should be based on surgeon’s training, experience, and
for long-term treatment of symptomatic uterine fibroids comfort and on clinical practice guidelines.93 The least
by repeated intermittent 3-month open-label UPA courses invasive approach feasible should be used.
(10 mg daily), each followed by randomized double-
blind 10-day courses of NETA 10 mg daily or placebo. The advantages of abdominal supracervical or total
The study concluded that NETA did not affect fibroid hysterectomy are questionable, as randomized trials have
volume or endometrial histology, and repeated 3-month demonstrated no differences in sexual and urinary function
UPA courses effectively and safely controlled bleeding and outcomes in women treated with the 2 procedures.
shrunk fibroids in patients with symptomatic fibroids.90 However, there may be less blood loss and complications
Fibroid volume reduction in patients receiving UPA also associated with supracervical hysterectomy.94–96
appears to be maintained in the majority of patients for 6 Summary Statement
months after the end of treatment.88
7. Hysterectomy is the most effective treatment for
Summary Statements symptomatic uterine fibroids. (III)
5. Effective medical treatments for women with
Myomectomy
abnormal uterine bleeding associated with uterine
Myomectomy is an alternative to hysterectomy for women
fibroids include the levonorgestrel intrauterine
who wish to retain their uterus, regardless of their fertility
system, (I) gonadotropin-releasing hormone
desire. Removal of fibroids should be considered if they
analogues, (I) selective progesterone receptor
are thought to be associated with heavy mentrual bleeding,
modulators, (I) oral contraceptives, (II-2)
pelvic pain and/or pressure symptoms, and in some cases
progestins, (II-2) and danazol. (II-2)
6. Effective medical treatments for women with reproductive issues.19
bulk symptoms associated with fibroids include Although myomectomy allows preservation of the uterus,
selective progesterone receptor modulators and there is a higher risk of blood loss and greater operative time
gonadotropin-releasing hormone analogues. (I) with myomectomy than with hysterectomy, athough the risk
of ureteric injury may be decreased with myomectomy.
Recommendation Fibroids have a 15% recurrence rate and 10% of women
2. Treatment of women with uterine leiomyomas must undergoing a myomectomy will eventually require
be individualized based on symptomatology, size and hysterectomy within 5 to 10 years.97 Risk of recurrence is
location of fibroids, age, need and desire of the patient associated with age, preoperative number of fibroids, uterine
to preserve fertility or the uterus, the availability of size, associated disease, and childbirth after myomectomy.98
therapy, and the experience of the therapist. (III-B) Five years following laparoscopic myomectomy, the
cumulative probability of recurrence (new or unremoved
SURGICAL THERAPIES fibroids) in women who subsequently gave birth was 42%.
In those who did not give birth, it was 55%.99
Hysterectomy
In women who have completed childbearing, hysterectomy Women should be counselled about the risks of requiring
is indicated as a permanent solution for symptomatic a hysterectomy at the time of a planned myomectomy.
leiomyomas. The only indications for hysterectomy in This would depend on the intraoperative findings and the
a woman with completely asymptomatic fibroids are course of the surgery. Hysterectomy remains the treatment
enlarging fibroids after menopause without HRT, which of choice for the vast majority of women who require a
raises concerns of leiomyosarcoma, even though it remains surgical solution.93
very rare. 91,92 Women with asymptomatic fibroids should be
reassured that there is no evidence to substantiate concern Surgical planning
about malignancy, and that hysterectomy is not indicated. Myomectomy can be performed according to the number,
size, and location of fibroids by laparotomy, mini-
Hysterectomy need not be recommended as a prophylaxis laparotomy, laparoscopy, hysteroscopy, or a combination of
these.100 Surgical planning should be based on an accurate a large defect or heavy bleeding. If perforation occurs with
mapping of the location, size, and number of fibroids with an activated electrode, until proven otherwise a visceral
preoperative imaging. It is particularly important to identify or vascular injury should be assumed, and laparoscopy or
the presence and size of the submucosal component to laparotomy is recommended.109,110
myomas as this may affect the approach taken.
Excessive fluid absorption is another potential risk.
Summary Statement An AAGL practice guideline for the management of
8. Myomectomy is an option for women who wish to hysteroscopic distending media was published in 2013.111
preserve their uterus or enhance fertility, but carries The use of the lowest distention pressure necessary for
the risk of requiring further intervention. (II-2) good visualization and the careful selection of the safest
distending medium will lower the risks and sequelae of
Hysteroscopic myomectomy
excessive fluid absorption.110
An AAGL practice guideline for the diagnosis and manage
ment of submucous leiomyomas was published in 2012.101 Burns to the vulva, vagina, and cervix from stray electrical
current during resectoscopic procedures have been
Hysteroscopic myomectomy has been shown to be effective
documented.112–114
for treatment of AUB in 5 series involving 1422 women.
Failure rates ranged from 14.5% to 30% at 3 to 4 years’ Laparoscopic myomectomy
follow-up.102 It should be considered as first-line conservative The benefits of the laparoscopic approach are well
surgical therapy for the management of symptomatic known and have been found superior to laparotomic
intracavitary fibroids. In general, submucous myomas (types myomectomy in terms of less blood loss, diminished
0, I, and II) up to 4 to 5 cm in diameter can be removed postoperative pain, fewer overall complications, faster
hysteroscopically by experienced surgeons. Type II myomas recovery, and significant cosmetic advantage.115–118
are more likely to require a 2-staged procedure than types 0 However, laparoscopic myomectomy usually takes
and I because of the risk of excessive fluid absorption and longer to accomplish and requires extra training, surgical
uterine perforation, and caution should be used particularly expertise, and specialized equipment. The size or the
with those with less than 5 mm thickness between the number of fibroids that can be removed by laparoscopy
fibroid and the uterine serosa.103,104 seem to be limited only by the surgeon’s experience and
Myomectomy plus endometrial ablation technique.119 Multilayer suturing may be challenging, as
When the main symptom is heavy menstrual bleeding, may the identification and excision of smaller fibroids.
consideration should be given to concomittant EA at Laparoscopic removal of larger fibroids in more difficult
the time of transcervical resection of myoma when locations such as in the lower segment or at the cervical
preservation of fertility is not desired. A cohort study junction may present more risk of complications such as
showed a higher success rate in controlling bleeding when profuse bleeding; in those cases an open approach may
ablation was added to myomectomy.105 be preferable. Consideration should also be given to the
prolonged operative time required with the laparoscopic
In selecting patients for transcervical resection of myoma, approach when faced with cases of very large (> 10 cm)
it is important to consider other factors that increase the or multiple leiomyomas; in these cases a myomectomy by
risk of needing subsequent surgery. Women in whom laparotomy may be more appropriate.
myomectomy results in a normal uterus without residual
myomas are at a low risk of requiring further treatment. Injuries can occur with laparoscopic entry, and their
Predictors of an increased risk for additional treatment occurrence should be minimized by following good
include the presence of multiple myomas, large intramural surgical principles and the recommendations in the SOGC
or subserous myomas, adenomyosis, and young age at the clinical practice guideline on laparoscopic entry.120 A
time of treatment.106–108 prospective study reported that the short-term morbidity
of laparoscopic myomectomy was similar to that of
Perforation of the uterus can occur with uterine sounding, laparoscopic hysterectomy.121
dilation, or use of the resectoscope. The preoperative use
of laminaria or misoprostol decreases the force needed Uterine scar integrity and rupture following laparoscopic
for cervical dilation and reduces the risk of perforation. myomectomy have not been fully evaluated. Uterine
If perforation occurs with mechanical instruments and rupture during subsequent pregnancy seems to be a
no visceral injury is suspected the patient can be observed rare event and its possibility should not systematically
expectantly. Laparoscopy should be considered if there is preclude a trial of vaginal delivery.122–124 However,
because of the relatively poor quality of available in benign gynaecological surgery and is more costly than
evidence, close follow-up should be exercised in all cases. conventional laparoscopic surgery.134
Uterine rupture during pregnancy after myomectomy has
been reported to possibly be linked to the absence of Specimen morcellation
multilayer closure in cases of deep intramural leiomyoma Because laparoscopic hysterectomy and myomectomy often
or to the excessive use of electrosurgical energy.125,126 requires morcellation of the specimen, complications related
Some indirect evidence based on MRI assessment of to this step may occur, including vascular or visceral trauma
myometrial repair after Caesarian section suggests that with the use of a mechanical rotating blade.135 Furthermore,
a waiting period of 6 months between myomectomy and morcellation can lead to dissemination of leiomyoma
subsequent pregnancy would allow for optimal tissue chips leading to parasitic leiomyomas (leiomyomatosis) or
repair of the myometrium.127 dissemination of incidental leiomyosarcoma.136–144
A meta-analysis of 6 randomized controlled trials from The currently available evidence indicates that one in 400
1996 to 2007 concluded that rates of major complications, women undergoing surgery for fibroids is at risk of having
pregnancy rates and outcomes, and myoma recurrence a leimomyosarcoma.39 According to the American Cancer
in laparoscopic and laparotomic myomectomy were Society’s surveillance, epidemiology, and end results data,
comparable.115 Two RCTs on laparoscopic versus 5-year survival for leiomyosarcoma is 60% for stage I, 35%
laparotomic myomectomy reported pregnancy rates of for stage II, 22% for stage III, and 15% for stage IV.145
54% and 57%, respectively.128,129 An increased rate of recurrence and lower rate of survival
following morcellation of a uterine sarcoma has been
Mini-laparotomy
reported in several studies, implying that morcellation
Mini-laparotomy, used as an alternative to laparoscopy,
results in the upstaging of the disease. In cases of
has the proposed advantage of easier suturing of the
myomectomy, the initial steps of the procedure, including
myometrium while providing a less invasive approach
uterine incision and myoma manipulation and enucleation,
than conventional laparotomy. A randomized study of
are likely to spread and upstage the disease prior to myoma
laparoscopic versus mini-laparotomic myomectomy
extraction by any method of morcellation.
reported lower decline in hemoglobin, reduced
postoperative ileus and pain, and shorter hospitalization in These findings reinforce the need for careful preoperative
the laparoscopy group.117 assessment of patients and consideration of using enclosed
morcellation techniques if feasible. For laparoscopic
Mini-laparotomy can also be used in laparoscopically
morcellation, spillage may be minimized by placing the
assisted mini-laparotomy. In one study, 51 women were
specimen in a bag and using the mechanical morcellator
randomized to open myomectomy, mini-laparotomy, or
inside the bag. However use of a bag may limit visualization
laparoscopically-assisted mini-laparotomy. The latter 2
and has not been well studied. For larger specimens, a mini-
approaches were associated with decreased postoperative
laparotomy with or without use of self-retaining retractor
pain and less blood loss than myomectomy by laparotomy.100
can be performed and the specimen be morcellated
In another prospective study of 116 patients, a shorter
mechanically or with a scalpel blade within a bag. If the
uterine incision was found in the laparoscopically assisted
specimen is delivered vaginally and requires morcellation,
myomectomy, but the estimated blood loss was greater.
again a bag can be used to enclose it to mimimize spillage.
Complications and postoperative return to normal
activities were comparable between the groups.130 In light of concerns over morcellation of unsuspected
leiomyosarcomas, the FDA issued a warning about
Robotic assisted laparoscopy
laparoscopic power morcellation in April 2014. This
Robotic assisted gynaecological surgery has increased
prompted Health Canada (May 2014) to make the following
exponentially in popularity in the last decade. Up to 9.5%
recommendations to health-care professionals treating
of hysterectomies were done with the assistance of the
women with uterine fibroids146:
robot in a retrospective U.S. cohort of 264 758 cases.131
However, robotic assisted myomectomy was associated •• Recognize the prevalence of unsuspected uterine
in one study with greater blood loss than standard sarcoma in patients under consideration for
laparoscopic myomectomy.132 This, along with other hysterectomy or myomectomy for the treatment of
well-designed studies that consistently show a longer uterine fibroids.
operative time,133 prompted the AAGL to state that at •• Consider the treatment alternatives for women with
this time robotic surgery offers no significant advantage symptomatic uterine fibroids and review these options
with each prospective surgical patient. Apart from a regarding the alternatives and risks, hysterectomy
laparoscopic approach, alternative surgical procedures by the least invasive approach possible may be
exist that do not require electric morcellation and offered as the definitive treatment for symptomatic
potential tissue spread to the peritoneal cavity. Also, uterine fibroids and is associated with a high level of
some surgeons and centres may recommend closed satisfaction. (II-2A)
morcellation in a bag as a way to reduce the risk of 4. Hysteroscopic myomectomy should be considered first-
inadvertent spread of uterine tissue. line conservative surgical therapy for the management
•• Be aware and inform patients that laparoscopic electric of symptomatic intracavitary fibroids. (II-3A)
morcellation of unsuspected uterine sarcoma during 5. Surgical planning for myomectomy should be based
hysterectomy or myomectomy may disseminate the on mapping the location, size, and number of
disease and negatively impact prognosis. fibroids with the help of appropriate imaging. (III-A)
Numerous societies have responded to the FDA warning 6. When morcellation is necessary to remove the
with very thorough reviews and discussion of the issue specimen, the patient should be informed about
(Table 2).147–150 possible risks and complications, including the fact
that in rare cases fibroid(s) may contain unexpected
Recommendations malignancy and that laparoscopic power morcellation
3. In women who do not wish to preserve fertility and/ may spread the cancer, potentially worsening their
or their uterus and who have been counselled prognosis. (III-B)
Pre-operative Evaluation and Adjuncts parameters reported in these studies and surgical experience
Prior to proceeding with surgery for fibroids, appropriate is variable.
evaluation and patient preparation, including correction
of anemia and shrinkage of fibroid and uterine volume, Intraoperative Adjuncts
are of paramount importance since preoperative anemia A number of intraoperative adjuncts have been used in an
and uterine size can have a significant bearing on surgical effort to reduce blood loss and improve surgical outcomes
outcomes. A recent large study reported that preoperative in leiomyoma surgery.
anemia, even to a mild degree, is independently associated Misoprostol
with an increased risk of 30-day morbidity and mortality in Misoprostol is a prostaglandin E1 analogue which
patients undergoing major non-cardiac surgery.151 reduces uterine blood flow, increases myometrial
For preoperative treatment, a variety of pharmacological contractions, and has potential to reduce blood loss
agents have been shown to be safe and effective. Iron during uterine surgery.156 The evidence for misoprostol
should be provided in the presence of anemia together as an adjunct for hysterectomy is limited and conflicting.
with preoperatve adjuncts to correct the anemia. In one randomized trial, no benefit was observed in the
use of misoprostol alone for abdominal hysterectomy,
GnRH agonists but misoprostol 400 μg by rectum combined with
A Cochrane review showed significant improvement with intravenous oxytocin (10 U/hour) in women undergoing
GnRH agonist over placebo or no treatment in preoperative laparoscopically assisted vaginal hysterectomy was found
hemoglobin and hematocrit and in reduction of uterine to significantly improve operative outcomes compared
and myoma volumes.152 Compared with no treatment prior with placebo.156
to hysterectomy, GnRH agonists reduce intraoperative
bleeding and operative time, increase postoperative Placebo-controlled randomized studies have shown that
hemoglobin and haematocrit values, and decrease a single dose of misoprostol 400 μg given vaginally 1
postoperative complications and length of hospital stay. hour prior 157 or rectally 30 minutes prior158 to abdominal
They also increase the proportion of hysterectomies myomectomy resulted in a statistically significant reduction
performed vaginally rather than abdominally and decrease in operative time,157 operative blood loss, postoperative
the proportion of vertical incisions compared with no hemoglobin drop, and need for postoperative blood
treatment.152 transfusion.157,158 No differences were observed in length
of hospital stay.157
In a 2001 systematic review and meta-analysis, when GnRH
agonists were used prior to myomectomy, intraoperative The role of misoprostol for cervical priming before
bleeding and rates of vertical incisions were also reduced, operative hysteroscopy has also been reported, though not
while postoperative hemoglobin was slightly increased. all patients in this study had fibroids as the indication for
However, patients treated with GnRH agonists were more surgery. The authors found that the misoprostol group
likely to have recurrence of fibroids at 6 months after had significantly smaller initial dilation estimated by Hegar
myomectomy compared to no treatment. No differences dilator, less need for surgical dilation, shorter time for
were seen in rates of postoperative complications. No cervical dilation to Hegar 9, shorter operative time, and
differences were seen in rates of blood transfusion for fewer occurrences of cervical lacerations than the placebo
either type of surgery.153 A 2011 systematic review of group. Though not statistically significant, there were
GnRH-a showed no reduction in operative time but did also fewer instances of false passages (1.4% vs 6.3%) and
show decreased introperative blood loss.154 However there perforations (0% vs. 2.5%) observed.159
is controversy over the ability to dissect myomas from
myometrium after exposure to GnRH agonist.155 Oxytocin
While recent evidence suggests the presence of oxytocin
A double-blind, placebo-controlled trial of GnRH agonist receptors in uterine myomas,160 the evidence for its use as
prior to hysteroscopic myomectomy found no differences an intraoperative adjunct is somewhat conflicting.
in the number of complete fibroid resections, operative
times, or amounts of fluid absorbed.156 One study of women undergoing laparoscopically assisted
vaginal hysterectomy indicated reduced blood loss and
Ulipristal acetate transfusion rates with intraoperative 20 U of oxytocin
The 2 RCTs mentioned previously have shown the in 1000 mL of saline solution running at 40 mu/min
effectiveness of 3 months’ treatment to correct anemia compared to saline placebo. No differences were seen in
and reduce uterine fibroid size.89,90 There were no surgical postoperative complications and length of stay.161
blood loss during myomectomy and the need for blood failure (4.0%), and postembolization syndrome (2.9%).
transfusion.173,174 The study concluded that overall, UAE has a significantly
lower rate of major complications relative to surgery, but
Anti-adhesion barriers it comes at the cost of increased risk of re-intervention
After the completion of myomectomy, application of anti- in the future.181
adhesion barriers has been proposed and there is evidence
of significant reduction in adhesion formation with some Educating patients about the rate and types of
of them.175–177 However, none of these adjuncts has complications of UAE versus surgery, as well as the
demonstrated an improvement in fertility and pregnancy potential for reintervention, should help the patient and
outcomes. clinician come to a reasoned decision.
Recommendations Recommendation
7. Anemia should be corrected prior to proceeding 9. Uterine artery occlusion by embolization or
with elective surgery. (II-2A). Selective progesterone surgical methods may be offered to selected
receptor modulators and gonadotropin-releasing women with symptomatic uterine fibroids who
hormone analogues are effective at correcting wish to preserve their uterus. Women choosing
anemia and should be considered preoperatively in uterine artery occlusion for the treatment of
anemic patients. (I-A) fibroids should be counselled regarding possible
8. Use of vasopressin, bupivacaine and epinephrine, risks, including the likelihood that fecundity and
misoprostol, peri-cervical tourniquet, or gelatin- pregnancy outcomes. (II-3A)
thrombin matrix reduce blood loss at myomectomy
Focused Energy Delivery Systems
and should be considered. (I-A)
A number of focused energy delivery systems have been
tested in the past decade including those based upon
OTHER CONSERVATIVE TREATMENTS radiofrequency electricity, supercooled cryoprobes, and
Uterine Artery Embolization
most recently, MRg-FUS or high frequency ultrasound
guided transcutaneous focused ultrasound ablation.182–185
An SOGC clinical practice guideline on UAE has
been published,178 and an up-to-date-review of UAE A major disadvantage of all systems and techniques used
to treat uterine fibroids is included in the upcoming to desiccate or ablate fibroids may be that they treat one
SOGC guideline.19 UAE is a procedure carried out by fibroid at a time and they target the centre of fibroids,
interventional radiologists and consists of injecting an while fibroids have been shown to grow mostly from their
occluding agent into one or both uterine arteries. First periphery.186
described in 1995, it has become one of the most common
alternative conservative therapies offered to women with These technologies are relatively new and although many
sympotomatic uterine fibroids. The procedure is minimally are promising, they often lack long-term data, which
invasive and performed with the patient awake, but it is interferes with our ability to present all risks and benefits
associated with significant immediate post-procedure with assurance. Ongoing research and data collection are
discomfort, although recovery and return to function are required to assess the relative merit of newer options as
rapid. Very large uteri (over 20 weeks) may not have a the technology continues to expand.
clinically significant response. Single submucosal fibroids
MR-guided focused ultrasound
or subserosal fibroids may respond better to surgery than
The ExAblate 2000 (InSightec Inc., Haifa, Israel) was the
UAE.
first clinical MRg-FUS system approved by the FDA for
Though successful pregnancies have been reported treating uterine fibroids. Case series for MRg-FUS ranging
following UAE,179 an RCT comparing UAE to myomectomy from 51 to 359 patients have been published and short-
showed that pregnancy rates were lower and miscarriage term efficacy is adequate, but complications such as skin
rates higher following UAE.180 This option is still best burns have occurred in up to 7% of patients and at least
reserved for women who do not desire future pregnancy. one bowel perforation was reported.182,187,188 Disadvantages
of the MRg-FUS system include high exclusion rate,
A 2013 review and meta-analysis reported on requirement of an MR machine, prolonged time (minutes
complications and re-intervention of UAE for to several hours), treatment of 1 fibroid at a time, and
symptomatic uterine fibroids. Common complications ablation of fibroids centrally, while fibroids seem to grow
were vaginal discharge and fever (4.0%), bilateral UAE peripherally.
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This document reflects emerging clinical and scientific advances on the date issued and is subject to change. The information
should not be construed as dictating an exclusive course of treatment or procedure to be followed. Local institutions can dictate
amendments to these opinions. They should be well documented if modified at the local level. None of these contents may be
reproduced in any form without prior written permission of the SOGC.
Table 1. Key to evidence statements and grading of recommendations, using the ranking of the Canadian Task Force
on Preventive Health Care
Quality of evidence assessment* Classification of recommendations†
I: Evidence obtained from at least one properly randomized A. There is good evidence to recommend the clinical preventive action
controlled trial
II-1: Evidence from well-designed controlled trials without B. There is fair evidence to recommend the clinical preventive action
randomization
II-2: Evidence from well-designed cohort (prospective or C. The existing evidence is conflicting and does not allow to make a
retrospective) or case–control studies, preferably from recommendation for or against use of the clinical preventive action;
more than one centre or research group however, other factors may influence decision-making
II-3: Evidence obtained from comparisons between times or D. There is fair evidence to recommend against the clinical preventive action
places with or without the intervention. Dramatic results in
uncontrolled experiments (such as the results of treatment with E. There is good evidence to recommend against the clinical preventive
penicillin in the 1940s) could also be included in this category action
III: Opinions of respected authorities, based on clinical experience, L. There is insufficient evidence (in quantity or quality) to make
descriptive studies, or reports of expert committees a recommendation; however, other factors may influence
decision-making
*The quality of evidence reported in these guidelines has been adapted from The Evaluation of Evidence criteria described in the Canadian Task Force on
Preventive Health Care.125
†Recommendations included in these guidelines have been adapted from the Classification of Recommendations criteria described in the Canadian Task Force
on Preventive Health Care.125
8. Non-steroidal anti-inflammatories and acetaminophen are the of severe perineal tears include abscess formation, wound
first-line analgesics. Opioids should only be used with caution.
breakdown, and rectovaginal fistulae.
Constipation should be avoided by using a laxative or stool
softener. (I-A)
Injury to the anal sphincter is recognized as the most
9. Following obstetrical anal sphincter injury, providers should disclose
to women the degree of injury and arrange follow-up. Detailed
common cause of anal incontinence and anorectal symptoms
documentation of the injury and its repair is required. (III-L) in otherwise healthy women. Obstetrical sphincter injuries
10. Women with anal incontinence following obstetrical anal sphincter have a variety of long-term complications of which anal
injury should be referred for pelvic floor physiotherapy. (I-A) incontinence is the most distressing and disabling. Anal
incontinence incorporates a range of symptoms including:
INTRODUCTION flatal incontinence, passive soiling, or incontinence of liquid or
solid stool.1 Fecal urgency can also be a symptom experienced
incident rises from 11% to 24.5% when the obstetrical care GRADING OF SEVERITY
provider’s examination was repeated by a trained fellow.5
Traditionally, the severity of perineal tear was limited to 4
The inspection should be done with adequate lighting and grades: grade 1 (superficial vaginal and/or perineal skin),
analgesia and include: grade 2 (vaginal muscles), grade 3 (in or through external
•• inspection of perineum with labial parting, anal sphincter muscle), and grade 4 (external and internal
anal sphincters and anorectal lumen).6
•• inspection of the distal (caudal) posterior vagina, and
•• inspection for a third degree tear behind an “intact As there was a lack of consistency in the classification
perineum.” of a partial anal sphincter, with up to 33% of consultant
obstetricians classifying a complete or partial tear of the
Palpation is best done3 with the examiner’s dominant index EAS as a second degree tear,7 Sultan8 devised a more
inserted in the anus, and the ipsilateral thumb in the vagina. specific classification, later adopted by the WHO9 and
The 2 fingers then palpate with a “pill-rolling” motion to the International Consultation on Incontinence.10 In this
assess thickness. classification, grade 3 is further refined as involving the anal
When the external sphincter tears, the ends retract and a cavity sphincter complex and is divided into 3a, 3b, 3c (Table 2).
is often palpated along the course of the sphincter muscle. The type of third degree tear seems to have an impact on
This may be less evident in the presence of an epidural. symptoms, with OASIS grade 3a and 3b having a better
Special attention should then be given to the IAS. The prognosis than 3c. In fact, those with a 3c OASIS had
IAS is a continuation of the circular smooth muscle of symptoms similar in severity to those with a fourth degree
the rectum. This muscle appears pale (like raw white fish), laceration.11
is not very thick, and can be found 6 to 8 mm above A button-hole injury, where only the vaginal and rectal mucosa
(cephalad to) the anal margin (Figure 1; for a more detailed are involved, should not be reported as a third or fourth degree
illustration, see online eFigure 1). Examination of the IAS tear if found in isolation. Documentation of the presence or
will also permit detection of a button-hole injury.
absence of a tear, as evidenced on rectal examination, should
Recommendation be disclosed to the patient and incorporated into the delivery
note, and repair should be done to avoid fistulization.
1. All women should be carefully examined for
perineal or vaginal tears; those with a tear that Such a grading system takes into account the degree of tearing
is more than superficial in depth should have a experienced by the external sphincter separately from that of
systematic rectal examination for obstetrical anal the internal sphincter. Such distinction is meant to improve
sphincter injury prior to repair. (II-2B) reporting, guide repair, and facilitate outcome research.
that study of primiparous women, all women were examined Vacuum 2.9
by a trained fellow after the examination and grading of tear Forceps 3.9
by the obstetrical care provider and confirmed by endoanal Epidural23 1.1 to 2.2
ultrasound prior to repair (considered the gold standard). Second stage >1 h‡ 1.5
When examined systematically as described above, all but Shoulder dystocia 2.7 to 3.3
1.6% (3/182) of women were correctly diagnosed on VBAC21,32 1.4 to 5.5
exam; the other 3 had occult OASIS representing the false- Water birth27 1.46
negative rate of examination, 2 of which only affected the Oxytocin augmentation‡33 1.2
internal sphincter, and would have thus been undetectable Infant risks factors OR
on physical examination. Birth weight > 4000 gm20 2.2 to 3.0
Malpresentation23 2.0
When the diagnosis of OASIS is obtained from endoanal
ultrasound evaluation within 2 months of delivery, Postmaturity20,24 1.1 to 2.5
the incidence of any degree of anal sphincter defect in Fetal distress 1.3
for OR
124.4
191.8
239.5
Delivery Risk Factors
23.2
12.6
10.1
62.6
86.5
75.6
30.8
43.2
8.6
7.6
6.2
—
Risks factors occurring at the time of delivery
that may be independently associated with OASIS
are included in the second section of Table 3. The
impact of midline episiotomy and forceps, together
or in isolation, are presented in Table 4.37
confidence limit
95% lower
for OR
10.2
13.5
Infant Risk Factors
7.9
3.8
4.0
3.6
3.8
1.6
6.9
8.6
6.2
3.0
5.8
4.8
—
Specific infant characteristics appearing to
independently increase the risk of OASIS are
presented in the third section of Table 3.
related to tear
13.6
25.3
24.4
41.0
40.6
21.6
15.9
33.8
1.0
7.0
6.3
5.6
5.3
3.2
9.7
factor in vaginal
control group
Number with
Head Control
Slowing down the delivery of the head and instructing
235
103
336
25
21
38
66
6
3
4
2
3
4
5
1
0
Perineal Support
Number with
tear group
101
138
220
366
91
52
63
32
61
32
26
15
33
18
17
OP + episiotomy
Characteristic
OP + vacuum
OP + forceps
Vacuum
(towards the rectum) is applied with steady, lateral Figure 2. Episiotomy sites
strokes, which last 1 second in each direction.43
Delivery Position
While kneeling versus sitting has no impact on rate of
OASIS, a standing position (upright position without
buttocks support: upright standing, squatting, kneeling)
versus a sitting position (upright position but with
support of the ischial tuberosities, with or without sacral
support) might increase the risk of OASIS, as shown in
a retrospective analysis of 814 women (650 standing, 264
sitting, any parity) in which women standing for their
delivery had a nearly 7-fold increase in OASIS (2.5% vs.
0.38%).44 A 2012 RCT comparing traditional method of
delivery (no passive second stage, and active second stage
in the dorsal lithotomy) versus “alternate” method of
delivery (passive second stage lasting up to strong urge or
120 min, and active second stage in the lateral “Gasquet”
position – with upper hip flexed, foot on stirrup higher
than knee) showed no difference in rate of OASIS.45 woman, and in fact, may decrease the incidence of OASIS
compared with no episiotomy.
Episiotomy
There is no doubt that restricted use of episiotomy, of any There is only one published RCT (published in 1980)
type, is preferable in women having a spontaneous vaginal comparing rates of OASIS between midline and mediolateral
delivery.46 The results of a pilot RCT of routine versus episiotomy in nulliparas.55 In that study, 12% of women who
restrictive mediolateral episiotomy in nulliparous women, had a midline episiotomy sustained an OASIS, versus 2%
undergoing instrumental delivery did not reach statistical of those who had a mediolateral. This study had significant
significance due to a small sample size.47 limitations including a number of protocol violations. For
example, if an obstetrical care provider was opposed to
Most studies identify midline episiotomy as a risk factor,48 midline incisions, a mediolateral episiotomy was performed
but some do not.19 This might be related to poor coding instead and the patient excluded from the analysis. In a
in those studies that assess the outcome based on database prospective cohort study of 1302 women who delivered
information.49 However, while the published rate of OASIS vaginally, and who all received an episiotomy, 426 received
following mediolateral episiotomy varies between 0.5% to midline and 876 mediolateral episiotomy, according to the
7%, it may reach as high as 17% to 19% following a midline practitioner’s preferences.56 Deep perineal tears (which
episiotomy.26–50 In those having an operative vaginal delivery, included but were not limited to OASIS) were present in
a retrospective large Dutch database study suggested that a 14.8% of those who had a midline episiotomy versus 7% of
mediolateral or lateral episiotomy lead to less anal sphincter those who had a mediolateral episiotomy.
injuries than no episiotomy or a midline episiotomy.29
The terminology used in the literature is at times unclear
The impact of mediolateral episiotomy is somewhat between midline, mediolateral, and lateral episiotomies. A
controversial in instrumental deliveries in primiparous standardization has been proposed57 (as shown in Figure 2;
women. Some authors report an independent increased for a more detailed illustration, see online eFigure 2).
risk of OASIS if a mediolateral episiotomy is performed A midline episiotomy (line #1) should indicate those
during instrumented birth (OR 4.04);51 however, once starting in the midline and continuing at a 0° angle from
adjusted for instrumental delivery, the type of episiotomy the vertical; mediolateral (line #4) episiotomies should
no longer remained a risk factor. Others report a lower represent those done starting in the midline but at an angle
rates of OASIS 52–54 and severe perineal trauma (high greater than 0° from the vertical line; while a lateral (#5)
vaginal sulcus and OASIS combined)46 with mediolateral episiotomy starts off the midline and is carried at an angle
episiotomy than with no episiotomy (OR 0.2 to 0.8). greater than 0° from the vertical. Other incisions shown
The balance of the evidence suggests that a mediolateral include: modified median (inverted “T” incision, #2),
episiotomy likely does not increase the risk of OASIS “J”-shaped episiotomy (#3), and the seldom used radical
at the time of instrumental delivery of a primiparous lateral (Schuchardt incision, #6).58
The angle of the episiotomy affects the occurrence of a midline episiotomy is performed concurrently with an
OASIS. A more acute (vertical) angle appears to increase operative vaginal delivery, it acts synergistically in increasing
the risk of OASIS; in an RCT comparing mediolateral OASIS.30,68 It is possible that early removal of forceps
episiotomies made at 60° and 40° angles from the vertical, (after delivery is assured, but before the largest diameter of
the risk of OASIS was 2.4% versus 5.5%, respectively the head is expelled) may also assist in limiting OASIS in
(did not reach statistical significance); however, 60º forceps and vacuum deliveries, when combined with other
episiotomies carried higher short-term pain.59 This likely practices such as rotating an occiput posterior baby to an
reflects how far away from the anal sphincter complex occiput anterior position, selecting a vacuum instead of a
the incision is. forceps, performing a mediolateral episiotomy rather than
a midline (only if an episiotomy is deemed necessary), and
The impact of the starting point of the episiotomy using minimal necessary maternal expulsive efforts at time
(mediolateral vs. lateral) appears less important. In a large of expulsion.64 Some have raised the point of informed
RCT, published only in abstract form in 2014, comparing consent at the time of instrumental delivery, arguing that
mediolateral to lateral episiotomies.60 In this trial of 790 disclosure of the OASIS risk should be included, as well as
women, the incidence of OASIS did not differ between the risks and benefits of any alternative such as Caesarean
a mediolateral (60° off the midline) and a lateral incision section.69
(1 to 2 cm laterally from the midline, angled towards the
ischial tuberosity): 1.5% versus 1.3%, respectively. There Clearly, performing a Caesarean would prevent OASIS, but
also seem to have no impact on postpartum pain or performing it late in labour may not fully protect the anal
sexually between mediolateral and lateral.61 canal, as nerve injury can still occur.70,71
PRINCIPLES AND TYPES OF REPAIRS to compare suture material. Randomized trials with longer
term outcomes including anal incontinence are required to
Obstetric anal sphincter injuries should be repaired by compare suture materials.
appropriately trained clinicians comfortable with such
repairs. Repairs are typically carried out in the delivery Repair of the Anal Mucosa
room or the operating room. The operating room offers Following a fourth degree perineal tear, the anal mucosa
the benefits of access to optimal lighting, appropriate can be approximated by a number of techniques.78 The
equipment, and aseptic conditions.3 Additional equipment mucosal repair can be carried out with an interrupted
may be required for anal sphincter repairs including self- 3-0 Vicryl suture with the knots tied in the anal lumen or
retaining retractors and Allis clamps. There have been no external to the anal canal. Alternatively the anal mucosa can
studies that have evaluated anaesthetics used in the repair be approximated with a 3-0 PDS suture with a submucosal
of obstetric anal sphincter injuries. Although commonly continuous suture. There are currently no studies that
repaired under local anaesthetic, general or regional suggest a benefit from any of these repair techniques
anaesthesia maybe optimal as they provide both analgesia for the anal mucosa with respect to outcomes including
and muscle relaxation.3 The EAS has inherent tone and anovaginal and rectovaginal fistulas. However figure-of-
when torn does retract within its capsular sheath. With eight sutures should not be used as they can cause ischemia
muscle relaxation, the extent of the tear can be thoroughly and poor healing of the anorectal mucosa.
evaluated and the sphincter ends can be identified,
grasped, and repaired by either the end-to-end or the Separate Repair of the IAS
overlap technique. Local anaesthetic may be sufficient The literature related to the techniques of repairing the anal
when only the superficial fibres of the EAS are disrupted,78 sphincter following obstetric trauma has primarily focused
although without good analgesia, it may be difficult on the repair of the external anal sphincter. However, the
to make a proper diagnosis. In the United Kingdom, muscles involved in maintaining anal continence include
experts recommend completing the repair under general not only the EAS but also the internal anal sphincter.
or epidural anaesthesia.79 The SOGC Urogynaecology
Committee does not feel this is always necessary, as long as The internal sphincter is a 3 to 5 mm thick continuation of
adequate analgesia is provided, either using local infiltration the rectal smooth muscle and is under autonomic control.
or pudendal nerve block. The IAS is responsible for maintaining continence at rest,
by contributing to 70% to 85% of the resting anal pressure,
Suture Material and, to a lesser degree, of the anal pressure in response
Although the type of suture material used in the repair of to sudden and constant rectal distension (40% and 65%,
obstetric anal sphincter tears may be important, there has respectively).10
been very little research carried out comparing different
suture types used for sphincter repairs. Both absorbable and In response to rectal distension by feces, liquids, or gases,
delayed absorbable sutures are commonly used. Although the pressures in the IAS drop to allow “sampling” (whereby
some colorectal surgeons use non-absorbable sutures for the rectal content transiently enters in contact with
secondary repairs of anal sphincters, there is concern that sensory nerve ending of the anal canal to determine the
such sutures may result in stitch abscesses or suture ends bowel content (liquid, gas, or solid) and allow processing
may cause discomfort requiring their removal.80 The suture and decision about appropriateness of evacuation),
ends should be cut short and the knots covered by the associated with a reflex recto-anal contractile reflex if time
overlying superficial perineal muscles in order to minimize is inconvenient.82 Damage to the IAS muscle may lead to
any discomfort from suture ends and knots. Monofilament a poor seal and an impaired sampling reflex,10 leading to
sutures maybe beneficial as they are less likely to harbour passive incontinence.
organisms and predispose to infection.78
Sultan and Thakar78 described identifying and
A randomized trial by Williams et al.81 (n = 112), compared approximating the IAS with interrupted sutures in addition
OASIS repairs with polyglactin (Vicryl) and polydioxanone to the overlap repair of the EAS. It can be difficult to
(PDS). At 6 weeks, there was no significant difference in identify the IAS which lies between the EAS and the
suture-related morbidity. There may be benefit to delayed anal mucosa. In comparison to the striated muscle of the
absorbable suture with respect to longer term functional EAS, the IAS is thin with a pale pink appearance in close
outcomes but this has yet to be evaluated in clinical trials. proximity to the anal mucosa. It may appear similar to a
Many of the more recently published studies have used “fascial” layer. A small prospective study, with historical
delayed absorbable sutures but have not been undertaken controls, published by Lindqvist and Jernetz in 2010,83
suggested that identifying and separately suturing the IAS hours with no impact on anal incontinence and pelvic floor
may improve anal continence at 1 year. Both previously symptoms.87
mentioned studies approximated the IAS in an “end-
Summary Statement
to-end” fashion using delayed absorbable sutures. In a
randomized trial of obstetric sphincter repairs,84 9 women 3. Obstetrical anal sphincter injuries (OASIS) repair:
had sphincter tears that included the IAS and were a. Suture-related morbidity is similar at 6 weeks
independently approximated. In all 9 women the IAS was following the use of either polyglactin 2-0 or
intact on follow-up endoanal ultrasound. polydioxanone 3-0 following repair. (I)
b. Repair of the internal anal sphincter is
Studies looking at functional results following OASIS recommended as women who demonstrate an
repair report that more women with an IAS defect on internal anal sphincter defect on postpartum
endoanal ultrasound 6 months postpartum have anal ultrasound have more anal incontinence. (III)
incontinence, and those with incontinence report worse c. Repair of the external anal sphincter should
degree of symptoms than those without IAS.22,65,85,86 include the fascial sheath. An overlapping
technique often requires more dissection and
EAS Repair Techniques mobilization of the sphincter ends and is only
When repairing a torn anal sphincter following vaginal possible with full thickness 3b sphincter tears
delivery the external anal sphincter can be approximated or greater. (III)
by 1 of 2 repair techniques; end-to-end repair or overlap d. A persistent defect of the external anal
repair. The torn ends of the EAS, normally under tonic sphincter remote from delivery may increase
contraction, tend to retract within their sheaths and can be the risk of worsening symptoms following
found latero-posteriorly to the tear, often by palpation of a subsequent vaginal deliveries. (II-2)
depression downward rather than lateral. The muscle ends
must be identified and grasped with Allis clamps. Recommendation
With an end-to-end repair (for a detailed illustration, see 5. Repair can be delayed for 8 to 12 hours with
online eFigure 3), the EAS ends may need to be mobilized no detrimental effect. Delay may be required so a
using Metzenbaum scissors for the dissection. The muscle more experienced care provider is available for the
ends are then approximated end-to-end with 2 or 3 repair. (I-A)
mattress sutures. In theory, mattress sutures may cause less
Comparison of Repair Techniques
tissue necrosis although there is no evidence to support
Historically, the most popular technique for the primary
one technique over the other. Sutures should include the
repair of obstetrical anal sphincter injuries has been the
fascial sheath.3
end-to-end approximation of the external anal sphincter
With an overlap repair (for a detailed illustration, see online with interrupted or figure-of-eight sutures. In contrast, the
eFigure 3), the torn EAS muscle ends often needs much technique commonly used by colorectal surgeons to repair
more dissection and mobilization.3 The dissection is carried anal sphincter tears remote from delivery or unrelated to
out using the ischioanal fat laterally as a landmark. The delivery is the overlap technique. The overlap technique,
full lengths of the torn ends of the EAS (including fascial described by Parks and McPartlin88 for the secondary
sheath) are overlapped in a double-breasted fashion.80 This repair of anal sphincters, was first evaluated for the
type of repair is only possible with 3b or greater OASIS.50 primary repair of obstetric anal sphincter tears by Sultan
et al. in his 1999 seminal study.89 The small study (n = 27)
Following the anal sphincter repair, which approximates showed that in comparison to matched historical controls
the disrupted anal sphincter complex, the perineal body is with end-to-end repairs, overlap repairs resulted in less anal
reconstructed by suturing the perineal muscles. This takes incontinence (8% vs. 41%).90 Following this study several
tension off and provides support for the underlying muscle randomized trials have been published comparing end-to-
repair. The vaginal mucosa and perineal skin are repaired in end approximation and overlap repair of the EAS.
the usual fashion. A rectovaginal exam at the completion of
the repair is carried out to confirm the adequacy of the repair. A 2013 Cochrane review compared the effectiveness of
these 2 immediate primary repair techniques in reducing
If an obstetrical care provider is insufficiently experienced subsequent anal incontinence, perineal pain, dyspareunia
in the repair of third and fourth degree tear and an and improving quality of life.50 The authors included 6 trials
experienced obstetrical care provider is not available involving 588 women.81,84,91 Three trials followed women
immediately or locally, repair can be delayed for 8 to 12 for 12 months.91 The only outcomes showing a difference
was for fecal urgency and fecal incontinence score, in favour (codeine phosphate) in the 3 days following repair of
of the overlapping repair from one trial with 52 women primary OASIS in 105 women. Laxative use was associated
followed up at 12 months.91 An overlap repair resulted in with a significantly earlier and less painful first bowel motion
fewer with deterioration of incontinence from 6 weeks to and an earlier hospital discharge postpartum. Troublesome
12 months later (n = 41).91 Another trial showed that at 36 constipation was noted in 19% of women receiving the
months, these differences were no longer present.92 constipating regimen compared to 5% receiving the laxative
regimen. Two patients that received the constipating regimen
However, the data are limited given the heterogeneity in required hospital admission for fecal impaction. Overall
the outcome measures, time points, and reported results. there were no significant differences in continence scores
These studies included primiparous and parous women or anal manometry and endoanal scan findings between the
and partial and complete third degree tears. Furthermore, groups at 3 months postpartum.
their surgical experience is not evaluated in the included
studies. Consequently, the current literature does not In 2007 Eogan et al.96 randomized (n = 147) women to
support recommending one obstetric anal sphincter repair receive laxatives alone (lactulose) or laxatives and a bulking
technique over the other agent (lactulose and ispaghula husk, Fybogel) for 10 days
after the repair of OASIS. Incontinence in the immediate
postnatal period was more frequent in women taking the
POSTOPERATIVE MANAGEMENT
2 preparations than in those taking lactulose alone (33%
Prophylactic Antibiotics vs. 18%). There were no significant differences between
Only one randomized trial compared the effect of a single the groups with respect to time to first bowel motion,
IV dose of a second generation cephalosporin (cefotetan length of hospital stay, or overall satisfaction related to
or cefoxitin) on postpartum perineal wound complications bowel habits, and no significant difference in functional
(purulent discharge, or abscess and breakdown of repair) 2 outcomes at 3 months.
weeks following third and fourth degree tears.80 Prophylactic Recommendation
antibiotics given at the time of obstetrical anal sphincter
7. Laxatives (e.g., lactulose) should be prescribed
repair decreases maternal morbidity related to perineal wound
following the primary repair of obstetrical anal
complications: 8.2% of women who received antibiotics and sphincter injury as they are associated with earlier
24.1% of women who received placebo suffered a wound and less painful first bowel motions and earlier
complication (P < 0.05), with a relative risk of 0.34 (95% discharge from hospital. Constipating agents and
CI 0.12 to 0.96).93,94 This Cochrane review reported that the bulking agents are not recommended (I-A).
study was limited by a high (27.2%) proportion of lack of
follow-up. There are currently no studies that have evaluated Postoperative Analgesia
the value of additional doses of antibiotics following repair While there are no data regarding the use of analgesics
of third and fourth degree perineal tears. following repair of OASIS, a Cochrane review published
Recommendation
in 200397 found that rectal analgesia including diclofenac
reduces perineal trauma related pain during the first 24
6. Prophylactic single dose intravenous antibiotics hours following birth and results in women using less
(2nd generation cephalosporin, e.g., cefotetan or additional analgesia during the first 48 hours. Because
cefoxitin) should be administered for the reduction of the constipating effect of opioids, an NSAID in
of perineal wound complications following the conjunction with acetaminophen is likely preferable as
repair of obstetrical anal sphincter injury. (I-A) first-line management of perineal pain. Although rectal
Postoperative Bowel Regimen administration of NSAID may be better, it should be
Postoperative bowel regimens following the primary repair of avoided in cases of fourth degree laceration, because it
OASIS vary. Some regimens consist of laxatives and bulking theoretically could impair.98 However, opioids should not
agents to avoid constipation and any potential disruption of be withheld, but rather used along with a stool softener.
the repair from the passage of hard stool. Other regimens Recommendation
consist of bowel confinement techniques with the concern 8. Non-steroidal anti-inflammatories and
that bowel motions in the immediate postoperative period acetaminophen are the first-line analgesics. Opioids
may threaten the integrity of the repair. should only be used with caution. Constipation
Mahony et al.95 performed a randomized trial to compare should be avoided by using a laxative or stool
a laxative regiment (lactulose) with a constipating regiment softener. (1-A)
The pathophysiology of postpartum urinary retention Following OASIS, the incidence of anal incontinence
related to perineal injury is unclear but maybe related to may increase with time: from 3–6 months to 3–8 years
perineal discomfort, urethral and perineal edema, and following delivery, the rate went from 31% to 54%.107
neurologic damage. Women’s continence over time may be affected by aging,
subsequent deliveries, and lifestyle factors.
Summary Statement
4. Obstetrical anal sphincter injuries are associated Overall, the outcomes following the primary repair
with an increased risk of postpartum urinary of OASIS are not encouraging, with studies reporting
retention. (II-2) that many women suffer from various degrees of anal
incontinence. Fortunately, the management of anal
incontinence, including that following repaired OASIS, can
RISK MANAGEMENT/DOCUMENTATION be successful with pelvic floor physiotherapy. 108,109
Operative delivery, while often indicated, is a risk factor for Recommendation
sphincter tear, and obstetrical care providers should consider 10. Women with anal incontinence following obstetrical
discussing the possibility of operative delivery and any potential anal sphincter injury should be referred for pelvic
sequelae prior to labour. The decision for instrumental delivery floor physiotherapy. (I-A)
should take into consideration the potential for anal sphincter
injury. In addition, prolonged labour may be associated with
sphincter tears and practitioners may consider discussing this SUBSEQUENT PREGNANCY
with patients in situations when labour progression is slow. Many factors may be taken into account in counselling
When faced with an OASIS, the obstetrical care giver women following an OASIS: the functional status (i.e.
should document (ideally as a formal operative note) the symptoms experienced shortly and remotely from the
delivery course, including indication for operative vaginal index delivery), the extent of residual anatomical and/or
delivery, consent obtained, description of procedure, functional defects as shown on anal ultrasound and/or
type and extent of perineal injury, repair method and anal manometry, and the patient’s wishes.
suture used, and antibiotics administered. Furthermore, A woman who had an OASIS after her first delivery has 3.8-
the patient should be informed of the injury sustained, to 5.9-fold greater odds of a repeat OASIS at her next delivery
and upon discharge a follow-up plan should be made. than a woman without prior OASIS (Table 7).103–105,110–114
Recommendation
Although higher than in women without a prior OASIS,
9. Following obstetrical anal sphincter injury, providers the risk of having a recurrent OASIS is the same for a
should disclose to women the degree of injury and woman with previous OASIS as the baseline risk at first
arrange follow-up. Detailed documentation of the delivery; both around 5.3% in Ontario.33 The vast majority
injury and its repair is required. (III-L) of women with a previous OASIS will not have a recurrent
OASIS during a subsequent vaginal delivery. In fact, 64%
OUTCOMES FOLLOWING REPAIR to 90% of all OASIS occurring at a second delivery are in
women without a previous OASIS.112,113
The outcomes following the primary repair of obstetric
anal sphincter injuries are difficult to establish as there Overall, the rate of anal incontinence in women with
is significant heterogeneity between studies. Studies vary OASIS and a subsequent vaginal delivery worsens in 19% to
greatly with respect to repair techniques, outcome measures, 56% of women,115–118 particularly if a women had transient
and follow-up intervals. A summary of outcomes following anal incontinence after the index OASIS.116 On the basis
primary OASIS repair is presented in Table 5.3,103–105 of these studies, the Royal College of Obstetrics and
Table 6. Outcomes following OASIS repairs according to the extent of the initial sphincter tear.
Degree of Type of Follow-up
Reference injury repair Interval(s) Outcome measure(s) Prevalence
Nichols et al. 2005 4th, n = 17 unspecified 6 to 8 weeks Anal incontinence and/or fecal 3rd: 28%
3rd, n = 39 urgency 4th: 59%
Roos et al. 201011 3a or 3b: n = 439 End-to-end 8 to 12 weeks Bothersome fecal incontinence 3c and 4th had worse scores
3b or 4: n = 92 or overlap or fecal urgency on symptoms questionnaires
Any incontinence to liquid stool than 3a and 3b
Fenner et al 200326 3rd and 4th, unspecified 6 months Worsening bowel control after 4th: 30.8%
n = 165 pregnancy 3rd: 3.6%
Table 7. Risks of OASIS at next delivery, based on presence of OASIS at 1st delivery
OASIS at 1st delivery No OASIS at 1st delivery
OASIS at subsequent delivery 3.7% to 7.5% 104,105,110–114
0.6% to 3.2%104,105,112,113
Gynaecologistsis recommend that “All women who have the cost of increased maternal risks, including an increased
sustained an obstetric anal sphincter injury in a previous morbidity rate from 4.2% following vaginal delivery to
pregnancy and who are symptomatic or have abnormal 11.3% after Caesarean section. Furthermore, there would
endoanal ultrasonography and/or manometry should have be one maternal death for 1880 cases of anal incontinence
the option of elective Caesarean birth.”79 averted. The balance of risks and benefits should be
discussed when counselling women on the route of future
A 2003 study using a decision analysis modeling explored deliveries after OASIS in a previous pregnancy.
universal Caesarean section in continent women with
previous OASIS.119 Based on the literature, they used the Outcome of Subsequent Vaginal Delivery
following assumptions: 5.1% risk of repeat OASIS, anal Depending on Symptoms Following OASIS
incontinence rate of 44% after 2nd OASIS. To prevent at Index Delivery
one case of anal incontinence (flatus, liquid, or stool) in Only one published study assessed anal symptoms
women with prior OASIS who were presumed continent in women with a subsequent delivery based on their
2.3 elective Caesarean sections would need to be done, at symptoms after the index OASIS.116 Women who
sustained a fourth degree tear in a previous delivery Women who had substantial anal compromise were
associated with transient anal incontinence had a greater counselled on having a Caesarean section. All others
rate of developing subsequent anal incontinence after were counselled on vaginal delivery. In those women who
a subsequent vaginal delivery (39%, 9/23; 4 of these delivered as counselled (75% of the study group), results
women became permanently incontinent compared with on anal manometry did not significantly change and
7% [2/29] of asymptomatic women after their OASIS). anorectal symptoms did not worsen following delivery.
In a recent preliminary report, low baseline symptom Similar results have been presented as abstracts.123
scores may predict good outcomes after a vaginal delivery
Summary Statements
in women with prior OASIS.120
5. After a successful repair of obstetrical anal sphincter
Outcome of Subsequent Vaginal Delivery injuries, most women can safely deliver vaginally in
Depending on Finding on Endoanal a future pregnancy. (III)
Ultrasound Following OASIS at Index Delivery 6. Counselling women about future delivery plans:
The literature is limited in number and size of studies, but a. The risk of recurrence of an obstetrical anal
the presence of a persistent defect appears to increase the sphincter injuries at a subsequent delivery is 4%
risk of worsening symptoms. In women who had ultrasound to 8%. (II-2)
evidence of anal sphincter injury 3 months following a first b. It was calculated that 2.3 Caesarean sections at
vaginal delivery (any degree of tear), a subsequent vaginal the cost of increased maternal risk would be
delivery may increase the rate of abnormal anorectal required to prevent one case of anal incontinence
symptoms (38%), compared with women who did not in a woman with prior obstetrical anal sphincter
have another child (16%; not statistically significant). injuries. (II-2)
Women without ultrasound evidence of OASIS 3 months
postpartum had a rate of anal incontinence of 3% in the LEARNING MODEL
absence of a subsequent pregnancy versus 10% if they
delivered again (not statistically significant).118 For the past decade, Sultan and his group has devised a
hands-on workshop on OASIS repair. The hands-on
In women who have a second vaginal delivery, the part uses both an artificial model and a repair of fresh
presence of anal injury on antenatal ultrasound between anuses originating from male pig.4 It has been shown that
deliveries increases the rate of worsening anorectal a surgical skill laboratory improves learners’ acquisition
symptoms: from 7% of women following a subsequent of the skills necessary to repair OASIS as evidenced on
vaginal delivery without evidence of persistent defect, the Objective Structured Assessment of Technical Skills
to 37% if ultrasound showed a pre-existing injury (no and written examination administered before and after an
significant difference).121 OASIS repair workshop.124
Outcome of Subsequent Vaginal Delivery
SUMMARY
Depending on Combined Finding on Endoanal
Ultrasound and Anal Manometry Following Obstetrical anal sphincter injuries represent a significant
OASIS at Index Delivery morbidity encountered after vaginal delivery. Some
Sultan reported his results following antenatal counselling intrapartum measures can be taken to diminish the risk
for the route of delivery in subsequent pregnancy for of occurrence. Careful examination after every delivery
women with previous OASIS,114 with updated results is of paramount importance to avoid missing an OASIS.
presented in 2013.122 In his study, substantial anal Systematic repair of the entire anal sphincter complex
compromised was defined as either: should be done by a trained caregiver; full disclosure and
•• external sphincter defect on ultrasound > 30° and a close follow-up should be offered. Most women following
maximum squeeze pressure increment of < 20 mmHg OASIS are good candidates to have a subsequent vaginal
on anal manometry; delivery; antenatal evaluation of symptoms and anal function
OR testing can help guide the choice of future mode of delivery.
•• defect <30° and a maximum squeeze pressure
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This Clinical Practice Guideline was prepared by the Aideen Moore, MD, Toronto ON
Genetics Committee, reviewed by the Family Physician
William Mundle, MD, Windsor ON
Advisory Committee, and approved by the Executive and
Board of the Society of Obstetricians and Gynaecologists Deborah O’Connor, PhD RD, Toronto ON
of Canada. Joel Ray, MD, Toronto ON
R. Douglas Wilson, MD, Calgary AB Disclosure statements have been received from all contributors.
GENETICS COMMITTEE
R. Douglas Wilson (Chair), MD, Calgary AB
Abstract
François Audibert, MD, Montreal QC Objective: To provide updated information on the pre- and post-
conception use of oral folic acid with or without a multivitamin/
Jo-Ann Brock, MD, Halifax NS
micronutrient supplement for the prevention of neural tube
June Carroll, MD, Toronto ON defects and other congenital anomalies. This will help physicians,
Lola Cartier, MSc, Montreal QC midwives, nurses, and other health care workers to assist in the
education of women about the proper use and dosage of folic
Alain Gagnon, MD, Vancouver BC acid/multivitamin supplementation before and during pregnancy.
Jo-Ann Johnson, MD, Calgary AB Evidence: Published literature was retrieved through searches of
Sylvie Langlois, MD, Vancouver BC PubMed, Medline, CINAHL, and the Cochrane Library in January
2011 using appropriate controlled vocabulary and key words (e.g.,
Lynn Murphy-Kaulbeck, MD, Moncton NB folic acid, prenatal multivitamins, folate sensitive birth defects,
Nanette Okun, MD, Toronto ON congenital anomaly risk reduction, pre-conception counselling).
Results were restricted to systematic reviews, randomized control
Melanie Pastuck, RN, Calgary AB
trials/controlled clinical trials, and observational studies published
in English from 1985 and June 2014. Searches were updated on
SPECIAL CONTRIBUTORS
a regular basis and incorporated in the guideline to June 2014
Paromita Deb-Rinker, PhD, Ottawa ON Grey (unpublished) literature was identified through searching the
Linda Dodds, MD, Halifax NS
Juan Andres Leon, MD, Ottawa ON J Obstet Gynaecol Can 2015;37(6):534–549
Hélène Lowell, RD DtP, Ottawa ON
Key Words: Folic acid, folate, prenatal multivitamins,
Wei Luo, MB MSc, Ottawa ON micronutrients, neural tube defect, spina bifida, myelomeningocele,
Amanda MacFarlane, PhD, Ottawa ON congenital anomalies, fetal anomalies, folate sensitive birth
defects, congenital anomaly risk reduction, preconception
Rachel McMillan, BSc, Ottawa ON
counseling, birth defects, pregnancy, prevention
This document reflects emerging clinical and scientific advances on the date issued and is subject to change. The information
should not be construed as dictating an exclusive course of treatment or procedure to be followed. Local institutions can dictate
amendments to these opinions. They should be well documented if modified at the local level. None of these contents may be
reproduced in any form without prior written permission of the SOGC.
Table 1. Key to evidence statements and grading of recommendations, using the ranking of the Canadian Task Force
on Preventive Health Care
Quality of evidence assessment* Classification of recommendations†
I: Evidence obtained from at least one properly randomized A. There is good evidence to recommend the clinical preventive action
controlled trial
II-1: Evidence from well-designed controlled trials without B. There is fair evidence to recommend the clinical preventive action
randomization
II-2: Evidence from well-designed cohort (prospective or C. The existing evidence is conflicting and does not allow to make a
retrospective) or case–control studies, preferably from recommendation for or against use of the clinical preventive action;
more than one centre or research group however, other factors may influence decision-making
II-3: Evidence obtained from comparisons between times or D. There is fair evidence to recommend against the clinical preventive action
places with or without the intervention. Dramatic results in
uncontrolled experiments (such as the results of treatment with E. There is good evidence to recommend against the clinical preventive
penicillin in the 1940s) could also be included in this category action
III: Opinions of respected authorities, based on clinical experience, L. There is insufficient evidence (in quantity or quality) to make
descriptive studies, or reports of expert committees a recommendation; however, other factors may influence
decision-making
*The quality of evidence reported in here has been adapted from The Evaluation of Evidence criteria described in the Canadian Task Force on Preventive Health
Care.193
†Recommendations included in these guidelines have been adapted from the Classification of Recommendations criteria described in the Canadian Task Force
on Preventive Health Care.193
websites of health technology assessment and health technology- supplementation for women with a risk for primary or recurrent
related agencies, clinical practice guideline collections, clinical trial neural tube or other folic acid-sensitive congenital anomalies who
registries, and national and international medical specialty societies. are considering a pregnancy. It is recommended that folic acid
Costs, risks, and benefits: The financial costs are those of daily be taken in a multivitamin including 2.6 ug/day of vitamin B12 to
vitamin supplementation and eating a healthy folate-enriched mitigate even theoretical concerns. (II-2A)
diet. The risks are of a reported association of dietary folic acid 4. Women at HIGH RISK, for whom a folic acid dose greater than 1
supplementation with fetal epigenetic modifications and with an mg is indicated, taking a multivitamin tablet containing folic acid,
increased likelihood of a twin pregnancy. These associations may should be advised to follow the product label and not to take more
require consideration before initiating folic acid supplementation. than 1 daily dose of the multivitamin supplement. Additional tablets
The benefit of folic acid oral supplementation or dietary folate containing only folic acid should be taken to achieve the desired
intake combined with a multivitamin/micronutrient supplement is dose. (II-2A)
an associated decrease in neural tube defects and perhaps in
other specific birth defects and obstetrical complications. 5. Women with a LOW RISK for a neural tube defect or other folic
acid-sensitive congenital anomaly and a male partner with low
Values: The quality of evidence in the document was rated using the risk require a diet of folate-rich foods and a daily oral multivitamin
criteria described in the Report of the Canadian Task Force on supplement containing 0.4 mg folic acid for at least 2 to 3 months
Preventative Health Care (Table 1). before conception, throughout the pregnancy, and for 4 to 6 weeks
postpartum or as long as breast-feeding continues. (II-2A)
Summary Statement
6. Women with a MODERATE RISK for a neural tube defect or
In Canada multivitamin tablets with folic acid are usually available in 3 other folic acid-sensitive congenital anomaly or a male partner
formats: regular over-the-counter multivitamins with 0.4 to 0.6 mg folic
with moderate risk require a diet of folate-rich foods and daily oral
acid, prenatal over-the-counter multivitamins with 1.0 mg folic acid,
supplementation with a multivitamin containing 1.0 mg folic acid,
and prescription multivitamins with 5.0 mg folic acid. (III)
beginning at least 3 months before conception. Women should
continue this regime until 12 weeks’ gestational age. (1-A) From
Recommendations
12 weeks’ gestational age, continuing through the pregnancy,
1. Women should be advised to maintain a healthy folate-rich diet; and for 4 to 6 weeks postpartum or as long as breast-feeding
however, folic acid/multivitamin supplementation is needed to continues, continued daily supplementation should consist of a
achieve the red blood cell folate levels associated with maximal multivitamin with 0.4 to 1.0 mg folic acid. (II-2A)
protection against neural tube defect. (III-A)
7. Women with an increased or HIGH RISK for a neural tube defect,
2. All women in the reproductive age group (12–45 years of age) a male partner with a personal history of neural tube defect, or
who have preserved fertility (a pregnancy is possible) should history of a previous neural tube defect pregnancy in either partner
be advised about the benefits of folic acid in a multivitamin require a diet of folate-rich foods and a daily oral supplement
supplementation during medical wellness visits (birth control with 4.0 mg folic acid for at least 3 months before conception
renewal, Pap testing, yearly gynaecological examination) and until 12 weeks’ gestational age. From 12 weeks’ gestational
whether or not a pregnancy is contemplated. Because so many age, continuing throughout the pregnancy, and for 4 to 6 weeks
pregnancies are unplanned, this applies to all women who may postpartum or as long as breast-feeding continues, continued daily
become pregnant. (III-A) supplementation should consist of a multivitamin with 0.4 to 1.0
3. Folic acid supplementation is unlikely to mask vitamin B12 mg folic acid. (I-A). The same dietary and supplementation regime
deficiency (pernicious anemia). Investigations (examination should be followed if either partner has had a previous pregnancy
or laboratory) are not required prior to initiating folic acid with a neural tube defect. (II-2A)
FOLIC ACID SUPPLEMENTATION AND Oral pre-conception folic acid dietary intake or
THE PREVENTION OF BIRTH DEFECTS supplementation is required as it is the primary source
for the trans-placental transfer of folate/folic acid to the
The initial NTD translational research study investigated embryo/fetus. No specific studies have been published
folic acid supplementation for recurrence prevention of looking at the embryonic cell folate availability in
NTDs in a randomized double-blind clinical trial involving humans during this embryonic target period of 0 to 8
1195 completed high risk pregnancies in women from weeks (conception to 10 gestational weeks). Canadian
33 centres.2 The NTD recurrence rate decreased from researchers have made strong contributions in this area
3.5% in a non-supplemented group to 1% for women
of prevention.41–76
randomized to the group receiving an oral 4 mg folic acid
supplementation daily prior to pregnancy and throughout Women should be advised to maintain a nutritionally healthy
the first 6 weeks of pregnancy. diet, as recommended in Eating Well with Canada’s Food
Guide.42 Good or excellent sources of natural folate include
The second NTD translational research study was a
broccoli, spinach, peas, Brussels sprouts, corn, lentils, and
randomized controlled trial for the primary prevention
oranges.
of NTD occurrence.3 The frequency of NTDs was zero
in 2471 women receiving 0.8 mg per day of folic acid Counselling should emphasize that the recurrence risk
compared with 6 cases in 2391 women not receiving folic for a fetus with an NTD is shared by both mother’s and
acid. This RCT study supported previous case–control father’s personal reproductive history, but only the mother
studies that had provided evidence that pregnant women is treated with the supplemental dose of pre-conception/
using multivitamins containing folic acid or dietary folic first trimester folic acid.
acid had a lower risk of occurrence NTDs than women
not taking supplements.10–14 Folic Acid Food Fortification and
Oral Supplementation
In Canada, since 1998, in an effort to reduce the rate of
ABBREVIATIONS NTDs, there has been mandatory folic acid fortification
aOR adjusted odds ratio
of white flour, enriched pasta, and cornmeal. Food
BMI body mass index
fortification coincided with an observed decrease in
NTDs in live-born infants,1,6,16 but a proportion of the
CI confidence interval
documented NTD decrease may also be related to an
GI gastrointestinal
increased use of prenatal tests and subsequent pregnancy
MTHFR 5,10-methylenetetrahydrofolate reductase
termination (secondary prevention) rather than to
NTD neural tube defect
fortification alone.45,46 It is possible that certain prevalence
OR odds ratio data populations may not have included termination of
RBC red blood cell pregnancy prior to the 20 weeks’ gestation information
RCT randomized controlled trial in their reported rate.
Sherwood et al. assessed the dietary folate intake of vitamin supplementation,78–80 as well as to an increase of
pregnant and lactating women at the presently mandated prenatal diagnosis/termination.45,46
and predicted folic acid fortification levels to determine
the prevalence of inadequate and excessive intakes. The Recurrence risks may reflect the genetic contribution in
conclusion was, at the present mandated levels of food different regional or population incidence and folic acid
fortification, many pregnant and lactating women are still NTD sensitivity (Table 2), as there is still an estimated
unlikely to meet their appropriate folate requirements 1% recurrence rate even with the 4 to 5 mg folic acid
from dietary sources alone, however the actual level of prophylaxis supplementation approach.1,6,7,81–91
inadequacy cannot be determined until the level of folic Table 2 summarizes the increasing NTD clinical risk groups,
acid in the food supply is known with greater precision.50 based on the family relationship of the affected individual
RBC folate testing/screening for the prevention of birth to the “at-risk” fetus and the specific NTD population
defects in certain co-existing maternal health conditions background risk (based on ethnic/genetic population
requires more investigation to determine the actual demographics). The Canadian population risk varies across
effectiveness and use of this testing. the country, with the highest NTD risk in Newfoundland
and the lowest NTD risk in British Columbia.77
Factors that may affect the ability to achieve
Table 3 summarizes the evidence-based risk factors for low
adequate maternal folic acid tissue levels
maternal RBC or serum folate status that are associated
Optimization of oral maternal folic acid supplementation
specifically with neural tube defects.15,19-22,41,77–79,81,82,92–106
is difficult because it relies on folic acid dose, type of
folate supplement, bio-availability of the folate from Table 4 summarizes the commonly used medications/
foods, timing of supplementation initiation, maternal drugs prescribed for certain medical therapies that have
metabolism/genetic factors, and many other factors.71–76 been shown to have interactions with folate metabolism
and may alter RBC folate levels with a resulting increased
Recommendations
risk for congenital anomaly outcomes.100–103
1. Women should be advised to maintain a healthy
folate-rich diet; however, folic acid/multivitamin Table 5 summarizes the studies with case–control, cohort, or
supplementation is needed to achieve the red blood RCT comparisons (odds ratio) and decreased, increased, or
cell folate levels associated with maximal protection no effects on specific congenital anomalies.15,30,37,38,40,53 Folic
against neural tube defect. (III-A) acid in combination with multivitamin supplements has been
2. All women in the reproductive age group shown to reduce certain other congenital anomalies such as
(12–45 years of age) who have preserved fertility heart defects,15,26–30 urinary tract anomalies,15,28,31 oral facial
(a pregnancy is possible) should be advised clefts,15,32–40 and limb defects.15At present, multifactorial
about the benefits of folic acid in a multivitamin inheritance (genetic and environmental factors)79,107,108 is
supplementation during medical wellness the most commonly reported etiology for NTDs, but
visits (birth control renewal, Pap testing, yearly monogenic, chromosomal, and teratogenic etiologies have
gynaecological examination) whether or not a specific effects and have not been well studied in their
pregnancy is contemplated. Because so many association with folic acid deprivation or supplementation.109
pregnancies are unplanned this applies to all women
who may become pregnant. (III-A) The risk categories for fetal NTD outcome should consider
the 2 major effect pathways:
1. Genetic factors including gene polymorphisms that
FOLIC ACID FOR CONGENITAL ANOMALIES
PREVENTION AND EVALUATION
affect the efficiency of folate metabolism, gene
mutations, affects related to DNA methylation/
Background for NTD Prevention epigenetics, and associated chromosomal anomalies, and
Neural tube defects are severe congenital anomalies that 2. Environmental factors such as dietary folate intake
occur due to a lack of neural tube closure at either the (food fortification and/or dietary supplementation),
upper, middle, or lower portion of the spine in the third gastrointestinal absorption efficiency, teratogenic
to fourth week after conception (day 26 to day 28 post-
medication exposure (epilepsy or folate antagonist
conception).77
medications), glucose metabolism (obesity, diabetes
In Canada, the prevalence of NTDs in newborns has type I and II), drugs, smoking, alcohol, and
declined since 1998 due to food fortification and increased “proposed” folate receptor auto-antibodies.
Table 2. Anencephaly and spina bifida approximate recurrence risk with no food
folic acid fortification or folate supplementation
Recurrence risk, % based on population NTD incidence
Population Population Population
Relationship of NTD affected incidence incidence incidence
individual to the at-risk fetus 5 per 1000 2 per 1000 1 per 1000
One sibling 5 2 2
Two siblings 12 10 10
One parent 4 4 4
One second-degree relative 2 1 1
One third degree relative 1 0.75 0.5
Adapted from Firth HV, Hurst JA, Hall JG. Oxford desk reference. Clinical genetics. Oxford: Oxford University
Press; 2006.77
NTD: neural tube defect
Table 3. Identified increased risk factors for fetal NTD or low maternal RBC
folate status
Personal/family history NTD: maternal or paternal affected, previous affected fetus for
or ethnic risk1–5,19–22 either parent, child, sibling, or second /third degree relative
MTHFR genotype 677TT carrier homozygous
677CST carrier heterozygous
Medical/surgical GI: malabsorption/inflammatory bowel, Crohn’s, active Celiac
condition41,77–79,100–103 disease, gastric bypass surgery, advanced liver disease
Renal: kidney dialysis
Pre-gestational diabetes (type I or II)
Anti-epilepsy or folate-inhibiting medications (see Table 4)
Maternal Maternal obesity: BMI > 30 kg/m2 or 80 kg
co-morbidities81,92–97 (pre-pregnancy weight)
Maternal lifestyle Smoking
factors82,98,99,190–192
Alcohol overuse
Non-prescription drug use/abuse
Low socio-economic status
Poor/restricted diet
NTD: neural tube defect; RBC: red blood cell; MTHFR: methylenete trahydrofolate reductase; GI: gastrointestinal
Details for the genetic and environmental factors/ from oral folic acid intake due to vitamin supplements
considerations with fetal and pediatric outcomes are and/or fortified foods is low. Folic acid is a water soluble
available in the references.19–22,110–149 vitamin, so any excess intake is anticipated to be excreted
in the urine.
POTENTIAL CAUTION FOR MATERNAL, FETAL,
CHILDHOOD, OR GENERAL POPULATION WITH Folic acid has not been shown to promote or to prevent
FOLIC ACID SUPPLEMENTATION breast cancer.153–155
Evidence has been reported for a decreased pre- Risks and Cautions
valence of preeclampsia with maternal folic acid Folic acid and multivitamin supplementation is possibly
supplementation.143,157–160 associated with an increased incidence of twins, although
positive and negative twinning findings have been reported
An Australian study found that high serum folate did with the possible confounders of in vitro fertilization and
not mask the macrocytosis of cobalamin (vitamin B12) ovarian stimulation or other environmental hormones. A
deficiency of pernicious anemia.161 clear relationship between folic acid supplementation and
twinning has not been confirmed.60,181–183
A Cochrane Review found no conclusive evidence of benefit
of folic acid supplementation on pregnancy outcomes A slightly increased risk of wheeze and respiratory infection
(preterm birth, stillbirths, neonatal deaths, low birth weight was found in the offspring whose mothers took folic acid
babies, pre-delivery anemia, or low pre-delivery red cell supplements during pregnancy.184 It was suggested that methyl
folate).162 donors in the maternal diet during pregnancy may influence
respiratory health in children consistent with epigenetic
Risks and Cautions
mechanisms. Zetstra-van der Woude et al. reported maternal
Folic acid dosing above the recommended supplement- high-dose folic acid (5 mg) was associated with an increased
ation amounts (supra-physiologic doses) has not been rate of asthma medication among children (recurrent asthma
shown to have any added fetal/maternal health or medication IRR [incidence rate ratio] = 1.14, 1.04 to 1.30 and
developmental benefits, although recent epigenetic/ recurrent inhaled corticosteroids IRR = 1.26, 1.07 to 1.47).
methylation studies in animals and humans have In the cohort of 39 602 pregnancies, 2.9% were exposed
indicated that some caution and research is required. to high-dose folic acid.185 Associations were clustered on
The folic acid doses of 5 mg have not been reported the mother and adjusted for maternal age, maternal asthma
to have maternal or fetal risks, but long-term high-dose medication, and dispensing of benzodiazepines during
5 mg folic acid use has not been well studied in a prenatal pregnancy.186 Veeranki et al. used a retrospective cohort of
population.3,10–14,35,36, 54,55,163 167 333 mother–infant pairs to compare no prenatal folic
acid exposure with first trimester only folic acid exposure and
Recent summary conclusions from colorectal cancer
reported higher relative odds of bronchiolitis diagnosis (aOR
reviews of the topic are still cautionary.164–177 Two studies
1.17, 1.11 to 1.22) and greater severity (aOR 1.16, 1.11 to
show no association of folic acid with colorectal adenoma
1.22). The effect was not significant in the other 2 exposed
or recurrence.178,179
groups of “after the first trimester” or “both first trimester
and after the first trimester”.186
FETAL AND PEDIATRIC ISSUES
Magdelijns et al.187 and Crider188 et al. did not confirm any
Benefit meaningful association between folic acid supplementation
Pediatric ongoing health benefits have been identified during pregnancy with atopic diseases in the offspring.
following prenatal multivitamin supplementation before and
in early pregnancy.40,128 Maternal use of prenatal multivitamins More population studies are required to understand
is associated with a decreased risk for pediatric brain tumours whether there is an exposure and an effect risk for
(OR 0.73, 95% CI 0.60 to 0.88),40,146,180 neuroblastoma (OR pediatric outcomes, but for now some caution in favour
0.53, 95% CI 0.42 to 0.68),40 leukemia (OR 0.61, 95% CI 0.50 of using the lowest effective folic acid supplementation
to 0.74),40,147 Wilms’ tumour,142 primitive neuroectodermal dose is required.
tumours,145 and ependymomas.145 It was stated that it is Recommendations
not known which constituent(s) among the multivitamins
3. Folic acid supplementation is unlikely to mask
confers this protective effect.
vitamin B12 deficiency (pernicious anemia).
A study looking at maternal use of folic acid supplementation Investigations (examination or laboratory) are not
and the diagnosis of childhood autism found that folic required prior to initiating folic acid supplementation
acid supplementation around the time of conception was for women with a risk for primary or recurrent
associated with lower risk of autistic disorder in a Norwegian neural tube or other folic acid-sensitive congenital
cohort. The adjusted OR for autistic disorder in children anomalies who are considering a pregnancy. It
of folic acid users was 0.61 (95% CI 0.41 to 0.90). These is recommended that folic acid be taken in a
findings cannot establish causality but they do support the multivitamin including 2.6 ug/day of vitamin B12 to
use of prenatal folic acid supplementation.148,149 mitigate even theoretical concerns. (II-2A)
4. Women at HIGH RISK, for whom a folic acid dose case–control evaluation and expert opinion extrapolation.
greater than 1 mg is indicated, taking a multivitamin Alternate opinions regarding oral supplemental dosing
tablet containing folic acid, should be advised to have been published by Motherisk.192
follow the product label and not to take more Other long-term uses for folic acid in the other clinical use
than 1 daily dose of the multivitamin supplement. context (alcoholics, anemia, liver disease, kidney disease,
Additional tablets containing only folic acid should malabsorption, cardiac disease, cancer treatment, regular
be taken to achieve the desired dose. (II-2A) multivitamin wellness use) are not considered or discussed
in this guideline.
COUNSELLING AND FOLIC
ACID SUPPLEMENTATION Summary Statement
In Canada multivitamin tablets with folic acid are
Canadian data indicates clear socio-demographic differences usually available in 3 formats: regular over-the-
among women with respect to their knowledge and use of counter multivitamins with 0.4 to 0.6 mg folic acid,
folic acid. Although most women understood the benefits prenatal over-the-counter multivitamins with 1.0 mg
of folic acid supplementation, greater than 33% did not folic acid, and prescription multivitamins with 5.0 mg
take folic acid supplements prior to becoming pregnant folic acid. (III)
and less than 50% supplemented according to national
guidelines. Targeted education and other interventions to The 3 clinically at-risk groups that will benefit from folic
improve folic acid use in younger women and women with acid supplementation are derived from evidence-based
lower socio-economic status is recommended.189 review and expert opinion, and are based on the folic acid-
sensitive risk of teratogenic or genetic congenital anomaly,
Han et al. reported that certain groups of women (from or the estimated risk of maternal folic acid deficiency. The
the Caribbean, Latin America, North Africa, Middle supplemental folic acid requirements for the best benefit-
East, China, and South Pacific) who are immigrants to to-risk outcome have used the published Canadian female
Canada take fewer folic acid supplements than Canadian- population (post fortification) RBC folate values.
born women. This immigrant group may benefit from
enhanced or directed pre-conception education and It is important to emphasize that all 3 risk recommendations
counselling.66 for the clinically “at-risk” groups have pregnant women
returning to or continuing the oral low dose 1.0 mg folic
Folic acid supplementation and the NTD risk stratified acid multivitamin supplementation at 12 weeks’ gestational
for maternal BMI requires more consideration. A recent age and continuing to minimize any unknown or potential
Chinese cohort study reported the association between risk for folic acid supplementation and the exposed mother
folic acid supplementation and the reduced NTDs risk was or fetus/newborn.
weaker in overweight/obese mothers (overweight/obese
was defined as BMI ≥ 24.0 kg/m2) than in underweight/ LOW risk group: Women or their male partners with no
normal mothers (BMI < 24.0 kg/m2).190 personal or family history of health risks for folic acid-
sensitive birth defects.
Oral supplementation success may be variable because
of compliance issues with daily oral tablet use (nausea, MODERATE risk group: Women with the following
“forgot,” “don’t like to take pills”) but as a result of food personal or co-morbidity scenarios (1 to 5) or their male
fortification with folic acid, Canada has almost eliminated partner with a personal scenario (1 and 2):
folate deficiency.191 The best predictor of prenatal 1. Personal positive or family history of other folate
multivitamin adherence in pregnant women is related to sensitive congenital anomalies (limited to specific
the women’s previous experiences with multivitamin use. anomalies for cardiac, limb, cleft palate, urinary tract,
The most important factors inhibiting prenatal vitamin congenital hydrocephaly)
use are fear or the experience of nausea, vomiting, and 2. Family history of NTD in a first or second-degree
gagging. For women who took the supplemental vitamins, relative
the most important factors were the dosing regimen, health
care provider advice, and the mode of product distribution 3. Maternal diabetes (type I or II) with secondary fetal
(prescription, over-the-counter, covered by insurance).191 teratogenic risk. Measurement of red blood cell
folate levels could be part of the pre-conception
The limited RCT data for folic acid supplementation in evaluation to determine the multivitamin and folic acid
certain clinical scenarios requires the use of cohort and supplementation dose strategy (1.0 mg with RBC folate
< 906 and 0.4 to 0.6 mg with RBC folate > 906) with a consist of a multivitamin with 0.4 to 1.0 mg folic
multivitamin) acid. (I-A). The same dietary and supplementation
4. Teratogenic medications with secondary fetal regime should be followed if either partner has had a
teratogenic effects by folate inhibition via previous pregnancy with a neural tube defect. (II-2A)
anticonvulsant medications (carbamazepine, valproic
To achieve a dose of 4.0 mg/day folic acid, women should
acid, phenytoin, primidone, phenobarbital), metformin,
methotrexate, sulfasalazine, triamterene, trimethoprim consume a multivitamin containing 1.0 mg folic acid and
(as in cotrimoxazole), and cholestyramine add 3 single 1.0 mg folic acid tablets. (See the appendix for
a summary of the risk statuses, risk groups, and appropriate
5. Maternal GI malabsorption conditions secondary to folic acid dosing.)
co-existing medical or surgical conditions that have
been shown to result in decreased RBC folate levels Recognizing the challenge some clinical offices might face
(Crohn’s or active Celiac disease, gastric bypass surgery, implementing the above recommendations based on the
advanced liver disease, kidney dialysis, alcohol overuse) mode of product distribution (prescription, over-the-
counter, covered by insurance) and compliance issues with
INCREASED/HIGH risk group: Women or their male taking daily multiple oral tablets,188 the following simplified
partners with a personal NTD history or a previous neural regimen could be considered. However, it is important to
tube defect pregnancy keep in mind that the folic acid intake should be at the
Recommendations lowest effective and safest dose.
5. Women with a LOW RISK for a neural tube Low or moderate risk group: a diet of folate-rich foods
defect or other folic acid-sensitive congenital in addition to pre-conception and first trimester folic acid
anomaly and a male partner with low risk require supplementation with an over-the-counter daily prenatal
a diet of folate-rich foods and a daily oral multivitamin containing 1.0 mg of folic acid.
multivitamin supplement containing 0.4 mg
folic acid for at least 2 to 3 months before Increased/high risk group: a diet of folate-rich foods in
conception, throughout the pregnancy, and for 4 addition to preconception and first trimester folic acid
to 6 weeks postpartum or as long as breast-feeding supplementation with a prescription daily multivitamin
continues. (II-2A) containing 5.0 mg of folic acid.
6. Women with a MODERATE RISK for a neural
tube defect or other folic acid-sensitive congenital See the Figure for a detailed decision tree.
anomaly or a male partner with moderate risk
require a diet of folate-rich foods and daily oral SUMMARY
supplementation with a multivitamin containing
1.0 mg folic acid, beginning at least 3 months Folic acid (in the diet and/or as a prenatal oral
before conception. Women should continue this supplement) with a multivitamin/micronutrient has
regime until 12 weeks’ gestational age. (1-A) From been shown to decrease or minimize specific congenital
12 weeks’ gestational age, continuing through the anomalies including neural tube defects with associated
pregnancy, and for 4 to 6 weeks postpartum or as hydrocephalus, oral facial clefts with or without cleft palate,
long as breast-feeding continues, continued daily congenital heart disease, urinary tract anomalies, and limb
supplementation should consist of a multivitamin defects, as well as some pediatric cancers. The 1998 public
with 0.4 to 1.0 mg folic acid. (II-2A) health initiative for fortification of flour has been very
7. Women with an increased or HIGH RISK for a beneficial with respect to primary prevention of certain
neural tube defect, a male partner with a personal folic acid-sensitive birth defects. The comprehensive
history of neural tube defect, or history of a Canadian analysis of neural tube reduction after folic
previous neural tube defect pregnancy in either acid flour fortification has reported a 46% reduction. The
partner require a diet of folate-rich foods and a daily observed reduction was greater for spina bifida (53%) than
oral supplement with 4.0 mg folic acid for at least for anencephaly (38%) and encephalocele (31%). Further
3 months before conception and until 12 weeks’ reductions in the incidence of other congenital anomalies
gestational age. From 12 weeks’ gestational age, sensitive to folic acid and multivitamins should be possible
continuing throughout the pregnancy, and for 4 to with the participation of key stakeholders. Public health
6 weeks postpartum or as long as breast-feeding surveillance strategies should be implemented to look for
continues, continued daily supplementation should any adverse health outcomes (maternal; pediatric) that
If pregnancy does not occur after 6 to 8 months, change to 0 .4 mg/day* for 6 months; if
pregnancy is not achieved in the following 6 months, consider referral to fertility services
and RBC folate testing to ensure level >900 nmol/L .
BOX 1 BOX 2
Congenital anomalies which may be sensitive Practical list of folate-inhibiting medications:
to folate (see text for anomaly detail):
– Anticonvulsant medications: phenytoin, primidone, phenobarbital,
– Oral facial cleft (and palate) carbamazepine, valproic acid
– Certain cardiac defects – Metformin
– Certain urinary tract anomalies – Methotrexate (a medication that is highly teratogenic to the fetus).
– Limb reduction defects – Sulfasalazine
– Triamterene
– Trimethoprim (as found in cotrimoxazole)
*Folic acid should be taken in the form of a multivitamin containing vitamin B12. Women should not take more than one
multivitamin supplement each day. In large doses, some substances in multivitamins could be harmful.
†Does NOT include spina bifida occulta as this is not a risk for NTD.
‡There are additional folate sensitive congenital anomalies that would benefit from the folic acid levels described.
§To provide a dose of 4 mg/day folic acid, a multivitamin containing 1 mg folic acid should be consumed, with single folic acid
tablets added to achieve the desired folic acid dose.
‖Peri-conceptional glycemic control is strongly recommended to reduce the risk of a congenital anomaly in the offspring of a
woman with pre-pregnancy diabetes.
¶Folic acid intake should be at the safest and lowest effective dose; however, clinical offices that face challenges implementing
recommendations for 4 mg folic acid daily because of the mode of product distribution or compliance issues with taking daily
multiple oral tablets may consider the simplified regimen of one 5 mg folic acid multivitamin tablet daily.
NTD: neural tube defect; GI: gastrointestinal
could possibly be related to folic acid food fortification and 17. Lopez-Camelo JS, Orioli IM, Dutra MDG, Nazer-Herrera J, Rivera N,
Ojeda ME, et al. Reduction of birth prevalence rates of neural
additional folic acid supplementation recommendations. tube defects after folic acid fortification in Chile. Am J Med Genet
2005;135A:120–5.
ACKNOWLEDGEMENTS 18. Boulet SL, Yang Q, Mai C, Kirby RS, Collins JS, Robbins JM, et al. Trends
in the postfortification prevalence of spina bifida and anencephaly in the
Expert opinion and guideline review were obtained from United States. Birth Defects Res A Clin Mol Teratol 2008;82:517–32.
the Public Health Agency of Canada and Motherisk. 19. Greene NDE, Stanier P, Copp AJ. Genetics of human neural tube defects.
Hum Mol Genet 2009;17:R113-R129.
20. Shaw GM, Lu W, Zhu H, Yang W, Briggs FSB, Carmichael SL, et al.
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APPENDIX
FOLIC ACID SUPPLEMENTATION
Diabetes type I or II
Teratogenic medications by folate
inhibition
GI malabsorption that decreases
RBC folate
High Personal NTD history. Personal NTD history. Multivitamin including 1.0 mg folic acid plus
Previous NTD pregnancy Previous NTD pregnancy 3 × 1.0 mg folic acid (for total of 4.0 mg) OR
prescription multivitamin including 5.0 mg folic
acid* at least 3 months before conception
until 12 weeks’ gestation, then a multivitamin
including 0.4 to 1.0 mg folic acid for remainder
of pregnancy and 6 weeks postpartum or to
completion of lactation
*It is important to keep in mind that folic acid intake should be at the safest and lowest effective dose (4 mg/daily). However, clinical offices that face a challenge
in implementing the recommended dose because of the mode of product distribution (prescription vs. over-the-counter, covered by insurance or not) and
compliance issues with taking multiple oral tablets daily could consider the simplified regimen of the 5.0 mg folic acid prescription multivitamin.
NTD: neural tube defect; GI: gastrointestinal; RBC: red blood cell
This document reflects emerging clinical and scientific advances on the date issued and is subject to change. The information
should not be construed as dictating an exclusive course of treatment or procedure to be followed. Local institutions can dictate
amendments to these opinions. They should be well documented if modified at the local level. None of these contents may be
reproduced in any form without prior written permission of the SOGC.
Table 1. Key to evidence statements and grading of recommendations, using the ranking of the Canadian Task Force
on Preventive Health Care
Quality of evidence assessment* Classification of recommendations†
I: Evidence obtained from at least one properly randomized A. There is good evidence to recommend the clinical preventive action
controlled trial
II-1: Evidence from well-designed controlled trials without B. There is fair evidence to recommend the clinical preventive action
randomization
II-2: Evidence from well-designed cohort (prospective or C. The existing evidence is conflicting and does not allow to make a
retrospective) or case–control studies, preferably from recommendation for or against use of the clinical preventive action;
more than one centre or research group however, other factors may influence decision-making
II-3: Evidence obtained from comparisons between times or D. There is fair evidence to recommend against the clinical preventive action
places with or without the intervention. Dramatic results in
uncontrolled experiments (such as the results of treatment with E. There is good evidence to recommend against the clinical preventive
penicillin in the 1940s) could also be included in this category action
III: Opinions of respected authorities, based on clinical experience, L. There is insufficient evidence (in quantity or quality) to make
descriptive studies, or reports of expert committees a recommendation; however, other factors may influence
decision-making
*The quality of evidence reported in these guidelines has been adapted from The Evaluation of Evidence criteria described in the Canadian Task Force on
Preventive Health Care.78
†Recommendations included in these guidelines have been adapted from the Classification of Recommendations criteria described in the Canadian Task Force
on Preventive Health Care.78
15. Health care professionals must be trained in standardized proce or premalignant cells. The establishment of cord blood
dures (ex utero and in utero techniques) for cord blood collection to
ensure the sterility and quality of the collected unit. (II-2A)
banks has allowed rapid access to well-characterized CBU
by transplant centres around the world, and to date, cord
16. Umbilical cord blood should be collected with the goal of
maximizing the content of hematopoietic progenitors through the blood has been used in over 30 000 transplants.2
volume collected. The decision to bank the unit will depend upon
specific measures of graft potency. (II-2A) Hematopoietic Stem Cell Transplantation
17. Umbilical cord blood collection must not adversely affect the Transplantation of blood-forming stem cells to
health of the mother or newborn. Cord blood collection should not regenerate the blood and immune system following
interfere with delayed cord clamping. (III-E) dose-intensive radiation treatment remains a potentially
18. Health care professionals should inform pregnant women and life-saving procedure for patients with malignant and
their partners of the benefits of delayed cord clamping and of its non-malignant blood and immune disorders such as
impact on cord blood collection and banking. (II-2A)
leukemia, lymphoma, aplastic anemia, and inherited
19. Cord blood units collected for public or private banking can be
used for biomedical research, provided consent is obtained,
metabolic diseases.3 Blood-forming progenitors can be
when units cannot be banked or when consent for banking is harvested from patients (autologous) or from healthy
withdrawn. (II-3B) HLA-compatible (allogeneic) donors who are related
10. Mothers may be approached to donate cells for biomedical research. or unrelated. Blood stem cells can be procured from
Informed consent for research using cord blood should ideally be bone marrow harvests, via apheresis of peripheral blood
obtained prior to the onset of active labour or elective Caesarean
section following established research ethics guidelines. (II-2A)
following cytokine stimulation or from umbilical cord
blood.4–6 Health care professionals should understand
that UCB contains blood-forming stem cells that can
INTRODUCTION be used in HSC transplantation and also contains other
progenitor cells that are involved in tissue repair and in
S ince the first umbilical cord blood transplant in 1988,
cord blood has been established as an alternative source
of HSC for bone marrow reconstitution.1 Cord blood
the modulation of immune responses.
blood donors. More than 23 million volunteer donors on The major disadvantage of cord blood transplantation
73 worldwide registries from 53 countries may be searched is the limited dose of stem cells available in CBUs. UCB
on a website facilitated by BMDW2 in accordance with volume limits the utility of cord blood transplantation
standards established by the WMDA,8 which permits the for larger recipients, including most adults, but it remains
identification of potential unrelated donors who are willing an issue even in pediatric transplantation. Despite being
to donate bone marrow or peripheral blood stem cells, highly enriched for HSCs, the limited volume that can be
including donors listed in the Canadian Blood Services One collected (100 to 200 mL) means the total dose of stem
Match Marrow and Stem Cell Network9 and the Stem Cell cells may contribute to delayed engraftment following
Donor Registry at Héma-Québec.10 The BMDW-affiliated transplantation and increased risk of bleeding or infection
registries include banked umbilical cord blood from more in recipients.14,15 Several strategies to augment the speed
than 611 000 donors from 48 public cord blood banks of engraftment following UCB transplantation have
in 33 countries, which expands the options even further, been investigated, including methods to expand to HSCs
especially for patients with more unusual HLA haplotypes.2 ex vivo before transplantation, co-transplantation of
mesenchymal stromal cells to accelerate homing and
Role of Umbilical Cord Blood
Umbilical cord blood is highly enriched for blood-forming engraftment, and double cord blood transplantation16,17
stem cells and offers some advantages in the setting of These strategies, however, will likely introduce significant
allogeneic transplantation. Cord blood inventories can additional costs, and their role in transplantation remains
be searched rapidly using sophisticated and coordinated under development.
global computerized search algorithms in accordance with The cost of CBUs poses another significant barrier to
guidelines established by the WMDA and units are readily more widespread use of cord blood as an alternative source
available from a network of accredited banks worldwide.8 of stem cells, especially with the high cost of obtaining
Another advantage of using cord blood is its greater
CBUs from international public banks. It may be possible
flexibility in HLA matching. Although fully matched
to acquire domestic CBUs at lower prices than typical
CBUs are associated with optimal outcomes in cord blood
international fees of US$25 000 to $40 000 per cord.18
transplantation,11,12 disparities in HLA between donor and
During an era of cost containment, banks and transplant
recipient are better tolerated than with unrelated donor
centres will need to address economic factors for banking
transplantation because HLA matching requirements are
establishments to remain viable and to allow transplant
less stringent and the risks of GVHD and graft failure are
centres to embrace greater utilization of cord blood.19,20
lower.13 Unrelated donor workups require confirmatory
HLA typing and other testing for transmissible diseases Indications for Use of Cord Blood from a
and the general health status of the donor, and there Family Member
may be logistical challenges that delay the collection of A recent analysis of data from the CIBMTR reviewed the
cells from unrelated donors; however, unrelated donors use of related allogeneic transplantation using umbilical
offer the prospect of future donor leukocyte infusions or cord blood stored in private family banks or through
additional cells for boosting the graft function, which is a directed donation program with a public bank. This
not possible with CBUs. approach may be useful when bone marrow or peripheral
blood stem cells cannot be collected readily from a
sibling, such as when siblings are infants. A total of 244
patients from 73 centres were reported to the CIBMTR
ABBREVIATIONS between 2000 and 2012. Transplants were performed most
AABB American Association of Blood Banks
commonly for acute leukemia (37%), thalassemia or sickle
BMDW Bone Marrow Donors Worldwide cell disease (29%), Fanconi anemia (7%), and inherited red
CBU cord blood unit cell, immune, or metabolic disorders (18%). The Eurocord
CIBMTR Center for International Blood and Marrow Transplant registry has identified more than 500 patients transplanted
Research
with related cord blood from 1988 to 2010.21 Most recipients
FACT Foundation for the Accreditation of Cellular Therapy
were children, and all but 29 were HLA-matched. Patients
GVHD graft-versus-host disease
and their families who travel abroad to undergo related
HLA human leukocyte antigen cord blood transplantation may be exposed to increased
HSC hematopoietic stem cell risks of complications that may jeopardize their safety
UCB umbilical cord blood and also be associated with significant personal expense.22
WMDA World Marrow Donor Association The regulatory oversight concerning transplantation is
dramatically different from Canada in some jurisdictions therefore, should include a careful assessment of how
and for the safety of patients this form of medical tourism well the bank can address issues such as ethnic diversity
is highly discouraged. within the population of expectant mothers and issues that
may impact access to mothers and the collection of large
Recommendation
volume CBUs.
1. Health care professionals should be well-informed
about cord blood collection and storage and about The goal of public cord blood banks is to create an
factors that influence volume, quality, and ability to inventory of assessable CBUs suitable for hematopoietic
collect a cord blood unit. (III-A) stem cell transplantation. Public banks set very strict
criteria for collection volume and total nucleated cell
PUBLIC CORD BLOOD BANKING doses to create an inventory of high quality units that
will be associated with more rapid engraftment and with
Public cord blood banks are sponsored and funded nationally acceptable rates of transplant-related complications. As a
or locally to process and store donated umbilical CBUs. The consequence, a significant number of CBUs donated to
donated CBUs are HLA-typed and entered into a national public banks are discarded or donated to research.
or international registry that allows them to be searched, in
a manner similar to bone marrow registries, by transplant Public cord blood banks are designed to serve the needs
centres around the world in need of a donor. A CBU stored of patients and cannot reasonably accommodate every
in a public bank is made available to any patient in need of a mother’s desire to donate cells. The practices of banking
transplant for which it is a suitable match and is not reserved establishments and partner hospitals must adhere to the
for the donating family. With public banks, there is no regulations outlined by Health Canada,23 and this imposes a
guarantee that donors or their family members will necessarily level of standardization and reliance on protocols for health
have access to their specific donor unit in the future. care professionals that often exceeds normal health care
practices. Managing the impact of public cord blood banking
Public banks do not directly charge the family for the on the perinatal routines and practices of the health care
processing and storage of the donated CBU, but a CBU team and mothers is an important consideration. Mothers
obtained from a public bank outside of Canada can be need to learn about public cord blood banking options well
extremely costly.18 The high cost of obtaining international before delivery and should ideally provide permission to
CBUs has been the subject of much discussion, and prices collect before the onset of active labour or early in labour
for these units are beginning to decline. The cost of while consent can reasonably be given. Working closely with
establishing and running a national public bank, however, health care professionals in the community, many public
is formidable and is borne by the general public. It may banking establishments obtain consent to collect first and
be possible to recover some costs of the public banking
then determine whether the unit is bankable based on
efforts through fees to international transplant centres,
the volume and total nucleated cell count at the time of
but reciprocity in reducing costs would allow transplant
collection. These parameters are meant to identify units with
centres greater access to CBUs.
the greatest utility in the setting of transplantation. More
Considerations Regarding Public Banking than 80% of units selected for transplantation from the
Both public and family cord blood banking establishments in inventory of cord blood banks contain more than 1.2 × 109
Canada must meet Health Canada regulatory requirements nucleated cells,18 and more established banks replenish their
for cells, tissues, and organs.23 These regulations include inventories exclusively with units of more than 1.5 × 109
all aspects of recruitment, collection, transportation, cells. If a collected unit meets initial screening criteria for
storage, testing, and documentation, and ultimately, the eligibility, a more complete acquisition of maternal history,
release of the units to transplant centres. Moreover, public clinical findings, and lab testing for transmissible infectious
banks should seek accreditation from international bodies diseases is performed. This 2-stage approach focuses time
such as AABB24 and FACT25 to remain relevant on the and resources on the units with the greatest likelihood of
international stage. This is essential to their economic being requested by transplant centres. The extensive time
viability and the assurance of optimal quality and safety and resources required to administer the maternal health
of the products. Public cord blood banking is ideally questionnaire and arrange for the testing of infectious
suited to addressing the needs of patients from ethnic disease markers necessitates the involvement of personnel
minorities and patients with uncommon HLA haplotypes dedicated to the banking effort. These personnel need to
who remain underrepresented on worldwide registries work cooperatively with health care professionals to ensure
of unrelated donors. The selection of partner hospitals, that banking efforts are fruitful and that the needs of the
mothers and babies are not compromised. When units are Indeed, early Eurocord studies in patients with leukemia
collected but do not meet the threshold for volume or total suggest that rates of GVHD following related cord blood
nucleated cell count needed for the unit to be banked, the transplants26 may be less than rates following unrelated cord
cord blood can be made available for biomedical research blood transplantation.27 Similarly, in non-malignant diseases
through programs such as the Cord Blood for Research treated by related or unrelated cord blood transplants,
Program at Canadian Blood Services. Public cord blood Bizzetto found that the risk of acute GVHD was lower with
banking is resource-intensive and banking facilities need related cord blood transplants compared to unrelated cord
to partner with birth units to meet the demands and blood and the 3-year survival rate was better.28
expectations of transplant centres and their patients. Public
banks and collecting hospitals should work collaboratively Since CBUs are already paid for and stored in private
to identify compatible donors from underrepresented ethic banks, there is no cost to the medical system when the
groups, particularly First Nations, Inuit, and Metis. units are used except for specific hospital costs. The cost
of obtaining public units, however, can be prohibitive,
although they may be discounted or waived for domestic
PRIVATE CORD BLOOD BANKING
use and continue to decrease as worldwide inventories
Private (also known as family) cord blood banks store increase.
processed umbilical CBUs for the private use of the family.
The goal of private cord blood banks is to cryopreserve
The family of the newborn child pays a fee to process and
quality CBUs that may be used for hematopoietic stem cell
store the CBU and the mother is typically named the legal
transplantation or future regenerative medicine therapies.
custodian of the banked CBU. Thus the banked CBU is
Thus private banks typically do not use the same banking
accessible only to the family who banked it and will be
criteria as public banks in terms of collection volume and
available to them if and when required. Some Canadian
total nucleated cell doses. Private banks appeal to families
private UCB banks also fund “medical needs” programs
whose intended recipient for a hematopoietic stem cell
whereby the cost to process and store the UCB is waived
transplant may be much smaller than the 60 kg recipient
for families whose expected child has a sibling in need of a
targeted by public banks. Several new technologies in
bone marrow transplant.
development are intended to either expand the number
Private banks charge the family for processing and storing of HSCs in a given CBU or improve the homing of the
the CBU for their exclusive use by the family The average HSCs to the bone marrow with the aim of improving the
cost in Canada is about $1200 for processing and first speed of engraftment. These developing technologies
year of cryopreservation. Subsequent yearly storage fees are not routinely available at this time. Success in these
generally run between $100 and $130. Alternative payment technologies, however, would allow “small” units banked
plans are often offered, including an 18-year single-cost today to be useful for larger recipients in the future.
plan in some cases. Eighteen years is a logical term for
such a plan, since the child from which the cord blood Regenerative medicine refers to the process of replacing
was collected will have reached the age of majority at the or repairing human cells, tissues or organs to return or
end of the term and can then decide whether or not to establish normal functioning. Cord blood stem cells are
continue to bank the CBU. presently being examined for use in regenerative medicine
or for treating non-blood diseases including type 1 diabetes,
Considerations Regarding Private Banking cardiovascular repair, traumatic brain injury, cerebral palsy,
Because of the inheritance of HLA, the chance of any autism, and hearing loss. Some of these trials are restricted
sibling being a full HLA match to another sibling is to patients having access to their own (autologous) cord
essentially 25%, and this chance increases with the number blood, whereas many of these research protocols have
of siblings. The use of HLA-matched related CBUs may reported the use of allogeneic CBUs.29 Therapeutic cell
reduce the risk of GVHD and improve transplant outcomes doses have yet to be established. Private cord blood banks
over the use of unrelated cord blood transplantation if the set their own acceptance criteria for banking CBUs, which
number of cells in the stored unit is sufficient and if tests results in a much higher percentage of their collected units
for transmissible disease are satisfactory. being banked than those of public banks.
Although GVHD occurs less commonly following HLA- A banked CBU from a person with no family history
matched marrow and peripheral blood stem cell transplant of disease treatable by bone marrow transplantation
in an era of high resolution HLA typing, studies of cord arguably has a very low chance of being used. The chance
blood transplants show a significant reduction in GVHD. that a person will contract a disease treatable by their
stored cord blood by age 21 has been estimated to be accreditation standards applicable for publicly banked
approximately 0.005% to 0.04%.17 A more recent analysis units, and the requirement for separate storage away from
of the likelihood of requiring a bone marrow transplant units that do not meet public banking criteria.8 In addition,
has taken into account treatable diseases up to the age of the safety of infusing autologous banked units has been
70 years, the upper limit for bone marrow or peripheral demonstrated in numerous settings although significant
blood stem cell transplants at some centres. This is a model differences in indicators of CBU quality were reported
more representative of the concept of family banking, in a recent study compared with publicly banked units.31
although it remains unclear how long autologous units can Increased collaboration between private and public banks
be stored with current cryopreservation methods. In that may help to improve the quality of all CBUs collected.
calculation, the probability of the need for hematopoietic
transplantation for a family member is about 1/400 and EDUCATION OF PARENTS AND
may be as high as 1/200.30 HEALTH CARE PROFESSIONALS
With future advances in medical technology such as gene Despite growing evidence of the therapeutic benefits
therapy, tissue therapeutics for treatment of non-blood of umbilical cord derived stem cells and promotion of
diseases, and ex vivo cell expansion, the probability of a umbilical cord blood collection for allogeneic, family-
banked CBU, especially an autologous CBU, may increase, directed, or autologous use in the media, surveys reveal
and this provides a compelling rationale for some families that the majority of pregnant women (70 to 80%) lack
to privately bank their children’s cord blood. On the other knowledge about stem cells and cord blood banking and
hand, improvement in medical treatment of serious disease want more information.32–36 While most women (80%
may make the need for stem cell transplantation less to 90%) would prefer to receive information about cord
necessary in the future and result in a reduced probability blood banking from their health care professionals,
of using a banked CBU. As a result, it is now impossible prenatal education and counselling is only provided to a
to predict the future value of family UCB banking. Private minority (15 to 30%).33,36,37 Consequently, many pregnant
cord blood banks must provide accurate and transparent women receive information through printed material, the
information regarding fees, likelihood of using the CBU, internet, or the media.36,37 Surveys from Canada, Europe,
methods of opting out and other costs to patients and and the United States suggest that once informed, the
families. majority of women would consider donating cord blood
for therapeutic use.32,36,37 Overall, women appear to be more
Recommendation
inclined to donate to public banks than to private or mixed
2. Health care professionals caring for women and banks.32,36,37 Approximately 80% of practicing obstetricians
families who choose private umbilical cord blood in the United States feel confident in discussing cord blood
banking must disclose any financial interests or options with their patients, but less than 50% indicate that
potential conflicts of interest. (III-B) they have sufficient knowledge of cord blood donation to
effectively answer patients’ questions about donation.38
COORDINATION OF PRIVATE AND PUBLIC BANKS
Not surprisingly, women are often misinformed and
CBUs that are stored in private banks cannot be searched confused about the risks and benefits of umbilical cord
by transplant centres for unrelated patients but may be blood donation and the advantages and limitations of
used for autologous hematopoietic transplantation or cord blood banking options. In evaluating their choices,
allogeneic transplantation for another family member. women may be motivated to donate their baby’s umbilical
Although uncommon at present, the use of autologous or cord blood to a public cord blood bank as an altruistic
related UCB transplantation may change in the future in act of civic responsibility or to a private bank for the
response to ongoing studies of novel applications in areas potential future benefit of their child or immediate
such as regenerative therapy. Guidelines and transparency family.39 Physicians and other health care professionals
with respect to fees, chances of using the unit, methods of are recognized as the primary source of information
opting out and other costs should be available to patients and guidance for pregnant women and should be well-
and families. Transferring banked units from private banks informed about the practical implications of umbilical
to public banks is challenging and guiding principles have cord blood collection and storage and the benefits and
been established by the WMDA that highlight issues such limitations of public and private cord banks. Health care
as the requirement for donor consent for public banking professionals in perinatal facilities should become actively
at the time of collection, the need to meet regulatory and involved in the provision of education about cord blood
banking and policies regarding cord blood collection and to the onset of active labour and ideally during the third
in the development of collection protocols to improve trimester of the prenatal period.50 A phased consent policy
cord blood volume and quality.33,40,41 Though storage of for cord blood donation has been proposed and endorsed
cord blood for autologous use remains controversial, by the American Academy of Pediatrics.51 In phase one,
therapeutic indications for umbilical cord blood stem cells information about cord blood banking including risks,
and the use of autologous and family-directed CBUs for benefits, advantages, and limitations is provided to parents
transplantation is growing.42–46 Information about cord as part of prenatal care. Donor registration with the cord
blood collection and banking provided by health care blood bank and perinatal institution is also recommended.
professionals must be balanced and accurate about its The second phase of the consent policy occurs when a
advantages and disadvantages.47 Prospective parents should woman is admitted to the birth unit for labour and delivery.
understand that infants with an underlying genetic disease Eligibility criteria for cord blood collection include the
are very unlikely to be transplanted with autologous cord absence of active labour, intact membranes, term singleton
blood that generally harbours the same gene abnormality pregnancy, no history of viral, congenital, or genetic diseases
and that many diseases may not be amenable to therapy and the ability of the mother to understand the implications
until new treatments are developed.42 Parents also should of cord blood collection.
be informed about maternal infectious disease and genetic The procedure for obtaining consent is limited to an
testing and the process for disclosure of abnormal findings. explanation of the need to collect blood immediately
Physicians and health care professionals should provide following delivery, a description of the collection
unbiased information about both public and private cord technique, and information about the possible risks of
blood banking and should encourage directed donation the procedure. The post-collection consent procedure
for immediate family members with specific treatable addresses maternal infectious and genetic disease testing,
diseases.48 Health care professionals are discouraged from access to health record information and newborn screening
endorsing specific cord blood banks and are obliged to tests, maternal medical history, cord blood processing and
disclose any financial or other conflicts of interest.42 storage, and the potential use of cord blood for therapeutic
and research purposes. The mother’s right to refuse
Obstetricians should be knowledgeable enough about the
collection, processing, or storage of the cord blood at any
present uses of umbilical cord blood to be able to have a
time without prejudice must be inherent in the consent
discussion with patients and answer most questions. It is
process. It is also important for parents to be assured that
important to be able to discuss the differences between information related to the infant donor and the donor’s
public and family banking and to know which options are family will remain confidential and maintained by the cord
available. blood bank so that parents or physicians can be notified of
Recommendation infectious or genetic diseases.49
3. Pregnant women should be provided with unbiased Consent policies and procedures vary widely across
information about umbilical cord blood banking regional and national jurisdictions, public and private cord
options, including the benefits and limitations of blood banks, and perinatal care facilities. Standardization
public and private banks. (III-A) of informed consent for umbilical cord blood
donation following AABB24 and FACT25 guidelines is
INFORMED CONSENT recommended. Institutional review and approval of cord
blood donation consent policies are also encouraged.49 If
Because newborn infants are unable to consent to the cord blood does not meet criteria for clinical use or when
collection, testing, donation, and storage of their cord blood, donors decide to terminate storage of a CBU, cord blood
informed consent must be obtained and documented from banks are encouraged to offer donors the opportunity
the mother or father. Cord blood collected for therapeutic to donate the cord blood to research, subject to donor
use or research is not considered waste material and it is consent.52
generally agreed that informed consent for collection is
required.49 Prenatal, pre-labour, and post-collection consent Recommendation
policies have been developed by cord blood banks and 4. Health care professionals should obtain consent
professional organizations to address the procedural and from mothers for the collection of umbilical cord
financial priorities of public and private blood banks,43,44 blood prior to the onset of active labour, ideally
and so could be obtained at presentation in early labour. It during the third trimester, with ample time to
is generally agreed that consent should be obtained prior address any questions. (III-A)
UMBILICAL CORD BLOOD COLLECTION infant on the maternal abdomen after delivery have also
been reported to improve recovery volume and CD34+
Umbilical cord blood is collected from the umbilical cell content;63,64 however, this early clamping defeats the
vein either before the placenta is delivered (in utero) or benefits of delayed clamping.
following placental delivery (ex utero). Both methods
have advantages and disadvantages.53 Both techniques are Ex utero cord blood collection is performed by
in use at Canadian public cord blood banks, although the dedicated, trained personnel in a separate room and
in utero technique is preferred by most public banks in standard collection bag as soon as possible after delivery
the United States and many European countries because it of the placenta. The cord blood is collected by gravity
can be performed in the delivery room by birth unit staff, with the placenta suspended on a specifically designed
is easy to learn, and does not usually require additional stand.54,65 Although this method allows birth unit staff
personnel or resources.53,54 All private banks use in to focus on maternal and infant health, the procedure
utero collection methods. Evidence from comparative requires additional trained personnel, resources, and
studies suggest that the in utero technique yields slightly cost but reduces the frequency of non-conformances
higher volumes of cord blood and higher yields of total associated with collection of units from staff that are not
nucleated cells compared to the ex utero technique.55–57 affiliated with the bank. Disadvantages of this method
are the possibility of lower cord blood volume and total
The standard in utero method for cord blood collection nucleated cell counts. As with in utero collection, factors
uses a closed collection system to reduce the risk of associated with increased collected volume using the ex
infection and maternal fetal fluid contamination. The utero technique include: singleton pregnancy, post-term
umbilical cord is double-clamped approximately 3 to pregnancy, induced labour, prolonged labour, CS, cord
5 cm from the umbilicus and transected between the length greater than 30 cm, birth weight ≥ 3500 g, and
clamps. After the infant has been removed from the field, placental weight > 700 g.48,54,66
the cord is prepared for venipuncture using a povidone
iodine applicator. The needle of the cord collection kit Umbilical cord collection poses a number of logistical
is then inserted into the umbilical vein and the CBU is issues that may increase the burden for busy birth units.
collected by gravity. The time required to perform the The consent procedure and associated paperwork adds
cord collection procedure is approximately 5 to 10 minutes time and inconvenience to the work of health care
and additional personnel are not required.54,58,59 Factors professionals. Collection procedures performed during
known to reduce cord blood volume include maternal the third stage of labour at a time when both mother
hypertension, smoking, multiple gestation, preterm and baby require attentive care and risk of postpartum
delivery, intrauterine growth restriction, abnormal hemorrhage must not jeopardize maternal newborn
placentation, emergency CS, precipitous delivery, and health. Birth unit personnel feel under pressure to obtain
maternal transfer.17,59 Factors associated with higher cord adequate volume of cord blood and to avoid bacterial
blood volumes and greater yield of nucleated cells include contamination. Attention to the cord blood collection
birth weight, placental weight, gestational age, induction may also impact on the care of other mothers and infants.
of labour, prolonged labour, CS, early cord clamping, Consequently, umbilical cord blood collection should
first born infants, Caucasian ethnicity, and female infant not interfere with the normal management of the third
gender.60 Umbilical cord blood obtained after CS for stage or compromise the safety of mother and baby.59,67
acute fetal distress also appears to significantly increase Contraindications to cord blood collection include
total nucleated cells, CD34+ cells, and white blood preterm birth, serious maternal medical or obstetric
cells without compromising cord volumes and should complications, such as cardiac arrest, stroke, eclampsia or
not preclude cord blood collection unless maternal and massive hemorrhage, and perinatal asphyxia.
newborn safety may be compromised.61,62
Regulatory Issues and Practice Standards for
A number of manoeuvres have been proposed to optimize Collecting and Processing Umbilical Cord Blood
cord blood volume. Using large syringes (50 to 60 cc) Cord blood banks must adhere to strict regulatory
and a syringe withdrawal-saline flush-syringe withdrawal requirements and focus on additional factors to ensure that
technique as part of the closed collection system have UCB units stored in the bank are of the highest quality
yielded significantly higher mean volume collected (150 and thus remain beneficial to transplant centres and their
to 175 mL), compared with standard in utero collection patients. Accreditation and compliance with nationally and
by gravity (75 to 100 mL). Clamping the umbilical cord internationally recognized regulatory bodies ensure that
within 30 seconds of delivery and placing the newborn all aspects of recruitment, donor screening, collection
and transport, processing, testing, freezing, storage, and Delayed cord clamping in term infants has been consistently
distribution are standardized and meet international shown to enhance placental transfusion at birth and increase
thresholds of quality. The use of current measures of hemoglobin, hematocrit, ferritin levels, and iron stored
graft potency is also critical so transplant centres and up to 6 months of age.70,73,74 Though prevailing evidence
patients have confidence regarding the assurance of timely also suggests that delayed cord clamping promotes higher
engraftment following transplantation. The collection and iron stores in the longer term,70 delayed cord clamping
storage of UCB must adhere to Health Canada regulations did not affect iron status or neurodevelopment at age 12
under the cells, tissues, and organs guidelines23 to ensure months in a recent randomized controlled trial of healthy
the quality of CBUs in terms of HSC content, absence of term-born infants in Sweden.75 Concerns have been raised
infectious agents, and risk of transmitting genetic disease. regarding the increased risk of phototherapy for postnatal
In addition, international guidelines are provided by FACT jaundice and polycythemia associated with delayed cord
and AABB. These shape operational issues related to cord clamping.74 WHO recommends a 1 to 3 minute delayed
blood banking in Canada and around the world through cord clamping in term infants, particularly in populations
the International NetCord Foundation). where iron deficiency anemia is endemic and provided
there is provision for screening and treatment of neonatal
Recommendations jaundice.76 SOGC recommends weighing the risk of
5. Health care professionals must be trained in neonatal jaundice against the physiological benefit of
standardized procedures (ex utero and in utero increased hemoglobin and iron levels,71 whereas ACOG
techniques) for cord blood collection to ensure the concludes that there is insufficient evidence to support or
sterility and quality of the collected unit. (II-2A) refute delayed cord clamping in term infants.72 Based on the
6. Umbilical cord blood should be collected with the available evidence, delayed cord clamping in health term
goal of maximizing the content of hematopoietic infants appears to be beneficial provided that treatment for
progenitors through the volume collected. The jaundice requiring phototherapy is available.70
decision to bank the unit will depend upon specific
measures of graft potency. (II-2A) Umbilical cord collection in preterm infants (< 37
7. Umbilical cord blood collection must not adversely weeks gestation) is generally contraindicated. Early cord
affect the health of the mother or newborn. Cord clamping within 30 seconds of delivery is associated
blood collection should not interfere with delayed with optimal volume and progenitor cells for cord
cord clamping. (III-A) blood collection while delayed cord clamping for 1 to 3
8. Health care professionals should inform pregnant minutes decreases the volume of cord blood available for
women and their partners of the benefits of collection. While cord blood collection following delayed
delayed cord clamping and of its impact on cord cord clamping is not contraindicated, parents should
blood collection and banking. (II-2A) be aware that the practice may preclude collection of
sufficient cord blood for banking.
Timing of Umbilical Cord Clamping
There is growing evidence of the benefit of delayed cord
RESEARCH AND POTENTIAL FUTURE
clamping for 1 to 3 minutes in preterm infants (< 37
USE OF UMBILICAL CORD BLOOD
weeks).68–71 Systematic reviews have demonstrated that
delayed cord clamping in preterm infants results in reduced There is increasing interest in the use of cord blood for
need for transfusions, better circulatory stability, improved novel indications in regenerative therapy or as a means
blood pressure and decreased risk of intraventricular of immune modulation. A recent systematic review
hemorrhage and necrotizing colitis.68,71 Recent evidence identified a small number of published studies involving
suggests that delayed cord clamping in very preterm and approximately 300 patients.29 The most common
very low birth infants protects against motor disability emerging area described in these studies addressed the
at 7 months of age.70 In light of the this evidence, repair of neurological conditions, including cerebral
several professional organizations have recommended palsy. A large study using umbilical cord blood in the
implementation of delayed cord clamping for preterm treatment of cerebral palsy is ongoing.77 Other diseases
infants despite health care professionals’ concerns about the that may be amenable to cord blood transplantation
need for immediate resuscitation and risk of hypothermia.72 include type I diabetes and liver disease. Some studies
Since umbilical cord banking is generally contraindicated in have investigated the use of mesenchymal stromal cells
preterm infants, delayed cord clamping in this population expanded from umbilical cord blood. It is not yet clear
should have no impact on cord blood banking. how effective cord blood-derived cells are in these novel
indications as most studies are uncontrolled and involve Public Cord Blood Collection in Canada as of 2015
few subjects and are proof-of-principle in nature only. The National Public Cord Blood Bank at Canadian
Moreover, strategies to culture cells from cord blood may Blood Services has been collecting and storing units since
complicate banking efforts and introduce new regulatory September 30, 2013, building on the recognized need for
challenges. It remains to be seen whether public banks a national effort in public cord blood banking in Canada.
will develop methods to screen for umbilical CBUs that The initial collection and manufacturing site is in Ottawa. A
are better suited to applications in regenerative therapy second manufacturing site and collection site in Edmonton
or immune modulation or whether increasing numbers became operational in July 2014, and additional collection
of public banks will develop methods to store HSCs sites in Vancouver and Brampton began contributing to the
or other cell types expanded from cord blood. UCB bank in January 2015. The bank intends to store more than
represents a rich source of progenitor cells with a broad 10 000 high quality units by 2018 and the units will have
range of biological functions and tremendous potential high cell content and engraftment potency, be searchable
for the development of novel cell-based therapies. internationally through the BMDW, and reflect the ethnic
diversity of Canada, including First Nations, Inuit, and
Recommendations Metis who have low UCB representation. Héma-Québec
9. Cord blood units collected for public or private has a public cord blood bank that is FACT-accredited and
banking can be used for biomedical research, provided has more than 9000 units stored since they first started
consent is obtained, when units cannot be banked or collecting in 2004. The units are searchable through the
when consent for banking is withdrawn. (II-3B) BMDW and they have supplied cord blood for more than
10. Mothers may be approached to donate cells for 100 Canadian and international patients. The collection
biomedical research. Informed consent for research hospitals are in Montreal and Laval. The Victoria Angel of
using cord blood should ideally be obtained prior Hope Registry is a third Canadian public cord blood bank
to the onset of active labour or elective Caesarean affiliated with the Cells for Life family bank in Toronto
section following established research ethics that continues to recruit expectant mothers. It has recently
guidelines. (II-2A) registered with BMDW and offers international searching
of its inventory of several hundred CBUs.
CORD BLOOD BANKING IN CANADA
SUMMARY
Current banking efforts reflect state of the art practices
which will make the Canadian contribution important. The National Public Cord Blood Bank was established
Public banking activity has occurred in some regions of by the Canadian Blood Services in 2013 and public cord
the country for several years (Alberta Cord Blood Bank, blood banking will be available in selected Canadian sites
Héma-Québec Cord Blood Bank, and the Victoria Angel focussed on the storage of a diverse ethnic cross-section
Registry of Hope), and the launch of the National Public of HLA-typed CBUs. Public cord blood banking at
Cord Blood Bank at Canadian Blood Services began in HémaQuebec and the Victoria Angel of Hope Registry
2013. The establishment of a public bank with the capacity continues to grow. Private cord blood banking facilities are
to store many high quality HLA-typed CBUs from a diverse located in major urban centres in Canada and provide the
cross-section of ethnicities should benefit both Canadian opportunity for family cord blood collection and storage
and international patients. Such a bank would increase the from coast to coast.
odds of finding a suitably matched CBU for patients in
need of a hematopoietic cell transplant who do not have a Health care professionals should be aware of current
matched sibling or unrelated donor. Recently, some public recommendations for education, counselling, obtaining
banks such as Héma-Québec have instituted a medical informed consent, collection, and storage of umbilical
needs program to store, for up to 2 years, a CBU from cord blood. Information regarding cord blood banking
a sibling of a child requiring a bone marrow transplant options in Canada should be presented in a comprehensive
for the express use of that family member in need of the and unbiased manner.
transplant. Private banks existed in Canada prior to public
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practices: recruitment, donation, and the timing of consent. Transfusion transfusion at preterm birth on maternal and infant outcomes. Cochrane
2013;53:679–87. Database Syst Rev 2012;8:CD003248.
51. Vawter DE, Rogers-Chrysler G, Clay M, Pittelko L, Therkelsen D, Kim D, 69. Mercer JS, Vohr BR, Erickson-Owens DA, Padbury JF, Oh W.
et al. A phased consent policy for cord blood donation. Transfusion Seven-month developmental outcomes of very low birth weight infants
2002;42:1268–74. enrolled in a randomized controlled trial of delayed versus immediate
cord clamping. J Perinatol 2010;30:11–6, 22.
52. Petrini C, Farisco M. Informed consent for cord blood donation.
A theoretical and empirical study. Blood Transfus 70. McDonald SJ, Middleton P, Dowswell T, Morris PS. Effect of timing
2011;9:292–300. of umbilical cord clamping of term infants on maternal and neonatal
outcomes. Cochrane Database Syst Rev 2013;7:CD004074.
53. Solves P, Moraga R, Saucedo E, Perales A, Soler MA, Larrea L, et al.
Comparison between two strategies for umbilical cord blood collection. 71. Garofalo M, Abenhaim HA. Early versus delayed cord clamping in term
Bone Marrow Transplant 2003;31:269–73. and preterm births: a review. J Obstet Gynaecol Can 2012;34:525–31.
72. American College of Obstetricians and Gynecologists, Committee on 76. World Health Organization. Optimal timing of cord clamping for
Obstetric Practice, Committee Opinion No. 543. Timing of umbilical the prevention of iron deficiency anaemia in infants. Geneva (CH):
cord clamping after birth. Obstet Gynecol 2012;12:1522–6. WHO; 2015. Available at: http://www.who.int/elena/titles/cord_
clamping/en. Accessed on May 27, 2015.
73. Grisaru D, Deutsch V, Pick M, Fait G, Lessing JB, Dollberg S, et al.
Placing the newborn on the maternal abdomen after delivery increases the 77. U.S. National Institutes of Health. ClinicalTrials.gov. NCT00593242,
volume and CD34 cell content in the umbilical cord blood collected: an old NCT01072370, NCT01147653, NCT01193660, NCT01506258,
maneuver with new applications. Am J Obstet Gynecol 1999;180:1240–3. NCT01528436, NCT01601158, NCT01649648. Bethesda (MD):
74. Hutton EK, Hassan ES. Late vs early clamping of the umbilical cord in U.S. National Library of Medicine; 2015. Available at:
full-term neonates: systematic review and meta-analysis of controlled http://www.clinicaltrials.gov. Accessed on May 27, 2015.
trials. JAMA 2007;297:1241–52.
78. Woolf SH, Battista RN, Angerson GM, Logan AG, Eel W.
75. Andersson O, Domellöf M, Andersson D, Hellström-Westas L. Effects of Canadian Task Force on Preventive Health Care. New grades for
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This document reflects emerging clinical and scientific advances on the date issued and is subject to change. The information
should not be construed as dictating an exclusive course of treatment or procedure to be followed. Local institutions can dictate
amendments to these opinions. They should be well documented if modified at the local level. None of these contents may be
reproduced in any form without prior written permission of the SOGC.
Table 1. Key to evidence statements and grading of recommendations, using the ranking of the Canadian Task Force
on Preventive Health Care
Quality of evidence assessment* Classification of recommendations†
I: Evidence obtained from at least one properly randomized A. There is good evidence to recommend the clinical preventive action
controlled trial
II-1: Evidence from well-designed controlled trials without B. There is fair evidence to recommend the clinical preventive action
randomization
II-2: Evidence from well-designed cohort (prospective or C. The existing evidence is conflicting and does not allow to make a
retrospective) or case–control studies, preferably from recommendation for or against use of the clinical preventive action;
more than one centre or research group however, other factors may influence decision-making
II-3: Evidence obtained from comparisons between times or D. There is fair evidence to recommend against the clinical preventive action
places with or without the intervention. Dramatic results in
uncontrolled experiments (such as the results of treatment with E. There is good evidence to recommend against the clinical preventive
penicillin in the 1940s) could also be included in this category action
III: Opinions of respected authorities, based on clinical experience, L. There is insufficient evidence (in quantity or quality) to make
descriptive studies, or reports of expert committees a recommendation; however, other factors may influence
decision-making
*The quality of evidence reported in here has been adapted from The Evaluation of Evidence criteria described in the Canadian Task Force on Preventive Health
Care.76
†Recommendations included in these guidelines have been adapted from the Classification of Recommendations criteria described in the Canadian Task Force
on Preventive Health Care.76
Recommendations
1. Following initial therapy, treatment success of recurrent
V ulvovaginal candidiasis is a very common condition
that affects up to 75% of women at least once in their
lifetime.1 Risk factors for VVC include sexual activity, recent
vulvovaginal candidiasis is enhanced by maintenance of weekly
oral fluconazole for up to 6 months. (II-2A) antibiotic use, pregnancy, and immunosuppression from such
2. Symptomatic vulvovaginal candidiasis treated with topical azoles conditions as poorly controlled HIV infection or diabetes.2,3
may require longer courses of therapy to be resolved. (1-A)
3. Test of cure following treatment of trichomoniasis with oral
The Organisms
metronidazole is not recommended. (I-D) VVC is most often caused by Candida albicans4; however,
4. Higher-dose therapy may be needed for treatment-resistant cases other species of Candida such as glabrata, parapsilosis, and
of trichomoniasis. (I-A) tropicalis are emerging.5
5. In pregnancy, treatment of symptomatic Trichomonas vaginalis
with oral metronidazole is warranted for the prevention of preterm The main reservoir for Candida is thought to be the
birth. (I-A) rectum, but vaginal colonization is also common. The
6. Bacterial vaginosis should be diagnosed using either clinical factors associated with evolution from colonization
(Amsel’s) or laboratory (Gram stain with objective scoring system) to symptomatic infection are multiple and involve a
criteria. (II-2A)
combination of host susceptibility, host inflammatory
7. Symptomatic bacterial vaginosis should be treated with oral
metronidazole 500 mg twice daily for 7 days. Alternatives
responses, and Candidal virulence factors. Symptoms are
include vaginal metronidazole gel and oral or vaginal clindamycin thought to be caused by an overabundance of yeast and its
cream. (I-A) penetration of vulvovaginal epithelial cells.6
8. Longer courses of therapy for bacterial vaginosis are
recommended for women with documented multiple The Disease
recurrences. (I-A) The signs and symptoms of uncomplicated VVC include a
thick cottage-cheese–like discharge associated with vaginal
ABBREVIATIONS
and vulvar pruritus, pain, burning, erythema, and/or
edema. External dysuria and dyspareunia may also occur.
HIV human immunodeficiency virus
NAAT nucleic acid amplification test Complicated VVC may be defined as that which is recurrent
PHAC Public Health Agency of Canada (4 or more episodes in a 12 month period), associated with
STI sexually transmitted infection severe symptoms, the result of a non-albicans species, or
VVC vulvovaginal candidiasis present in a compromised host.7 This condition is more
the organism.29 Although the organism may be detected on with either of these regimens are as high as 88%, and
Papanicolaou screening tests, this is not considered diagnostic are even higher when sexual partners are simultaneously
because of the test’s low sensitivity for T. vaginalis.30 treated.32 Approximately 5% of T. vaginalis strains will
be resistant to metronidazole. High dose and/or longer
Antigen testing
metronidazole therapy tends to be effective in these
Immunoassay dipstick testing is available as a rapid antigen
situations.33 An alternate therapy for metronidazole-
test with results available in 10 minutes. Sensitivity (82–95%)
treatment–resistant cases is Tinidazole 2 g orally once.34,35
and specificity (97–100%) are both high.29 NAATs are the
This is only available through Health Canada’s Special
most sensitive tests currently available for use with vaginal
Access to Drugs and Health Products Program.36
swabs. Urine and cervical swabs can also be used. Sensitivity
and specificity for NAATs are both 95% to 100%.31 Partner Treatment
The PHAC 2010 guidelines on STI do not recommend
Because T. vaginalis is an STI, its diagnosis affords the
opportunity to screen for other STIs. partner screening but do recommend treatment for all
partners.7 Many men will be asymptomatic. Both patients
Treatment and partners should be given the same type of treatment
Treatment for T. vaginalis consists of oral metronidazole regimen. The 2010 Centres for Disease Control STI
either 2 g once or 500 mg twice daily for 7 days. Cure rates Guidelines suggest abstaining from intercourse until both
patients are treated and asymptomatic.37 Test of cure is not microorganisms and accounting for greater than 95% of
recommended, but re-evaluation is suggested with symptom all bacteria present.41,42 Lactobacilli are believed to provide
recurrence. There is an increased risk of HIV acquisition defense against infection in part by maintaining an acidic
for both men and women with concomitant T. vaginalis pH in the vagina and ensuring hydrogen peroxide is present
infection, so it would be particularly important to screen and in the environment. In contrast, bacterial vaginosis is a
treat for this disease in HIV discordant couples.38 polymicrobial syndrome resulting in a decreased concentration
of lactobacilli and an increase in pathogenic bacteria. There
Pregnancy is no single organism whose presence confirms the diagnosis
T. vaginalis infection in pregnancy has been associated of bacterial vaginosis, but rather many different bacteria may
with preterm delivery. If the patient is symptomatic and be present, including Gardnerella vaginalis, Mobiluncus species,
testing reveals infection, treatment is warranted. Screening Bacteroides and Prevotella species, and Mycoplasma species.43,44
and treatment for asymptomatic infection in women with
a history of preterm birth or preterm premature rupture The Disease
of membranes is controversial. Some studies have shown Bacterial vaginosis is the most common lower genital
benefit and others have shown higher rates of preterm tract disorder among women of reproductive age, the
birth in the treated group.39 The use of metronidazole most common cause of vaginitis in both pregnant and
in pregnancy is considered safe; numerous meta-analyses non-pregnant women, and the most prevalent cause of
show no increased risk of teratogenic effects with vaginal discharge and odour.45,46 Prevalence rates are
metronidazole.40 The recommended dose of metronidazole similar in pregnant and non-pregnant women. It has
in pregnancy is the same as for non-pregnant women. been linked to many different obstetric and gynaecologic
complications such as preterm labour and delivery,
Side effects
preterm premature rupture of membranes, spontaneous
Side effects of metronidazole may include nausea, vomiting,
abortion, chorioamnionitis, postpartum endometritis,
headache, insomnia, dizziness, drowsiness, rash, dry
post-Caesarean delivery wound infections, postsurgical
mouth, and metallic taste. A disulfiram reaction can occur
infections, and subclinical pelvic inflammatory disease.47–55
if combined with alcohol. Avoidance of alcohol for at least
one day after completing the treatment is recommended in Several risk factors have been identified that increase the
the drug manufacturer’s product monograph. risk of acquisition of bacterial vaginosis. It is more common
Summary Statements in black women,56 women who smoke,57 and women who
use vaginal douches or intravaginal products. 58,59 Although
3. Trichomonas vaginalis is a common non-viral sexually
not currently considered an STI, bacterial vaginosis has
transmitted infection that is best detected by antigen
testing using vaginal swabs collected and evaluated by been consistently associated with sexual activity. It is more
immunoassay or nucleic acid amplification test. (II-2) common among women who are sexually active, and the
4. Cure rates are equal at up to 88% for trichomoniasis risk seems to increase with both number of sexual partners
treated with oral metronidazole 2 g once or 500 mg and frequency of intercourse.60,61
twice daily for 7 days. Partner treatment, even Diagnosis
without screening, enhances cure rates. (I-A) Bacterial vaginosis can be diagnosed clinically and/or
microbiologically. The clinical diagnostic criteria published
Recommendations in 1983 by Amsel et al., still in use today, recommend
3. Test of cure following treatment of trichomoniasis diagnosis of bacterial vaginosis if 3 of the 4 following
with oral metronidazole is not recommended. (I-D) signs are present62: adherent and homogenous vaginal
4. Higher-dose therapy may be needed for treatment- discharge; vaginal pH greater than 4.5; detection on saline
resistant cases of trichomoniasis. (I-A) wet mount of clue cells (vaginal epithelial cells with such
5. In pregnancy, treatment of symptomatic a heavy coating of bacteria that the peripheral borders
Trichomonas vaginalis with oral metronidazole is are obscured); and/or amine odour after the addition of
warranted for the prevention of preterm birth. (I-A) potassium hydroxide (positive whiff test).
BACTERIAL VAGINOSIS Gram stain of vaginal fluid is the most widely used and
evaluated microbiologic method for the diagnosis of
The Organism bacterial vaginosis. Most laboratories use an objective
Normal vaginal flora consists of both aerobic and anaerobic diagnostic scheme that quantifies the number of Lactobacillus
bacteria, with Lactobacillus species being the predominant morphotypes and pathogenic bacteria, resulting in a score
that is used to determine whether the infection is present. 3 months,69 and with more women recurring the longer
The most commonly used system was developed by the length of follow-up.70,71 Before embarking on multiple
Nugent and colleagues and is known as the Nugent score courses of therapy, it is recommended to reconfirm the
(Table 3).63 Bacterial vaginosis is diagnosed by a score of 7 diagnosis. In women with documented recurrences,
or higher. A score of 4 to 6 is considered intermediate and extending the course of therapy to continually suppress
a score of 0 to 3 is considered normal. the growth of abnormal bacteria has been shown to be
an effective strategy to decrease the likelihood of further
Treatment
recurrences. The first option is to use oral metronidazole
Although bacterial vaginosis has been associated with 500 mg twice daily for 10 to 14 days. If this is not effective,
adverse gynaecologic outcomes, there is no compelling
the recommended therapy is metronidazole vaginal gel
evidence that treatment decreases the likelihood of these
0.75% one applicator (5 g) daily for 10 days, then 2 times
complications. Therefore, treatment is usually reserved for
per week for 3 to 6 months.7,72 This regimen results in a
women with bothersome symptoms.
significant decrease in the likelihood of recurrences while
The treatments for bacterial vaginosis recommended in on treatment and thereafter compared to placebo.72 There
Canada in the PHAC’s guidelines on STI are presented in is also some evidence that condom use may decrease the
Table 4.7 The first line therapy is oral metronidazole 500 mg likelihood of recurrence among sexually active women.49
twice daily for 1 week. Reported cure rates following
Recently there has been increasing interest in exploring the
therapy have ranged from 75% to 85% and do not differ
use of probiotics and other agents for the treatment of
between oral and vaginal metrondiazole.64–66 Oral tinidazole
incident and recurrent bacterial vaginosis. Unfortunately
has been studied as an alternative to metronidazole in trials
very little literature exists to guide clinicians in the use of
in Europe and the United States. The evidence to date
reveals similar cure rates with the possibility of a reduction these products. There is one published study from China
in the number of doses required and in gastrointestinal in which women with recurrent bacterial vaginosis were
side effects with tinidazole.67,68 This drug is not currently randomized to either daily vaginal probiotic use or placebo.
readily available in Canada. Women in the probiotic group had lower recurrence
rates than those in the placebo group.73 Another study
Recurrent Bacterial Vaginosis investigated the use of vaginal vitamin C tablets compared
Unfortunately, recurrence rates following treatment to placebo for the treatment of bacterial vaginosis. More
for bacterial vaginosis have been high in many studies, women in the placebo group still had bacterial vaginosis
with up to one third of treated women recurring within at the end of the study period.74 Unfortunately, in both
studies diagnosis was based on clinical (Amsel’s) criteria 4. Odds FC. Candidosis of the fenitalia. In: Odds FC. Candida and
candidosis: a review and bibliography, 2nd ed. London: Bailliere Tindal;
rather than Nugent score or Gram stain, and the total 1988, p.124.
length of follow-up in the vitamin C study was only
5. Vermitsky JP, Self MJ, Chadwick SG, Trama JP, Adelson ME,
20 days. Until there is more published data from well- Mordechai E, et al. Survey of vaginal-flora Candida species isolates from
designed trials in this area, it is premature to make a women of different age groups by use of species-specific PCR detection.
judgement on the efficacy of these alternative therapies. J Clin Microbiol 2008;46:1501–3.
6. Sobel JD. Vulvovaginal candidosis. Lancet 2007;369:1961–71.
Pregnancy
7. Public Health Agency of Canada. Canadian guidelines on sexually
Vaginal discharge is common in pregnancy and may be transmitted infections—updated January 2010. Ottawa: PHAC; 2010.
physiologic. In women with persistent discharge, screening Available at: http://www.phac-aspc.gc.ca/std-mts/sti-its/cgsti-ldcits/
for lower genital tract infections (vaginal and cervical) is index-eng.php. Accessed on November 6, 2013.
recommended. If bacterial vaginosis is diagnosed in a 8. Nyirjesy P, Sobel JD. Genital mycotic infections in patients with diabetes.
Postgrad Med 2013;125:33–46.
symptomatic pregnant woman, treatment is indicated. The
PHAC guidelines on STI recommend using metronidazole 9. Watts DH, Springer G, Minkoff H, Hillier SL, Jacobsen L, Moxley M,
et al. The occurrence of vaginal infections among HIV-infected and high-
500 mg orally twice daily for 7 days or clindamycin 300 mg risk uninfected women: longitudinal findings of the Women’s Interagency
orally twice daily for 7 days.7 Topical agents are not HIV Study. J Aquir Immune Defic Syndr 2006;43:161–8.
recommended. Treatment has relatively moderate rates of 10. Sobel JD, Kapernick PS, Zervos M, Reed BD, Hooton T, Soper D,
success with high rates of recurrence in some women. et al. Treatment of complicated Candida vaginitis: comparison of
single and sequential doses of fluconazole. Am J Obstet Gynecol
For a detailed discussion of the implications of bacterial 2001;185:363–9.
vaginosis in pregnancy and links to adverse pregnancy 11. Pirotta MV, Garland SM. Genital Candida species detected in samples
outcomes, including screening and treatment strategies in from women in Melbourne, Australia, before and after treatment with
antibiotics. J Clin Microbiol 2006;44:3213–7.
pregnant women, please see the SOGC Clinical Practice
Guideline on the screening and management of bacterial 12. Nurbai M, Grimshaw JM, Watson M, Bond CM, Mollison J, Ludbrook A.
Oral versus intra-vaginal imidazole and triazole anti-fungal treatment of
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Summary Statements
13. Sobel JD, Wiesenfeld HC, Martens M, Danna P, Hooton TM, Rompalo A,
5. Current evidence of the efficacy of alternative et al. Maintenance fluconazole therapy for recurrent vulvovaginal
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vitamin C) is limited. (I) 14. Pappas PG, Rex JH, Sobel JD, Filler SG, Dismukes WE, Walsh TJ,
et al.; Infectious Diseases Society of America. Guidelines for treatment
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7. Symptomatic bacterial vaginosis should be treated 16. Sobel JD. Recurrent vulvovaginal candidiasis. A prospective study
with oral metronidazole 500 mg twice daily for 7 of the efficacy of maintenance ketoconazole therapy. N Engl J Med
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recommended for women with documented multiple
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60. Verstraelen H, Verhelst R, Vaneechoutte M, Temmerman M. The
40. Burtin P, Taddio A, Ariburnu O, Einarson TR, Koren G. Safety of epidemiology of bacterial vaginosis in relation to sexual behaviour.
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61. Fethers KA, Fairley CK, Hocking JS, Gurrin LC, Bradshaw CS. Sexual risk
41. Spiegel CA, Amsel R, Eschenbach D, Schoenknecht F, Holmes KK. factors and bacterial vaginosis: a systematic review and meta-analysis. Clin
Anaerobic bacteria in nonspecific vaginitis. N Engl J Med 1980;303:601–7. Infect Dis 2008;47:1426–35.
62. Amsel R, Totten PA, Spiegel CA, Chen KCS, Eschenbach D, Holmes KK. vaginosis in nonpregnant and pregnant women: a synthesis of data. Clin
Nonspecific vaginitis: diagnostic criteria and microbial and epidemiologic Infect Dis 2002;35(Suppl 2):S152–S72.
associations. Am J Med 1983;74:14–22.
71. Bradshaw CS, Morton AN, Hocking J, Garland SM, Morris MB,
63. Nugent RP, Krohn MA, Hillier SL. Reliability of diagnosing bacterial Moss LM, et al. High recurrence rates of bacterial vaginosis over the
vaginosis is improved by a standardized method of Gram stain course of 12 months after oral metronidazole therapy and factors
interpretation. J Clin Microbiol 1991;29:297–301. associated with recurrence. J Infect Dis 2006;193:1478–86.
64. Lugo-Miro VI, Green M, Mazur L. Comparison of different 72. Sobel JD, Ferris D, Schwebke J, Nyirjesy P, Wiesenfeld HC, Peipert J,
metronidazole therapeutic regimens for bacterial vaginosis. et al. Suppressive antibacterial therapy with 0.75% metronidazole vaginal
A meta-analysis. JAMA 1992;268:92–5. gel to prevent recurrent bacterial vaginosis. Am J Obstet Gynecol
2006;194:1283–9.
65. Hanson JM, McGregor JA, Hillier SL, Eschenbach DA, Kreutner AK,
Galask AP, et al. Metronidazole for bacterial vaginosis. A comparison of 73. Ya W, Reifer C, Miller LE. Efficacy of vaginal probiotic capsules for
vaginal gel vs. oral therapy. J Reprod Med 2000;45:889–96. recurrent bacterial vaginosis: a double-blind, randomized, placebo-
controlled study. Am J Obstet Gynecol 2010:203:120.e1–e6.
66. Hillier S, Lipinski C, Briselden AM, Eschenbach DA. Efficacy of
intravaginal 0.75% metronidazole gel for treatment of bacterial vaginosis. 74. Petersen EE, Magnani P. Efficacy and safety of vitamin C vaginal
Obstet Gynecol 1993;81:963–7. tablets in the treatment of non-specific vaginitis. A randomised,
double blind, placebo-controlled trial. Eur J Ob Gyn Reprod Biol
67. Livengood CH, Ferris DG, Wiesenfeld HC, Hillier SL, Soper DE,
2004;117:70–5.
Nyirjesy P, et al. Effectiveness of two tinidazole regimens in treatment
of bacterial vaginosis. A randomized controlled trial. Obstet Gynecol 75. Yudin MH, Money DM; Society of Obstetricians and Gynaecologists of
2007;110:302–9. Canada Infectious Diseases Committee. Screening and management of
bacterial vaginosis in pregnancy. SOGC Clinical Practice Guideline,
68. Schwebke JR, Desmond RA. Tinidazole vs metronidazole for the treatment
No. 211, August 2008. J Obstet Gynaecol Can 2008;30:702–8.
of bacterial vaginosis. Am J Obstet Gynecol 2011;204:211.e1–e6.
76. Woolf SH, Battista RN, Angerson GM, Logan AG, Eel W. Canadian
69. Hay P. Recurrent bacterial vaginosis. Curr Infect Dis Rep 2000;2:506–12.
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Indications for therapy and treatment recommendations for bacterial 2003;169:207–8.
This document reflects emerging clinical and scientific advances on the date issued and is subject to change. The information
should not be construed as dictating an exclusive course of treatment or procedure to be followed. Local institutions can dictate
amendments to these opinions. They should be well documented if modified at the local level. None of these contents may be
reproduced in any form without prior written permission of the SOGC.
Table 1. Key to evidence statements and grading of recommendations, using the ranking of the Canadian Task Force
on Preventive Health Care
Quality of evidence assessment* Classification of recommendations†
I: Evidence obtained from at least one properly randomized A. There is good evidence to recommend the clinical preventive action
controlled trial
II-1: Evidence from well-designed controlled trials without B. There is fair evidence to recommend the clinical preventive action
randomization
II-2: Evidence from well-designed cohort (prospective or C. The existing evidence is conflicting and does not allow to make a
retrospective) or case–control studies, preferably from recommendation for or against use of the clinical preventive action;
more than one centre or research group however, other factors may influence decision-making
II-3: Evidence obtained from comparisons between times or D. There is fair evidence to recommend against the clinical preventive action
places with or without the intervention. Dramatic results in
uncontrolled experiments (such as the results of treatment with E. There is good evidence to recommend against the clinical preventive
penicillin in the 1940s) could also be included in this category action
III: Opinions of respected authorities, based on clinical experience, L. There is insufficient evidence (in quantity or quality) to make
descriptive studies, or reports of expert committees a recommendation; however, other factors may influence
decision-making
*The quality of evidence reported in these guidelines has been adapted from The Evaluation of Evidence criteria described in the Canadian Task Force on
Preventive Health Care.154
†Recommendations included in these guidelines have been adapted from the Classification of Recommendations criteria described in the Canadian Task Force
on Preventive Health Care.154
12. Routine dose adjustment of the combination antiretroviral 16. As for all pregnant women, those living with HIV should be
therapy is not recommended in pregnancy. (III-D) screened periodically for substance use, and drug addiction
should be addressed as needed in conjunction with HIV
13. The woman’s clinical, virological, and immunological
management. (III-A)
statuses should be assessed every 4 to 8 weeks during
pregnancy, and again 6 weeks postpartum. Routine criteria 17. Mode of delivery should be discussed in detail with all
should be used to assess the woman’s response to, and women:
the possible failure of, antiretroviral therapy. The toxicity of
a. Women on optimal antiretroviral therapy with
the antiretrovirals should also be monitored at these times.
acceptable plasma viral load suppression (less than
Specific testing should be individualized for the known
1000 c/mL) over the last 4 weeks prior to delivery
toxicities of the woman’s antiretroviral therapy regimen. (III-B)
are recommended to have a vaginal delivery in the
14. As for all pregnant women, all those living with HIV, absence of other obstetrical indications for Caesarean
regardless of age, should be offered, through an informed section. If Caesarean section is recommended for
consent process, dating ultrasound and non-invasive prenatal obstetrical indications, it can be conducted at 39 weeks,
genetic screening for the most common clinically significant as usual for those indications. (I-A)
fetal aneuploidies. (III-A)
b. Women not on optimal antiretroviral therapy (i.e., no
15. A detailed obstetrical ultrasound at 19 to 20 weeks’ gestation antiretroviral therapy, monotherapy only, or with an
is recommended. Additional ultrasounds, for fetal growth incompletely suppressed viral load) should be offered a
and amniotic fluid volume, are recommended at least each scheduled pre-labour Caesarean section at approximately
trimester, or as guided by obstetrical indications. (II-3B) 38 weeks’ gestation. (II-2A)
18. Intravenous zidovudine should be initiated as soon as labour
onset until delivery, in combination with an oral combination
ABBREVIATIONS antiretroviral regimen, regardless of mode of delivery, current
antiretroviral regimen, or viral load. (III-B)
ALT alanine aminotransferase
AST aspartate aminotransferase 19. Intrapartum, a single dose of oral nevirapine (200 mg)
remains an option in the unusual circumstance of a woman
cART combination antiretroviral therapy living with HIV who has not received antenatal antiretroviral
CBC complete blood count therapy in pregnancy. (II-2B)
CD4-cell CD4+ T-lymphocyte cell 20. Plans for ongoing HIV care should be established prenatally,
CDC Centre for Disease Control and unless otherwise indicated, maternal antiretroviral
therapy should be continued after delivery and reassessed for
CMV cytomegalovirus ongoing therapy by providers of adult HIV care. (II-1A)
CPHSP Canadian Perinatal HIV Surveillance Program 21. HIV-exposed newborns should receive antiretroviral therapy
DDI didanosine for 6 weeks to prevent vertical transmission of HIV. (I-A)
DMPA medroxyprogesterone acetate 22. Health care practitioners who care for HIV-exposed newborns
EIA enzyme immunoassay should provide timely diagnostic HIV testing: HIV polymerase
chain reaction at birth, 1 month, and 3 to 4 months and HIV
FDA (United States) Food and Drug Administration serology at 18 months (II-A), and they should monitor both
FPV fosamprenavir short- and long-term outcomes, including screening for
HBV hepatitis B virus adverse effects of antiretroviral therapy and for developmental
delay. (III-A)
HCV hepatitis C virus
23. Breast-feeding is not recommended regardless of plasma HIV
HIV human immunodeficiency virus viral load and use of antiretroviral therapy. (I-E)
IDV indinavir
24. The pregnancy should be registered with surveillance
IV intravenous programs to allow the collection of provincial and national
LDH lactate dehydrogenase data to guide future pregnancy policies. Women undergoing
antiretroviral therapy in pregnancy should also be offered
MAC mycobacterium avium complex
inclusion in appropriate studies. (III-B)
NIH (United States) National Institutes of Health
NNRTI non-nucleoside/nucleotide analogue reverse transcriptase
inhibitor
NRTI nucleoside/nucleotide analogue reverse transcriptase
inhibitor
NVF nelfinavir
PCP pneumocystis jiroveci pneumonia
PCR polymerase chain reaction
PI protease inhibitor
PO per os
This document’s Executive Summary
RNA ribonucleic acid was previously published in:
RR relative risk
J Obstet Gynaecol Can 2014;36(8):721–734
ZDV zidovudine
Adult HIV infection therapeutic guidelines http://www.cfenet.ubc.ca/therapeutic-guidelines/adult BC Centre for Excellence in HIV/AIDS
Opportunistic infections therapeutic guidelines http://www.cfenet.ubc.ca/therapeutic-guidelines/opportunistic-infection
Primary care guidelines http://cfenet.ubc.ca/therapeutic-guidelines/primary-care
Guidelines for the use of antiretroviral agents in HIV-1 http://www.aidsinfo.nih.gov/guidelines Centers for Disease Control and Prevention,
infected adults and adolescents. National Institutes of Health, HIV Medicine
Association of the Infectious Diseases
Society of America
Guidelines for prevention and treatment of opportunistic
infections in adults and adolescents
Recommendations for the use of antiretroviral drugs in
pregnant HIV-1 infected women for maternal health and
interventions to reduce perinatal HIV transmission in the
United States
Canadian HIV pregnancy planning guidelines http://www.sogc.org/guidelines/documents/gui278CPG1206E.pdf Society of Obstetricians and Gynaecologists
of Canada
Alcohol use and pregnancy consensus clinical guidelines http://www.sogc.org/guidelines/documents/gui245CPG1008E.pdf
Substance use in pregnancy clinical practice guidelines http://www.sogc.org/guidelines/documents/gui256CPG1104E.pdf
HIV screening in pregnancy clinical practice guidelines http://sogc.org/wp-content/uploads/2013/01/185E-CPG-December2006.pdf
Management of nausea and vomiting of pregnancy clinical http://sogc.org/wp-content/uploads/2013/01/120E-CPG-October2002.pdf
practice guidelines
Canadian contraception consensus http://sogc.org/wp-content/uploads/2013/01/143E-CPG1-February2004.pdf
http://sogc.org/wp-content/uploads/2013/01/143E-CPG2-March2004.pdf
http://sogc.org/wp-content/uploads/2013/01/143E-CPG3-April2004.pdf
Recommendation Recommendation
1. All women living with HIV who are planning a 2. All pregnant women should be offered HIV testing,
pregnancy or who become pregnant should have their with appropriate pre- and post-test counselling, as
individual situations discussed with experts in the area, part of their routine prenatal care in each pregnancy.
with referral to both HIV treatment programs and This testing should be repeated in each trimester
obstetrical care providers, and an overall plan should in women who are recognized to be at high and
be made for their pregnancy care. (II-2A) ongoing risk for HIV infection. (II-2A)
Table 3. Continued
Emtricitabine (FTC) Recommendations for use in pregnancy
FDA pregnancy category B Alternative NRTI for dual NRTI backbone of combination regimens
High placental transfer (cord-to-maternal blood ratio 1.2)162,163 One of preferred NRTI for dual NRTI backbone (in combination with
TDF) for women with chronic hepatitis B infection
Animal data 3
Table 3. Continued
Stavudine (d4T) Recommendations for use in pregnancy
FDA pregnancy category C Alternate NRTI for dual NRTI backbone of combination regimens
High placental transfer (cord-to-maternal blood ratio 0.5–0.8 in Do not combine with ZDV (antagonistic mechanism of action);
macaques)169 discontinue d4T at time of administration of intrapartum IV ZDV.
Do not combine with DDI (risk of fatal lactic acidosis).
Animal data3
No evidence of developmental toxicity or teratogenicity in rats at 399 Dosing
times usual human dose or rabbits at 183 times usual human dose Zerit ≥ 60 kg: 40 mg twice daily, < 60 kg: 30 mg twice daily
Human data Take without regard to meals.
No adequate or well-controlled studies in pregnant women A phase I/II study showed pharmacokinetics in pregnancy were
similar to those in non-pregnant adults.170 No dose alteration is
No evidence of human teratogenicity: APR birth defects with first
required in pregnancy.
trimester exposure 2.5% (20 of 801 births; 95% CI 1.5%–3.8%)42
Adverse events/concerns in pregnancy
Fatal lactic acidosis has been reported in pregnant women who
received the combination of DDI and d4T. Physicians should avoid
prescribing this combination.
Non-nucleoside reverse transcriptase inhibitors NRTI class concerns
NNRTIs are recommended for use in combination regimens with 2 Hypersensitivity reactions, including hepatic toxicity and (more
NRTI drugs (alternative to using a PI). common in women) rash; it is unclear whether these reactions are
increased in pregnancy.
Table 3. Continued
Efavirenz (EFV) Recommendations for use in pregnancy
FDA pregnancy category D Contraindicated in first trimester of pregnancy
Moderate placenta transfer (cord blood concentrations similar to Women receiving EFV should be instructed to avoid pregnancy;
maternal plasma concentration in rats, rabbits, primates)3 recommend barrier contraception in combination with other
hormonal contraceptives.
Animal data3
Hepatocellular carcinoma and adenoma and pulmonary alveolar/ Dosing
bronchiolar adenomas reported in female mice; however, no indication Sustiva 600 mg once daily at bedtime
of this effect in male mice or in rats Atripla (TDF 300 mg/FTC 200 mg/EFV 600 mg) 1 tablet once daily
Significant central nervous system malformations (anencephaly, at bedtime
anopthmalmia, cleft palate) reported in monkeys receiving EFV in first May take on an empty stomach to reduce side effects
trimester at doses comparable to human therapeutic exposure
Limited pharmacokinetic data available; one pharmacokinetic
Human data study has shown that EFV AUC is lower in the third trimester
than postpartum; however, a majority of third trimester levels
Limited well-controlled studies in pregnant women; a meta-analysis
were above target exposure.173 No dose alteration is required in
of birth defects observed in cohorts of infants with first trimester
pregnancy.
exposure (1437 live births) found no increased risk of overall birth
defects than in infants exposed to non-EFV-based regimens Adverse events/concerns in pregnancy
(RR 0.85; 95% CI 0.61–1.20), with one neural tube defect observed43;
a large prospective study of a cohort of antiretroviral-exposed infants Avoid in first trimester of pregnancy as described above.
(13 124 live births) found significant association between EFV
exposure in the first trimester and neurological defects (adjusted OR
3.15; 95% CI 1.09–9.09).44
APR 2.7% (18 of 679 births, 95% CI 1.6%–4.2%); 6 retrospective
case reports of central nervous system defects (including 3 cases of
meningomyelocele), 1 prospective case report of neural tube defect,
and 1 prospective case report of bilateral facial clefts and anopthalmia
in humans receiving EFV in first trimester42
Etravirine (ETR) Recommendations for use in pregnancy
FDA pregnancy category B Insufficient safety and pharmacokinetic data to recommend use
Placental transfer unknown (cord-to-maternal blood ratio from case during pregnancy
report data 0.33)174
Dosing
Animal data3 Intelence 200 mg twice daily
Hepatocellular carcinoma and adenoma reported in mice; however, Take with food to increase total AUC drug concentration.
no indication of this effect in rats Single pharmacokinetic study in 4 pregnant women reported
No evidence of embryotoxicity or teratogenicity in rabbits or rats at that drug levels and AUC were similar to those in non-pregnant
doses comparable to human therapeutic exposure adults.174 Dose adjustment is not currently required in pregnancy.
Human data
No adequate or well-controlled studies and few case report data in
pregnant women
Rilpivirine (RPV) Recommendations for use in pregnancy
FDA pregnancy category B Insufficient safety and pharmacokinetic data to recommend use
Placental transfer unknown during pregnancy
Table 3. Continued
Protease inhibitors PI class concerns
PIs are recommended for use in combination regimens with 2 NRTI Hyperglycemia and new onset or exacerbation of existing diabetes
drugs (alternative to using an NNRT). have been reported with PIs; unclear whether pregnancy increases
risk. Data regarding preterm delivery in women receiving PIs are
conflicting (see text for details).
Lopinavir-ritonavir (LPV/r) Recommendations for use in pregnancy
FDA pregnancy category C Preferred PI for use in combination with dual NRTI backbone
Low placental transfer (cord-to-maternal blood ratio LPV 0.20, RTV
Dosing
minimal)
Kaletra (LPV/r 200 mg/50 mg; LPV/r 100 mg/50 mg; oral solution
Animal data3 LPV/r 400 mg/100 mg in each 5 mL) 400 mg LPV twice daily; take
Hepatocellular carcinoma and adenoma reported in mice at doses 2 with food to reduce stomach upset.
times (LPV) and 5 times (RTV) usual human dose Pharmacokinetic studies show AUC is decreased in third
trimester.175,176 Increasing the dose of LPV/r from 400 mg/100 mg
Embryotoxic in rats; no evidence of teratogenicity in rats or rabbits twice a day to 600 mg/150 mg twice a day resulted in AUC similar
to non-pregnant adults taking the standard dose177,178; may consider
Human data increased dose to LPV/r 600 mg/150 mg twice daily in third
There are no adequate or well-controlled studies in pregnant women. trimester, particularly in women who have previously had PI.
No evidence of human teratogenicity; APR 2.4% (21 of 883 births, No data exist evaluating LPV/r drug levels using once-daily dosing
95% CI 1.5%–3.6%)42 in pregnancy; once-daily dosing is not recommended.
Table 3. Continued
Ritonavir (RTV) Recommendations for use in pregnancy
FDA pregnancy category B Use only at low-dose in combination with a second PI to increase
Minimal placental transfer the serum drug levels of the second PI.
Table 3. Continued
Nelfinavir (NVF) Recommendations for use in pregnancy
FDA pregnancy category B Use in special circumstances when alternative agents are not
Minimal placental transfer tolerated in combination with dual NRTI backbone.
Table 3. Continued
Tipranavir (TPV) Recommendations for use in pregnancy
FDA pregnancy category C Safety and pharmacokinetic data are insufficient to recommend use
Placental transfer unknown; moderate transfer reported in one case during pregnancy.
report (cord-to-maternal blood ratio 0.41)189
Dosing
Animal data3 Must be combined with low-dose ritonavir (TPV/r).
Hepatocellular carcinoma and adenoma was observed in mice; this Aptivus TPV/r 500 mg/200 mg twice daily
effect was not observed in rats. No pharmacokinetic studies in pregnancy have been reported; it is
No evidence of embryotoxicity or gross structural abnormalities in not known whether dose adjustment is required.
rats or rabbits at doses 0.2 to 1.1 times usual human dose have been
reported; however, growth in inhibition was observed in rats at 0.8 Adverse events/concern in pregnancy
times human doses. Severe potentially fatal clinical hepatitis and intracranial
hemorrhage have been reported in non-pregnant population; no
Human data evidence pregnancy increases risk.
No adequate or well-controlled studies in pregnant women have been
reported.
Few pregnancy exposures have been reported to the APR;
no conclusion can be made about risk of birth defects.
Entry Inhibitors
Enfuviritide (T20) Recommendations for use in pregnancy
FDA pregnancy category B Safety and pharmacokinetic data are insufficient to recommend use
No placental transfer based on single case report189 in pregnancy.
No evidence of teratogenicity in rats or rabbits at 27 or 3 times the Dosing
usual human dose, respectively3
Fuzeon 90 mg (1 mL) subcutaneously twice daily
No adequate or well-documented studies in pregnant women have
No pharmacokinetics studies in pregnancy have been reported; it is
been reported.
not known whether dose adjustment is required.
Maraviroc (MVC) Recommendations for use in pregnancy
FDA pregnancy category B Safety and pharmacokinetic data are insufficient to recommend use
Placental transfer unknown during pregnancy.
Human Data
No adequate or well-documented studies in pregnant women have
been reported.
Few pregnancy exposures have been reported to the APR;
no conclusion can be made about the risk of birth defects.
continued
Table 3. Continued
Elvitegravir (EVG)-Cobicistat (COBI) Recommendations for use in pregnancy
FDA pregnancy category B Safety and pharmacokinetic data are insufficient to recommend use
Placental transfer unknown during pregnancy.
Human Data
No adequate or well-documented studies have been reported in
pregnant women.
APR: Antiretroviral Pregnancy Registry; IV: intravenous, FTC: emtricitabine; EVF: efavirenz; RR: relative risk; OR: odds ratio; AUC: area under the curve;
RPV: rilpinavir; LPV/r: lopinavir/ritonavir; SQV: saquinavir; ECG: electrocardiogram; CYP: cytochrome P450; EMS: ethyl methanesulfonate
rapidly crosses the placenta and achieves adequate infant and not withheld during pregnancy. The benefits of cART
blood levels,26,27 is easily administered, and is well tolerated for the overall health of the woman and for prevention
in both women and infants, it has been recommended as a of vertical transmission are known; however, there is
treatment strategy for women living with HIV who present need for improved understanding of the short- and long-
in labour and are not receiving antenatal antiretroviral term effects of antiretroviral drug therapy in pregnancy;
therapy. Nevirapine possesses a long half-life, however, and therefore parameters of maternal and fetal well-being need
therefore use of even a single dose exposes women to an to be closely monitored. Overall, the benefit of prevention
extended period of nevirapine monotherapy, potentially of vertical transmission of HIV is considered to outweigh
increasing the risk of nevirapine drug-resistant mutations.28 the potential risks associated with antiretroviral medications,
One strategy to limit the emergence of nevirapine resistance provided these agents are administered per treatment
after single-dose nevirapine is to provide the woman with an recommendations and with close monitoring and follow-up
antiretroviral tail (e.g., postpartum addition of 2 NRTIs for by experts in the area of HIV and obstetrics.
a period of 3 to 14 days).29–33
Selection of a specific antiretroviral drug therapy regimen
The HPTN 040/PACTG 040 study evaluated the alternative in a pregnant woman living with HIV must take into
treatment strategy of administering prophylactic cART account the inter-related issues of:
to infants born to women living with HIV who were not
1. the stage of pregnancy,
receiving antenatal antiretroviral therapy.25 Forty-one percent
of women in this study received intrapartum intravenous 2. the current and co-morbid health status of the woman,
zidovudine and the majority of infants were formula-fed. 3. her HIV-resistance profile,
This study demonstrated that the cART (the addition of
4. what is currently known about the use of specific drugs
either 3 doses of infant nevirapine or 2 weeks of lamivudine/
in pregnancy and the risk of teratogenicity,
nelfinavir to 6 weeks of zidovudine) was superior in
reducing the risk of vertical HIV transmission (2.2% and 5. unique pharmacokinetic considerations, including
2.4%, respectively) to 6 weeks of infant zidovudine therapy altered kinetics in pregnancy and issues of placental
alone (4.8%, P = 0.046). The rate of neutropenia was higher passage of medications,
in the 3-drug regimen (27.5% with zidovudine/nelfinavir/
lamivudine) than in the 2-drug (14.9% with zidovudine/ 6. the woman’s social status and intravenous drug use, and
nevirapine) and 1-drug (16.4% with zidovudine) regimens. 7. the ability of the woman to cope with the antiretroviral
drug therapy pill burden.
Principles behind using combination
antiretroviral therapy in pregnancy Timing of initiation of combination
Antiretroviral treatment recommendations for the pregnant antiretroviral therapy in pregnancy
woman living with HIV are based on the principle that The timing of initiation will depend on the woman’s HIV
therapies of known benefit to the woman should be offered disease status (e.g., CD4-cell count and HIV viral load), her
preparedness to start cART, and her degree of nausea and placenta) may be safely used throughout pregnancy; however,
vomiting of pregnancy. Adult HIV treatment guidelines are consideration should be given to increasing the folic acid
available elsewhere2 and are not discussed in detail here. In dose to 5 mg per day in the first trimester and monitoring
brief, they recommend initiation of cART for all individuals infants postpartum due to increased risk of neonatal
regardless of CD4-cell counts. In the obstetrical setting there hyperbilirubinemia.39
are controversies about the timing of cART initiation in
pregnant women who have not already been treated. While Continuation of therapy in women already
cART may reduce the risk of HIV vertical transmission,34 receiving combination antiretroviral therapy
there may also be risks in exposing the fetus to cART. prior to pregnancy
In most cases, the current antiretroviral regimen should be
Women with CD4-cell counts < 200 cells/mm3 are at continued if the regimen is effective in suppressing HIV
high risk of opportunistic infections35,36; therefore, cART viral load and is tolerated by the woman. Significant nausea
should be started immediately, regardless of gestational and vomiting of pregnancy may complicate a woman’s
age, in conjunction with prophylaxis for opportunistic ability to adhere to medication and needs to be addressed
infections as described below. Women with CD4-cell and aggressively managed.40
counts between 200 to 350 cells/mm3 may be at risk of
experiencing more common infections (e.g., herpes zoster, There are two main populations of women in whom
bacterial pneumonia), therefore cART should be initiated switching of antiretroviral medications may be considered.
as soon as possible—usually after the first trimester is The first is pregnant women living with HIV who are
completed (week 14). In other cases, although 14 weeks is receiving efavirenz and present pre-conception or very
the general recommendation for cART initiation, delayed early for care in the first trimester. As discussed below and
initiation of cART until the detailed anatomy ultrasound more thoroughly in Appendix 2, efavirenz is not a desirable
(i.e., week 18) may be considered in women with CD4-cell choice in the first trimester due to its association with neural
counts > 350 cells/mm3 on a case-by-case basis. tube defects in primates and in case reports in humans.41–44
Because most women will present after the 5- to 6-week
Antiretroviral drug resistance testing should be performed gestational age time window for neural tube closure, the
before starting an antiretroviral regimen; however, if it NIH guidelines endorse continuation of efavirenz in all
is determined that cART needs to be started urgently, pregnant woman including those who present for care in
decisions to start can be made based on the woman’s the first trimester.3 However because women may not always
antiretroviral history and adjusted later if necessary. All present after neural tube closure, and because there is a risk
women should be counselled about the importance of of women remaining on a potentially teratogenic medication
adherence to the regimen, and should be recommended to postpartum, particularly those who do not receive adequate
continue therapy after delivery. contraception, these guidelines still recommend considering
switching the woman from efavirenz to an alternative
Detailed guidelines regarding management and prophylaxis of
antiretroviral agent that has greater safety and efficacy
opportunistic infections, including specific recommendations
data in pregnancy. If efavirenz is received during the first
for pregnant women, are available35 and are not discussed in
trimester, however, ultrasound evaluation of neural tube
detail here. In brief, consideration for antibiotic prophylaxis
closure is very important.
against the following opportunistic infections must be
made based on CD4-cell count: < 200 cells/mm3 requires Changing antiretroviral medications may also be considered
prophylaxis against PCP; < 100 cells/mm3 requires additional in women who are receiving an antiretroviral agent for
prophylaxis against Toxoplasmosis gondii (if Toxoplasmosis which there is little known safety and efficacy data for use
immunoglobulin G serology is positive and an agent in pregnancy (see Appendix 2). It is important to consider
other than cotrimoxazole is used as prophylaxis for PCP); the safety and risk of continuing each antiretroviral
< 50 cells/mm3 requires additional prophylaxis against MAC medication, and prior to any changes to medication there
after obtaining MAC blood cultures and an ophthalmology should be discussion between the woman, her HIV care
referral to rule out CMV retinitis. Treatment and prophylaxis provider, and her obstetrical care provider.
of all opportunistic infections must be provided as required
with consideration of potential toxicities in pregnancy. While Selection of cART regimen in pregnancy
this is well discussed in available guidelines,35 agents of note Antiretroviral drug resistance testing should be performed
to avoid, particularly in the first trimester of pregnancy, as described above before starting cART and test results
include continuous oral fluconazole and clarithromycin.37,38 used to help determine the optimal regimen. A cART
Cotrimoxazole (a folate antagonist which readily crosses the regimen should usually include a dual NRTI backbone
that includes one or more NRTIs with high levels of regimen in these women is tenofovir-emtricitabine and
transplacental passage (e.g., zidovudine, lamivudine, boosted atazanavir/ritonavir as described above. HBV DNA
emtricitabine, tenofovir, abacavir) and an additional levels should be monitored and should become undetectable
boosted protease inhibitor (see Appendix 2). on this regimen. Because chronic administration of tenofovir
to pregnant monkeys has resulted in a slight reduction in
Consistent adherence to antiretroviral therapy is critical fetal bone porosity (a finding which has conflicting results
to its efficacy and to preventing the development of in human studies) and is associated with nephrotoxic
resistance. In particular, with complications in pregnancy effects, tenofovir is not recommended as a first-line agent in
such as nausea and vomiting of pregnancy, there may
pregnancy except with an HBV co-infection, drug resistance,
be circumstances when cART needs to be discontinued.
and/or medication adherence issues.3,56,57
In this case, regardless of reason, the woman should be
advised to discontinue all drugs at once, and to resume If women are unable to tolerate or are resistant to the PIs
all drugs simultaneously to minimize the risk of viral lopinavir and/or atazanavir, alternative cART regimens may
resistance developing during therapy (unless on an NNRTI, need to be considered including (a) boosted darunavir/
then a tail of 2 NRTIs is recommended for 1 week). ritonavir (darunavir 800 mg PO daily with ritonavir 100 mg
Resume antiretroviral therapy as quickly as possible after PO daily or darunavir 600 mg PO twice daily with ritonavir
discontinuing, to minimize the risk of rebound viremia 100 mg PO twice daily), or (b) efavirenz 600 mg PO at
and the potentially increased risk of vertical transmission. nighttime, if the virus is sensitive and after the early first
trimester of pregnancy, ideally after a detailed ultrasound
In the antiretroviral naive and in a presumed or proven
and screening have confirmed the absence of a neural
pan-sensitive virus the recommended NRTI backbone is
zidovudine-lamivudine 300 mg/150 mg 1 tablet PO twice tube defect. Nevirapine initiation in pregnancy has been
daily with lopinavir-ritonavir 200 mg/50 mg 2 tablets PO associated with 10% life-threatening toxicity (fatal rash
twice daily. This regimen requires twice-daily dosing and and hepatotoxicity) and its initiation in pregnancy is not
monthly hemoglobin monitoring as zidovudine can cause recommended if there is a suitable alternative.2,3 Although
pure red cell aplasia.45 If women are unable to tolerate or some data have suggested that nevirapine may be safe if a
adhere to a twice-daily dosing regimen an alternative regimen woman’s CD4 cell count is > 250 cells/mm3, Canadian data
is abacavir-lamivudine 600 mg/300 mg 1 tablet PO once have suggested that toxicity has occurred at a wide range
daily and boosted atazanavir (atazanavir 300 mg plus ritonavir of CD4-cell counts in women exposed to nevirapine for
100 mg PO once daily). Testing for, and confirmation of the the first time during pregnancy.58 Women who have been
absence of the inherited HLA*B5701 gene must be done receiving and tolerating nevirapine prior to becoming
prior to initiation of any abacavir-containing medication pregnant (regardless of CD4-cell count) can continue to
to reduce the risk of a severe allergic reaction.46 Atazanavir receive this agent.2,3 All other antiretroviral agents used in
is associated with increased maternal indirect bilirubin. adult HIV care must be individually assessed on a case-by-
Although the clinical significance has not been determined, case basis, depending on the woman’s clinical and personal
bilirubin should be monitored monthly in the mother and the circumstances, co-infections, HLA*B5701 results, genotype
infant after delivery.47,48 It is important to note that both of the of virus, and available options. Detailed information on each
above listed boosted protease inhibitor regimens may require antiretroviral agent is provided in Appendix 2; however, it is
increased dosing (e.g., abacavir-lamivudine 3 tablets PO twice recommended that consultation be made with experts in the
daily, atazanavir 400 mg PO once daily with ritonavir 100 mg areas of HIV and obstetric care.
PO once daily) in the third trimester as a result of increased
Because antiretroviral medications are used as a part
volume of distribution of pregnancy.47,49–53 These empiric dose
of combination regimens it is difficult to ascertain the
increases should be considered, particularly if the woman’s
contribution that an individual agent has on potential
HIV viral load becomes detectable, cART adherence has been
maternal and/or fetal toxicity. Studies that have evaluated
verified and HIV resistance has been ruled out. If available,
therapeutic drug level monitoring may also be considered in the results of cART have shown variable results. Some
the third trimester to guide the need for protease inhibitor early studies have reported serious maternal toxicities
dose adjustment.54 including hepatotoxicity,59–61 higher rates of neonatal
malformations,62,63 increased risk of prematurity and low
In pregnant women with HIV and HBV co-infection, the birth weight,64–70 or serious neonatal complications including
dual NRTI backbone should include 2 NRTI agents that mitochondrial toxicity.69–75 Other studies, however, suggest
are also active against HBV (e.g., lamivudine, emtricitabine, that there are generally few serious effects for the mother or
tenofovir)2,3,55,56; therefore, the recommended first-line infant associated with cART.17,76–82
The concerns surrounding the use of efavirenz 8. Whenever possible, drugs with no safety data should
(teratogen), nevirapine (rash and hepatotoxicity), tenofovir be avoided during the period of organogenesis.
(bone abnormalities, nephrotoxicity), and atazanavir Efavirenz should not be prescribed in the first
(hyperbilirubinemia) in pregnancy have been discussed. trimester of pregnancy because of its possible
Women living with HIV who are on antiretroviral teratogenicity; however, if exposure has occurred
therapy are also at a higher risk of preterm delivery than and the neural tube has closed, efavirenz can be
those who are not (18% vs. 9% in Canada).83,84 There continued. Nevirapine should not be started in
is conflicting evidence about whether cART further pregnancy, unless indicated by the woman’s resistance
increases this risk.67,85–92 Data to suggest an association patterns, because it is associated with a high rate of
between antiretroviral drug therapy (including protease serious adverse outcomes in this situation; however
inhibitor use) and premature delivery or low birth weight ongoing, pre-pregnancy treatment with nevirapine
infants are mixed; however, a causal relationship has not can be continued through pregnancy if tolerance and
been established88,93–95 and PIs should not be withheld efficacy are established. (II-3D)
during pregnancy. There is also conflicting evidence 9. If antiretroviral therapy is discontinued for any
as to whether women taking regimens that include PIs reason during pregnancy, all drugs should be
are at increased risk for impaired glucose tolerance or discontinued at once (unless the woman is on non-
gestational diabetes in pregnancy.64,96–98 Standard glucose nucleoside reverse transcriptase inhibitors; in that
screening at 24 to 28 weeks is recommended in pregnant case a tail of 2 nucleoside reverse transcriptase
women living with HIV; if a woman is receiving a PI- inhibitors is recommended for 1 week), and
based regimen, the clinician may choose to perform this all drugs should be resumed simultaneously to
screening test earlier.3,99 minimize the risk of viral resistance developing
during therapy. Antiretroviral therapy should
Recommendations
be resumed as quickly as possible after
4. All pregnant women living with HIV should be discontinuance to minimize the risk of rebound
treated with combination antiretroviral therapy viremia and the potentially increased risk of
regardless of baseline CD4 and viral load. (II-2A) vertical transmission. (II-1A)
5. Antiretroviral therapy should not be discontinued 10. If a pregnant woman has significant nausea of
during the first trimester for obstetrical reasons, pregnancy, do not begin antiretroviral therapy
but if the woman is not on therapy and there is until her nausea is adequately controlled. Most
no urgent medical indication for combination antinauseants used in pregnancy can be co-
antiretroviral therapy, it can be delayed until after 14 administered with antiretrovirals. If the woman is
weeks’ gestation. (III-B) already on antiretrovirals and has hyperemesis of
6. All women living with HIV (both those who still have pregnancy, discontinue all antiretrovirals at once,
a detectable viral load after exposure to antiretroviral and then reinstate all at once, when nausea and
therapy and those who are antiretroviral-naive) should vomiting are controlled (unless the woman is on
have their virus genotyped and, if possible, tested non-nucleoside reverse transcriptase inhibitors
for phenotypic resistance to assist in optimizing [NNRTIs], in which case a tail of 2 nucleoside
antiretroviral therapy. It is advisable to discuss the reverse transcriptase inhibitors is recommended for
interpretation of the genotype testing and any 1 week to prevent future NNRTI resistance). (II-2D)
changes to the antiretroviral therapy with experienced 11. Therapy should be individualized to maximize
clinicians. Testing for HLA-B*5701, if not done adherence to the prescribed antiretroviral
previously, is recommended in case abacavir might be regimen. (III-A)
required. (II-2B) 12. Routine dose adjustment of the combination
7. A combination antiretroviral therapy regimen antiretroviral therapy is not recommended in
including a dual nucleoside reverse transcriptase pregnancy. (III-D)
inhibitor (NRTI) backbone that includes one or
more NRTIs and a boosted protease inhibitor
should be favoured because there is higher ANTEPARTUM MANAGEMENT
confidence in its safety and efficacy in pregnancy. General Considerations
Whenever possible, antiretrovirals known to cross It is important to consider the broad context of a
the placenta to the fetal compartment should be woman’s life when managing her HIV and prenatal care.
used. (II-2B) Considerations include:
•• Providing empathetic, non-judgemental care to women using purified protein derivative); and evaluation of
living with HIV and their children, in the spirit of immunization status. In addition to standard prenatal blood
professionalism.100 work, the following blood work should also be obtained:
•• Addressing early and systematically the woman’s need CD4-cell count (absolute count and fraction), HIV viral
for social support, with at least one interview with load, baseline CBC and differential, and liver (AST, ALT,
a social worker. Pregnant women living with HIV LDH) and renal (urea, serum creatinine) function testing
in Canada commonly experience challenging social (see Table 4 and Table 5).
and economic environments, with 25% of infections All pregnant women who are living with HIV, regardless
linked to drug use.10,11 The aim of the comprehensive of age, should be offered, through an informed
assessment by a social worker is to determine the consent process, dating ultrasound and prenatal genetic
woman’s needs and to propose culturally relevant screening for the most common clinically significant fetal
support and follow-up if required. aneuploidies. Timely referral is critical to ensure women
•• Maintaining confidentiality, including with relatives.100 are able to undergo the type of screening test they have
•• Encouraging the testing of partners and previous chosen. Ideally, first trimester biochemical screening and
children if their HIV status is unknown.101 The medical nuchal translucency measurements (at 11 to 14 weeks)
and psychological needs of the fathers should be should be obtained to integrate with second trimester
addressed, and the men referred to other health care biochemical screening, and these results should be used
providers if necessary.102 to inform the need for invasive testing.105 If integrated
prenatal screening is not accessible, then pregnant women
•• Advising on the use of, and facilitating access to, living with HIV should be offered the non-invasive
condoms for the purpose of preventing transmission screening for aneuploidy based on gestational age that is
of HIV and other sexually transmitted infections.103 available in the area. As maternal serum testing of fetal
If both members of the couple are living with HIV, aneuploidy becomes more available, this method of testing
they should be informed of the possible risk of will be preferred over amniocentesis, particularly in this
superinfection associated with unprotected sex.104 population.
•• Respecting the wishes of a mother who refuses
antenatal cART after being fully informed and Nausea and vomiting can be a significant issue for all
counselled. A plan for the care of the newborn should pregnant women, and in women living with HIV, it may
be prepared prior to delivery.100 affect their ability to adhere to the prescribed antiretroviral
regimen. Evaluation of nausea and vomiting of pregnancy
Inclusion of de-identified data of the mother and infant should be conducted and aggressive management of this
pairs in provincial and national surveillance programs is condition, starting with a prescription for doxylamine-
highly recommended. The CPHSP, an initiative of the pyridoxine as needed,40 is necessary to facilitate the initiation
Canadian Pediatric AIDS Research Group (CPARG) and/or continuation of antiretroviral medications.
collects important public health data, which inform Important considerations when evaluating nausea and
allocation of resources and management of future vomiting of pregnancy in a woman living with HIV should
pregnancies.10,11 include antiretroviral-related lactic acidosis or pancreatitis,
as well as opportunistic infections including intestinal
First Trimester (Weeks 0 to 13) protozoa if the woman is at risk (e.g., CD4-cell count
Early pregnancy offers the opportunity for complete HIV < 200 cells/mm3) and symptoms are accompanied by
and obstetrical assessments and permits planning for prenatal diarrhea. In particular, in women with very advanced HIV
genetic screening. In addition to the standard antenatal disease, alternative causes for nausea should be considered
assessments for all pregnant women, assessment should (e.g., gastric lymphoma, central nervous system lesions, or
include the following: documentation of history of prior infections causing increased intracranial pressure).35
HIV-related illnesses and past CD4-cell counts and plasma
HIV viral loads; assessment for symptoms of opportunistic As outlined above, the timing of initiation of antiretroviral
infections; complete physical examination including a pelvic therapy will depend on current CD4-cell count and maternal
examination and cervical Pap smear; screening for sexually conditions including nausea and vomiting. Antiretroviral
transmitted infections (including chlamydia, gonorrhea, therapy and prophylaxis or treatment of opportunistic
syphilis); screening for HBV (using HBsAg, anti-HBs, and infections should be started immediately if CD4-cell count
anti-HBc), HCV (HCV antibody and HCV PCR status if is < 200 cells/mm3 and/or there are AIDS-defining illnesses
antibody positive) and tuberculosis (induration of > 5 mm requiring therapy. In other cases, it is advisable to ensure
**Group B streptococcus anorectal swab is recommended at 35 to 37 weeks, or sooner if delivery is anticipated within 5 weeks.
SOGC CLINICAL PRACTICE GUIDELINE
Table 5. United States Food and Drug Administration pharmaceutical pregnancy categories213
A Adequate and well-controlled studies have failed to demonstrate a risk to the fetus in the first trimester of pregnancy (and
there is no evidence of risk during later trimesters).
B Animal reproduction studies have failed to demonstrate a risk to the fetus and there are no adequate and well-controlled
studies in pregnant women
OR
Animal studies have shown an adverse effect, but adequate and well-controlled studies in pregnant women have failed to
demonstrate a risk to the fetus in any trimester.
C Animal reproduction studies have shown an adverse effect on the fetus and there are no adequate and well-controlled studies
in humans, but potential benefits may warrant use of the drug in pregnant woman despite potential risks.
D There is positive evidence of human fetal risk based on adverse reaction data from investigational or marketing experiences
or studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks.
X Studies in animals or humans have demonstrated fetal abnormalities and/or there is positive evidence of human fetal risk
based on adverse reaction data from investigational or marketing experience, and the risks involved in use of the drug in
pregnant women clearly outweigh potential benefits.
nausea and vomiting is controlled prior to initiating clinical, virological, and immunologic status including
antiretroviral therapy. Women who are receiving antiretroviral CD4-cell count, HIV viral load, CBC, AST, ALT, LDH,
therapy prior to pregnancy should not discontinue their bilirubin, blood urea nitrogen, creatinine, as well as any
medication regimen during the first trimester. All drug other blood work as indicated by clinical history and
therapy should be reviewed for safety in pregnancy, specific cART regimen, should be assessed every 4 to
particularly in the first trimester period of embryogenesis. 8 weeks throughout pregnancy (see Table 4). Because
comorbidities affect many women living with HIV, more
Women should be counselled on all relevant aspects of
frequent evaluations may be appropriate. Consideration
ensuring a healthy pregnancy including maintaining a
for repeat urine cultures in second and third trimester
healthy diet and lifestyle. Women should start or ideally
should be made given the higher rates of hospitalization
continue taking folic acid 1 mg daily for at least the first 3
for urinary tract infections in women living with HIV.110
months of their pregnancy. If necessary, in cases of food
All women should be screened for gestational diabetes
insecurity, resources should be offered to improve nutrition.
between 24 and 28 weeks as recommended in most recent
Notably, malnutrition and micronutrient deficiencies have
been linked to vertical transmission risk.106 Live vaccines guidelines.99 As discussed above, there is conflicting
(varicella zoster and measles, mumps and rubella) are evidence on whether cART regimens containing PIs
contraindicated in pregnancy.107 Women with negative increase the risk of hyperglycemia or new-onset or
serologies for these infections should be considered for exacerbated diabetes in pregnancy (see also Appendix 2).
immunization postpartum, depending on their CD4 count, If a woman is receiving a PI-based regimen, particularly
and the schedule of recommended immunization for one initiated before pregnancy, consideration can be given
adults living with HIV should be followed.33 In particular, to earlier screening for gestational diabetes.
HBV, pneumococcus, and influenza vaccines can be safely The second part of the integrated prenatal screening
administered in pregnancy. Within a harm reduction
tests (i.e., second trimester biochemical screening) should
model, women should be encouraged to stop smoking,
be performed at 15 to 19 weeks.105 A detailed ultrasound
drinking alcohol, and using recreational drugs and should
at 18 to 20 weeks is recommended to assess growth and
be referred for appropriate counselling support and/or
fetal anatomy.105 If aneuploidy or any other fetal infection
treatment.1,108,109 Other harm reduction strategies that can
or syndrome that has prenatal diagnostics is a concern,
be offered if appropriate include nicotine replacement
invasive testing should be considered. Invasive testing
treatment and opiate harm reduction measures such as
should only occur if statistical risk of the condition is higher
methadone and/or buprenorphine programs.
than the risk of the procedure, taking into consideration
Second Trimester (Weeks 14 to 27) the biochemical, serologic, and ultrasound results.105 When
Assessment of the status of the woman’s HIV, review amniocentesis is performed, the woman should ideally be on
of laboratory investigations from the first trimester, and cART, but the timing may not permit full suppression of her
re-evaluation of antiretroviral drug therapy should be HIV viral load prior to the procedure. In the pre-cART era,
completed during the second trimester. The women’s the risk of vertical transmission in women who underwent
amniocentesis was twice as high as those who did not (30% Between 30 to 35 weeks it is important that a plan for location
vs. 16%, RR = 1.85; 95% CI 0.69–4.98.111 Since the initiation and mode of delivery is established and a formula-feeding
of cART and the recommendation to treat all pregnant plan has been arranged for the infant. Women living with
women, there have been no documented transmissions.112–115 HIV are recommended to formula feed their infants; to
However, it is impossible to rule out a residual small increase avoid the 9.3% (3.8 to 14.8%) increased risk of post-natal
in risk of transmission with amniocentesis in women transmission of HIV through breast milk, breastfeeding is
on cART with a fully suppressed plasma viral load. Non- not recommended.119–121 The risk of disclosure that may arise
invasive molecular prenatal testing should be considered as when a women does not breastfeed may compromise her
an option to avoid invasive testing.116 confidentiality. Health care providers should assist with a plan
before delivery that can help women feel more comfortable
General obstetrical management with referral of the when discussing feeding with family and friends.
woman to support services as needed is appropriate at
this time. A review of the care providers involved and Plans for ongoing HIV care should also be established at
the delivery plan, including location of delivery, can be this time (see Postpartum Management).
initiated at this time (at the 19- to 20-week and 23- to
24-week visits). Delivery Plans and Mode of Delivery
Planning the hospital location for delivery should take
Third Trimester (Weeks 28 to 40) into consideration the woman’s gestational history, home
The efficacy and toxicity of the particular cART regimen location and transportability, facilities at her regional
for each woman should be determined by CD4-cell count, hospital, and the comfort and experience of the local care
HIV viral load, and hematologic, liver, and renal parameters providers. If delivery is being considered outside a regional
in the third trimester, approximately every 4 to 8 weeks (see tertiary care facility, information on pregnancy history and
Table 4). Given the risk of placental dysfunction associated management plans should be provided to the facility prior
with increased rates of intrauterine growth restriction and to the woman’s estimated date of delivery, communication
oligohydramnios in the pregnancies of women living with with local care providers should be established, and
HIV,117 follow-up growth ultrasound should preferably be arrangements should be made to ensure that required
done monthly, but if this is not possible, a third trimester intrapartum and postpartum antiretroviral drugs are
scan can assist in determining whether there has been available at the designated facility.
placental or fetal compromise. Considering the higher
rate of preterm birth in this population,67,83,86,92 close Mode of delivery has been reviewed extensively with
clinical follow-up is recommended and the schedule of both cohort studies and a randomized controlled trial
some obstetrical assessments (e.g., group B streptococcus of intended mode of delivery. The burden of evidence
screening) and prophylaxis (e.g., genital herpes prophylaxis) supports a vaginal delivery if obstetrically appropriate and
may need to be adjusted. if virologic suppression has been achieved.8,16,122–124 The
initial studies that identified elective Caesarean section as
Adherence to cART regimens should be emphasized at a method to reduce vertical transmission were conducted
each visit throughout pregnancy; however, this is critical in women who were not receiving any antiretroviral drug
in the third trimester because virologic suppression (HIV therapy or who received monotherapy with zidovudine
viral load < 50 copies/mL) should be achieved at this only. Evidence to support elective Caesarean section in the
time. If the woman’s viral load has not been suppressed current cART era, when all women (even with viral loads
or has appeared to rebound, a number of factors must be < 1000 copies/mL) are recommended to initiate cART
considered. Health care providers should reassess overall in pregnancy,16 is absent. European surveillance data124,125
adherence, clarify any reasons for non-adherence, and did not show a significant benefit of elective Caesarean
attempt to implement strategies or provide tools to assist delivery in the cohort of women with undetectable viral
the woman in taking her medication. Inpatient directly loads while on cART. Therefore, the evidence supports
observed therapy may be considered.118 Clinicians should elective Caesarean section at 38 weeks to minimize the
also reassess dosing adequacy and consider the need for risk of presentation in spontaneous labour only in women
increased dosing of antiretroviral medications in the third who have an unknown viral load, who have a viral load
trimester. Therapeutic drug level monitoring may also be > 1000 copies/mL, or who are not on cART regardless
considered to guide the need for dose adjustment.54 In of viral load. The booking time of 38 weeks for Caesarean
all cases viral genotype history should be reassessed and section, rather than the usual 39 weeks, is proposed
current HIV viral load sample sent for repeat genotyping because avoidance of labour in this setting is paramount.
if applicable. Considering the potential complications of operative
in the NIH perinatal guidelines,3 where intrapartum IV prophylaxis according to protocol; and, if a woman
zidovudine (but not single-dose oral nevirapine) and has ruptured membranes and is not in labour, initiate
combination infant antiretroviral with zidovudine plus oxytocin induction of labour in addition to intravenous
3 doses of nevirapine is recommended for women who zidovudine (the medications are compatible).
were not receiving antepartum antiretroviral therapy (or
those with incomplete viral load suppression). However, Intrapartum management for woman of
in our experience a number of practicalities must be unknown HIV status and/or ongoing HIV risk
considered when women present in labour, including the Many women who are at risk for HIV infection do not
frequent difficulty of obtaining IV access, which makes the receive antenatal care and present late in their pregnancy
administration of IV zidovudine difficult or impossible. or in early labour with unknown HIV status. Women at
Because single-dose oral nevirapine has been demonstrated particular risk of HIV infection include those who use
to reduce vertical transmission of HIV,23 it continues to be injection drugs and have shared needles; have had a recent
recommended for intrapartum administration to women illness suggestive of seroconversion; have had regular
living with HIV who have not received antenatal therapy, unprotected sex with a partner known to be living with
HIV or at significant risk for HIV infection; or have had
in addition to administration of cART to their infants. The
a diagnosis of a sexually transmitted infection during the
addition of 7 days of lamivudine-zidovudine postpartum
pregnancy. Women who have been recently incarcerated or
for the mother is recommended in order to mitigate the
who have emigrated from areas with endemic HIV are also
risk of nevirapine resistance.31
at increased risk if they have not been recently screened.
Mode of delivery has been described in detail above. Elective
Women with unknown HIV status or at continued risk of HIV
Caesarean section at 38 weeks of gestation to reduce the
infection since their last negative HIV serology result should
risk of vertical transmission of HIV is recommended for
be offered (if available in the institution) rapid HIV antibody
women with a viral load > 1000 copies/mL at delivery or
testing in the labour and delivery setting with appropriate
those with an unknown viral load (e.g., have not accessed
pre- and post-test counselling. If the test result is positive, the
care and/or are not taking antiretroviral drug therapy) near
woman should be informed of the result, and confirmatory
the time of delivery. Importantly, there are limited data to
HIV PCR and antibody tests should be performed.12,13
support the benefit of emergency Caesarean section for the
Maternal intrapartum antiretroviral drug therapy (intravenous
purpose of reducing the risk of vertical HIV transmission.
zidovudine and single-dose oral nevirapine) plus postpartum
Women on optimal antiretroviral therapy with acceptable
zidovudine-lamivudine (Combivir, 1 tablet orally twice daily for
plasma viral load suppression (less than 1000 c/mL) over
7 days; see Postpartum Management) and infant prophylactic
the last 4 weeks prior to delivery are recommended to
cART (see Infant Management) should be initiated pending
have a vaginal delivery (in the absence of other obstetrical
results of the confirmatory test. If the confirmatory test
indications for Caesarean section). If Caesarean section
is negative, maternal and infant antiretroviral drugs may be
is recommended for obstetrical indications, this can be
discontinued.
conducted at 39 weeks usual for those indications.
It is recommended that all women who have not been
Data from the pre-cART era indicate that obstetrical
tested in pregnancy, particularly those who are recognized
interventions that increase the exposure of the infant
to be at high and ongoing risk for HIV infection, be
to maternal blood, such as invasive monitoring or offered HIV testing as soon as possible, with appropriate
episiotomies, may increase the risk of transmission.129–132 pre- and post-test counselling. Women involved in
Extrapolating these data into the present era of cART, it is ongoing high-risk HIV transmission activities who are
recommended that interventions that potentially increase HIV negative on initial testing should be retested each
fetal exposure, including scalp electrodes, intrauterine trimester,12 and if possible again near term. HIV testing
catheters,133 prolonged rupture of membranes, operative should also occur with the woman’s knowledge and verbal
vaginal deliveries, and episiotomies, should be avoided consent, and appropriate pre- and post-test counselling
if possible. However, some Canadian data have been should accompany each test.
reassuring about the risk of HIV transmission in
HIV-suppressed women with prolonged membrane If rapid HIV antibody testing is not available within
rupture.133 Additional important considerations during the institution and/or delivery is imminent and HIV
the intrapartum period include, among others: epidural seropositivity is a possibility, HIV PCR and HIV antibody
anaesthesia is not contraindicated; if a woman is group tests should be performed. Intrapartum and postpartum
B streptococcus positive, continue to initiate antibiotic (IV zidovudine, single-dose oral nevirapine, Combivir)
antiretroviral drugs therapy should be offered to the woman, report higher rates of endometritis and pneumonia
and all infants should receive prophylactic antiretroviral following Caesarean section in women living with HIV than
therapy pending results (see Infant Management). If the in women without,136 but others do not.135 Endometritis
HIV antibody test is negative and the woman is out of the does, however, occur in a higher percentage of all women
seroconversion period (e.i., has not engaged in high-risk following Caesarean section, and routine preoperative
activities within the previous 4 weeks) and/or HIV PCR prophylactic antibiotics have been demonstrated to
is negative, infant antiretroviral prophylactic therapy and decrease postoperative infection.140 Preoperative antibiotics
maternal zidovudine-lamivudine may be discontinued. If are therefore recommended for all women who undergo
the woman at risk is found to be living with HIV, a full elective or emergent Caesarean section, including women
6-week course of infant antiretroviral prophylactic therapy living with HIV, to decrease infectious postoperative
should be completed and the woman should receive a complications.141 Women who were receiving antenatal
complete 7-day course of oral zidovudine-lamivudine to antiretroviral therapy should have their complete regimen
prevent the emergence of nevirapine-resistant virus. A resumed after delivery as soon as oral intake is tolerated.
referral should be made for ongoing HIV assessment and Women who were not receiving antenatal antiretroviral
care for both the mother and the infant for all women therapy but who received single-dose nevirapine during
who are determined to be living with HIV during labour labour should receive 7 days of zidovudine-lamivudine, 1
or delivery. Appendix 3 summarizes intrapartum and tablet orally twice daily, to reduce the risk of developing
postpartum recommendations and includes a management nevirapine resistance. Zidovudine-lamivudine therapy
algorithm for women known to be living with HIV or in can be discontinued before completion of the 7-day
whom HIV infection has not been ruled out. treatment period if confirmatory HIV testing results show
that the woman is not living with HIV. Plans for ongoing
Recommendations HIV care should be established prenatally, and unless
18. Intravenous zidovudine should be initiated as otherwise indicated, maternal antiretroviral therapy should
soon as labour onset until delivery, in combination be continued after delivery and reassessed for ongoing
with an oral combination antiretroviral regimen, therapy by providers of adult HIV care. Based on future
regardless of mode of delivery, current pregnancy planning and adult HIV status, antiretroviral
antiretroviral regimen, or viral load. (III-B) treatment modifications may be appropriate. Adherence in
19. Intrapartum, a single dose of oral nevirapine the postpartum period can be challenging142,143 and support
(200 mg) remains an option in the unusual is important.
circumstance of a woman living with HIV who
has not received antenatal antiretroviral therapy in There is a risk of HIV transmission through breast
pregnancy. (II-2B) milk119,121; therefore breastfeeding is contraindicated
regardless of maternal antiretroviral therapy or viral load.
Management of the effects of not breastfeeding should
POSTPARTUM MANAGEMENT include measures such as acetaminophen, ibuprofen, and
cold compresses to minimize pain from engorgement.
Postpartum care involves collaborative efforts between Bromocriptine and cabergoline, the classical therapies
obstetric care providers, HIV specialists, and other used for lactation suppression, are ergot derivates, whose
multidisciplinary health care providers to ensure co-administration with PIs is contraindicated. Women
coordinated HIV care for both the mother and her infant. who test positive on rapid HIV antibody testing or who
A number of comprehensive issues that must be addressed are believed to be at high risk of HIV (when rapid HIV
include contraception, continuation of and adherence to antibody testing is not available) are advised to pump their
antiretroviral drug therapy regimens, infant feeding and breast milk, but they should not feed it to the infant unless
pediatric care, and the woman’s needs for mental health a confirmatory HIV test is negative.
services, social services, and/or treatment of substance use.
An early return to fertility can be expected as a result
The use of ergotamine should be avoided because of the of not breastfeeding. It is critical to discuss safer sex
risk of exaggerated vasoconstriction in women receiving practices and effective contraception methods with the
protease inhibitor therapy.134 Oxytocin, misoprostol, women. Condom use is recommended to reduce the
and prostaglandin F2 alpha are recommended agents for risk of transmission between partners; however, the
managing postpartum hemorrhage. A number of studies contraception failure rate with condoms is reported to be
have evaluated the risk of infectious morbidity following as high as 14% as commonly used.144 Oral contraceptives
delivery in women living with HIV.135–139 Some studies may also be used by women living with HIV, particularly
with the use of condoms as part of a dual-protection or to a mother known to be living with HIV and who
strategy. Drug interactions between antiretroviral drugs did not receive any antepartum antiretroviral therapy
and oral contraceptives have been documented; therefore (this includes a mother who is presumed to be living with
it is important to assess for potential interactions between HIV based on a positive rapid HIV antibody test result)
specific antiretroviral agents and oral contraceptives. should receive prophylactic cART with a 3-drug regimen
This information is available in the NIH Perinatal HIV including zidovudine for 6 weeks combined with 3 doses
Guidelines3 and on the Motherisk website.145 Non- of nevirapine in the first week of life (at birth, day 2,
oral contraceptive methods including DMPA (Depo- and day 6 of life) and twice-daily oral lamivudine for 2
Provera), contraceptive patch or vaginal ring, and weeks. This recommendation is made on the basis of the
levonorgestrel IUD are also options; however, data for HPTN040/PACTG 1043 trial which enrolled women living
them in combination with antiretroviral medications is with HIV who were not receiving antenatal antiretrovirals
not available. The side effect profile of DMPA has been and demonstrated that combination regimens had better
shown to be the same in women living with and without efficacy (2.2%) in reducing vertical transmission to infants
HIV146; however, consideration should be given to the intrapartum than zidovudine alone (4.8%).25 While this
bone loss seen in women using DMPA, since bone loss trial does not address whether prophylactic cART provides
in women living with HIV is already faster than in their additional protection against transmission in infants born to
uninfected counterparts. Data on copper or levonorgestrel mothers who have suboptimal viral suppression near delivery
IUD use in women living with HIV are limited, but given (i.e., > 1000 copies/mL), extrapolation of those results
the value of this method for successful contraception suggests that prophylactic cART should be recommended,
and low general rates of infection, use in women with particularly in situations involving vaginal delivery. Although
CD4-cell counts > 200 cells/mm3 is appropriate.144 the HTPN040/PACTG 1043 trial evaluated a 2-drug
Linkage to care is important for all women living with zidovudine and nevirapine combination regimen, the
HIV, particularly those who are newly diagnosed with addition of a third agent, lamivudine, is recommended in
HIV during labour and delivery. All women should order to prevent the emergence of nevirapine resistance
have arrangements for follow-up care with providers should the infant be infected with HIV. The rationale for this
experienced in the management of HIV. recommendation is to provide a highly active antiretroviral
regimen throughout the first 2 weeks of life when nevirapine
Recommendation is expected to be circulating at decreasing but significant
20. Plans for ongoing HIV care should be established levels, due to its very long half-life (median 30 hours, range
prenatally, and unless otherwise indicated, maternal 18 to 50 hours in newborns).27 In settings where rapid HIV
antiretroviral therapy should be continued after antibody testing is not yet available, the optimal management
delivery and reassessed for ongoing therapy by strategy for infants born to women with unknown HIV
providers of adult HIV care. (II-1A) status and considered at high risk of HIV infection has
not been established in a randomized clinical trial. In this
INFANT MANAGEMENT clinical scenario, the potential benefit of preventing vertical
transmission of HIV is believed to outweigh the potential
Mothers should be offered antiretroviral prophylaxis for risks of the infant’s unnecessary exposure to antiretrovirals;
their infants regardless of maternal antenatal or intrapartum therefore combination infant prophylaxis (with zidovudine,
antiretroviral therapy, viral load, or mode of delivery. The 3-dose nevirapine, and lamivudine) is recommended until
recommended regimen will depend on the presumed level confirmatory HIV test results are available. Surveillance
of risk. Infants born to a mother known to be living with and poll-result data reported out of the United Kingdom,
HIV and a viral load < 1000 copies/mL should be offered Ireland, and United States indicate increasing use of
prophylactic therapy with oral zidovudine for 6 weeks. prophylactic cART for infants in high-risk situations.147,148
Intravenous zidovudine may be used if the infant is unable Until HIV-negative status can be confirmed, pumping breast
to tolerate oral intake. The dose of zidovudine is determined milk, but not feeding it to the infant is recommended.
based on gestational age, with a twice-daily dosing regimen
now recommended for all infants (see Appendix 4). The Dosing recommendations and commercial names for
infant zidovudine prophylaxis should be started as soon as the prophylactic antiretroviral agents are specified in
possible, no later than 6 to 12 hours after birth. Appendix 1. Of note, hepatic clearance is slower in preterm
infants, but pharmacokinetic data informing dosing are
Infants born to a mother known to be living with HIV and limited, particularly in infants with a birth weight below
who has a known or projected viral load > 1000 copies/mL 1.5 kg.149,150
Breastfeeding remains contraindicated for mothers living and expected to be further decreased with continued
with HIV regardless of maternal viral load, antepartum zidovudine exposure, early discontinuation of zidovudine
cART regimen, and continuation of postpartum prophylaxis at 4 weeks may be considered. Hematologic
antiretroviral therapy. In Malawi, peripartum HIV toxicity may be more common with exposure to cART;
transmission through breastfeeding was found to be as high however, data are limited.3 In high-risk newborns receiving
as 4% at 48 weeks when mothers were prescribed cART cART prophylaxis for the first 2 weeks of life, clinicians
or infants received daily nevirapine prophylaxis versus should consider obtaining an earlier CBC to monitor for
7% in the absence of maternal or infant antiretrovirals.118 toxicity. There is no evidence for nevirapine associated
Canadian surveillance data and a meta-analysis also show rash or hepatic toxicity in infants receiving either single-
high rates of postpartum virologic rebound due to non- dose or extended-dose nevirapine. Infants rarely present
adherence among women who are prescribed ongoing symptoms of mitochondrial toxicity; however, if an infant
cART.142,143 presents with unexplained neurologic or gastrointestinal
symptoms, hepatic function (ALT, AST) and serum lactate
It is important to discuss feeding practices with the mother should be measured.71,73
during antenatal visits, using a sensitive approach and
acknowledging the mother’s cultural beliefs about infant All infants born to women living with HIV should be
feeding. Because premastication by caregivers living with referred for ongoing assessment and care to a pediatrician
HIV has been implicated as a potential route of HIV with expertise in this area. Developmental follow-up is
transmission to young infants, health care practitioners crucial for HIV-exposed uninfected children. Factors such
should also inquire specifically about premastication and as poverty, food insecurity, low literacy, inexperience in
advise caregivers living with HIV to avoid this practice. parenting, and parental substance or alcohol use put infants
at higher risk for failure-to-thrive, developmental delay, and
Infants exposed to HIV should be tested for HIV infection behavioural disorders. Family physicians and pediatricians
by a virological test at birth, 4 weeks, and 3 to 4 months play an essential role in identifying and addressing such
of age to determine HIV status. Additional testing for issues in uninfected HIV-exposed infants and children,
infants at high risk of vertical transmission should be and they should facilitate referrals to specialists and
discussed with a pediatric HIV specialist. HIV RNA PCR developmental resources.
(or nucleid acid amplification test) is the virological test
currently used for diagnostic purposes. HIV infection Long-term follow-up of children who were perinatally
can be excluded when two HIV virological tests are non- exposed to HIV and antiretrovirals is recommended into
reactive, one collected after 4 weeks of age and the other at adulthood, due to unknown and theoretical concerns
least 4 weeks after the end of prophylactic antiretrovirals. regarding the potential for carcinogenicity of nucleoside
Serological EIA tests are not indicative of infant status due analogue antiretroviral drugs or other long-term effects of
to the presence of detectable maternal HIV antibodies up antiretroviral medications. 3
to 18 to 24 months of age. A confirmatory HIV EIA test Including all HIV-exposed mother-infant pairs in the
is recommended to document seroconversion after 18 national surveillance program (CPHSP) is essential to
months of age. keep generating important epidemiological data and
to support continued access to resources for these
If an HIV PCR is reactive, a confirmatory RNA PCR test
vulnerable families.
should be requested immediately. When an infant is found
to be infected with HIV, antiretroviral prophylaxis should Recommendations
be discontinued, and an urgent referral to an HIV specialist
21. HIV-exposed newborns should receive
should be made for HIV therapy and comprehensive care.
antiretroviral therapy for 6 weeks to prevent vertical
Early initiation of cART has been shown to improve long-
transmission of HIV. (I-A)
term outcomes151 and may prevent the establishment of
22. Health care practitioners who care for HIV-exposed
viral reservoirs in infected infants.152
newborns should provide timely diagnostic HIV
Infants should also be monitored with a CBC and testing: HIV polymerase chain reaction at birth,
differential at baseline and at 4 weeks of age. Zidovudine 1 month, and 3 to 4 months and HIV serology at
prophylaxis is generally well tolerated, but low grade 18 months (II-A), and they should monitor both
anemia or neutropenia with elevated platelet count are short- and long-term outcomes, including screening
not uncommon after receipt of 4 weeks of zidovudine for adverse effects of antiretroviral therapy and for
prophylaxis.18,19,93,153 If hemoglobin levels are below 100 g/L developmental delay. (III-A)
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continued
APPENDIX 1. Continued
Preliminary reactive (preliminary positive): antibodies to HIV were detected OR indeterminate: unable to interpret result
Discuss with woman:
– the possibility of HIV infection;
– the need for a confirmatory blood test (diagnostic HIV PCR results available in approximately one week);
– immediate treatment recommendations to prevent HIV vertical transmission;
– steps to prevent transmission;
– the follow-up care and support available to her.
Post-test documentation
Notify the local health authority of any preliminary positive result.
Document discussions in the woman’s Health Record.
Ensure contact information for the woman is available in the Health Record.
HIGH risk of HIV and undocumented prenatal HIV serology (or ongoing risk of HIV risk since most recent HIV test)
Preliminary reactive or Initiate treatment for prevention of HIV vertical transmission
Indeterminate or
Invalid:
Non-reactive but involved in high-risk HIV transmission activity Initiate treatment for prevention of HIV vertical transmission
in previous 4-weeks (within possible ‘window’ period
of infection):
Non-reactive and no identifiable risk within the past 4 weeks No further intervention.
LOW risk of HIV and undocumented prenatal HIV serology
Preliminary reactive or Initiate treatment for prevention of HIV vertical transmission
Indeterminate
Non-reactive or No further intervention
Invalid
continued
APPENDIX 1. Continued
MANAGEMENT ALGORITHM FOR WOMAN OF UNKNOWN HIV STATUS OR ONGOING HIV RISK
in institutions where rapid HIV antiboby test is AVAILABLE
(ZDV = Zidovudine, 3TC = Lamivudine, NVP = Nevirapine)
Unknown HIV status or ongoing HIV risk since last HIV serology was performed
Contact local health services authority to access serology results if available
and and
and and
continued
APPENDIX 1. Continued
MANAGEMENT ALGORITHM FOR WOMAN OF UNKNOWN HIV STATUS OR ONGOING HIV RISK
in institutions where rapid HIV antiboby test is NOT AVAILABLE
(ZDV = Zidovudine, 3TC = Lamivudine, NVP = Nevirapine)
Unknown HIV status or ongoing HIV risk since last HIV serology was performed
Contact local health services authority to access serology results if available
Single-dose NVP B) If all HIV EIA and HIV PCR tests drawn are
NEGATIVE in mother and infant:
and
DISCONTINUE ALL antiretroviral drug therapy
ZDV-3TC (Combivir®) x 7 days postpartum
ZDV x 6 weeks
and
continued
APPENDIX 2. Continued
Protease Inhibitors
Drugs in this class function as competitive inhibitors that bind to the HIV protease enzyme and prevent the conversion of HIV viral particles into
mature infectious forms.153 PIs are recommended in pregnancy in combination with a dual NRTI backbone. Individual PIs are most commonly
administered together with low-dose ritonavir (r), which functions as a pharmacokinetic booster to increase serum drug levels of the first PI.
Short-term studies have demonstrated the safety and tolerance of the co-formulated combination of lopinavir/ritonavir (LPV/r), and as a result
of this and clinical experience with its use, LPV/r is considered the first-line agent for use in pregnancy. Alternative agents for use include
boosted atazanavir (ATV/r), which has growing short-term safety and efficacy data in pregnancy; boosted darunavir (DRV/r), and boosted
saquinavir (SQV/r), which has also been shown to be well tolerated and safe in short-term studies, but requires a baseline electrocardiogram
prior to the start of therapy. Because of associated adverse effect profiles and/or pharmacokinetic limitations in pregnancy, boosted indinavir
(IDV/r) and nelfinavir (NVF) should be reserved for use in special circumstances when other agents cannot be used. Current data in pregnancy
are insufficient to recommend use of the newer agents including boosted fosamprenavir (FPV/r) or tipranavir (TPV/r).
The pharmacokinetics of PIs are variable in pregnancy, particularly in the second and third trimester. Current data suggest that exposure
to LPV/r, ATV, and NVF is decreased during the second and third trimesters. However, the clinical significance of reduced exposure to
antiretroviral drugs during pregnancy is not clear. The need for a dose increase in pregnancy will depend on the treatment experience of the
specific woman, the use of concomitant interacting medications (e.g., TDF or histamine receptor antagonists with ATV), and virologic response
to the prescribed dose throughout pregnancy. HIV viral load must be followed closely, particularly in the second and third trimesters, to ensure
virology failures due to increased plasma volumes, and subsequent reduced PI concentrations, do not occur. Consideration should be given
to a PI dose increase in this situation. There is currently no standard recommendation for monitoring drug levels in pregnancy; however, if
available, therapeutic drug monitoring may also be considered to guide the need for PI dose adjustment.53 All PIs have minimal to low placental
transfer to the fetus, with cord-to-maternal blood ratios < 0.3. All PIs are classified as FDA pregnancy category B or C. None of the PIs have
been demonstrated to cause gross structural abnormalities in animals; however, minor skeletal variations (e.g., increase in supernumerary ribs,
ossification delays) and growth inhibition has been reported with high dose ritonavir (RTV), IDV, TPV/r , and FPV. The majority of PIs have not
been demonstrated to be teratogenic in human studies; however, data with the use of DRV, FPV or TPR/r in human pregnancy are limited.3,41
continued
APPENDIX 2. Continued
Integrase Inhibitors
This class of drugs includes 2 agents, raltegravir and elvitegravir (EVG), that function as competitive inhibitors of the HIV integrase enzyme,
preventing the insertion or integration of HIV genetic DNA into the host cell DNA (i.e., strand transfer inhibition). Elvitegravir is currently
only available as part of a fixed-dose combination tablet with the pharmacokinetic enhancer cobicistat (COBI) and the NRTIs tenofovir and
emtricitabine (TDF 300 mg/FTC 300 mg/EVG 150 mg/COBI 150 mg).
Current data are insufficient to recommend the use of integrase inhibitors in pregnancy. No pharmacokinetic data or placental transfer
information is available for elvitegravir-cobicistat. Limited pharmacokinetic data suggest that although raltegravir shows extensive variability
in the third trimester, postpartum and historical data show consistent exposure, and standard dosing appears appropriate in pregnancy.
Case report data suggest a high placental transfer rate to the fetus, with a reported cord-to-maternal blood ratio of approximately 1.0.41,209
Raltegavir is classified as FDA pregnancy category C; animal studies have not found evidence of gross developmental abnormalities;
however, increases in the incidence of supernumerary ribs have been observed in rats receiving raltegravir doses 3 times the
recommended human dose. There is only limited experience with raltegravir in human pregnancy; case report data show the addition of
raltegravir in the third trimester to rapidly decrease viral load at the time of delivery.190,210,211
Elvitegravir and colbicistat (as components of the combination antiretroviral Stribil) are classified as FDA pregnancy category B; animal
studies have not shown evidence of teratogenicity or gross structural abnormalities. There are no reported data in human pregnancies.212
This Appendix applies to women with known HIV infection, to women with potential HIV infection based on rapid HIV antibody test results,
and (when rapid HIV antibody testing is not available) to women considered at high risk of HIV infection, but whose HIV status is unknown.
2. Standard universal precautions should be undertaken for protection from blood and bodily fluids (use gown, mask, eye protection, and
gloves during delivery) according to details available in an infection control manual. No additional precautions are required.
3. Laboratory tests:
a. On admission, tests should be performed for
• CBC, differential, creatinine, urea, AST, ALT, bilirubin, and glucose;
• HIV viral load; and
• CD4-cell count.
b. Performance of prenatal blood tests, including HBV and HCV serology, RPR, rubella, and varicella IgG, should be verified.
c. The placenta should be sent to pathology for examination after delivery.
d. Appropriate blood test results should be obtained for any study in which the woman has previously consented to participate.
5. Mode of delivery should be discussed in detail with women known to be living with HIV.
a. Women on optimal antenatal antiretroviral therapy with a recent (within last 4 weeks) HIV viral load ≤ 1000 copies/mL are
recommended to have a vaginal delivery if obstetrically appropriate and the woman was adherent to antenatal antiretroviral therapy.
b. Women not on optimal antiretroviral therapy (e.g., no antenatal antiretroviral therapy or with a recent [within last 4 weeks] HIV viral
load or projected viral load > 1000 copies/mL) should be offered a pre-labour Caesarean section at approximately 38 weeks of
completed gestation. If the woman is in labour or there has been rupture of membranes, Caesarean section has not been shown to
reduce transmission.
6. Antenatally prescribed antiretroviral therapy should usually be continued for as long as possible during labour; however, oral stavudine
(d4T or Zerit) should be discontinued because of its antagonistic interaction with intravenous zidovudine.
continued
APPENDIX 3. Continued
9. Prophylaxis against opportunistic infections should be offered to women who are immunocompromised.
10. Assessment and discussion of contraception, mental health, need for social services, or treatment of substance use indicated should
be undertaken prior to discharge.
11. Breastfeeding is contraindicated in women with known HIV infection regardless of maternal antiretroviral therapy and viral load. In
women in whom HIV infection has not been ruled out, breast milk pumping and avoidance of breast milk infant feeding is recommended
until HIV negative status is confirmed,
Combination ART:
Infant
ZDV x 6 weeks*
ZDV x 6 weeks and 3-doses NVP (day 0, 2, 6) and 2-weeks 3TC
* Use of combination ART for prophylaxis may be warranted in circumstances when infant is born to a mother with poor adherence to antenatal ART
and/or with non-suppressed VL (i.e., VL 40-999 copies/mL) particularly when delivered vaginally. Consult with pediatrician with expertise in HIV.
This Appendix applies to infants born to mothers with known HIV infection, mothers with potential HIV infection based on rapid HIV antibody
test result, and mothers considered at high risk of HIV infection but with unknown HIV status when rapid HIV antibody test is not available.
2. Standard universal precautions should be undertaken for protection from blood and bodily fluids (use gown, mask, eye protection, and
gloves during delivery) according to details available in an infection control manual. No additional precautions are required.
4. Breastfeeding is contraindicated in women with known HIV infection regardless of maternal antiretroviral therapy and viral load. In
women in whom HIV infection has not been ruled out, breast milk pumping and avoidance of breast milk infant feeding is recommended
until HIV negative status is confirmed.
5. Prophylaxis should be offered to prevent HIV vertical transmission to the infant, whether or not the mother received antiretroviral
therapy at delivery.
a. All infants should be given oral or intravenous zidovudine beginning immediately after birth. Oral therapy is preferred, but if the
infant is unable to tolerate oral feeds, intravenous therapy may be used.
b. Combination antiretroviral therapy with nevirapine and lamivudine (in addition to zidovudine) is given to infants born to mothers
who were not on optimal antiretroviral therapy (e.g., received no antenatal antiretroviral therapy) or with a recent HIV viral load
(measured within last 4 weeks) or projected HIV viral load greater than 1000 copies/mL.
Note: For infants born to mothers considered at high risk of HIV infection, but with unknown HIV status, when the rapid HIV antibody
test is not available prophylaxis with only single agent zidovudine may still be considered.
Nevirapine dosage (there is no IV formulation available):
• Infant > 2 kg: 12 mg PO for a total of 3 doses. First dose given immediately after birth (day 0), second dose given at 2 days
of age, third dose given at 6 days of age.
• Infant 1.5–2 kg: 8 mg PO for a total of 3 doses. First dose given immediately after birth (day 0), second dose given at 2 days
of age, third dose given at 6 days of age.
Lamivudine (3TC) dosage (there is no IV formulation available):
• Infant > 2 kg: 6 mg PO every 12 hours for 2 weeks.
• Infant 1.5–2 kg: 4 mg PO every 12 hours for 2 weeks.
6. Laboratory tests to be ordered within 48 hours after birth:
• CBC, differential, creatinine, urea, AST, ALT, bilirubin
• For infants born to mothers with known HIV infection or potential HIV infection based on rapid HIV antibody testing, infant
diagnostic HIV PCR should be performed with blood (minimum 2 mL in EDTA tube) and appropriate requisition sent to the local
CDC.
continued
APPENDIX 4. Continued
• For infants born to mothers with unknown HIV status (where rapid HIV antibody testing is not available), HIV EIA (antibody) is
the priority test over HIV PCR if a blood sample from the infant is difficult to obtain. Blood (minimum 2 mL in gold top tube) and
appropriate requisition should be sent to the local CDC. Infant diagnostic HIV PCR should be conducted within 48 hours, with
blood (minimum 2 mL in EDTA tube) and appropriate requisition sent to the local CDC.
7. Check maternal hepatitis B status. If the mother tests positive for hepatitis B surface antigen or has unknown status, administer first
dose of hepatitis B vaccine and hepatitis B immune globulin to the infant within 12 hours after birth.
8. The remainder of the zidovudine bottle should be supplied to the parent/guardian on discharge to treat the infant for the entire 6-week
course. If nevirapine and lamivudine (3TC) are required for the infant, adequate medication should be provided to the parent/guardian
on discharge from hospital to complete the treatment course.
9. Infants born to mothers considered at high risk of HIV infection, but with unknown HIV status (when the rapid HIV antibody test is not
available) should be referred to the local multidisciplinary HIV clinic if any HIV test (HIV EIA or HIV PCR) drawn is positive in mother
or infant. If all HIV tests (HIV EIA and HIV PCR) drawn are negative in both mother and infant all antiretroviral drug therapy may be
discontinued.
This document reflects emerging clinical and scientific advances on the date issued and is subject to change. The information
should not be construed as dictating an exclusive course of treatment or procedure to be followed. Local institutions can dictate
amendments to these opinions. They should be well documented if modified at the local level. None of these contents may be
reproduced in any form without prior written permission of the SOGC.
Table 1. Key to evidence statements and grading of recommendations, using the ranking of the Canadian Task Force
on Preventive Health Care
Quality of evidence assessment* Classification of recommendations†
I: Evidence obtained from at least one properly randomized A. There is good evidence to recommend the clinical preventive action
controlled trial
II-1: Evidence from well-designed controlled trials without B. There is fair evidence to recommend the clinical preventive action
randomization
II-2: Evidence from well-designed cohort (prospective or C. The existing evidence is conflicting and does not allow to make a
retrospective) or case–control studies, preferably from recommendation for or against use of the clinical preventive action;
more than one centre or research group however, other factors may influence decision-making
II-3: Evidence obtained from comparisons between times or D. There is fair evidence to recommend against the clinical preventive action
places with or without the intervention. Dramatic results in
uncontrolled experiments (such as the results of treatment with E. There is good evidence to recommend against the clinical preventive
penicillin in the 1940s) could also be included in this category action
III: Opinions of respected authorities, based on clinical experience, L. There is insufficient evidence (in quantity or quality) to make
descriptive studies, or reports of expert committees a recommendation; however, other factors may influence
decision-making
*The quality of evidence reported in these guidelines has been adapted from The Evaluation of Evidence criteria described in the Canadian Task Force on
Preventive Health Care.118
†Recommendations included in these guidelines have been adapted from the Classification of Recommendations criteria described in the Canadian Task Force
on Preventive Health Care.118
T
ultrasound is limited, it is reasonable to use a second-trimester
he accurate dating of pregnancy is critically important
scan to assess gestational age. (I)
for pregnancy management from the first trimester to
4. Notwithstanding Summary Statements 1, 2, and 3, women vary
greatly in their awareness of their internal functions, including delivery, and is particularly necessary for determining viability
ovulation, and this self-knowledge can sometimes be very in premature labour and in post-dates deliveries.1 Prior to
accurate. (III) the widespread use of ultrasound, caregivers relied on a
Recommendations combination of history and physical examination to clinically
1. First-trimester crown-rump length is the best parameter for
determine gestational age. Ultrasound gave clinicians a method
determining gestational age and should be used whenever to measure the fetus and therefore to estimate gestational
appropriate. (I-A) age. Much of our current clinical practice is based on studies
2. If there is more than one first-trimester scan with a mean sac from the 1980s and 1990s. As new information emerges in
diameter or crown-rump length measurement, the earliest
fields, such as reproductive biology, perinatal epidemiology,
ultrasound with a crown-rump length equivalent to at least 7
weeks (or 10 mm) should be used to determine the gestational and medical imaging, our current clinical practice is being
age. (III-B) challenged. “Certain” menstrual dating, for example, is less
3. Between the 12th and 14th weeks, crown-rump length and certain than previously thought.
biparietal diameter are similar in accuracy. It is recommended
that crown-rump length be used up to 84 mm, and the biparietal When ultrasound is performed with quality and precision,
diameter be used for measurements > 84 mm. (II-1A)
there is evidence to suggest that dating a pregnancy using
4. Although transvaginal ultrasound may better visualize
ultrasound measurements is clinically superior to using
early embryonic structures than a transabdominal approach,
it is not more accurate in determining gestational age. menstrual dating with or without ultrasound, and this has
Crown-rump length measurement from either transabdominal been advocated and adopted in other jurisdictions.2–6
or transvaginal ultrasound may be used to determine
gestational age. (II-1C)
5. If a second- or third-trimester scan is used to determine GESTATIONAL AGE ESTIMATES
gestational age, a combination of multiple biometric parameters USING CLINICAL DATING
(biparietal diameter, head circumference, abdominal
circumference, and femur length) should be used to determine The clinical estimate of gestational age typically relies on
gestational age, rather than a single parameter. (II-1A)
clinical history (menstrual cycle length, regularity, and recall
6. When the assignment of gestational age is based on a third- of the first day of the last menstrual period), followed by
trimester ultrasound, it is difficult to confirm an accurate due date.
Follow-up of interval growth is suggested 2 to 3 weeks following confirmation by physical examination or other signs and
the ultrasound. (III-C) symptoms.7–9
Dating Based on Menstrual History 11 days, and this may affect fetal size and growth.15 Even
Dating by certain menstrual history is inexpensive and in women who are certain of menstrual dating, delayed
readily available. Typically, the EDD is based on a 280- ovulation is an important cause of perceived prolonged
day gestation from the first day of the LMP. Certain pregnancy and is more likely to occur than early ovulation.16
menstrual dating criteria assume regular cycles, ovulation Some authors have suggested that 282 days should be used
at the midpoint of the cycle, fertilization on the middle instead of 280 to improve dating accuracy, since it is more
day of the cycle, correct recall of the onset of the LMP, likely that women will ovulate later rather than earlier than
and the woman having been free of oral contraceptives predicted.9 All of these factors conspire to make it difficult
for several months prior. Women vary greatly in their to accurately predict gestational age based on menstrual
awareness of their internal functions, including ovulation. history.
Their self-knowledge of ovulation can sometimes be very
accurate; however, the only truly certain clinical history Dating Based on Clinical Examination
is one in which the dates of ovulation, fertilization, The size of the uterus, estimated through pelvic or
and implantation are precisely known, as in ART, in abdominal examination, can be roughly correlated with
which records include the date of oocyte retrieval, and gestational age; however, factors that affect uterine size
other methods of timed ovulation and fertilization. (such as fibroids) and maternal body characteristics (such
Unfortunately, without timed ovulation and fertilization as obesity) will affect such an estimate. The uterus is
as in ART and other timed methods, clinical history is approximately the size of a grapefruit at 10 to 12 weeks.
often not reliable.10 Campbell et al. demonstrated that At 20 weeks the fundus reaches the umbilicus. After 20
45% of pregnant women are uncertain of menstrual weeks the symphysis fundal height, in centimetres, should
dates as a result of poor recall, irregular cycles, bleeding correlate with the week of gestation.7,17 Fetal heart tones
in early pregnancy, or oral contraceptive use within 2 are audible at 11 to 12 weeks with electronic Doppler
months of conception.11 devices, and this audibility can also assist in the clinical
assignment of gestational age.10
Even if menstrual history is correct, the exact time
of ovulation, fertilization, and implantation cannot be Gestational Age Estimation Based
known. Women may undergo several “waves” of follicular on Ultrasound Findings
development during a normal menstrual cycle, which Ultrasound biometric measurements determine
may mean ovulatory inconsistency during any given gestational age based on the assumption that the size of
cycle.12,13 Sperm may survive for 5 to 7 days in the female the embryo or fetus is consistent with its age. Biological
reproductive tract, a “known” conception date is therefore variation in size is less during the first trimester than in
not completely reliable.14 Recent studies suggest the the third trimester. Ultrasound estimation of gestational
ovulation-to-implantation duration can vary by as much as age in the first trimester is therefore more accurate than
later in pregnancy.18 Full descriptions of each parameter
and published ranges of accuracy are outlined in Table 2.
(Table 2).18,53 Maternal and fetal pathology may affect them, warranted. There is also a concern that when gestational
so their inclusion or exclusion in the determination of age assessment is based on a third trimester scan only, the
gestational age requires clinical judgement. fetus may in fact be growth restricted,61 and gestational
age therefore underestimated. Hence, a follow-up scan
The BPD is less reliable in determining gestational age when for growth in such circumstances should be considered to
there are variations in skull shape, such as dolichocephaly evaluate interval growth.
or brachycephaly; hence some authors feel that BPD is less
reliable than HC.9,53–57 As a single parameter, HC correlates Recommendations
better to gestational age than the other 3 standard parameters 5. If a second- or third-trimester scan is used to
in the second trimester, and as with all others, it becomes determine gestational age, a combination of multiple
less accurate with increasing gestational age.58–61 biometric parameters (biparietal diameter, head
circumference, abdominal circumference, and femur
It is more challenging to measure the fetal AC than the other length) should be used to determine gestational age,
parameters. The abdomen has no bright echoes of bone, it rather than a single parameter. (II-1A)
is not always symmetrical, and its size will vary with fetal 6. When the assignment of gestational age is based
respiration and central body flexion/extension. Of all the on a third-trimester ultrasound, it is difficult to
fetal biometric parameters, this measurement has the most confirm an accurate due date. Follow-up of interval
variability as it is somewhat dependant on fetal growth growth is suggested 2 to 3 weeks following the
factors and body position.54,61–63 ultrasound. (III-C)
Femur length varies somewhat with ethnicity. Short femurs Other Biometry
are commonly a normal variant, however this finding may Measurement of the transcerebellar diameter, foot length,
also indicate fetal growth restriction, aneuploidy, and— clavicle length, intra/interorbital diameters, kidney length,
when severely shortened—skeletal dysplasias.53,64–69 sacral length, scapula length, as well as the length of other
long bones of the extremity have also been evaluated to
Composite Versus Single Biometry Measurement
determine gestational age. Studies have not shown that
Using multiple parameters is superior to using a single
these parameters improve the assessment of gestational
second trimester parameter.63,70,71 As more parameters are
age beyond that achieved with standard biometry, however
used, accuracy improves; however, there is no significant
they may be useful in clinical situations in which traditional
benefit beyond 3 commonly used parameters.3,61,70–73
biometry is difficult to attain (such as uteroplacental
Multiple parameters are also useful if any one parameter insufficiency) or when fetal abnormalities are present.76–86
is affected by a fetal condition/syndrome, such as
Signs of Fetal Maturity
achondroplasia on femur length. It is prudent to evaluate
Identification of certain US findings suggest that a fetus
the etiology of an aberrant measurement to determine its
has reached the third trimester and may correlate with
clinical significance.
fetal lung maturity and gestational age. These parameters
Commonly, clinicians use the unweighted mean of all 4 are the epiphyseal ossification centres of the distal femur,
biometric parameters (BPD, HC, AC, and FL). However, it is proximal tibia, and proximal humerus. The measurement of
clear that all 4 are not equally correlative, thus many authors these ossification centres does not precisely correlate with
have created regression equations using various combinations gestational age; however, their presence may be helpful late
of biometric parameters to improve accuracy.54,61,74,75 It is not in pregnancy when the gestational age is not known. The
clear which method is superior in determining gestational presence of distal femoral epiphysis has a PPV of 96% for
age.61,72 Until more research is available, it is reasonable to use indicating a pregnancy of at least 32 weeks, the proximal
either when estimating second or third trimester gestational tibial epiphysis has a PPV of 83% for indicating a pregnancy
age. Up to 23 weeks, second trimester US has a 95% CI of of at least 37 weeks, and the proximal humeral epiphysis
less than a week for predicting gestational age, comparable has a PPV of 100% for indicating a pregnancy of at least
to first trimester US.61 In the late second trimester, clinical 38 weeks.87–91
judgement should be exercised.
WHAT IS THE BEST METHOD
Since the confidence intervals in the third trimester FOR ASSIGNING GESTATIONAL AGE?
are quite large (2 to 2.4 weeks), it is not clear that US
determined gestational age is superior to clinical history Currently, most centres in Canada use a combined
and the application of judicious clinical judgement may be approach in which US is used to confirm reliable
menstrual dating. If there is an unreliable menstrual between menstrual and US estimates of gestational
history, the US prediction of EDD is used. Clinical age is associated with an increased risk of obstetrical
judgement is used to resolve conflicting data. However, complications.107–114 Interestingly, an unreliable
centres vary in terms of confidence intervals and menstrual history itself confers an increased risk of
biometry charts used. adverse pregnancy outcomes.112 Although there may be
a risk in using US dating exclusively, some of this risk
Many studies evaluating menstrual dating, compared with would remain whenever there is discordance between
US dating, in the first and second trimesters have found US menstrual and US estimates, regardless of which method
dating superior for predicting the actual date of delivery.92–98 of gestational age assignment is used. Furthermore, the
No study has shown that it is inferior to menstrual dating. clinical management of such situations is unclear. More
Menstrual dating underestimates the US-based EDD by research is needed in this area.
an average of 2 to 3 days.95 Ultrasound dating alone was
significantly better in predicting the actual date of delivery Summary Statements
than any of the dating policies using menstrual dates alone 1. When performed with quality and precision,
or in combination with US.9,99 ultrasound alone is more accurate than a “certain”
menstrual date for determining gestational age
Many studies document that the use of US dates reduces in the first and second trimesters (≤ 23 weeks) in
the rate of post-dates pregnancy by about 70% even in spontaneous conceptions, and it is the best method
the face of certain menstrual history.92,96,97,99,100 The most for estimating the delivery date. (II)
recent Cochrane systematic review found reduced rates 2. In the absence of better assessment of gestational
of induction for post-term pregnancy (OR 0.59; 95% CI age, routine ultrasound in the first or second
0.42 to 0.83) among women who underwent routine US trimester reduces inductions for post-term
in early pregnancy (< 24 weeks) and concluded that early pregnancies. (I)
pregnancy US enables better gestational age assessment, as
well as conferring other benefits.101 SHOULD ROUTINE FIRST TRIMESTER
Using US-based gestational age assignment would also DATING ULTRASOUNDS BE
OFFERED TO ALL PREGNANT WOMEN?
result in improved performance of prenatal screening
programs. Using US estimates exclusively would increase A routine first trimester US has many advantages: early
sensitivity for Down syndrome anywhere from 9% to 16%, identification of gross anomalies and multiple gestations,
and/or decrease false-positive rates (for a set sensitivity) more precise dating, improved performance of prenatal
by 2.6%.102,103 There might be a very slight increase in the screening, and an opportunity to perform nuchal
screening positive rate for open neural tube defects, but translucency as part of prenatal genetic screening. In many
this is more than offset by the decrease in false-positive jurisdictions, a dating US is performed routinely in all
rates for Down syndrome. The common practice of women, regardless of menstrual history. The availability,
using certain menstrual dates confirmed by US is inferior quality, and health care cost of obstetrical US is a significant
to using US alone.104 In the context of serum screening, factor in local patterns of practice.2 Crowther et al. found
first and early second-trimester US parameters perform routine early US (< 17 weeks) provided more precise
similarly.100,102,104–106 estimates of gestational age than later US (18 to 22 weeks),
reduced the need to adjust the EDD in mid-gestation, and
Some clinicians fear that the exclusive use of US-based
decreased maternal anxiety.115
estimates of gestational age would result in pregnancy
complications because of the potential to miss early The balance of the literature supports using first trimester
growth discordance. A large-for-gestational-age fetus US to reduce the incidence of induction for post-dates
might be mistakenly assigned a greater gestational age pregnancy.18,99,100,116–118 Although no comprehensive cost
because of its larger size or an early growth-restricted benefit analysis has been done on routine early US for
fetus may be incorrectly assigned a later due date. This dating, the current literature suggests significant benefits
may potentially mask an underlying fetal or placental are present. Ideally, where it is readily available, a first
problem leading to pregnancy complications, such trimester US for dating should be performed. Where
as preterm birth, preeclampsia, and fetuses small for nuchal translucency is available, this scan can serve both
gestational age, or it may cause a delay in the recognition functions. When a first trimester US cannot be obtained,
of fetal abnormalities. There is disagreement in the the available evidence suggests the second trimester US
literature as to whether a significant discordance can be used for similar benefits.101
10. Johnson TR, Niebyl JR. Preconception and prenatal care: part of the
Summary Statements continuum. In: obstetrics: normal and problem pregnancies. 4th ed.
3. Ideally, every pregnant woman should be offered Philadelphia: Churchill Livingstone; 2002.
a first trimester dating ultrasound; however, if the 11. Campbell S, Warsof SL, Little D, Cooper DJ. Routine ultrasound
availability of obstetrical ultrasound is limited, it is screening for the prediction of gestational age. Obstet Gynecol
1985;65:613–20.
reasonable to use a second trimester scan to assess
gestational age. (I) 12. Baerwald AR, Adams GP, Pierson RA. A new model for ovarian
follicular development during the human menstrual cycle. Fertil Steril
4. Notwithstanding Summary Statements 1, 2, and 2003;80:116–22.
3, women vary greatly in their awareness of their 13. Baerwald AR, Adams GP, Pierson RA. Characterization of ovarian
internal functions, including ovulation, and this self- follicular wave dynamics in women. Biol Reprod 2003;69:1023–31.
knowledge can sometimes be very accurate. (III) 14. Leppaluoto P. Vaginal flora and sperm survival. J Reprod Med
1974;12:99–107.
SUMMARY 15. Mahendru AA, Daemen A, Everett TR, Wilkinson IB, McEniery CM,
Abdallah Y, et al. Impact of ovulation and implantation timing on first
The accurate determination of gestational age is required for trimester crown-rump length and gestational age. Ultrasound Obstet
Gynecol 2012;40:630–5.
many aspects of antenatal care. In the past, it was probably
16. Saito M, Keijiro Y, Akinori H, Takahiro K, Nozumu N, Kohei K. Time of
felt that a few days of inaccuracy was acceptable; however, ovulation and prolonged pregnancy. Am J Obstet Gynecol 1976;112:31–8.
emerging data suggests that a few days inaccuracy can
17. Beazley JM, Underhill RA. Fallacy of the fundal height. BMJ
affect things, such as the performance of maternal serum 1970;4:404–6.
screening, the assessment of post-dates pregnancy, and 18. Caughey AB, Nicholson JM, Washington AE. First- vs second-trimester
the subsequent induction of labour. Based on the available ultrasound: the effect on pregnancy dating and perinatal outcomes. Am J
research, the use of US-derived dates is the best method Obstet Gynecol 2008;198:703–5.
to determine gestational age for clinical use. It is not, 19. Laing FC, Frates MC. Ultrasound evaluation during the first trimester
however, intended to be used to determine the exact date of of pregnancy. In: Callen PW, ed. Ultrasonography in obstetrics and
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The guideline summarized here has been prepared by the Karen L. MacDonell, PhD, Vancouver BC
Canadian Hypertensive Disorders of Pregnancy Working Jean-Marie Moutquin, MD, Sherbrooke QC
Group, reviewed and approved by the Hypertension
Guideline Committee, reviewed by the Maternal Fetal Ilana Sebbag, MD, Vancouver BC
Medicine and Family Physician Advisory committees, and Disclosure statements have been received from all members of
approved by the Executive and Council of the Society of the committee.
Obstetricians and Gynaecologists of Canada. The literature searches and bibliographic support for this
guideline were undertaken by Becky Skidmore, Medical
PRINCIPAL AUTHORS Research Analyst, Society of Obstetricians and Gynaecologists
Laura A. Magee, MD, Vancouver BC of Canada.
This document reflects emerging clinical and scientific advances on the date issued and is subject to change. The information
should not be construed as dictating an exclusive course of treatment or procedure to be followed. Local institutions can dictate
amendments to these opinions. They should be well documented if modified at the local level. None of these contents may be
reproduced in any form without prior written permission of the SOGC.
Table 1. Key to evidence statements and grading of recommendations, using the ranking of the Canadian Task Force
on Preventive Health Care
Quality of evidence assessment* Classification of recommendations†
I: Evidence obtained from at least one properly randomized A. There is good evidence to recommend the clinical preventive action
controlled trial
II-1: Evidence from well-designed controlled trials without B. There is fair evidence to recommend the clinical preventive action
randomization
II-2: Evidence from well-designed cohort (prospective or C. The existing evidence is conflicting and does not allow to make a
retrospective) or case–control studies, preferably from recommendation for or against use of the clinical preventive action;
more than one centre or research group however, other factors may influence decision-making
II-3: Evidence obtained from comparisons between times or D. There is fair evidence to recommend against the clinical preventive action
places with or without the intervention. Dramatic results in
uncontrolled experiments (such as the results of treatment with E. There is good evidence to recommend against the clinical preventive
penicillin in the 1940s) could also be included in this category action
III: Opinions of respected authorities, based on clinical experience, L. There is insufficient evidence (in quantity or quality) to make
descriptive studies, or reports of expert committees a recommendation; however, other factors may influence
decision-making
*The quality of evidence reported in these guidelines has been adapted from The Evaluation of Evidence criteria described in the Canadian Task Force on
Preventive Health Care.39
†Recommendations included in these guidelines have been adapted from the Classification of Recommendations criteria described in the Canadian Task Force
on Preventive Health Care.39
● Classification of HDPs: 25–31 ● Timing of Delivery for Women With Preeclampsia: 81–88
● Investigations to Classify HDPs: 32–37 ● Timing of Delivery for Women With Gestational Hypertension:
89, 90
CHAPTER 2: ● Timing of Delivery for Women with Pre-existing
PREDICTION AND PREVENTION Hypertension: 91
● Predicting Preeclampsia: 38–40
● Mode of Delivery: 92–97
● Preventing Preeclampsia and its Complications in Women
● Anaesthesia: General Principles: 98–101
at Low Risk: 41–46
● Anaesthesia: Fluid Administration: 102–105
● Preventing Preeclampsia and its Complications in Women
at Increased Risk: 47–54 ● Monitoring: 106–108
● Coagulation: 109, 110
CHAPTER 3:
TREATMENT OF THE HDPs ● Aspects of Care Specific to Women Wth Pre-Existing
Hypertension: 111–115
● Dietary and Lifestyle Changes: 55–59
● Aspects of Care for Women With Preeclampsia: Magnesium
● Place of Care: 60, 61
Sulphate for Preventing or Treating Eclampsia: 116–123
● Aspects of Care for Women With Preeclampsia: Plasma
ABBREVIATIONS Volume Expansion: 124
BP blood pressure ● Therapies for HELLP Syndrome: 125–131
HDP hypertensive disorder of pregnancy ● Care in the 6 Weeks Postpartum: 132–142
HELLP hemolysis, elevated liver enzymes, low platelets ● Care Beyond 6 Weeks Postpartum: 143–148
IUGR intrauterine growth restriction ● Effects of Maternal Hypertension and its Therapies on Child
NICU neonatal intensive care unit Neurobehavioural Development: 149, 150
30. Severe preeclampsia, as defined in this guideline, diminished, or no, nocturnal BP decrease.4 Maternal
warrants delivery. (II-2B) end-organ dysfunction and fetal manifestations of
31. The term PIH (pregnancy-induced hypertension) preeclampsia illustrated in the Figure are all non-specific.
should be abandoned, as its meaning in clinical In this model of its origins we describe preeclampsia that
practice is unclear. (III-D) arises primarily through imperfect placentation (early-
onset or “placental” preeclampsia [pink]) or through either
Definition of Preeclampsia a lowered maternal threshold or excessive physiological
Preeclampsia is most commonly defined by new-onset placentation (late-onset or “maternal” preeclampsia
proteinuria and, potentially, other end-organ dysfunction. [blue]). Some aspects of the preeclampsia process are
Hypertension and proteinuria are discussed above under specific to it, while others are shared with normotensive
“Diagnosis of Hypertension”’ and “Management of IUGR. A lowered maternal threshold may also influence
Proteinuria.” Women with preeclampsia may have a the development of early-onset preeclampsia through
maternal syndrome
EVT: extravillous trophoblast; SNP: single nucleotide polymorphism; ARDS: acute respiratory distress syndrome; CNS: central nervous system;
TIA: transient ischemic attack; RIND: reversible ischemic neurological deficit; CVA: cerebrovascular accident; PRES: posterior reversible
encephalopathy syndrome; GCS: Glasgow Coma Scale; ATN: acute tubular necrosis; AKI: acute kidney injury; DIC: disseminated intravascular
coagulation; DbM: diabetes mellitus; LV: left ventricle
direct endothelial cell activation. The consequences of The adverse conditions are manifestations of preeclampsia that
endothelial cell activation that appear consistent between increase the risk of adverse maternal or perinatal outcomes.6
all women with preeclampsia include a variable impact Table 3 lists the adverse conditions by maternal organ
on multiple vulnerable organ systems. Disease severity system. Of particular importance are preterm preeclampsia,
generally correlates with the degree and number of organ chest pain or dyspnea, and abnormality of one or more of
dysfunctions. Fetal manifestations may occur before, with, oxygen saturation by pulse oximetry, platelet count, serum
or in the absence of maternal manifestations.5 creatinine, or aspartate transaminase.6 Proteinuria predicts
neither short-term adverse outcomes nor long-term maternal
Table 3 outlines the end-organ dysfunctions
renal prognosis.7,8 HELLP syndrome is represented by its
of preeclampsia: adverse conditions and severe
component parts (hemolysis, elevated liver enzymes, and low
complications. Adverse conditions consist of maternal
platelets), to which we react to by initiating delivery.
symptoms, signs, and abnormal laboratory results, and
abnormal fetal monitoring results that may herald the How maternal adverse conditions may predict fetal or
development of severe maternal or fetal complications neonatal outcomes in preeclampsia is unclear. The perinatal
(including stillbirth). The adverse conditions are those that literature suggests that abnormal fetal monitoring of various
we wait for and respond to (e.g., low oxygen saturation) types may identify increased fetal risk. The biophysical
in an effort to avoid entirely the severe complications profile has unproven utility in high risk women,9,10 and may
(e.g., pulmonary edema). That response could be falsely reassure with early-onset IUGR11 or preeclampsia.12
more intensive maternal or fetal monitoring, specific
treatment, or delivery. Severe maternal complications of Currently, there is no single fetal monitoring test to
preeclampsia warrant delivery. accurately predict fetal compromise in women with
Continued
FETAL TESTING Abnormalities are not specific to the cause of poor placentation and/or placental dysfunction
Uterine artery Doppler Unilateral/bilateral notching, or elevated pulsatility index or resistance index may support a diagnosis of placental insufficiency including preeclampsia
velocimetry‡
Fetal monitoring Abnormal or atypical FHR tracing (e.g., decreased variability)
Deepest amniotic fluid Oligohydramnios associated with adverse perinatal outcomes
pocket
Ultrasonographic Usually intrauterine fetal growth restriction (typically asymmetrical but can be symmetrical if early and/or severe)
assessment of fetal growth
Umbilical artery Doppler Increased resistance, absent or reversed end-diastolic flow
Ductus venosus Doppler Increased resistance, especially absent or reverse A wave
Middle cerebral artery Cerebral redistribution (decreased resistance or “brain-sparing effect”). May be lost in extreme cases prior to fetal death
Doppler
RBC: red blood cell; TTP-HUS: thrombotic thrombocytopenic purpur–hemolytic uremic syndrome; UTI: urinary tract infection; SpO2: oxygen saturation; CBC: complete blood count; HELLP: hemolysis, elevated liver
enzyme, low platelet syndrome; WBC: white blood cell; APS: antiphopholipid antibody syndrome; AFLP: acute fatty liver of pregnancy; DIC: disseminated intravascular coagulation; INR international normalized
ratio; aPTT: activated partial thromboplastin time; vWF: von Willebrand Factor; HCTZ: hydrochlorothiazide; AST: aspartate aminotransferase; ALT: alanine aminotransferase; PET: preeclampsia-eclampsia;
LDH: lactate dehydrogenase; FHR: fetal heart rate
*Tests of coagulation are recommended if there is thrombocytopenia or placental abruption.
†“PET imitators” include AFLP, catastrophic APS, TTP-HUS, malignant hypertension, and scleroderma renal crisis.
‡Abnormal uterine artery Doppler velocimetry is practically defined at 22 to 24 weeks as bilateral notching with mean resistance index (RI) > 0.55 (i.e., > 50th centile), unilateral notching with mean RI > 0.65
(> 90th centile), or no notching with mean RI > 0.70 (> 95th centile).
Diagnosis, Evaluation, and Management of the Hypertensive Disorders of Pregnancy: Executive Summary
46. There is insufficient evidence to make a 50. The following may be useful: L-arginine (I-B),
recommendation about a heart-healthy diet (II-2L); increased rest at home in the third trimester (I-C),
workload or stress reduction (including bedrest) and reduction of workload or stress. (III-C)
(II-2L); supplementation with iron with or without 51. The following may be useful for prevention of other
folate (I-L); vitamin D (I-L); pyridoxine (I-L); or pregnancy complications: prostaglandin precursors
food rich in flavonoids. (I-L) (I-B), magnesium supplementation (I-C), and heparin
to prevent venous thromboembolic disease. (I-B)
Preventing Preeclampsia and its 52. The following are recommended for other
Complications in Women at Increased Risk established beneficial effects in pregnancy (as
discussed for women at low risk of preeclampsia):
Women at increased risk of preeclampsia are most abstention from alcohol (II-2E), periconceptual
commonly identified by a personal or family history of an use of a folate-containing multivitamin (I-A), and
HDP, chronic medical disease, and/or abnormal uterine smoking cessation. (I-E)
artery Doppler before 24 weeks’ gestation. Combining 53. The following are not recommended: calorie
clinical, biochemical, and/or ultrasonographic risk markers restriction in overweight women during pregnancy
may better identify women at increased preeclampsia risk (I-D), weight maintenance in obese women during
(see “Prediction”); however, no intervention trial has used pregnancy (III-D), antihypertensive therapy
such an approach to evaluate preventative therapy.33,34 specifically to prevent preeclampsia (I-D), and
vitamins C and E. (I-E)
Recommendations 54. There is insufficient evidence to make a
47. Low-dose acetylsalicylic acid and calcium recommendation about the usefulness of the
supplementation (of at least 1 g/d) for women with following: the heart-healthy diet (III-L); exercise
low calcium intake are recommended for preventions (I-L); selenium (I-L); garlic (I-L); zinc, pyridoxine,
of preeclampsia in women at high risk. (I-A) iron (with or without folate), vitamin D, or
48. Acetylsalicylic acid should be: taken in a low dose multivitamins with/without micronutrients. (III-L)
(75–162 mg/d), (III-B) administered at bedtime,
(I-B) initiated after diagnosis of pregnancy but
CHAPTER 3:
before 16 weeks’ gestation, (I-B) and considered for
TREATMENT OF THE HDPs
continuation until delivery. (I-C)
49. Prophylactic doses of low-molecular-weight Dietary and Lifestyle Changes
heparin may be discussed in women with previous
placental complications (including preeclampsia) Recommendations
to prevent the recurrence of severe or early-onset 55. There is insufficient evidence to make a
preeclampsia, preterm delivery, and/or infants that recommendation about the usefulness of the
are small for gestational age. (I-B) following: new severe dietary salt restriction for
Maternal age ≥ 40 years‡ Lower maternal birthweight and/or Overweight/obesity Elevated BP (gestational hypertension)¶
Family history of preeclampsia preterm delivery First ongoing pregnancy Abnormal AFP, hCG, inhA, or E3#
(mother or sister) Heritable thrombophilias§ New partner Excessive weight gain in pregnancy
Family history of early-onset cardiovascular Increased pre-pregnancy triglycerides Short duration of sexual relationship Infection during pregnancy
disease Non-smoking with current partner (e.g., UTI, periodontal disease)
Cocaine and metamphetamine use Reproductive technologies‖ Abnormal uterine artery Doppler**
Previous miscarriage at ≤ 10 weeks Inter-pregnancy interval ≥ 10 years IUGR
with same partner Booking† sBP ≥ 130 mmHg, or booking Investigational laboratory markers††
dBP ≥ 80 mmHg
Vaginal bleeding in early pregnancy
Gestational trophoblastic disease
Abnormal PAPP-A or free βhCG
AFP: alfafetoprotein; inhA: inhibin A; E3: estradiol; UTI: urinary tract infection; sBP: systolic BP; dBP: diastolic BP; PAPP-A: pregnancy-associated plasma protein A.
*Women at increased risk (who should be considered for specialty referral) are those with one of the bolded factors, or two or more of the unbolded markers.
†First antenatal visit, usually early in pregnancy.
‡Maternal age was considered as a continuous variable in the SCOPE study.
§Heritable thrombophilia includes factor V Leiden gene mutation and protein S deficiency.
‖Subfertility and its treatment (especially the use of donor eggs, sperm and/or gametes), after correction for multiple gestations.
¶Elevated BP is defined as dBP ≥ 110 mmHg before 20 weeks, 2nd trimester mean arterial pressure of ≥ 85 mmHg, or a 2nd trimester sBP ≥ 120 mmHg. standardized cut-offs for 24-hour ambulatory BP or home BP
monitoring have not been established.
#Decreased first trimester PAPP-A ≤ 5th centile, 110 decreased first or second trimester placental growth factor, unexplained increased second trimester AFP, increased second trimester hCG, increased first or second
trimester inhA, increased second trimester activin.
**Abnormal uterine artery Doppler velocimetry is practically defined at 22 to 24 weeks as bilateral notching with mean resistance index (RI) > 0.55 (i.e., > 50th centile), unilateral notching with mean RI > 0.65 (> 90th
centile), or no notching with mean RI > 0.70 (> 95th centile).
††Investigational markers include, in the first trimester: PAPP-A, PlGF, PP-13, and in the second trimester: elevated sFlt-1/PlGF (soluble fms-like tyrosine kinase, placental growth factor), PAI-1/PAI-2 (plasminogen
activator inhibitor) von Willebrand factor, and leptin.
Table 7. The most commonly used agents for treatment of blood pressure ≥ 160/110 mmHg
Agent Dosage Onset Peak Duration Comments
Labetalol Start with 20 mg IV; repeat 20 to 5 min 30 min 4 hr Best avoided in women with asthma
80 mg IV q 30 min, or 1 to 2 mg/min, or heart failure. Neonatology should
max 300 mg (then switch to oral) be informed if the woman is in labour,
as parenteral labetalol may cause
neonatal bradycardia.
Nifedipine 5 to 10 mg capsule to be swallowed, 5 to 10 min 30 min ~6 hr Staff should be aware of the
or bitten then swallowed, every 30 distinction between short-acting
min nifedipine capsules used to treat
severe hypertension and both the
intermediate-acting PA tablet (which
can be used for treatment of non-
severe or severe hypertension), and
the slow-release tablets (XL) that are
used for non-severe hypertension.
Hydralazine Start with 5 mg IV; repeat 5 to 5 min 30 min May increase the risk of maternal
10 mg IV every 30 min, or 0.5 to hypotension.
10 mg/hr IV, to a maximum of
20 mg IV (or 30 mg IM)
IV: intravenous; IM: intramuscular; PA: prolonged action; XL: slow release
women with any HDP, ongoing salt restriction Antihypertensive Therapy for Severe Hypertension
among women with pre-existing hypertension, Recommendations
heart-healthy diet, and calorie restriction for obese
62. Blood pressure should be lowered to
women. (III-L)
< 160 mmHg systolic and < 110 mmHg
56. There is insufficient evidence to make a
diastolic. (I-A)
recommendation about the usefulness of exercise,
63. Initial antihypertensive therapy in the hospital
workload reduction, or stress reduction. (III-L)
setting should be with nifedipine short-acting
57. For women with gestational hypertension
capsules, parenteral hydralazine, or parenteral
(without preeclampsia), some bed rest in hospital
labetalol. (I-A) (Table 7)
(vs. unrestricted activity at home) may be useful
64. Alternative antihypertensive medications include
to decrease severe hypertension and preterm
a nitroglycerin infusion (I-B), oral methyldopa
birth. (I-B)
(I-B), oral labetalol (I-B), oral clonidine (III-B), or
58. For women with preeclampsia who are hospitalized, postpartum, oral captopril. (III-B)
strict bed rest is not recommended. (I-D) 65. Refractory hypertension may be treated with
59. For all other women with an HDP, the evidence sodium nitroprusside. (III-B)
is insufficient to make a recommendation 66. Nifedipine and magnesium sulphate can be used
about the usefulness of some bed rest, which contemporaneously. (II-2B)
may nevertheless be advised based on practical 67. Magnesium sulphate is not recommended solely as
considerations. (III-C) an antihypertensive agent. (I-E)
The following recommendations apply to women with 68. Continuous fetal heart rate monitoring is advised
either pre-existing or gestational hypertension. until blood pressure is stable. (III-L)
Place of Care
Antihypertensive Therapy for Non-Severe
Recommendations
Hypertension Without Comorbid Conditions
60. In-patient care should be provided for women with
severe hypertension or severe preeclampsia. (II-2B). Recommendations
61. A component of care through hospital day units or 69. Antihypertensive drug therapy may be used to
home care can be considered for women with non- keep systolic blood pressure at 130 to
severe preeclampsia or non-severe pre-existing or 155 mmHg and diastolic blood pressure at
gestational hypertension. (I-B, II-2B) 80–105 mmHg. (I-B)
Table 8. Doses of the most commonly used agents for treatment of blood pressures 149 to 159/90 to 105 mmHg
Agent Dosage Comments
Methyldopa 250 to 500 mg po bid-qid (max 2 g/d) There is no evidence to support a loading dose of methyldopa.
Labetalol 100 to 400 mg po bid-tid (max 1200 mg/d) Some experts recommend a starting dose of 200 mg po bid.
Nifedipine* XL preparation (20 to 60 mg po OD, max 120 mg/d) Ensure that the correct form of nifedipine has been prescribed
so that the XL preparation is not confused with the capsules.
XL: slow release
*The prolonged action nifedipine tablet is no longer available in Canada.
70. The choice of antihypertensive agent for initial proteinuria or adverse conditions) only if delivery is
treatment should be based on characteristics of the contemplated within the next 7 days. (III-L)
patient, contraindications to a particular drug, and 79. A rescue dose of corticosteroids may be considered
physician and patient preference. (III-C) for women at ≤ 34+6 weeks’ gestation who remain
71. Initial therapy in pregnancy can be with one of at high risk of preterm delivery 7 days or more after
a variety of antihypertensive agents available in an initial course of antenatal corticosteroids. (I-C)
Canada: methyldopa (I-A), labetalol (I-A), other 80. Antenatal corticosteroids may be considered for
beta-blockers (acebutolol, metoprolol, pindolol, and women delivered by elective Caesarean delivery
propranolol), (I-B) and calcium channel blockers at ≤ 38+6 weeks’ gestation to reduce respiratory
(nifedipine). (I-A) (Table 8) morbidity. (I-B)
72. Angiotensin-converting enzyme inhibitors and
angiotensin receptor blockers should not be used Comments
during pregnancy. (II-2E) When administered at ≤ 34+6 weeks’ gestation, antenatal
73. Atenolol and prazosin are not recommended prior corticosteroids accelerate fetal pulmonary maturity and
to delivery. (I-D) decrease neonatal mortality and morbidity, including among
women with HDPs.35 RCTs that administered steroids at
33+0 to 34+6 weeks resulted in reduced neonatal RDS.35
For Non-Severe Hypertension (BP of 140–159/
90–109 mmHg) With Comorbid Conditions Prior to elective Caesarean section at ≤ 38+6 weeks’
gestation, antenatal corticosteroids decrease the excess
Recommendations neonatal respiratory morbidity and NICU admissions.36,37
74. For women with comorbid conditions, All subgroup analyses have not necessarily revealed such
antihypertensive drug therapy should be used to benefits following Caesarean or vaginal delivery.35
keep systolic blood pressure at < 140 mmHg and
diastolic blood pressure at < 90 mmHg. (III-C) Timing of Delivery for Women With Preeclampsia
75. Initial therapy in pregnancy can be with one of Delivery is the only intervention that initiates resolution of
a variety of antihypertensive agents as listed for preeclampsia, and women with gestational hypertension or
women without co-morbidities. (III-C) pre-existing hypertension may develop preeclampsia.
76. Captopril, enalapril, or quinapril may be used
postpartum, even during breastfeeding. (III-B) Recommendations
81. Consultation with an obstetrician (by telephone
if necessary) is mandatory in women with severe
Corticosteroids for Acceleration of
preeclampsia. (III-B)
Fetal Pulmonary Maturity
82. All women with severe preeclampsia should be
Recommendations delivered immediately (either vaginally or by
77. Antenatal corticosteroid therapy should be Caesarean), regardless of gestational age. (III-C)
considered for all women who present with 83. For women with non-severe preeclampsia at < 24+0
preeclampsia at ≤ 34+6 weeks’ gestation. (I-A) weeks’ gestation, counselling should include, as an
78. Antenatal corticosteroid therapy should be considered option, information about delivery within days. (II-2B)
for women who present at ≤ 34+6 weeks’ gestation 84. For women with non-severe preeclampsia at 24+0
with gestational hypertension (despite the absence of to 33+6 weeks’ gestation, expectant management
should be considered, but only in perinatal centres 93. If vaginal delivery is planned and the cervix is
capable of caring for very preterm infants. (I-B) unfavourable, then cervical ripening should be
85. For women with non-severe preeclampsia at 34+0 used to increase the chance of a successful vaginal
to 36+6 weeks’ gestation, there is insufficient delivery. (1-A)
evidence to make a recommendation about the 94. At a gestational age remote from term, women with
benefits or risks of expectant management. (III-L) a hypertensive disorder of pregnancy with evidence
86. For women with preeclampsia at ≥ 37+0 weeks’ of fetal compromise may benefit from delivery by
gestation, immediate delivery is recommended. (I-A) emergency Caesarean section. (II-2B)
87. For women with non-severe preeclampsia 95. Antihypertensive treatment should be continued
complicated by hemolysis, elevated liver enzymes, throughout labour and delivery to maintain systolic
low platelets syndrome at 24+0 to 34+6 weeks’ blood pressure at < 160 mmHg and diastolic blood
gestation, consider delaying delivery long enough pressure at < 110 mmHg. (II-2B)
to administer antenatal corticosteroids for 96. The third stage of labour should be actively
acceleration of fetal pulmonary maturity if there managed with oxytocin, 5 units intravenous or 10
is temporary improvement in maternal laboratory units intramuscular, particularly in the presence of
testing. (II-2B) thrombocytopenia or coagulopathy. (I-A)
88. All women with hemolysis, elevated liver enzymes, 97. Ergometrine maleate should not be administered
low platelets syndrome at ≥ 35+0 weeks’ to women with any hypertensive disorder of
gestation should be considered for immediate pregnancy, particularly preeclampsia or gestational
delivery. (II-2B) hypertension; alternative oxytocics should be
considered. (II-3D)
Recommendations Recommendations
89. For women with gestational hypertension (without 98. The anaesthesiologist should be informed when
preeclampsia) at ≥ 37+0 weeks’ gestation, delivery a woman with preeclampsia is admitted to the
within days should be discussed. (I-B) delivery suite. (II-3B)
90. For women with gestational hypertension (without 99. Early insertion of an epidural catheter (in the
preeclampsia) at < 37+0 weeks’ gestation, there is absence of contraindications) is recommended for
insufficient evidence to make a recommendation control of labour pain. (I-A)
about the benefits or risks of expectant 100. In the absence of contraindications, all of the
management. (III-L) following are acceptable methods of anaesthesia
for women undergoing Caesarean delivery:
epidural, spinal, combined spinal-epidural, and
Timing of Delivery for Women With general anaesthesia. (I-A)
Pre-Existing Hypertension 101. A routine fixed intravenous fluid bolus should not
be administered prior to neuraxialanaesthesia. (I-E)
Recommendation
91. For women with uncomplicated pre-existing
hypertension who are otherwise well at ≥ 37+0
Anaesthesia: Fluid Administration
weeks’ gestation, delivery should be considered at
38+0 to 39+6 weeks’ gestation. (II-1B) Recommendations
102. Intravenous and oral fluid intake should be
Mode of Delivery minimized in women with preeclampsia, to avoid
pulmonary edema. (II-2B)
Recommendations 103. Fluid should not be routinely administered to
92. For women with any hypertensive disorder of treat oliguria (< 15 mL/hr for 6 consecutive
pregnancy, vaginal delivery should be considered hours). (III-D)
unless a Caesarean delivery is required for the usual 104. For treatment of persistent oliguria, neither
obstetric indications. (II-2B) dopamine nor furosemide is recommended. (I-E)
Contraindicated
4 hr after last dose and a
normal aPTT
Therapeutic dose (IV) Unclear
X
4 hr after last dose and a
normal aPTT
LMWH
Prophylactic dose Unclear
10 to 12 hr after last dose
Therapeutic dose Unclear
24 hr after last dose
Low dose ASA + prophylactic UFH Unclear║ Unclear
or LMWH§
INR: international normalized ratio; aPTT: activated partial thromboplastin time; UFH: unfractionated heparin; SC: subcutaneous; IV: intravenous;
LMWH: low-molecular-weight heparin
Note: These recommendations are based on the absence of a rapidly falling platelet count or a known platelet dysfunction (e.g., von Willebrand’s disease).
*Other than a lupus anticoagulant
†Prophylactic dosing is defined as ≤ 10 000 IU/d
‡Therapeutic dosing (SC) is defined as > 10 000 IU/d
§Prophylactic doses of UFH are defined as ≤ 10 000 IU/d
║Unless ASA is stopped 7 days or more before delivery
122. In women with pre-existing or gestational severe hypertension, headaches/visual symptoms, right
hypertension, magnesium sulphate should be upper quadrant/epigastric pain, platelet count < 100 000 ×
considered for fetal neuroprotection in the setting 109/L, progressive renal insufficiency, and/or elevated
of imminent preterm birth (within the next 24 liver enzymes.
hours) at ≤ 31+6 weeks. (1-A)
123. Delivery should not be delayed in order to Aspects of Care for Women With Preeclampsia:
administer antenatal magnesium sulphate for Plasma Volume Expansion
fetal neuroprotection if there are maternal Recommendation
and/or fetal indications of emergency 124. Plasma volume expansion is not recommended for
delivery. (III-E) women with preeclampsia. (I-E)
There is no international consensus on what defines severe
preeclampsia. This document defines it as preeclampsia Therapies for HELLP Syndrome
requiring delivery due to serious maternal end-organ
Recommendations
involvement and/or fetal compromise (see “Classification
of HDPs”). For eclampsia prevention in the setting of 125. Every obstetrical centre should be aware of
non-severe preeclampsia, we have added to the indication the local delay between ordering and receiving
for magnesium sulphate (in Recommendation 120) the platelets units. (III-B)
following symptoms/signs as these are included in the 126. For a platelet count of < 20 × 109/L with
definition of severe preeclampsia by other organizations: hemolysis, elevated liver enzymes, low platelets
Table 10. Recommendations for the transfusion of platelets related to mode of delivery
in HELLP
Mode of delivery
Platelet count Caesarean delivery Vaginal delivery
< 20 × 10 /L
9
20 to 49 × 109/L Consider in presence of:
• excessive active bleeding
• known platelet dysfunction
• platelet count falling rapidly
• coagulopathy
≥ 50 × 10 /L
9
Consider in presence of: Consider in presence of:
• excessive active bleeding • excessive active bleeding
• known platelet dysfunction • known platelet dysfunction
• platelet count falling rapidly • platelet count falling rapidly
• coagulopathy • coagulopathy
Regardless of the platelet count No platelets should be transfused if there is a strong suspicion of HIT
or TTP-HUS
HIT: heparin-induced thrombocytopenia; TTP-HUS: thrombotic thrombocytopenic purpura–hemolytic uremic syndrome
140. There should be confirmation that end-organ Effects of Maternal Hypertension and Its Therapies
dysfunction of preeclampsia has on Child Neurobehavioural Development
resolved. (III-C) Recommendations
141. Non-steroidal anti-inflammatory drugs should
149. Clinicians should be aware that gestational
not be given postpartum if hypertension is
hypertension and preeclampsia may each be
difficult to control, there is evidence of kidney
associated with an increase in adverse paediatric
injury (oliguria and/or creatinine≥ 90 µM), or neurodevelopmental effects, such as inattention
platelets are < 50 to 109/L. (III-C) and externalizing behaviours (e.g.,
142. Postpartum thromboprophylaxis should be aggressiveness). (II-2B).
considered in women with preeclampsia, 150. Clinicians should be reassured that there is
particularly in the presence of other risk no compelling evidence that antihypertensive
factors. (II-2B) medications (specifically labetalol, nifedipine, or
methyldopa) are themselves associated with clear
adverse neurodevelopmental effects. (I-B)
Care Beyond 6 Weeks Postpartum
Recommendations CHAPTER 4:
143. Women with a history of severe preeclampsia PATIENT PERSPECTIVE
(particularly those who presented or delivered
before 34 weeks’ gestation) should be screened Recommendations
for pre-existing hypertension and underlying renal 151. Health care providers should be alert to symptoms
disease. (II-2B) of posttraumatic stress following a hypertensive
144. Referral for internal medicine or nephrology disorder of pregnancy and refer women for
consultation (by telephone if necessary) appropriate evaluation and treatment. (II-2B)
should be considered for women with: 152. Health care providers should inform their patients,
(i) postpartum hypertension that is difficult antepartum and postpartum, about preeclampsia,
to control, or its signs and symptoms, and the importance of
(ii) women who had preeclampsia and have timely reporting of symptoms to health care
at 3-6 months postpartum either ongoing providers. (II-2B)
proteinuria, decreased estimated glomerular 153. Information should be re-emphasized at
filtration rate (eGFR) (< 60 mL/min), or subsequent visits. (III-C)
another indication of renal disease, such as
abnormal urinary sediment. (III-A) CHAPTER 5:
145. Women who are overweight should be encouraged KNOWLEDGE TRANSLATION TOOLS AND
to attain a healthy body mass index to decrease IMPLEMENTATION OF THE GUIDELINE
risk in future pregnancy (II-2A) and for long-term
health. (I-A) The Appendix (Table 10 in the full document3) lists tools
146. Women with pre-existing hypertension or to support the application of this guideline. Some websites
persistent postpartum hypertension should provide general information about BP measurement for
undergo the following investigations (if not non-pregnant patients, but the recommendations are
done previously) at least six weeks postpartum: similar enough to those for pregnant women to be useful.
urinalysis; serum sodium, potassium and Patients, their partners, and their care providers should be
creatinine; fasting glucose; fasting lipid well educated about the HDP, and relevant sites are listed.
profile; and standard 12-lead electrocardio-
Implementation of any evidence depends on individual
graphy. (III-L)
147. Women who are normotensive but who have had knowledge and beliefs, as well as institutional culture. Strong
a hypertensive disorder of pregnancy, may benefit recommendations should be incorporated into clinical
from assessment of traditional cardiovascular risk practice. In well-resourced settings, almost all preeclampsia-
markers. (II-2B) related maternal deaths involve substandard care.38
148. All women who have had a hypertensive disorder Some updates to the 2008 SOGC guidelines on the HDP
of pregnancy should pursue a healthy diet and may require additional effort to implement.
lifestyle. (I-B)
Recommendation 9 states that all measurement devices 6. von Dadelszen P, Payne B, Li J, Ansermino JM, Broughton Pipkin F,
Côté AM, et al.; PIERS Study Group. Prediction of adverse maternal
used in hospitals or offices should be checked regularly outcomes in pre-eclampsia: development and validation of the fullPIERS
against a calibrated device may not be possible for all model. Lancet 2011;377(9761):219–27.
Canadian hospitals and offices to do on a regular basis. 7. Payne B, Magee LA, Menzies J, Côté AM, Hutcheon JA, Kyle P, et al.;
PIERS Study Group. PIERS proteinuria: relationship with
Physicians should consider the category “other HDP” adverse maternal and perinatal outcome. J Obstet Gynaecol Can
(white-coat and masked hypertension) as part of the 2011;33:588–97.
classification of hypertensive women and consider using 8. Lampinen KH, Rönnback M, Groop PH, Kaaja RJ. Renal and vascular
some form of out-of-office BP measurement to evaluate function in women with previous preeclampsia: a comparison of low-
and high-degree proteinuria. Kidney Int 2006;70:1818–22.
women with non-severe pre-existing or gestational
hypertension. 9. Gruslin A, Lemyre B. Pre-eclampsia: fetal assessment and
neonatal outcomes. Best Pract Res Clinl Obstet Gynaecol
Health care providers should inform pregnant women 2011;25:401–507.
about the symptoms and signs of the HDPs and refer 10. Lalor JG, Fawole B, Alfirevic Z, Devane D. Biophysical profile for fetal
assessment in high risk pregnancies. Cochrane Database Syst Rev.
them to appropriate knowledge translation tools.
2008 Jan 23;(1):CD000038.
We recommend the use of corticosteroids for women 11. Kaur S, Picconi JL, Chadha R, Kruger M, Mari G. Biophysical profile in
≤ 34+6 weeks’ gestation who are at high risk of delivery the treatment of intrauterine growth-restricted fetuses who weigh
<1000 g. Am J Obstet Gynecol 2008;199:264.e1–4.
within the next seven days. This gestational age cut-off
12. Payne BA, Kyle PM, Lim K, Lisonkova S, Magee LA, Pullar B, et al.
represents a fundamental change in practice that will require An assessment of predictive value of the biophysical profile in women
discussion. with preeclampsia using data from the full PIERS database. Pregnancy
Hypertens 2013;3:166–71.
Physicians should be familiar with the blood bank policies
13. Urquia ML, Ying I, Glazier RH, Berger H, De Souza LR, Ray JG. Serious
of their own hospital. preeclampsia among different immigrant groups. J Obstet Gynaecol Can
2012;34:348–52.
Physicians should be aware of postpartum signs of
14. Magee LA, Helewa M, Moutquin JM, von Dadelszen P; Hypertension
maternal posttraumatic stress disorder and the maternal Guideline Committee; Strategic Training Initiative in Research in the
and perinatal long-term effects of HDPs, especially at this Reproductive Health Sciences (STIRRHS) Scholars. SOGC Clinical
vulnerable time in maternal care when the maternity care Practice Guidelines, No. 206, March 2008. Diagnosis, evaluation, and
management of the hypertensive disorders of pregnancy. J Obstet
provider is often handing back care to the primary care Gynaecol Can 2008;30(3 Suppl 1):S1–S48.
physician.
15. American College of Obstetricians and Gynecologists; Task Force on
Hypertension in Pregnancy. Hypertension in pregnancy. Report of the
The reader is reminded to refer to the full open-access
American College of Obstetricians and Gynecologists’ Task Force on
guideline published in Pregnancy Hypertension,3 which contains Hypertension in Pregnancy. Obstet Gynecol. 2013;122:1122–31.
not only the recommendations and tables presented here, 16. Brown MA, Lindheimer MD, de Swiet M, Van Assche A, Moutquin
but also all explanatory text and additional references. JM. The classification and diagnosis of the hypertensive disorders
of pregnancy: statement from the International Society for the
Study of Hypertension in Pregnancy (ISSHP). Hypertens Pregnancy
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Hypertens Pregnancy 2009;28:168–77.
BJOG 2011;118(Suppl 1):1–203.
19. Brown MA, Mangos G, Davis G, Homer C. The natural history of white
3. Magee LA, Pels A, Helewa M, Rey E, Von Dadelszen P; Canadian
coat hypertension during pregnancy. BJOG 2005;112:601–6.
Hypertensive Disorders of Pregnancy (HDP) Working Group.
Diagnosis, evaluation, and management of the hypertensive 20. Magee LA, Ramsay G, von Dadelszen P. What is the role of out-of-
disorders of pregnancy. Pregnancy Hypertens 2014. Available at: office BP measurement in hypertensive pregnancy? Hypertens Pregnancy
http://www.pregnancyhypertension.org/article/S2210- 2008;27:95–101.
7789(14)00004-X/fulltext. Accessed on February 28, 2014. 21. Saudan P, Brown MA, Buddle ML, Jones M. Does gestational
4. Ogedegbe G, Pickering T. Principles and techniques of blood pressure hypertension become pre-eclampsia? Br J Obstet Gynaecol
measurement. Cardio Clin 2010; 28:571–86. 1998;105:1177–84.
5. Redman CWG. The placenta, pre-eclampsia and chronic villitis. 22. Reinders A, Cuckson AC, Lee JT, Shennan AH. An accurate automated
In: Redman CWG, Sargent IL SP, eds. The human placenta. Oxford: blood pressure device for use in pregnancy and pre-eclampsia:
Blackwell Scientific; 1993:433–67. the Microlife 3BTO-A. BJOG 2005;112:915–20.
23. Villar J, Say L, Shennan A, Lindheimer M, Duley L, Conde-Agudelo A, 32. Ogge G, Chaiworapongsa T, Romero R, Hussein Y, Kusanovic JP, Yeo L,
et al. Methodological and technical issues related to the diagnosis, et al. Placental lesions associated with maternal underperfusion are more
screening, prevention, and treatment of pre-eclampsia and eclampsia. frequent in early-onset than in late-onset preeclampsia. J Perinat Med
Int J Gynaecol Obstet 2004;85(Suppl 1):S28–S41. 2011;39:641–52. doi: 10.1515/JPM.2011.098.
24. Bellomo G, Narducci PL, Rondoni F, Pastorelli G, Stangoni G, Angeli G, 33. Akolekar R, Syngelaki A, Poon L, Wright D, Nicolaides KH. Competing
et al. Prognostic value of 24-hour blood pressure in pregnancy. JAMA risks model in early screening for preeclampsia by biophysical and
1999;282:1447–52. biochemical markers. Fetal Diagn Ther 2013;33:8–15.
25. Hermida RC, Ayala DE, Iglesias M. Circadian rhythm of blood pressure 34. Scazzocchio E, Figueras F, Crispi F, Meler E, Masoller N, Mula R,
challenges office values as the “gold standard” in the diagnosis of et al. Performance of a first-trimester screening of preeclampsia
gestational hypertension. Chronobiol Int 2003;20:135–56. in a routine care low-risk setting. Am J Obstet Gynecol
2013;208(3):203.e1–203.e10.
26. Eguchi, Kazuo O, Akihide O, Takako H, Chikako T, Kayo S, et al.
[abstracts of American Society of Hypertension 27th Annual 35. Roberts D, Dalziel SR. Antenatal corticosteroids for accelerating fetal lung
Scientific Meeting and Exposition]. J Clin Hypertens maturation for women at risk of preterm birth. Cochrane Database of
2012;14(Suppl 1):doi: 10.1111/j.1751-7176.2011.00665.x. Systematic Reviews 2006;(3)CD004454.
27. Sibai BM. Imitators of severe preeclampsia. Obstet Gynecol 36. Stutchfield P, Whitaker R, Russell I; Antenatal Steroids for Term Elective
2007;109:956–66. Caesarean Section (ASTECS) Research Team. Antenatal betamethasone
and incidence of neonatal respiratory distress after elective caesarean
28. Fesenmeier MF, Coppage KH, Lambers DS, Barton JR, Sibai BM. Acute section: pragmatic randomised trial. BMJ 2005;331:662.
fatty liver of pregnancy in 3 tertiary care centers. Am J Obstet Gynecol
2005;192:1416–9. 37. Roberts D; Royal College of Obstetricians and Gynaecologists. Antenatal
corticosteroids to reduce neonatal morbidity and mortality.
29. Erkan D, Espinosa G, Cervera R. Catastrophic antiphospholipid Green-top Guideline No. 7. London: Royal College of Obstetricians
syndrome: updated diagnostic algorithms. Autoimmun Rev and Gynaecologists; 2010. Available at: http://www.rcog.org.uk/files/
2010;10:74–9. rcog-corp/GTG%207.pdf. Accessed on February 28, 2014.
30. Martin JN Jr, Bailey AP, Rehberg JF, Owens MT, Keiser SD, May WL. 38. Shennan AH, Redman C, Cooper C, Milne F. Are most maternal deaths
Thrombotic thrombocytopenic purpura in 166 pregnancies: 1955–2006. from pre-eclampsia avoidable? Lancet 2012;379(9827):1686–7.
Am J Obstet Gynecol 2008;199:98–104.
39. Woolf SH, Battista RN, Angerson GM, Logan AG, Eel W. Canadian
31. Mouthon L, Berezne A, Bussone G, Noel LH, Villiger PM, Guillevin Task Force on Preventive Health Care. New grades for recommendations
L. Scleroderma renal crisis: a rare but severe complication of systemic from the Canadian Task Force on Preventive Health Care. CMAJ
sclerosis. Clin Rev Allergy Immunol 2011;40:84–91. 2003;169:207–8.
• Preeclampsia FAQ
• Preeclampsia and heart diseases
Hôpital Maisonneuve-Rosemont, Centre affilié à http://biblio.hmr.qc.ca/Publications_pdf/H/hypertension_sfe080.pdf French brochure for patients about preeclampsia.
l’Université de Montréal: Brochure on preeclampsia.
Patient education after preeclampsia
Preeclampsia Foundation; APEC: http://www.preeclampsia.org/market-place Educational brochure about cardiovascular risks
Educational pamphlet associated with preeclampsia.
HEALTH CARE PROVIDER INFORMATION
BP measurement
WHO document: detecting preeclampsia, http://www.who.int/reproductivehealth/publications/maternal_ This document contains instructions how to measure
a practical guide, 2005 perinatal_health/MSM_92_3_/en/index.html blood pressure and proteinuria in pregnant women,
and how to diagnose hypertensive disorders in
pregnancy. This tool is for health care providers.
Approved BP measurement devices
Canadian Hypertension Education Program (CHEP) http://www.hypertension.ca/devices-endorsed-by-hypertension- This website gives an oversight of recommended
canada-dp1 blood pressure devices.
Educational Trust http://www.dableducational.org/sphygmomanometers/devices_1_ This website gives an oversight of recommended
clinical.html blood pressure devices, outside of and during
pregnancy.
Clinical practice guidelines from other countries
NICE guidelines (UK, 2010) http://www.nice.org.uk/nicemedia/live/13098/50475/50475.pdf Graded recommendations
Australasian guidelines (Australia and New Zealand, http://www.somanz.org/pdfs/somanz_guidelines_2008.pdf Very practical but evidence not graded
2008)
College of Obstetricians and Gynecologists http://www.acog.org/~/media/Task%20Force%20and%20Work% Graded recommendations
20Group%20Reports/HypertensioninPregnancy.pdf
WHO guidelines http://whqlibdoc.who.int/publications/2011/9789241548335_eng.pdf
SOGC CLINICAL PRACTICE GUIDELINES
This document reflects emerging clinical and scientific advances on the date issued and is subject to change. The information
should not be construed as dictating an exclusive course of treatment or procedure to be followed. Local institutions can dictate
amendments to these opinions. They should be well documented if modified at the local level. None of these contents may be
reproduced in any form without prior written permission of the SOGC.
Table 1. Key to evidence statements and grading of recommendations, using the ranking of the Canadian Task Force
on Preventive Health Care
Quality of evidence assessment* Classification of recommendations†
I: Evidence obtained from at least one properly randomized A. There is good evidence to recommend the clinical preventive action
controlled trial
II-1: Evidence from well-designed controlled trials without B. There is fair evidence to recommend the clinical preventive action
randomization
II-2: Evidence from well-designed cohort (prospective or C. The existing evidence is conflicting and does not allow to make a
retrospective) or case–control studies, preferably from recommendation for or against use of the clinical preventive action;
more than one centre or research group however, other factors may influence decision-making
II-3: Evidence obtained from comparisons between times or D. There is fair evidence to recommend against the clinical preventive action
places with or without the intervention. Dramatic results in
uncontrolled experiments (such as the results of treatment with E. There is good evidence to recommend against the clinical preventive
penicillin in the 1940s) could also be included in this category action
III: Opinions of respected authorities, based on clinical experience, L. There is insufficient evidence (in quantity or quality) to make
descriptive studies, or reports of expert committees a recommendation; however, other factors may influence
decision-making
*The quality of evidence reported in these guidelines has been adapted from The Evaluation of Evidence criteria described in the Canadian Task Force on
Preventive Health Care.176
†Recommendations included in these guidelines have been adapted from the Classification of Recommendations criteria described in the Canadian Task Force
on Preventive Health Care.176
pregnancy is estimated to be low, at less than 1 in 5000. The 07. There is growing evidence that pregnancy outcomes are better
exact biological etiology for this increased imprinting risk is likely for cryopreserved embryos fertilized in vitro than for fresh embryo
heterogeneous and requires more research. (II-2) transfers. This finding supports a policy of elective single embryo
transfer for women with a good prognosis (with subsequent use of
Recommendations cryopreserved embryos as necessary), and may reassure women
who are considering in vitro fertilization. (II-2A)
01. All men with severe oligozoospermia or azoospermia
(sperm count < 5 million/hpf) should be offered genetic/ 08. Women and couples considering assisted human reproduction
clinical counselling, karyotype assessment for chromosomal and concerned about perinatal outcomes in singleton pregnancies
abnormalities, and Y-chromosome microdeletion testing prior to in should be advised that (1) intracytoplasmic sperm injection does
vitro fertilization with intracytoplasmic sperm injection. (II-2A) not appear to confer increased adverse perinatal or maternal risk
over standard in vitro fertilization, and (2) the use of donor oocytes
02. All men with unexplained obstructive azoospermia should be increases successful pregnancy rates in selected women, but even
offered genetic/clinical counselling and genetic testing for cystic when accounting for maternal age, can increase the risks of low
fibrosis prior to in vitro fertilization with intracytoplasmic sperm birth weight and preeclampsia. (II-2B)
injection. (II-2A)
09. Any assisted reproductive technology procedure should be
03. Multiple pregnancy is the most powerful predictive factor for prefaced by a discussion of fetal outcomes and the slight
adverse maternal, obstetrical, and perinatal outcomes. Couples increase in the risk of congenital structural abnormalities, with
should be thoroughly counselled about the significant risks emphasis on known confounding factors such as infertility and
of multiple pregnancies associated with all assisted human body mass index. (II-2B)
reproductive treatments. (II-2A) 10. In pregnancies achieved by artificial reproductive technology,
04. The benefits and cumulative pregnancy rates of elective single routine anatomic ultrasound for congenital structural abnormalities
embryo transfer support a policy of using this protocol in couples is recommended between 18 and 22 weeks. (II-2A)
with good prognosis for success, and elective single embryo 11. Pregnancies conceived by intracytoplasmic sperm injection may
transfer should be strongly encouraged in this population. (II-2A) be at increased risk of chromosomal aberrations, including sex
05. To reduce the incidence of multiple pregnancy, health care chromosome abnormalities. Diagnostic testing should be offered
after appropriate counselling. (II-2A)
policies that support public funding for assisted human
reproduction, with regulations promoting best practice 12. The possible increased risk for late onset cancer due to gene
regarding elective single embryo transfer, should be strongly dysregulation for tumour suppression requires more long-term
encouraged. (II-2A) follow-up before the true risk can be determined. (III-A)
06. Among singleton pregnancies, assisted reproductive technology 13. The clinical application of preimplantation genetic testing in
is associated with increased risks of preterm birth and low fertile couples must balance the benefits of avoiding disease
birth weight infants, and ovulation induction is associated with transmission with the medical risks and financial burden of in vitro
an increased risk of low birth weight infants. Until sufficient fertilization. (III-B)
research has clarified the independent roles of infertility and 14. Preimplantation screening for aneuploidy is associated with
treatment for infertility, couples should be counselled about the inconsistent findings for improving pregnancy outcomes. Any
risks associated with treatment. (II-2B) There is a role for closer discussion of preimplantation genetic screening with patients
obstetric surveillance of women who conceive with assisted should clarify that there is no adequate information on the long-
human reproduction. (III-L) term effect of embryo single cell biopsy. (I-C)
Infertility, generally considered to be the inability to conceive Infertility is associated with male factor or abnormal
after one year of attempting pregnancy,19 has been identified sperm parameters in approximately 50% of cases.39 Studies
as a significant independent predictor of adverse obstetrical have shown that 4.6% of oligozoospermic men and 13.7%
and perinatal outcomes.20–22 Unadjusted analyses suggest a of azoospermic men have constitutional chromosomal
2-fold increased risk of preeclampsia, placental abruption, abnormalities, the most common being sex chromosomal
Caesarean section, and vacuum extraction, and a 5-fold abnormalities and autosomal translocations.40 Karyotype
increased risk of placenta previa in spontaneous singleton analysis of men with fewer than 5 million spermatozoa per
pregnancies in women with a history of infertility compared milliliter of semen has been recommended as routine by
with women in the general population.23 the World Health Organization since 2000.41 As expected,
infertile men with chromosomal abnormalities are more
Table 2 summarizes a number of studies documenting likely to have genetically abnormal spermatozoa and to
adjusted obstetrical, perinatal, and neonatal risks in father chromosomally abnormal pregnancies.42
populations of women with infertility or subfertility
compared with control women.13,23–29 Some of these studies Azoospermia can be classified as non-obstructive or
compared women with various delays in time to pregnancy obstructive. The most common cause of obstructive
who eventually conceived spontaneously to populations of azoospermia is a congenital bilateral absence of vas deferens,
women with short TTP, and found significant differences a feature associated strongly with mutations in the cystic
in a number of adverse outcomes, including preterm birth, fibrosis transmembrane conductance regulator genes.43,44 In
LBW, and perinatal mortality. Other studies compared either presentation, a consultation with a urologist may lead
populations of women with delays in TTP with and to surgical extraction of sperm for use with IVF/ICSI.
without ART and found insignificant differences between
Microsurgical testis sperm extraction is estimated to
these 2 groups, but increases in adverse outcomes between
be successful in 50% of attempts in non-obstructive
these 2 groups and a control group of women with no azoospermia.45 Success with extracted sperm used in
delay in TTP.30,31 IVF/ICSI procedures has been documented with a
Maternal factors related to an increased risk of infertility pregnancy rate approaching 40%.46 A recently published
systematic review summarized the potential reproductive
also have an independently associated risk of adverse
outcomes of various male reproductive genetic
obstetrical outcomes. Advancing maternal age is associated abnormalities associated with azoospermia. (Table 3).47
with both declining fertility and multiple adverse
outcomes of ongoing pregnancy, as noted recently in Recommendations
an SOGC committee opinion on delayed childbearing.32 1. All men with severe oligozoospermia or azoospermia
Research shows obesity impairs fertility, 33,34 although (sperm count < 5 million/hpf) should be offered
whether this effect is primarily ovarian or endometrial is genetic/clinical counselling, karyotype assessment
controversial.35–37 Obesity is also independently related for chromosomal abnormalities, and Y-chromosome
to adverse obstetrical outcomes, many of them similar microdeletion testing prior to in vitro fertilization with
to those associated with advancing maternal age38 and intracytoplasmic sperm injection. (II-2A)
overlapping with those associated with AHR. 2. All men with unexplained obstructive azoospermia
should be offered genetic/clinical counselling
Although there is little remaining debate about the
and genetic testing for cystic fibrosis prior to in
association of infertility or subfertility with adverse
vitro fertilization with intracytoplasmic sperm
obstetrical outcomes following AHR, more specific
injection. (II-2A)
associations between ovarian/ovum or testicular/sperm
factors, endometrial factors, or other factors and adverse
outcomes are not well understood. OBSTETRICAL, PERINATAL, AND
LONG-TERM OUTCOMES ASSOCIATED WITH
Summary Statement ASSISTED REPRODUCTIVE TECHNOLOGY
1. There is increasing evidence that infertility or Multiple Pregnancy and Adverse
subfertility is an independent risk factor for Obstetrical and Perinatal Outcomes
obstetrical complications and adverse perinatal Over the last 30 years, multiple birth rates have risen
outcomes, even without the addition of assisted dramatically internationally, associated partly with increased
human reproduction. (II-2) maternal age at pregnancy, but mostly with infertility
Social status
Gender of baby
Basso and Olsen 200527 Maternal age 4142 women with TTP > 12 months Neonatal mortality within 28 days 3.32 (1.47 to 7.53)
BMI 16 305 women with TTP < 12 months with no treatment
Smoking 2.21 (0.88 to 5.55)
with treatment
Social class
Thomson et al. 200523 Age 1437 subfertile women Preeclampsia 1.9 (1.5 to 2.5)
Parity 21 688 control subjects Placenta previa 3.9 (2.2 to 7.0)
Abruption 1.8 (1.1 to 3.0)
Induction of labour 1.5 (1.3 to 1.6)
Caesarean section 2.1 (1.8 to 2.4)
Instrumental delivery 2.2 (1.8 to 2.6)
LBW 1.4 (1.3 to 1.7)
Zhu et al. 200628 Maternal age 9727 pregnancies with TTP < 12 months Genital organ malformations hazard ratio:
BMI 50 897 pregnancies with TTP < 12 months 2.32 (1.24 to 4.35)
Alcohol
Smoking
Occupational status
Zhu et al. 200713 Maternal age 10 104 pregnancies with TTP > 12 months SGA < 5th percentile 1.24 (1.10 to 1.40)
Partiy 51 041 pregnancies with TTP < 12 months with no treatment
Smoking 1.40 (1.23 to 1.60)
with treatment
Romundstad et al. 200831 Maternal age 1 127 739 spontaneous conceptions SGA (< 2 SD below mean for GA 1.26 (1.10 to 1.44)
Parity 7474 ART conceptions and sex) 1.31 (1.05 to 1.65)
Offspring sex 2204 women having one spontaneous conception and one Perinatal death 0.99 (0.62 to 1.57)
Year of birth ART conception (comparing outcomes in these pregnancies) 0.36 (0.20 to 0.67) only
Time from previous birth to significant if spontaneous
conception conception preceded ART
conception
continued
Pregnancy Outcomes After Assisted Human Reproduction
Scarred uterus
Prior abortion
Maternal age
Parity
Table 3. Potential reproductive outcomes of various male reproductive genetic abnormalities associated with
azoospermia
Test Finding Adverse consequences
Y-chromosome microdeletion AZFc microdeletion Male offspring with severe spermatogenetic failure/
sterility
AZFc microdeletions with aberrations in Male offspring with severe spermatogenetic failure/
pseudoautosomal regions (PARs) sterility; possible skeletal or other anomalies
gr/gr microdeletion Male offspring with severe spermatogenetic failure/
sterility; possible skeletal or other anomalies
Karyotype analysis 47, XXY (Klinefelter syndrome) Hypogonadism, slightly increased rate of autosomal and
sex chromosomal disomy in sperm; offspring with 46XX
or 46XY karyotype with no genetic anomalies
Isodicentric Y chromosome Possible offspring with 45X, Turner’s syndrome, or mixed
gonadal dysgenesis (45,X/46,XY)
Chromosome translocations Depends on chromosomes involved; recurrant pregnancy
loss or aneuploidy of offspring
CF mutation analysis Congenital bilateral absence of vas Offspring with possible mild cystic fibrosis disease
deferens spectrum if partner is a carrier; renal abnormalities if no
CFTR mutation identified
Sperm morphology Structural aberrations of the spermatozoon No obvious congenital anomalies in offspring reported
(e.g. Globozoospermia, dysplasia of the but possible higher rates of embryo aneuploidy
fibrous sheath)
CFTR: Cystic fibrosis transmembrane conductance regulator
Adapted from Harnisch and Oates, 2012.47
twin pregnancies conceived after AHR with those of risks from Caesarean section, and postpartum hemorrhage
spontaneously conceived twins,61–67 as well as 2 systematic are of increased concern with multiple pregnancy.72
reviews,68,69 reveal data that are somewhat conflicting. The
study quality is hampered by several factors, including small As well as medical complications, multiple births
sample size, retrospective design, and inability to accurately generate significant economic and psychosocial costs.73–75
identify pregnancies conceived by ART (IVF or IVF/ICSI) Interestingly, a recent study found, among parents of both
versus other forms of AHR (OI, OH, or OI/OH–IUI), ART and spontaneous pregnancies, that the mental health
with some studies likely incorrectly classifying the latter in of both parents was more adversely affected by multiples
the “spontaneous” group. As well, the known effects of than by singletons, but that ART did not have an additional
chorionicity and subfertility themselves are inconsistently adverse effect.76
controlled. Finally, the fact that women undergoing AHR
Multifetal reduction can be very emotionally difficult
treatments generally attend prenatal care earlier, and are
for couples who have gone through fertility treatment,
followed more closely, could confound the results.
particularly when the procedure may result in the loss of
With these limitations in mind, recent studies have suggested the entire pregnancy.77 Although some studies document
very little independent influence of ART on adverse outcome a risk of long-term adverse emotional consequences
between these 2 comparison groups, with some showing for the couple,78–80 current evidence supports multifetal
better outcomes within the ART group. Joy et al. found an pregnancy reduction of higher order multiples to twins
increase in preterm birth, lower birth weight, and congenital in order to improve pregnancy outcomes.81,82 Compared
anomalies among the spontaneously conceived twins, but with spontaneously conceived twin pregnancies, twin
these findings were negated when the monochorionic pregnancies remaining after fetal reduction continue to
twins were removed.70 Morcel et al. found that differences have an increased risk of preterm birth, LBW, very low
in outcomes were related to chorionicity and method of birth weight, and fetal growth restriction.62,83
AHR, with higher risk among pregnancies conceived by OI
than by ART,66 and Verstraelen et al. suggest that subfertility Because of these maternal and perinatal risks, there has
itself plays a significant role in adverse outcomes.64 been significant international effort to reduce the incidence
of multiple pregnancy associated with AHR. Transfer of
Maternal complications are more common in multiple fewer embryos per cycle will reduce multiple pregnancy
pregnancies than in singletons. Anemia, gestational rates, but this beneficial effect may be accompanied by a
hypertension,71 preeclampsia, gestational diabetes, operative less than acceptable pregnancy rate.
Two recent systematic reviews examined this topic. A 2009 terms of number of embryos transferred, and the current
Cochrane review compared the live birth rate of elective recommendations93 suggest that individual IVF-ET
DET with that of elective single, triple, or quadruple programs should evaluate their own data to identify patient-
embryo transfer. The review concluded that a single cycle specific, embryo-specific, and cycle-specific determinants
of eSET resulted in a lower live birth rate than DET, but of implantation and live birth in deciding on the number
that the cumulative live birth rate in a fresh eSET cycle of embryos to transfer. Updated recommendations will
followed by a frozen eSET was not significantly different likely consider the age of the woman or the egg donor to
from a single DET cycle.84 be paramount in this decision-making process.
A second meta-analysis by Grady et al. in 2012 compared Internationally, in some jurisdictions the proportion of
perinatal outcomes between DET and eSET pregnancies. eSET has increased and the multiple birth rate has fallen.
They found an RCT-based relative risk of 0.37 (0.25 to The 2010 US data report an approximate 15% eSET rate94
0.55) for preterm birth < 37 weeks, and a RCT-based (twice that of 2000), while 2011 data from the UK report a
RR of 0.25 (0.15 to 0.45) for birth weight < 2500 g in 16.8% eSET rate.95 The 2011 UK data show a significantly
the eSET group.85 Upon consideration of these results, it lower (20.6%) multiple pregnancy rate95 than the 2010 US
appears likely that with a policy of fresh eSET followed, as rate of 31%.94
necessary, by a cycle of frozen eSET, the cumulative live
birth rate would be very similar to DET. Recently, AHRC analyzed the current international and
national state of AHR policy on embryo transfer. An
Many clinicians differentiate between live birth rates overriding factor that surfaced as a barrier to a broader
and perinatal outcomes with IVF in women under and practice of eSET was active government legislation,
over 40 years of age, but these 2 studies did not. A often linked to reimbursement. Those jurisdictions with
recent observational UK study of 33 514 live births in
legislation and funded programs had much higher rates
124 148 IVF cycles examined these outcomes according
of eSET; Belgium, Finland, and Australia approach 50%
to whether 1, 2, or ≥ 3 embryos were transferred in
eSET rates, with funded programs and linked legislation
women aged < 40 or ≥ 40. The study found that the
promoting maximal use of eSET.
overall live birth rate was better in the < 40 age group,
that the live birth rate was higher for DET than for SET In Canada, an expert panel in Ontario has recommended
in both age groups, that perinatal outcomes were worse consideration of legislation and public funding for higher
in both age groups for DET than for SET, but, notably, rates of eSET.96 As of August 5, 2010, the provincial
that the difference in adverse perinatal outcomes in DET government of Quebec began funding 3 cycles of IVF
versus SET was less in the > 40 age group. This large with OS or up to 6 cycles of natural or modified natural
observational study supports consideration of DET for cycles of IVF, with IVF funding tied to eSET for clinically
women ≥ 40. The study showed that transferring more favourable situations. An initial report on the first 3 months
than 2 embryos did not increase live birth rates in either of the program in 2009 found an increase in the rate of
age group, and it discouraged transferring 3 or more eSET from 1.6% to 50%, and a reduction in the multiple
embryos at any stage.86 pregnancy rate from 25.6% to 3.7%.97 The most recent
The potential impact of a policy of eSET in appropriately report indicates an eSET rate of 49%, a 5.2% multiple
selected women on perinatal and maternal outcomes is pregnancy rate, and a predicted cumulative pregnancy rate
significant, and such a policy could result in substantial cost of 60% per cycle.”98
savings. One modelling study examined the cost utility of
Although most of the attention in reducing multiple
this policy,87 and a multi-centre cohort examining the long-
pregnancy rates has been directed at strategies related to
term effects and cost implications of the Dutch policy of
IVF, studies are increasingly addressing strategies related
eSET is ongoing.88
to OI and OH with gonadotropin medications. This latter
Based on this research, ESHRE,89 HFEA,90 ASRM,91 and literature is complicated by heterogeneity in both the
SOGC and CFAS (jointly)92 have modified their guidelines patient population and the medication regimens aimed at
and recently endorsed a policy of eSET for women with OI or OH, with or without IUI. In addition, unlike ART/
clinical factors predictive of a high chance of success for IVF, there is even less regulation and capture of data on
cumulative live birth in centres with a good cryopreservation treatment outcomes in this population, as it is not subject
facility. However, there is no current specific predictive to either mandatory or voluntary AHR reporting in North
model to facilitate broad policy recommendations in America or Europe.
A recent review99 and ASRM committee opinion on ways stage), and the effect of “vanishing” fetuses are some of
to reduce multiple pregnancy rates following OI/OS the factors that could affect perinatal, obstetrical, and long-
reviews several strategies that have been studied, including term outcomes in different but significant ways.
longer initial treatment with clomiphene citrate prior to
gonadotropin use, lower doses of gonadotropins, and There are, however, some evolving trends that continue
monitoring and altering cycle management on the basis of to support the association between AHR and increased
estradiol levels and follicle size. The committee concludes risk of adverse obstetrical and perinatal outcomes among
that useful work has been done, but larger, prospective singleton pregnancies.
studies are needed prior to the issue of a formal guideline
Preterm Birth
on this issue.100
Along with multiple pregnancy, preterm birth and LBW
Recommendations are the most commonly examined measures of adverse
3. Multiple pregnancy is the most powerful predictive perinatal outcome in singleton pregnancies conceived after
factor for adverse maternal, obstetrical, and perinatal AHR.101,102 Table 4 summarizes these data.96–99,101,103
outcomes. Couples should be thoroughly counselled
about the significant risks of multiple pregnancies Several studies have found an increased risk of preterm
associated with all assisted human reproductive birth, whether defined as birth before 37 weeks, at 32 to
treatments. (II-2A) 36 weeks, or before 32 weeks, in IVF versus spontaneous
4. The benefits and cumulative pregnancy rates of singleton pregnancies. Adjusted odds ratios/relative risks
elective single embryo transfer support a policy are between 1.95 and 3.22.104–108 It is not as convincing
of using this protocol in couples with good that OI alone increases the risk of preterm birth once
prognosis for success, and elective single embryo other factors are controlled,109,110 although one recent large
transfer should be strongly encouraged in this Finnish cohort study found an independent effect on
population. (II-2A) preterm birth in all categories of gestational age cut-offs.111
5. To reduce the incidence of multiple pregnancy, health
Low Birth Weight
care policies that support public funding for assisted
In almost all studies of singleton pregnancies resulting
human reproduction, with regulations promoting best
from any type of AHR, LBW is found more often than
practice regarding elective single embryo transfer,
should be strongly encouraged. (II-2A) in spontaneous pregnancies. As in preterm birth, all
systematic reviews have associated IVF with reduced birth
Singleton Pregnancies and Perinatal Outcome weight, as indicated in Table 4.69,82,105–108 LBW in these cases
AHR resulting in singleton pregnancies has also been shown reflects not only decreased gestational age, but also less
to be associated with adverse obstetrical and perinatal than optimal growth for a given gestational age.
outcomes, but this is challenging literature to analyze.
There are many individual factors that can independently OI is also quite consistently associated with LBW.109–111
and significantly contribute to adverse outcomes, but they Exposure to gonadotropic stimulation, which produces
are difficult to isolate as they are interrelated with the increased physiologic levels of circulating estradiol
couple’s clinical profile (reason for infertility/subfertility) combined with in vitro culture may be cumulatively
and treatment regime. detrimental to normal embryo growth.112
The quality of studies has improved as accumulated data Many emerging studies are attempting to isolate the
from large registries have been published, but these still do causative factors responsible for growth disturbance in
not allow the isolation of likely important but interrelated women undergoing AHR by comparing outcomes in various
clinical details, such as maternal and paternal background subsets within cohort studies of the AHR population and
factors and individual factors within the treatment regimes. with outcomes in spontaneous pregnancies. Consistent
Different forms of OI versus OH, donor versus own eggs, with the data on the contribution of the diagnosis and
timing and/or method of aspiration of eggs, maturation causes of infertility itself, Sasanova et al. performed logistic
in an artificially high hormonal milieu in the mother (OH) regression analysis on 8941 singleton pregnancies after
or in the laboratory (in vitro maturation), fresh or frozen IVF to determine predictive factors for preterm birth and
embryos, method of freezing embryos or eggs, origin LBW. They found that primiparity, smoking, BMI, and the
of sperm (ejaculated, testicular, epididymal), quality of vanishing twin phenomenon increased the risk of preterm
sperm, number of embryos formed, number of embryos birth, and that maternal age, smoking, BMI, and duration
transferred, stage of transfer (cleavage vs. blastocyst of infertility increased the risk of LBW.113
Table 4. Controlled studies of preterm birth and LBW among singleton pregnancies after
AHR, compared with spontaneously conceived pregnancies
RR ovulation
RR IVF induction alone
Perinatal outcomes (95% CI) (95% CI)
Preterm delivery < 37 weeks 1.98 (1.77 to 2.22)97 1.32 (1.15 to 1.50)104
2.00 (1.70 to 2.20) 98
A number of studies that compared IVF cycles with found a higher risk of LBW and lower mean birth weight
fresh versus frozen (cryopreserved) embryos found that in fresh IVF-ICSI pregnancies than in FET, and an overall
frozen embryo transfers result in higher birth weights, a lower birth weight with any ART than with spontaneous
lower chance of SGA infants, and a lower rate of preterm pregnancy.120
birth.114–116 A large Australian cohort study performing
regression analysis to determine predictive factors for The most recent data from a cohort of 25 777 births
LBW reports a significant increase in LBW with fresh documents a significant difference in birth weight of 90.9 g
versus FET, with an aOR of 1.9 (95% CI 1.6 to 2.4).117 in singletons conceived in frozen versus fresh transfer
cycles.121
A systematic review on the topic also reports that the preterm
birth rate is either unchanged or decreased, and the LBW/ There is speculation that the endometrial environment may
SGA rate is unchanged or improved with cryopreserved be improved by the lower doses of OS agents required
versus fresh IVF cycles.118 A recent American cohort study for FET, or that better quality embryos are recruited and
of 24 334 singleton fresh IVF pregnancies compared with persevere through cryopreservation procedures. However,
13 806 singleton FET IVF pregnancies found no significant another cohort study of 32 416 singleton IVF or ICSI
increase in aORs for preterm birth with FET, but an pregnancies found no independent relationship between
increase in the overall rate of LBW, with an aOR of 1.35 the parameters of OS used in these cycles and birth
(95% CI 1.20 to 1.51) among pregnancies of fresh IVF weight.122
cycles. In donor oocyte cycles with no OS, the rate of LBW An interesting study of 292 singletons examined serum
was not increased.119 These findings suggest that changes estradiol levels during IVF cycles found that adjusted for
in the uterine environment associated with multiple follicle patient age, BMI, parity, number of embryos transferred,
production increases the risk of LBW. day of transfer, and gonadotropin dose, high serum
An interesting Danish cohort study of sibling singleton estradiol levels (> 3450 pg/mL or > 90th percentile) were
births comparing 5 groups of successive pregnancies associated with preeclampsia (OR 4.8; 95% CI 1.6 to 14.8)
and SGA (OR 9.4; 95% CI 3.2 to 27.5).123
•• fresh IVF-ISCI vs. spontaneous,
•• fresh IVF-ICSI vs. FET, Other studies have compared pregnancies conceived
•• FET vs. FET, after ICSI/IVF to spontaneous pregnancies with regard
to preterm birth and LBW. Two small studies (N = 41
•• fresh IVF-ICSI vs. fresh IVF-ICSI, ICSI/147 control subjects124; N = 276 ICSI/273 control
•• spontaneous vs. spontaneous subjects125) comparing IVF/ICSI pregnancies with
spontaneous pregnancies did not find an increase in LBW an overlapping cohort from the same database controlling
or preterm birth. A study comparing 81 singleton ICSI for, but not excluding, multiples, reports an increased
pregnancies to 81 matched-control IVF pregnancies did risk for preeclampsia with IVF (OR 1.78; 95% CI 1.05 to
not find any significant difference in preterm birth or 3.06), but not for IUI or OI.135 Small studies have linked
low birth weight.126 A Canadian study comparing ICSI donor oocytes with an increased risk of preeclampsia over
(n = 104), IVF (n = 133) and in vitro ovum maturation autologous oocytes.130,136
(n = 31) did not find any significant differences in rates
of preterm birth or LBW.127 The source of sperm for Other placental complications reported to occur with
ICSI (ejaculated, epididymal, or testicular) does not increased frequency with ART include placenta previa,
appear to influence birth weight parameters.128,129 ICSI placental abruption, and antepartum and postpartum
itself does not appear to adversely affect preterm birth hemorrhage. In a review of 42 placenta accreta cases, the
or LBW rates. OR for IVF versus spontaneous pregnancies was 13.2
(95% CI 6.7 to 25.8).137 A large Australian cohort study
Use of donor, versus autologous, oocytes has been of 6730 IVF/ICSI pregnancies compared with 24 619
reported to increase the risk of preterm birth and LBW. A spontaneous pregnancies found an aOR of 2.0 (95% CI 1.8
small case-controlled study comparing 81 IVF donor cycles to 2.3) for antepartum hemorrhage, 2.3 (95% CI 1.9 to 2.9)
to 77 autologous oocyte IVF cycles found an increased for placenta previa, 2.1 (95% CI 1.4 to 3.0) for abruption,
aOR of 2.6 (95% CI 1.04 to 6.3) for preterm birth.130 A and 1.3 (95% CI 1.2 to 1.4) for postpartum hemorrhage.138
SART report comparing 60 037 standard IVF cycles with A recent systematic review of 13 studies did not indicate
10 176 donor egg cycles and 1180 gestational carrier cycles an increased risk of postpartum depression associated
found aORs of 1.21 (95% CI 1.13 to 1.30) for birth weight with ART.139
< 2500 g and 1.28 (95% CI 1.10 to 1.49) for birth weight
The timing of the transfer of the embryo in IVF or IVF/
< 1500 g when comparing donor egg with autologous egg
ICSI may influence the outcome. Optimal timing has
IVF cycles.37
evolved from the cleavage-stage to the blastocyst stage,
Other Obstetrical Outcomes as the success rate after blastocyst transfer is higher,
There has been some question of whether AHR leads to resulting in a higher live birth rate.140 In a meta-analysis
placental abnormalities as a mediating factor for some of 4 studies of 1102 blastocyst transfer cycles versus
adverse outcomes, such as LBW, preeclampsia, abnormal 1485 cleavage-stage cycles, the ratio of males to females
implantation, placenta accreta, antepartum hemorrhage, was higher (OR 1.29; 95% CI 1.10 to 1.51) in blastocyst
and postpartum hemorrhage. Possible early placental transfer cycles. In the same report a meta-analysis of 7
abnormalities are consistent with the finding of altered studies of 9316 blastocyst cycles versus 31 601 cleavage-
levels of maternal serum marker levels for Down syndrome stage cycles found the rate of monozygotic twinning to
and open neural tube defects in the first and second be increased with blastocyst transfer (OR 3.04; 95% CI
trimester. Several studies, including that reported from 1.54 to 6.01).141 In another study of 1311 blastocyst transfer
the Danish cohort, found a significantly lower PAPP-A cycles versus 12 562 cleavage-stage cycles, the rate of birth
level among ART pregnancies (except those with FET) of < 37 weeks was slightly increased in the blastocyst transfer
0.8 MoM131 and an elevated total hCG.132 group (OR 1.35; 95% CI 1.07 to 1.71), but the LBW rate
was unchanged.142
Several studies report an increased risk of preeclampsia
with AHR. Calhoun reports an aOR of 2.2 (95% CI 1.03 Long-Term Child Outcomes
to 4.72), when controlling for factors including multiple Several large registry-based studies examining long-term
gestation, for preeclampsia with AHR; the risk was greatest child outcomes have been published recently. There
for IVF (aOR 5.3; 95% CI 1.74 to 15.89), and there was appears to be little, if any, increased risk of significant
no reported association between IUI and preeclampsia.133 neurodevelopmental or behavioural adverse outcomes at
2-year124 or 5-year125,143 follow-ups. A 10-year follow-up
Two separate cohort studies from the same Ontario study found no significant difference between ICSI and
database report somewhat contradictory findings. Sun et spontaneously conceived children.144 Physical health, thus
al. found a non-significant increased risk of a composite far, appears equal, although there has been a reported
outcome of placenta-mediated complications (stillbirth, increase in undescended testes and resulting urogenital
growth restriction, preeclampsia, and abruption) with IUI surgery in boys after ICSI.145 Although small studies
(OR 1.30; 95% CI 0.94 to 1.80) but not with IVF or OI in a reported an increase in certain childhood cancers, registry
matched-control study in singletons.134 Another analysis on data do not support this relationship.146
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a meta-analysis. Fertil Steril 2004;82:1514–20. weight: an analysis of 25,777 children in the national assisted reproduction
105. Jackson RA, Gibson KA, Wu YW, Croughan MS. Perinatal outcomes in registry of Japan. Fertil Steril 2013;99:450–5.
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2004;103:551–63. stimulation for IVF has no quantitative association with birthweight:
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and meta-analysis. J Obstet Gynaecol Can 2005;27(5):449–59. et al. Peak serum estradiol level during controlled ovarian hyperstimulation
107. McDonald SD, Han Z, Mulla S, Murphy KE, Beyene J, Ohlsson A. is associated with increased risk of small for gestational age and
Preterm birth and low birth weight among in vitro fertilization singletons: preeclampsia in singleton pregnancies after in vitro fertilization.
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108. Klemetti R, Sevon T, Gissler M, Hemminki E. Health of children
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Neuromotor development and mental health at 5.5 years of age of
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126. Knoester M, Helmerhorst FM, Vandenbroucke JP, van der Westerlaken LA,
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127. Buckett WM, Chian RC, Holzer H, Dean N, Usher R, Tan SL. Obstetric 145. Ludwig AK, Katalinic A, Thyen U, Sutcliffe AG, Diedrich K, Ludwig M.
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128. Belva F, De Schrijver F, Tournaye H, Liebaers I, Devroey P, Haentjens P, 146. Brinton LA, Krüger Kjaer S, Thomsen BL, Sharif HF, Graubard BI,
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129. Tsai CC, Huang FJ, Wang LJ, Lin YJ, Kung FT, Hsieh CH, et al. Clinical 147. Schieve LA, Rasmussen SA, Buck GM, Schendel DE, Reynolds MA,
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148. Ericson A, Kallen BA. Nonsteroidal anti-inflammatory drugs in early
130. Klatsky PC, Delaney SS, Caughey AB, Tran ND, Schattman GL,
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Rosenwaks Z. The role of embryonic origin in preeclampsia:
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131. Gjerris AC, Loft A, Pinborg A, Christiansen M, Tabor A. First-trimester born after ICSI. Hum Reprod 2000;15:944–8.
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Ultrasound Obstet Gynecol 2009;33:8–17. Rasmussen SA. Assisted reproductive technology and major structural
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151. Wen SW, Leader A, White RR, Léveillé MC, Wilkie V, Zhou J, et al.
Hum Reprod Update 2006;12:513–8.
A comprehensive assessment of outcomes in pregnancies conceived by in
133. Calhoun KC, Barnhart KT, Elovitz MA, Srinivas SK. Evaluating vitro fertilization/intracytoplasmic sperm injection. Eur J Obstet Gynecol
the association between assisted conception and the severity of Reprod Biol 2010;150:160–5.
preeclampsia. ISRN Obstet Gynecol 2011;2011:928592. doi:
10.5402/2011/928592. 152. Hansen M, Kurinczuk JJ, Bower C, Webb S. The risk of major birth
defects after intracytoplasmic sperm injection and in vitro fertilization.
134. Sun LM, Walker MC, Cao HL, Yang QY, Duan T, Kingdom JCP. Assisted N Engl J Med 2002;346:725–30.
reproductive technology and placenta-mediated adverse pregnancy
outcomes. Obstet Gynecol 2009;114:818–24. 153. Katalinic A, Rösch C, Ludwig M; German ICSI Follow-Up Study
Group. Pregnancy course and outcome after intracytoplasmic
135. Chen XK, Wen SW, Bottomley J, Smith GN, Leader A, Walker MC. sperm injection: a controlled, prospective cohort study. Fertil Steril
In vitro fertilization is associated with an increased risk for preeclampsia. 2004;81:1604–16.
Hypertens Pregnancy 2009;28:1–12.
154. Chen T, McDonald A, Shadbolt B, Talaulikar D. Precision of histological
136. Wiggins DA, Main E. Outcomes of pregnancies achieved by donor egg
bone marrow staging in follicular lymphoma and diffuse large B-cell
in vitro fertilization—a comparison with standard in vitro fertilization
lymphoma. Clin Invest Med 2012;35:E358.
pregnancies. Am J Obstet Gynecol 2005;192:2002–6.
137. Esh-Broder E, Ariel I, Abas-Bashir N, Bdolah Y, Celnikier DH. Placenta 155. Bonduelle M, Van Assche E, Joris H, Keymolen K, Devroey P,
accreta is associated with IVF pregnancies: a retrospective chart review. Van Steirteghem A, et al. Prenatal testing in ICSI pregnancies: incidence
BJOG 2011;118:1084–9. of chromosomal anomalies in 1586 karyotypes and relation to sperm
parameters. Hum Reprod 2002;17:2600–14.
138. Healy DL, Breheny S, Halliday J, Jaques A, Rushford D, Garrett C, et al.
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139. Ross LE, McQueen K, Vigod S, Dennis CL. Risk for postpartum 157. Chitayat D, Langlois S, Wilson RD; SOGC Genetics Committee; CCMG
depression associated with assisted reproductive technologies and multiple Prenatal Diagnosis Committee. Prenatal screening for fetal aneuploidy in
births: a systematic review. Hum Reprod Update 2011;17:96–106. singleton pregnancies. Society of Obstetricians and Gynaecologists of
Canada Clinical Practice Guideline, No. 261, July 2011. J Obstet Gynaecol
140. Blake DA, Farquhar CM, Johnson N, Proctor M. Cleavage stage versus
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Database Syst Rev 2007(4):CD002118. 158. Ranta JK, Raatikainen K, Romppanen J, Pulkki K, Heinonen S. Increased
141. Chang HJ, Lee JR, Jee BC, Suh CS, Kim SH. Impact of blastocyst transfer time-to-pregnancy and first trimester Down’s syndrome screening. Hum
on offspring sex ratio and the monozygotic twinning rate: a systematic Reprod 2010;25:412–7.
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142. Kallen B, Finnstrom O, Lindam A, Nilsson E, Nygren KG, Olausson Pregnancies conceived using assisted reproductive technologies (ART)
PO. Blastocyst versus cleavage stage transfer in in vitro fertilization: have low levels of pregnancy-associated plasma protein-A (PAPP-A)
differences in neonatal outcome? Fertil Steril 2010;94:1680–3. leading to a high rate of false-positive results in first trimester screening
for Down syndrome. Hum Reprod 2009;24:1330–8.
143. Ponjaert-Kristoffersen I, Tjus T, Nekkebroeck J, Squires J, Verté D,
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144. Leunens L, Celestin-Westreich S, Bonduelle M, Liebaers I,
Ponjaert-Kristoffersen I. Follow-up of cognitive and motor development 161. Shulman A, Maymon R. Mid-gestation Down syndrome screening
of 10-year-old singleton children born after ICSI compared with test and pregnancy outcome among unstimulated assisted-conception
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162. Steptoe PC, Edwards RG. Birth after the reimplantation of a human 171. Fiorentino F, Spizzichino L, Bono S, Biricik A, Kokkali G, Rienzi L,
embryo. Lancet 1978;2:366. et al. PGD for reciprocal and Robertsonian translocations using
array comparative genomic hybridization. Hum Reprod
163. Zeilmaker GH, Alberda AT, van Gent I, Rijkmans CM, Drogendijk AC.
2011;26:1925–35.
Two pregnancies following transfer of intact frozen-thawed embryos.
Fertil Steril 1984;42:293–6. 172. Liebaers I, Desmyttere S, Verpoest W, De Rycke M, Staessen C,
Sermon K, et al. Report on a consecutive series of 581 children born after
164. Palermo G, Joris H, Devroey P, Van Steirteghem AC. Pregnancies after blastomere biopsy for preimplantation genetic diagnosis. Hum Reprod
intracytoplasmic injection of single spermatozoon into an oocyte. Lancet 2010;25:275–82.
1992;340:17–8.
173. Middelburg KJ, van der Heide M, Houtzager B, Jongbloed-Pereboom M,
165. Ishida M, Moore GE. The role of imprinted genes in humans. Mol Fidler V, Bos AF, et al. Mental, psychomotor, neurologic, and behavioral
Aspects Med 2013;34:826–40. outcomes of 2-year-old children born after preimplantation genetic
166. Iliadou AN, Janson PC, Cnattingius S. Epigenetics and assisted screening: follow-up of a randomized controlled trial. Fertil Steril
reproductive technology. J Intern Med 2011;270:414–20. 2011;96:165–9.
167. Wilkins-Haug L. Epigenetics and assisted reproduction. Curr Opin 174. Schendelaar P, Middelburg KJ, Bos AF, Heineman MJ, Kok JH,
Obstet Gynecol 2009;21:201–6. La Bastide-Van Gemert S, et al. The effect of preimplantation
genetic screening on neurological, cognitive and behavioural
168. Lim DH, Maher ER. Genomic imprinting syndromes and cancer. development in 4-year-old children: follow-up of a RCT.
Adv Genet 2010;70:145–75. Hum Reprod 2013;28:1508–18.
169. Savage T, Peek J, Hofman PL, Cutfield WS. Childhood outcomes 175. Audibert F; SOGC Genetics Committee. Preimplantation genetic testing.
of assisted reproductive technology. Hum Reprod Society of Obstetricians and Gynaecologists Canada, Technical Update
2011;26:2392–400. No. 232, August 2009. J Obstet Gynaecol Can 2009;31:761–75.
170. Colls P, Escudero T, Fischer J, Cekleniak NA, Ben-Ozer S, Meyer B, et al. 176. Woolf SH, Battista RN, Angerson GM, Logan AG, Eel W. Canadian
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This document reflects emerging clinical and scientific advances on the date issued and is subject to change. The information
should not be construed as dictating an exclusive course of treatment or procedure to be followed. Local institutions can dictate
amendments to these opinions. They should be well documented if modified at the local level. None of these contents may be
reproduced in any form without prior written permission of the SOGC.
Key to evidence statements and grading of recommendations, using the ranking of the Canadian Task Force on
Preventive Health Care
Quality of evidence assessment* Classification of recommendations†
I: Evidence obtained from at least one properly randomized A. There is good evidence to recommend the clinical preventive action
controlled trial
II-1: Evidence from well-designed controlled trials without B. There is fair evidence to recommend the clinical preventive action
randomization
II-2: Evidence from well-designed cohort (prospective or C. The existing evidence is conflicting and does not allow to make a
retrospective) or case–control studies, preferably from recommendation for or against use of the clinical preventive action;
more than one centre or research group however, other factors may influence decision-making
II-3: Evidence obtained from comparisons between times or D. There is fair evidence to recommend against the clinical preventive action
places with or without the intervention. Dramatic results in
uncontrolled experiments (such as the results of treatment with E. There is good evidence to recommend against the clinical preventive
penicillin in the 1940s) could also be included in this category action
III: Opinions of respected authorities, based on clinical experience, L. There is insufficient evidence (in quantity or quality) to make
descriptive studies, or reports of expert committees a recommendation; however, other factors may influence
decision-making
*The quality of evidence reported in these guidelines has been adapted from The Evaluation of Evidence criteria described in the Canadian Task Force on
Preventive Health Care.35
†Recommendations included in these guidelines have been adapted from the Classification of Recommendations criteria described in the Canadian Task Force
on Preventive Health Care.35
reproductive age is 1% to 2%.11,12 A British Columbia be counselled that very few studies have properly
study reported a prevalence of HCV infection of around addressed this possibility (II-2C). More research on
0.9% in the pregnant population, although only half of this topic is recommended (III-L).
those women would have been detected through testing
based on risk-factors.13 In women in the Canadian federal
HUMAN IMMUNODEFICIENCY VIRUS
penitentiary system, however, the prevalence is 40%,14 and in
antenatal clinics in Scotland it is 0.6%.14 The rate of vertical The prevalence of HIV in an obstetric population varies
transmission is approximately 5% to 10%.15–18 The exact greatly, depending on the population studied. The reported
timing of vertical transmission is unknown, but elective prevalence in British Columbia is 0.03%, while in some inner
Caesarean section does not appear to be preventive.18 The city populations in the United States, the prevalence is as
risk of vertical transmission appears to be increased in high as 1.5%.23,24 The AIDS Clinical Trials Group 076 study
women whose hepatitis C is associated with active liver clearly demonstrated a 26% vertical transmission rate, which
disease, in those whose level of HCV RNA is greater than was lowered to 8% in patients who received antepartum,
106/mL, and in women co-infected with HIV.15,18 Only a intrapartum, and neonatal zidovudine therapy.25 Many
few series discuss the use of amniocentesis in pregnant HIV-positive women are now taking cART.26 In those, the
women infected with HCV. One series reported the use vertical transmission rate has decreased to less than 1%.27
of amniocentesis in 22 women with hepatitis C, of whom
16 had HCV RNA identified in their serum. All women In a French series of 1632 HIV-positive women, of whom
(median age 39 years) underwent amniocentesis in the 4th only 5% received antenatal zidovudine therapy, the rate
month of pregnancy.19 The amniotic fluid samples were of vertical transmission was 19%.28 Amniocentesis was
tested using polymerase chain reaction for HCV RNA. performed on 13 women and amnioscopy on 26 women, with
Of the 16 viremic women, HCV RNA was detected in the a vertical transmission rate of 36%. This rate was significantly
amniotic fluid of only one, whose placenta was anterior. higher than that observed in women who did not have
On postnatal testing, none of the children from these invasive needling procedures (18%). Five series reporting on
pregnancies, including the child from the pregnancy with a total of 159 women on cART provide contemporary data
HCV RNA-positive amniotic fluid, was found to be HCV on this topic. No case of vertical transmission was reported in
RNA-positive.19 A case–control study, published as an those series for women having undergone an amniocentesis
abstract only, of factors involved in vertical transmission while on cART.29 A contemporaneous French cohort of 2528
reported a similar rate of amniocentesis in infected (8/51) women on cART who had not had an amniocentesis had a
and non-infected (28/110) children.20 In contrast, a case reported 1.2% transmission rate.30 With this reassuring data,
series of 44 vertically infected children reported a history experts now suggest that indicated amniocentesis should not
of amniocentesis in 10 (22.5%) of the pregnancies, a be avoided in women with HIV who are on cART, particularly
rate higher than seen in the general population.21 Finally, if their viral loads are low, but that the best non-invasive
Minola et al. reported a case of a twin pregnancy in which screening available should be used prior to invasive testing by
only one sac was sampled, and only that one fetus was amniocentesis.
infected at 12 months of age.22 Although the 2 best studies López and Coll suggest that 2 weeks of cART prior to
are somewhat reassuring, little is learned from these series, the amniocentesis were sufficient to provide the therapy’s
as the various methodologies do not allow for a meta- observed benefit of reduced vertical transmission.29 Others
analysis. In summary, amniocentesis in women infected recommend waiting for an undetectable viral load before
with hepatitis C does not significantly increase the risk of proceeding.31 These factors should be considered in the choice
vertical transmission, but women should be counselled that of antiretroviral, which should be made in consultation with
very few studies have properly addressed this possibility, infectious diseases specialists and obstetrical care providers.
nor have factors that could affect the transmission rate For example, raltegravir could be used to rapidly decrease a
been well studied. high maternal viral load before the amniocentesis.32
There are no studies available on other prenatal invasive Somigliana et al. reported in their series 3 women having
procedures such as CVS or fetal blood sampling. undergone CVS and 4 having undergone a cordocentesis,
all while on cART.33 No cases of vertical transmission
Recommendation
were reported in those 7 women. With such limited
5. Amniocentesis in women infected with hepatitis C data, however, the use of these procedures cannot be
does not appear to significantly increase the risk of recommended if amniocentesis is an option, because more
vertical transmission, but women should data is available on amniocentesis.
Recommendations REFERENCES
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et al. Routine prenatal screening for HIV in a low-prevalence setting. in pregnancy. AIDS Patient Care STDS 2012;26:714–7.
CMAJ 1998;159:942–7. 33. Somigliana E, Bucceri AM, Tibaldi C, Alberico S, Ravizza M, Savasi V,
24. Guinan ME, Hardy A. Epidemiology of AIDS in women in the United et al. Early invasive diagnostic techniques in pregnant women who are
States. 1981 through 1986. J Am Med Assoc 1987;257:2039–42. infected with the HIV: a multicenter case series. Am J Obstet Gynecol
2005;193:437–42.
25. Connor EM, Sperling RS, Gelber R, Kiselev P, Scott G, O’Sullivan MJ,
et al. Reduction of maternal-infant transmission of human 34. Giorlandino C, Gambuzza G, D’Alessio P, Santoro ML, Gentili P,
immunodeficiency virus type 1 with zidovudine treatment. Pediatric Vizzone A. Blood contamination of amniotic fluid after
AIDS Clinical Trials Group Protocol 076 Study Group. N Engl J Med amniocentesis in relation to placental location. Prenat Diagn
1994;331:1173–80. 1996;16:180–2.
26. Carpenter CC, Fischl MA, Hammer SM, Hirsch MS, Jacobsen DM, 35. Woolf SH, Battista RN, Angerson GM, Logan AG, Eel W. Canadian
Katzenstein DA, et al. Antiretroviral therapy for HIV infection in 1998: Task Force on Preventive Health Care. New grades for recommendations
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management.
This document reflects emerging clinical and scientific advances on the date issued and is subject to change. The information
should not be construed as dictating an exclusive course of treatment or procedure to be followed. Local institutions can dictate
amendments to these opinions. They should be well documented if modified at the local level. None of these contents may be
reproduced in any form without prior written permission of the SOGC.
Key to evidence statements and grading of recommendations, using the ranking of the Canadian Task Force on
Preventive health Care
RECOMMENDATIONS
Screening Evaluation
4. Positive screening results for open/closed neural tube defect Pregnancy Management
10. Following the detection of an isolated open/closed neural tube
referral to appropriate experienced providers for genetic review,
management options after diagnostic and genetic testing results
are available. Options should include information about
Diagnostic Evaluation
5. If the second trimester screening fetal ultrasound indicates a or fetal contraindications for prenatal repair at 20–26 weeks’
probable diagnosis of neural tube defects, the women should be
prognosis, and
for a more detailed ultrasound examination looking for the
6. Prenatal magnetic resonance imaging can be considered as request. For an encephalocele, individualized counselling is
an additional fetal imaging technique if further detailed fetal
INTRODUCTION
maximize testing accuracy, achieve a low FPR, and allow 16.3% incidence.33–37 Syndromes or sequences associated with
optimal management of affected pregnancies.4,10,15–27 NTDs include amniotic band syndrome, cloacal extrophy,
Factors that have been reported to affect the accuracy limb body wall complex, OEIS (omphalocele, extrophy,
and interpretation of OCNTD screening results include imperforate anus, spinal) syndrome, cerebrocostomandibular
type of NTD malformation, gestational age, maternal syndrome, and caudal regression.38 Other syndromic
weight, maternal insulin-dependent diabetes, multiple OCNTDs are associated with single gene disorders such as
gestations, ethnicity, environmental factors (prescription
and non-prescription medications), and concurrent fetal (cranial ONTD and holoprosencephaly) genes. Other single
anomalies.1,9,13,17,22 gene disorders reported include Waardenburg syndrome and
Curarino syndrome.38
Early prenatal screening for ONTD gives parents and
health care practitioners the ability to evaluate the anomaly There are reports of gene mutations or alterations of gene
and the overall health of the fetus during the second expression leading to ONTDs, such as polymorphisms
trimester. This guideline focuses on NTD screening, or SNPs in genes responsible for folate transport, the
diagnosis, and post-diagnostic pregnancy management. methionine/homocysteine metabolic cycle, methylation,
and nucleotide biosynthesis. Rare mechanisms contributing
GENETICS OF NTD
autoantibodies to the folate receptors, and infertility or
In humans, the neural tube closes between 21 to 28 days assisted reproductive technology therapy.39–42
of embryonic development, and abnormal closure is
characterized by the improper fusion of the neural tube in NON-INVASIVE NTD SCREENING TEChNIQUES
the developing embryo.1,2,7 NTD prevalence ranges from 1
in 300 to 1 in 1000 pregnancies and is affected by ethnic, Ultrasound Screening
genetic, and dietary factors, with the highest NTD rates in Ultrasound is the non-invasive screening modality of choice
the United Kingdom and the United States and the lowest for the detection of fetal anomalies including NTDs because
4,21,22,43,44
rates in Japan.9,10,28–31
The current generation of ultrasound machines allow for
Certain chronic maternal medical conditions will increase the highly detailed fetal imaging. National screening policy
risk of NTDs, including poorly controlled maternal insulin- documents cite detection rates of approximately 68% to
dependent diabetes (OR 11.5), antiepileptic medications 94% for NTDs,9,22,45–47 with EUROCAT reporting a 68%
(valproic acid, carbamazepin), therapy with folic acid 48
and British
antagonists, and maternal obesity (OR 3.5).28–31 Columbia an 86% detection rate (1997–1999).4
NTDs are described by their anatomical location and A second trimester screening ultrasound should be offered
neural content type as follows: to all pregnant women, as recommended in a number of
SOGC guidelines43,49,50 for the detection of congenital
93% ONTDs (neural placode at the base of the NTD) anomalies from 18 to 22 weeks’ gestation, avoiding the
and 7% CNTDs (MC = dural sac only; MMC = neural need for a second trimester MSAFP screening test.15,43,45,47,48
elements attached to the dural sac); Ultrasound is recommended routinely in all second trimester
pregnancies and is a more effective screen for OCNTD
2. anencephaly (closure failure of caudal NT folds (improved sensitivity with lower FPR although more
causing failure of brain development) 40%; expensive) than MSAFP screening, and diagnostically it is
3. encephalocele (outpouching of the brain through a safer than amniocentesis which carries the risk of infection
bony skull defect; occipital is most common, with or spontaneous abortion.9,11,45,47,51–53 In addition, ultrasound
anterior and lateral locations) 8.5%; and has the major advantage of screening for multiple congenital
4. inencephaly/craniorachischisis (abnormal skull and anomalies at a single ultrasound imaging visit. The factors
upper spine development) 1.5%.32 that may affect ultrasound screening for NTDs include
Seventy percent of NTDs related to genetic abnormalities of fetuses, and maternal BMI. Other factors to consider
are isolated, non-syndromic anomalies or malformations, are parental ethnicity, “at risk” maternal medication use,
and with current genetic knowledge, are considered to have maternal diabetic status, and personal, pregnancy, and family
a multi-factorial inheritance. Chromosomal abnormalities histories.1,15,43,54–61 In a fetus with an OCNTD, features visible
associated with an “apparently isolated” NTD have a 2.4% to by ultrasound in the second trimester include anencephaly
Fetal MRI
Obstetric application of MRI began approximately 20 years additional anomalies,76 but its expense, lack of a standard
ago, 10 years after its discovery and initial use.66,67 The main of reference for imaging, and limited availability are factors
use of fetal MRI is as an adjunct to the primary ultrasound that continue to favour ultrasound as the imaging choice
for the detection of OCNTDs.77,78
detail could be obtained for management planning and
Maternal serum AFP
counselling.68–70 Fetal MRIs are usually conducted between
the late second and early third trimesters, between 23 and MSAFP screening was once considered the gold standard
32 weeks’ gestation.21,59,70 This gestational age allows for of prenatal ONTD screening, but with advances in
optimal imaging of the entire fetal brain and subarachnoid technology, research, and knowledge, MSAFP screening
space15,21,67,71; however, late gestation MRI can delay now has limited value when reliable second trimester
decisions regarding pregnancy management, including ultrasound (screening and diagnostic) is available. Since
termination of pregnancy. the mid-1970s, non-invasive MSAFP has been used for the
detection of ONTDs.10,11,19,27,51,79 MSAFP levels rise early
The use of fetal MRI, primarily known for its superior in the pregnancy, and ONTD screening was optimized
brain imaging capabilities, has now been expanded to to discern normal from abnormal MSAFP results in the
detect non-CNS abnormalities.22,27,67,70 Although there second trimester between 15 and 18 weeks’ gestation.14,15,18,45
have been many advances in MRI technology such as the MSAFP levels are measured in multiples of the median,
use of T2-weighted sequences, which allow for better using unaffected pregnancies of the same gestational age as
An amniocentesis is most often performed for the risk of recurrence, and prediction of long-term
detection of chromosomal aneuploidy or genetic neonatal and childhood outcomes of open/closed
neural tube defect for family counselling. (II-2A)
the detection of NTDs.18,23,74,81–84 The procedure is 8. When a routine diagnostic amniocentesis indicates
usually conducted between the 15th and 20th gestational
only a risk
weeks.6,17,45,85–88
anomalies, it is not necessary to take an amniotic
karyotype, chromosomal microarray, and AFAFP and
AFAChE levels. When amniocentesis is performed with a
fetoprotein and acetylcholinesterase testing to
suspicion of OCNTD, the information from the karyotype,
screen for open neural tube defects. (II-2E)
chromosomal microarray, AFAFP, and the AFAChE levels
an open/closed neural tube defect (isolated or in a
with counselling regarding prognosis.
more complex multiple-anomaly grouping) requires
If amniocentesis is being performed for aneuploidy referral for comprehensive genetic, maternal–fetal
medicine, and pediatric neurosurgical counselling
for complete patient-focused care. (II-2A)
AChE is not routinely required.
PREGNANCY MANAGEMENT
aneuploidy still require a routine second trimester screening Counselling Information for
ultrasound for fetal congenital anomalies, including NTD Continuing Pregnancies
screening if a complete ultrasound anatomic assessment is Counselling should be based on the recognition of the
personal impact that a physical or mental disability could
have on a child and its family.
Risks associated with amniocentesis include spontaneous
abortion (estimated procedural risk of 0.5% to 1.0% One of the major questions a family asks when their fetus
added to the no-procedure background spontaneous risk is given an isolated, non-syndromic, non-chromosomal
of pregnancy loss), post-procedure spotting, infections, myelomeningocele diagnosis is “What will the quality
rupture of membranes, and fetal damage or loss.48,86–88 of life be for my child?” Król et al. reported a follow-
up study of 33 children (19 female; 14 male) with a
Amniocentesis for genetic testing is especially important
myelomeningocele at ages 5 to 20 years. They were
when considering prenatal or postnatal repair of congenital
evaluated in 2 age groups: 5 to 12 (n = 17) and 13 to
20 (n = 16) using the Health-Related Quality of Life in
fetal genetic factors is important as these factors may
interfere with the neonatal outcome.73,74,81–83
study reported good, very good, and average QoL in
Although an amniocentesis is an important diagnostic 64%, 30%, and 6% of participants respectively. None
option for high-risk pregnancies in the detection of of the participants felt their QoL was poor. Issues of
chromosomal abnormalities and ONTDs, amniocentesis visual perception in the younger group and ambulation
should not be used as a method for laboratory NTD in the older group were related to lower QoL scores. The
(AFAFP, AFAChE) screening because of the risks and cost vast majority of children had a history of good specialist
associated with the test. care. The most common medical issues were related to
hydrocephalus and neurogenic bladder.89
Recommendations
Invasive Prenatal Diagnostic Methods In a larger study of 119 patients with hydrocephalus and
MMC, Barf et al. reported a near equal overall QoL in the
amniocentesis (following the ultrasound detection study group (76%) as in an age-matched peer group (72%),
suspected open/closed neural tube defect), life, but less satisfaction with their sex lives and abilities to
should be evaluated for a fetal karyotype (and, if
indicated and available, a chromosomal microarray), that the severity of disease and the level of the lesion had
little bearing on self-reported QoL.90
acetylcholinesterase. These test results will allow In a retrospective cohort study Hunt and Oakeshott reported
comprehensive evaluation of the etiology, estimated on 117 open MMC patients. The cohort had had 54%
mortality and, at evaluation, had an average age of 35 years. sections as a safer method of delivery for the MMC-affected
Among the survivors, 40% were independent in activities fetus.97–102 Breech presentation is common in the MMC-
of daily living, meeting medical needs, transportation, and affected fetus as a result of decreased lower limb neurologic
continence care.91 function and megacephaly, and hence requires delivery by
Caesarean section.
Bowman et al. reported a 25-year follow-up of 118
MMC patients in which 75% lived to early adult age, 85% Prenatal in Utero Repair of MMC
had high school or college education, 80% were able to The Randomized Trial of Prenatal versus Postnatal Repair
maintain social bladder continence with catheterization, of Myelomeningocele74 showed that prenatal fetal surgery
90% reported acceptable levels of bowel continence, for MMC reduced the need for ventricular peritoneal
and 86% of long-term survivors were shunt-dependent. shunting (40% vs. 82%) and showed improved lower limb
motor outcomes at 30 months of age. However, the surgery
childhood or early adulthood was an unrecognized shunt was associated with maternal and fetal risks. Additional
malfunction.92 improvement in the child composite score for mental
development and motor function at 30 months of age was
For more complete counselling knowledge, the health
care provider could consider an economic assessment of score: prenatal surgery [n = 64] 148.6 ± 57.5; postnatal
the cost of continuing care for the MMC patient. Yi et al. surgery [n = 70] 122.6 ± 57.2; P = 0.007). Improved
hindbrain herniation at 12 months and ambulation at 30
reported across all.93 The lifetime direct medical costs for months was also reported. This landmark study provides
an important treatment option for parents because it clearly
being for inpatient care, treatment at initial diagnosis in
childhood, and co-morbidities in adult life. The caregiver surgery, albeit at the cost of increased maternal risks for
the index and subsequent pregnancies.74 An accompanying
editorial counselled caution regarding the initiation of this
Continuing Pregnancy Surveillance new prenatal treatment in multiple fetal therapy/treatment
and Method of Delivery centres and emphasized that most women who expressed
Pregnancy surveillance and delivery recommendations an interest in the experimental trial were either ineligible or
for fetuses with OCNTDs are controversial because declined to participate, with only 15% of screened women
increased pregnancy termination has limited the study of participating in the study.103 A legal and ethical opinion that
the MMC delivery model for more than 2 decades. The drew attention to prioritizing the fetus stated that:
ACOG Practice Bulletin94 reports that most pregnancies
complicated by MMC will deliver with appropriate lung unlike a born child, a fetus is not a patient in the real
maturity at term, and there is no evidence that antenatal sense, but only a metaphor. However, it would be
fetal heart rate testing for an MMC indication improves unethical if a care provider, without the woman’s
outcome. It is recognized that anomalous fetuses frequently informed consent, promoted the interests of the
fetus over those of the woman.104
interpret.95
When considering the consent to fetal surgery
Serial ultrasounds for fetal growth, head size, and
the parents have clear legal responsibilities to provide
ventricular size may be helpful in continued prognosis
or consent to their born children’s necessary medical
counselling and delivery planning. The fetus should be
care but the maternal duties to fetuses in utero are
delivered at a centre with a level III NICU and pediatric
not generally recognized.”104
neurosurgery services.90 A latex-free delivery and surgical
repair plan should be considered because individuals with Regarding whether this study was research or a therapeutic
MMC are at an increased risk of developing a severe and innovation they stated that:
life-threatening allergy to latex.96
the research component of the study was not in
The mode of delivery for an MMC-affected fetus with a vertex the prenatal surgical and postnatal management
presentation remains controversial. There are no RCTs, but at of each child but in the systematic control of
least 5 studies representing a total of 400 patients suggested each case according to the research protocol and
vaginal delivery does not adversely affect neonatal outcome, the retrospective comparative review for all the
and one large study of 200 patients suggested Caesarean outcome data.104
Their conclusion was that “women, diagnosed with a fetal For families choosing to terminate a pregnancy because of
MMC and where open fetal surgery is available, will have to an MMC, anencephaly, or encephalocele, the health care
be informed of this treatment option.”104 This prenatal repair provider should discuss fetal autopsy and chromosomal
option needs therefore to be presented to families in Canada
as part of the informed consent process because although it is provide important information about the etiology for
not available here, it is available in the United States.104 the NTD and the recurrence risk.107 Measures to prevent
recurrence, including maternal supplementation with 5 mg
Postnatal Repair of MMC of preconception folic, are recommended in subsequent
The decision to perform postnatal repair is the most likely pregnancies because folic acid supplementation has
clinical scenario in Canada for the MMC fetus or neonate been shown in an RCT to reduce the isolated recurrence
because only mothers who have travelled to in utero MMC risk of NTD by 72%, with a resulting reduction of the
treatment centres in the United States will have received in non-supplementation prevalence rate of 3% to a post
utero MMC repair. supplementation recurrence rate of 1%.5,108
The postnatal group in the Randomized Trial of Prenatal Recommendations
74
is used Pregnancy Management
as the clinical outcome for comparison because the RCT 10. Following the detection of an isolated open/closed
study was done in selected Children’s Hospital facilities neural tube defect, families should be offered a
with organized and comprehensively controlled pediatric choice of 3 obstetrical care management options
neurosurgery services. The placement of a shunt within the after diagnostic and genetic testing results are
available. Options should include information about
group (82%, compared to prenatal group 40%; P = 0.001). prenatal myelomeningocele repair and prognosis (if
Other abnormal cranial and brain features were higher in the there are no maternal or fetal contraindications for
postnatal group than in the prenatal repair group (degree of prenatal repair at 20–26 weeks’ gestation), postnatal
hindbrain herniation, P = 0.001; brainstem kinking, P = 0.001; myelomeningocele surgical repair and prognosis,
abnormal location of the 4th ventricle, P = 0.002). and pregnancy termination with autopsy. Because
anencephaly is a lethal condition, pregnancy with
anencephaly may be interrupted at any gestational
lower with postnatal repair than with prenatal repair, but this age on the woman’s request. For an encephalocele,
was mainly due to differences in motor function between the individualized counselling is recommended because
spinal anatomical levels of the defects (P = 0.001); the Bayley of the possibly unique circumstances of the
anomaly. (II-2A)
(P 11. Caesarean section is the most common method of
delivery for a fetus with a myelomeningocele (MCC)
independently with prenatal repair and 21% with postnatal in either vertex or breech presentation, but is it
repair (relative risk 2.01 ([95% CI 1.16–3.48]; P = 0.01).
with intrapartum fetal heart rate monitoring can be
lower WeeFIM scores for self-care (P = 0.02) and mobility considered in selected MMC vertex presentation
(P = 0.003), but not for cognitive ability (P = 0.67). cases that have no macrocephaly related to
gestational age and a small or no MMC sac. (II-2A)
Immediate postnatal care for MMC is required whether 12. Delivery management for a fetus with complex
the birth was by Caesarean section or vaginal delivery. multiple anomalies including a neural tube defect
Neonatology specialists should attend in the labour will need to be individually determined by the
room for MMC protection and care, probable neonatal multidisciplinary health care providers at the
prematurity (less than 37 weeks’ gestation), and planning anticipated delivery centre based on the differential
and performing subsequent primary neurosurgical MMC
closure within 24 hours of delivery, especially if the MMC testing results, prenatal care requirements, anticipated
is open or the MMC sac was ruptured at delivery neonatal morbidity or mortality, and family
Termination of Pregnancy
consultation and requests. (III-A)
13. Autopsy is recommended for all cases of prenatal
Over the last 3 decades an estimated 70% to 80% of
and postnatal open/closed neural tube defect
women and couples with a fetus affected by OCNTD have
(isolated or complex) following either termination
chosen termination of the pregnancy.4,105,106
of pregnancy or prenatal/postnatal death. Although it may be cost effective, the MSAFP screen
Induction of labour may be the preferred method can detect only open NTDs; it has poor sensitivity and
for pregnancy termination, allowing for a more
complete autopsy evaluation of the fetal central used as an adjunct to ultrasound when more detail of the
nervous system. If autopsy is declined, fetal CNS is required or when fetal therapy is being considered.
magnetic resonance imaging should be considered MRI is more expensive and is not as readily available as
to better evaluate fetal abnormalities either in utero ultrasound; further research is necessary to ensure its
or after postnatal death. If genetic studies have reported safety and to allow the creation of reference
not been completed prior to the termination, at standards.
the minimum, chromosomal karyotyping and/or
chromosomal microarray should be considered or Amniocentesis is an invasive diagnostic procedure that
encouraged, even if a full autopsy is not performed. is accurate in the detection of ONTDs and in analyses
This procedure will maximize information for for chromosomal or genetic abnormalities. With the use
postnatal review and counselling. (II-2A) of ultrasound for guidance, amniocentesis performed
by experienced hands, can greatly reduce the risks of
Pregnancy Follow-up miscarriage, infection, and harm to the fetus. However,
14. Follow-up consultation is recommended when although amniocentesis has a greater than 99% detection
postnatal genetic and pathologic studies are rate for ONTD, it is neither cost effective nor necessary
complete, to provide the woman with information for the detection of ONTD unless performed for the
related to the etiology, risk of recurrence,
recurrence prevention, and the possible impact on
other family members of the congenital isolated or Improved prenatal screening and diagnosis will enable
complex anomaly. (II-2A) mothers or couples to obtain precise information about
15. When a previous pregnancy history is complicated detected anomalies so they can make informed decisions
by a presumed folic acid-sensitive open/closed about whether to continue or interrupt the pregnancy and
neural tube defect (i.e., no karyotype, chromosomal what their options are for fetal or postnatal repair.
etiology) for either member of the couple, or Our current knowledge and experience indicates that
if either member of the couple planning the pregnant woman should be offered 2 prenatal screening
pregnancy is personally affected with an isolated approaches:
neural tube disorder, oral folic acid supplementation 1. risk screening for fetal aneuploidy and fetal anomalies,
of 5 mg within a multivitamin preparation should
using a combination of non-invasive techniques that
be recommended to the female partner, starting at
includes ultrasound (fetal anatomic and structural
least 3 months prior to pregnancy conception and
detail) and
2. maternal serum testing for placental biochemical
SUMMARY
trimester screening approaches) or for placental cell-
NTDs occur early in embryologic development, secondary free fetal DNA (for future direct fetal molecular DNA
to failure of fusion of the neural groove and formation screening or diagnostic testing).
of the neural tube. NTDs include malformations or
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Jon Havelock, MD, Burnaby BC Grey (unpublished) literature was identified through searching the
websites of health technology assessment and health technology-
Sarah Healey, MD, St. John’s NL related agencies, clinical practice guideline collections, clinical
Robert Hemmings, MD, Montreal QC trial registries, and national and international medical specialty
societies.
Kimberly Liu, MD, Toronto ON
Values: The quality of evidence in this document was rated using the
Tarek Motan, MD, Edmonton AB criteria described in the Report of the Canadian Task Force on
Ward Murdock, MD, Fredericton NB Preventive Health Care (Table 1).
This document reflects emerging clinical and scientific advances on the date issued and is subject to change. The information
should not be construed as dictating an exclusive course of treatment or procedure to be followed. Local institutions can dictate
amendments to these opinions. They should be well documented if modified at the local level. None of these contents may be
reproduced in any form without prior written permission of the SOGC.
Table 1. Key to evidence statements and grading of recommendations, using the ranking of the Canadian Task Force
on Preventive Health Care
Quality of evidence assessment* Classification of recommendations†
I: Evidence obtained from at least one properly randomized A. There is good evidence to recommend the clinical preventive action
controlled trial
II-1: Evidence from well-designed controlled trials without B. There is fair evidence to recommend the clinical preventive action
randomization
II-2: Evidence from well-designed cohort (prospective or C. The existing evidence is conflicting and does not allow to make a
retrospective) or case–control studies, preferably from recommendation for or against use of the clinical preventive action;
more than one centre or research group however, other factors may influence decision-making
II-3: Evidence obtained from comparisons between times or D. There is fair evidence to recommend against the clinical preventive action
places with or without the intervention. Dramatic results in
uncontrolled experiments (such as the results of treatment with E. There is good evidence to recommend against the clinical preventive
penicillin in the 1940s) could also be included in this category action
III: Opinions of respected authorities, based on clinical experience, L. There is insufficient evidence (in quantity or quality) to make
descriptive studies, or reports of expert committees a recommendation; however, other factors may influence
decision-making
*The quality of evidence reported in these guidelines has been adapted from The Evaluation of Evidence criteria described in the Canadian Task Force on
Preventive Health Care.65
†Recommendations included in these guidelines have been adapted from the Classification of Recommendations criteria described in the Canadian Task Force
on Preventive Health Care.65
3. Coasting for longer than 3 days reduces in vitro fertilization 7. Avoiding pregnancy by freezing all embryos will prevent severe
pregnancy rates. (II-2) prolonged ovarian hyperstimulation syndrome in patients at high
risk. (II-2)
4. The use of either luteinizing hormone or human chorionic
gonadotropin for final oocyte maturation does not influence the 8. Pregnancy rates are not affected when using gonadotropin-
incidence of ovarian hyperstimulation syndrome. (I) releasing hormone (GnRH) agonists in GnRH antagonist protocols
for final egg maturation when embryos are frozen by vitrification for
5. There is no clear published evidence that lowering the human later transfer. (II-2)
chorionic gonadotropin dose will result in a decrease in the rate of
ovarian hyperstimulation syndrome. (III)
Recommendations
6. Cabergoline starting from the day of human chorionic 1. The addition of metformin should be considered in patients with
gonadotropin reduces the incidence of ovarian hyperstimulation polycystic ovarian syndrome who are undergoing in vitro fertilization
syndrome in patients at higher risk and does not appear to lower because it may reduce the incidence of ovarian hyperstimulation
in vitro fertilization pregnancy rates. (II-2) syndrome. (I-A)
2. Gonadotropin dosing should be carefully individualized, taking into
account the patient’s age, body mass, antral follicle count, and
previous response to gonadotropins. (II-3B)
ABBREVIATIONS 3. Cycle cancellation before administration of human chorionic
ART assisted reproductive technology gonadatropin is an effective strategy for the prevention of ovarian
hyperstimulation syndrome, but the emotional and financial burden
CI confidence interval it imposes on patients should be considered before the cycle is
FSH follicle-stimulating hormone cancelled. (III-C)
GnRH gonadotropin-releasing hormone 4. Gonadotropin-releasing hormone (GnRH) antagonist stimulation
hCG human chorionic gonadotropin protocols are recommended in patients at high risk for ovarian
hyperstimulation syndrome (OHSS). The risk of severe OHSS in
HES hydroxyethyl starch patients on GnRH antagonist protocols who have a very robust
IVF in vitro fertilization ovarian stimulation response can be reduced by using a GnRH
agonist as a substitute for human chorionic gonadotropin to trigger
LH luteinizing hormone
final oocyte maturation. (I-B)
LPS luteal phase support
5. A gonadotropin-releasing hormone (GnRH) antagonist protocol with
OHSS ovarian hyperstimulation syndrome a GnRH agonist trigger for final oocyte maturation is recommended
OR odds ratio for donor oocyte and fertility preservation cycles. (III-C)
PCOS polycystic ovary syndrome 6. Albumin or other plasma expanders at the time of egg retrieval are
not recommended for the prevention of ovarian hyperstimulation
RCT randomized control study syndrome. (I-E)
SC subcutaneously 7. Elective single embryo transfer is recommended in patients at high
VEGF vascular endothelial growth factor risk for ovarian hyperstimulation syndrome. (III-C)
8. Progesterone, rather than human chorionic gonadotropin, should Table 2. Classification of OHSS
be used for luteal phase support. (I-A)
Grade Symptoms
9. Outpatient culdocentesis should be considered for the prevention
of disease progression in severe ovarian hyperstimulation Mild OHSS Abdominal bloating
syndrome. (II-2B) Mild abdominal pain
Ovarian size usually < 8 cm
INTRODUCTION Moderate OHSS Moderate abdominal pain
Nausea with/without vomiting
The degree of hCG exposure has been associated with the 43.8%, P = 0.04).14 The same first author also showed
risk of OHSS.18 It is recognized that hCG has no direct that pregnancy rates are not compromised in patients
effect on the vascular system33; however, vasoactive given cabergoline.41 The second RCT by Carriza et al.
substances such as VEGF are released in the ovary in randomized women who were undergoing IVF and at
response to hCG administration and are most likely high risk for OHSS (estradiol ≥ 14 700 pmol/L on day of
responsible for inducing vascular hyperpermeability and hCG trigger) into two groups: the study group received
third-spacing in high-risk women.34 A retrospective series 20 grams of prophylactic intravenous albumin and 0.5 mg
of 94 IVF cycles showed that when hCG doses were of Cabergoline orally once daily for 3 weeks commencing
lowered, both pregnancy rates and the rate of severe the day after oocyte retrieval and the control group received
OHSS remained unchanged.35 However, a lower incidence only albumin.42 The risk of early OHSS (occurring within
of severe OHSS has been observed with the use of lower the first 9 days after hCG trigger) decreased significantly
doses of hCG for final oocyte maturation in an at-risk (P < 0.001) in the cabergoline group; none of the patients
population. Because serum levels of hCG are dependent who had taken cabergoline progressed to early OHSS, but
on body mass,36,37 one Canadian fertility centre uses hCG 15.0% of the control group did. The risk of late OHSS did
5000 IU SC to trigger final egg maturation in patients at not decrease. In both of the RCTs examined, the use of
risk for OHSS who have a BMI < 28 kg/m2, despite the cabergoline did not affect the pregnancy outcome (clinical
lack of published data. Women with a BMI ≥ 28 kg/m2 pregnancy rate or miscarriage rate), nor was it associated
are all given hCG 10 000 IU SC for final egg maturation with an increased risk of adverse events.43
because yields of mature eggs have been observed to be
lower with a dose reduction in this population.36 Two published abstracts have demonstrated the safety
and efficacy of using cabergoline at even smaller doses:
Summary Statement 0.5 mg twice weekly for 6 doses44 and 0.5 mg twice weekly
5. There is no clear published evidence that lowering for 3 doses.45 Clinicians at one Canadian fertility centre use
human chorionic gonadotropin dose will result in a dose of cabergoline 0.5 mg every 3 days to a total of 4
a decrease in the rate of ovarian hyperstimulation doses starting on the day of oocyte maturation trigger and
syndrome. (III) a significant reduction in the incidence of severe OHSS
has been anecdotally observed since the introduction of
Cabergoline cabergoline into the prevention strategies for OHSS.
VEGF produced by granulosa cells of developing follicles
is thought to be a key mediator in both hCG-dependent Although still somewhat preliminary, current data suggest
ovarian angiogenesis and the pathophysiology of OHSS.38 that cabergoline is associated with a reduction in moderate
Recently, the dopamine agonist cabergoline has been OHSS in patients at high risk and has no adverse effect on
introduced as a secondary prevention strategy in women the pregnancy rate.
deemed to be at high risk for OHSS because of a very
robust gonadotropin response at the end of a controlled Summary Statement
ovarian stimulation cycle. Dopamine agonists show similar 6. Cabergoline starting from the day of human
effects to anti-angiogenic drugs on vascular permeability, chorionic gonadotropin reduces the incidence of
and except for occasional nausea, they appear not to have ovarian hyperstimulation syndrome in patients at
undesirable side effects.33,39 Evidence from animal models higher risk and does not appear to lower in vitro
shows that cabergoline blocks VEGF-mediated increase fertilization pregnancy rates. (II-2)
in vascular permeability without affecting angiogenesis.33
Carbergoline’s postulated mechanism of action is partial Cycle Cancellation
inhibition of the phosphorylation of its associated OHSS will not develop in the absence of exposure to
receptor, the VEGF receptor 2.40 exogenous hCG or LH or to an endogenous LH surge
as long as a pregnancy does not develop. Therefore,
A recent Cochrane review included 2 RCTs addressing withholding hCG in cycles at risk for OHSS and cancelling
cabergoline and OHSS. In the RCT conducted by Alvarez the cycle is the most effective method of preventing OHSS.
et al. on oocyte donors at risk for OHSS (20 to 30 follicles This prevention strategy is especially important in agonist
at > 12 mm and > 20 eggs retrieved), in which the cycles in which the option to substitute an agonist trigger
treatment group received oral cabergoline 0.5 mg daily for for hCG does not exist. However, because the emotional
8 days starting on the day of hCG and the control group and financial costs of cancellation are significant, other
received a placebo, the incidence of moderate OHSS was prevention strategies should be exhausted before cycle
significantly reduced in the cabergoline group (20% vs. cancellation is considered.
embryo transfer should be advised. This may decrease the the addition of metformin in patients with PCOS
risk of multiple gestations and should in turn decrease the undergoing IVF should be considered as it may reduce the
risk of severe OHSS. incidence of OHSS. During the treatment cycle, clinical
risk factors should be used in judging the starting doses of
Recommendation
gonadotropins. In patients with a very robust response to
7. Elective single embryo transfer is recommended in gonadotropins, coasting should be considered to prevent
patients at high risk for ovarian hyperstimulation later OHSS. At the time of hCG trigger, the use of
syndrome. (III-C) Cabergoline has been shown to reduce the risk for severe
In patients undergoing controlled superovulation with OHSS in patients at risk for this complication. There is no
pituitary suppression and oocyte retrieval, luteal phase strong evidence to support hCG trigger dose as an effective
hormonal supplementation is needed to maximize the means to decrease the risk of OHSS. Cycle cancellation by
chance of pregnancy.53 HCG is effective at providing LPS, withholding hCG has consistently been shown to obviate
however, it plays a vital role in precipitating OHSS and may the risk of OHSS. Avoiding pregnancy by freezing all
worsen established OHSS. In a meta-analysis of RCTs, embryos will prevent severe prolonged OHSS in patients
progesterone was established as being equally effective at high risk. Evidence also suggests that a GnRH agonist
as hCG for LPS and it is associated with a lower risk of trigger followed by cryopreservation of all embryos is
OHSS.62 comparable to cycle cancellation in its efficacy at preventing
OHSS with little compromise in success rates in those
Recommendation IVF centres that have a good embryo cryopreservation
8. Progesterone, rather than human chorionic program. Finally, progesterone should be used for LPS
gonadotropin, should be used for luteal phase rather than hCG. Continued research is required to gain
support. (I-A) a better appreciation of the pathophysiology of OHSS,
which may advance our ability to predict and prevent this
Culdocentesis
potentially serious illness.
Active outpatient intervention in the early stages of OHSS
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64. Borenstein R, Elhalah U, Lunenfeld B, Schwartz ZS. Severe ovarian
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Jon Havelock, MD, Burnaby BC Grey (unpublished) literature was identified through searching the
websites of health technology assessment and health technology-
Sarah Healey, MD, St. John’s NL related agencies, clinical practice guideline collections, clinical
Robert Hemmings, MD, Montreal QC trial registries, and national and international medical specialty
societies.
Kimberly Liu, MD, Toronto ON
Values: The quality of evidence in this document was rated using the
Tarek Motan, MD, Edmonton AB criteria described in the Report of the Canadian Task Force on
Ward Murdock, MD, Fredericton NB Preventive Health Care (Table 1).
This document reflects emerging clinical and scientific advances on the date issued and is subject to change. The information
should not be construed as dictating an exclusive course of treatment or procedure to be followed. Local institutions can dictate
amendments to these opinions. They should be well documented if modified at the local level. None of these contents may be
reproduced in any form without prior written permission of the SOGC.
Table 1. Key to evidence statements and grading of recommendations, using the ranking of the Canadian Task Force
on Preventive Health Care
Quality of evidence assessment* Classification of recommendations†
I: Evidence obtained from at least one properly randomized A. There is good evidence to recommend the clinical preventive action
controlled trial
II-1: Evidence from well-designed controlled trials without B. There is fair evidence to recommend the clinical preventive action
randomization
II-2: Evidence from well-designed cohort (prospective or C. The existing evidence is conflicting and does not allow to make a
retrospective) or case–control studies, preferably from recommendation for or against use of the clinical preventive action;
more than one centre or research group however, other factors may influence decision-making
II-3: Evidence obtained from comparisons between times or D. There is fair evidence to recommend against the clinical preventive action
places with or without the intervention. Dramatic results in
uncontrolled experiments (such as the results of treatment with E. There is good evidence to recommend against the clinical preventive
penicillin in the 1940s) could also be included in this category action
III: Opinions of respected authorities, based on clinical experience, L. There is insufficient evidence (in quantity or quality) to make
descriptive studies, or reports of expert committees a recommendation; however, other factors may influence
decision-making
*The quality of evidence reported in these guidelines has been adapted from The Evaluation of Evidence criteria described in the Canadian Task Force on
Preventive Health Care.65
†Recommendations included in these guidelines have been adapted from the Classification of Recommendations criteria described in the Canadian Task Force
on Preventive Health Care.65
3. Coasting for longer than 3 days reduces in vitro fertilization 7. Avoiding pregnancy by freezing all embryos will prevent severe
pregnancy rates. (II-2) prolonged ovarian hyperstimulation syndrome in patients at high
risk. (II-2)
4. The use of either luteinizing hormone or human chorionic
gonadotropin for final oocyte maturation does not influence the 8. Pregnancy rates are not affected when using gonadotropin-
incidence of ovarian hyperstimulation syndrome. (I) releasing hormone (GnRH) agonists in GnRH antagonist protocols
for final egg maturation when embryos are frozen by vitrification for
5. There is no clear published evidence that lowering the human later transfer. (II-2)
chorionic gonadotropin dose will result in a decrease in the rate of
ovarian hyperstimulation syndrome. (III)
Recommendations
6. Cabergoline starting from the day of human chorionic 1. The addition of metformin should be considered in patients with
gonadotropin reduces the incidence of ovarian hyperstimulation polycystic ovarian syndrome who are undergoing in vitro fertilization
syndrome in patients at higher risk and does not appear to lower because it may reduce the incidence of ovarian hyperstimulation
in vitro fertilization pregnancy rates. (II-2) syndrome. (I-A)
2. Gonadotropin dosing should be carefully individualized, taking into
account the patient’s age, body mass, antral follicle count, and
previous response to gonadotropins. (II-3B)
ABBREVIATIONS 3. Cycle cancellation before administration of human chorionic
ART assisted reproductive technology gonadatropin is an effective strategy for the prevention of ovarian
hyperstimulation syndrome, but the emotional and financial burden
CI confidence interval it imposes on patients should be considered before the cycle is
FSH follicle-stimulating hormone cancelled. (III-C)
GnRH gonadotropin-releasing hormone 4. Gonadotropin-releasing hormone (GnRH) antagonist stimulation
hCG human chorionic gonadotropin protocols are recommended in patients at high risk for ovarian
hyperstimulation syndrome (OHSS). The risk of severe OHSS in
HES hydroxyethyl starch patients on GnRH antagonist protocols who have a very robust
IVF in vitro fertilization ovarian stimulation response can be reduced by using a GnRH
agonist as a substitute for human chorionic gonadotropin to trigger
LH luteinizing hormone
final oocyte maturation. (I-B)
LPS luteal phase support
5. A gonadotropin-releasing hormone (GnRH) antagonist protocol with
OHSS ovarian hyperstimulation syndrome a GnRH agonist trigger for final oocyte maturation is recommended
OR odds ratio for donor oocyte and fertility preservation cycles. (III-C)
PCOS polycystic ovary syndrome 6. Albumin or other plasma expanders at the time of egg retrieval are
not recommended for the prevention of ovarian hyperstimulation
RCT randomized control study syndrome. (I-E)
SC subcutaneously 7. Elective single embryo transfer is recommended in patients at high
VEGF vascular endothelial growth factor risk for ovarian hyperstimulation syndrome. (III-C)
8. Progesterone, rather than human chorionic gonadotropin, should Table 2. Classification of OHSS
be used for luteal phase support. (I-A)
Grade Symptoms
9. Outpatient culdocentesis should be considered for the prevention
of disease progression in severe ovarian hyperstimulation Mild OHSS Abdominal bloating
syndrome. (II-2B) Mild abdominal pain
Ovarian size usually < 8 cm
INTRODUCTION Moderate OHSS Moderate abdominal pain
Nausea with/without vomiting
The degree of hCG exposure has been associated with the 43.8%, P = 0.04).14 The same first author also showed
risk of OHSS.18 It is recognized that hCG has no direct that pregnancy rates are not compromised in patients
effect on the vascular system33; however, vasoactive given cabergoline.41 The second RCT by Carriza et al.
substances such as VEGF are released in the ovary in randomized women who were undergoing IVF and at
response to hCG administration and are most likely high risk for OHSS (estradiol ≥ 14 700 pmol/L on day of
responsible for inducing vascular hyperpermeability and hCG trigger) into two groups: the study group received
third-spacing in high-risk women.34 A retrospective series 20 grams of prophylactic intravenous albumin and 0.5 mg
of 94 IVF cycles showed that when hCG doses were of Cabergoline orally once daily for 3 weeks commencing
lowered, both pregnancy rates and the rate of severe the day after oocyte retrieval and the control group received
OHSS remained unchanged.35 However, a lower incidence only albumin.42 The risk of early OHSS (occurring within
of severe OHSS has been observed with the use of lower the first 9 days after hCG trigger) decreased significantly
doses of hCG for final oocyte maturation in an at-risk (P < 0.001) in the cabergoline group; none of the patients
population. Because serum levels of hCG are dependent who had taken cabergoline progressed to early OHSS, but
on body mass,36,37 one Canadian fertility centre uses hCG 15.0% of the control group did. The risk of late OHSS did
5000 IU SC to trigger final egg maturation in patients at not decrease. In both of the RCTs examined, the use of
risk for OHSS who have a BMI < 28 kg/m2, despite the cabergoline did not affect the pregnancy outcome (clinical
lack of published data. Women with a BMI ≥ 28 kg/m2 pregnancy rate or miscarriage rate), nor was it associated
are all given hCG 10 000 IU SC for final egg maturation with an increased risk of adverse events.43
because yields of mature eggs have been observed to be
lower with a dose reduction in this population.36 Two published abstracts have demonstrated the safety
and efficacy of using cabergoline at even smaller doses:
Summary Statement 0.5 mg twice weekly for 6 doses44 and 0.5 mg twice weekly
5. There is no clear published evidence that lowering for 3 doses.45 Clinicians at one Canadian fertility centre use
human chorionic gonadotropin dose will result in a dose of cabergoline 0.5 mg every 3 days to a total of 4
a decrease in the rate of ovarian hyperstimulation doses starting on the day of oocyte maturation trigger and
syndrome. (III) a significant reduction in the incidence of severe OHSS
has been anecdotally observed since the introduction of
Cabergoline cabergoline into the prevention strategies for OHSS.
VEGF produced by granulosa cells of developing follicles
is thought to be a key mediator in both hCG-dependent Although still somewhat preliminary, current data suggest
ovarian angiogenesis and the pathophysiology of OHSS.38 that cabergoline is associated with a reduction in moderate
Recently, the dopamine agonist cabergoline has been OHSS in patients at high risk and has no adverse effect on
introduced as a secondary prevention strategy in women the pregnancy rate.
deemed to be at high risk for OHSS because of a very
robust gonadotropin response at the end of a controlled Summary Statement
ovarian stimulation cycle. Dopamine agonists show similar 6. Cabergoline starting from the day of human
effects to anti-angiogenic drugs on vascular permeability, chorionic gonadotropin reduces the incidence of
and except for occasional nausea, they appear not to have ovarian hyperstimulation syndrome in patients at
undesirable side effects.33,39 Evidence from animal models higher risk and does not appear to lower in vitro
shows that cabergoline blocks VEGF-mediated increase fertilization pregnancy rates. (II-2)
in vascular permeability without affecting angiogenesis.33
Carbergoline’s postulated mechanism of action is partial Cycle Cancellation
inhibition of the phosphorylation of its associated OHSS will not develop in the absence of exposure to
receptor, the VEGF receptor 2.40 exogenous hCG or LH or to an endogenous LH surge
as long as a pregnancy does not develop. Therefore,
A recent Cochrane review included 2 RCTs addressing withholding hCG in cycles at risk for OHSS and cancelling
cabergoline and OHSS. In the RCT conducted by Alvarez the cycle is the most effective method of preventing OHSS.
et al. on oocyte donors at risk for OHSS (20 to 30 follicles This prevention strategy is especially important in agonist
at > 12 mm and > 20 eggs retrieved), in which the cycles in which the option to substitute an agonist trigger
treatment group received oral cabergoline 0.5 mg daily for for hCG does not exist. However, because the emotional
8 days starting on the day of hCG and the control group and financial costs of cancellation are significant, other
received a placebo, the incidence of moderate OHSS was prevention strategies should be exhausted before cycle
significantly reduced in the cabergoline group (20% vs. cancellation is considered.
embryo transfer should be advised. This may decrease the the addition of metformin in patients with PCOS
risk of multiple gestations and should in turn decrease the undergoing IVF should be considered as it may reduce the
risk of severe OHSS. incidence of OHSS. During the treatment cycle, clinical
risk factors should be used in judging the starting doses of
Recommendation
gonadotropins. In patients with a very robust response to
7. Elective single embryo transfer is recommended in gonadotropins, coasting should be considered to prevent
patients at high risk for ovarian hyperstimulation later OHSS. At the time of hCG trigger, the use of
syndrome. (III-C) Cabergoline has been shown to reduce the risk for severe
In patients undergoing controlled superovulation with OHSS in patients at risk for this complication. There is no
pituitary suppression and oocyte retrieval, luteal phase strong evidence to support hCG trigger dose as an effective
hormonal supplementation is needed to maximize the means to decrease the risk of OHSS. Cycle cancellation by
chance of pregnancy.53 HCG is effective at providing LPS, withholding hCG has consistently been shown to obviate
however, it plays a vital role in precipitating OHSS and may the risk of OHSS. Avoiding pregnancy by freezing all
worsen established OHSS. In a meta-analysis of RCTs, embryos will prevent severe prolonged OHSS in patients
progesterone was established as being equally effective at high risk. Evidence also suggests that a GnRH agonist
as hCG for LPS and it is associated with a lower risk of trigger followed by cryopreservation of all embryos is
OHSS.62 comparable to cycle cancellation in its efficacy at preventing
OHSS with little compromise in success rates in those
Recommendation IVF centres that have a good embryo cryopreservation
8. Progesterone, rather than human chorionic program. Finally, progesterone should be used for LPS
gonadotropin, should be used for luteal phase rather than hCG. Continued research is required to gain
support. (I-A) a better appreciation of the pathophysiology of OHSS,
which may advance our ability to predict and prevent this
Culdocentesis
potentially serious illness.
Active outpatient intervention in the early stages of OHSS
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25. Coomarasamy A, Afnan M, Cheema D, van der Veen F, Bossuyt PM,
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44. Faghih M, DiPaolo L, Willoughby K, Karnis M, Hughes E, Neal M. oocyte maturation after cotreatment with GnRH antagonist in high-risk
Dostinex use for OHSS prevention does not affect IVF success. Fertil patients undergoing in vitro fertilization prevents the risk of ovarian
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Fertil Steril 2008;89:84–91.
45. Bhangoo R, Karunis M, Ballas J, San Roman GA, Stelling JR.
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has no effect on pregnancy rate during in vitro fertilization. Fertil Steril corpus luteum function with peri-ovulatory HCG supplementation in
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46. Al-Inany HG, Youssef MA, Aboulghar M, Broekmans F, Sterrenburg M,
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Diedrich K, et al. Nonsupplemented luteal phase characteristics after a systematic review and meta-analysis. Reprod Biomed Online
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recombinant luteinizing hormone, or gonadotropin-releasing hormone
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patients after ovarian stimulation with recombinant follicle-stimulating Elective cryopreservation of all pronucleate embryos in women at risk of
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Devroey P, Diedrich K, et al. A lower ongoing pregnancy rate can Recombinant versus urinary human chorionic gonadotrophin for
be expected when GnRH agonist is used for triggering final oocyte ovulation induction in assisted conception. Cochrane Database Syst Rev
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antagonists. Hum Reprod 2005;20:2887–92. 61. Kumbak B, Oral E, Karlikaya G, Lacin S, Kahraman S. Serum oestradiol
51. Humaidan P, Ejdrup BH, Bungum L, Bungum M, Grondahl ML, and β-HCG measurements after day 3 or 5 embryo transfers in
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antagonist IVF/ICSI cycles: a prospective randomized study. Hum 62. van der Linden M, Buckingham K, Farquhar C, Kremer JA, Metwally M.
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64. Borenstein R, Elhalah U, Lunenfeld B, Schwartz ZS. Severe ovarian
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Triggering Workshop Group. GnRH agonist for triggering of final Steril 1989;51:791–5.
oocyte maturation: time for a change of practice? Hum Reprod Update
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This document reflects emerging clinical and scientific advances on the date issued and is subject to change. The information
should not be construed as dictating an exclusive course of treatment or procedure to be followed. Local institutions can dictate
amendments to these opinions. They should be well documented if modified at the local level. None of these contents may be
reproduced in any form without prior written permission of the SOGC.
Table 1. Key to evidence statements and grading of recommendations, using the ranking of the Canadian Task Force
on Preventive Health Care
Quality of evidence assessment* Classification of recommendations†
I: Evidence obtained from at least one properly randomized A. There is good evidence to recommend the clinical preventive action
controlled trial
II-1: Evidence from well-designed controlled trials without B. There is fair evidence to recommend the clinical preventive action
randomization
II-2: Evidence from well-designed cohort (prospective or C. The existing evidence is conflicting and does not allow to make a
retrospective) or case–control studies, preferably from recommendation for or against use of the clinical preventive action;
more than one centre or research group however, other factors may influence decision-making
II-3: Evidence obtained from comparisons between times or D. There is fair evidence to recommend against the clinical preventive action
places with or without the intervention. Dramatic results in
uncontrolled experiments (such as the results of treatment with E. There is good evidence to recommend against the clinical preventive
penicillin in the 1940s) could also be included in this category action
III: Opinions of respected authorities, based on clinical experience, L. There is insufficient evidence (in quantity or quality) to make
descriptive studies, or reports of expert committees a recommendation; however, other factors may influence
decision-making
*The quality of evidence reported in these guidelines has been adapted from The Evaluation of Evidence criteria described in the Canadian Task Force on
Preventive Health Care.187
†Recommendations included in these guidelines have been adapted from the Classification of Recommendations criteria described in the Canadian Task Force
on Preventive Health Care.187
08. Vitamin K antagonists should only be considered in exceptional 18. Therapeutic dose anticoagulation should be initiated for confirmed
circumstances for the treatment of venous thromboembolism in cerebral venous thrombosis. (II-2A)
pregnancy. (II-2A) 19. Thromboprophylaxis should be considered in future pregnancies
09. We recommend against the use of oral Xa inhibitors and following a cerebral venous thrombosis. (II-1C)
oral direct thrombin inhibitors for the treatment of venous 20. For superficial thrombophlebitis, compression ultrasound should be
thromboembolism in pregnancy. (III-D) performed to exclude deep vein thrombosis (II-2A), and it should
10. For the treatment of acute venous thromboembolism in be repeated if proximal extension is suspected based on worsening
pregnancy we recommend adhering to the manufacturer’s phlebitis. (III-C)
recommended dosing for individual low molecular weight 21. Prophylactic or intermediate dose low molecular weight heparin for
heparins based on the woman’s current weight. (II-1A) Low 1 to 6 weeks is recommended for women with bilateral superficial
molecular weight heparin can be administered once or twice a thrombophlebitis, for very symptomatic women, and for superficial
day depending on the agent selected. (III-C) thrombophlebitis located ≤ 5 cm from the deep venous system
11. For pregnant women initiated on therapeutic low molecular (saphenofemoral and saphenopopliteal junctions) or affecting ≥ 5 cm
weight heparin, baseline platelet counts should be done of vein. (I-A)
and repeated a week later to screen for heparin-induced 22. Observation alone is recommended in women with superficial
thrombocytopenia. (III-C) thrombophlebitis at low risk of deep vein thrombosis and for those
who do not require symptom control. Clinical follow-up of these
12. For pregnant women with an acute venous thromboembolism
women should occur within 7 to 10 days, with a repeat compression
we recommend therapeutic anticoagulation for a minimum of 3
ultrasound within one week. (I-A)
months. (I-A)
23. Computed tomography and/or magnetic resonance imaging (with or
13. Following initial treatment, anticoagulation intensity can be
without angiography) are the definitive imaging modalities to rule out
decreased to intermediate or prophylactic dose for the remainder
ovarian vein thrombosis. (II-2A)
of the pregnancy and for at least 6 weeks postpartum. (III-C)
24. For confirmed ovarian vein thrombosis, we recommend parenteral
14. In pregnant women with acute proximal leg deep vein thrombosis, broad-spectrum antibiotics, continued for at least 48 hours after
the use of graded compression stockings can be considered for defervescence and clinical improvement. (II-2A) Longer antibiotic
relief of symptoms. (III-C) therapy is necessary for septicemia or complicated infections. (III-C)
15. Thrombolytic therapy in pregnancy should only be considered 25. For confirmed ovarian vein thrombosis, therapeutic dose
in limb-threatening deep vein thrombosis or massive pulmonary anticoagulation could be considered for 1 to 3 months. (III-C)
embolism. (III-C)
26. Routine screening for all inherited thrombophilias in all women with a
16. Vena cava filters should only be used in pregnant women first episode of venous thromboembolism diagnosed in pregnancy is
with acute pulmonary embolism or deep vein thrombosis and not indicated. (III-C)
contraindications to anticoagulation. (III-C)
27. Testing for protein S, protein C, and antithrombin deficiencies is
17. Computed tomographic venography and/or magnetic resonance indicated following a venous thromboembolism in pregnancy if there
imaging should be performed to rule out cerebral venous is a family history of these particular thrombophilias, or if thrombosis
thrombosis if suspected. (I-C) occurs in an unusual site. (III-C)
28. Testing for antiphospholipid antibodies is indicated if the results 33. We recommend therapeutic thromboprophylaxis during
would affect the duration of anticoagulation. (III-C) pregnancy in the following situations:
29. Individual risk assessment for venous thromboembolism should a. long-term therapeutic anticoagulation used prior to pregnancy
be performed prior to all pregnancies, once pregnancy is for a persistent indication; (III-B)
achieved, and repeated throughout pregnancy as new clinical
b. personal history of multiple previous venous
situations arise. The woman’s preferences and values should
thromboembolism. (III-B)
be taken into account when considering the use of antepartum
thromboprophylaxis. (III-B) 34. We recommend intermediate or therapeutic thromboprophylaxis
during pregnancy in the following situation:
30. Women at increased risk should be advised of the symptoms and
signs of venous thromboembolism. (III-B) a. personal history of a previous venous thromboembolism
and a high-risk thrombophilia (antithrombin deficiency,
31. Low molecular weight heparin is the preferred pharmacologic
antiphospholipid syndrome) not previously on
agent over unfractionated heparin for antepartum
anticoagulation. (III-B)
thromboprophylaxis. (III-A) Low molecular weight heparin doses
should be used as per the manufacturer’s recommendation. (III-C) 35. We recommend prophylactic dose thromboprophylaxis during
pregnancy in the following situations (absolute risk > 1%):
32. Routine anti-Xa medication and platelet-level monitoring are
not recommended when a patient is on a prophylactic dose of a. personal history of a previous unprovoked venous
thromboprophylaxis. (II-2E) thromboembolism; (II-2A)
b. personal history of a previous venous thromboembolism
related to oral contraceptives or pregnancy; (II-2A)
c. personal history of a previous provoked venous
thromboembolism and any low risk thrombophilia; (I-A)
ABBREVIATIONS
APLS antiphospholipid syndrome d. asymptomatic homozygous factor V Leiden; (II-2A)
aPTT activated partial thromboplastin time e. asymptomatic homozygous prothrombin gene mutation
20210A; (III-B)
ART assisted reproductive technology
f. asymptomatic combined thrombophilia; (III-B)
AT antithrombin
g. asymptomatic antithrombin deficiency; (III-B)
ASA acetylsalicylic acid
h. non-obstetrical surgery during pregnancy, with the duration
ASRA American Society of Regional Anesthesia
of thromboprophylaxis being procedure- and patient-
BMI body mass index dependent; (III-B)
CT computed tomography i. strict antepartum bedrest for ≥ 7 days in a woman with
CTA CT angiography a body mass index of > 25 kg/m2 at her first antenatal
visit. (II-2B)
CUS compression ultrasound
36. Antepartum thromboprophylaxis for isolated pregnancy-related
CVT cerebral venous thrombosis risk factors is not recommended. (III-E)
DVT deep vein thrombosis 37. Antepartum thromboprophylaxis should be considered in the
FVL factor V Leiden presence of multiple clinical or pregnancy-related risk factors
where the overall absolute risk of venous thromboembolism is
HIT heparin-induced thrombocytopenia
estimated to be > 1%, especially in women admitted to hospital
IUGR intrauterine growth restriction for bed rest. (II-2B)
LDA low-dose ASA 38. Routine thromboprophylaxis is not required for all women
LMWH low molecular weight heparin undergoing ovulation induction. (III-C)
MRI magnetic resonance imaging 39. If severe ovarian hyperstimulation syndrome occurs with assisted
reproductive technology, we recommend thromboprophylaxis
NSAID non-steroidal anti-inflammatory drug
with low molecular weight heparin for at least 8 to 12 weeks after
OHSS ovarian hyperstimulation syndrome resolution of the syndrome. (III-B)
OVT ovarian vein thrombosis 40. Thromboprophylaxis with low molecular weight heparin should
PGM prothrombin gene mutation 20210A be considered for any women at increased risk for venous
thromboembolism undergoing assisted reproductive technology
PC protein C at the time of ovarian stimulation. (III-B)
PE pulmonary embolism 41. Women who develop a venous thromboembolism in association
PS protein S with the use of assisted reproductive technology but who do
not conceive in that cycle should be treated with therapeutic
SGA small for gestational age
anticoagulation for a minimum of 3 months. (II-3A) Those who
SLE systemic lupus erythematosus conceive in that assisted reproductive technology cycle should
ST superficial thrombophlebitis be treated as per recommendations 12 and 13 for acute venous
thromboembolism in pregnancy. (I-A, III-C)
UH unfractionated heparin
42. Women on prophylactic dose, intermediate dose, or therapeutic
VQ ventilation/perfusion
anticoagulation should have a discussion about options for
VTE venous thromboembolism analgesia/anaesthesia prior to delivery. (III-B)
43. Switching from thromboprophylactic low molecular weight heparin postpartum risk factors after every delivery and repeat as new
to a prophylactic dose of unfractionated heparin at term (37 clinical situations arise. (II-2B)
weeks) may be considered to allow for more options with respect
57. Low molecular weight heparin is the preferred pharmacologic
to labour analgesia. (III-L)
agent over unfractionated heparin for postpartum thrombo
44. Discontinue prophylactic or intermediate dose low molecular prophylaxis. (III-A) Low molecular weight heparin doses should
weight heparin or unfractionated heparin upon the onset of be used as per the manufacturer’s recommendation. (III-C)
spontaneous labour or the day prior to a planned induction of
58. Pharmacologic thromboprophylaxis postpartum is recommended
labour or Caesarean section. (II-3B)
in the following situations:
45. A recent platelet count should be available on admission in labour
Any 1 of the following risk factors (each with an absolute risk of
or before Caesarean delivery in women who have been, or are,
venous thromboembolism > 1%):
on anticoagulants. (III-B)
a. history of any prior venous thromboembolism; (II-2A)
46. For women on low molecular weight heparin, neuraxial
anaesthesia can be administered as a: b. any high-risk thrombophilia: antiphospholipid syndrome,
antithrombin deficiency, homozygous factor V Leiden
a. prophylactic dose: a minimum of 10 to 12 hours after the last
or prothrombin gene mutation 20210A, or combined
dose; (III-B)
thrombophilia; (II-2B)
b. therapeutic dose: after 24 hours since the last dose. (III-B)
c. strict bedrest prior to delivery for 7 days or more; (II-2B)
47. For women on unfractionated heparin, neuraxial anaesthesia can
be administered as a: d. peripartum or postpartum blood loss of > 1 litre or
blood product replacement, and concurrent postpartum
a. prophylactic dose (maximum 10 000 U/day): after no surgery; (II-2B)
delay; (III-B)
e. peripartum/postpartum infection. (II-2B)
b. therapeutic intravenous infusion: at least 4 hours after
stopping the infusion and when the activated partial 59. Postpartum thromboprophylaxis should be considered in the
thromboplastin time is normal; (III-B) presence of multiple clinical or pregnancy-related risk factors
when the overall absolute risk is estimated to be greater than 1%
c. therapeutic subcutaneous unfractionated heparin: when the drawn from the following groupings:
activated partial thromboplastin time is normal. This may be
12 hours or longer after the last injection. (III-B) a. any 2 of the following risk factors (each with an absolute risk
of venous thromboembolism < 1% in isolation):
48. Neuraxial anaesthesia must be avoided in a woman who is
fully anticoagulated or in whom there is evidence of altered i. body mass index ≥ 30 kg/m2 at first antepartum
coagulation. (II-3A) visit; (II-2B)
49. Removal of a neuraxial catheter left in situ postpartum should ii. smoking > 10 cigarettes/day antepartum; (II-2B)
only be done 4, 10 to 12, or 24 hours following the administration iii. preeclampsia; (II-2B)
of prophylactic dose unfractionated heparin (maximum
10 000 U/day), prophylactic low molecular weight heparin (single iv. intrauterine growth restriction; (II-2B)
daily dose), or therapeutic dose low molecular weight heparin, v. placenta previa; (II-2B)
respectively, or in the case of therapeutic unfractionated heparin,
vi. emergency Caesarean section; (II–2B)
when the activated partial thromboplastin time is normal. (II-3B)
50. Prophylactic dose low molecular weight heparin (single daily vii. peripartum or postpartum blood loss of > 1 litre or blood
dose) may be started or restarted 4 hours after neuraxial catheter product replacement; (II-2B)
removal, providing there is full neurological recovery and no viii. any low risk thrombophilia: PC or PS deficiency,
evidence of active bleeding or coagulopathy. (III-B) heterozygous factor V Leiden, or prothrombin gene
51. Therapeutic low molecular weight heparin may be started or mutation 20210A; (III-B)
restarted at least 24 hours after a single injection neuraxial block ix. maternal cardiac disease, SLE, sickle cell disease,
and a minimum of 4 hours after neuraxial catheter removal, inflammatory bowel disease, varicose veins, gestational
providing there is full neurological recovery and no evidence of diabetes; (III-B)
active bleeding or coagulopathy. (III-B)
x. preterm delivery; (III-B)
52. Subcutaneous unfractionated heparin may be started or restarted
at least 1 hour after a single injection neuraxial block, providing xi. stillbirth. (III-B)
there is full neurological recovery and no evidence of active b. Any 3 or more of the following risk factors (each with an
bleeding or coagulopathy. (III-B) absolute risk of venous thromboembolism < 1%):
53. Do not administer antiplatelet agents (acetylsalicylic acid or non- i. age > 35 years; (II-2B)
steroidal anti-inflammatory drugs) concomitantly with heparin if a
ii. parity ≥ 2; (II-2B)
neuraxial catheter is left in situ postpartum. (III-D)
iii. any assisted reproductive technology; (II-2B)
54. Women on therapeutic anticoagulation who have received
neuraxial anesthesia should be monitored closely for the iv. multiple pregnancy; (II-2B)
development of a spinal hematoma. (III-B)
v. placental abruption; (II-2B)
55. Universal postpartum thromboprophylaxis is not
vi. premature rupture of membranes; (II-2B)
recommended. (III-D)
vii. elective Caesarean section; (II-2B)
56. Assess women for increased risk of postpartum venous
thromboembolism based on antepartum, intrapartum, and viii. maternal cancer. (III-B)
60. Intermittent or sequential pneumatic compression devices the existing evidence that supports the recommendations,
are alternatives in women when heparin is contraindicated
and it is meant to be complementary to other international
postpartum. When the risk of postpartum venous
thromboembolism is high they may be used in combination with guidelines on this topic.8–15
low molecular weight heparin or unfractionated heparin. (III-B)
61. Women with ongoing and persistent risk factors should receive ACUTE VENOUS THROMBOEMBOLISM
postpartum thromboprophylaxis for a minimum of 6 weeks
IN PREGNANCY
postpartum. (II-3B)
62. Women with transient antepartum or intrapartum risk factors Due to hormonal influences on vascular tone and
should receive postpartum thromboprophylaxis until discharged
from hospital or up to 2 weeks postpartum. (III-C)
compressive effects on veins by the enlarging uterus, DVT
in pregnancy generally presents in the lower extremities,
63. Universal screening for thrombophilias in women experiencing
adverse pregnancy outcomes (severe preeclampsia, intrauterine with a predisposition for the left leg (70 to 80%).16,17 In
growth restriction, stillbirth) is not indicated. (II-2D) contrast to their presentation in non-pregnant patients,
64. Women with recurrent miscarriage or late pregnancy loss should DVTs are often isolated to the iliac and/or femoral vein
be screened for antiphospholipid syndrome. (I-B) during pregnancy (61%).18 Consequently diagnostic
65. Low-dose acetylsalicylic acid or low-dose acetylsalicylic acid plus approaches advocated for use in non-pregnant patients
low molecular weight heparin is recommended in pregnancy in require modification in pregnancy.8
women with confirmed antiphospholipid syndrome. (I-C)
66. Low-dose acetylsalicylic acid plus low molecular weight heparin Diagnosis of VTE in Pregnancy
is not recommended for women with a history of recurrent In non-pregnant patients, diagnostic approaches for
miscarriage in the absence of confirmed antiphospholipid
syndrome. (I-E) VTE use a combination of validated structured clinical
67. Low molecular weight heparin should not be used routinely to
prediction rules with or without the use of D-dimer testing,
reduce the risk of recurrent placenta-mediated complications in followed by objective testing with CUS.8 Extrapolating the
women with or without thrombophilia (excluding antiphospholipid same approach to pregnancy is difficult because:
syndrome). (I-C)
1. structured prediction rules have not been validated in
pregnant women,
INTRODUCTION 2. the anatomic presentation of lower extremity DVT in
T his guideline summarizes the available data and the pregnant women could affect the sensitivity of CUS,18
quality of the evidence to provide practical approaches and
to the diagnosis, management, and prevention of VTE in 3. current validated D-dimer level cut-off points are of
pregnancy. VTE remains an important cause of maternal limited utility.19,20
morbidity and mortality in Canada with an overall incidence
of DVT and PE of 12.1 per 10 000 and 5.4 per 10 000 The potential use of a pregnancy-specific structured
pregnancies, respectively.1 VTE occurs at a rate of 5.4 per prediction rule and pregnancy-specific D-dimer thresholds
10 000 antepartum, 7.2 per 10 000 peripartum, and 4.3 per has been reported,21–23 but currently neither test should be
10 000 pregnancies postpartum.1 These rates are consistent used alone or in combination to diagnose or exclude VTE
with published literature from around the world.2–4 The first without further validation studies.
and second trimesters of pregnancy convey similar risks Our recommended diagnostic algorithm for DVT in
for DVT, with a higher risk in the third trimester and the pregnancy is shown in Figure 1. When a pregnant woman
first 3 weeks postpartum.5,6 PE occurs more commonly presents with a suspected DVT, she should undergo an
postpartum, decreasing in incidence after the first 6 weeks.3,7 ultrasound including direct visualization of the entire
This guideline sequentially reviews key components in proximal venous system from the iliac to the popliteal
reducing the risk VTE in pregnancy, which include accurate vein.24 Doppler studies should be performed at the level of
diagnosis and treatment of DVT and PE, antepartum the iliac vein to ensure that flow is present. Compression
thromboprophylaxis in appropriate patients, peripartum manoeuvers should be performed along the entire venous
management of anticoagulants, and postpartum system from the femoral to the popliteal vein. The sensitivity
thromboprophylaxis, and concludes with a discussion of and negative predictive value of this method are 90.9%
the use of heparin to prevent adverse pregnancy outcomes. (95% CI 69.4 to 98.4) and 98.9% (95% CI 95.5 to 99.8),
respectively.24 Published evidence is currently insufficient
Making decisions about the management of individual to support the safety of performing a single ultrasound
patients can be challenging and complex. Wherever examination in pregnant women with suspected DVT.
possible, this guideline attempts to summarize and organize Hence, we would recommend repeat testing with CUS and
Figure 1. Algorithm for the diagnosis of deep venous thrombosis in pregnant patients
Suspected DVT
Clinical follow-up
Doppler imaging as above at least once again over the next for subsequent childhood malignancy.27–29 The calculated
7 days if the initial study is negative. If isolated iliac vein minimum radiation dose to each breast for an average 60 kg
obstruction (i.e. absence of flow) is suspected on Doppler woman is 20 to 35 mGy from CTA and 0.28 mGy from VQ
examination, two options are available: scan.30,31 While little is known about the long-term effects of
1. institute therapeutic anticoagulation followed by repeat radiation exposure to breast tissue during pregnancy, there
CUS in 2 to 3 days, or are data linking imaging procedures to an increased risk of
breast cancer.32 The iodinated contrast agent required for
2. proceed with MRI. computed tomographic angiography to diagnosis PE crosses
The option chosen depends on patient preference, the placenta and can theoretically result in fetal or neonatal
availability of expertise, and access to imaging. The hypothyroidism. However, this risk was not significant in an
specificity and sensitivity of MRI and the specific technique observational study of over 300 pregnancies.33
used to diagnose DVT in pregnancy remains uncertain.25,26 In pregnancy the observed sensitivity and negative
When PE is suspected clinically, definitive diagnosis requires predictive values of CTA and VQ scan appears to be high,
diagnostic imaging. Several factors should be considered in using clinical outcome as a surrogate measure.34–38 The
the choice of VQ scan or CTA: specificity of a CTA in pregnancy cannot be ascertained,
but studies in non-pregnant patients suggest CTA might
1. the maternal and fetal risks associated with the tests be less specific in younger patients.39 The decision to use
(radiation and contrast agent), CTA or VQ scan is also dictated by local availability and
2. the sensitivity of the tests, and expertise. The CTA technique used to diagnose PE in non-
3. their availability. pregnant patients should be modified as 5% to 36% of
scans can be inadequate in pregnancy due to physiological
For both VQ scan and CTA the calculated radiation risk to changes.32,40–42 We currently advocate the use of the VQ
the fetus is low, with levels below the threshold of 50 mGy scan as the diagnostic test in pregnancy whenever possible
Suspected PE
Start
VQ scan
treatment
High/moderate
Low pretest†
pretest†
*Bilateral US should include examination of the iliac veins with Doppler manoeuvers
†Pretest determined by clinician’s subjective assessment
‡Modification in spiral CT protocol should be considered for pregnant patients
Table 2. Incidence of side effects related to low molecular weight heparins in pregnancy
Therapeutic dose Prophylactic dose Any dose References
Antepartum bleeding 0% to 0.57% 0.42% 0% to 0.43% 51, 171 to 173
Postpartum bleeding 1.15% to 5.6% 0.92% 0.94% to 1.6% 51, 171 to 173
Wound hematoma 1.39% 0% 0.5% to 0.61% 51, 171 to 173
Major skin reaction/allergy 1.15% 0.96% 0.5% to 1.8% 51, 173
Osteoporosis 0% 0.26% 0.04% to 0.2% 51, 173
HIT 0% 0% 0% 51, 173
extended NSAID use is discouraged in pregnancy after of septicemia. Even though a small randomized study
26 to 28 weeks’ gestation, we recommend prophylactic or (N = 14) did not report a difference in the resolution of the
intermediate dose LMWH for 1 to 6 weeks in symptomatic fever with antibiotics alone versus antibiotics plus UH,78
women and in women with bilateral ST, ST of 5 cm or concurrent anticoagulation is often recommended.79,82–84
more, or ST located less than 5 cm from the deep venous We recommend anticoagulation for 1 to 3 months. There
system. Observation alone is recommended in women are no studies to guide the risk of recurrence of OVT
with ST who are at low risk of DVT and for those who do and the need for thromboprophylaxis in subsequent
not require symptom control. Clinical follow-up of these pregnancies. The risk is likely low.84
women should occur within 7 to 10 days, with a repeat
Recommendations
CUS within one week.
23. Computed tomography and/or magnetic resonance
Recommendations imaging (with or without angiography) are the
20. For superficial thrombophlebitis, compression definitive imaging modalities to rule out ovarian
ultrasound should be performed to exclude deep vein thrombosis. (II-2A)
vein thrombosis (II-2A), and it should be repeated 24. For confirmed ovarian vein thrombosis, we
if proximal extension is suspected based on recommend parenteral broad-spectrum antibiotics,
worsening phlebitis. (III-C) continued for at least 48 hours after defervescence
21. Prophylactic or intermediate dose low and clinical improvement. (II-2A) Longer antibiotic
molecular weight heparin for 1 to 6 weeks is therapy is necessary for septicemia or complicated
recommended for women with bilateral superficial infections. (III-C)
thrombophlebitis, for very symptomatic women, 25. For confirmed ovarian vein thrombosis, therapeutic
and for superficial thrombophlebitis located ≤ 5 cm dose anticoagulation could be considered for 1 to 3
from the deep venous system (saphenofemoral and months. (III-C)
saphenopopliteal junctions) or affecting ≥ 5 cm of
vein. (I-A)
THROMBOPHILIA SCREENING AFTER
22. Observation alone is recommended in women with
THE DIAGNOSIS OF ACUTE VTE
superficial thrombophlebitis at low risk of deep
vein thrombosis and for those who do not require There is no consensus as to whether or not patients require
symptom control. Clinical follow-up of these women thrombophilia testing following the diagnosis of an acute
should occur within 7 to 10 days, with a repeat VTE in the non-pregnant state. The acute management
compression ultrasound within one week. (I-A) of the current or subsequent pregnancies is generally not
altered by knowledge of the thrombophilia status, nor is
OVARIAN VEIN THROMBOSIS counselling regarding subsequent risks of VTE. However,
patients with VTE and a known family history of PS, PC,
Ovarian vein thrombosis is an uncommon event, or AT deficiency would benefit from screening, as these
complicating 0.05% to 0.18% of pregnancies and affecting might affect the duration of anticoagulation required
the right vein in up to 90% of cases.78,79 Risk factors include for the initial episode.85 Screening for other inherited
Caesarean section, multiple gestation, and infection.79 thrombophilias is unnecessary because the presence of
Complications include extension of the thrombus into the these will not change management.86,87
vena cava and/or renal veins, and sepsis. PE occurs in 13%
of cases.80 Symptoms and signs of OVT include nausea, Screening for acquired thrombophilia, i.e. APLS, has been
vomiting, guarding, constant lower abdominal or flank advocated for non-pregnant patients, since a persistently
pain, palpable sausage-shaped tender abdominal masses, positive screen (over 12 weeks) could affect the duration
fever, rigors, and leukocytosis in the first 15 days after a of anticoagulation.86 There are concerns about applying
delivery, abortion, or ruptured ectopic pregnancy. A pelvic this to pregnant women:
ultrasound should be done initially, followed by CT and/or 1. the risk of a false positive, leading to patient anxiety, is
MRI in the case of a negative or equivocal result.81 significant,
Broad-spectrum parenteral antibiotics should be initiated 2. the need to prolong anticoagulation beyond the usual
with the diagnosis of OVT and continued for at least 48 recommended duration for pregnant patients with
hours after defervescence and clinical improvement.82,83 APLS is uncertain, and
A longer treatment course is required in the presence 3. repeat testing is required 8 to 12 weeks after delivery.
We therefore recommend against routine screening for towards the avoidance of VTE during pregnancy, while
APLS during pregnancy, unless thrombosis occurs in an minimizing the number of women who would experience
unusual site or if the results would affect the duration of heparin side effects. Hence, we recommend antepartum
anticoagulation. thromboprophylaxis when the overall estimated absolute
risk of VTE is greater than 1%.
Recommendations
26. Routine screening for all inherited thrombophilias Unfortunately, the magnitude to which additional biological
in all women with a first episode of venous factors in the antepartum period increase the risk for a
thromboembolism diagnosed in pregnancy is not given patient is imprecisely reported in the literature (see
indicated. (III-C) Table 4). Involvement of appropriate specialists should be
27. Testing for protein S, protein C, and antithrombin considered in cases of clinical uncertainty.
deficiencies is indicated following a venous
thromboembolism in pregnancy if there is a family Previous objectively documented VTEs which were
history of these particular thrombophilias, or if unprovoked or related to hormonal therapy or pregnancy
thrombosis occurs in an unusual site. (III-C) confer the highest risk of recurrence during pregnancy and
28. Testing for antiphospholipid antibodies is indicated warrant antepartum thromboprophylaxis.89–92 Unprovoked
if the results would affect the duration of or idiopathic VTEs are those occurring in the absence
anticoagulation. (III-C) of clinical risk factors such as surgery, hospitalization or
plaster cast immobilization within one month, and cancer.
OCP- or pregnancy-related)
FVL (hetero- and homozygosity) •100 •89
FVL homozygosity •100
Combined FVL and PGM heterozygosity •94
AT deficiency •• 176,177
Asymptomatic thrombophilia
FVL homozygosity ••••101,178,181,182 •••96,98,179
PGM homozygosity •96
Combined FVL and PGM heterozygosity •• 98,182
••• 94,96,179
However, a large case–control study of 613 232 births with approximately 6% in the large case–control study,109 warranting
559 cases of antepartum and postpartum VTE (overall antepartum thromboprophylaxis with this combination of
incidence of 1/1000 live births) showed that most previously clinical factors (see Table 4). While we recognize that strict
identified pregnancy-related risk factors in isolation did not bedrest is rarely indicated in hospitalized obstetrical patients
increase the absolute risk of antepartum VTE above 1%.109 today, the significant increase in risk of VTE incurred when
This has recently been supported by a large population- it is instituted cannot be overemphasized. Hence, antepartum
based cohort study from the UK.4 For example, although thromboprophylaxis should be considered in the presence of
maternal obesity has been identified as a risk factor, the multiple clinical or pregnancy-related risk factors when the
absolute risk of VTE associated with maternal obesity overall absolute risk of VTE is estimated to be greater than
alone would not warrant the use of thromboprophylaxis, 1%, especially in patients who are in hospital, where bedrest
even accounting for various definitions of increased BMI is often prescribed.
presented in the literature.107,110 Notably, the combination
of antenatal bedrest for ≥ 7 days (defined as > 90% of the Due to its lower side-effect profile, LMWH is the
time in bed) and a booking (first antenatal visit) BMI of preferred pharmacologic agent over UH for antepartum
≥ 25 kg/m2 increased the risk of antenatal VTE to thromboprophylaxis. Table 3 presents the doses of
Table 5. Literature review of incidence of symptomatic VTE antepartum without prophylaxis according to
various clinical or pregnancy-related risk factors
Incidence of symptomatic VTE*
< 0.3% 0.3% to 0.5% > 0.5% to < 1.0%
Maternal pre-pregnancy risk factors
Age > 35 years ••••2,4,108,109
BMI > 30 kg/m2 or weight > 90 kg at first antenatal visit •••••4,106,108–110 •107
Weight > 120 kg at first antenatal visit • 110
Pre-existing diabetes •4
Inflammatory bowel disease •4
Varicose veins • 4
Cancer •4
Risk factors related to present pregnancy
Multiple pregnancy •••2,4,109 •106
ART (singleton) ••3,109 •109
ART (twins) •109
Strict bedrest ≥ 7 days + BMI < 25 kg/m2 at first antenatal visit •186 •109
Preeclampsia/pre-existing hypertension •• 4,109
IUGR •109
Preeclampsia + IUGR •109
Gestational diabetes ••3,109
*Each dot represents one study; the superscript numerals are references to those studies.
the heparins currently available in Canada, as per the 30. Women at increased risk should be advised of
manufacturers’ recommendations. However, some women the symptoms and signs of venous
may need a dose adjustment because of their weight, and thromboembolism. (III-B)
weight increases as pregnancy progresses. 31. Low molecular weight heparin is the preferred
Women who are known to require antepartum pharmacologic agent over unfractionated heparin
thromboprophylaxis should start LMWH once the for antepartum thromboprophylaxis. (III-A) Low
decision is made and the patient becomes pregnant. For molecular weight heparin doses should be used as
others, ongoing evaluation of the need for antepartum per the manufacturer’s recommendation. (III-C)
thromboprophylaxis should be made throughout pregnancy, 32. Routine anti-Xa and platelet level monitoring
taking into account the patient’s risk factors and preferences are not recommended when a patient is on a
and the side-effects associated with LMWH. Antepartum prophylactic dose of thromboprophylaxis. (II-2E)
thromboprophylaxis should be continued until the onset of 33. We recommend therapeutic thromboprophylaxis
labour, and restarted after delivery (see relevant sections). during pregnancy in the following situations:
a. long-term therapeutic anticoagulation used prior
Recommendations to pregnancy for a persistent indication; (III-B)
29. Individual risk assessment for venous b. personal history of multiple previous venous
thromboembolism should be performed thromboembolism. (III-B)
prior to all pregnancies, once pregnancy is 34. We recommend intermediate or therapeutic
achieved, and repeated throughout pregnancy thromboprophylaxis during pregnancy in the
as new clinical situations arise. The woman’s following situation:
preferences and values should be taken into a. personal history of a previous venous
account when considering the use of antepartum thromboembolism and a high-risk thrombophilia
thromboprophylaxis. (III-B) (antithrombin deficiency, antiphospholipid
syndrome) not previously on For women undergoing IVF with no risk factors for
anticoagulation. (III-B) VTE, routine thromboprophylaxis is unnecessary.
35. We recommend prophylactic dose However, for women who develop severe OHSS,
thromboprophylaxis during pregnancy in the thromboprophylaxis should be considered for at least 8 to
following situations (absolute risk > 1%): 12 weeks after resolution of the OHSS. Ongoing need for
a. personal history of a previous unprovoked thromboprophylaxis would depend on whether pregnancy
venous thromboembolism; (II-2A) is achieved in that cycle and on the presence of other
b. personal history of a previous venous antepartum risk factors (such as those in Table 5).
thromboembolism related to oral contraceptives
or pregnancy; (II-2A) Recommendations
c. personal history of a previous provoked 38. Routine thromboprophylaxis is not required for all
venous thromboembolism and any low risk women undergoing ovulation induction. (III-C)
thrombophilia; (I-A) 39. If severe ovarian hyperstimulation syndrome
d. asymptomatic homozygous factor V occurs with assisted reproductive technology
Leiden; (II-2A) we recommend thromboprophylaxis with low
e. asymptomatic homozygous prothrombin gene molecular weight heparin for at least 8 to 12 weeks
mutation 20210A; (III-B) after resolution of the syndrome. (III-B)
f. asymptomatic combined thrombophilia; (III-B) 40. Thromboprophylaxis with low molecular weight
g. asymptomatic antithrombin deficiency; (III-B) heparin should be considered for any women
h. non-obstetrical surgery during pregnancy, with at increased risk for venous thromboembolism
the duration of thromboprophylaxis procedure- undergoing assisted reproductive technology at the
and patient-dependent; (III-B) time of ovarian stimulation. (III-B)
i. strict antepartum bedrest for ≥ 7 days in a 41. Women who develop a venous thromboembolism
woman with a body mass index of > 25 kg/m2 at in association with the use of assisted reproductive
her first antenatal visit. (II-2B) technology but who do not conceive in that cycle
36. Antepartum thromboprophylaxis for isolated should be treated with therapeutic anticoagulation
pregnancy-related risk factors is not
for a minimum of 3 months. (II-3A) Those who
recommended. (III-E)
conceive in that assisted reproductive technology
37. Antepartum thromboprophylaxis should be
cycle should be treated as per recommendations
considered in the presence of multiple clinical or
12 and 13 for acute venous thromboembolism in
pregnancy-related risk factors where the overall
absolute risk of venous thromboembolism is pregnancy. (I-A, III-C)
estimated to be > 1%, especially in women
admitted to hospital for bedrest. (II-2B) PERIPARTUM ANTICOAGULATION
AND NEURAXIAL ANAESTHESIA
ASSISTED REPRODUCTIVE TECHNOLOGY Management Before Delivery and
The risk of VTE in women undergoing ART is estimated Neuraxial Anaesthesia
to be 0.11% per cycle of in vitro fertilization111; however, Current consensus guidelines on the use of neuraxial
in the presence of severe OHSS it is as high as 0.78%.112 (epidural, spinal, combined spinal/epidural) analgesia
Additionally, up to 70% of VTEs in OHSS involve or anaesthesia in patients on anticoagulants largely refer
the upper extremity, a much higher incidence than to the management of non-obstetric patients.10,116,117
expected.113,114 VTE associated with ART and OHSS may Similar recommendations for obstetric patients are
also present weeks or even months after the resolution of extrapolated from recommendations for non-obstetric
the OHSS.115 There is currently little to guide clinicians patients and “weak” evidence (e.g. case reports, case
in the use of thromboprophylaxis in women undergoing series, pharmacokinetic studies), and do not take into
ART. Extrapolating from the observational data from account the physiological changes of pregnancy. These
studies in pregnant women, we believe that in women at changes generally alter the pharmacokinetics of heparin
high risk for VTE (those identified in Table 4), instituting (both LMWH and UH) in the third trimester such that a
thromboprophylaxis at the start of ovarian stimulation, “prophylactic dose” in the third trimester may be greater
and maintaining it for the duration of the ART, would be than that used early in pregnancy. The recommendations
sensible. If pregnancy is achieved, thromboprophylaxis in this document are taken mainly from those of the
should be continued in the antepartum period. ASRA.10 It is important to note that guidelines from other
societies may differ117 and that the recommendations units of UH or less, some anaesthesiologists would check
regarding timing may not apply to all types of LMWH. an aPTT prior to neuraxial anaesthesia in all women on
Early consultation with an anaesthesiologist to assess UH.
risks and benefits will inform the patient of her options
for intrapartum anaesthesia. Full informed consent must Recommendations for the interval delay between the
be obtained for neuraxial analgesia and the reasons for last administered dose of heparin and the insertion or
deciding whether or not to proceed must be documented. removal of a neuraxial blockade or catheter are shown in
Table 6. A recent platelet count should be available in the
Whenever possible, women should withhold their labour suite or before Caesarean section for women on
thromboprophylaxis at the onset of labour or after anticoagulants. In the exceptional situation of a pregnant
their dose on the day prior to a planned induction of woman who has had a VTE within the past 2 to 4 weeks,
labour or Caesarean section. For women on therapeutic peripartum use of intravenous UH during the latent stage
anticoagulation, a planned date and mode of delivery of labour may be necessary. In these women the risk
is recommended to help simplify their peripartum of stopping the heparin should be weighed against the
management. benefit of a neuraxial anaesthesia, based on the anticipated
duration of labour and mode of delivery. In this situation,
Switching from thromboprophylactic LMWH to a neuraxial anaesthesia could be considered 4 hours after
prophylactic dose of UH at term (37 weeks) may allow discontinuation of intravenous UH if the platelet count
for more options with respect to labour analgesia, since and aPTT are normal.
neuraxial anaesthesia is contraindicated for at least 10 to
12 hours after LMWH but there is no recommended delay Although a spinal hematoma is a rare complication
after a maximum dose of 10 000 units of UH per day.118 (estimated incidence is < 1:150 000 with epidural
Although the ASRA Guidelines suggest no delay following anaesthesia and < 1:220 000 with spinal anaesthetics in
up to 10 000 units of UH per day, many anaesthesiologists healthy patients119), it can result in permanent neurological
prefer to wait a minimum of 4 hours. For women on an dysfunction.10,120 If a spinal hematoma is suspected (new
intermediate or therapeutic LMWH dose, the risks and onset or progressive neurological signs, back pain, or
benefits of discontinuing subcutaneous LMWH and bowel/bladder dysfunction), early confirmation by MRI
changing to therapeutic subcutaneous or intravenous should be done and surgical intervention undertaken, if
UH to allow for neuraxial anaesthesia once the aPTT is warranted, to achieve better outcomes.10,121,122 In women
normal could be considered. The switch is not necessarily on heparin, the co-existence of any factors that can
advantageous, however, as at these doses coagulation increase the risk of spinal hematoma (e.g. NSAIDs, LDA
may be impaired for a duration similar to that with either in combination with heparin, thrombocytopenia, multiple
heparin. Although not required with women on 10 000 neuraxial attempts, traumatic tap) should prompt a
Table 8. Literature review of incidence of postpartum thromboprophylaxis recommended for any two
risk factors
Incidence of symptomatic VTE*
< 0.3% 0.3% to 0.5% > 0.5% to > 1.0%
Maternal pre-pregnancy risk factors
BMI > 30 kg/m2 at first antenatal visit •••106,107,109 ••4,140
Smoking > 10 cigarettes/day or current versus •••• 2,4,107,129
•109
never smoked
Maternal cardiac disease •••4,106,140
SLE ••4,140
Sickle cell disease •140
Inflammatory bowel disease • 4
Varicose veins •4
Risk factors related to present pregnancy
Preeclampsia •4 •••2,3,109
Preterm birth • 4
•129
IUGR •109
Gestational diabetes •109
Placenta previa •3
Stillbirth •4
Risk factors related to delivery and postpartum period
Emergency Caesarean section ••3,109
Any Caesarean section ••••4,106,129,140 •2 •170
>1 L postpartum haemorrhage or transfusion postpartum • 4
• 109
•• 129,140
Placental abruption •3
PROM • 109
As the puerperium is inherently a higher risk period for viii. any low risk thrombophilia: PC or PS
VTE than the non-pregnant state, good hydration and deficiency, heterozygous factor V Leiden, or
mobilization should be encouraged for every woman prothrombin gene mutation 20210A; (III-B)
postpartum. ix. maternal cardiac disease, SLE, sickle cell
disease, inflammatory bowel disease,
Recommendations varicose veins, gestational diabetes; (III-B)
55. Universal postpartum thromboprophylaxis is not x. preterm delivery; (III-B)
recommended. (III-D) xi. stillbirth. (III-B)
56. Assess women for increased risk of postpartum b. any 3 or more of the following risk factors (each
venous thromboembolism based on antepartum, with an absolute risk of venous thromboembolism
intrapartum, and postpartum risk factors after < 1% in isolation):
every delivery and repeat as new clinical situations i. age > 35 years; (II-2B)
arise. (II-2B) ii. parity ≥ 2; (II-2B)
57. Low molecular weight heparin is the preferred iii. any assisted reproductive technology; (II-2B)
pharmacologic agent over unfractionated heparin iv. multiple pregnancy; (II-2B)
for postpartum thromboprophylaxis. (III-A) Low v. placental abruption; (II-2B)
molecular weight heparin doses should be used as vi. premature rupture of the membranes; (II-2B)
per the manufacturer’s recommendation. (III-C) vii. elective Caesarean section; (II-2B)
58. Pharmacologic thromboprophylaxis postpartum is viii maternal cancer. (III-B)
recommended in the following situations:
Any 1 of the following risk factors (each with an Mechanical Compression Devices
absolute venous thromboembolism risk > 1%): Mechanical methods of thromboprophylaxis include both
a. history of any prior venous graded compression stockings and intermittent pneumatic
thromboembolism; (II-2A) compression devices. Older evidence suggested that
b. any high-risk thrombophilia: antiphospholipid graded compression stockings were beneficial in reducing
syndrome, antithrombin deficiency, homozygous post-operative VTE, leading to their widespread use.135
factor V Leiden or prothrombin gene mutation However, their benefit has recently been challenged by
20210A, combined thrombophilia; (II-2B) two large trials in stroke patients (N = 5632). Thigh-high
c. strict bed rest prior to delivery for 7 days or stockings did not reduce symptomatic VTE or proximal
more; (II-2B) DVT,136 and knee-high stockings increased the risk of
d. peripartum or postpartum blood loss of > 1 litre thrombosis.137 In light of this new evidence we do not
or blood product replacement, and concurrent advocate the routine use of graded compression stockings
postpartum surgery; (II-2B) in postpartum women to reduce the risk of VTE.
e. peripartum/postpartum infection. (II-2B)
Intermittent pneumatic compression devices have not
59. Postpartum thromboprophylaxis should be been studied in pregnancy. Following major gynaecologic
considered in the presence of multiple clinical or surgery associated with a high risk of VTE, they are
pregnancy-related risk factors when the overall effective if left on for 5 days or until hospital discharge,
absolute risk is estimated to be greater than 1% but not if removed the day after surgery.138 In general
drawn from the following groups: surgery trials, they are associated with fewer major bleeding
a. any 2 of the following risk factors (each with an episodes than heparin but have a lower VTE risk reduction
absolute risk of venous thromboembolism < 1% rate.9 Most of these RCTs were underpowered to prove
in isolation): efficacy in preventing PE or mortality postoperatively.139
i. body mass index ≥ 30 kg/m2 at first When pharmacologic treatment is not possible, such as
antepartum visit; (II-2B) with active bleeding, thrombocytopenia, known heparin
ii. smoking > 10 cigarettes/day allergy or HIT, intermittent pneumatic compression
antepartum; (II-2B) devices are a good alternative. In women at very high risk
iii. preeclampsia; (II-2B) for VTE postpartum (> 10%), combined mechanical and
iv. intrauterine growth restriction; (II-2B) pharmacologic thromboprophylaxis is recommended.
v. placenta previa; (II-2B)
vi. emergency Caesarean section; (II-2B) Recommendation
vii. peripartum or postpartum blood loss of > 1 60. Intermittent or sequential pneumatic compression
litre or blood product replacement; (II-2B) devices are alternatives in women when heparin
is contraindicated postpartum. When the risk of in women experiencing adverse pregnancy outcomes is
postpartum venous thromboembolism is high they not indicated.148 What remains unknown is whether more
may be used in combination with low molecular severe placenta-mediated pregnancy complications (e.g.
weight heparin or unfractionated heparin. (III-B) severe or early-onset preeclampsia, SGA < 3rd percentile,
major abruption) are more strongly associated with specific
Postpartum Thromboprophylaxis: thrombophilia and potentially improved with antenatal
Duration of Anticoagulation thromboprophylaxis.
Up to 60% of postpartum PE occurs in the 4 to 6 weeks
after delivery.3,5,7 The duration of thromboprophylaxis Recommendations
varies with the underlying risk factors. Women with prior 63. Universal screening for thrombophilias in women
VTE have the highest risk and require a minimum of 6 experiencing adverse pregnancy outcomes (severe
weeks.89,140 Women with persistent risks that will be present preeclampsia, intrauterine growth restriction,
throughout the puerperium (e.g. high risk thrombophilia stillbirth) is not indicated. (II-2D)
or prolonged immobility), should also have extended 64. Women with recurrent miscarriage or late
thromboprophylaxis for a full 6 weeks. pregnancy loss should be screened for
antiphospholipid syndrome. (I-B)
There is no evidence to guide the duration of treatment in
women having only transient antepartum or intrapartum LMWH to Prevent Recurrent
risks. Given the logistics involved in discharging women on Adverse Pregnancy Conditions
heparin injections, individual institutions and practitioners The benefit of heparin plus LDA in women with APLS
may vary with respect to the duration of postpartum and recurrent miscarriage or late fetal loss (variably
thromboprophylaxis they choose in these cases. Other defined in the different studies) is controversial.151–154 A
guidelines recommend both options: until discharge from meta-analysis looking at 5 trials (N = 334) showed that
hospital fully mobile as a minimum54,118 or up to 1 to 2 LMWH plus LDA significantly increased the live birth rate
weeks postpartum.11,15 (74.3%) compared to LDA alone (55.8%) with a number
needed to treat of 5.6, but with significant heterogeneity.155
Recommendation
This evidence modestly supports screening women with
61. Women with ongoing and persistent risk factors recurrent miscarriage or late pregnancy loss for APLS and
should receive postpartum thromboprophylaxis for using LMWH alone or with LDA to prevent recurrent
a minimum of 6 weeks postpartum. (II-3B) miscarriage when APLS is confirmed.
62. Women with transient antepartum or intrapartum
risk factors should receive postpartum Recent RCTs, however, showed no benefit of LMWH
thromboprophylaxis until discharged from hospital alone or LMWH plus LDA versus no treatment or
or up to 2 weeks postpartum. (III-C) LDA alone to prevent recurrent miscarriage in women
without APLS.156–161 Although there were no significant
THROMBOPROPHYLAXIS TO PREVENT complications related to LMWH use in these trials, there
ADVERSE PREGNANCY OUTCOMES were reports of injection site bruising and skin reactions
highlighting the fact that heparin is not a benign treatment
Adverse Pregnancy Conditions: Screening and should not be prescribed in the absence of evidence
In the 1990s reports of an increase in placenta-mediated to support its use.
pregnancy complications (e.g. recurrent miscarriage,
late fetal loss, preeclampsia, placental abruption, Given that placental thrombosis is a part of the common
and intrauterine growth restriction) in women with pathophysiology of placenta-mediated pregnancy
thrombophilia appeared in the literature.141–144 Whereas complications, it is plausible that LDA alone, heparin
these early studies suggested a weak association between alone, or the combination of LDA plus LMWH might
inherited thrombophilia and placenta-mediated pregnancy prevent recurrence of adverse pregnancy outcomes in
complications, subsequent prospective cohort studies subsequent pregnancies for women with and without
suggested no association between most thrombophilia and thrombophilia.162–168 A review of 6 trials (N = 848 women)
preeclampsia or SGA infants.127,145–149 Women with APLS showed that LMWH, compared to no treatment, reduced
do have an increased risk of recurrent and late pregnancy the risk of early-onset preeclampsia (RR 0.16, 95% CI
loss.127,150 However, there is only a weak association 0.07 to 0.36), birth before 37 weeks (RR 0.77, 95% CI
between these complications and FVL and no association 0.62 to 0.96), and SGA infants (RR 0.42, 95% CI 0.29 to
with PGM.149 Hence, universal thrombophilia screening 0.59) without any significant effect on perinatal mortality.
There was an overall reduction in a composite outcome of isolation or in combination, which supersede the risk of
complications (preeclampsia, abruption, SGA infants, or thromboprophylaxis, we extrapolated data mostly from
fetal loss after 12 weeks) from 42.9% to 18.7% (RR 0.52, retrospective studies. Data from further large prospective
95% CI 0.32 to 0.86).169 A 2013 Cochrane review of 9 registries could yield more information on the absolute
trials (N = 979) concluded that prophylactic dose heparin risks associated with various biologic and clinical
(UH or LMWH), compared to no treatment, decreased factors, or combination of factors, which would warrant
perinatal mortality (RR 0.40, 95% CI 0.20 to 0.78), preterm thromboprophylaxis.
delivery < 34 weeks (RR 0.46, 95% CI 0.29 to 0.73) and
We anticipate data from further prospective studies will
SGA infants (RR 0.41, 95% CI 0.27-0.61) in women at
become available which will shed light on the effectiveness
high risk.170 Although this data appears promising, given
of LMWH, plus or minus LDA, in preventing recurrent
that LMWH is not risk free, it should not be used routinely
adverse pregnancy outcomes in women with or without
to reduce the risk of recurrence of all placenta-mediated
inherited thrombophilia.
complications in women, with or without thrombophilia,
pending the publication of larger trials or individual
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24;7:CD00678. 2003;169:207–8.
This document reflects emerging clinical and scientific advances on the date issued and is subject to change. The information
should not be construed as dictating an exclusive course of treatment or procedure to be followed. Local institutions can dictate
amendments to these opinions. They should be well documented if modified at the local level. None of these contents may be
reproduced in any form without prior written permission of the SOGC.
Table 1. Key to evidence statements and grading of recommendations, using the ranking of the Canadian Task Force
on Preventive Health Care
Quality of evidence assessment* Classification of recommendations†
I: Evidence obtained from at least one properly randomized A. There is good evidence to recommend the clinical preventive action
controlled trial
II-1: Evidence from well-designed controlled trials without B. There is fair evidence to recommend the clinical preventive action
randomization
II-2: Evidence from well-designed cohort (prospective or C. The existing evidence is conflicting and does not allow to make a
retrospective) or case–control studies, preferably from recommendation for or against use of the clinical preventive action;
more than one centre or research group however, other factors may influence decision-making
II-3: Evidence obtained from comparisons between times or D. There is fair evidence to recommend against the clinical preventive action
places with or without the intervention. Dramatic results in
uncontrolled experiments (such as the results of treatment with E. There is good evidence to recommend against the clinical preventive
penicillin in the 1940s) could also be included in this category action
III: Opinions of respected authorities, based on clinical experience, L. There is insufficient evidence (in quantity or quality) to make
descriptive studies, or reports of expert committees a recommendation; however, other factors may influence
decision-making
*The quality of evidence reported in these guidelines has been adapted from The Evaluation of Evidence criteria described in the Canadian Task Force on
Preventive Health Care.88
†Recommendations included in these guidelines have been adapted from the Classification of Recommendations criteria described in the Canadian Task Force
on Preventive Health Care.88
The occurrence of cancer in pregnancy is a rare and chemotherapeutic and potentially teratogenic medications.
challenging event, complicating up to 0.02% to 0.1% of The devastating effects of fetal exposure to teratogenic
pregnancies annually.4,5 Because of the rise in delayed child- drugs are not limited to thalidomide: diethylstilbestrol was
bearing, the rates of cancer in pregnancy are expected to withdrawn from the Canadian market, and isotretinoin
rise with the increased incidence of several age-dependent capsules are available only through a company-sponsored
malignancies.5 The cancers most commonly diagnosed pregnancy prevention program.2,4,5,10
during pregnancy are breast cancer, cervical cancer,
thyroid cancer, Hodgkin’s lymphoma, and non-Hodgkin’s Beyond awareness and education, the health care
lymphoma.4 professional and the patient must examine the patient’s
risk of pregnancy, including fertility and/or menopausal
Although surgery is generally considered safe during status (with consideration of previous chemotherapy and
pregnancy, there is little information regarding the safety of age), frequency or potential of sexual activity with a male
cytotoxic agents, which are often required in the optimal partner, and desire to prevent pregnancy.
management of cancer.4,6 Anticancer drugs aim, through
different mechanisms, to arrest cell division and cell growth. After completing a pregnancy risk assessment, the patient
By doing so, they pose direct risk to the developing embryo and health care provider must fully discuss methods of
during the first trimester of pregnancy. Knowledge of contraception, giving careful consideration to the efficacy and
pregnancy outcomes following cancer treatment has been availability of contraceptive options, the patient’s previous
limited by the low prevalence of cancer during pregnancy, high choices and her motivation to adhere to a contraceptive
rates of pregnancy terminations in women with cancer, and regimen, the rate of adherence, ease of use, cost, side-
the decision not to treat during critical fetal periods. The scarce effect profile (considering disease state and chemotherapy
evidence regarding the fetal safety of maternal chemotherapy regimen), and access to emergency contraception.
during pregnancy is limited to small retrospective studies and
case reports that are often underpowered, making their results While a contraceptive plan may be in place, health care
difficult to interpret and generalize. Additionally, because providers should check frequently with the patient
cytotoxic agents are usually administered in multiple-drug to assess adherence and satisfaction with the chosen
regimens, it is difficult to estimate the potential teratogenic methods. Additional considerations may be necessary
effects of each individual drug.7 In contrast to this paucity of for higher risk populations, including teenage patients.
information, there is a plethora of animal studies showing high This additional support and optimal prevention of fetal
rates of teratogenicity for most cancer chemotherapeutics. exposure to teratogens for all women of child-bearing age
The main problem in interpreting these experimental data is can be achieved with the implementation of an effective
the substantially higher dose per kg (or m2) used in the animal controlled distribution program such as RevAid.3
experiments, and inability to extrapolate these data to human
experience. DEFINING TERATOLOGY
Several issues highlight the problems of drug therapy Physiological Background
facing pregnant women. An estimated 50% of pregnancies Teratogenesis is defined as the structural or functional
are unplanned, so many women are exposed to teratogens dysgenesis of fetal organs.11 Broadly, exposures that
before they realize they are pregnant.8 Also, women may irreversibly affect the normal growth, structure, or
decline treatment, even for life-threatening conditions, for function of a developing embryo or fetus are defined as
fear of being exposed to medication that could harm their teratogenic.12 Known teratogens include environmental
fetus.9 factors such as radiation, certain viruses such as rubella,
Following a diagnosis of cancer in pregnancy, the pregnant chemicals such as alcohol, and therapeutic drugs such as
woman, her family, and her medical team are required to thalidomide and isotretinoin.9 Teratogenic effects vary
make complex treatment decisions, often in the absence widely in severity and range, and include death (miscarriage
of definitive evidence. Without standardized guidelines or stillbirth), malformations, impaired organ functioning,
concerning chemotherapy in pregnant women, a woman impaired fertility, and mutagenicity.8
may compromise her health or the health of the developing Congenital malformations, defined as defects in organ
fetus. structure or function, occur in 1% to 3% of the general
population.9 Of the major defects, about 25% are of
PREGNANCY PREVENTION genetic origin and 65% are of unknown etiology.9 Only
2% to 3% of malformations are believed to be associated
The detrimental impact of thalidomide worldwide in the with drug treatment.8
late 1950s and early 1960s1 provides clear evidence of the
need for careful education, administration, monitoring The teratogenic potential of any drug depends on a variety
and restricted distribution in prescribing and dispensing of factors that include the extent of its placental transfer,
the dose administered, the duration of exposure, the In summary, the teratogenic potential of a drug is dynamic,
genetic variability in drug metabolism of the mother and affected by the timing, the dose, and the molecular
the fetus, and the timing of exposure. properties of the teratogens, and by cumulative exposure.
The conditions that must be met for access to thalidomide CANCER AND PREGNANCY
or lenalidomide are the most stringent for women of child-
bearing age. Women must be warned of the potential for The diagnosis of cancer during pregnancy poses difficult
birth defects and that, because of the risk to others, they dilemmas for the pregnant patient, her family, and the
medical team. Cancer in pregnancy is rare, complicating up
must never share their medication or give blood up to
to 0.02% to 0.1% of pregnancies annually.4,5,16
4 weeks after ceasing to take the medication. To ensure
prevention of pregnancy, the RevAid program requires The cancers most commonly diagnosed in pregnancy are
that women use 2 methods of contraception in parallel, breast cancer, cervical cancer, thyroid cancer, Hodgkin’s
starting 4 weeks before they begin taking the medication lymphoma, and non-Hodgkin’s lymphoma. See Table 2 for
and continuing until 4 weeks after cessation of therapy. details on particular cancers during pregnancy.
In addition, they must consent to regular pregnancy
tests before and during treatment. Two pregnancy tests ANTINEOPLASTIC AGENTS AND PREGNANCY
are given before the first prescriptions; a pregnancy test
is done weekly during the first 4 weeks of therapy; and, The main challenge in managing cancer during pregnancy
with regular therapy, pregnancy tests are performed every is treating the patient with the optimal anti-cancer regimen
4 weeks with both regular or no periods, and every 2 weeks without harming the developing fetus. Critically, for the
if periods are irregular. best chance at survival for the mother, chemotherapy
cannot always be postponed until the end of the
The RevAid program represents a safe, controlled way to pregnancy, and no current regimen has been confirmed
provide these useful drugs to people who are not at risk of (by studies with sufficient statistical power) safe for use
suffering their negative effects. As many chemotherapeutic during gestation.
agents are potentially teratogenic, and as women of
Because of their relatively low molecular weight, most
childbearing age often require prompt pharmacological cytotoxic agents cross the placenta and reach the fetus.17,18
intervention, guidelines like those of the RevAid program The pharmacology of various anti-cancer drugs may be
are necessary to prevent pregnancy during chemotherapy altered by the normal physiological changes that occur
treatment. during pregnancy, such as increased plasma volume,
enhanced renal and hepatic elimination, and decreased
In Canada, a program similar to RevAid outlines the use
albumin concentration. Dosing similar to that of non-
of isotretinoin.10 Women are informed of fetal risks, are pregnant women of the same weight may lead to under-
prescribed 2 contraceptive methods in parallel, and sign treatment of pregnant women with cancer.18 However, it is
a document attesting to compliance. However, unlike the still not clear whether pregnant women should be treated
RevAid program, it does not require registration and has with different doses of chemotherapy, and no studies
no mandatory follow-up. The lack of these measures has have addressed the effectiveness of treatment regimens in
resulted in unplanned pregnancies and fetal exposures to pregnancy.
this teratogen, highlighting the importance of thorough
guidelines outlining the distribution of all teratogenic Chemotherapy during the first trimester may increase
substances in women of child-bearing age. the risk of spontaneous abortions, fetal death, and
major congenital malformations. The teratogenic effects
Currently, no guidelines exist for the use of chemotherapy depend on the dosage, time of administration, and
in non-pregnant women of child-bearing age. The cumulative exposure to the chemotherapeutic agent. Fetal
development of a program similar to RevAid to monitor malformations reflect the gestational age at exposure, and
the distribution of chemotherapeutic agents and follow-up the most vulnerable period is during weeks 2 to 8, when
on all women enrolled in the program are needed to ensure organogenesis occurs. The eyes, ears, teeth-palate, genitalia,
hematopoietic system, and CNS remain vulnerable to
pregnancy prevention during chemotherapy treatment.
chemotherapy beyond organogenesis.17
Additional guidelines are necessary to address the use of
Almost all chemotherapeutic agents are teratogenic in
chemotherapy when it is indicated during pregnancy. The animals. For many chemotherapeutic agents, the risk of
importance of these guidelines is 2-fold. First, they would teratogenesis in humans is unknown. However, the risk of
give health care providers a conclusive resource on which teratogenesis in humans following cancer treatment appears
to base their treatment plans. Second, they would help to to be lower than is commonly estimated from animal data
dispel common misconceptions patients have about the because of the proportionately larger doses used in animals
use of chemotherapy during pregnancy; this will encourage First trimester exposure to chemotherapy has been estimated
pregnant women to pursue care that ensures the best long- to have a 10% to 20% risk for major malformations. It
term outcome for themselves and their infants. has been suggested that this risk may decline to about 6%
Hodgkin’s 0.016% to 0.1% • Painless lymph node • Physical exam • Nodular sclerosis most common. • Survival rates found to be similar
Lymphoma enlargement • Blood tests • Histological subtypes are the to that of non-pregnant control
• Lymph node biopsy • Bone marrow biopsy same as in non-pregnant women matched for age, stage and
• Abdominal ultrasonography < 40 years. treatment protocol.
or chest X-ray with abdominal
shielding
• MRI
Intracranial Unknown • Headache • MRI — • Very limited data suggest that
tumours • Nausea and vomiting pregnancy does not exacerbate
• Nonspecific symptoms to focal tumour growth or affect the
neurologic deficits such as outcome of the patients.
hemiparesis and visual field
defects.
• Pregnancy can exacerbate
neurology with the patient
presenting with impending or
actual cerebral herniation.
• Common symptoms of
intracranial pressure can
potentially be confused with
routine pregnancy-related
conditions.
continued
Table 2. Continued
Frequency in
Cancer pregnancy Diagnosis Staging Pathology Prognosis
Leukemia 0.001% • Blood work • Ultrasounds • Acute myeloid leukemia • Spontaneous abortion,
• Bone marrow biopsy • MRI • Acute lymphoblastic leukemia prematurity, IUGR, and death
• Chronic myeloid leukemia have been associated with
• Chronic lymphocytic leukemia maternal leukemia.
• Survival rates found to be similar
to that of non-pregnant control
matched for age, stage and
treatment protocol.
Lung Unknown • Symptoms such as blood- • Anteroposterior and lateral chest • Non-small cell lung cancers, in • No evidence that pregnancy
streaked sputum, persistent radiographs. order of most to least frequent: alters the prognosis of lung
cough or change in cough • Ultrasound adenocarcinoma, squamous cell, cancer.
pattern, wheezing, decreased • MRI large cell, and bronchoalveolar. • Maternal outcome for both small
appetite with poor weight gain, • Sputum cytology • Small cell lung cancer. cell and non-small cell lung
along with other loco-regional • Fine needle aspiration biopsy cancer has been poor and is a
symptoms are commonly seen. • Bronchoscopy with biopsy reflection of the advanced stage
• Delays in diagnosis may • Bronchoalveolar lavage at diagnosis.
occur because of low index of
suspicion, tendency to attribute
symptoms such as fatigue and
dyspnea on the pregnant state
and the reluctance to order chest
radiography during pregnancy.
Malignant 0.014% to 0.28% • Changes to the shape or • Assessment of tumour site. • Superficial spreading • Malignant melanoma is the
melanoma colour of existing moles or • Ultrasound melanomas most common most frequent cancer that
any pigmented lesion, or the • Fine needle aspiration biopsy. (41%). metastasizes to the placenta
appearance of a new lump • Lymphatic mapping with blue or fetus, accounting for 31% of
anywhere on the skin. dye or radio-labelled tracer reported cases.
injected at tumour site plus • When matched for age,
sentinel lymph node biopsy. anatomic site and stage, most
• MRI studies have not demonstrated
a difference in survival between
pregnant and non-pregnant
women.
Non-Hodgkin’s 0.016% • Painless lymph node • Physical exam • Degrees of severity from • Survival rates found to be similar
Lymphoma enlargement • Blood tests indolent to very aggressive. to that of non-pregnant control
• Lymph node biopsy • Bone marrow biopsy • Histological subtypes in matched for age, stage and
• Abdominal ultrasonography pregnancy appear to be treatment protocol.
or chest X-ray with abdominal aggressive with diffuse large • There may be a trend toward
shielding B-cell or peripheral T-cell lower birth weight infants born to
• MRI lymphomas being the most mothers who had non-Hodgkin’s
common. lymphoma in pregnancy.
continued
treatment protocol.
malformations but may increase the risk for IUGR, low
birth weight, and stillbirth. A review of 376 cases of fetuses
exposed to chemotherapy in utero, most after organogenesis,
Prognosis
• Surface epithelial-stromal
risk for IUGR. Only 2 of the 159 live born infants suffered
teratomas) (39%)
tumour (50.6%)
before treatment.
The major message is that most fetuses whose exposure is
• Significant numbers of patients
born healthy.
• Pain in the neck region,
• New thyroid nodule or
Alkylating agents
Alkylating agents are commonly used for the treatment of
hoarseness
present
nodule
commonly used.22
Frequency in
Thyroid
Cancer
atresia.24–28 Included in this, one set of twin infants in MOPP treatment, involving exposure to alkylating agents
which the male twin, born with congenital anomalies, mechlorethamine and procarbazine was reported in 14
later developed thyroid cancer at age 11 and stage III patients.21,32,34,35 One patient treated during the first trimester
neuroblastoma at age13.28 His twin sister was unaffected delivered an infant with hydrocephaly that died 4 hours
by the exposure and was developing normally at the time after birth.35 A second trimester exposure to MOPP/ABV
of the study, suggesting differential pharmacogenetic resulted in bilateral partial syndactyly of second and third
effects on the drug metabolism into the active form of digits in the fetus.21 Twelve exposures to MOPP/ABV
the drug. Cyclophosphamide exposures in the second or ABVD described by Avilés et al., with an unspecified
and third trimester of pregnancy are more frequent. amount occurring in the first trimester, all resulted in
One study examined the outcomes of 61 patients treated normal outcomes.32 These data suggest mechlorethamine
for different malignancies during the second and third and procarbazine are not associated with an increased risk in
trimester and found 59 infants were born with no the second and third trimesters.
malformations.21 One infant whose mother was treated
also with doxorubicin was born with hip subluxation and Platinum compounds
another infant who was exposed to the EFC protocol Platinum compounds form DNA adducts that result in
(epirubicin, cisplatin, fluorouracil) was born with DNA crosslinking. DNA crosslinks inhibit replication,
rectal atresia. Another 110 patients exposed during the transcription, and other nuclear functions. The combination
second and third trimesters to an assortment of multi- of these events arrests cell proliferation and ultimately
drug protocols, including cyclophosphamide, resulted tumour growth. Cisplatin and carboplatin are among the
in 105 normal births and 5 congenital malformations: most commonly used platinum compounds.
1 intrauterine death with normal autopsy, 1 neonatal death
due to autoimmune disorder, 1 infant with IgA deficiency, Cisplatin exposure in the second and third trimesters has
1 with pyloric stenosis, and 1 with holoprosencephaly.20 been frequently described. Four patients who had cervical
Intrauterine growth restriction occurred in 7 cases (6%). cancer during pregnancy and who were treated in the
An additional 81 women who were treated with the FAC second trimester with cisplatin all delivered healthy infants
regimen for breast cancer during the second to third with no congenital malformations.36–39 Another 3 patients
trimesters demonstrated 3 congenital abnormalities, treated for small cell lung carcinoma and 2 treated for
including 1 case of Down syndrome, 1 infant with ovarian cancer delivered healthy infants after exposures
ureteral reflux, and another with talipes.29,30 Finally, to cisplatin.40–42 Finally, 6 of 7 infants born to 7 patients
28 patients treated for breast cancer with different exposed to cisplatin in various regimens for different
cyclophosphamide-containing regimens during the malignancies were healthy. Only 1 infant was born with a
second and third trimesters all had normal deliveries and congenital malformation, hearing loss that was attributed
outcomes.31 This information suggests that second and to genetic factors from the parents.20 Cisplatin use in the
third trimester exposure to cyclophosphamide may not second and third trimesters of pregnancy has not been
increase the risk for adverse effects. found to be associated with any pattern or increased risk
of adverse fetal effects.
Dacarbazine exposures occur most frequently in
pregnancy during administration of ABVD protocols, or Carboplatin exposure occurred during the second and third
in combination MOPP, ABVD or MOPP/AVD protocols. trimesters of 5 patients. Four were women with ovarian
In 19 patients treated for lymphoma with ABVD after the cancer, all of whom delivered healthy infants. The 1 case
first trimester, 17 healthy infants were born, and 2 with of CNS malignancy was the only report of an adverse
congenital malformations: 1 infant with plagiocephaly, and pregnancy outcome, with a spontaneous abortion of a
1 infant with fourth and fifth syndactyly.20 In another 12 fetus with gastroschisis, as reported by Cardonick et al.20
reports of lymphoma patients treated with ABVD (83.3%),
MOPP/ABVD (8.3%), or MOPP/ABD (8.3%) protocols, Although evidence is limited, carboplatin exposure in the
all resulted in normal deliveries and healthy outcomes.32 second and third trimesters does not appear to increase the
Through this limited information, it appears that exposure risk for major malformations.
to dacarbazine during the later stages of pregnancy is not
associated with a specific set of malformations. Use in the Antimetabolites
first trimester cannot be recommended. Antimetabolites are small compounds used to treat
leukemia, lymphoma, and breast cancer. They act as false
Two case reports of ifosfamide treatment, combined with substrates during DNA or RNA synthesis, resulting in
doxorubicin for Ewing sarcoma in pregnancy were located.33,34 inhibition of cellular metabolism. This process occurs
One exposure occurred during the second trimester and the independently of the phase of the cell cycle. Common
other in the third trimester. Both pregnancies had normal examples of chemotherapeutic agents of this drug class
outcomes. Scarcity of information regarding ifosfamide is a are methotrexate, 5-fluorouracil, aminopterin, cytarabine,
recommendation for using a better-studied alternative. tioguanine, and mercaptopurine.22
Methotrexate exposure during the first trimester of pregnancy and healthy outcome.20 A second patient treated
pregnancy has been associated with malformations similar for non-small cell lung cancer delivered prematurely, at
to the aminopterin syndrome, including cranial dysostosis 28 weeks, but with no congenital malformations.53
with delayed ossification, hypertelorism, wide nasal bridge,
micrognathia, and ear anomalies.43 In a series of 20 Anti-tumour antibiotics
exposures during the first trimester, 7 infants developed Microorganisms produce these cytotoxic agents that
this pattern of anomalies.44–52 In addition, there were 5 cases interact directly with DNA resulting in anti-cancer activity.
of miscarriage and 1 case of skeletal abnormalities with The manner in which antibiotics interact with DNA differs
ambiguous genitalia. Exposure to methotrexate (together considerably between agents.
with cyclophosphamide and 5-fluorouracil) in the second
and third trimesters in 12 patients did not show the same Bleomycin creates DNA breaks and is commonly used
pattern of malformations: all infants were born healthy.31 in the ABVD protocol. Cardonick et al.20 reported on
Because of the suspected teratogenicity of methotrexate, 23 exposures to bleomycin in pregnancy, with varying
it should not be considered a first-line therapy, and should malignancies and regimens.20 Twenty of the women were
not be used at any stage of pregnancy. being treated for lymphoma, while the remaining 3 had
ovarian cancer. Treatment occurred during the second and
One study reported on 53 exposures to 5-fluorouracil, third trimesters, and 3 congenital malformations resulted.
with 5 occurring in the first trimester.17 One of these One infant was born with plagiocephaly and another with
patients spontaneously miscarried, and there were 6 cases fourth and fifth finger syndactyly. A third infant was born
of IUGR. The rest of the infants had normal outcomes. with genetic hearing loss, of which his parents were both
A further 12 patients exposed to 5-fluorouracil, along genetic carriers.20 Another patient treated with bleomycin
with cyclophosphamide and methotrexate, in the second (in combination with etoposide and cisplatin) for teratoma
and third trimesters had normal outcomes.31 Similarly, during the third trimester had a normal delivery and
18 patients treated with 5-fluorouracil for breast and healthy infant.42 Bleomycin therapy in the second and
colorectal cancers during the second and third trimester third trimesters of pregnancy was not associated with any
all had normal pregnancy outcomes.20 Hahn et al. reported grouping of malformations.
3 congenital malformations out of 35 exposures to
5-fluorouracil in an FAC protocol during the second and Topoisomerase inhibitors
third trimesters for the treatment of breast cancer.29 One
infant was born with Down syndrome, 1 with clubfoot, Anthracyclines
and 1 with congenital bilateral ureteral reflux. As these Anthracyclines commonly used are doxorubicin, daunoru
are fairly common congenital abnormalities, the authors bicin, epirubicin, idarubicin, and mitoxantrone.
compared these rates with expected population frequencies
and determined that the chemotherapy may not have been Van Calsteren et al. reported on a number of pregnant
the cause. As an antimetabolite, 5-fluorouracil is not one patients treated with topoisomerase inhibitors.18 A total of 36
of the first-line agents recommended, but it has not been patients treated for various malignancies with doxorubicin
associated with any increased risk for malformation in the during the second and third trimester were evaluated. One
second and third trimesters. infant, also exposed to cyclophosphamide, was born with
hip subluxation. A second infant exposed to FAC regimen
Capecitabine exposure in 1 patient treated during the was born with doubled cartilage rings in both ears. The
first trimester for colorectal cancer resulted in a normal rest of the infants (34/36) had normal outcomes. Another
pregnancy with a healthy outcome.20 Evidence is insufficient 25 patients in this series were exposed to daunorubicin-
for conclusions to be made about the safety of capecitabine. containing treatments for various malignancies during the
In 9 patients treated with various regimens including second and third trimesters. Two infants had congenital
cytosine arabinoside for leukemia, 5 of them during the first malformations: 1 with bilateral partial syndactyly of
trimester, no congenital malformations were reported.23 second and third digits, and the other with rectal atresia.
Two more patients treated during the second and third The remaining 23 outcomes were normal. Cardonick et al.
trimesters with this antimetabolite for non-Hodgkin’s detailed the pregnancy outcomes of 118 patients treated
lymphoma and acute myeloid leukemia also had healthy for breast cancer (98) and lymphoma (20) with various
pregnancy outcomes.20 Although information is limited, topoisomerase inhibitor-containing regimens, all during
there is so far no evidence to indicate that administration the second and third trimesters.20 A total of 5 abnormal
of cytosine arabinoside in pregnancy results in fetal outcomes were observed: 1 infant with IgA deficiency, 1
malformations. neonatal death due to autoimmune disorder, 1 infant with
pyloric stenosis, 1 infant with holoprosencephaly, and 1
One patient treated with gemcitabine for a pancreatic intrauterine demise with normal autopsy. In another series
tumour during the second and third trimesters had a normal of 11 patients treated with doxorubicin together with
cyclophosphamide during the second and third trimesters with no congenital malformations.61 These data suggest that
of pregnancy, all infants had normal outcomes.31 paclitaxel may be compatible with therapy in the second and
third trimesters of pregnancy.
Epirubicin exposure was noted in 5 patients concomitant
with cyclophosphamide during the second and third Vincristine exposures in 11 patients treated for various cancers
trimesters. No congenital malformations were reported.31 during the second and third trimesters resulted in healthy
outcomes for 10 infants.20 As previously noted, 1 infant
In 1 case, a patient treated for acute myeloid leukemia exposed to vincristine, doxorubicin, cyclophosphamide,
was exposed to idarubicin together with all-trans retinoic prednisone, and rituximab died in utero at 30 weeks, and
acid during the first trimester and had a normal pregnancy the autopsy results were normal. These limited exposures
outcome. 54 A further 9 cases of patients treated for various suggest that vincristine therapy does not increase risk for
malignancies during the second and third trimesters, malformation during the second and third trimesters.
however, resulted in 4 congenital malformations,32,55–59
including 1 case of transient dilated cardiomyopathy and 2 Of 20 patients treated in the second and third trimesters for
cases of permanent dilated cardiomyopathy.55–57 As data on Hodgkin’s lymphoma and non-Hodgkin’s lymphoma with
possible effects to the fetal heart are inconclusive, caution varying vinblastine-containing regimens, 2 had infants with
should be exercised with respect to the use of idarubicin malformations.20 After in utero exposure to doxorubicin,
during pregnancy. bleomycin, dacarbazine, and vinblastine throughout
second and third trimesters for Hodgkin’s lymphoma,
One patient treated for teratoma with mitoxantrone
there was 1 case of plagiocephaly. Another infant exposed
and bleomycin and cisplatin during the third trimester
to the same regimen was born with fourth and fifth finger
had a normal delivery, and the infant had no congenital
syndactyly. Although evidence to date suggests there is not
malformations.42
a significant concern with unique vinblastine treatment in
the second and third trimesters, more research is needed.
Plant alkaloids and taxanes
Plant alkaloids and natural products, such as taxanes, may Etoposide exposure in 6 patients during the second and
inhibit mitosis or inhibit enzymes needed for reproduction third trimesters did not appear to cause any congenital
of the cell. These agents are specific to the M phase of malformations.20,40,42 One infant was born with genetic
the cell. They include paclitaxel, docetaxel, etoposide, hearing loss ruled unrelated to exposure to etoposide,
vinblastine, and vincristine.22 cisplatin, and bleomycin. Although there is only limited
In 19 patients, 2 in the first trimester, exposed to experience with etoposide, there were no patterns of
docetaxel for the treatment of breast cancer, 3 congenital congenital malformations noted with etoposide exposure in
malformations were noted.60 Two infants had cerebral the later stages of pregnancy.
ventriculomegaly; however, in both cases the diagnosis was
made before administration of chemotherapy. The only Molecularly targeted agents
malformation potentially related to cytotoxicity is 1 case of Recently, the choice of treatment for the pregnant patient
pyloric stenosis in an infant whose mother was exposed to with cancer has become even more complicated because
doxorubicin, cyclophosphamide, paclitaxel, and docetaxel. of the increasing use of targeted anti-cancer therapies. The
Therefore, the use of docetaxel appears to be safe in the benefit of the targeted agents has been well demonstrated
second and third trimesters. for various malignancies; however, their safety during
pregnancy has not been established. Currently, significant
Exposures to paclitaxel in multi-drug therapies for various experience with exposure during pregnancy is available
malignancies in 19 patients resulted in 1 congenital only for the tyrosine kinase inhibitor, imatinib and the
malformation and 1 intrauterine or postnatal demise.20 Pyloric monoclonal antibody, rituximab.
stenosis was reported in an infant exposed to paclitaxel,
docetaxel, cyclophosphamide, and doxorubicin as discussed The largest report regarding exposure to imatinib during
above. In a patient treated with doxorubicin, vincristine, pregnancy included 180 pregnant women with chronic
cyclophosphamide, prednisone, and rituximab for non- myeloid leukemia. Outcome data were available for 125
Hodgkin’s lymphoma, intrauterine fetal demise occurred at patients.62 Congenital malformations were identified in
30 weeks. The autopsy results were normal. Twenty-four 12 infants, 3 of whom had strikingly similar complex
more cases of exposure to paclitaxel for the treatment of malformations (a combination of omphalocele with severe
breast cancer in the second and third trimester resulted in renal and skeletal malformations) that are clearly cause for
23 healthy outcomes. The 1 congenital malformation was concern. All congenital malformations were associated with
the case of pyloric stenosis following multi-drug exposure first trimester exposure to imatinib. It appears that although
reported previously. Finally, 1 patient treated with paclitaxel most pregnancies exposed to imatinib are likely to have a
weekly from 20 weeks’ gestation delivered a healthy infant successful outcome, this exposure may result in serious fetal
malformations. These concerns suggest that imatinib should Treatment during the second and third trimesters does not
not be administered during the first trimester.62,63 carry a risk for morphological congenital malformation;
however, infants may be born earlier than expected and
Rituximab is an anti-CD20 monoclonal B-cell antibody small for gestational age, and some of the agents used in
indicated mainly for diffuse large B cell and follicular treatment are neurotoxins, which may theoretically affect
non-Hodgkin’s lymphomas. Recently it has been also brain development. The timing of delivery should be
administered to patients with several autoimmune diseases. planned to avoid myelosuppression, but no long-term
A 2011 report described 231 pregnancies associated developmental sequelae have been reported. If possible,
with maternal rituximab exposure.64 Most cases were delivery should be postponed for 2 to 3 weeks following
confounded by the concomitant use of potentially anti-cancer treatment to allow bone marrow recovery.4,69
teratogenic medications (most commonly methotrexate). Furthermore, neonates, especially preterm infants, have
Of the 153 pregnancies with outcome data, 90 resulted in limited capacity to metabolize and eliminate drugs because
live births. First trimester miscarriages were reported in 33 of liver and renal immaturity. The delay of delivery after
(21%) cases, and 28 pregnancies were electively terminated. chemotherapy will allow fetal drug excretion by the placenta.
Twenty-two infants were born prematurely, and there was
1 neonatal death. Eleven neonates had hematological POSTPARTUM CARE
abnormalities without corresponding infections. Two
congenital malformations were identified: 1 case of Breastfeeding
talipes, and 1 of cardiac malformation (a combination of As a rule, women using cancer chemotherapeutic agents
ventricular septal defect, persistent foramen ovale, and after delivery should not be breastfeeding as neither short-
persistent ductus arteriosus). The limited experience to term nor long-term safety has been established. Exceptions
date suggests that the administration of rituximab may be include azathioprine, with which repeated measures failed
to show accumulation in milk.
considered safe during the second and third trimesters.
If the lactating mother requires drug therapy, safety of
TREATMENT GUIDELINES breastfed infants is a concern because almost all drugs the
mother ingests are excreted into milk. Of many factors that
Patients with a slowly growing cancer diagnosed during determine magnitude of drug excretion into milk, plasma
the first trimester may be followed at short intervals for protein binding, ionization characteristics and lipophilicity
signs of disease progression without treatment until the of drug are the most important.70
second trimester. However, when aggressive, advanced,
Recently, expression and function of carrier-mediated drug
or progressive disease is diagnosed in the first trimester, a transport in the mammary gland have been elucidated. For
delay in therapy may adversely affect maternal survival.3,63–67 example, the lactating mammary gland highly expresses
Therefore, treatment with appropriate, often combination, breast cancer resistant protein (BCRP: ABCG2), which
chemotherapy should be given promptly. However, carries its substrates from maternal circulation into milk.
this should be accompanied by detailed counselling to Initially, its role as a toxin transporter was perplexing as it
ensure that the woman and her family understand the appeared to actively contaminate mother’s milk. However,
potential teratogenic effects of chemotherapy in the first it was later shown that breast cancer resistant protein in
trimester. In specific cases, the treatment with single- the mammary gland is a major vitamin B2 transporter.71
agent chemotherapy (preferably a vinca alkaloid or an Some organic cation transporters carry both xenobiotics
anthracycline) during the first trimester followed by and nutrients, and mammary gland drug transporters
conventional multi-agent therapy at the beginning of the have a nutrient carrier function that is taken over by
second trimester may be considered. Such therapeutic maternal xenobiotics. In addition to the above mentioned
approaches appear to be safe; however, data regarding attributes of drugs, such as protein binding and ionization
their efficacy for the maternal cancer is lacking. Most characteristics, transporter affinity as a substrate is another
multi-drug protocols may be administered during the important factor for defining milk excretion of drugs.70
second and third trimesters without an apparent increase Risk assessment of drug therapy, including cancer
in the risk for severe malformations. Regimens based on a chemotherapy, during lactation must consider several factors
combination of cyclophosphamide and an anthracycline that are distinct from those of pregnancy. First, average
administered to women with breast cancer or lymphoma levels of drug exposure in the infant are usually an order
have been most commonly used during pregnancy, and of magnitude lower in lactation-mediated exposure than in
their administration after the end of the first trimester transplacental exposure. Second, the mother has an option
found to be safe. Weekly fractionated-dose chemotherapy to discontinue, or temporarily interrupt, breastfeeding if
may be preferred to allow ease of pregnancy monitoring, the risk is perceived to be high. Third, cancer chemotherapy
and interruption of treatment if necessary.6 schedules may allow breastfeeding women to store their
own milk for near-future use. In addition, women with milk concentrations of doxorubicin and doxorubicinol
cancer who are being treated with chemotherapy may were 128 mg/L (0.24 mM) and 111 mg/L (0.20 mM),
perceive the importance of breastfeeding and the risks respectively, 24 hours after the dose.72 Anthracyclines may
associated with it differently from women who are taking not be absorbed orally, and the dose to the infant, based
non-cancer related medications. on the peak levels, may be in the low range of 2% of the
weight-adjusted dose. However, safety data are too scant to
Published clinical studies on excretion of cancer make a firm recommendation at this point.
chemotherapy agents into milk, and resultant infant plasma
levels, are very limited. Breastfeeding-related information A 28-year-old woman with acute promyelocytic
is available for the following chemotherapeutic agents leukemia received chemotherapy during pregnancy and
in cancer treatment, but levels of evidence are not high breastfeeding.79 After first consolidation therapy, she
enough to make firm recommendations. delivered healthy baby at 34 weeks’ gestation. After delivery
she received second consolidation therapy. Then she
Cisplatin was treated with intravenous etoposide (80 mg/m2/day:
There are 3 published case reports on use of cisplatin in days 1 to 5) and other drugs including mitoxantrone
lactating women with cancer.72–74 At various post-dose time (6 mg/m2/day: days 1 to 3) and cytarabine (170 mg/m2/day:
points, plasma cisplatin concentrations were measured as days 1 to 5) as third consolidation therapy. The post-infusion
platinum. The maternal plasma levels ranged from 0.8 mg/ peak milk concentrations of etoposide ranged from
mL to about 3 mg/mL when measured and expressed as 580 mg/L to 800 mg/L, which quickly declined and became
plasma platinum levels, but the maternal plasma ratio varied undetectable in 24 hours. Breastfeeding was resumed 3
widely from nearly zero (milk levels were below the detection weeks after the end of the therapy without incident.
limit of platinum) to 1.1. Cisplatin pharmacokinetic studies in
non-lactating patients indicate that average plasma platinum In the same woman described above, mitoxantrone milk
concentrations after 100 mg/m2 dosing (a high therapeutic concentration reached 120 mg/mL immediately after the
dose) are about 3.91 ± 1.41 mg/mL.75 Assuming maternal third dose. Mitoxantrone milk concentrations decreased to
plasma ratio to be the reported highest (1.1), the infant about 20 mg/mL by 7 days after the last (third) dose, and
would receive 4.3 mg/kg/day of platinum. Taken together, remained at that level 4 weeks after the last dose.79
evidence of cisplatin safety/toxicity in breastfeeding is
After maternal oral doses of imatinib (400 mg/day),
weak. Because of the relatively long half-life of cisplatin,
milk concentrations are approximately in the range of
most experts recommend discontinuation of breastfeeding,
0.5 mg/mL to 3.2 mg/mL. Its active metabolite is also in a
but emerging data on benefits of breastfeeding and lack
similar range of concentrations (1 mg/mL to 2.5 mg/mL).
of clear toxicity data may require revisiting the current
One infant was breastfed during the maternal imatinib
recommendation.
treatment without incident.80–83
Cyclophosphamide
Methotrexate
Three case reports of use of cyclophosphamide during
A 25-year-old woman with choriocarcinoma received
breastfeeding exist; however, there are no quantitative
methotrexate 22.5 mg orally (15 mg/m2/day). Peak
data on cyclophosphamide levels in milk.76–78 In one case,
methotrexate concentrations in milk samples were
a woman with leukemia received weekly intravenous
2.6 ng/mL on 2 different dosing occasions.84 In the case
doses of cyclophosphamide 800 mg and vincristine 2
of a woman who received a single dose of 65 mg of
mg over a 6-week period, in addition to prednisolone
methotrexate intramuscularly (50 mg/m2) for ectopic
(30 mg/day). Her 4-month-old infant was breastfed
pregnancy, 6 milk samples taken over the following
during this treatment cycle and found to be neutropenic
24-hour period did not show detectable levels of the drug.85
at the end of the treatment, but returned to normal after
breastfeeding was discontinued.76 Another patient with Studies on excretion of cancer chemotherapeutic agents
Burkitt lymphoma received daily cyclophosphamide into human milk are scarce, but accumulating evidence
6 mg/kg intravenously. At 23 days of life, her infant is overwhelmingly supportive of the tangible benefit of
developed neutropenia and thrombocytopenia over a human milk for many aspects of infant development.
3-day period. The limited information from these reports Given the nature of the maternal diseases in question,
suggests that cyclophosphamide is not compatible with risk-benefit assessment of breastfeeding during maternal
breastfeeding.77 chemotherapy needs to be carefully individualized.
Doxorubicin Follow-Up
In milk samples of a woman receiving doxorubicin While treating pregnant women during the second and third
70 mg/m2 (an intravenous dose of 90 mg), the drug and its trimesters, it is important to bear in mind that the CNS
active metabolite, doxorubicinol, were detected. The peak is still developing and that treatment can have long-term
side effects on the child’s development. Long-term follow- the family physician, hematologist and/or oncologist,
up data on children born to mothers treated for leukemia obstetrician, social worker, psychologist, and in some cases
during pregnancy have been published.32 The children’s religious advisors, should be assembled whenever possible
psychological, physical, and neurological development were to optimize the physical and mental well-being of the
reported as normal. The grandchildren of exposed pregnant woman, her baby, and her family.
women were also followed up in the same study. Even
those children had normal neurological and psychological SUMMARY STATEMENTS AND
development. No congenital malformations were reported. RECOMMENDATIONS
One review included 111 children born to women treated
during pregnancy, who were followed for up to 19 years. All Summary Statements
the children had normal neurological development.86 1. As women are postponing child-bearing, more of
them are experiencing cancer in pregnancy. (II-2)
Another concern is the possibility of secondary malignancies 2. Chemotherapeutic agents used to combat cancer
in exposed children. Avilés and Neri followed 84 children to
cross the placenta and may adversely affect
a median age of 18 years: no secondary malignancies and no
embryogenesis by affecting cell division. (II-1)
fertility issues were reported.32 Yet, in a case of twin exposure
3. Exposure to such agents after the first trimester of
to cyclophosphamide, 1 infant developed 2 different cancers
pregnancy has not been associated with increased
(neuroblastoma and thyroid) over his lifetime.28
risk of malformations but is associated with
To date, there is no other large-scale follow-up. A recent increased risk of stillbirth, intrauterine growth
registry reported on well-being of infants born to treated restriction, and fetal toxicities. (II-2)
mothers, but the follow-up period is only a few years.20
Recommendations
Ongoing observation is underway to provide a full and
1. The health care provider should examine the
detailed report in the coming years.
patient’s risk of pregnancy and desire to prevent
At birth, the placenta should be examined for invasion pregnancy during chemotherapy. (I-A)
of malignant cells. Any infant with placental involvement 2. Decisions about the best course of management
should be considered high risk and subsequently monitored. in pregnancy, including timing of delivery, should
Cardonick et al. recommend follow-up every 6 months for balance maternal and fetal risks. Most authorities
at least 2 years, with a focus on the primary malignancy. concur that maternal health and well-being must
A physical examination, blood chemistry, and chest X-ray prevail. (I-A)
may also be of value.20 3. Women diagnosed with cancer in pregnancy should
be optimally managed by a multidisciplinary team
ETHICAL CONSIDERATIONS
that includes oncologists and/or hematologists
(depending on the malignancy), perinatologists,
When considering the treatment of cancer during family physicians, psychologists, social workers, and
pregnancy with chemotherapeutic agents, it is important spiritual advisors, if sought by the family. (I-A)
to balance maternal and fetal interests Decisions about
the management of cancer in pregnancy should be made REFERENCES
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ESMO Clinical practice guidelines for diagnosis, treatment and follow-up. recommendations from the Canadian Task Force on Preventive Health
Ann Oncol 2010;21(5):v266–v273. Care. CMAJ 2003;169:207–8.
Anne Roggensack, MD, Calgary AB 02. Detailed evaluation of risk factors should be undertaken in
women following a mid-trimester pregnancy loss or early
Frank Sanderson, MD, Saint John NB premature delivery, or in cases where such complications have
Vyta Senikas, MD, Ottawa ON occurred in a preceding pregnancy. (III-B)
Disclosure statements have been received from all contributors. 03. In women with a history of cervical insufficiency, urinalysis for
culture and sensitivity and vaginal cultures for bacterial vaginosis
The literature searches and bibliographic support for this should be taken at the first obstetric visit and any infections so
guideline were undertaken by Becky Skidmore, Medical found should be treated. (I-A)
Research analyst, Society of Obstetricians and Gynaecologists
of Canada. 04. Women with a history of three or more second-trimester
pregnancy losses or extreme premature deliveries, in whom
no specific cause other than potential cervical insufficiency is
identified, should be offered elective cerclage at 12 to 14 weeks
Key words: Cervical insufficiency, cervical incompetence, cervical of gestation. (I-A)
cerclage, preterm delivery, prematurity, Shirodkar cerclage,
MacDonald cerclage, abdominal cerclage, rescue cerclage,
cervical shortening, trans-vaginal ultrasound, cervical length
J Obstet Gynaecol Can 2013;35(12):1115–1127
This document reflects emerging clinical and scientific advances on the date issued and is subject to change. The information
should not be construed as dictating an exclusive course of treatment or procedure to be followed. Local institutions can dictate
amendments to these opinions. They should be well documented if modified at the local level. None of these contents may be
reproduced in any form without prior written permission of the SOGC.
Key to evidence statements and grading of recommendations, using the ranking of the Canadian Task Force on
Preventive Health Care
Quality of evidence assessment* Classification of recommendations†
I: Evidence obtained from at least one properly randomized A. There is good evidence to recommend the clinical preventive action
controlled trial
II-1: Evidence from well-designed controlled trials without B. There is fair evidence to recommend the clinical preventive action
randomization
II-2: Evidence from well-designed cohort (prospective or C. The existing evidence is conflicting and does not allow to make a
retrospective) or case–control studies, preferably from recommendation for or against use of the clinical preventive action;
more than one centre or research group however, other factors may influence decision-making
II-3: Evidence obtained from comparisons between times or D. There is fair evidence to recommend against the clinical preventive action
places with or without the intervention. Dramatic results in
uncontrolled experiments (such as the results of treatment with E. There is good evidence to recommend against the clinical preventive
penicillin in the 1940s) could also be included in this category action
III: Opinions of respected authorities, based on clinical experience, L. There is insufficient evidence (in quantity or quality) to make
descriptive studies, or reports of expert committees a recommendation; however, other factors may influence
decision-making
*The quality of evidence reported in these guidelines has been adapted from The Evaluation of Evidence criteria described in the Canadian Task Force on
Preventive Health Care.156
†Recommendations included in these guidelines have been adapted from the Classification of Recommendations criteria described in the Canadian Task Force
on Preventive Health Care.156
05. In women with a classic history of cervical insufficiency in role of cervical cerclage and indications for it remain ill-
whom prior vaginal cervical cerclage has been unsuccessful,
abdominal cerclage can be considered in the absence of
defined and controversial, with wide practice variations in
additional mitigating factors. (II-3C) different clinical settings. In part, the lack of clarity that
06. Women who have undergone trachelectomy should have surrounds cerclage is fostered by uncertainty in identifying
abdominal cerclage placement. (II-3C) those patients who will truly benefit from its use (i.e., those
07. Emergency cerclage may be considered in women in whom with true cervical insufficiency or truly increased risk of
the cervix has dilated to < 4 cm without contractions before early preterm delivery).1,2
24 weeks of gestation. (II-3C)
08. Women in whom cerclage is not considered or justified, but Cervical insufficiency has no consistent definition, but is
whose history suggests a risk for cervical insufficiency (1 or usually characterized by dilatation and shortening of the
2 prior mid-trimester losses or extreme premature deliveries),
should be offered serial cervical length assessment by
cervix before the 37th week of gestation in the absence
ultrasound. (II-2B) of preterm labour, and is most classically associated with
0 9. Cerclage should be considered in singleton pregnancies in painless, progressive dilatation of the uterine cervix in
women with a history of spontaneous preterm birth or possible the second or early third trimester resulting in membrane
cervical insufficiency if the cervical length is ≤ 25 mm before prolapse, premature rupture of the membranes, mid-
24 weeks of gestation. (I-A)
trimester pregnancy loss, or preterm birth.3,4 Cervical
10. There is no benefit to cerclage in a woman with an incidental
insufficiency arises from the woman’s inability to support a
finding of a short cervix by ultrasound examination but no prior
risk factors for preterm birth. (II-1D) full-term pregnancy due to a functional or structural defect
11. Present data do not support the use of elective cerclage in of the cervix.1
multiple gestations even when there is a history of preterm birth;
therefore, this should be avoided. (I-D) The incidence of true cervical insufficiency is estimated
12. The literature does not support the insertion of cerclage in at less than 1% of the obstetric population. In Denmark
multiple gestations on the basis of cervical length. (II-1D) from 1980 to 1990, cervical insufficiency was diagnosed in
4.6 per 1000 women,2 and it is estimated to occur in 8% of
INTRODUCTION women with recurrent mid-trimester losses.5 A variety of
risk factors have been identified and are divided here into
C ervical insufficiency may be present in up to 1% of
obstetric populations, and it therefore represents a
concern frequently enough that a guideline to address the
those that may be identified from prior maternal history
and those that may arise in the index pregnancy itself.
dilemmas in its management is overdue. Despite having The classic history that raises the suspicion of cervical
been part of obstetric practice for over a century, both the insufficiency is that of recurrent mid-trimester
pregnancy losses. A previous preterm pre-labour force required to withdraw an inflated Foley catheter
rupture of membranes at less than 32 weeks should be through the internal os, the force required to stretch the
noted, as should a prior pregnancy with a cervical length cervix using an intracervical balloon) none of these meet
measurement of less than 25 mm prior to 27 weeks the criteria required for a diagnostic test.17–21 Part of the
of gestation.6 Any history of prior cervical trauma diagnosis is based upon the exclusion of other causes
(e.g. repeated therapeutic abortion, repetitive cervical of preterm delivery or mid-trimester pregnancy loss. In
dilatation, cone biopsy, cervical tears and lacerations, recent practice, transvaginal ultrasonography has been
trachelectomy) should also be noted. A risk factor increasingly used as a demonstrably valid and reproducible
reducing in incidence is that of the mother herself having method of cervical assessment, and cervical shortening
been exposed to diethylstilbestrol in utero. 6 A variety correlates with the risk of preterm delivery.12,22–25
of other maternal risk factors include the presence of
a congenital uterine anomaly or a maternal connective Without a reliable diagnostic test, it becomes necessary
tissue disease or abnormalities, e.g. Ehlers-Danlos to screen for or to predict the likelihood of cervical
syndrome,7 that impacts upon the integrity of normal insufficiency. This process is based upon the identification
collagen development and function. Recently, polycystic and recognition of key risk factors in the woman’s history
ovarian syndrome has been suggested as a risk factor and in the index pregnancy.
for cervical insufficiency, especially in women of South The most common factors in the patient history that
Asian or Black origin.8 In many cases, especially when indicate she may be at risk are a prior second trimester
clinical features and findings lead to suspicion of the pregnancy loss or a prior preterm birth. It should be noted,
diagnosis in the first pregnancy, these risk factors may however, that although in some situations there may be
not be present and the cause may remain idiopathic.9–12 a continuum between cervical insufficiency and preterm
In the index pregnancy, findings indicative of possible cervical labour and delivery, in others these are distinct and
insufficiency include cervical funnelling, cervical shortening,12 unrelated processes. A history of preterm labour or the
and overt cervical dilatation.13 Even in the absence of identification of factors that increase the risk for preterm
funnelling, a cervical length determined by ultrasound to be birth do not always necessarily indicate risk for cervical
< 25 mm prior to 27 weeks10,11 increases the risk of pregnancy insufficiency.26,27
loss or preterm birth. A history of prior cervical surgery, e.g. loop electrosurgical
Up to 85% of the cervix’s dry weight is collagen. Petersen and excision procedure (LEEP), may also present a risk for
Uldbjerg examined cervical collagen in non-pregnant women cervical insufficiency. In such patients there may also be a
with previous cervical insufficiency and found that they had role for cervical length assessment by ultrasound. In patients
markedly lower median cervical hydroxyproline concentrations who have had a prior LEEP, a 30 mm cervical length has
than parous women without cervical insufficiency.14 The a positive predictive value for preterm birth of 54%, but
causes of this have yet to be ascertained, but this seems to a negative predictive value of 95%.23 However, because of
be a key factor in understanding the mechanism of cervical the low overall frequency of cervical insufficiency even in
failure in such cases. this group, some data do not support the routine use of
mid-trimester ultrasound in such women.23 Other forms
In addition to its mechanical strength, the cervix may of cervical trauma, for example cervical tears, may also be
also play a role in protecting the uterine contents from significant.28
ascending infection,4,15 with one key factor in this being
the role of the cervical mucous as a barrier between the Less frequent in current practice is the identification of
uterus and ascending infection. Data suggest that 80% of women who were exposed to diethylstilboestrol when in
cases of acute cervical insufficiency may be associated with utero themselves.29–31
intra-amniotic infection.16 The key finding in the current pregnancy is the
identification of cervical shortening. Cervical length
DIAGNOSIS OF CERVICAL INSUFFICIENCY assessment by ultrasound is an established means of
assessing the risk for preterm labour and delivery (cervical
There is no diagnostic test for cervical insufficiency. length < 25 mm).11,12,22,25,32,33
Although many tests have been reported or are
used (assessment of the cervical canal width by Patients may also be found to have cervical dilatation rather
hysterosalpingogram, assessment of the ease of insertion than just shortening, or they may present with preterm
of cervical dilators [size 9 Hegar] without resistance, the membrane rupture. Identification of cervical dilatation in
the absence of a maternal history of contractions, with Data from the UK MRC/RCOG RCT36 did not
or without membrane rupture, is considered tantamount demonstrate the benefit of cerclage after 1 or 2 prior
to a diagnosis of cervical insufficiency. Models based on deliveries preceding 33 weeks’ gestation; however, the
the recognition of these two main risk factors (cervical numbers were small and this might have had an impact
shortening and cervical dilatation) have been described on the observed effect, particularly in the case of mid-
and may be of value in determining which patients are trimester losses as opposed to premature deliveries. The
at greatest risk, but further assessment of such screening benefit of cerclage after 2 or 3 mid-trimester losses alone,
tools is required.34 as opposed to losses and deliveries up to and including
33 weeks, is undefined. The findings of this UK study
Recommendations
might be influenced by the inclusion of cases in which
1. Women who are pregnant or planning pregnancy the treating obstetrician was unsure that the cerclage
should be evaluated for risk factors for cervical would be of benefit. However, other smaller studies
insufficiency. A thorough medical history at initial also failed to demonstrate the benefit of cerclage.37,38 A
evaluation may alert clinicians to risk factors in a first recent Cochrane review analyzed data from 12 studies
or index pregnancy. (III-B) of women considered at sufficient risk to justify cerclage
2. Detailed evaluation of risk factors should be who were randomized to cerclage, alternative treatments
undertaken in women following a mid-trimester (e.g., progesterone), or no treatment. This analysis
pregnancy loss or early premature delivery, or in presents somewhat conflicting findings in reporting that
cases where such complications have occurred in a cerclage has a statistically significant effect on reducing
preceding pregnancy. (III-B) gestational age at delivery and no significant impact on
perinatal morbidity and mortality, but it is associated with
MANAGEMENT OF CERVICAL INSUFFICIENCY increased maternal morbidity and Caesarean section rates
(the latter perhaps also accounting for a non-significant
The management of cervical insufficiency can be viewed increase in respiratory morbidity amongst infants born to
as falling broadly into two main types: those in which it is women with a cerclage).39
clear that surgical intervention in the form of cerclage is
indicated, and those in which a conservative path will be A prophylactic cerclage is normally placed between 12 and
pursued. 14 weeks’ gestation. Although placement can be delayed,
the gestational age of prior pregnancy losses should be
Indications for the insertion of a cerclage may arise from taken into account, particularly in women whose losses
the clinical history or the finding of cervical shortening present at progressively earlier gestations.
and/or dilatation in the index pregnancy, and therefore may
be divided into prophylactic cerclage versus therapeutic Prerequisites for prophylactic cerclage placement
cerclage. Alternatives to cerclage include the cervical Prior to placement of a cerclage it is essential to confirm the
pessary; some data suggest this may be of benefit in some viability of the pregnancy by ultrasound. It is wise therefore,
cases, but these data are sparse and conflicting. Further at the same time to exclude significant malformations
investigation of such techniques is required before they can and determine whether there is a significantly elevated
be considered as part of a guideline for the management aneuploidy risk by first trimester ultrasound nuchal
of cervical insufficiency.35 translucency screening, if possible combined with serum
marker screening. In cases found to be at elevated risk
Prophylactic Transvaginal Cerclage for aneuploidy or with fetal malformations, placement
Consider elective cerclage if there appears to be a high risk may be delayed until after karyotype results are obtained
of cervical insufficiency based on the woman’s obstetric (using chorionic villus sampling for earlier karyotype
history. The level of risk is typically determined by determination than amniocentesis, where available) or until
identifying and assessing the significance of the risk factors a more detailed ultrasound assessment is performed.
described in the “Diagnosis of Cervical Insufficiency”
section. Most frequently the assessment of risk will be Before admission for cerclage, urinalysis for culture and
founded upon a history of second-trimester pregnancy sensitivity and vaginal cultures for bacterial vaginosis should
losses or early preterm deliveries in the absence of other be taken and any infections found should be treated.16,40–46
mitigating risk factors.36–38 Therefore a detailed evaluation Microbial invasion of the amniotic cavity has been reported
of risk factors should be undertaken in women presenting to occur in around 50% of women with cervical insufficiency
with a history of a mid-trimester pregnancy loss or early and exposed fetal membranes.45,47 Amniocentesis has therefore
premature delivery. been suggested for evaluating and treating such colonization
prior to cerclage placement; however, no clear benefit in cerclage in place are limited. The use of progesterone
prolonging pregnancy has been shown for amniocentesis over with cerclage is not new, but despite more recent data
cerclage alone, and therefore its routine use is not advised.48 for the use of progesterone therapy in women at risk of
preterm delivery, overall data do not presently support
Cerclage techniques and materials this approach. Although one early study implied a benefit
The two main techniques of transvaginal cerclage involve to progesterone, it was an uncontrolled cohort study,69
the MacDonald approach and the Shirodkar approach. In and a contemporaneous controlled cohort evaluation
the McDonald approach the suture is inserted as close as demonstrated a reduction in hospital admission, but not
possible to the junction of the cervix with the vagina, with no in the rate of pregnancy loss.70 A more recent study of
dissection of tissue planes.49 In the Shirodkar approach a sub- 17-alpha-hydroxyprogesterone caproate in women with
epithelial suture is inserted above the junction of the cervix cerclage essentially demonstrated no advantage, although
with the vagina with dissection of the bladder and rectum; this study was retrospective and the criteria for cerclage
this allows for higher placement (closer to the internal cervical placement were ill-defined.71 Two further studies also
os) of the suture than the McDonald approach.50 indicated that 17-alpha-hydroxyprogesterone caproate
injections do not provide additional benefit for the
There are no data to indicate an advantage of one
prevention of preterm birth in women who received an
technique over another, so the choice between a McDonald
ultrasound-indicated cerclage.72,73
approach or modification thereof or a Shirodkar approach
or modification thereof should be left to the discretion There are no specific data comparing the efficacy of systemic
and skills of the surgeon.51–55 Both techniques, influenced and vaginal progesterones in women with a cerclage in place.
by patient selection, are associated with an increased
Caesarean section rate, which is perhaps marginally higher Complications
following the Shirodkar approach, although this data has Three randomized clinical trials have shown that cerclage
not been replicated.56 is associated with increased medical interventions and
doubles the risk of puerperal pyrexia.36–38 The use of
Two forms of double cerclage are also described. The first tocolytics increases with cerclage, as does the rate of
simply involves the insertion of two cervical cerclages in hospital admissions, and one study found a higher rate
an attempt to buttress the cervix more strongly. This has of Caesarean sections.37 However, the risk and nature of
been shown to be of no benefit.57 In the second double complications is influenced by whether the cerclage is
cerclage, a second occlusive suture is placed at the external inserted electively or as an emergency with membranes
os to retain the mucous plug and help the cervix maintain bulging through the cervix. The complications reported
itself as a barrier to infection. Only limited data regarding with cerclage include sepsis, premature rupture of
this are available at present.58 membranes, premature labour, cervical dystocia,
cervical laceration at delivery (11% to 14%),74–76,77 and
No data indicate any advantage or disadvantage of particular
hemorrhage.
suture materials. The most frequently used is a braided
Mersilene tape, although some surgeons use Prolene. However, meta-analysis of a number of studies has not
Meshes are also reportedly used, but no comparisons have confirmed higher rates of chorioamnionitis or preterm
been made with existing techniques.59,60 There are data pre-labour membrane rupture in women managed with
indicating that delayed absorbable suture materials may cerclage than in those managed by other means.78 Although
also be used, but the benefits or disadvantages of different cervical dystocia is frequently cited as a complication of
materials still require greater evaluation.61 cerclage due to cervical scarring,79 data do not support
its being truly attributable to cerclage80; the increased risk
Unless it is contraindicated, regional anaesthesia is usually
of cervical laceration, however, although it appears to be
preferred to general anaesthesia in light of its lesser
unrelated to the timing of the removal of the cerclage, can
associated risks.62,63
be attributed to the cerclage.74–76,81
It should be noted that for prophylactic cerclage, no
Recommendations
randomized trials have presented findings free of
confounding variables to support the routine use of 3. In women with a history of cervical insufficiency,
tocolytics,64,65 corticosteroids, or antibiotics,66–68 although urinalysis for culture and sensitivity and vaginal
for cerclages placed in gestations close to fetal viability, cultures for bacterial vaginosis should be taken at
corticosteroid usage should be considered. Similarly, the first obstetric visit and any infections so found
data on the use of progesterone in women who have a should be treated. (I-A)
4. Women with a history of three or more second additional mitigating factors.96–100 This should also be
trimester pregnancy losses or extreme premature considered for women who have undergone trachelectomy
deliveries, in whom no specific cause other than or who have had an effective trachelectomy.101,102 The
potential cervical insufficiency is identified, should placement of an abdominal suture may be undertaken by
be offered elective cerclage at 12 to 14 weeks of either laparoscopic or open surgical techniques. The former
gestation. (I-A) is generally preferred in current practice,103,104 although both
techniques are associated with higher maternal morbidity
Cerclage follow-up than a transvaginal cerclage approach. Abdominal cerclage
Lengthening of the cervix following cerclage has been should be undertaken by a surgeon experienced in the
observed, and the immediate assessment of the cervix placement of such sutures. A prophylactic abdominal
following suture placement may correlate with gestational cerclage is often inserted at the same time as a trachelectomy
age at delivery82–84; however, the data are inconsistent on is performed in women of reproductive age who plan to
the efficacy of continued cervical length assessment post pursue the option of childbirth.105
cerclage in determining when delivery might occur.85,86
This is somewhat supported by the inconsistency in Recommendations
studies evaluating whether the placement of a second 5. In women with a classic history of cervical
suture is beneficial in women whose cervix is found to insufficiency in whom prior vaginal cerclage has
shorten further post cerclage placement, with two studies been unsuccessful, abdominal cerclage can be
demonstrating contradictory effects of such a measure.87,88 considered in the absence of additional mitigating
Therefore at present routine post-cerclage follow-up by factors. (II-3C)
ultrasound is not recommended. The positive predictive 6. Women who have undergone trachelectomy should
value of fibronectin as a predictor of preterm delivery have abdominal cerclage placement. (II-3C)
appears to be adversely affected by a cerclage, although the
Emergency Cerclage
negative predictive value is not.89
An emergency (or salvage or rescue) cerclage is typically one
Removal of cerclage placed in a woman whose cervix is already dilated. Emergency
The cerclage is generally removed electively at 36 to 38 should be considered when there is clinical or sonographic
weeks’ gestation. Removal can usually be performed identification of a cervix dilated > 1 to 2 cm with no
without anaesthesia or with only short-acting narcotics, perceived uterine contractions (with or without membranes
such as Fentanyl administered intravenously. The onset of bulging through the external os).106,107 It is important to note
premature labour unresponsive to tocolysis and or a strong that there must be no clinical evidence of chorioamnionitis.
suspicion of sepsis are indications for emergency removal Although some groups advocate amniocentesis prior to
of the cerclage. emergency cerclage in order to both exclude infection and
aid in reducing intrauterine pressure, no randomized studies
A number of studies have addressed the question of confirm the effect of this approach.108,109
cerclage removal with premature membrane rupture and
no associated contractions. Meta-analysis has shown an A small randomized clinical trial has shown prolongation
increased neonatal mortality rate with delayed removal, of pregnancies by 4 weeks with emergency cerclage
with sepsis the principal cause; therefore a policy of placement,110 and other observational studies have reported
removal within 48 hours (allowing time for corticosteroid pregnancy prolongation of between 6 and 9 weeks with
administration if appropriate) is advocated.90–93 C-reactive emergency cerclage placement compared with under 4
protein estimation may be used as a predictor of weeks with conservative management (bed rest).111–114
chorioamnionitis following preterm membrane rupture Scoring systems have been considered to evaluate which
and may therefore aid the decision between immediate cases will benefit from emergency cerclage (based on cervical
or delayed (< 48 hours) suture removal.94,95 Incidentally, it effacement, dilatation, and membrane prolapse).115,116 The
should be noted that clear documentation of the cerclage benefit of cerclage even with cervical dilatation to 4 cm
placement, specifically knot placement and number, will has been shown and should be considered, and the scoring
facilitate the removal of the cerclage prior to delivery. systems can be used to counsel patients about the likely
outcome of undergoing emergency cerclage.
Prophylactic Transabdominal Cerclage
In women with a good history of cervical insufficiency Adjunctive measures
in whom prior vaginal cerclage has been unsuccessful, The administration of a course of indomethacin prior to
abdominal cerclage can be considered in the absence of cerclage placement might reduce protruding membranes
through its effect on reducing fetal urine production history is not considered to indicate enough risk to
(thereby reducing intrauterine pressure) and through its warrant immediate prophylactic cerclage.132 In such
tocolytic value.110 Bed rest with or without Trendelenburg women, ultrasound cervical length assessment will
may further help to reduce bulging membranes and identify a cohort who is at increased risk of a further
facilitate suture placement, as may using a Foley balloon pregnancy loss or preterm delivery, some of whom
inserted into the cervix and then inflated to mechanically may then benefit from the subsequent placement of a
reduce the membranes.117 Broad-spectrum antibiotic cerclage. Conservative management should be based on
coverage is usually prescribed, although there are no data and include the following steps:
to support this.
1. Urine for culture and sensitivity and vaginal cultures
Amniocentesis may have a greater role to play in emergency for bacterial vaginosis40–42 should be taken at the first
cerclage than in prophylactic cerclage. The first potential obstetric visit, and any infections found should be
benefit of amniocentesis in emergency cases is in identifying treated.16,40–46
those women who may not benefit from cerclage, based 2. Serial transvaginal ultrasonography should be
upon evidence of infection109 or on a more complex performed every 7 to 14 days from 16 weeks of
evaluation of proteonomic markers that investigates gestation or at least 2 weeks prior to the gestational age
infection as well as other factors believed to affect the of the earliest preceding pregnancy loss.133
efficacy of cerclage.109,118 Its second benefit is in removing
a larger volume of amniotic fluid (cf. amniodrainage), 3. Consider advising the patient to reduce physical
permitting bulging membranes to withdraw into the cervix activity, especially those with physical employment,
by reducing intrauterine pressure and thereby facilitating prolonged periods of standing, or frequent and
cerclage placement.119–121 repetitive lifting, although there are no data to
confirm or deny the efficacy of bed rest in such
Cerclage removal cases.134
The criteria for removal of an emergency cerclage are the 4. Strongly encourage the cessation of smoking with
same as for a prophylactic cerclage. referral to support programs.
Recommendation 5. Beyond 23 weeks consider the prophylactic
7. Emergency cerclage may be considered in women use of corticosteroids if there are signs or
in whom the cervix has dilated to < 4 cm without symptoms suggestive of an increased risk of
contractions before 24 weeks of gestation. (II-3C) preterm delivery.
Cervical Pessary
Ultrasound assessment of cervical length
The use of pessaries in the management of cervical Ultrasound has been shown reliably and reproducibly to
insufficiency or preterm delivery is not new, with the use allow estimation of cervical length. The length of the cervix
of a glass pessary having first been described in 1977.122 as measured by ultrasound has in turn been demonstrated
Since then various designs and materials have been used to be a useful tool in the prediction of the risk of preterm
and reported.123–129 Although many of these reports and delivery.12,25,33,135 Transvaginal ultrasonography is the gold
reviews showed promise, a Cochrane review found no standard technique of assessment, but if this cannot
studies suitable for inclusion in an analysis of the benefits be performed then an assessment may be made either
of this technique.35 Since then a number of studies have abdominally or transperineally.136
been undertaken, some of which are still in progress. Two
recent studies have again suggested a benefit of cervical Assessment of the cervix typically reports the cervical
pessaries in the management of cervical insufficiency, length and identifies any evidence of cervical funnelling.
preterm delivery, or short cervix.130,131 However, to date the Although funnelling is typically reported when the cervix
data supporting such techniques in the routine management is assessed, it should be noted that data do not support
of cervical insufficiency remain insufficient. the placement of a cerclage on the basis of funnelling, but
rather on residual cervical length.12 Transfundal pressure
CONSERVATIVE OBSERVATIONAL MANAGEMENT created by applying fundal pressure in the direction of
the uterine axis for 15 seconds is more effective than
A conservative strategy including cervical length assess coughing or standing in eliciting cervical changes and signs
ment may be adopted in the management of women of progressive second trimester cervical shortening during
considered to have cervical insufficiency, but whose active assessment of the cervix.137–139
Flow diagram
Consider abdominal
suture if previous If no chorioamnionitis If contracting manage
Vaginal cerclage Expectant or contractions as threatened preterm
vaginal cerclage management
unsuccessful or if consider emergency labour
inadequate cervical Serial cervical length cerclage Consider tocolysis and
tissue to place assessment Consider steroids steroids depending on
cerclage depending on the gestational age
gestational age
indicated in many of the cases included.148 However, a study 2. Lidegaard O. Cervical incompetence and cerclage in Denmark 1980-1990.
A register based epidemiological survey. Acta Obstet Gynecol Scand
evaluating the effects of progesterone on cervical length in 1994;73:35–8.
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pregnancy loss in women. Cochrane Database Syst Rev. 2003:CD003253.
is not recommended and further evaluation is needed. Further
information regarding the use of progesterones to prevent 6. Althuisius SM, Dekker GA, Hummel P, Bekedam DJ, van Geijn HP. Final
results of the Cervical Incompetence Prevention Randomized Cerclage
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1999;14:244–7.
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sonographic short cervix in the midtrimester decreases preterm delivery Task Force on Preventive Health Care. New grades for recommendations
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patient data. Am J Obstet Gynecol 2012;206:124 e1–e19. 2003;169:207–8.
This clinical practice guideline has been prepared by the Erin Nelson, LLB, LLM, Edmonton AB
Social Sexual Issues Committee and the Ethics Committee,
Marianne Pierce, MD, Halifax NS
and reviewed by the Clinical Practice Gynaecology
Committee, the Canadian Paediatric and Adolescent Deborah Robertson, MD, Toronto ON
Gynaecology and Obstetricians Committee, and the Family Anne Simmonds, RN, PhD, Scotsburn NS
Physicians Advisory Committee, and approved by the
Executive and Council of the Society of Obstetricians and Disclosure statements have been received from all members of
Gynaecologists of Canada. the committees.
The literature searches and bibliographic support for this
PRINCIPAL AUTHORS guideline were undertaken by Becky Skidmore, Medical
Liette Perron, MSW, Ottawa ON Research Analyst, Society of Obstetricians and Gynaecologists
of Canada.
Vyta Senikas, MD, Ottawa ON
Margaret Burnett, MD, Winnipeg MB
Victoria Davis, MD, Scarborough ON Abstract
SOCIAL SEXUAL ISSUES COMMITTEE Objective: To strengthen the national framework for care of
Margaret Burnett, MD (Chair), Winnipeg MB adolescents and women affected by female genital cutting
(FGC) in Canada by providing health care professionals with:
Anjali Aggarwal, MD, Toronto ON (1) information intended to strengthen their knowledge and
Jeanne Bernardin, MD, Moncton NB understanding of the practice; (2) directions with regard to the
legal issues related to the practice; (3) clinical guidelines for the
Virginia Clark, MD, Golden BC
management of obstetric and gynaecological care, including
Victoria Davis, MD, Scarborough ON FGC related complications; and (4) guidance on the provision of
culturally competent care to adolescents and women with FGC.
William Fisher, BA, MS, PhD, London ON
Evidence: Published literature was retrieved through searches of
Rosana Pellizzari, MD, Peterborough ON
PubMed, CINAHL, and The Cochrane Library in September
Viola Polomeno, RN, PhD, Ottawa ON 2010 using appropriate controlled vocabulary (e.g.,
Maegan Rutherford, MD, Halifax NS Circumcision, Female) and keywords (e.g., female genital
mutilation, clitoridectomy, infibulation). We also searched Social
Jeanelle Sabourin, MD, Edmonton AB Science Abstracts, Sociological Abstracts, Gender Studies
Database, and ProQuest Dissertations and Theses in 2010 and
ETHICS COMMITTEE 2011. There were no date or language restrictions. Searches
Jodi Shapiro, MD (Chair), Toronto ON were updated on a regular basis and incorporated in the
guideline to December 2011. Grey (unpublished) literature was
Saima Akhtar, MD, London ON identified through searching the websites of health technology
Bruno Camire, MD, Quebec QC assessment and health technology-related agencies, clinical
practice guideline collections, clinical trial registries, and national
Jan Christilaw, MD, Vancouver BC
and international medical specialty societies.
Julie Corey, RM, St Jacobs ON
Values: The quality of evidence in this document was rated using
the criteria described in the Report of the Canadian Task Force
on Preventive Health Care (Table 1).
Key words: Female genital cutting, female genital mutilation,
female circumcision, pregnancy, gynecological care, adolescents,
Canada.
J Obstet Gynaecol Can 2013;35(11):e1–e18
This document reflects emerging clinical and scientific advances on the date issued and is subject to change. The information
should not be construed as dictating an exclusive course of treatment or procedure to be followed. Local institutions can dictate
amendments to these opinions. They should be well documented if modified at the local level. None of these contents may be
reproduced in any form without prior written permission of the SOGC.
Table 1. Key to evidence statements and grading of recommendations, using the ranking of the Canadian Task Force
on Preventive Health Care
Quality of evidence assessment* Classification of recommendations†
I: Evidence obtained from at least one properly randomized A. There is good evidence to recommend the clinical preventive action
controlled trial
II-1: Evidence from well-designed controlled trials without B. There is fair evidence to recommend the clinical preventive action
randomization
II-2: Evidence from well-designed cohort (prospective or C. The existing evidence is conflicting and does not allow to make a
retrospective) or case–control studies, preferably from recommendation for or against use of the clinical preventive action;
more than one centre or research group however, other factors may influence decision-making
II-3: Evidence obtained from comparisons between times or D. There is fair evidence to recommend against the clinical preventive action
places with or without the intervention. Dramatic results in
uncontrolled experiments (such as the results of treatment with E. There is good evidence to recommend against the clinical preventive
penicillin in the 1940s) could also be included in this category action
III: Opinions of respected authorities, based on clinical experience, L. There is insufficient evidence (in quantity or quality) to make
descriptive studies, or reports of expert committees a recommendation; however, other factors may influence
decision-making
*The quality of evidence reported in these guidelines has been adapted from The Evaluation of Evidence criteria described in the Canadian Task Force on
Preventive Health Care.59
†Recommendations included in these guidelines have been adapted from the Classification of Recommendations criteria described in the Canadian Task Force
on Preventive Health Care.59
Summary Statements 08. There is a perception that the care of women with female genital
cutting is not optimal in receiving countries. (III)
01. Female genital cutting is internationally recognized as a harmful
practice and a violation of girls’ and women’s rights to life, 09. Female genital cutting is not considered an indication for
physical integrity, and health. (II-3) Caesarean section. (III)
02. The immediate and long-term health risks and complications of
Recommendations
female genital cutting can be serious and life threatening. (II-3)
01. Health care professionals must be careful not to stigmatize
03. Female genital cutting continues to be practised in many
women who have undergone female genital cutting. (III-A)
countries, particularly in sub-Saharan Africa, Egypt, and
Sudan. (II-3) 02. Requests for re-infibulation should be declined. (III-B)
04. Global migration patterns have brought female genital cutting to 03. Health care professionals should strengthen their understanding
Europe, Australia, New Zealand, and North America, including and knowledge of female genital cutting and develop greater
Canada. (II-3) skills for the management of its complications and the provision
of culturally competent care to adolescents and women who
05. Performing or assisting in female genital cutting is a criminal
have undergone genital cutting. (III-A)
offense in Canada. (III)
04. Health care professionals should use their knowledge and
06. Reporting to appropriate child welfare protection services
influence to educate and counsel families against having female
is mandatory when a child has recently been subjected to
genital cutting performed on their daughters and other family
female genital cutting or is at risk of being subjected to the
members. (III-A)
procedure. (III)
05. Health care professionals should advocate for the availability of
07. There is concern that female genital cutting continues to be
and access to appropriate support and counselling services. (III-A)
perpetuated in receiving countries, mainly through the act of
re-infibulation. (III) 06. Health care professionals should lend their voices to community-
based initiatives seeking to promote the elimination of female
genital cutting. (III-A)
07. Health care professionals should use interactions with patients
ABBREVIATIONS as opportunities to educate women and their families about
female genital cutting and other aspects of women’s health and
BMA British Medical Association
reproductive rights. (III-A)
FGC female genital cutting
08. Research into female genital cutting should be undertaken to
FGM female genital mutilation explore women’s perceptions and experiences of accessing
FIWG Federal Interdepartmental Working Group (on Female sexual and reproductive health care in Canada. (III-A) The
Genital Mutilation) perspectives, knowledge, and clinical practice of health care
professionals with respect to female genital cutting should also
HIV human immunodeficiency virus
be studied. (III-A).
IUD intrauterine device
09. Information and guidance on female genital cutting should
SERC Sexuality Education Resource Centre (Manitoba) be integrated into the curricula for nursing students, medical
students, residents, midwifery students, and students of other of the communities that practice FGC. In French, FGC is
health care professions. (III-A)
often referred to as “excision”—a general term covering all
10. Key practices in providing optimal care to women with female types of the practice. The term “female genital cutting” was
genital cutting include:
chosen for this document because it is considered medically
a. determining how the woman refers to the practice of
female genital cutting and using this terminology throughout
correct, neutral, and culturally sensitive. When reference
care; (III-C) material or direct quotations from other authors are used,
b. determining the female genital cutting status of the their original terminology is retained.
woman and clearly documenting this information in her
medical file; (III-C) Definition of Female Genital Cutting
c. ensuring the availability of a well-trained, trusted, and neutral WHO defines female genital mutilation as “all procedures
interpreter who can ensure confidentiality and who will not involving partial or total removal of the external female
exert undue influence on the patient–physician interaction
when providing care to a woman who faces language
genitalia or injury to the female genital organs for non-
challenges; (III-C) medical reasons.”1 Genital tattooing, piercing, hair removal,
d. ensuring the proper documentation of the woman’s medical and labiaplasty could technically be included in the WHO
history in her file to minimize the need for repeated medical definition of Type IV FGM, but for the purpose of this
histories and/or examinations and to facilitate the sharing of document, we define FGC as WHO Types I, II, and III.
information; (III-C)
e. providing the woman with appropriate and well-timed Glossary
information, including information about her reproductive Cultural competence: “A set of congruent behaviors,
system and her sexual and reproductive health; (III-C)
attitudes, and policies that come together in a system,
f. ensuring the woman’s privacy and confidentiality by limiting
attendants in the room to those who are part of the health
agency, or among professionals that enables the system
care team; (III-C) or professionals to work effectively in cross-cultural
g. providing woman-centred care focused on ensuring that situations.”2
the woman’s views and wishes are solicited and respected,
including a discussion of why some requests cannot be Defibulation: Incision of the vulva to open the vagina of
granted for legal or ethical reasons; (III-C) a woman who has undergone infibulation.
h. helping the woman to understand and navigate the
health system, including access to preventative care Infibulation: Excision of part of the external genitalia and
practices; (III-C) stitching of the vulvovaginal opening to partially cover the
i. using prenatal visits to prepare the woman and her family for vaginal opening.
delivery; (III-C)
j. when referring, ensuring that the services and/or practitioners Medicalization: The “situations in which FGM is
who will be receiving the referral can provide culturally practiced by any category of trained healthcare provider,
competent and sensitive care, paying special attention to
concerns related to confidentiality and privacy. (III-C)
whether in a public or a private clinic, at home or
elsewhere. It also includes the surgical procedure of re-
infibulation at any time in a woman’s life.” (WHO, 2010).3
Epub ahead of print.
This document will be published in: Re-infibulation: The re-suturing of the vulvar opening
J Obstet Gynaecol Can 2013;35(11) that has been opened with defibulation.
Classification
INTRODUCTION WHO classifies FGM procedures into 4 types
(Table 2).1 The types of procedure vary considerably
practices listed are legally accepted and not generally While there is no evidence that any type of FGC is practiced
considered FGM in many countries (e.g., genital cosmetic in Canada, there is concern that girls from practising
surgery, hymen repair, piercing). WHO recommends communities may still be at risk. In their exploratory study of
that in determining whether genital practices should be the perceptions of Somali women of their earlier experience
categorized as FGM, human rights principles should of FGC, Chalmers and Omer-Hashi13 found that only one
be applied, including the right of health, the rights of third of respondents supported the Canadian law prohibiting
children, and the right to non-discrimination on the basis the practice, while two thirds reported ambivalent feelings.
of sex.1 Furthermore, when asked “whether or not they would
(hypothetically) wish to have [their daughters] circumcised,”
Prevalence in Canada almost half said they would. In their study exploring FGC as
Although the magnitude of the practice of FGC in it relates to gender identity and the acculturation process in
Canada remains unknown, literature from as early as the Canada, Vissandjée et al. were unable to determine whether
1990s confirms that FGC has been found among certain these practices had been abandoned by new arrivals to Canada;
immigrant communities.5–11 Table 3 brings together two their findings suggested that “the need to maintain a status
sets of data: equal to that of the country of origin potentially increased
1. a list of countries in which FGC of Types I, II, III, the risk of the practices being performed [on girls].”11 Finally,
SERC Manitoba, in their work with immigrants affected
and IV has been documented as a traditional practice,1
by FGC, reported that women were split in their opinions
and
of the issue; although some women strongly supported
2. Canadian immigration data related to the number of discontinuation of the practice, others either supported it
permanent and temporary residents received in Canada or remained conflicted about what should be done about
from 2005 to 2009 from countries in which FGC has it.14 These findings are supported by a number of European
been documented.12 studies that show the practice is not necessarily abandoned
with migration and that girl children remain at risk.15–17
Although the Canadian immigration data should be
considered with caution, it provides insight into the Summary Statement
continual arrival in Canada of newcomers from countries 1. Female genital cutting is internationally recognized
where the practice is prevalent, including adolescents and as a harmful practice and a violation of girls’
women who may have undergone FGC and girls who may and women’s rights to life, physical integrity, and
be at risk. health. (II-3)
Table 3. Countries in which female genital mutilation of Types I, II, III, and IV has been
documented as a traditional practice, and number of permanent and temporary residents
(both sexes) received in Canada from those countries in the years 2005 to 2009
Estimated prevalence of
FGM in girls and women Residents received
15 to 49 years in Canada
Country Year* % (2005 to 2009)12
Benin 2001 16.8 815
Burkina Faso 2005 72.5 632
Cameroon 2004 1.4 3790
Central African 2005 25.7 88
Chad 2004 44.9 481
Cote d’Ivoire 2005 41.7 2766
Djibouti 2006 93.1 313
Egypt 2005 95.8 10 482
Eritrea 2002 88.7 2391
Ethiopia 2005 74.3 7126
Gambia 2005 78.3 178
Ghana 2005 3.8 4071
Guinea 2005 95.6 1643
Guinea-Bissau 2005 44.5 N/A
Kenya 2003 32.2 3389
Liberia† 45.0 424
Mali 2001 91.6 629
Mauritania 2001 71.3 272
Niger 2006 2.2 298
Nigeria 2003 19.0 11 259
Senegal 2005 28.2 1878
Sierra Leone 2005 94.0 406
Somalia 2005 97.9 4596
Sudan, Northern (approx. 80% of 2000 90.0 3752
total population in survey)
Togo 2005 5.8 701
Tanzania 2004 14.6 1115
Uganda 2006 0.6 1113
Yemen 1997 22.6 888
*Year of national data reports from which the data were derived.
†Estimate derived from a variety of local and sub-national studies.
Columns 1, 2, and 3 reproduced with permission of the World Health Organization. (WHO. Eliminating female genital mutilation:
an interagency statement. Geneva: WHO; 2008: p 29).
caused by FGC or other factors, their findings suggested 4. Global migration patterns have brought female
that Somali women represented a higher risk group in genital cutting to Europe, Australia, New Zealand,
obstetrics.20 Finally, Bragg,21 in reviewing the results of the and North America, including Canada. (II-3)
2003–2005 UK Confidential Enquiry into Maternal and
Children Health noted that maternal mortality was 6 times
higher in black African women than in white women in Recommendations
the United Kingdom. Among the new factors documented 1. Health care professionals must be careful not to
as potential contributing causes were unsatisfactory stigmatize women who have undergone female
arrangements for interpretation and lack of health care genital cutting. (III-A)
provider awareness of FGC. 2. Requests for re-infibulation should be declined. (III-B)
3. Health care professionals should strengthen
Little is known of how FGC affects the psychological their understanding and knowledge of female
well-being of girls and adolescents.22,23 Anecdotal evidence genital cutting and develop greater skills for the
suggests that the girls and/or adolescents’ concerns about management of its complications and the provision
the practice “are very much intertwined with other concerns of culturally competent care to adolescents and
common to all adolescents regarding sexuality, body image, women who have undergone genital cutting. (III-A)
attractiveness, identity, belonging and conforming with
peers.”22 Legal Issues Related to FGC in Canada
FGC is illegal in Canada and anyone who performs or
Traditional and Cultural Beliefs, Values,
assists with the practice can be criminally charged and
and Attitudes Upholding the Practice
convicted. The Criminal Code also makes it a crime for
The practice continues to be perpetuated due to an array of
parents or family members to take a girl out of Canada for
complex social, religious, and cultural reasons intrinsically
the purpose of having FGC/FGM performed elsewhere.
linked to traditional beliefs, values, and attitudes related
Appendix 1 provides the main sections of the Canadian
to women’s sexuality and the perceived need to control
Criminal Code that state that anyone who “wounds” or
their sexual and reproductive capacity.24 Parents submit
“maims” a female person by excision, infibulation, or
their daughters to FGC not as means of punishment or
mutilation of the labia or clitoris is committing aggravated
abuse, but as a way to protect them and give them “the
assault. Exceptions are made for surgery conducted for
best possible chance to have a future that will ensure
legitimate medical reasons.
[their] social acceptance and economic security.”25 FGC
is performed in order to prepare girls for adulthood and Although not explicitly mentioned in any Canadian provincial
marriage, to ensure their virginity until marriage, to ensure child welfare legislation, the Federal Interdepartmental
their fidelity in marriage, to make them clean, beautiful, Working Group on Female Genital Mutilation considered
and pure, and to maintain the family’s honour. In certain FGC “a form of child physical abuse and as such, any child
communities, it is seen as a rite of passage or an initiation suspected of being at risk of the practice would justify
into a secret women’s society; in others it is thought to intervention by child protection authorities.”8 Because FGC
increase fertility and to enhance the sexual pleasure of is a recognized violation of human rights, a child or woman
men. at risk for FGC has a legitimate claim for asylum.8
FGC is often performed by “older women who carry on Statements and Policies of
the tradition and make sure girls in their family undergo Provincial Medical Organizations in Canada
the practice.”15 Men play a role by remaining passive Appendix 2 provides information related to the position
and not intervening in matters related to the practice, by statements or directives issued by provincial medical
preferring to marry a woman who has undergone FGC, organizations that have addressed the subject of FGC.
or by insisting that it is performed on their daughters.11,15,26 These professional organizations have consistently
Summary Statements condemned the practice of FGC and make it clear that
a physician who engages in this practice is guilty of
2. The immediate and long-term health risks and
professional misconduct.
complications of female genital cutting can be
serious and life threatening. (II-3) Challenges in Responding to the Health
3. Female genital cutting continues to be practised in Needs of Women and Adolescents with FGC
many countries, particularly in sub-Saharan Africa, In a study exploring the birthing experience of Somali
Egypt, and Sudan. (II-3) women in Ontario, Chalmers and Omer-Hashi found
that although not all women had negative experiences circumcised women with extra care”, but also anger and
in accessing health care, many considered the care not hatred “towards tradition, religion, men and especially the
optimal, and further reported that “they were treated in husbands.”34 Significant gaps in both theoretical knowledge
ways that they perceived harsh and even offensive to [their] and practice related to FGC were found among health
cultural values.”13 Women’s reported concerns were mainly professionals in United Kingdom, Sweden, Spain, and the
with lack of services and care including assistance with United States.36–39
baby care, especially when they were in pain due to their
Summary Statements
FGC; warm, caring, and sympathetic staff; privacy during
5. Performing or assisting in female genital cutting is a
labour and in the wards; confidence in the capacity of the
criminal offense in Canada. (III)
clinicians to provide adequate care; and appropriate clinical
6. Reporting to appropriate child welfare protection
care, including the ability to refuse what they considered
services is mandatory when a child has recently been
unwarranted Caesarean sections.
subjected to female genital cutting or is at risk of
A consultation process undertaken in 2000 by the FIWG being subjected to the procedure. (III)
with community and health care providers identified the 7. There is concern that female genital cutting
following as key health care issues affecting women with continues to be perpetuated in receiving countries,
FGC in Canada: their lack of knowledge of the health mainly through the act of re-infibulation. (III)
consequences of the practice and the relation of FGC to 8. There is a perception that the care of women with
their own health symptoms; differences in their health- female genital cutting is not optimal in receiving
seeking behaviours and practices from those of other countries. (III)
women in Canada; their reluctance to seek health care due to
lack of knowledge of how the system works; their distrust CLINICAL MANAGEMENT OF
of authority figures (especially if they have experienced WOMEN LIVING WITH FGC
political prosecution); past adverse experience with health
Gynaecologic Care
care providers; preference for women physicians; financial
Women experiencing distressing symptoms related to vaginal
barriers; difficult and traumatic experiences in accessing care
obstruction or mass effect, or those considering intercourse
due to language and cultural barriers; lack of confidentiality
or pregnancy can be offered surgery, defibulation, or excision.
and health care providers’ lack of training of in how to
For defibulation, under general anaesthesia, the infibulated
deal with complications of FGC; and issues related to scar is incised in the midline from the neo-introitus to the
what affected women considered the high Caesarean level of the urethral orifice using scissors, coagulation/
section rate at childbirth.8 These factors deter women with cutting, or laser.40 The labial edges may need interrupted
FGC and their families from seeking care until absolutely sutures to ensure hemostasis and/or approximation of
necessary.8,10,27 Studies exploring the perceptions of women the ipsilateral labial edges. Postoperatively, topical analgesic
with FGC in the United States, Europe, and Australia of the gels can help with pain relief, as can generous application
perinatal care they received report similar findings.28–33 of lubricants and frequent sitz baths. Estrogen cream
Recent European studies shed light on the experiences and topical antibiotic ointment may also be helpful.
and clinical practices of health providers providing care Unfortunately, because FGC is not reversible some of its
complications may not be amenable to therapy. Vaginal
to women with FGC and how these contribute to the
dilators may be appropriate for some women. Vaginal calibre
quality of care provided. Vangena et al. (2002)28 found
is best sustained, postoperatively, when the woman is willing
that health care providers in Norway faced difficulties
to use gentle vaginal dilation to help prevent re-stenosis of
initiating discussion about the practice with women; lacked
the introitus. Additional guidance related to defibulation is
clinical skills in how and when to defibulate women and
available in the online WHO document entitled Management
in determining the extent of repair after delivery; and at
of Pregnancy, Childbirth and the Postpartum Period in the
times performed Caesarean sections because they lacked
Presence of Genital Mutilation.41
knowledge related to care management. Widmark et al.34
and Johansen35 reported that health care providers found Contraceptive measures remain the same as for other
providing care to infibulated women at childbirth especially women. Infertility rates may be higher in women who have
stressful and emotionally challenging. Of particular undergone FGC.42 The incidence of infertility appears
concern were the strong emotional and sometimes to be related to the extent of FGC. Introital stenosis can
contradictory feelings of health providers, which included make intercourse difficult or impossible, and there may be
“deep empathy, protectiveness and the desire to treat the tubal damage from infection or endometriosis. Artificial
reproductive technologies can be more challenging in by the Canadian Criminal Code; however, requests for
a woman with FGC because of the need for a vaginal re-infibulation should be declined on medical grounds
approach (hysterosonogram, intrauterine insemination, because repetitive cutting and suturing of the vulva is
trans-vaginal ovum retrieval). likely to increase scar tissue, thus causing or perpetuating
dyspareunia or voiding difficulties. If incisions are made or
It is important for health care professionals to avoid tearing occurs during childbirth, it is reasonable to repair
verbal and non-verbal reactions to women with FGC defects in a way that will promote good hemostasis, vaginal
that may make the women feel stigmatized. Well-woman support, and normal appearance. Typically, high vaginal
examinations and cervical screening need to be fully tears should be sought and sutured first; it is important
explained so the woman understands the need for the tests. to keep in mind that obstructed labour secondary to
A wide variety of small, narrow specula should be available infibulation may be associated with “blow out” lacerations
to perform the exam with the least amount of discomfort. of the vagina and vulva. Episiotomy incisions and
The use of a lubricant is encouraged. perineal tears may then be repaired in the usual manner.
Infibulated tissue may be tough and relatively avascular.
Obstetrical Care
A small anterior tear or incision may not require suturing.
Most forms of FGC do not directly impact obstetrical
In other cases, re-approximation of the cut edges may be
care. Infibulation may cause obstructed labour and
appropriate. Alternatively, the raw edges can be over-sewn
is associated with an increased risk of vaginal/vulvar
with interrupted, delayed absorbable suture in an effort to
lacerations. When treating pregnant and labouring women
preserve the capacity of the vulvar opening. The vulvar
it is important to demonstrate a professional and non-
tissues have a tendency to heal together as the raw edges
judgemental approach to FGC. Many of these women
sit in apposition. Gentle self-dilatation after defibulation
originate from communities where FGC is the norm. They
may be required while the edges heal in the postpartum
are used to the way their genitals feel and look. They may
period. It is common for women to be concerned about
be fearful of the changes that may occur as a result of
the appearance of their genitals and to request that their
the delivery, particularly if the delivery is conducted by
appearance be preserved or restored as much as possible.
someone who is not familiar with FGC. If defibulation will
Reassurance and information sharing are important. A
be necessary to allow vaginal birth, it can be performed in
patient-centred approach requires us to hear our patients’
advance or at the time of delivery. There may be medical
requests and to be sensitive to the cultural context in which
indications to offer defibulation in advance to decrease the
these requests are made. The health care professional
incidence of Caesarean section.43 However, many women
should support a culturally competent approach in which
prefer to wait until delivery and have defibulation only if
the autonomy of the patient is honoured as much as
absolutely necessary to facilitate the birth.44 If defibulation
possible without compromising her health or breaching
is performed intrapartum, an episiotomy performed at
the ethical principle of non-maleficence.
the same time facilitates delivery and minimizes vaginal
tearing. Possible scenarios should be discussed in advance Caesarean section seems to be more common in women
so the woman has ample opportunity to state her views, ask with FGC than in the general population. Caesarean section
questions, and understand the reasoning behind common rates in low-resource countries tend to be considerably
interventions such as analgesia in labour, defibulation, lower than in North America and cultural differences
episiotomy, and Caesarean section. It is advisable to discuss exist in women’s acceptance of Caesarean. Health care
hospital policies on labour companions, rooming in, and professionals should be aware that FGC is not an indication
visiting hours because local practices may be at odds with for Caesarean delivery. Frequency of Caesarean delivery
the expectations of the woman and her family. Sympathetic may be reduced if defibulation is performed antenatally.43
post-delivery care, good analgesia, and assistance with care
of the newborn are essential given the likelihood of vulvar Population studies have suggested that women with FGC
pain experienced by women with FGC.13 have statistically increased risks of perinatal mortality,
postpartum hemorrhage, and fetal distress. Currently there
It is vital that women who have had FGC are treated with is insufficient data to determine whether these findings
respect and sensitivity. In some communities, it is customary are related to FGC or to socioeconomic factors affecting
to re-infibulate the genitals after each childbirth.45 WHO health care access and quality of care.46
and other international health organizations strongly
Summary Statement
oppose all medicalization of FGC including re-infibulation
because it may legitimize the practice of FGC/M in 9. Female genital cutting is not considered an indication
general.3 Re-infibulation is not specifically prohibited for Caesarean section. (III)
including her race, nationality, socioeconomic background, •• Do you have any problems passing your urine? Does
length of time in Canada or in other Western countries, it take you a long time to urinate? (Note that women
education, religion, and sexual orientation. If she is a refugee with obstruction may take several minutes to pass
or an asylum seeker, her experience may also differ from urine.)
immigrant women by the possibility that she left her home •• Do you have any pain with menstruation? Does your
under extreme circumstances, may be separated from her menstrual blood get stuck?
family, and may have been subjected to significant personal
trauma such as rape or other violence. Consequently, in their •• Do you have any itching or burning or discharge from
interaction with women with FGC, health care professionals’ your pelvic area?
focus should be directed towards addressing the woman’s •• (If sexually active) Do you have any pain or difficulty
health concerns as a priority and taking a holistic approach. when having relations?
physical, breast, or internal examination. As in all health making process. In some other cultures, birth is considered
professional–patient interactions, the way the information women’s business and consequently, men are not expected
is shared (i.e., what is said and how it is said) will to participate in the pregnancy nor the birth, nor are they
influence the outcome of the treatment. Communicating the birth companion of choice of many women.58
in a professional manner can contribute to creating a
safe environment for women who find obstetrical and The health care professional in his/her interactions
gynaecological care difficult and stressful. with the woman should explore and assess the decision-
making process of the woman and her family and be sure
To ensure adequate information is provided to the to solicit the woman’s views and wishes. The health care
woman, the health care professional should be sure to professional should also enquire who the woman’s choice
speak slowly and clearly and to use simple but accurate of birth companion is, and respect it.
terms. If the woman’s knowledge of reproductive care is
limited, the health care professional should make use of Health-seeking behaviours and practices
the interaction to share information with her. Pictures, and preventative care
diagrams, or anatomical models may be used to facilitate The health-seeking behaviours and practices of many
these discussions. Consideration should also be given to immigrant women, including women with FGC, often
making longer appointments available. vary from Canadian norms. They may be unfamiliar
with health services for screening and illness prevention
Confidentiality and privacy and be more accustomed to seeking care when ill. They
In many countries where FGC is practiced, sex and may also continue to use traditional medicine or health
sexuality including issues related to FGC are considered methods in their health care practices. Many may find our
very private matters and are not openly discussed. Some health care services difficult to understand and navigate,
women refrain from seeking care because of their fear of and frightening and intimidating, especially if they do not
being humiliated and judged when they disclose that they speak English or French.
have undergone the practice. Finally, many women may
experience embarrassment when asked to disrobe and The health care professional should assist the woman in
uncover their bodies in front of a health care practitioner. understanding how the health system works and help her
In many cultures affected by FGC women prefer to be navigate it. Every opportunity should be taken to educate
cared for by female attendants. the woman about preventive care practices important
for herself and potentially for her daughters. Culturally
The health care professional should ensure the woman’s appropriate educational pamphlets should also be made
privacy and confidentiality by limiting the attendants in available.
the room (including delivery room) to those who are part
of the health care team. Respect of a woman’s wish for Preparation for delivery
modesty can be expressed by offering her a long-sleeved In many countries where FGC is practiced, prenatal
gown, knocking and waiting before entering the room, care similar to that in Canada may not be available,
and draping the woman carefully when examining her. and many births take place without skilled attendants.
Care should be taken to ensure that the examination is Health care may only be sought when complications
done using a gentle touch, especially when examining the arise. Many women with FGC prefer natural childbirth
woman’s sensitive areas. Telling her what you are about and fear Caesarean section and other unfamiliar medical
to do, what you are doing, and what you have observed procedures. The health care professional should take
(good or bad) can be calming and reassuring for her. advantage of the prenatal visits to properly prepare the
Finally, it is important to ensure that the woman is not part woman and her family for the delivery. The focus should
of a teaching session unless informed consent has been be on developing a detailed birth plan with her and her
obtained. Trainees should be introduced and the reasons family. Attention should be given to sharing information
for their presence and their role in the health care of the verbally and in other formats (if available) about when
woman should be explained. to come to the hospital, admission procedures, hospital
policies, what to expect in the delivery room, who
Woman-centred care will be part of the health care team, the care she can
In many cultures where FGC is practiced, women who expect from hospital nurses and staff, how interpreters
seek care may be accompanied by their husbands and other are used at the hospital, length of stay, etc. Providing
family members such as mothers-in-law and male relatives information about when and why defibulation will take
and these may expect to be involved in the decision- place, when and why Caesarean sections are performed,
the pain medication options available (during and g. providing woman-centred care focused on
after labour), other medical procedures that might be ensuring that the woman’s views and wishes are
necessary, and the call schedule also help the woman solicited and respected, including a discussion of
prepare for delivery. why some requests cannot be granted for legal
or ethical reasons; (III-C)
Referrals
h. helping the woman to understand and
Referrals to other health care professionals and/or services
navigate the health system, including access to
are integral to the provision of quality and comprehensive
preventative care practices; (III-C)
care. Many women, however, may consider referrals for
i. using prenatal visits to prepare the woman and
counselling to be foreign, not beneficial, and a waste of
her family for delivery; (III-C)
their time.
j. when referring, ensuring that the services and/
When referring a woman, the health care professional or practitioners who will be receiving the referral
should ensure that the services and/or practitioners who can provide culturally competent and sensitive
receive the referral can provide culturally appropriate and care, paying special attention to concerns related
sensitive care to women with FGC. The professional should to confidentiality and privacy. (III-C)
also explain to the woman beforehand why and where the
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Adolesc Gynecol 2001;14(3):109–12. maternal_perinatal_health/RHR_01_13_/en/index.html.
Accessed on August 3, 2013.
24. UNICEF Office of Research. Changing a harmful social convention:
female genital mutilation/cutting. New York: UNICEF; 2005. Available at: 42. Almroth L, Elmusharaf S, El Hadi N, Obeid A, El Sheikh MA,
http://www.unicef-irc.org/publications/396. Accessed on August 3, 2013. Elfadil SM, et al. Primary infertility after genital mutilation in girlhood
in Sudan: a case-control study. Lancet 2005;366:385–91.
25. UNICEF Office of Research. The Dynamics of social change: towards
the abandonment of FGM/C in five African countries. New York: 43. Raouf SB, Ball T, Hughes A, Holder R, Papaioannou S. Obstetric and
UNICEF; 2010. Available at: http://www.unicef-irc.org/publications/618. neonatal outcomes for women with reversed and non-reversed type III
Accessed on August 3, 2013. female genital mutilation. Int J Gynaecol Obstet 2011;113:141–3.
26. Morison LA, Dirir A, Elmi S, Warsame J, Dirir S. How experiences 44. Wuest S, Rajo L, Wyssmueller MD, Muller M, Stadlmaryr W, Surbek DV,
and attitudes relating to female circumcision vary according to age on et al. Effects of female genital mutilation on birth outcomes in
arrival in Britain: a study among young Somalis in London. Ethn Health Switzerland. BJOG 2009;116:1204–9.
2004;9:75–100. 45. BMA Ethics. Female genital mutilation: caring for patients and
27. Buckland RL. The everyday experience of Somali women in Canada: safeguarding children. BMA Guideline. 2011. Available at:
implications for health. Thesis. Ottawa: University of Ottawa; 1997. http://bma.org.uk/search?query=Female%20genital%20mutilation.
Accessed on August 3, 2013.
28. Vangena S, Johansen RE, Sundby J, Traeen B, Stray-Pedersen B.
Qualitative study of perinatal care experiences among Somali women and 46. Ndiaye P, Diongue M, Faye A. Ouedraogo D, Tal Dia A. [Female genital
local health care professionals in Norway. Eur J Obstet Gynecol Reprod mutilation and complications in childbirth in the province of Gourma
Biol 2004;15;112:29–35. (Burkina Faso)]. Sante Publique 2010;22:563–70.
47. Okonofu FE, Larsen U, Oronsaye F, Snow RC, Slanger TE. The 53. Horowitz C, Jackson JC. Female “circumcision”: African women confront
association between female genital cutting and correlates of sexual and American medicine. J Gen Intern Med 1997;12:513–5.
gynaecological morbidity in Edo State, Nigeria. BJOG 2002;109:1089–96.
54. Carroll J, Epstein R, Fiscella K, Gipson T, Volpe E, Jean-Pierre P. Caring
48. Krause E, Brandner S, Mueller MD, Kuhn A. Out of Eastern Africa: for Somali women: implications for clinician–patient communication.
defibulation and sexual function in woman with female genital mutilation. Patient Educ Couns 2007;66:337–45.
J Sex Med 2011;8:1420–5.
55. Turner D. Female genital cutting: implications for nurses. Nurs Womens
49. Almroth L, Almroth-Bergren V, Hassanein OM, Al-Said SSE, Hasan SSA, Health 2007;11:366–72.
Lithell UB, et al. Male complications of female genital mutilation. Soc Sci
Med 2001;53:1455–60. 56. London Safeguarding Children Board. London FGM resource pack.
London: London Safeguarding Children Board; 2009. Available at:
50. Berendt A, Moritz S. Post-traumatic stress disorder and memory problems http://www.londonscb.gov.uk/fgm. Accessed on August 20, 2013.
after female genital mutilation. Am J Psychiatry 2005;162:1000–2.
57. Omer-Hashi K. Commentary: female genital mutilation: perspectives from
51. Sexuality Education Resource Centre Manitoba. Working a Somalian midwife. Birth 1994;21:224–6.
with women and girls who have experienced female genital
cutting/female genital mutilation. Winnipeg: SERC; 2000. 58. Ford AR, Legault P, Russell J, Van Wagner V; Equity Committee of the
Available at: http://www.serc.mb.ca/content/dload/ Interim Regulatory Council on Midwifery. Midwifery care for immigrant
WorkingWithWomenAnd GirlsWhoHaveExperiencedFemaleGenital and refugee women in Ontario. Can Womens Stud 1994;14:83.
CuttingFemaleGenitalMutiliationCulturallySensitiveCounselling/file.
59. Woolf SH, Battista RN, Angerson GM, Logan AG, Eel W. Canadian
Accessed on March 13, 2011.
Task Force on Preventive Health Care. New grades for recommendations
52. Adamson F. Female genital mutilation: a counselling guide for from the Canadian Task Force on Preventive Health Care. CMAJ
professionals. London: FORWARD; 1995. 2003;169:207–8.
Sections of the Criminal Code of Canada that address or could be used to address FGC (Criminal Code of Canada, December 14, 2011)1
Aggravated assault
268. (1) Every one commits an aggravated assault who wounds, maims, disfigures or endangers the life of the complainant.
Punishment
(2) Every one who commits an aggravated assault is guilty of an indictable offence and liable to imprisonment for a term not
exceeding fourteen years.
Excision
(3) For greater certainty, in this section, “wounds” or “maims” includes to excise, infibulate or mutilate, in whole or in part, the labia
majora, labia minora or clitoris of a person, except where
(a) a surgical procedure is performed, by a person duly qualified by provincial law to practise medicine, for the benefit of the
physical health of the person or for the purpose of that person having normal reproductive functions or normal sexual
appearance or function; or
(b) the person is at least eighteen years of age and there is no resulting bodily harm.
Consent
(4) For the purposes of this section and section 265, no consent to the excision, infibulation or mutilation, in whole or in part, of the
labia majora, labia minora or clitoris of a person is valid, except in the cases described in paragraphs (3)(a) and (b).
Criminal negligence
219. (1) Every one is criminally negligent who
(a) in doing anything, or
(b) in omitting to do anything that it is his duty to do, shows wanton or reckless disregard for the lives or safety of other persons.
REFERENCE
1. Department of Justice. Consolidation Criminal Code (R.S.C., 1985, c. C-48). Act current to 2011-12-14. Available at: http://laws-lois.justice.gc.ca/eng/
acts/C-46. Accessed on August 2, 2013.
POLICY
Physicians must not perform any FGC/M procedures. Further, physicians must not refer patients to any person for the performance of
FGC/M procedures.
The performance of, or referral for, FGC/M procedures by a physician will be regarded by the College as professional misconduct.
Where there is doubt if a procedure is considered to be FGC/M physicians should seek advice from the Canadian Medical Protective
Association and/or legal counsel.
During the course of a vaginal delivery of a woman who has been previously subjected to an FGC/M procedure, a physician may find it
necessary to surgically disrupt the scar tissue resulting from the earlier procedure. In this circumstance, at the conclusion of the delivery,
the physician must confine activities to repairing the surgical incision or laceration required during the delivery, and must not, for example,
endeavour to reconstruct an infibulation. Wherever possible, the physician should advise the patient of this limitation prior to delivery; ideally
this conversation should be had prior to pregnancy and during the course of prenatal care.
Reporting
The performance of FGC/M procedures on a female under the age of 18 by any person may constitute child abuse. Physicians who have
reasonable grounds to believe than an FGC/M procedure has been performed on, or is being contemplated for, any female under the age of
18, must notify the appropriate child protection authorities, regardless of where the procedure has been or will be undertaken. [4]
In the event that a physician has reasonable grounds to believe that another physician is performing FGC/M procedures, the matter should
immediately be brought to the attention of the College. This expectation is based in professionalism and ethics, and is distinct from the legal
obligation to report child abuse discussed above.
Continued
APPENDIX 2. Continued
Care of Patients
As appropriate, physicians should provide culturally sensitive counseling regarding the dangers related to performing FGC/M procedures.
As part of their commitment to treat patients with compassion, physicians who encounter patients subjected to FGC/M procedures should
educate themselves on the appropriate management of possible complications, in order to provide appropriate counsel and care.
Endnotes
3. See the CPSO’s Practice Guide at http://www.cpso.on.ca under Policies and Publications.
4. Pursuant to Child and Family Services Act, R.S.O. 1990, c.C11, s.72(1) and the Criminal Code, R.S.C. 1985, c. C-46, s 273(1) and the
CPSO’s Mandatory Reporting policy.
Duty to Report3
A physician must report to the College and the Ministry of Children and Family Development if:
– A physicians learns of another physician performing female genital mutilation;
– A physician is requested to perform female genital mutilation or learns that these procedures may be performed on a child or person
under 18 years of age; or
– A physician considers that a child may be at risk in relation to the practice of female genital mutilation.
REFERENCES
1. The College of Physicians and Surgeons of Ontario. Female genital cutting (mutilation). Policy #2-11. Available at:
http://www.cpso.on.ca/policies/policies/default.aspx?ID=1596. Accessed on August 2, 2013.
2. The College of Physicians and Surgeons of Manitoba. Female circumcision (2011 rev.) Statement 111. Available at:
http://cpsm.mb.ca/cjj39alckF30a/wp-content/uploads/st111.pdf. Accessed on August 2, 2013.
3. College of Physicians and Surgeons of British Columbia. Professional standards and guidelines: female genital mutilation. Available at:
https://www.cpsbc.ca/files/u6/Female-Genital-Mutilation.pdf. Accessed on August 2, 2013.
Options: The areas of clinical practice considered in formulating this 9. As patients who undergo surgery in surgical daycare units may
guideline are prevention and prophylaxis, treatment, both medical have PONV after they are discharged, they should be given
and alternative, and patient education. instructions for its management. (III-B)
Outcomes: Implementation of this guideline should optimize the 10. Patients at high risk of developing PDNV should be provided with
prevention of and prophylaxis against PONV and the prompt rescue treatment. (III-B)
treatment of women who suffer from PONV following gynaecologic J Obstet Gynaecol Can 2008;30(7):600–607
surgery. Increased awareness of options for management should
help minimize the effects of PONV.
INTRODUCTION
Benefits, Harms, and Costs: PONV results not only in increased
patient discomfort and dissatisfaction but also in increased costs ostoperative nausea and vomiting, defined as nausea
related to length of hospital stay. Cost of medications to prevent
and treat PONV must be weighed against improved surgical
P and/or vomiting occurring within 24 hours after sur-
experience for the patient and decreased costs to the system. gery, affects between 20% and 30% of patients.1–4 As many
Values: Recommendations were made according to the guidelines as 70% to 80% of patients at high risk may be affected.5 The
developed by the Canadian Task Force on Preventive Health
Care.
etiology of PONV is thought to be multifactorial, involving
Recommendations
individual, anaesthetic, and surgical risk factors.2,5,6 PONV
1. Physicians should be aware of the risk factors associated with
results in increased patient discomfort and dissatisfaction6
PONV, and the baseline risks should be reduced whenever and in increased costs related to length of hospital stay. One
possible. (III-A)
study revealed that the time to discharge was increased by
25% in patients with PONV.7 Serious medical complica-
tions such as pulmonary aspiration, although uncommon,
are also associated with vomiting.6
Key Words: Postoperative nausea, postoperative vomiting
This document reflects emerging clinical and scientific advances on the date issued and is subject to change. The information
should not be construed as dictating an exclusive course of treatment or procedure to be followed. Local institutions can dictate
amendments to these opinions. They should be well documented if modified at the local level. None of these contents may be
reproduced in any form without prior written permission of the SOGC.
Table 1. Key to evidence statements and grading of recommendations, using the ranking of the
Canadian Task Force on Preventive Health Care
I: Evidence obtained from at least one properly randomized A. There is good evidence to recommend the clinical preventive
controlled trial action
II-1: Evidence from well-designed controlled trials without B. There is fair evidence to recommend the clinical preventive
randomization action
II-2: Evidence from well-designed cohort (prospective or C. The existing evidence is conflicting and does not allow to
retrospective) or case-control studies, preferably from more make a recommendation for or against use of the clinical
than one centre or research group preventive action; however, other factors may influence
decision-making
II-3: Evidence obtained from comparisons between times or
places with or without the intervention. Dramatic results in D. There is fair evidence to recommend against the clinical
uncontrolled experiments (such as the results of treatment preventive action
with penicillin in the 1940s) could also be included in this E. There is good evidence to recommend against the clinical
category preventive action
III: Opinions of respected authorities, based on clinical L. There is insufficient evidence (in quantity or quality) to make
experience, descriptive studies, or reports of expert a recommendation; however, other factors may influence
committees decision-making
*The quality of evidence reported in these guidelines has been adapted from The Evaluation of Evidence criteria described in the Canadian Task Force
on Preventive Health Care.75
†Recommendations included in these guidelines have been adapted from the Classification of Recommendations criteria described in the The Canadian
Task Force on Preventive Health Care.75
PONV is a significant problem for patients: in one study, afferent pathways involved in stimulating the vomiting cen-
patients were more concerned about PONV than about tre are:
postoperative pain8; in another, patients were willing to 1. the chemoreceptor triggering zone,
spend up to US $100 for an effective antiemetic treatment.9
2. the vagal mucosal pathway in the gastrointestinal system,
Several thousand studies examining PONV have been pub-
lished, and several hundred new papers are published each 3. neuronal pathways from the vestibular system,
year on the topic. Guidelines for the prevention and man- 4. reflex afferent pathways from the cerebral cortex C2,3,
agement of PONV have been published by anaesthetic and
journals and societies.10–12
5. midbrain afferents.
Management of PONV for gynaecological patients in most
hospitals continues to be on an ad hoc basis. The aim of Stimulation of one of these afferent pathways can activate
these guidelines is to provide information on the manage- the vomiting centre via cholinergic (muscarinic),
ment of PONV in gynaecological patients. dopaminergic, histaminergic, or serotonergic receptors.
presumably due to the high concentration of histamine and antiemetic properties found in over-the-counter sleeping
muscarinic cholinergic receptors within the vestibular medication) and 10 mg pyridoxine hydrochloride (vitamin
system.50 B6), in a delayed release formulation. Pyridoxine may have
Promethazine and prochlorperazine belong to a group of intrinsic antiemetic properties and also may be synergistic
drugs known as phenothiazines, which act primarily via a with the antinauseant property of antihistamines.54–56
central antidopaminergic mechanism in the CTZ. The use Diclectin has been used since the 1950s and is considered to
of these drugs has decreased because of their significant be a safe treatment for nausea and vomiting associated with
side effects: sedation, dizziness, and extrapyramidal pregnancy.57 The International Cochrane Collaboration has
symptoms. systematically reviewed randomized trials of Diclectin and
concluded that it safely provides considerable relief for nau-
Scopolamine is an anticholinergic that blocks emetic sea and vomiting in pregnancy.58
muscarinic receptors in the cerebral cortex.51 It is very
effective, with a NNT of 3.8 for prevention of PONV.52 Its Aprepitant was the first neurokinin-1 (NK-1) receptor
use is limited because of its two- to four-hour onset of antagonist approved for the treatment of PONV. This drug
effect and side effect profile as listed above. blocks NK1 receptors in the central and peripheral nervous
systems thus preventing emesis. In one study, patients given
A recent publication has shown Diclectin to be as effective oral aprepitant alone or in combination with intravenous
as ondansetron for the prevention of late postoperative ondansetron had significantly fewer emetic episodes than
vomiting in women undergoing laparoscopic tubal ligation, those given ondansetron alone.59 In a report of combined
with an average NNT of 5.9.53 data from 2 large trials, oral aprepitant 40 mg was superior
Diclectin is an antiemetic medication that contains 10 mg to intravenous ondansetron 4 mg for the prevention of
doxylamine succinate (a common antihistamine with PONV.60 Complete response (no nausea, vomiting, or need
for rescue therapy) was achieved in 37.9% of the aprepitant Non-pharmacologic Prophylaxis
group compared with 31.2% of the ondansetron group. Its
acquisition cost is relatively high, making it less appealing as Acupuncture has been shown to be effective in the manage-
a first line agent. ment of PONV. Coloma et al.65 compared acustimulation
with ondansetron for the treatment of established PONV
None of the available agents is entirely effective for pre- in outpatient laparoscopic surgery patients. They concluded
venting PONV, particularly for high-risk patients. As there that acustimulation may be a satisfactory alternative to
are four major receptor systems involved in the etiology of ondansetron for established PONV, and that ondansetron
PONV, a combination of agents that act on different recep- seems to enhance the efficacy of acustimulation for treat-
tors results in better prophylaxis.61,62 The most commonly ment of established PONV.
studied combinations have included 5-HT3 receptor antag-
onists with droperidol or dexamethasone, and both are Ginger root is a commonly used non-medical therapy
equally efficacious.63,64 The Figure illustrates a proposed but is not effective for PONV prophylaxis.66 Similarly,
algorithm for the management of PONV cannabinoids have not been confirmed to be effective in the
Recommendations management of PONV.
Rescue Treatment for PONV In a study by Gan et al.73 4 mg IV ondansetron for PONV
In the presence of persistent nausea and vomiting, possible prophylaxis was administered. Patients were then random-
contributing factors, such as patient-controlled morphine ized to receive either ondansetron oral disintegrating tablet
analgesia, presence of blood in the pharynx, or an abdomi- (ODT) 8 mg or placebo immediately before discharge from
nal obstruction, should be excluded before rescue therapy the ambulatory surgery centre and again 12 hours later.
may be initiated. Patients who received ondansetron ODT had less severe
When prophylaxis with one drug has failed, a repeat dose of nausea and fewer vomiting episodes (3% vs. 23%) after
this drug should not be initiated as a rescue therapy. Instead discharge.
a drug from a different class of antiemetics should be Al-Sadi et al.74 assessed the efficacy of acupuncture as a pro-
administered.67 However, if the PONV occurs more than 6 phylactic antiemetic. They found a significant difference
hours after surgery, repeat dosing of the initial prophylactic between groups before and after discharge, with the pla-
drug may be considered. Repeat doses of dexamethasone cebo group four times more likely to have post-discharge
and transdermal scopolamine should not be administered nausea and vomiting than the acupuncture group.
regardless of the time interval.10 Recommendations
If a patient has received no prophylaxis, treatment with a 9. As patients who undergo surgery in surgical daycare units
5-HT3 receptor antagonist may be considered.68 Rescue may have PONV after they are discharged, they should
treatment doses for 5-HT3 receptor antagonists are be given instructions for its management. (III-B)
approximately 25% the dose of those used for prophylaxis
(e.g., 1 mg ondansetron). 10. Patients at high risk of developing PDNV should be
provided with rescue treatment. (III-B)
Recommendations
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30 April 1993. Oxford: Cochrane Updates on Disk 1994. vomiting after discharge from outpatient surgery centers. Anesth Analg
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et al. Substance P (Neurokinin 1) antagonist prevents postoperative
71. Gan TJ. Postoperative nausea and vomiting: Can it be eliminated? JAMA
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2002; 13:1233–6.
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aprepitant vs. ondansetron for prevention of PONV: combined data from Ondansetron versus metoclopramide in the treatment of postoperative
2 large trials (abstract A125). Presented at: American Society of nausea and vomiting. Anesth Analg 1997;85:395–9.
Anesthesiologists 2006 Annual Meeting, Chicago, IL, October 14–18, 2006. 73. Gan TJ, Franiak R, Reeves J. Ondansetron orally disintegrating tablet versus
61. Habib AS, Gan TJ. Combination therapy for postoperative nausea and placebo for the prevention of postdischarge nausea and vomiting after
vomiting—a more effective prophylaxis? Ambul Surg 2001;9:59–71. ambulatory surgery. Anesth Analg 2002;94:1199-200.
62. Habib AS, Gan TJ. Combination antiemetic. What is the evidence? Int 74. al-Sadi M, Newman B, Julious SA. Acupuncture in the prevention of
Anesthesiol Clin Fall 2003;41:119–44. postoperative nausea and vomiting. Anaesthesia 1997;52:658-61.
63. Sanchez-Ledesma MJ, Lopez-Olaondo L, Pueyo FJ, Carrascosa F, Ortega A. 75. Woolf SH, Battista RN, Anderson GM, Logan AG, Eel W. Canadian Task
A comparison of three antiemetic combinations for the prevention of force on Preventive Health Care. New grades for recommendations from
postoperative nausea and vomiting. Anesth Analg 2002;95:1590–5. the Canadian Task force on Preventive Health Care. CMAJ 2003;169:207–8.
This document reflects emerging clinical and scientific advances on the date issued and is subject to change. The information
should not be construed as dictating an exclusive course of treatment or procedure to be followed. Local institutions can dictate
amendments to these opinions. They should be well documented if modified at the local level. None of these contents may be
reproduced in any form without prior written permission of the SOGC.
monitored by the Clinical Practice Obstetrics Committee 2. Leduc D, Biringer A, Lee L, Dy J; Clinical Practice Obstetrics
Committee, Society of Obsetricians and Gynaecologists of
for potential change of practice implications. Canada. Induction of labour. SOGC Clinical Practice Guideline
No. 296, September 2013. J Obstet Gynaecol Can 2013;36:248–52.
It is to be noted that, to ensure the best quality of care, the
3. Eunice Kennedy Shriver National Institute of Child Health and
SOGC is currently developing a standard of practice under Human Development (NICHD). A Randomized Trial of Induction
which evidence will be reviewed on a regular basis to decide Versus Expectant Management (ARRIVE). Bethesda, MD: US National
whether all or part of a guideline should be updated based Institute of Health; 2014. Available at: http://clinicaltrials.gov/ct2/show/
on new robust (Canadian Task Force on Preventive Health NCT01990612?term=ARRIVE&rank=2. Accessed on December 10, 2014.
Care5 level I) evidence. 4. Nottingham Clinical Trials Unit. Induction of labour versus
expectant management for women over 35 years of age. Nothingham, GB:
NCTU; 2013. Available at: http://www.35-39trial.org.
REFERENCES Accessed on December 10, 2014.
5. Woolf SH, Battista RN, Angerson GM, Logan AG, Eel W;
1. Mishanina E, Rogozinska E, Thatthi T, Uddin-Khan R, Khan KS, Canadian Task Force on Preventive Health Care. New grades for
et al. Use of labour induction and risk of cesarean delivery: a systematic recommendations from the Canadian Task Force on Preventive
review and meta-analysis. CMAJ 2014;186:665–73. Health Care. CMAJ 2003;169:207–8.
Induction of Labour
Abstract
This clinical practice guideline has been prepared by the
Clinical Practice Obstetrics Committee, reviewed by the Objective: To review the most current literature in order to provide
Maternal Fetal Medicine and Family Practice Advisory evidence-based recommendations to obstetrical care providers
Committees, and approved by the Executive and Council on induction of labour.
of the Society of Obstetricians and Gynaecologists of
Options: Intervention in a pregnancy with induction of labour.
Canada.
Outcomes: Appropriate timing and method of induction,
PRINCIPAL AUTHORS appropriate mode of delivery, and optimal maternal and
Dean Leduc, MD, Ottawa ON perinatal outcomes.
Evidence: Published literature was retrieved through searches
Anne Biringer, MD, Toronto ON
of PubMed, CINAHL, and The Cochrane Library in 2010
Lily Lee, MSN, Vancouver BC using appropriate controlled vocabulary (e.g., labour, induced,
Jessica Dy, MD, Ottawa ON labour induction, cervical ripening) and key words (e.g.,
induce, induction, augmentation). Results were restricted
to systematic reviews, randomized control trials/controlled
CLINICAL PRACTICE OBSTETRICS COMMITTEE
clinical trials, and observational studies. There were no
Thomas Corbett, MD (Co-chair), Edmonton AB date or language restrictions. Searches were updated on a
Dean Leduc, MD (Co-chair), Ottawa ON regular basis and incorporated in the guideline to the end of
2010. Grey (unpublished) literature was identified through
Anne Biringer, MD, Toronto ON searching the websites of health technology assessment and
Louise Duperron, MD, Kirkland QC health technology-related agencies, clinical practice guideline
collections, clinical trial registries, and national and international
Jessica Dy, MD, Ottawa ON medical specialty societies.
Ian Lange, MD, Calgary AB Values: The evidence in this document was rated using criteria
Lily Lee, MSN, Vancouver BC described in the Report of the Canadian Task Force on
Preventative Health Care (Table 1).
Suzanne Muise, MD, St. Thomas ON
Barbara Parish, MD, Halifax NS Summary Statements
Lexy Regush, MD, Saskatoon SK 01. Prostaglandins E2 (cervical and vaginal) are effective
agents of cervical ripening and induction of labour for an
Kathi Wilson, RM, Ilderton ON
unfavourable cervix. (I)
Grace Yeung, MD, London ON 02. Intravaginal prostaglandins E2 are preferred to intracervical
prostaglandins E2 because they results in more timely vaginal
SPECIAL CONTRIBUTORS deliveries. (I)
Joan Crane, MD, St. John’s NL
Robert Gagnon, MD, Montreal QC
Diane Sawchuck, RN, PhD, Vancouver BC
Vyta Senikas, MD, Ottawa ON
Disclosure statements have been received from all contributors. J Obstet Gynaecol Can 2013;35(9)
This document reflects emerging clinical and scientific advances on the date issued and is subject to change. The information
should not be construed as dictating an exclusive course of treatment or procedure to be followed. Local institutions can dictate
amendments to these opinions. They should be well documented if modified at the local level. None of these contents may be
reproduced in any form without prior written permission of the SOGC.
Table 1. Key to evidence statements and grading of recommendations, using the ranking of the Canadian Task Force
on Preventive Health Care
Quality of evidence assessment* Classification of recommendations†
I: Evidence obtained from at least one properly randomized A. There is good evidence to recommend the clinical preventive action
controlled trial
II-1: Evidence from well-designed controlled trials without B. There is fair evidence to recommend the clinical preventive action
randomization
II-2: Evidence from well-designed cohort (prospective or C. The existing evidence is conflicting and does not allow to make a
retrospective) or case–control studies, preferably from recommendation for or against use of the clinical preventive action;
more than one centre or research group however, other factors may influence decision-making
II-3: Evidence obtained from comparisons between times or D. There is fair evidence to recommend against the clinical preventive action
places with or without the intervention. Dramatic results in
uncontrolled experiments (such as the results of treatment with E. There is good evidence to recommend against the clinical preventive
penicillin in the 1940s) could also be included in this category action
III: Opinions of respected authorities, based on clinical experience, L. There is insufficient evidence (in quantity or quality) to make
descriptive studies, or reports of expert committees a recommendation; however, other factors may influence
decision-making
*The quality of evidence reported in these guidelines has been adapted from The Evaluation of Evidence criteria described in the Canadian Task Force on
Preventive Health Care.111
†Recommendations included in these guidelines have been adapted from the Classification of Recommendations criteria described in the Canadian Task Force
on Preventive Health Care.111
Recommendations 07. Care providers need to consider that induction of women with
an unfavourable cervix is associated with a higher failure rate
01. The indication for induction must be documented, and discussion
should include reason for induction, method of induction, and in nulliparous patients and a higher Caesarean section rate in
risks, including failure to achieve labour and possible increased nulliparous and parous patients. (II-2A)
risk of Caesarean section. (III-B) 08. Every woman should ideally have an ultrasound, preferably in
the first trimester, to confirm gestational age. (I-A)
02. If induction of labour is unsuccessful, the indication and method
of induction should be re-evaluated. (III-B) 09. Institutions should have quality assurance programs and
induction policies, including safety tools such as checklists,
03. Inductions should not be performed solely for suspected fetal
to ensure that inductions are performed only for acceptable
macrosomia. (III-D)
indications. (II-2B)
04. Inductions should not be performed solely because of patient 10. Women should be offered induction of labour between
or care provider preference. (III-D) 41+0 and 42+0 weeks as this intervention may
05. Health care providers should assess the cervix (using the reduce perinatal mortality and meconium aspiration
Bishop score) to determine the likelihood of success and to syndrome without increasing the Caesarean section
select the appropriate method of induction. (II-2A) rate. (I-A)
06. The Bishop score should be documented. (III-B) 11. Women who chose to delay induction > 41+0 weeks
should undergo twice-weekly assessment for fetal
well-being. (I-A)
12. Intracervical Foley catheters are acceptable agents (II-2B)
ABBREVIATIONS that are safe both in the setting of a vaginal birth after
Caesarean section (I-B) and in the outpatient setting. (II-2B)
ARM artificial rupture of membranes
13. Double lumen catheters may be considered a second-line
ART artificial reproductive technologies
alternative. (II-2B)
CFAS Canadian Fertility and Andrology Society
14. Prostaglandins E2 (cervical and vaginal) should not be used in
FHR fetal heart rate the setting of vaginal birth after Caesarean section due to the
increased risk of uterine rupture. (II-2D)
GBS group B streptococcus
15. Vaginal prostaglandins E2 may be considered with ruptured
NNT number needed to treat
membranes at term and can be used in this setting. (I-A)
NST non-stress test
16. Misoprostol can be considered a safe and effective agent for
PG prostaglandins labour induction with intact membranes and on an inpatient
basis. (I-A)
PGE1 prostaglandins E1
17. Misoprostol should not be used in the setting of vaginal birth
PGE2 prostaglandins E2
after Caesarean section due to the increased risk of uterine
PROM pre-labour rupture of membranes rupture. (II-3D)
18. Oxytocin should be started no earlier than 4 hours after the DEFINITIONS
last dose of misoprostol. (III-B)
19. Amniotomy should be reserved for women with a favourable Induction of labour is the initiation of contractions in a
cervix. Particular care should be given in the case of
unengaged presentation because there is a risk of cord
pregnant woman who is not in labour to help her achieve a
prolapse. (III-B) vaginal birth within 24 to 48 hours.
20. After amniotomy, oxytocin should be commenced early in
order to establish labour. (III-B)
Successful induction is defined as a vaginal delivery
within 24 to 48 hours of induction of labour.
21. In the setting of ruptured membranes at term, oxytocin should
be considered before expectant management. (I-A)
Elective induction is the induction of labour in the
22. Women positive for group B streptococcus should be started
absence of acceptable fetal or maternal indications.
on oxytocin as early as possible after ruptured membranes in
order to establish labour within 24 hours. (III-B)
Cervical ripening is the use of pharmacological or other
23. Both high- and low-dose oxytocin may be considered within a
hospital protocol. (III-B)
means to soften, efface, or dilate the cervix to increase the
likelihood of a vaginal delivery.
24. Because of the various concentrations, oxytocin infusion rates
should always be recorded in mU/min rather than mL/hr. (III-L)
Tachysystole refers to > 5 contractions per 10-minute
25. Oxytocin induction maybe considered in the hospital setting of period averaged over 30 minutes. This is further subdivided
vaginal birth after Caesarean section. (II-3B)
into two categories, one with and one without fetal heart
rate changes.4
Epub ahead of print.
This document will be published in: Hypertonus refers to excessive uterine contractions lasting
J Obstet Gynaecol Can 2013;35(9) > 120 seconds without FHR changes. This term should
be abandoned and has been replaced in this guideline by
tachystole without FHR changes.4
showed that women with a score of > 9 were equally likely Table 2. Modified Bishop Scoring System9
to deliver vaginally whether induced or allowed to labour Score
spontaneously.8 In 1966, Burnett modified the scoring Factor 0 1 2
scheme (still in use and still known as the Bishop score) Dilatation, cm 0 1–2 3–4
so that each variable was assigned a maximum value of 2
Effacement, % 0–30 40–50 60–70
points (for a maximum score of 10).9 A favourable pre-
Length, cm >3 1–3 <1
induction Bishop score of > 6 is predictive of a successful
Consistency Firm Medium Soft
vaginal delivery. Initial studies were limited to parous
Position Posterior Mid Anterior
women, but the score was later found also to be applicable
Station Sp −3 or above Sp −2 Sp −1 or 0
to nulliparous women (Table 2).
score to predict successful labour induction with ultrasound Reprinted with permission from Wolters Kluwer Health: Xenakis EM,
assessment of the cervix with conflicting results. Peregrine Piper JM, Conway DL, Langer O. Induction of labor in the nineties:
conquering the unfavorable cervix. Obstet Gynecol 1997;90(2):235–9.
et al. reported cervical length > 1 cm to be a predictor for
CS with induction of labour.22 In contrast, Hatfield et al.
found that cervical length was not predictive of successful
labour induction,23 and Rozenberg et al. reported that the
Bishop score was a better predictor of time interval from
induction to delivery.24 Using ultrasound to assess cervical
ripeness, Bartha et al. found that fewer women were of an open cervix or cervical massage rather than a pelvic
induced with PG with no difference in outcomes.25 exam had more spontaneous labour within 7 days (73.7% vs.
45.5%, OR 0.2 95%, CI 0.18 to 0.46, P < 0.0001) and a greater
Fetal fibronectin and transvaginal ultrasound have been number of women went into spontaneous labour before
shown to predict successful induction, but neither have 41 weeks (90.5% vs. 70.7%, OR 2.46, 95% CI 1.22 to 4.95).31
been shown to be superior to the Bishop score.10
An RCT by de Miranda et al. involving 742 low-risk women
Recommendations
showed that sweeping every 2 days starting at 41+0 weeks
5. Health care providers should assess the cervix reduced the number of pregnancies reaching 42 weeks.
(using the Bishop score) to determine the likelihood (NNT = 6).32
of success and to select the appropriate method of
induction. (II-2A) In the case of a planned VBAC, Hamdam studied
6. The Bishop score should be documented. (III-B) 108 women who underwent serial sweeping at term and
7. Care providers need to consider that induction of found there was no significant effect on the onset of labour,
women with an unfavourable cervix is associated duration of pregnancy, induction of labour, or repeat CS.33
with a higher failure rate in nulliparous patients and
a higher Caesarean section rate in nulliparous and The effect of coitus on promoting labour is unclear.
parous patients. (II-2A) A 2006 prospective study of 200 women by Tan et al.
used patient reported data of sexual intercourse after 36
weeks to estimate effect on gestational age and mode of
PREVENTION OF INDUCTION delivery.34 Coitus at term was independently associated
with earlier onset of labour (reduction of postdates
Routine antenatal ultrasound for confirmation of expected
pregnancy and less requirement for induction at 41 weeks).
date of delivery has been shown to reduce induction rates
However, a second prospective study of 210 women by
for postdates (> 41+0 weeks) pregnancies after correction
the same researcher compared a coitus-advised group to a
of dates (OR 0.68, 95% CI 0.57 to 0.82).26–28
no-advice group scheduled to have labour induction. The
There is evidence that routine sweeping (stripping) of coitus-advised group reported more sexual activity before
membranes promotes the onset of labour and that this delivery than the non-advised group, but there was no
simple technique decreases induction rates. It is believed significant difference in spontaneous labour.35
that the technique results in an increase of local production
Care provider use of appropriate or inappropriate indications
of prostaglandins.29
for induction has an impact on resources for performing
Membrane sweeping involves the insertion of a digit past induction and on the overall CS rate. Lydon-Rochelle et al.
the internal cervical os followed by three circumferential reviewed the records of 4541 induced pregnancies and found
passes of the digit causing separation of the membranes that 15% of inductions were either not clinically indicated
from the lower segment. In clinical studies when the or not documented.36 Le Ray et al. measured an increase in
cervix was closed, a massage of the cervical surface with CS rate (OR 4.1, 95% CI 1.3 to 12.9) when care providers
the forefinger and middle finger for 15 to 30 seconds violated guidelines for inductions by inducing labour before
was performed. The woman should be informed of the 38 weeks or with a Bishop score < 5 without an indication.37
discomfort and pain and the possibility of bleeding post-
Quality improvement programs have been shown to
procedure before consent is obtained.
reduce the number of elective inductions and unplanned
A 2005 Cochrane review including 32 trials found that CS. Several studies have shown a significant reduction in
routine sweeping performed weekly after 38 weeks resulted the number of elective inductions after the implementation
in a reduced duration of pregnancy beyond 41 and 42 of an induction committee. The role of the committee
weeks. The number needed to treat to prevent 1 induction was to review each request and enforce the use of proper
at 41 weeks was 8.30 This procedure has been associated with indications for induction.38–40
maternal discomfort during vaginal examination and other
minor adverse effects (e.g. bleeding, irregular contractions). Institutional factors may play a role in the CS rate of
induced labours. Brennan et al. compared CS rates in
Since the publication of the Cochrane review by Boulvain 10 different groups defined by the Robson criteria. In
et al.,30 several studies have been published evaluating the the group of low-risk women induced at term, the low
sweeping of membranes. Yildirim et al. found that women induction centres had a lower overall CS rate than the
(> 38 weeks’ gestation) who underwent sweeping in the case higher induction centres (17.7% vs. 27.8%, P < 0.008).41
with FHR changes (4.6% versus 0.51%, RR 4.14, 95% CI In the event of tachysystole, attempts should be made to
1.93 to 8.90). The tablet, pessary, and gel were equivalent, remove the prostaglandin from the vagina. Intrauterine
although the sustained released PGE2 insert was associated rescue may be required and use of a tocolytic agent may
with a decrease in instrumental deliveries. be considered (intravenous Nitroglycerin 50 mcg given
over 2 to 3 minutes and repeated every 3 to 5 minutes to a
A 2008 Cochrane review of intracervical gel versus placebo maximum of 200 mcg). To date, the evidence for safety and
included 28 trials with 3764 women undergoing cervical efficacy remains inconclusive. Another option is the use of
ripening or induction regardless of membrane status.58 nitroglycerin spray (0.4 mg, 1 to 2 puffs sublingual), which
There were fewer women in the PG group who did not has the advantage of a simple and rapid administration and
achieve vaginal delivery within 24 hours (RR 0.61 95% CI uptake, although there have been no clinical trials assessing
0.47 to 0.79). There was a non-significant reduction in the dosing.61
overall risk of CS for all women (RR 0.88, CI 0.77 to 1.00),
but there was a statistically significant reduction of CS Outpatient PG is an attractive option for reducing the use of
(RR 0.82, 95% CI 0.68 to 0.98) in women with an health care resources. Large studies are lacking to determine
unfavourable cervix and intact membranes, suggesting their overall safety, in particular for rare but serious adverse
that oxytocin alone can and should be used for induction effects. A 2003 RCT of 300 women evaluated outpatient
after term PROM. There was an increased risk of uterine versus in-patient induction with Cervidil. Three hundred
tachysystole without changes in FHR (RR 1.59 95% CI 1.09 eligible patients with uncomplicated, low-risk pregnancies
to 2.33) but no increase tachysystole with FHR changes.58 and a Bishop score ≤ 6, parity ≤ 5, gestation > 37 weeks,
a reactive NST, and singleton cephalic pregnancy with
The same review compared intracervical and intravaginal intact membranes. Cervidil was inserted and the patient
interventions in 3881 women in 29 trials. The risk of not monitored for 1 hour before being allowed to go home.
achieving vaginal delivery at 24 hours was greater in the Use of oxytocin, epidural rate, operative delivery rate, CS
intracervical group (RR 1.26, 95% CI 1.12 to 1.41) but rate, and median time to labour and delivery within 24
there were no differences in the risk of CS and tachysystole hours were the same for each group. The outpatient group
with or without fetal heart changes.58 spent a median of 8 hours at home and reported a higher
PGs have been used to induce labour with PROM at term. satisfaction during the initial 12 hours (56% vs. 39%).62
A 2006 Cochrane review included 12 trials (6814 women, Current recommendations for outpatient induction in
PROM > 37 weeks) and compared planned management low-risk pregnancies suggest continuous electronic fetal
with either oxytocin or vaginal prostaglandin with expectant monitoring for 1 to 2 hours after administration of PG
management. Overall, there was no difference for mode of and the use of intermittent auscultation when labour is
birth; results were similar for CS and vaginal delivery. For active.63
women who underwent planned delivery, there was less
chorioamnionitis or endometritis and fewer admissions to A 2010 Cochrane review including 28 RCTs with
NICU, but no difference in neonatal infection rates. One 2616 women who were induced with mechanical and
trial found that women in the planned group were more pharmacological methods concluded that the outpatient
likely to perceive the experience as being more positive.59 setting was feasible, but that there was insufficient evidence
to recommend which method was most effective and safe.64
The timing of insertion may have an influence on
interventions. One study of 620 women (nulliparous and Sweeping of the membranes during induction of labour
parous) compared admission in the morning versus the increases success rates. Two randomized trials recruited
evening and found that morning inductions were less likely women with term, cephalic, nulliparous and parous
to need oxytocin infusion (45% vs. 54%, RR 0.83, 95% CI pregnancies and intact membranes scheduled for induction
0.70 to 0.97). Nulliparous women admitted in the morning with PG vaginal gel if the cervix was unfavourable (Bishop
had fewer operative vaginal births (16.1% vs. 34.2%, ≤ 4) or with amniotomy if the cervix was favourable
RR 0.47, 95% CI 0.25 to 0.90).60 Adverse effects with the (Bishop > 4 or cervix > 3 cm). Both groups were treated
use of prostaglandin E2 include uterine tachysystole and according to institutional protocols for active management
maternal effects (i.e. fever, chills, vomiting, diarrhea). Care of labour. Both studies showed that membrane sweeping
must be taken to avoid application of the higher dose vaginal at the time of induction resulted in shorter induction to
preparations into the cervical canal. Rare, idiopathic adverse delivery time, lower use of oxytocin, and a higher rate
cardiovascular events may occur, but they almost always of spontaneous vaginal deliveries. Tan et al.35 benefit
occur immediately after the administration of the agent. applied to both nulliparous and parous women, while
Foong et al.65 found that the benefit of sweeping was Benefits of misoprostol include its stability at room
limited to nulliparous women with an unfavourable cervix. temperature, rapid onset of action, multiple potential
Tan et al. also found both higher maternal satisfaction in routes of administration (oral, buccal, sublingual, vaginal,
the birth process and higher post-sweeping pain.35 rectal), and low cost. These potential benefits make it an
attractive alternative to PGE2.
Summary Statements
1. Prostaglandins E2 (cervical and vaginal) are effective Dosing of misoprotol:
agents of cervical ripening and induction of labour •• Give 50 mcg orally with a drink of water (ensure that it
for an unfavourable cervix. (I) is swallowed quickly to avoid sublingual absorption) or
2. Intravaginal prostaglandins E2 are preferred to give 25 mcg vaginally.
intracervical prostaglandins E2 because they results
in more timely vaginal deliveries. (I) •• Repeat every 4 hours as long as contractions are absent
or non-painful.
Recommendations •• Oxytocin can only be used 4 hours after the last dose.
14. Prostaglandins E2 (cervical and vaginal) should
Serious adverse events with the use of misoprostol
not be used in the setting of vaginal birth after
are similar to those of other PG and include uterine
Caesarean section due to the increased risk of
tachysystole with its potential fetal and maternal effects
uterine rupture. (II-2D)
and meconium staining of liquor. It is generally agreed
15. Vaginal prostaglandins E2 may be considered with
that it is a potent uterotonic and should not be used in
ruptured membranes at term and can be used in
women with a previous CS because it will increase the risk
this setting. (I-A)
of uterine rupture.68,69 In general, large studies are required
to assess the rare, but life-threatening, uterine rupture that
Practice Points has been reported anecdotally in women with and without
•• PGE2 reduce CS rates of women with an unfavourable a previous CS.70 A 2010 Cochrane review of vaginal
cervix and result in greater maternal satisfaction. misoprostol for cervical ripening and induction of labour
•• Oxytocin can be started 30 minutes after removal of a included 121 trials that compared misoprostol to placebo/
dinpoprostone insert (Cervidil) and 6 hours hours after no treatment or to other methods (vaginal PG, cervical
gel (Prostin, Prepidil). PG, and oxytocin) of induction. Vaginal misoprostol
•• PGE2 in the setting of ruptured membranes had more was superior to placebo with a reduced failure to achieve
maternal but no more neonatal infections. vaginal delivery within 24 hours (RR 0.51, 95% CI 0.37 to
0.71) but increased tachysystole without fetal heart changes
•• Care must be taken to avoid the insertion of the higher (RR 3.53, 95% CI 1.78 to 6.99).71
dose of vaginal PGE2 (2 mg) into the cervical canal.
•• Uterine tachysystole without FHR changes is more Several studies have compared 25 mcg and 50 mcg doses.
common with PGE2 but does not lead to a higher Most have found that lower doses of misoprostol resulted
CS rate. in more need for oxytocin augmentation and less uterine
tachysystole, with and without FHR changes, compared
•• Nitroglycerin can be used to treat uterine tachysystole to higher doses.7,71 The induction to delivery time was
but requires more study. shorter with the higher 50 mcg dose.66,72 An RCT of
Misoprostol is a synthetic PGE1 analog that has been 124 women using several different doses (25, 50, 100,
approved and marketed for the prevention and treatment 200 mcg) resulted in more vaginal deliveries at 12 and
of gastric ulcers associated with the use of non-steroidal 24 hours, more tachysystole, and less need for oxytocin
anti-inflammatory drugs.66 Misoprostol has also been with each incremental dose.73 A double-blind RCT of
found to be an effective agent for cervical ripening and 374 women (> 36 weeks, Bishop ≤ 4) administered either
labour induction, and those off-label uses have been widely 100 mcg or 200 mcg misoprostol vaginal insert had similar
adopted. findings with the higher dose resulting in significantly more
women achieving vaginal delivery within 24 hours (24%
The first study to describe the successful induction of vs. 36%), shorter induction to delivery time (1181 vs. 1744
labour in the case of intrauterine fetal demise was published minutes), and less use of oxytocin (49% vs. 71%), but an
in 1987.67 Since then, there have been over 100 randomized increased rate of tachysystole (41% vs. 19.5%). There was a
trials studying the efficacy and safety of induction in viable non-significant reduction of CS in the higher 200 mcg dose
term inductions. group (22.9% vs. 32.4%).74
A 2006 Cochrane review including 4 trials (474 women) A 2009 systemic review that compared oral misoprostol
comparing oral misoprostol with placebo found the to vaginal dinoprostone included 5 studies (2281 women),
misoprostol group was less likely to have long labour only 1 of which was blinded, and found that women who
(RR 0.16, 95% CI 0.05 to 0.49), had less need for oxytocin had oral misoprostol had fewer CS (2% vs. 26%) but their
(RR 0.32, 95% CI 0.24 to 0.43), and had a lower CS rate need for oxytocin stimulation, incidence of tachysystole
(RR 0.62, 95% CI 0.40 to 0.96). The author recommended without FHR changes, and maternal adverse effects were
that the oral misoprostol dose should not exceed 50 mcg.75 similar to those who had vaginal dinoprostone.79 A similar
review found that the CS rate was the same, but that the
The same Cochrane review included 16 trials (3645 women) misoprostol group had a higher rate of vaginal deliveries
and found that women who were given oral misoprostol within 24 hours, a lower rate of oxytocin use, and a trend
had a lower incidence of uterine tachysystole without FHR towards higher meconium staining.80
changes (RR 0.37, 95% CI 0.23 to 0.59) and more need
for oxytocin (RR 1.28, 95% CI 1.11 to 1.48), but more A 2010 Cochrane review concluded that vaginal misoprostol
meconium stained liquor (RR 1.27, 95% CI 1.01 to 1.60) was also superior to other induction agents (vaginal
than women given vaginal misoprostol.75 A prospective prostaglandin, intracervical prostaglandin, and oxytocin),
RCT of 204 women comparing 25 mcg oral versus 50 mcg with less epidural use and fewer failures to achieve vaginal
vaginal given every 4 hours up to 4 doses found that the delivery within 24 hours, but more tachysystole with FHR
lower oral dose had lower incidence of tachysystole with changes.71
FHR changes (2.2% vs. 5.4%) and a lower CS rate (19.4%
vs. 32.4%), but no difference in induction to delivery time Several studies have reported on efficacy of sublingual
or side effects (nausea, vomiting, shivering, or diarrhea) misoprostol to be comparable to the oral route. An RCT
than the higher vaginal dose.76 An RCT of 120 women that of 212 women compared 50 mcg to 100 mcg sublingual
compared 12.5 mcg oral misoprostol with 25 mcg vaginal doses and reported the higher dose to be more effective
found no difference in outcomes in terms of mode of but to result in more tachysystole.81 A double blind RCT of
delivery, induction to delivery time, need for oxytocin, or 140 women found that 50 mcg of sublingual misoprostol
complications.77 had a similar efficacy to 25 mcg vaginal misoprostol.82 A
systemic review that included 5 studies (740 women) found
A 2008 RCT of 205 women comparing oral (20 mcg every no difference between sublingual (25 to 50 mcg every
hour for up to 4 doses until 3 contractions in 10 minutes) 4 hours) and vaginal misoprostol (25 to 50 mcg every
and vaginal (25 mcg every 4 hours until Bishop > 7) 4 hours) in the rates of vaginal deliveries at 24 hours,
misoprostol found that the oral group had a higher rate uterine tachysystole, or CS.83 Two studies reported that
of vaginal deliveries at 12 hours (74.4% vs. 25.5%) and a patient satisfaction was higher using the sublingual route
lower rate of tachysystole (0% vs. 11.3%), but more nausea than the vaginal route.84,85
(11% vs. 0%). This study was limited because the staff was
not blinded and the average total dose of misoprostol was A prospective randomized study of 96 patients with an
higher in the oral group (180 mcg vs. 50 mcg).78 unfavourable cervix underwent cervical ripening with
either vaginal misoprostol (50 mcg dose) or Foley catheter.
A 2009 systemic review included 9 studies (2937 women) The misoprostol group achieved a favourable cervix
comparing low-dose oral misoprostol (20 to 25 mcg) to (Bishop ≥ 6) faster than the Foley group (98% vs. 69%,
dinoprostone (PGE2), vaginal misoprostol, and oxytocin. P < 0.001), although the induction to delivery interval
Two of the trials compared oral and low-dose vaginal was equivalent. There was lower use of oxytocin in the
misoprostol and found that the oral route resulted in less misoprostol group, part of which could be attributed to
uterine tachysystole with FHR changes.79 the 6-hour wait required before starting oxytocin after the
last dose.86
Misoprostol (PGE1) versus Dinoprostone (PGE2)
A 2006 Cochrane review included 9 trials (2627 women) Another study of 100 women comparing a higher single
that compared oral misoprostol to vaginal dinoprostone dose of misoprostol (100 mcg vaginal) to Foley catheter
and found that women who received oral misoprostol for cervical ripening found that misoprostol had a shorter
were less likely to have a CS.75 However, this only reached induction to delivery time (11.8 h vs. 20.0 h, P < 0.05).
significance in women with intact membranes (RR 0.78, There were two uterine ruptures, both in the misoprostol
95% CI 0.66 to 0.94). There was more uterine tachysystole group. One occurred in a 39-year-old parous woman with 3
in the oral group, but this was not associated with adverse previous deliveries induced at term because of an impaired
fetal outcomes. glucose tolerance that developed persistent fetal tachycardia
7 hours post-insertion without uterine tachysystole. The •• The lower vaginal dose (25 mcg) tends to need more
second woman with uterine rupture was a nulliparous oxytocin stimulation and the higher vaginal dose
32-year-old induced because of prolonged pregnancy (≥ 50 mcg) tends to have more uterine tachysystole.
complicated by second stage dystocia due to cephalopelvic •• All doses of misoprostol can cause uterine
disproportion who developed uterine tachysystole with tachysystole.
abnormal FHR changes 11 hours post-insertion. Both
•• Fetal well-being is required before administration of
infants were delivered with Apgar ≥ 7 at 5 minutes.87
misoprostol. Electronic fetal monitoring should be
Few studies have used misoprostol in the case of PROM. performed for 30 minutes after administration of
An open RCT of 150 women with PROM at term misoprostol and for 60 minutes after any tachysystole.
compared vaginal misoprostol (25 mcg every 6 hours ×
4 doses) to expectant management followed by oxytocin OPTIONS FOR INDUCTION
induction if labour did not begin. The misoprostol group WITH A FAVOURABLE CERVIX
had a shorter latency time to achieve labour (9.4 vs. 15.8
hours), shorter recruitment to delivery time (18.9 vs. 27.5 Amniotomy
hours), a trend towards lower oxytocin use, and lower CS.88 Amniotomy can be a simple and effective component
of labour induction when the membranes are accessible
An RCT of 758 women compared low dose (25 mcg) and the cervix is favourable. This intervention creates a
oral (Bishop > 6) or vaginal (Bishop ≤ 6) misoprostol to commitment to delivery and must be done for convincing
vaginal dinoprostone with rupture of membranes > 34 and compelling reasons. However, the time interval from
weeks’ gestation. There was no difference in CS and vaginal amniotomy to established labour may not be acceptable
delivery rates but there was a trend towards the misoprostol to clinicians or to women, and in a number of cases, after
group requiring less oxytocin, less epidural use, and less amniotomy alone, labour will not commence.
CS for failure to progress. Misoprostol also seemed to
be more effective than dinoprostone in the setting of Contraindications include placenta previa, vasa previa, and
an unfavourable cervix, whereas oxytocin seemed to be active genital infection except for women colonized with
more effective than misoprostol in a favourable cervix. GBS. Cord prolapse is a risk of amniotomy, especially in a
Unfortunately, the predetermined sufficient sample size high presentation or unstable lie. After the membranes are
of 1890 women to provide meaningful results could not ruptured, the care provider should continue to palpate the
be reached due to lack of funding. Larger studies with presenting part until it rests against the cervix to ensure
sufficient numbers are required to complete the analysis.89 there has been no cord prolapse. The amount, colour, and
consistency of the fluid as well as fetal well-being should
Recommendations be assessed.
16. Misoprostol can be considered a safe and effective
There are no studies comparing amniotomy alone to
agent for labour induction with intact membranes
placebo.
and on an inpatient basis. (I-A)
17. Misoprostol should not be used in the setting of Amniotomy can be used for induction when the cervix is
vaginal birth after Caesarean section due to the favourable, but the onset of labour is unpredictable and
increased risk of uterine rupture. (II-3D) often requires oxytocin. A 2007 Cochrane meta-analysis
18. Oxytocin should be started no earlier than 4 hours of 17 trials with 2566 women measured the safety of
after the last dose of misoprostol. (III-B) amniotomy and intravenous oxytocin for induction of
labour. Amniotomy alone resulted in fewer vaginal deliveries
Practice Points in 24 hours then amniotomy plus oxytocin (RR 0.03,
•• Misoprostol is more effective than PGE2 to achieve 95% CI 0.01 to 0.49). Amniotomy and oxytocin resulted in
vaginal delivery and results in less epidural use but fewer instrumental deliveries than placebo (RR 0.18, 95%
more uterine tachysystole. CI 0.05 to 0.58). However, there was more postpartum
•• PGE1 and PGE2 both reduce CS rates in an hemorrhage (RR 5.5, 95% CI 1.26 to 24.07) and maternal
unfavourable cervix. dissatisfaction (RR 53, 95% CI 3.32 to 846.51) with
amniotomy and oxytocin than with vaginal PG.90
•• The oral and vaginal routes have a similar reduction
of CS rates. The oral route needs more oxytocin A more recent small RCT of amniotomy and immediate
stimulation but the vaginal route will have more oxytocin infusion versus amniotomy and delayed oxytocin
tachysystole. infusion for induction of labour in 123 women at term
found that women in the immediate group were more with a dose of 4 to 6 mU/min, with dose increments of
likely to be in established labour 4 hours post amniotomy, 4 to 6 mU/min every 15 to 30 minutes. The benefits of
have a shorter amniotomy to delivery interval (P < 0.001), the low-dose regimen include less risk of tachysystole and
and achieve vaginal delivery within 12 hours (RR 1.5; the use of a smaller overall dose. However, the high-dose
95% CI 1.2 to 12.6).91 There was no difference between oxytocin regimen has been shown to reduce the length of
the groups with regard to mode of delivery or incidence labour with no appreciable increase in neonatal morbidity97.
of uterine tachysystole with abnormal FHR recording. High-dose oxytocin has been associated with an increase
Although the study was underpowered to provide an in uterine tachysystole with associated FHR changes.61
adequate statistical analysis, women in the immediate Continuous fetal monitoring is recommended with the use
group were more likely to be satisfied with the induction of oxytocin.98 Because mixing methods vary, the rate of
process (RR 4.1, 95% CI 1.1 to 16.1) and the duration of infusion should always be documented in mU/min rather
labour (RR 1.8, 95% CI 1.0 to 3.3). than ml/hour.
Recommendations Example of low-dose protocol:
19. Amniotomy should be reserved for women with a
Initial dose of oxytocin..................................1 to 2 mU/min
favourable cervix. Particular care should be given in
the case of unengaged presentation because there is Increase interval......................................................30 minutes
a risk of cord prolapse. (III-B) Dosage increment....................................................1 to 2 mU
20. After amniotomy, oxytocin should be commenced
Usual dose for good labour.........................8 to 12 mU/min
early in order to establish labour. (III-B)
Maximum dose before reassessment.................30 mU/min
Practice Point Example of high-dose protocol:
•• Amniotomy creates a commitment to delivery
and should be performed when the indication for Initial dose of oxytocin..................................4 to 6 mU/min
induction is convincing and the reasons compelling Increase interval............................................15 to 30 minutes
and documented. Dosage increment...........................................4 to 6 mU/min
Oxytocin Usual dose for good labour.........................8 to 12 mU/min
Intravenous oxytocin, available since the 1950s, has been Maximum dose before reassessment.................30 mU/min
the most commonly used method of induction for women
with a viable pregnancy and favourable cervix. Oxytocin is a A 2009 Cochrane review included 61 studies (12 819
peptide produced naturally in the posterior hypothalamus that women) of the methods of cervical ripening and labour
binds to uterine receptors to produce uterine contractions, induction.99 Oxytocin alone versus vaginal prostaglandins
but it has no direct effect on the cervix. It has a half-life was associated with an increase in unsuccessful vaginal
of 5 to 12 minutes,92 a time to steady plasma concentration delivery within 24 hours (70% vs. 21%). Oxytocin versus
of 40 minutes,93 and a steady-state uterine response of 30 intracervical prostaglandins also had fewer vaginal deliveries
minutes or longer.94 The uterus is increasingly responsive (51% vs. 35%) and increase in CS rates (19.1% vs. 13.7%).
to oxytocin as pregnancy progresses.95 Other areas of the For all women with an unfavourable cervix regardless of
body that respond to oxytocin include the breast, vascular membrane status, the CS rates were increased (19.0% vs.
smooth muscle, and kidney. At dosages typically used for 13.1%, RR 1.42, 95% CI 1.11 to 1.82) when labour was
the induction of labour, there is not a demonstrable effect induced.99
on renal function or vascular smooth muscle tone. However,
IV boluses of as little as 0.5 U can transiently decrease In the case of a favourable cervix, the CS rate was no
peripheral vascular tone, leading to hypotension.96 Due to its different whether the pregnancy was induced or managed
antidiuretic activity, water intoxication is possible with high expectantly.8,17,21 Osmundson et al. measured a significantly
doses (> 40 mU/min). higher rate of oxytocin use in the elective induction group
than in the group managed expectantly (99.3 % vs. 30.6 %,
The physiological dose of oxytocin to produce regular P < 0.001).21
uterine contraction is 8 to 12 mU/min. The ideal dosing
regimen of oxytocin is not known and there are both low- Term PROM
dose and high-dose protocols. The low-dose regimen begins A 2006 Cochrane analysis reviewed the advantages of early
with 1 to 2 mU/min, increased incrementally by 1 to 2 mU intervention with either oxytocin or prostaglandin versus
at 30-minute intervals. The high-dose regimen commences expectant management in the setting of term PROM.59
and very low birth weight, small for gestational age, and 9. Burnett JE Jr. Preinduction scoring: an objective approach to induction of
labor. Obstet Gynecol 1966;28:479–83.
NICU admission as illustrated in a recent SOGC-CFAS
guideline.109 A prospective database review by the FASTER 10. Crane JM. Factors predicting labor induction success: a critical analysis.
Clin Obstet Gynecol 2006;49:573–84.
Research Consortium showed an adjusted OR (95% CI)
11. Laughon SK, Zhang J, Troendle J, Sun L, Reddy UM. Using a simplified
of 2.1 (1.3 to 3.6) for fetal loss or demise (> 24 weeks).110 Bishop score to predict vaginal delivery. Obstet Gynecol
Many women undergoing ART are older, which increases 2011;117:805–11.
their risk of the adverse perinatal outcomes listed above. 12. Vrouenraets FP, Roumen FJ, Dehing CJ, van der Akker ES, Aarts MJ,
Until there is more evidence available, induction should be Scheve EJ. Bishop score and risk of cesarean delivery after induction of
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13. Ennen CS, Bofill JA, Magann EF, Bass JD, Chauhan SP, Morrison JC.
Risk factors for cesarean delivery in preterm, term, and post-term patients
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This document reflects emerging clinical and scientific advances on the date issued and is subject to change. The information
should not be construed as dictating an exclusive course of treatment or procedure to be followed. Local institutions can dictate
amendments to these opinions. They should be well documented if modified at the local level. None of these contents may be
reproduced in any form without prior written permission of the SOGC.
Key to evidence statements and grading of recommendations, using the ranking of the Canadian Task Force on
Preventive Health Care
Quality of evidence assessment* Classification of recommendations†
I: Evidence obtained from at least one properly randomized A. There is good evidence to recommend the clinical preventive action
controlled trial
II-1: Evidence from well-designed controlled trials without B. There is fair evidence to recommend the clinical preventive action
randomization
II-2: Evidence from well-designed cohort (prospective or C. The existing evidence is conflicting and does not allow to make a
retrospective) or case–control studies, preferably from recommendation for or against use of the clinical preventive action;
more than one centre or research group however, other factors may influence decision-making
II-3: Evidence obtained from comparisons between times or D. There is fair evidence to recommend against the clinical preventive action
places with or without the intervention. Dramatic results in
uncontrolled experiments (such as the results of treatment with E. There is good evidence to recommend against the clinical preventive
penicillin in the 1940s) could also be included in this category action
III: Opinions of respected authorities, based on clinical experience, L. There is insufficient evidence (in quantity or quality) to make
descriptive studies, or reports of expert committees a recommendation; however, other factors may influence
decision-making
*The quality of evidence reported in these guidelines has been adapted from The Evaluation of Evidence criteria described in the Canadian Task Force on
Preventive Health Care.
†Recommendations included in these guidelines have been adapted from the Classification of Recommendations criteria described in the Canadian Task Force
on Preventive Health Care.
Woolf SH, Battista RN, Angerson GM, Logan AG, Eel W. Canadian Task Force on Preventive Health Care. New grades for recommendations from the
Canadian Task Force on Preventive Health Care. CMAJ 2003;169:207–8.
examination of the middle cerebral artery, ductus venosus, 10. In cases in which the fetus measures < 10th percentile
and umbilical vein can be considered. (II-2) by estimated fetal weight or abdominal circumference
measurement, the underlying cause of intrauterine growth
11. For a fetus with intrauterine growth restriction, the decision
restriction may be established by an enhanced ultrasound
for obstetrical intervention, including Caesarean section, in
examination to include a detailed review of fetal anatomy,
cases of abnormal fetal heart rate or malpresentation is largely
placental morphology, and Doppler studies of the uterine and
based on fetal viability, as assessed by ultrasound. (II-2)
umbilical arteries. (II-2A)
12. Maternal surveillance for the development of preeclampsia is
11. In cases of intrauterine growth restriction, determination
warranted. (II-2)
of amniotic fluid volume should be performed to aid in
the differential diagnosis of intrauterine growth restriction
Recommendations and increase the accuracy of the diagnosis of placental
01. Women should be screened for clinical risk factors for insufficiency. (II-2B)
intrauterine growth restriction by means of a complete 12. Umbilical artery Doppler should be performed in all fetuses
history. (II-2B) with an estimated fetal weight or an abdominal circumference
02. Women should be counselled on smoking cessation at any < 10th percentile. (I-A)
time during pregnancy. (II-2A) 13. In pregnancies affected by intrauterine growth restriction,
03. First and second trimester screening tests for aneuploidy umbilical artery Doppler studies after 24 weeks may prompt
maybe useful tests of placental function. If two screening intervention that reduces perinatal mortality and severe
test results are abnormal, health care providers should be perinatal morbidity due to intrauterine growth restriction. (I-A)
aware that the fetus is at increased risk of preterm intrauterine 14. In pregnancies in which intrauterine growth restriction has
growth restriction and associated stillbirth. (II-1A) been identified, invasive testing to rule out aneuploidy may
04. If intrauterine growth restriction is suspected, further be offered where fetal abnormalities are suspected, soft
assessment can assist in making the diagnosis. If available, markers are seen, or no supportive evidence of underlying
detailed ultrasound examination of the placenta (looking placental insufficiency is evident. (II-2A)
for evidence of a small, thickened placenta, or abnormal 15. In patients presenting with intrauterine growth restriction,
morphology) and uterine artery Dopplers should be considered maternal screening for infectious etiology may be
at 19 to 23 weeks. In the absence of available diagnostic considered. (II-2A)
testing, closer surveillance should be offered. A maternal–
fetal medicine consultation can be considered if the placenta 16. When intrauterine growth restriction is diagnosed,
appears abnormal on ultrasound, especially in the context of surveillance should be initiated. Serial ultrasound estimation
a growth-restricted fetus and abnormal uterine artery Doppler. of fetal weight (every 2 weeks), along with umbilical artery
In a rural setting, the caregiver needs to decide whether the Doppler studies should be initiated. If available, a placental
patient should be delivered immediately, or whether transfer to assessment and other Doppler studies such as middle
a tertiary centre is appropriate. A telephone consultation and cerebral artery, umbilical vein, and ductus venosis can be
telemedicine may help. (II-2A) performed. Increased frequency of surveillance may be
required. (II-2A)
05. In women without risk factors for intrauterine growth
restriction, comprehensive third trimester ultrasound 17. If fetal growth starts to plateau, amniotic fluid index starts to
examination including biophysical profile, fetal biometry, decline, or fetal tone or gross movements are diminished or
amniotic fluid volume, and umbilical artery Doppler studies is absent, then more intensive surveillance (e.g., 2 to 3 times
not recommended. (II-2D) per week) or admission to hospital and delivery planning is
required. (II-2A)
06. Low-dose aspirin should be recommended to women with a
previous history of placental insufficiency syndromes including 18. Abnormal umbilical cord Doppler (e.g., absent or reversed
intrauterine growth restriction and preeclampsia. It should be end-diastolic flow) in the presence of intrauterine growth
initiated between 12 and 16 weeks’ gestation and continued restriction is an ominous finding that requires intervention
until 36 weeks. (I-A) and possible delivery. (I-A)
07. Low-dose aspirin should also be recommended to women with 19. Cardiotocography (non-stress testing) performed antenatally
two or more current risk factors in pregnancy including, but as a test of fetal well-being should not be used in isolation to
not limited to, pre-gestational hypertension, obesity, maternal monitor fetuses with intrauterine growth restriction. (II-2E)
age > 40 years, history of use of artificial reproductive 20. Maternal administration of corticosteroids is indicated if there
technology, pre-gestational diabetes mellitus (type I or II), is a significant possibility of delivery at < 34 weeks’ gestation,
multiple gestation, previous history of placental abruption, and as administration may positively affect umbilical Doppler
previous history of placental infarction. It should be initiated studies. (I-A)
between 12 and 16 weeks’ gestation and continued until 36
21. If delivery was not indicated prior to 37 weeks in a
weeks. (I-A)
patient diagnosed with intrauterine growth restriction,
08. Umbilical artery Doppler studies are not recommended as a expectant management with close fetal and maternal
routine screening test in uncomplicated pregnancies. (I-E) surveillance versus delivery should be discussed after
37 weeks. (I-A)
09. An ultrasound examination for estimated fetal weight
and amniotic fluid volume should be considered after 22. Site of planned delivery should take into consideration
26 weeks if the symphysis-fundal height measurement facilities and expertise available at each institution
in centimetres deviates by 3 or more from the gestational including obstetricians, pediatricians or neonatologists
age in weeks or there is a plateau in symphysis-fundal as appropriate, anaesthesiologists, and access to Caesarean
height. (II-2B) section. (III-A)
I
Doppler studies. (I)
ntrauterine growth restriction is a problem faced by
7. In women with risk factors for intrauterine growth
obstetrical care providers on a daily basis. Neonatal
restriction, uterine artery Doppler screening at
mortality in both term and pre-term neonates is significantly
19 to 23 weeks may identify pregnancies at risk
increased in those diagnosed antenatally with IUGR.
of antepartum stillbirth and preterm delivery due
Despite the importance of the topic, there is a paucity of
to intrauterine growth restriction and placental
level I evidence. The purpose of this guideline is to provide
disease. (II-2)
summary statements and recommendations and to establish
8. In pregnancies in which intrauterine growth
a framework for screening, diagnosis, and management of
restriction due to uteroplacental vascular
pregnancies affected with IUGR. A previously published
insufficiency is diagnosed, maternal surveillance
review (Lausman et al., 2012) provides further background.
for the development of severe preeclampsia with
adverse features is warranted. (II-1)
Summary Statements
9. Once surveillance of a fetus with intrauterine
1. The definition of small-for-gestational age for growth restriction is instituted, umbilical artery
a fetus in utero is an estimated fetal weight that Doppler studies and biophysical profile scoring
measures < 10th percentile on ultrasound. This can be used as short-term predictors of fetal
diagnosis does not necessarily imply pathologic well-being. (I)
growth abnormalities, and may simply describe a 10. In the presence of abnormal umbilical artery
fetus at the lower end of the normal range. (III) Doppler studies, further investigation of the fetal
2. Intrauterine growth restriction refers to a fetus circulatory system by Doppler examination of
with an estimated fetal weight < 10th percentile the middle cerebral artery, ductus venosus, and
on ultrasound that, because of a pathologic umbilical vein can be considered. (II-2)
process, has not attained its biologically determined 11. For a fetus with intrauterine growth restriction,
growth potential. (III) A clinical estimation of the decision for obstetrical intervention, including
fetal weight or symphysis-fundal height has Caesarean section, in cases of abnormal fetal heart
poor sensitivity and specificity and should not rate or malpresentation is largely based on fetal
be relied upon to diagnose intrauterine growth viability, as assessed by ultrasound. (II-2)
restriction. Intrauterine growth restriction should 12. Maternal surveillance for the development of
be considered in the differential diagnosis when the preeclampsia is warranted. (II-2)
fetus is found to be small for gestational age. (II-1)
3. Effective screening for intrauterine growth
restriction requires accurate dating and includes a Recommendations
review of the mother’s menstrual history, relevant 1. Women should be screened for clinical risk factors
assisted reproductive technology information, and for intrauterine growth restriction by means of a
either a first trimester or early second trimester complete history. (II-2B)
dating ultrasound. (I) 2. Women should be counselled on smoking cessation
4. Symphysis-fundal height determination is of limited at any time during pregnancy. (II-2A)
value in routine obstetrical care, but continues to 3. First and second trimester screening tests for
be the only physical examination screening test aneuploidy maybe useful tests of placental function.
available. (I) If two screening test results are abnormal, the fetus
5. Fetal weight determination in fetuses between the is at increased risk of preterm intrauterine growth
10th and 90th percentiles by ultrasound biometry restriction and associated stillbirth. (II-1A)
alone has at least a 10% error rate across gestation, 4. If intrauterine growth restriction is suspected,
but is effective equally when measuring with further assessment can assist in making the
abdominal circumference alone or in combination diagnosis. If available, detailed ultrasound
with head size (biparietal diameter or head examination of the placenta (looking for evidence
circumference) and/or femur length to establish an of a small, thickened placenta, or abnormal
estimated fetal weight. (II-2) morphology) and uterine artery Dopplers should
6. Determining whether intrauterine growth be considered at 19 to 23 weeks. In the absence
restriction is symmetric or asymmetric is of less of available diagnostic testing, closer surveillance
clinical importance than careful re-evaluation of should be offered. A maternal–fetal medicine
consultation can be considered if the placenta intrauterine growth restriction and increase
appears abnormal on ultrasound, especially in the the accuracy of the diagnosis of placental
context of a growth-restricted fetus and abnormal insufficiency. (II-2B)
uterine artery Doppler. In a rural setting, the 12. Umbilical artery Doppler should be performed
caregiver needs to decide whether the patient in all fetuses with an estimated fetal weight or an
should be delivered immediately, or whether abdominal circumference < 10th percentile. (I-A)
transfer to a tertiary centre is appropriate. A 13. In pregnancies affected by intrauterine growth
telephone consultation and telemedicine may restriction, umbilical artery Doppler studies after
help. (II-2A) 24 weeks may prompt intervention that reduces
5. In women without risk factors for intrauterine perinatal mortality and severe perinatal morbidity
growth restriction, comprehensive third trimester due to intrauterine growth restriction. (I-A)
ultrasound examination including biophysical 14. In pregnancies in which intrauterine growth
profile, fetal biometry, amniotic fluid volume, restriction has been identified, invasive testing to
and umbilical artery Doppler studies is not rule out aneuploidy may be offered where fetal
recommended. (II-2D) abnormalities are suspected, soft markers are seen,
6. Low-dose aspirin should be recommended to or no supportive evidence of underlying placental
women with a previous history of placental insufficiency is evident. (II-2A)
insufficiency syndromes including intrauterine 15. In patients presenting with intrauterine growth
growth restriction and preeclampsia. It should be restriction, maternal screening for infectious
initiated between 12 and 16 weeks’ gestation and etiology may be considered. (II-2A)
continued until 36 weeks. (I-A) 16. When intrauterine growth restriction is diagnosed,
7. Low-dose aspirin should also be recommended surveillance should be initiated. Serial ultrasound
to women with two or more current risk factors estimation of fetal weight (every 2 weeks), along
in pregnancy including, but not limited to, pre- with umbilical artery Doppler studies should be
gestational hypertension, obesity, maternal age initiated. If available, a placental assessment and
> 40 years, history of use of artificial reproductive other Doppler studies such as middle cerebral
technology, pre-gestational diabetes mellitus artery, umbilical vein, and ductus venosis can be
(type I or II), multiple gestation, previous history performed. Increased frequency of surveillance
of placental abruption, and previous history of may be required. (II-2A)
placental infarction. It should be initiated between 17. If fetal growth starts to plateau, amniotic fluid
12 and 16 weeks’ gestation and continued until index starts to decline, or fetal tone or gross
36 weeks. (I-A) movements are diminished or absent, then more
8. Umbilical artery Doppler studies are not intensive surveillance (e.g., 2 to 3 times per week)
recommended as a routine screening test in or admission to hospital and delivery planning is
uncomplicated pregnancies. (I-E) required. (II-2A)
9. An ultrasound examination for estimated fetal 18. Abnormal umbilical cord Doppler (e.g., absent
weight and amniotic fluid volume should be or reversed end-diastolic flow) in the presence of
considered after 26 weeks if the symphysis-fundal intrauterine growth restriction is an ominous finding
height measurement in centimetres deviates by 3 or that requires intervention and possible delivery. (I-A)
more from the gestational age in weeks or there is a 19. Cardiotocography (non-stress testing) performed
plateau in symphysis-fundal height. (II-2B) antenatally as a test of fetal well-being should
10. In cases in which the fetus measures < 10th not be used in isolation to monitor fetuses with
percentile by estimated fetal weight or abdominal intrauterine growth restriction. (II-2E)
circumference measurement, the underlying 20. Maternal administration of corticosteroids is
cause of intrauterine growth restriction may be indicated if there is a significant possibility of
established by an enhanced ultrasound examination delivery at < 34 weeks’ gestation, as administration
to include a detailed review of fetal anatomy, may positively affect umbilical Doppler studies. (I-A)
placental morphology, and Doppler studies of the 21. If delivery was not indicated prior to 37 weeks
uterine and umbilical arteries. (II-2A) in a patient diagnosed with intrauterine growth
11. In cases of intrauterine growth restriction, restriction, expectant management with close fetal
determination of amniotic fluid volume should be and maternal surveillance versus delivery should be
performed to aid in the differential diagnosis of discussed after 37 weeks. (I-A)
22. Site of planned delivery should take into Doppler; add growth every 2 weeks; consider delivery
consideration facilities and expertise available at near term (38 to 40 weeks) if no other issues.
each institution including obstetricians, pediatricians •• If growth plateaus or stops < 34 weeks:
or neonatologists as appropriate, anaesthesiologists,
–– Administer corticosteroids; increase surveillance
and access to Caesarean section. (III-A)
to 2 to 3 times per week; consider hospitalization;
consider maternal–fetal medicine consultation;
FRAMEWORK FOR APPROACHING INTRAUTERINE consider pediatric consultation.
GROWTH RESTRICTION IN CLINICAL PRACTICE
–– If abnormal umbilical artery Doppler studies: add
Screening for intrauterine growth restriction MCA and DV studies.
History: maternal, fetal, and placental risk factors; establish –– If abnormal umbilical artery, MCA, and DV
dates by first trimester ultrasound and last menstrual period Doppler studies and abnormal NST: deliver. NST
Physical: SFH measurement can be used selectively if the BPP is abnormal.
Investigations to consider: –– If abnormal Doppler studies (e.g., absent or
•• biochemical screening tests for Trisomy 21 as a test of reversed end-diastolic flow) and normal BPP and
placental insufficiency; NST: continue intensive monitoring with BPP and
•• first trimester ultrasound for dating and nuchal umbilical Dopplers 2 to 3 times per week; deliver if
translucency; BPP or umbilical Dopplers worsen or if MCA/DV
are abnormal.
•• uterine artery Doppler at 19 to 23 weeks if
biochemical markers are abnormal; •• If > 34 weeks:
•• if SFH (in centimetres) is less than gestational age –– If normal AFV and DVP, BPP, and Doppler
(in weeks) by > 3, arrange ultrasound for EFW, AFV studies: conduct weekly surveillance and discuss
or DVP, biophysical profile, and/or umbilical Doppler delivery or ongoing monitoring after 37 weeks.
studies. –– If abnormal fluid (AFV < 5 cm or DVP < 2 cm),
BPP, and/or Doppler studies: consider delivery.
Diagnosis of intrauterine growth restriction
EFW or AC < 10th percentile
DISCUSSION
Management of intrauterine growth restriction
Investigations: IUGR is a problem associated with significant perinatal
•• Offer amniocentesis if there is high risk of aneuploidy; morbidity and mortality. Level 1 evidence to direct clinicians
in practice does exist, but is limited to a few high quality trials.
•• Consider TORCH screen. Several demographic factors, including advanced maternal
age, assisted conception technologies, and pregnancy with
Maternal management:
maternal comorbidities, interact to steadily increase the
•• Conduct ongoing monitoring for preeclampsia;
risk of IUGR and stillbirth in the third trimester. More
•• Encourage patient to quit smoking; effective use of current evidence may reduce this risk, but
•• Consider adding low-dose aspirin early in the further studies, especially to evaluate the role of systematic
pregnancy if patient fulfills the criteria for its use. screening of placental function in the second trimester, are
needed to improve the perinatal prognosis of IUGR due
Fetal management: to placental insufficiency. Since IUGR has many additional
•• If pre-viable (< 500 g ± < 24 weeks): offer counselling causes, when it is suspected, a detailed fetal anatomical
by multi-disciplinary health care team regarding fetal ultrasound examination should be performed including
monitoring and obstetrical intervention until viability. further testing when fetal abnormalities are suspected,
•• If viable (> 500 g and > 24 weeks): conduct initial soft markers are seen, or there is no apparent supportive
ultrasound assessment: EFW, AFV, umbilical Doppler; evidence of underlying placental insufficiency.
in third trimester (~ 26 weeks) consider weekly BPP In uncomplicated IUGR attributed to placental
and growth every 2 weeks. insufficiency, no pharmacological interventions are of
•• If growth continues along growth curve: conduct proven benefit, although the accumulated data from several
weekly biophysical profile and umbilical artery trials and meta-analyses of low-dose aspirin demonstrate
some preventive benefit. By contrast, no evidence currently Bricker L, Neilson JP, Dowswell T. Routine ultrasound in late pregnancy
(after 24 weeks’ gestation). Cochrane Database Syst Rev 2008;4:CD001451.
exists to support the preventive use of the parenteral
anticoagulant drug heparin for either the prevention or Bujold E, Roberge S, Lacasse Y, Bureau M, Audibert F, Marcoux S, et al.
Prevention of preeclampsia and intrauterine growth restriction with
treatment of IUGR. After 36 weeks of gestation, IUGR aspirin started in early pregnancy: a meta-analysis. Obstet Gynecol
due to suspected placental insufficiency can be managed 2010;116(2 Pt 1):402‑14. doi: 10.1097/AOG.0b013e3181e9322a.
equally effectively by early delivery or delayed delivery with Carberry AE, Gordon A, Bond DM, Hyett J, Raynes-Greenow CH,
increased fetal surveillance. Jeffery HE. Customised versus population-based growth charts as a
screening tool for detecting small for gestational age infants in low-risk
Further research is needed to define optimum management pregnant women. Cochrane Database Syst Rev 2011 Dec 7;12:CD008549.
of early-onset IUGR. Following delivery, pathological doi: 10.1002/14651858.CD008549.pub2.
examination of the placenta may provide key insights into Chauhan SP, Magann EF. Screening for fetal growth restriction. Clin Obstet
Gynecol 2006;49:284–94.
the underlying cause and form the basis of an effective
postpartum counselling visit to discuss that cause. Since Dayal AK, Manning FA, Berck DJ, Mussalli GM, Avila C, Harman CR, et al.
Fetal death after normal biophysical profile score: an eighteen-year experience.
the events leading up to and following delivery of an infant Am J Obstet Gynecol 1999;181(5 Pt 1):1231–6.
with severe IUGR may trigger significant emotional stress,
Dudley NJ. A systematic review of the ultrasound estimation of fetal weight.
a review of mental health status and family circumstances Ultrasound Obstet Gynecol 2005;25:80–9.
at this visit is prudent.
Dugoff L. First- and second-trimester maternal serum markers for aneuploidy
and adverse obstetric outcomes. Obstet Gynecol 2010;115:1052 61.
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CD008136.pub2. 2004;111:220–5.
Clinical Standards Committee gestational age are not considered in these Guidelines.
Throughout these Guidelines we use the term ‘embryo’
The International Society of Ultrasound in Obstetrics for before 10 weeks and ‘fetus’ thereafter, to reflect the
and Gynecology (ISUOG) is a scientific organization that fact that after 10 weeks of gestation organogenesis is
encourages safe clinical practice and high-quality teach- essentially complete and further development involves
ing and research related to diagnostic imaging in women’s predominantly fetal growth and organ maturation2,3 .
healthcare. The ISUOG Clinical Standards Committee
(CSC) has a remit to develop Practice Guidelines and Con-
sensus Statements that provide healthcare practitioners GENERAL CONSIDERATIONS
with a consensus-based approach for diagnostic imaging. What is the purpose of a first-trimester fetal ultrasound
They are intended to reflect what is considered by ISUOG scan?
to be the best practice at the time at which they are issued.
Although ISUOG has made every effort to ensure that In general, the main goal of a fetal ultrasound scan is
Guidelines are accurate when issued, neither the Society to provide accurate information which will facilitate the
nor any of its employees or members accept any liability delivery of optimized antenatal care with the best possible
for the consequences of any inaccurate or misleading data, outcomes for mother and fetus. In early pregnancy, it is
opinions or statements issued by the CSC. The ISUOG important to confirm viability, establish gestational age
CSC documents are not intended to establish a legal stan- accurately, determine the number of fetuses and, in the
dard of care because interpretation of the evidence that presence of a multiple pregnancy, assess chorionicity and
underpins the Guidelines may be influenced by individ- amnionicity. Towards the end of the first trimester, the
ual circumstances, local protocol and available resources. scan also offers an opportunity to detect gross fetal abnor-
Approved Guidelines can be distributed freely with the malities and, in health systems that offer first-trimester
permission of ISUOG (info@isuog.org). aneuploidy screening, measure the nuchal translucency
thickness (NT). It is acknowledged, however, that many
gross malformations may develop later in pregnancy or
INTRODUCTION may not be detected even with appropriate equipment and
in the most experienced of hands.
Routine ultrasound examination is an established part of
antenatal care if resources are available and access possi-
When should a first-trimester fetal ultrasound scan be
ble. It is commonly performed in the second trimester1 ,
performed?
although routine scanning is offered increasingly dur-
ing the first trimester, particularly in high-resource set- There is no reason to offer routine ultrasound simply to
tings. Ongoing technological advancements, including confirm an ongoing early pregnancy in the absence of
high-frequency transvaginal scanning, have allowed the any clinical concerns, pathological symptoms or specific
resolution of ultrasound imaging in the first trimester to indications. It is advisable to offer the first ultrasound
evolve to a level at which early fetal development can be scan when gestational age is thought to be between 11
assessed and monitored in detail. and 13 + 6 weeks’ gestation, as this provides an oppor-
The aim of this document is to provide guidance for tunity to achieve the aims outlined above, i.e. confirm
healthcare practitioners performing, or planning to per- viability, establish gestational age accurately, determine
form, routine or indicated first-trimester fetal ultrasound the number of viable fetuses and, if requested, evaluate
scans. ‘First trimester’ here refers to a stage of pregnancy fetal gross anatomy and risk of aneuploidy4 – 20 . Before
starting from the time at which viability can be confirmed starting the examination, a healthcare provider should
(i.e. presence of a gestational sac in the uterine cavity with counsel the woman/couple regarding the potential bene-
an embryo demonstrating cardiac activity) up to 13 + 6 fits and limitations of the first-trimester ultrasound scan.
weeks of gestation. Ultrasound scans performed after this (GOOD PRACTICE POINT)
Copyright 2013 ISUOG. Published by John Wiley & Sons, Ltd. ISUOG GUIDELINES
ISUOG Guidelines 103
Who should perform the first-trimester fetal ultrasound What if the examination cannot be performed in
scan? accordance with these Guidelines?
Individuals who perform obstetric scans routinely should These Guidelines represent an international benchmark
have specialized training that is appropriate to the practice for the first-trimester fetal ultrasound scan, but consider-
of diagnostic ultrasound for pregnant women. (GOOD ation must be given to local circumstances and medical
PRACTICE POINT) practices. If the examination cannot be completed in
To achieve optimal results from routine ultrasound accordance with these Guidelines, it is advisable to doc-
examinations it is suggested that scans should be per- ument the reasons for this. In most circumstances, it will
formed by individuals who fulfill the following criteria: be appropriate to repeat the scan, or to refer to another
healthcare practitioner. This should be done as soon as
1. have completed training in the use of diagnostic ultra- possible, to minimize unnecessary patient anxiety and
sonography and related safety issues; any associated delay in achieving the desired goals of the
2. participate in continuing medical education activities; initial examination. (GOOD PRACTICE POINT)
3. have established appropriate care pathways for suspi-
cious or abnormal findings;
4. participate in established quality assurance What should be done in case of multiple pregnancies?
programs21 .
Determination of chorionicity and amnionicity is impor-
tant for care, testing and management of multifetal preg-
What ultrasonographic equipment should be used?
nancies. Chorionicity should be determined in early preg-
It is recommended to use equipment with at least the nancy, when characterization is most reliable26 – 28 . Once
following capabilities: this is accomplished, further antenatal care, including the
timing and frequency of ultrasound examinations, should
– real-time, gray-scale, two-dimensional (2D) ultrasound;
be planned according to the available health resources
– transabdominal and transvaginal ultrasound
and local guidelines. (GOOD PRACTICE POINT)
transducers;
– adjustable acoustic power output controls with output
display standards; GUIDELINES FOR EXAMINATION
– freeze frame and zoom capabilities;
– electronic calipers; 1. Assessment of viability/early pregnancy
– capacity to print/store images;
– regular maintenance and servicing. In this Guideline, ‘age’ is expressed as menstrual or ges-
tational age, which is 14 days more than conceptional
age. Embryonic development visualized by ultrasound
How should the scan be documented?
closely agrees with the ‘developmental time schedule’
An examination report should be produced as an elec- of human embryos described in the Carnegie staging
tronic and/or paper document (see Appendix for an system3 . The embryo is typically around 1–2 mm long
example). Such a document should be stored locally and, when first detectable by ultrasound and increases in length
in accordance with local protocol, made available to by approximately 1 mm per day. The cephalic and caudal
the woman and referring healthcare provider. (GOOD ends are indistinguishable until 53 days (around 12 mm),
PRACTICE POINT) when the diamond-shaped rhombencephal cavity (future
fourth ventricle) becomes visible18 .
Is prenatal ultrasonography safe during the first
trimester? Defining viability
Fetal exposure times should be minimized, using the short- The term ‘viability’ implies the ability to live indepen-
est scan times and lowest possible power output needed to dently outside the uterus and, strictly speaking, cannot be
obtain diagnostic information using the ALARA (As Low applied to embryonic and early fetal life. However, this
As Reasonably Achievable) principle. (GOOD PRAC- term has been accepted in ultrasound jargon to mean that
TICE POINT) the embryonic or fetal heart is seen to be active and this is
Many international professional bodies, including taken to mean the conceptus is ‘alive’. Fetal viability, from
ISUOG, have reached a consensus that the use of B- an ultrasound perspective, is therefore the term used to
mode and M-mode prenatal ultrasonography, due to its confirm the presence of an embryo with cardiac activity at
limited acoustic output, appears to be safe for all stages of the time of examination. Embryonic cardiac activity has
pregnancy22,23 . Doppler ultrasound is, however, associ- been documented in normal pregnancies at as early as 37
ated with greater energy output and therefore more poten- days of gestation29 , which is when the embryonic heart
tial bioeffects, especially when applied to a small region of tube starts to beat30 . Cardiac activity is often evident
interest24,25 . Doppler examinations should only be used in when the embryo measures 2 mm or more31 , but is not
the first trimester, therefore, if clinically indicated. More evident in around 5–10% of viable embryos measuring
details are available in the ISUOG Safety Statement22 . between 2 and 4 mm32,33 .
Copyright 2013 ISUOG. Published by John Wiley & Sons, Ltd. Ultrasound Obstet Gynecol 2013; 41: 102–113.
104 ISUOG Guidelines
CRL measurements can be carried out transabdominally Nomograms are available for abdominal circumference
or transvaginally. A midline sagittal section of the whole (AC), femur length and most fetal organs, but there is no
embryo or fetus should be obtained, ideally with the reason to measure these structures as part of the routine
embryo or fetus oriented horizontally on the screen. An first-trimester scan.
image should be magnified sufficiently to fill most of the
width of the ultrasound screen, so that the measurement
line between crown and rump is at about 90◦ to the
4. Assessment of gestational age
ultrasound beam37,38 . Electronic linear calipers should be Pregnant women should be offered an early ultrasound
used to measure the fetus in a neutral position (i.e. neither scan between 10 + 0 and 13 + 6 weeks to establish accu-
flexed nor hyperextended). The end points of crown and rate gestational age. (Grade A recommendation)
rump should be defined clearly. Care must be taken to Ultrasound assessment of embryonic/fetal age (dating)
avoid inclusion of structures such as the yolk sac. In order uses the following assumptions:
to ensure that the fetus is not flexed, amniotic fluid should
– gestational (menstrual age) represents post-conception
be visible between the fetal chin and chest (Figure 1).
age + 14 days;
However, this may be difficult to achieve at earlier ges-
– embryonic and fetal size correspond to post-conception
tations (around 6–9 weeks) when the embryo is typically
(post fertilization) age;
hyperflexed. In this situation, the actual measurement rep-
resents the neck–rump length, but it is still termed the – structures measured are normal;
CRL. In very early gestations it is not usually possible to – measurement technique conforms to the reference
distinguish between the cephalic and caudal ends and a nomogram;
greatest length measurement is taken instead. – measurements are reliable (both within and between
The biparietal diameter (BPD) and head circumfer- observers);
ence (HC) are measured on the largest true symmetrical – the ultrasound equipment is calibrated correctly.
axial view of the fetal head, which should not be dis- Accurate dating is essential for appropriate follow-up
torted by adjacent structures or transducer pressure. At of pregnancies and has been the primary indication
about 10 weeks’ gestation, structures such as the mid- for routine ultrasound in the first trimester. It provides
line third ventricle, interhemispheric fissure and choroid valuable information for the optimal assessment of fetal
Copyright 2013 ISUOG. Published by John Wiley & Sons, Ltd. Ultrasound Obstet Gynecol 2013; 41: 102–113.
ISUOG Guidelines 105
Copyright 2013 ISUOG. Published by John Wiley & Sons, Ltd. Ultrasound Obstet Gynecol 2013; 41: 102–113.
106 ISUOG Guidelines
Robinson & Fleming52 (1975); quoted CRL 9 to 13 + 6 Selected for use by British Medical
by Loughna et al.41 (2009) Ultrasound Society41
Hadlock et al.83 (1992) CRL 5.0 to 18.0
Daya84 (1993) CRL 6.1 to 13.3
Verburg et al.43 (2008) CRL 6 + 2 to 15 + 0 Includes BPD, HC, AC, femur,
cerebellum
McLennan & Schluter85 (2008) CRL 5 to 14 Includes BPD to 14 weeks
Hadlock et al.86 (1982) BPD 12 to 40 In early pregnancy 1982 chart more
accurate than 1984 chart
Altman & Chitty39 (1997); quoted by BPD 12 + 6 to 35 + 4 Selected for use by British Medical
Loughna et al.41 (2009) Ultrasound Society41
Verburg et al.43 (2008) BPD 10 to 43 Includes CRL, HC, AC, femur,
cerebellum
Measurements should be performed according to techniques described in these articles and tested on the local population before being
adopted into practice. BPD, biparietal diameter; CRL, crown–rump length.
Table 2 Suggested anatomical assessment at time of 11 to However, in absence of obvious anomaly, failure to exam-
13 + 6-week scan ine the fetal face at this time should not prompt further
examination earlier than the mid-trimester scan.
Organ/anatomical
area Present and/or normal ?
Head Present
Neck
Cranial bones
Midline falx
Sonographic assessment of NT is part of the screening for
Choroid-plexus-filled ventricles chromosomal anomalies and is discussed below. Atten-
Neck Normal appearance tion should be paid to proper alignment of the neck with
Nuchal translucency thickness (if accepted the trunk and identification of other fluid collections such
after informed consent and as hygromas and jugular lymph sacs28,65 .
trained/certified operator available)*
Face Eyes with lens*
Nasal bone*
Normal profile/mandible* Spine
Intact lips*
Spine Vertebrae (longitudinal and axial)* Longitudinal and axial views should be obtained to show
Intact overlying skin* normal vertebral alignment and integrity, and an attempt
Chest Symmetrical lung fields should be made to show intact overlying skin (Figure 4).
No effusions or masses However, in the absence of obvious anomaly, failure to
Heart Cardiac regular activity examine the spine at this time should not prompt further
Four symmetrical chambers*
Abdomen Stomach present in left upper quadrant
examination earlier than the mid-trimester scan. Particu-
Bladder* lar attention should be paid to the normal appearance of
Kidneys* the spine when BPD < 5th centile66 .
Abdominal wall Normal cord insertion
No umbilical defects
Extremities Four limbs each with three segments Thorax
Hands and feet with normal orientation*
Placenta Size and texture The chest normally contains lungs of homogeneous
Cord Three-vessel cord* echogenicity on ultrasound, without evidence of pleural
*Optional structures. Modified from Fong et al.28 , McAuliffe
effusions or cystic or solid masses. Diaphragmatic conti-
et al.87 , Taipale et al.60 and von Kaisenberg et al.88 . nuity should be evaluated, noting normal intra-abdominal
position of stomach and liver.
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ISUOG Guidelines 107
Abdominal content
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108 ISUOG Guidelines
Limbs
The normal insertion of the umbilical cord should be The number of cord vessels, cord insertion at the
documented after 12 weeks (Figure 6c). The physi- umbilicus and presence of cord cysts should be noted.
ological umbilical hernia is present up to 11 weeks Brief evaluation of the paravesical region with color or
Copyright 2013 ISUOG. Published by John Wiley & Sons, Ltd. Ultrasound Obstet Gynecol 2013; 41: 102–113.
ISUOG Guidelines 109
Ultrasound-based screening for chromosomal anomalies Figure 8 Sonographic measurement of nuchal translucency
thickness.
in the first trimester may be offered, depending on pub-
lic health policies, trained personnel and availability of
healthcare resources. The first-trimester screening should the nose and rectangular shape of the palate anteriorly,
include NT measurement71,72 . Screening performance is the translucent diencephalon in the center and the nuchal
further improved by the addition of other markers, includ- membrane posteriorly. If the section is not exactly median,
ing biochemical measurement of free beta or total human the tip of the nose will not be visualized and the ortho-
chorionic gonadotropin (hCG) and pregnancy-associated gonal osseous extension at the frontal end of the maxilla
plasma protein-A (PAPP-A)73 . In appropriate circum- will appear. The ultrasound machine should allow mea-
stances, additional aneuploidy markers, including nasal surement precision of 0.1 mm. Calipers should be placed
bone, tricuspid regurgitation, ductal regurgitation and correctly (on-on) to measure NT as the maximum dis-
others, may be sought by personnel with appropriate tance between the nuchal membrane and the edge of
training and certification74 – 76 . Most experts recommend the soft tissue overlying the cervical spine (Figure 8). If
that NT should be measured between 11 and 13 + 6 more than one measurement meeting all the criteria is
weeks, corresponding to a CRL measurement of between obtained, the maximum one should be recorded and used
45 and 84 mm. This gestational age window is chosen for risk assessment. Multiple pregnancy requires special
because NT as a screening test performs optimally and considerations, taking into account chorionicity.
fetal size allows diagnosis of major fetal abnormalities,
thus providing women who are carrying an affected fetus How to train and control for the quality of NT
with the option of an early termination of pregnancy77 . measurement
NT implementation requires several elements to be in
place, including suitable equipment, counseling and man- A reliable and reproducible measurement of NT requires
agement as well as operators with specialized training and appropriate training. A rigorous audit of operator perfor-
continuing certification. Further details can be obtained mance and constructive feedback from assessors has been
from relevant national bodies and charities such as The established in many countries and should be considered
Fetal Medicine Foundation (www.fetalmedicine.com). essential for all practitioners who participate in NT-based
However, even in the absence of NT-based screening screening programs. (GOOD PRACTICE POINT)
programs, qualitative evaluation of the nuchal region of
any fetus is recommended and, if it appears thickened,
expert referral should be considered. 7. Other intra- and extrauterine structures
Copyright 2013 ISUOG. Published by John Wiley & Sons, Ltd. Ultrasound Obstet Gynecol 2013; 41: 102–113.
110 ISUOG Guidelines
the uterine isthmus at the site of the Cesarean section scar G. Yeo, Department of Maternal Fetal Medicine, Obstet-
should be scrutinized. In suspected cases, consideration ric Ultrasound and Prenatal Diagnostic Unit, KK Women’s
should be given to prompt specialist referral for further and Children’s Hospital, Singapore
evaluation and management79,80 . Although the issue of
*L. J. S. and Z. A. contributed equally to this article.
routine scans in women with a history of Cesarean section
may be raised in the future81,82 , there is currently insuf-
ficient evidence to support inclusion of such a policy in CITATION
routine practice.
These Guidelines should be cited as: ‘Salomon LJ,
Gynecological pathology, both benign and malignant,
Alfirevic Z, Bilardo CM, Chalouhi GE, Ghi T, Kagan
may be detected during any first-trimester scan. Abnor-
KO, Lau TK, Papageorghiou AT, Raine-Fenning NJ,
malities of uterine shape, such as uterine septa and
Stirnemann J, Suresh S, Tabor A, Timor-Tritsch IE, Toi
bicornuate uteri, should be described. The adnexa should
A, Yeo G. ISUOG Practice Guidelines: performance of
be surveyed for abnormalities and masses. The relevance
first-trimester fetal ultrasound scan. Ultrasound Obstet
and management of such findings are beyond the scope of
Gynecol 2013; 41: 102–113.’
these Guidelines.
Copyright 2013 ISUOG. Published by John Wiley & Sons, Ltd. Ultrasound Obstet Gynecol 2013; 41: 102–113.
ISUOG Guidelines 111
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112 ISUOG Guidelines
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The authorship of this article was incomplete as initially published. This version of the article correctly acknowledges
all authors who contributed to the development of the Guidelines.
Copyright 2013 ISUOG. Published by John Wiley & Sons, Ltd. Ultrasound Obstet Gynecol 2013; 41: 102–113.
ISUOG Guidelines 113
Copyright 2013 ISUOG. Published by John Wiley & Sons, Ltd. Ultrasound Obstet Gynecol 2013; 41: 102–113.
SOGC CLINICAL PRACTICE GUIDELINE
Melanie Pastuck, RN, Cochrane AB Values: The quality of evidence in this document was rated using the
criteria described in the Report of the Canadian Task Force on
Vyta Senikas, MD, Ottawa ON Preventive Health Care (Table 1).
Disclosure statements have been received from all contributors.
Recommendations
1. All patients with fetal hydrops should be referred promptly to a
tertiary care centre for evaluation. Some conditions amenable to
prenatal treatment represent a therapeutic emergency after 18
weeks. (II-2A)
Key Words: Non-immune hydrops fetalis, fetal hydrops, fetal
therapy, fetal metabolism 2. Fetal chromosome analysis and genetic microarray molecular
testing should be offered where available in all cases of
non-immune fetal hydrops. (II-2A)
3. Imaging studies should include comprehensive obstetrical
ultrasound (including arterial and venous fetal Doppler) and fetal
J Obstet Gynaecol Can 2013;35(10):923–936 echocardiography. (II-2A)
This document reflects emerging clinical and scientific advances on the date issued and is subject to change. The information
should not be construed as dictating an exclusive course of treatment or procedure to be followed. Local institutions can dictate
amendments to these opinions. They should be well documented if modified at the local level. None of these contents may be
reproduced in any form without prior written permission of the SOGC.
Table 1. Key to evidence statements and grading of recommendations, using the ranking of the Canadian Task Force
on Preventive Health Care
Quality of evidence assessment* Classification of recommendations†
I: Evidence obtained from at least one properly randomized A. There is good evidence to recommend the clinical preventive action
controlled trial
II-1: Evidence from well-designed controlled trials without B. There is fair evidence to recommend the clinical preventive action
randomization
II-2: Evidence from well-designed cohort (prospective or C. The existing evidence is conflicting and does not allow to make a
retrospective) or case–control studies, preferably from recommendation for or against use of the clinical preventive action;
more than one centre or research group however, other factors may influence decision-making
II-3: Evidence obtained from comparisons between times or D. There is fair evidence to recommend against the clinical preventive action
places with or without the intervention. Dramatic results in
uncontrolled experiments (such as the results of treatment with E. There is good evidence to recommend against the clinical preventive
penicillin in the 1940s) could also be included in this category action
III: Opinions of respected authorities, based on clinical experience, L. There is insufficient evidence (in quantity or quality) to make
descriptive studies, or reports of expert committees a recommendation; however, other factors may influence
decision-making
*The quality of evidence reported in these guidelines has been adapted from The Evaluation of Evidence criteria described in the Canadian Task Force on
Preventive Health Care.78
†Recommendations included in these guidelines have been adapted from the Classification of Recommendations criteria described in the Canadian Task Force
on Preventive Health Care.78
4. Investigation for maternal–fetal infections, and alpha-thalassemia cases of newborns with unexplained
in women at risk because of their ethnicity, non-immune hydrops. (II-2A)
should be performed in all cases of unexplained fetal
7. Autopsy should be recommended in all cases of fetal or neonatal
hydrops. (II-2A)
death or pregnancy termination. (II-2A) Amniotic fluid and/or fetal
5. To evaluate the risk of fetal anemia, Doppler measurement cells should be stored for future genetic testing. (II-2B)
of the middle cerebral artery peak systolic velocity should
be performed in all hydropic fetuses after 16 weeks of
gestation. In case of suspected fetal anemia, fetal blood sampling INTRODUCTION
and intrauterine transfusion should be offered
rapidly. (II-2A)
6. All cases of unexplained fetal hydrops should be referred to a
medical genetics service where available. Detailed postnatal
H ydrops fetalis is defined as the accumulation
of abnormal fluid in at least two different fetal
compartments. It implies an excess of total body water,
evaluation by a medical geneticist should be performed on all
which is usually evident as extracellular accumulation of
fluid in tissues and serous cavities.1,2 It generally presents as
subcutaneous edema, accompanied by effusions in two or
ABBREVIATIONS more serous cavities including pericardial or pleural effusions,
AF amniotic fluid and ascites. Polyhydramnios or placental thickening (> 6 cm)
CBC complete blood count are often associated. When the fluid accumulation is limited
CMV cytomegalovirus to one cavity, for example isolated ascitis or pleural effusion,
FISH fluorescent in situ hybridization the situation should be described in terms of the involved
Hb hemoglobin site, since this may be helpful in narrowing the differential
HbH hemoglobin H diagnosis. The three primary mechanisms associated with
MCA middle cerebral artery hydrops are intrauterine anemia, intrauterine heart failure,
MPS mucopolysaccharidosis and hypoproteinemia. In addition to these three basic
NICHD National Institute of Child Health and mechanisms, fetal hydrops has a causal relationship with
Human Development a variety of structural abnormalities that interfere with
NIHF non-immune hydrops fetalis the fetoplacental circulation. Chromosomal anomalies
QF-PCR quantitative fluorescent polymerase chain reaction (aneuploidy, deletion, duplication, genetic mutation) and
RT-PCR real-time polymerase chain reaction skeletal dysplasia may also be associated with hydrops
TORCH toxoplasmosis, rubella, cytomegalovirus, through a variety of mechanisms.1,2
herpes simplex
UA umbilical artery Fetal hydrops carries a poor prognosis; however, several
VZV Varicella-zoster virus etiologies can be treated in utero with potential good
results. The growing number of recognized etiologies the possibility of twin-to-twin transfusion syndrome. Review
requires a comprehensive and systematic search for causes, articles discussing the assessment and management of twin-
in particular for treatable or recurrent conditions. to-twin transfusion syndrome and other complications
specific to twin pregnancies are available elsewhere.13–17
Recommendation
1. All patients with fetal hydrops should be referred
ETIOLOGIES
promptly to a tertiary care centre for evaluation. Some
conditions amenable to prenatal treatment represent a Despite extensive investigations, the etiology of non-
therapeutic emergency after 18 weeks. (II-2A) immune fetal hydrops may remain unknown in 15% to
25% of patients.1,6,18–20 The goal of this guideline is to
DEFINITIONS propose a standardized approach to the investigation
and management of non-immune fetal hydrops with
Immune versus Non-Immune Fetal Hydrops a focus on the rare treatable or potentially recurring
Immune hydrops causes. A growing number of conditions can result in
Maternal red cell alloimmunization occurs when a NIHF. A systematic review has recently analyzed a total
pregnant woman has an immunological response to a of 225 relevant articles describing 5437 individual cases
paternally-derived antigen that is foreign to the mother of NIHF.21 All cases were sub-classified into one of the
and inherited by the fetus.3 The maternal antibodies may following diagnostic categories: cardiovascular (21.7%),
cross the placenta, bind to antigens present on the fetal hematologic (10.4%), chromosomal (13.4%), syndromic
erythrocytes, and cause hemolysis, hydrops fetalis, and (4.4%), lymphatic dysplasia (5.7%), inborn errors of
fetal death. The prognosis of this condition has been metabolism (1.1%), infections (6.7%), thoracic (6.0%),
considerably improved over the last decades, due to urinary tract malformations (2.3%), extra-thoracic
interventions including antenatal and postpartum Rhesus tumours (0.7%), twin-to-twin transfusion or placental
immune globulin, non-invasive prenatal surveillance (5.6%), gastrointestinal (0.5%), miscellaneous (3.7%), and
with cerebral Doppler, and intrauterine transfusion. The idiopathic (17.8%). See Table 2 for details.
complete description and management of this condition is
beyond the scope of this guideline.3,4 Chromosomal Abnormalities
Chromosomal abnormalities are the cause of NIHF in 25%
Non-immune hydrops to 70% of cases.22 The risk of fetal aneuploidy is higher
Non-immune hydrops fetalis refers to hydrops in the when identified earlier in gestation or when fetal structural
absence of maternal circulating red-cell antibodies.5 With the anomalies are seen.5,23 Standard fetal chromosome analysis
introduction of widespread immunoprophylaxis for red cell is indicated in all cases of hydrops. Additional genetic
alloimmunization and the use of in utero transfusions for microarray molecular testing should be considered in all
immune hydrops therapy, non-immune causes have become NIHF cases as the NICHD Microarray Study has shown
responsible for at least 85% of all cases of fetal hydrops.6 The additional genetic chromosomal anomalies (smaller than
reported incidence is around 3 per 10 000 births; however, can be seen by standard cytogenetic studies) in 7% of
the incidence is much higher at the first- and second-trimester fetuses with congenital anomalies and standard normal
ultrasounds because of higher fetal death rates.7 karyotype.24
Recommendation
Hydrops in the First Trimester and Cystic Hygroma
Signs of hydrops can be found as early as in the first 2. Fetal chromosome analysis and genetic microarray
trimester. This is usually seen in association with increased molecular testing should be offered where available
nuchal translucency and/or cystic hygroma,8,9 a septated in all cases of non-immune fetal hydrops where
cystic structure in the occipitocervical region and sometimes available. (II-2A)
the axillary region. The evaluation of increased nuchal
translucency and cystic hygromas with or without fetal
Cardiac Etiologies
hydrops differs from that of non-immune fetal hydrops
Cardiac etiologies account for 10% to 20% of cases of
and is beyond the scope of this guideline. Pertinent SOGC
NIHF.2,25 These include not only structural abnormalities,
guidelines can be found elsewhere.10–12
but also cardiac arrhythmias, tumours, physiological
Twin Gestation as a Different Situation dysfunction due to infection, inflammation, infarction,
Non-immune fetal hydrops in one or both twins may imply and arterial calcification. Cardiac and intrathoracic
a different etiology, especially in monochorionic twins, given lesions that result in right atrial pressure or volume
No
Infectious Diseases
Intrauterine infections are a common cause of fetal
laser therapy)
Yes
5.6
Hematological Disorders
Hematological disorders can be identified in 7% of
(Thoraco-
shunting)
Thoracic
amniotic
Yes
6.0
*including: inborn storage diseases, urinary tract malformations, extra-thoracic tumours, gastro-intestinal, miscellaneous
(IUT for
366
Yes
6.7
13.4
727
No
hydrops.33,34
(IUT)
10.4
564
Yes
(anti-arrythmic
only helps in predicting the outcome of the current Triage depends on gestational age, etiology, and severity.
pregnancy, but also has an impact on the management Ultrasound examination including umbilical artery
or screening of future pregnancies in the family.26 and middle cerebral artery Doppler studies may guide
lifesaving treatments such as in utero transfusions, fetal
Recent data suggest that metabolic disorders may be cardioversion, or placement of diversion shunts. Table 4
responsible for some idiopathic NIHF. Lysosomal outlines the baseline investigations for all fetal hydrops.
storage disorders are the group of disorders most One should not wait for complete results before initiating
commonly involved in NIHF. Hydrops fetalis is a referral, invasive diagnostic procedures, or treatments.
relatively common presentation in mucopoly-
saccharidosis type VII,37 infantile galactosialidosis,38 type Clinical Evaluation
2 Gaucher disease, and infantile free sialic acid storage A detailed history should be taken focusing on the mother’s
disease. At least 15 other inborn errors of metabolism past medical and reproductive history, including previous
may cause NIHF34,39: GM1 gangliosidosis, Niemann- fetal, neonatal, or infantile deaths. A clear determination
Pick type A, Niemann-Pick type C, MPS I, MPS IVA, of gestational age and history of viral exposure/illness,
mucolipidosis II, sialidosis, multiple sulfatase deficiency, travelling, bleeding, or use of medication during the
Farber disease, Wolman disease, I cell disease, glycogen pregnancy should be obtained. Parental past medical
storage disease IV,36 transaldolase deficiency,40 Pearson history, ethnic background, and consanguinity should be
syndrome (mitochondrial disorder), and congenital documented. A 3-generation pedigree, including specific
disorders of glycosylation. Specific enzyme assays questions on fetal loss, death in infancy, developmental
are available to test for these disorders on cultured delay, congenital malformation, genetic syndrome,
amniocytes or specific metabolite measurement in skeletal dysplasia, chronic infantile illness, inherited
amniotic fluid supernatant.41,42 cardiomyopathies, and neurodegenerative disorders should
be completed. Maternal history, physical examination, and
Diagnosing or ruling out a metabolic disorder as the
laboratory tests should be used to rule out developing
causal factor for NIHF is important because these
preeclampsia (mirror syndrome) and underlying chronic
single gene disorders carry a 25% risk of recurrence,
illness associated with fetal hydrops (e.g., Sjogren, lupus,
and their identification may allow for prenatal diagnosis
uncontrolled diabetes, Graves disease).
at an earlier stage in future pregnancies. Prenatal
diagnosis of such conditions also facilitates postnatal Non-invasive Testing
management. Despite thorough investigations, earlier Timely referral to a maternal–fetal medicine specialist
reports conclude that at least 28% of cases of NIHF allows for detailed and comprehensive ultrasound
remain unexplained2; a recent systematic review of the examination and the early identification of any treatable
literature found that 17.8% were considered idiopathic.21 causes. A careful search for structural fetal anomalies or
genetic syndromes, signs of fetal infection, and evidence
PRENATAL MANAGEMENT of umbilical cord or placental anomalies may rapidly
indicate the cause of hydrops.
Fetal hydrops mandates urgent referral to a maternal–
fetal medicine specialist for rapid evaluation because Multiple mechanisms of hydrops may coexist and the
some situations must be considered true prenatal primary cause is often not obvious. Determination of
medical emergencies, particularly after 16 to 18 weeks. prognosis is important and may be achieved by a semi-
STEP 1: Urgent
Fetal imaging
• Detailed morphology obstetrical ultrasound in a tertiary care centre and the assessment of the fetal venous and arterial circulation
• Doppler (MCA, venous, arterial)
• Fetal echocardiogram
Maternal blood
• CBC
• Kleihauer-Betke
• ABO blood type and antigen status
• Indirect Coombs (antibody screen)
• Venereal disease research laboratory test for syphilis
• Acute phase titres (parvovirus, toxoplasmosis, cytomegalovirus, rubella)
• Liver function tests, uric acid, coagulation tests (suspected mirror syndrome)
• SS-A, SS-B antibodies (fetal bradyarrhythmia)
• Depending on ethnic origin: hemoglobin electrophoresis, G6PD deficiency screen
STEP 3: Post-delivery
Examination of the placenta
Neonatal survival
• Detailed physical examination
• Cardiac monitoring
• Cranial ultrasound
• Abdominal ultrasound
• Cardiac monitoring
• Echocardiography
• CBC, liver function tests, creatinine kinase, albumin, protein
• TORCH, viral culture
• Specialized testing guided by results of prenatal work-up
Neonatal / fetal demise
• Clinical pictures
• Fetal cells culture (skin, others)
• Freeze fetal tissues and AF supernatant
• Bank fetal DNA
• Skeletal survey
• Placental pathology
• Autopsy10
quantitative measure of heart failure. Specific questions finding should not be considered a final diagnosis in and
may be addressed through arterial and venous Doppler of itself. A careful search for underlying maternal illness or
ultrasound in conjunction with fetal echocardiogram.43 single-gene disorder is indicated.
when available, to establish prior immune status and to focused on the most appropriate timing for performing
document seroconversion. Testing for rare infectious amniocentesis to yield the best sensitivity for detection
diseases (syphilis, enterovirus) may be considered in of fetal infection. These studies clearly indicated that AF
particular clinical situations (ultrasound findings, HIV should be collected after 21 gestational weeks and after at
positive mother, clinical symptoms). least 6 weeks maternal infection. Most studies state that
the timing of amniocentesis is more critical for sensitivity
Parvovirus B19 in detecting the virus in AF than the laboratory methods
Infection during pregnancy may affect the fetus, resulting used. If invasive testing is performed, PCR is the preferred
in hydrops or fetal demise.55 The predominant ultrasound method for detection of CMV in amniotic fluid. Problems
feature in fetuses infected by Parvovirus B19 is ascites,44 with molecular contamination (false positive results) and the
sometimes associated with poorly contractile echogenic need to address prognostic issues led to the development
myocardium. Early diagnosis of maternal infection will of quantitative PCR assays; the highly advanced real-time
allow fetal assessment and treatment by intrauterine blood PCR is the most up-to-date method.58,59
transfusion. Unfortunately, mothers are often unaware of
their infection until fetal signs are observed. Confirmation Laboratory testing to determinate intrauterine CMV
of B19 infection requires laboratory assessment, which is infection involves several steps that should be done
complicated by the nature of the viral infection and immune simultaneously in fetal hydrops. Maternal primary or
response. Serology, using enzyme-linked immunosorbent recurrent infection is assessed by serology using IgM,
assays, relies on recombinant antigens, and concordance is IgG, and IgG-avidity assays. A second blood sample
low among all commercial assays available. In the absence should be sought to demonstrate antibody kinetics typical
of a “gold standard” assay, false positive and false negative of the current infection and not of a remote infection or
results prevail. a non-specific reaction. If maternal primary infection has
been established and the pregnancy continues, prenatal
Furthermore, maternal IgM may have dropped below the diagnosis follows at 21 to 23 weeks gestation or at 6 to
detection limit by the time fetal hydrops is identified.56 9 weeks after seroconversion (if known). Detection of
Viral culture is difficult and virus detection is based on CMV in AF is achieved by virus culturing and/or PCR.
various molecular assays. In spite of several studies there Quantitative PCR in the amniotic fluid can determine the
is no consensus regarding the most appropriate clinical viral load and could be useful for the assessment of fetal
specimen and method for detection of viral DNA. impact and prognosis, although the clinical value of this
Currently, on practical grounds, it is recommended to test is still under investigation.60 Further information on
use ELISA IgM and IgG assays based on recombinant CMV infection in pregnancy is available in a previously
conformational epitopes of polyomavirus capsid proteins published SOGC guideline.58
1 and 2 or polyomavirus capsid protein 2 alone, and to use
amniotic fluid or fetal serum for detection of fetal infection Varicella-zoster virus
by the most sensitive molecular methods available (nested VZV is rarely found as a cause of fetal hydrops.61 The
PCR or RT-PCR).56 Recommendations for evaluation and primary tool for assessing maternal infection is isolation
treatment of parvovirus infection during pregnancy have of the virus from maternal lesions. Type-specific IgG
been published by the SOGC Maternal–Fetal Medicine assays must be applied to determine recurrent maternal
and Infectious Diseases Committees.57 infections. Antigen detection or DNA detection by PCR
in skin lesion samples are additional tools for the rapid
Rubella and sensitive diagnosis of symptomatic current infection.
If the patient is not immune to rubella, serial IgG and Prenatal diagnosis can be performed by PCR detection
IgM titres should be done. If congenital rubella is of the virus in AF, but false negative results are common
strongly suspected, amniotic fluid culture or fetal blood and positive results do not necessarily correlate with
sampling for IgM determination is indicated as infection fetal damage.62 Neonatal infection is diagnosed by virus
leads to severe fetal morbidity. Postnatal determination is culture or PCR in skin lesions or other clinical specimens
achieved through evaluation of IgG and IgM levels, along in case of a disseminated form.
with viral isolation.
Other viral infections
Cytomegalovirus A few studies report fetuses with NIHF caused by various
CMV is excreted in the urine of the infected fetus, so subtypes of Coxsackie virus and adenovirus identified
detection of the virus in AF has proven to be a highly through targeted PCR amplification in affected fetal
sensitive and reliable method.58 Numerous studies have tissues.19,63
Table 5. Lysosomal enzymatic assays used for NIHF fetal death.72 One baby with diaphragmatic hernia died in
a. Beta-galactosidase (GM1) the neonatal period from pulmonary hypoplasia despite
b. Beta-glucuronidase (MPS VII) reversal of hydrops by in utero shunting, and one baby
c. Beta-glucosidase (Gaucher) with treated polyhydramnios was born at 30 weeks and died
d. Neuraminidase (sialidose) on day 5. The remaining 5 cases, in which structural and
e. Beta-galactosidase and neuraminidase (galactosialidose) chromosomal abnormalities were excluded, had fetal therapy
f. Sphyngomyelinase (Niemann-Pick A and B) between 22 and 32 weeks’ gestation (4 shunt insertions, 1
g. Mucolipidosis type II blood transfusion) and in all the hydrops reversed and the
pregnancy continued to at least 35 weeks’ gestation. All 5
neonates were discharged from hospital alive and well.
Fetal therapy in cases of NIHF with normal structure and
PROGNOSIS karyotype was associated with a very good outcome.72
NIHF from all causes has a high mortality rate. Fetal Two recent studies address the issues of postnatal survival in
chromosomal anomaly, gestational age < 24 weeks and live-born neonates with hydrops. Data from a large national
fetal structural anomalies other than chylothorax are database73 reveals that mortality rates were highest among
indicators of a poor prognosis. However, fetal treatment
neonates with congenital anomalies (57.7%) and lowest
has significantly improved survival in selected cases.
among neonates with congenital chylothorax (5.9%). Factors
When a pregnancy is continued with known fetal hydrops, associated with death were younger gestational age, low
the occurrence of maternal “mirror” syndrome should 5-minute Apgar score, and need for high levels of support
be carefully monitored. Mirror syndrome, also referred to during the first 24 hours of life (high oxygen needs and
as Ballantyne’s syndrome, is defined as the development high-frequency ventilation). Of the 597 neonates included
of maternal edema secondary to fetal hydrops.21,69 Severe in the study, 115 were transferred from another hospital, 215
preeclampsia is usually associated with the syndrome. died before discharge, and 267 were discharged from the
Because the maternal prognosis can be poor, the option hospital.73 Huang et al. reported a 50% survival rate in a group
of continuing a pregnancy with fetal hydrops should be
of 28 live-born neonates with NIHF.74 The survival rate was
carefully discussed.
83% in infants with lymphatic malformations. Preterm birth
Excluding chromosomal abnormalities, the survival rate of at less than 34 weeks and low serum albumin concentration
NIHF is about 31% to 48%.7 Most of the causes, a large were two poor prognostic factors for survival.74
proportion of which are lethal disorders, respond poorly
to therapy. Without treatment the prognosis is generally Few studies have examined the long-term outcome of
poor, except in the rare case of spontaneous resolution of NIHF identified prenatally. Breur et al. reported normal
parvovirus B19 infection.70 neurodevelopmental outcomes in 5 children who presented
with fetal heart block and hydrops fetalis. In his series of 10
In a series of 38 cases of NIHF, Negishi et al. reported a fetuses, 3 died in utero, 2 died from dilated cardiomyopathy
23% survival rate in the treatment group.30 The presence
at age 9 months and 4 years, and 5 survived.75
of a chromosomal anomaly, along with an earlier age
at detection of NIHF, was associated with a poorer These results demonstrate that the prognosis of NIHF
outcome. In a series of 30 cases of NIHF diagnosed differs markedly between different etiological groups. It
between 10 and 14 weeks of gestation, all cases resulted is essential to attempt to identify the etiology to better
in spontaneous abortion, intrauterine fetal death, or
predict prognosis, offer prenatal treatment when available,
pregnancy termination.23 In another series of 45 cases
and deliver in a tertiary perinatal care centre to improve
diagnosed between 11 and 17 weeks, only 2 resulted in a
normal outcome.71 McCoy et al. reported a survival rate of postnatal outcome.
< 5% for infants with hydrops diagnosed before 24 weeks Recommendation
of gestation and 20% survival for infants diagnosed after 6. All cases of unexplained fetal hydrops should be
24 weeks of gestation.19 referred to a medical genetics service where available.
In a report on 23 women with NIHF, termination of Detailed postnatal evaluation by a medical geneticist
pregnancy was performed for 10 chromosomal and 5 should be performed on all cases of newborns with
structural abnormalities, and there was one intrauterine unexplained non-immune hydrops. (II-2A)
to evaluate possible dysmorphic syndrome or skeletal 8. Kharrat R, Yamamoto M, Roume J, Couderc S, Vialard F, Hillion Y, et al.
Karyotype and outcome of fetuses diagnosed with cystic hygroma in the
dysplasia. Autopsy should be strongly recommended, at first trimester in relation to nuchal translucency thickness. Prenat Diagn
least for non-chromosomal cases.10,76 Storage of fetal blood, 2006;26:369–72.
tissue, DNA, and amniotic fluid supernatant should be 9. Molina FS, Avgidou K, Kagan KO, Poggi S, Nicolaides KH. Cystic
collected in the appropriate tube and setting (i.e. frozen hygromas, nuchal edema, and nuchal translucency at 11-14 weeks of
at –70˚C). The preservation of a potentially dividing fetal gestation. Obstet Gynecol 2006;107:678–83.
cell line (amniocytes, skin biopsy) is indicated for future 10. Desilets V, Oligny LL; Genetics Committee of the Society of
Obstetricians and Gynaecology Canada; Family Physicians Advisory
biochemical or molecular genetic testing. Extensive sampling Committee; Medico–Legal Committee of the SOGC. Fetal and
from various sources is necessary to test for tissue-specific perinatal autopsy in prenatally diagnosed fetal abnormalities with
enzymatic activity or gene expression. Placental examination normal karyotype. SOGC Clinical Practice Guidelines, No. 267,
(microscopy, histopathology) focusing on tumours, fetal October 2011. J Obstet Gynaecol Can 2011;33:1047–57.
anemia, infection, and metabolic disorder is indicated.77 11. Gagnon A, Wilson RD, Allen VM, Audibert F, Blight C, Brock JA, et al.;
Genetics Committee of the Society of Obstetricians and Gynaecologists
Recommendation of Canada. Evaluation of prenatally diagnosed structural congenital
anomalies. SOGC Clinical Practice Guidelines, No. 234, September 2009.
7. Autopsy should be recommended in all cases of fetal J Obstet Gynaecol Can 2009;31:875–81.
or neonatal death or pregnancy termination. (II-2A) 12. Chitayat D, Langlois S, Wilson RD; Genetics Committee of the Society
Amniotic fluid and/or fetal cells should be stored for of Obstetricians and Gynaecologists of Canada; Prenatal Diagnosis
future genetic testing. (II-2B) Committee of the Canadian College of Medical Geneticists. Prenatal
screening for fetal aneuploidy in singleton pregnancies. SOGC Clinical
Practice Guidelines, No. 261, July 2011. J Obstet Gynaecol Can
CONCLUSION 2011;33:736–50.
13. Morin L, Lim K; SOGC Diagnostic Imaging Committee. Ultrasound in
The prognosis of NIHF differs markedly between twin pregnancies. SOGC Clinical Practice Guidelines, No. 260, June 2011.
different etiological groups. Recent progress in prenatal J Obstet Gynaecol Can 2011;33:643–56.
genetics and maternal–fetal medicine provides us with 14. Senat MV, Deprest J, Boulvain M, Paupe A, Winer N, Ville Y. Endoscopic
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access to maternal–fetal medicine units for fetal evaluation
15. Yamamoto M, Ville Y. Twin-to-twin transfusion syndrome: management
and treatment has improved outcomes. It is essential to options and outcomes. Clin Obstet Gynecol 2005;48:973–80.
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offer treatment when appropriate, and assess recurrence Specific complications of monochorionic twin pregnancies: twin-twin
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Semin Fetal Neonatal Med 2010;15:349–56.
17. Audibert F, Gagnon A; SOGC Genetics Committee; Prenatal Diagnosis
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2005;25:323–30. Gynecol 1997;177:894–8.
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Nonimmune hydrops fetalis due to enterovirus infection. Eur Jour Obstet hydrops fetalis, secondary to parvovirus B19 infection. J Obstet Gynaecol
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et al. In Utero diagnosis and management of a fetus with homozygous treatment. Fetal Diagn Ther 1995;10:101–5.
α-Thalassemia in the second trimester: a case report and literature review. 73. Abrams ME, Meredith KS, Kinnard P, Clark RH. Hydrops fetalis:
J Pediatr Hematol Oncol 2011;33:e358–e360. a retrospective review of cases reported to a large national database and
identification of risk factors associated with death. Pediatrics 2007;120:84–9.
66. Ramsay SL, Maire I, Bindloss C, Fuller M, Whitfield PD, Piraud M,
et al. Determination of oligosaccharides and glycolipids in amniotic 74. Huang HR, Tsay PK, Chiang MC, Lien R, Chou YH. Prognostic factors and
fluid by electrospray ionisation tandem mass spectrometry: in utero clinical features in liveborn neonates with hydrops fetalis. Am J Perinatol
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glycosylation type Ia (CDG-Ia) by cordocentesis and transferrin isoelectric 76. Rodriguez MM, Bruce JH, Jiménez XF, Romaguera RL, Bancalari E,
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Nancy Van Eyk, MD, Halifax NS Benefits, harms, and costs: There is a need for specific guidelines
on menstrual suppression in at-risk populations for health care
Disclosure statements have been received from all contributors. providers.
Recommendations
Abstract 1. Menstrual suppression and therapeutic amenorrhea should be
considered safe and viable options for women who need or want
Objective: To provide a Canadian consensus document for health to have fewer or no menses. (II-2A)
care providers with recommendations for menstrual suppression 2. Menstrual suppression should not be initiated in young women with
in patients with physical and/or cognitive challenges or those who developmental disabilities until after the onset of menses. (II-2B)
are undergoing cancer treatment in whom menstruation may have
a deleterious effect on their health. 3. Combined hormonal or progesterone-only products can be
used in an extended or continuous manner to obtain menstrual
suppression. (I-A)
4. Gynaecologic consultation should be considered prior to the
Key Words: menstruation, menstrual suppression, amenorrhea, initiation of treatment in all premenopausal women at risk for
chemotherapy, radiation, disability, contraception abnormal uterine bleeding from chemotherapy. (II-1A)
5. Leuprolide acetate or combined hormonal contraception
should be considered highly effective in preventing abnormal
uterine bleeding when initiated prior to cancer treatment in
J Obstet Gynaecol Can 2014;36(10):915–924 premenopausal women at risk for thrombocytopenia. (II-2A)
This document reflects emerging clinical and scientific advances on the date issued and is subject to change. The information
should not be construed as dictating an exclusive course of treatment or procedure to be followed. Local institutions can dictate
amendments to these opinions. They should be well documented if modified at the local level. None of these contents may be
reproduced in any form without prior written permission of the SOGC.
Table 1. Key to evidence statements and grading of recommendations, using the ranking of the Canadian Task Force
on Preventive Health Care
Quality of evidence assessment* Classification of recommendations†
I: Evidence obtained from at least one properly randomized A. There is good evidence to recommend the clinical preventive action
controlled trial
II-1: Evidence from well-designed controlled trials without B. There is fair evidence to recommend the clinical preventive action
randomization
II-2: Evidence from well-designed cohort (prospective or C. The existing evidence is conflicting and does not allow to make a
retrospective) or case–control studies, preferably from recommendation for or against use of the clinical preventive action;
more than one centre or research group however, other factors may influence decision-making
II-3: Evidence obtained from comparisons between times or D. There is fair evidence to recommend against the clinical preventive action
places with or without the intervention. Dramatic results in
uncontrolled experiments (such as the results of treatment with E. There is good evidence to recommend against the clinical preventive
penicillin in the 1940s) could also be included in this category action
III: Opinions of respected authorities, based on clinical experience, L. There is insufficient evidence (in quantity or quality) to make
descriptive studies, or reports of expert committees a recommendation; however, other factors may influence
decision-making
*The quality of evidence reported in these guidelines has been adapted from The Evaluation of Evidence criteria described in the Canadian Task Force on
Preventive Health Care.62
†Recommendations included in these guidelines have been adapted from the Classification of Recommendations criteria described in the Canadian Task Force
on Preventive Health Care.62
population,5,6 people with neurologic impairment have a population that examine the different routes for delivering
higher risk of precocious puberty,7 and neuroleptic drugs extended or continuous CHC, and no single regimen has
can lead to hyperprolactinemia and amenorrhea.5,7 While been recognized as superior to the others.11–13 Unscheduled
menstrual irregularities are common in the first 2 to 3 bleeding generally decreases over time.1,2
years post menarche because of anovulatory cycles, AUB
and dysmenorrhea in women with disabilities require the For patients without contraindications to estrogen, the
same investigations as those undertaken in the general OCP, contraceptive patch, or vaginal ring can be used to
population. In a retrospective study of 300 adolescents prevent cyclical or abnormal menstrual bleeding. The safety,
with developmental disabilities, 30% experienced heavy, efficacy, and acceptability of extended or continuous use
painful, or irregular menstrual bleeding, and rates of have been studied in randomized controlled studies14,15 and
behavioural or mood symptoms approached 22%.8 are similar to rates for contraceptives used cyclically. The
extended use of hormones for menstrual suppression for
In 2 retrospective studies, 32% to 43% of caregivers dysmenorrhea, endometriosis, heavy menstrual bleeding,
approached physicians for information on menstrual and menstrual-related symptoms is also well established.
suppression prior to the young woman’s menarche because For specific details, please refer to SOGC Clinical Practice
of their anxiety and concerns about coping with hygiene Guideline no. 195.2 There are no data on the long-term
and possible behavioural changes.4,8 Behavioural concerns safety of CHC in patients with cognitive or physical
can include mood changes, aggression, and self-mutilation,6 impairments.
which may also reflect pain.9 Defining the reasons for
intervention can assist in the formation of treatment The prescription of extended use of CHC has been
goals.1 Table 2 outlines the pertinent points to elicit from shown to be acceptable in adolescents16 and patients
history prior to initiation of therapy when considering with disabilities.4,8 CHC also suppresses ovulation,
menstrual suppression. There is a general consensus that which improves menstrual-related mood symptoms or
menstrual suppression therapy should not commence until behaviours. These are common presenting complaints in
menarche.4 Often, education and support of the normal adolescents with Down syndrome, autism, and cerebral
progression through puberty and menarche are all that palsy.6 Adjustment to a higher dose estrogen-containing
is required.4,8,9 Awaiting menarche also confirms normal formulation or to an alternate antiepileptic may be
hormonal function and the absence of an obstructive required because enzyme-inducing anti-epileptic drugs
anomaly. Once a decision is made to pursue treatment, can interfere with the cytochrome p450 system and
medical interventions that are the least intrusive, are metabolism of CHC.17 The need for frequent courses of
reversible, and have the lowest side effect profile are antibiotics may affect the efficacy of hormonal therapy.
desirable. Surgical or permanent interventions are rarely Malnutrition or gastric feeding tubes can affect the route
required and are fraught with ethical and legal issues if the of drug administration and absorption.5 Immobile and
individual is unable to participate fully in consent.1,5,7,9,10 wheelchair-bound individuals may be at increased risk of
All of the available options for reversible contraception venous thromboembolism.6,18 In a recent cohort study
are acceptable for menstrual suppression (Table 3) and of adolescents with disabilities, none of the permanent
satisfaction can be achieved in most disabled adolescents wheelchair users who used an OCP or the patch developed
and their families with 1 or 2 hormonal methods.8 thromboembolisms during the study period.8
Table 2. Considerations for menstrual The contraceptive patch delivers 35 mcg of ethinyl
suppression in girls and women with estradiol and 150 mcg of norelgestromin daily and requires
developmental disabilities weekly replacement. The patch may be considered in
Menarchal status patients with gastrointestinal issues (difficulty swallowing
Premenarchal: counselling and education or malabsorption) or in those with poor compliance using
Postmenarchal: menstrual suppression options daily oral contraceptives.1 In a randomized controlled
Quality of life trial evaluating continuous use of the patch in the general
Hygiene population, menstrual bleeding was delayed to 54 days
Degree of anxiety and amenorrhea rates of 28% and 12% were achieved
Activity restrictions through extended use to 8 and 12 weeks, respectively.11
Caregiver concerns The side effect profile is similar to that of OCP,20,21
Treatment goals with spotting as a common initial side effect. Based on
Degree of suppression or amenorrhea desired data analyzed for pregnancy outcome, the efficacy of
Contraceptive needs the patch appears to be reduced in patients who weigh
Type of disability or risk 90 kg or more.22 In a cohort study of adolescents with
Cognitive disabilities, 20% of patients and their families elected
Physical to use the patch as their first choice for menstrual
Communicative suppression.8 Disadvantages of the transdermal patch
Abuse included skin irritation, behavioural or mood concerns,
Degree of required support breast tenderness, and attempted removal of the patch by
Ambulatory vs. wheelchair user the disabled adolescent.
Support required with activities of daily living
The transvaginal ring is a preparation with daily delivery
Access to support (home, school, and respite care)
of 15 mcg ethinyl estradiol and 120 mcg etonogestrel.22
Menstrual symptoms
One randomized controlled trial in the general population
Menstrual bleeding patterns
evaluated continuous use of the ring versus extended use
Dysmenorrhea
with a 4-day ring-free interval, with the latter resolving
Behavioural, mood, and/or premenstrual symptoms
breakthrough bleeding or spotting.23 Continuous or
Medical history and comorbidities
extended use had high continuation rates and reduced
Cerebrovascular disease
menstrual flow and pelvic pain. An advantage of the
Complicated valvular heart disease
ring is that it can be used for one month before requiring
Diabetes with end-organ disease
replacement. Although the use of the transvaginal ring
Decreased BMD
has not been studied in the developmentally delayed
Liver disease
population, this option can be presented to patients with
Malnutrition or feeding tube
minor cognitive delay and familiarity with tampon use or
Migraines with neurological symptoms
no physical impairment to ring insertion.
Obesity
Seizure disorder Progestin-only Options
Thromboembolic risk or history Progestin-only options for menstrual suppression
Thyroid dysfunction offer alternatives to estrogen-containing contraceptives
Uncontrolled hypertension and can be administered by intramuscular, oral, or
Medications intrauterine routes. The progestin implant is not
Antiepileptics available in Canada.
Antibiotics
Neuroleptics
Oral progestins (0.35 mg norethindrone tablets) are
Steroids
prescribed daily without a pill-free interval. The POP
does not confer the same degree of amenorrhea (10% of
patients),24 but it is effective contraception with a failure
rate of only 0.5% with perfect use.22 Side effects are much
less common with POP than with OCP, but may include
breakthrough bleeding, emotional disturbances, acne, and
breast tenderness. POP treatment has not been studied
exclusively in patients with disabilities.
DMPA is an injectable progesterone of 150 mg gain on DMPA,36 and weight gain may be an important
administered intramuscularly every 12 weeks. Despite issue in individuals who require assistance with transfers.6
American and Canadian advisories in 2004 and 2005,
respectively, regarding concerns over loss of BMD, the Levonorgestrel Intrauterine System
advantages of DMPA have led to its continued use. Prior The LNG-IUS is indicated for control of heavy menstrual
to evidence of the association between DMPA and bone bleeding and long-acting reversible contraception.
loss, DMPA was the most commonly prescribed method Through daily delivery of 20 mcg of levonorgestrel, the
of menstrual suppression (59%) in adolescents with local effects of the device lead to inhibition of endometrial
developmental delay.4 Recent Canadian data have shown a proliferation, thickening of cervical mucus, and impaired
shift in prescribing methods to the extended combined oral sperm mobility.37 In the general population, menstrual
contraceptive, although DMPA remains a popular initial blood loss is reduced by 85% in 3 months,38 and rates of
choice in 12% of adolescent patients with disabilities.8 amenorrhea reach nearly 50% in 6 months39 and continue
to increase over time, while irregular spotting, particularly
The dosing schedule of DMPA, administered every 12 weeks in the months following insertion, diminishes. In a
or sometimes every 10 weeks in patients on anti-epileptic randomized controlled trial, LNG-IUS was shown to be
medications,25,26 confers a possible advantage in patients with more effective in reducing menstrual bleeding than a 10-
disabilities. DMPA also minimizes concerns over compliance day regimen of 10 mg oral medroxyprogesterone acetate
and is acceptable in patients who are unable to swallow pills or per month.40 In adolescents, the most common indication
tolerate a vaginal ring or transdermal patch. DMPA may also for use of the LNG-IUS was heavy menstrual bleeding,
be considered for the quick initial induction of amenorrhea, which occurred in 17% of patients.41
to be followed by the use of alternative longer-term methods
of menstrual suppression. Rates of amenorrhea at 12 to A significant benefit of the LNG-IUS is its length of
24 months reach 55% to 70% in the general population,25,27 treatment (5 years), after which it can be removed and
with irregular bleeding as a common initial side effect that alternatives can be re-evaluated or a new IUS can be
diminishes over time. It is an extremely effective contraceptive reinserted. Side effects are few and complications such as
with a failure rate of 0.3%.24 Additional advantages include a perforation, expulsion, and infection are rare in adult and
relative lack of drug interactions and reductions in seizures28 adolescent populations,18,40–42 with high rates of continuation
and sickle cell crises.29 in adolescents of 75% to 85%.41,43 In one study of 14 young
women with disabilities,44 50% achieved amenorrhea with
The reduction in estrogen levels from the use of DMPA LNG-IUS and there was 1 expulsion, which is in keeping
during adolescence is associated with bone loss of 3.1% at with the low rates of expulsion (7 to 8%) of IUDs in young
the lumbar spine and 6.1% at the hip.19,30 Fortunately, studies women with or without disabilities.41,43 In another study
suggest that loss of BMD is transient and its recovery has been of adolescents with cognitive and physical challenges,8 the
demonstrated in adult and adolescent patients with cessation LNG-IUS was a popular second-line option for menstrual
of the injection.30–33 Modifiable factors such as dietary calcium suppression in 19% of patients who switched from alternate
intake, even at levels lower than the daily recommended intake methods. Ovulation is not suppressed by the LNG-IUS, and
of 1300 mg per day, contribute to BMD gain in the femoral thus hormonal cycling and associated mood symptoms or
neck and lumbar regions in adolescents.34 The DEXA scan can behaviours may not be ameliorated.
be used to quantify bone mass during DMPA treatment. Age
Insertion in virginal or young women with disabilities may
appropriate norms should be used. However, whether this
require general anaesthesia or conscious sedation. Pre-
surrogate marker for bone strength translates into a measure
insertion considerations include vaginal and cervical swabs
of fracture risk has yet to be elucidated. Considerations of
in patients at risk for infection, screening for pregnancy,
bone density are particularly important in wheelchair-bound
ultrasound for vertical length of the uterine cavity (5 to 6
and immobile patients or those on systemic steroids, who
cm is recommended), and administration of oral or vaginal
are already at risk for lower BMD. Regular appointments
misoprostol.44,45 Long-term menstrual suppression with
to readdress the need for continued DMPA, to consider
LNG-IUS offers effective reduction in menstrual blood loss,
alternatives, and to encourage adequate dietary calcium with
high rates of amenorrhea, and low rates of complications.8,41,44
vitamin D supplementation and weight-bearing exercise are
strongly encouraged.35 Recommendation
Weight gain of 1 to 2 kg per year of use is also a possible 3. Combined hormonal or progesterone-only
side effect of DMPA through appetite stimulation.36 Obese products can be used in an extended or continuous
young women are more susceptible to increased weight manner to obtain menstrual suppression. (I-A)
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doi: 10.1002/pbc.23360. Epub 2012 Feb 13.
55. Elgindy EA, El-Haieg DO, Khorshid OM, Ismail EI, Abdelgawad M, 62. Woolf SH, Battista RN, Angerson GM, Logan AG, Eel W. Canadian
Sallam HN, et al. Gonadatrophin suppression to prevent chemotherapy- Task Force on Preventive Health Care. New grades for recommendations
induced ovarian damage: a randomized controlled trial. Obstet Gynecol from the Canadian Task Force on Preventive Health Care. CMAJ
2013;121:78–86. 2003;169:207–8.
Lola Cartier, MSc, CCGC, Montreal QC 1. Non-invasive prenatal testing using massive parallel sequencing
of cell-free fetal DNA to test for trisomies 21, 18, and 13 should
Alain Gagnon, MD, Vancouver BC be an option available to women at increased risk in lieu of
Jo-Ann Johnson, MD, Calgary AB amniocentesis. Pretest counselling of these women should
include a discussion of the limitations of non-invasive prenatal
Sylvie Langlois, MD, Vancouver BC
testing. (II-2A)
William MacDonald, MD, Halifax NS
2. No irrevocable obstetrical decision should be made in pregnancies
Lynn Murphy-Kaulbeck, MD, Moncton NB with a positive non-invasive prenatal testing result without
confirmatory invasive diagnostic testing. (II-2A)
Nanette Okun, MD, Toronto ON
3. Although testing of cell-free fetal DNA in maternal plasma
Melanie Pastuck, RN, Cochrane AB
appears very promising as a screening test for Down syndrome
Vyta Senikas, MD, Ottawa ON and other trisomies, studies in average-risk pregnancies and a
Disclosure statements have been received from all members of significant reduction in the cost of the technology are needed
the committee. before this can replace the current maternal screening approach
using biochemical serum markers with or without fetal nuchal
translucency ultrasound. (III-A)
Abstract
Objective: To provide a review of published studies on the use
of cell-free fetal DNA in maternal plasma for the non-invasive J Obstet Gynaecol Can 2013;35(2):177–181
diagnosis of Down syndrome, trisomy 18, and trisomy 13.
Evidence: PubMed was searched for articles published between Key Words: Non-invasive prenatal diagnosis, prenatal screening,
2006 and October 2012, using appropriate key words Down syndrome, trisomy 18, trisomy 13, cell-free fetal DNA
(e.g., non-invasive prenatal diagnosis, Down syndrome, cell-free
This document reflects emerging clinical and scientific advances on the date issued and is subject to change. The information
should not be construed as dictating an exclusive course of treatment or procedure to be followed. Local institutions can dictate
amendments to these opinions. They should be well documented if modified at the local level. None of these contents may be
reproduced in any form without prior written permission of the SOGC.
Table 1. Key to evidence statements and grading of recommendations, using the ranking of the Canadian Task Force
on Preventive Health Care
Quality of evidence assessment* Classification of recommendations†
I: Evidence obtained from at least one properly randomized A. There is good evidence to recommend the clinical preventive action
controlled trial
II-1: Evidence from well-designed controlled trials without B. There is fair evidence to recommend the clinical preventive action
randomization
II-2: Evidence from well-designed cohort (prospective or C. The existing evidence is conflicting and does not allow to make a
retrospective) or case–control studies, preferably from recommendation for or against use of the clinical preventive action;
more than one centre or research group however, other factors may influence decision-making
II-3: Evidence obtained from comparisons between times or D. There is fair evidence to recommend against the clinical preventive action
places with or without the intervention. Dramatic results in
uncontrolled experiments (such as the results of treatment with E. There is good evidence to recommend against the clinical preventive
penicillin in the 1940s) could also be included in this category action
III: Opinions of respected authorities, based on clinical experience, L. There is insufficient evidence (in quantity or quality) to make
descriptive studies, or reports of expert committees a recommendation; however, other factors may influence
decision-making
*The quality of evidence reported in these guidelines has been adapted from The Evaluation of Evidence criteria described in the Canadian Task Force on
Preventive Health Care.21
†Recommendations included in these guidelines have been adapted from the Classification of Recommendations criteria described in the Canadian Task Force
on Preventive Health Care.21
cohorts of pregnant women who had undergone an invasive screening. Before these methods can replace current prenatal
procedure (CVS or amniocentesis).8–16 The indications for screening options, validation studies using them in average-
invasive diagnostic testing included advanced maternal risk pregnancies need to be done. Only one cohort study
age, abnormal aneuploidy screening results, and/or of 2049 women has so far been done in women at average
sonographically diagnosed fetal abnormalities. Results of risk.19 As the cost of the technology is high compared
these clinical trials are summarized in Table 2. Only trials with current screening methods, cost-effectiveness studies
that collected maternal blood samples before invasive are also needed. Given the demonstrated value of NIPT
procedures are included. While all studies used massive in high risk pregnancies, this testing should be an option
parallel sequencing, there were differences in methodology available to pregnant women found to be at increased
and sequencing data analysis between studies that prevent risk of fetal Down syndrome, trisomy 18, and trisomy
summing of the results. However, the detection rate for 13 on the basis of currently available screening tests or
Down syndrome in all studies was, or approached, 100% ultrasound findings. It is important for these women to
with a false-positive rate less than 1%. The focus of studies receive detailed pretest counselling that explains the
so far has been the detection of Down syndrome; however,
benefits and limitations of the test.20 Counselling should
this technology has also been used to detect trisomy 18
include the following points:
and trisomy 13, although initially with less success because
of a larger coefficient of variation and therefore lower •• Non-invasive cffDNA testing should not be
precision in estimating the proportion of chromosomes considered equivalent to conventional cytogenetic
18 or 1311,17 to the total chromosomes. However, recent analysis of CVS or amniocytes.
publications suggest that this can be overcome by using
a targeted sequencing approach13,14,16 and/or a different •• Cytogenetic testing of CVS or amniocytes detects
sequencing data analysis approach.15,18 This is leading to the 100% of cases of Down syndrome, trisomy 18, and
utilization of this technology for the detection of trisomy trisomy 13 (thus is diagnostic), whereas the test done
18 and trisomy 13 in addition to Down syndrome. Results on cffDNA does miss some cases (see Table 2 and
of those studies are presented in Table 3. Table 3, detection rate).
Table 3. Results of validation studies for non-invasive detection of fetal trisomy 18 and trisomy 13
Sequencing Trisomy 18 Trisomy 18 Trisomy 13 Trisomy 13
Study approach detection rate false-positive rate detection rate false-positive rate
Lau et al. 201111 12-plex shotgun 90% (9/10) 0 100% (2/2) 0
Sehnert et al. 2011 12
1-plex shotgun 100% (8/8) 0 No data No data
Sparks et al. 201213 96-plex selective 100% (8/8) 0.8% No data No data
Ashoor et al. 201214 96-plex selective 98% (49/50) 0 No data No data
Bianchi et al. 2012 15
6-plex 97.2% (35/36) 0 78.6% (11/14) 0
Norton et al. 201216 96-plex selective 97.4% (37/38) 0.07% No data No data
Palomaki et al. 201218 4-plex shotgun 100% (59/59) 0.28% 91.7% (11/12) 0.97%
•• cffDNA testing has a higher rate of false-positive 2. No irrevocable obstetrical decision should be
results than current diagnostic tests based on made in pregnancies with a positive non-invasive
cytogenetic analysis of amniocytes or chorionic villi. prenatal testing result without confirmatory invasive
(Tables 2 and 3, false positive rate). diagnostic testing. (II-2A)
3. Although testing of cell-free fetal DNA in maternal
•• Some women will have a cffDNA positive result and plasma appears very promising as a screening test
not carry a fetus with Down syndrome, trisomy 18, or for Down syndrome and other trisomies, studies in
trisomy 13 (false positive). No irrevocable obstetrical average-risk pregnancies and a significant reduction
decision should be made in pregnancies with a in the cost of the technology are needed before this
positive cffDNA test for Down syndrome without can replace the current maternal screening approach
confirmatory invasive diagnostic testing. using biochemical serum markers with or without
fetal nuchal translucency ultrasound. (III-A)
•• cffDNA testing fails to provide a result in a small
percentage of women. REFERENCES
1. Avent ND, Chitty LS. Non-invasive diagnosis of fetal sex; utilisation
CONCLUSION of free fetal DNA in maternal plasma and ultrasound. Prenat Diagn
2006;26:598–603.
NIPT using massive parallel sequencing for the detection 2. Minon JM, Gerard C, Senterre JM, Schaaps JP, Foidart JM. Routine
of Down syndrome, trisomy 18, and trisomy 13 has shown fetal RHD genotyping with maternal plasma: a four-year experience in
promising results in clinical trials of women identified by Belgium. Transfusion 2008; 48:373–81.
screening as having a high-risk pregnancy. NIPT should be 3. Finning K, Martin P, Summers J, Massey E, Poole G, Daniels G. Effect of
high throughput RHD typing of fetal DNA in maternal plasma on use of
an option as a second-level contingent screening test (after anti-RhD immunoglobulin in RhD negative pregnant women; prospective
a positive result from currently used serum and ultrasound feasibility study. Br Med J 2008;336:816–8.
screening techniques) for women wishing to avoid invasive 4. Wright CF, Burton H. The use of cell-free fetal nucleic acids in maternal
testing. Further studies are needed to determine if this blood for non-invasive prenatal diagnosis. Hum Reprod Update
2009;15:139–51.
approach can be reliably used as a first-tier screening test in
5. Fan HC, Blumenfeld YJ, Chitkara U, Hudgins L, Quake SR. Noninvasive
average-risk pregnancies. Finally, cost-effectiveness studies diagnosis of fetal aneuploidy by shotgun sequencing DNA from maternal
are needed before this cffDNA approach can replace blood. PNAS 2008;105:16266–71.
current screening options. 6. Chiu RWK, Chan KCA, Gao Y, Lau VYM, Zheng W, Leung TY, et al.
Noninvasive prenatal diagnosis of fetal chromosomal aneuploidy by
Recommendations massively parallel genomic sequencing of DNA in maternal plasma.
PNAS 2008;105:20458–63.
1. Non-invasive prenatal testing using massive
7. Chiu RWK, Sun H, Akolekar R, Clouser C, Lee C, McKernan K, et al.
parallel sequencing of cell-free fetal DNA to test Maternal plasma DNA analysis with massively parallel sequencing by
for trisomies 21, 18, and 13 should be an option ligation for noninvasive prenatal diagnosis of trisomy 21. Clin Chem
available to women at increased risk in lieu of 2010;56:459–63.
amniocentesis. Pretest counselling of these women 8. Chiu RWK, Akolekar R, Zheng YWL, Leung TY, Sun H, Chan KCA,
should include a discussion of the limitations of et al. Non-invasive prenatal assessment of trisomy 21 by multiplexed
maternal plasma DNA sequencing: large scale validity study. BMJ
non-invasive prenatal testing. (II-2A) 2011;342:c7401.
9. Palomaki GE, Kloza EM, Lambert-Messerlian GM, Haddow JE, 16. Norton ME, Brar H, Weiss J, Karimi A, Laurent LC, Caughey AB,
Neveux LM, Ehrich M, et al. DNA sequencing of maternal plasma to et al. Non-invasive chromosomal evaluation (NICE) study: results of a
detect Down syndrome: an international clinical validation study. Genet multicenter prospective cohort study for detection of fetal trisomy 21
Med 2011;13:913–20. and trisomy 18. Am J Obstet Gynecol 2012; 207:e1–8.
10. Ehrich M, Deciu C, Zwiefelhofer T, Tynan JA, Cagasan L, Tim R,
17. Chen EZ, Chiu RW, Sun H, Akolekar R, Chan KC, Leung TY, et al.
et al. Noninvasive detection of fetal trisomy 21 by sequencing of DNA
Noninvasive prenatal diagnosis of fetal trisomy 18 and trisomy 13 by
in maternal blood: a study in a clinical setting. Am J Obstet Gynecol
maternal plasma DNA sequencing. PLoS ONE 2011;6:e21791.
2011;204(3):205e1–11.
11. Lau TK, Chan F, Pan X, Pooh RK, Jiang F, Li Y, et al. Noninvasive 18. Palomaki GE, Deciu C, Kloza EM, Lambert-Messerlian GM,
prenatal diagnosis of common fetal chromosomal aneuploidies by Haddow JE, Neveux LM, et al. DNA sequencing of maternal
maternal plasma DNA sequencing. J Matern Fetal Neonatal Med plasma reliably identifies trisomy 18 and trisomy 13 as well as
2012;25(8):1370–4. Down syndrome: an international collaborative study. Genet Med
2012;14(3):295–305.
12. Sehnert AJ, Rhees B, Comstock D, de Feo E, Heilek G, Burke J, et al.
Optimal detection of fetal chromosomal abnormalities by massively
19. Nicolaides KH, Syngelaki A, Ashoor G, Birdir C, Touzet G.
parallel DNA sequencing of cell-free fetal DNA from maternal blood.
Noninvasive prenatal testing for fetal trisomies in a routinely
Clin Chem 2011:57:1042–9.
screened first-trimester population. Am J Obstet Gynecol
13. Sparks AB, Struble ET, Wang ET, Song K, Oliphant A. Non-invasive 2012;207(5):374.e1–6
prenatal detection and selective analysis of cell-free DNA obtained from
maternal blood: evaluation for trisomy 21 and trisomy 18. Am J Obstet 20. Benn P, Borrell A, Cuckle H, Dugoff L, Gross S, Johnson J,
Gynecol 2012;206:319.e1–9. et al. Prenatal detection of Down syndrome using massively parallel
sequencing (MPS): a rapid response statement from a committee on
14. Ashoor G, Syngelaki A, Wagner M, Birdir C, Nicolaides KH.
behalf of the Board of the International Society for Prenatal Diagnosis,
Chromosome-selective sequencing of maternal plasma cell-free DNA
24 October 2011. Prenat Diagn 2012;32:1–2.
for first-trimester detection of trisomy 21 and trisomy 18. Am J Obstet
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21. Woolf SH, Battista RN, Angerson GM, Logan AG, Eel W. Canadian
15. Bianchi DW, Platt LD, Goldberg JD, Abuhamad AZ, Sehnert A, Rava RP. Task Force on Preventive Health Care. New grades for
Genome-wide fetal aneuploidy detection by maternal plasma. Obstet recommendations from the Canadian Task Force on Preventive
Gynecol 2012;119(5);890–901. Health Care. CMAJ 2003;169:207–8.
This document reflects emerging clinical and scientific advances on the date issued and is subject to change. The information
should not be construed as dictating an exclusive course of treatment or procedure to be followed. Local institutions can dictate
amendments to these opinions. They should be well documented if modified at the local level. None of these contents may be
reproduced in any form without prior written permission of the SOGC.
Table 1. Key to evidence statements and grading of recommendations, using the ranking of the Canadian Task Force
on Preventive Health Care
Quality of evidence assessment* Classification of recommendations†
I: Evidence obtained from at least one properly randomized A. There is good evidence to recommend the clinical preventive action
controlled trial
II-1: Evidence from well-designed controlled trials without B. There is fair evidence to recommend the clinical preventive action
randomization
II-2: Evidence from well-designed cohort (prospective or C. The existing evidence is conflicting and does not allow to make a
retrospective) or case–control studies, preferably from recommendation for or against use of the clinical preventive action;
more than one centre or research group however, other factors may influence decision-making
II-3: Evidence obtained from comparisons between times or D. There is fair evidence to recommend against the clinical preventive action
places with or without the intervention. Dramatic results in
uncontrolled experiments (such as the results of treatment with E. There is good evidence to recommend against the clinical preventive
penicillin in the 1940s) could also be included in this category action
III: Opinions of respected authorities, based on clinical experience, L. There is insufficient evidence (in quantity or quality) to make
descriptive studies, or reports of expert committees a recommendation; however, other factors may influence
decision-making
*The quality of evidence reported in these guidelines has been adapted from The Evaluation of Evidence criteria described in the Canadian Task Force on
Preventive Health Care.73
†Recommendations included in these guidelines have been adapted from the Classification of Recommendations criteria described in the Canadian Task Force
on Preventive Health Care.73
of negative maternal GBS screening. This emerging recommendations advised one of two approaches:
information from European and Canadian populations a universal screening or a risk-factor approach. The
was not available at the time of the Canadian Task Force on screening approach involved performing a rectovaginal
Preventative Health Care’s 2001 report on the prevention swab at 35 to 37 weeks and culturing in selective broth. All
of early-onset group B streptococcal infection in the women colonized with GBS were to receive intrapartum
newborn, which recommended that universal screening antibiotics, and women with negative cultures were
with selective intrapartum chemoprophylaxis be given to to receive antibiotics only if they developed signs of
colonized women with risk factors.35 chorioamnionitis. A risk-factor approach (onset of labour
at < 37 weeks’ gestation, membrane rupture > 18 hours,
Heavy colonization with GBS has been associated with intrapartum temperature > 38.0°C) was considered an
adverse pregnancy outcomes including preterm labour acceptable alternative. If women had GBS bacteriuria
and preterm pre-labour rupture of membranes.36,37 GBS in the current pregnancy or a previous infant who had
bacteriuria occurs in 2% to 4% of pregnancies and is invasive GBS disease, they were to receive intrapartum
associated with both maternal urinary tract disease and an chemoprophylaxis regardless of current colonization
increased risk of neonatal disease.17 Maternal colonization status, and would not require a vaginal/anal swab for
with GBS has been associated with endometritis and GBS culture at 35 to 37 weeks’ gestation.
wound infection.38,39 There is no convincing evidence that
GBS bacteriuria with low colony counts (< 108 CFU/L In June 1997, the Society of Obstetricians and
or < 105 CFU/mL) is associated with increased risks for Gynaecologists of Canada presented guidelines which
pyelonephritis, chorioamnionitis, or preterm birth, and were congruent to those recommended by the CDC.47
antepartum treatment (prior to the onset of labour or The Canadian guideline stated that two methods were
rupture of membranes) for low colony counts is therefore acceptable, either universal screening at 35 to 37 weeks
not recommended. Intrapartum IV antibiotic prophylaxis by combined vaginal/rectal swab and intrapartum
is still recommended for GBS bacteriuria in the current chemoprophylaxis of all colonized women, or intrapartum
pregnancy, regardless of colony count.40 Laboratory chemoprophylaxis of women with risk factors. It was
reporting of any colony count of GBS in the urine in acknowledged that additional research was required to
pregnancy is variable among centres in Canada. evaluate the prevention of neonatal GBS disease.
GBS and non-GBS organisms (primary outcome due to an increase in resistance in GBS seen recently),
analyses).54 However, analysis of secondary outcomes and updated and separate algorithms for women with
suggested a statistically significant reduction (80%) preterm labour (discontinue GBS prophylaxis if not
in the incidence of both confirmed early-onset GBS in labour) and PPROM (provide GBS prophylaxis
disease (RR 0.17, 95% CI 0.04 to 0.74, number needed intravenously for 48 hours [or less if the swab for GBS
to benefit 25) and probable early-onset GBS disease culture is subsequently negative], as well as antibiotics for
(RR 0.17, 95% CI 0.03 to 0.91, number needed to latency if other antibiotic regimens are usually used).13
benefit 20) in neonates following intrapartum antibiotics
compared to no prophylaxis. There was no reduction in Economic analyses of risk-based and universal culture-
based approaches have been conducted and showed that
the incidence of late-onset GBS neonatal disease. The
universal culture-based is equivalent in cost to risk-based
trials included in this meta-analysis were of poor quality
approach if one considers the cost savings involved with
and had significant methodological biases.54
reduction of morbidity and mortality. It has also been
shown that a risk-based versus screening approach is
RISK-BASED VERSUS SCREENING APPROACH essentially equivalent in cost and in the number of women
receiving antibiotics prophylaxis.58
No randomized trials have evaluated intrapartum antibiotic
prophylaxis based on risk factors versus universal screening Recommendations
approaches, although a number of non-randomized 1. Offer all women screening for colonization with
studies have attempted to evaluate the merits of screening group B streptococcus at 35 to 37 weeks’ gestation
versus a risk-based approach.55,56 In most studies, the with culture taken from one swab first to the vagina
screening approach included intrapartum prophylaxis and then to the rectum (through the anal sphincter).
for all women who were colonized at the time of labour (II-1A) This includes women with planned
or rupture of membranes. A large CDC multistate study Caesarean delivery because of their risk of labour
of a stratified random sample of 626 912 live births in or ruptured membranes earlier than the scheduled
1998 and 1999 demonstrated that of 5144 births, the risk Caesarean delivery. (II-2B)
of early-onset disease was significantly lower among the 2. Because of the association of heavy colonization
infants of screened women compared to those born to with early onset neonatal disease, provide
mothers managed with the risk-based approach (adjusted intravenous antibiotic prophylaxis for group B
RR 0.46; 95% CI 0.36 to 0.60).56 This information streptococcus at the onset of labour or rupture of
prompted the development of revised guidelines by the the membranes to:
CDC in 2002.57 The most significant recommendation • any woman positive for group B streptococcus by
in the CDC guideline at that time included a change vaginal/rectal swab culture screening done at 35
from a dual approach to universal prenatal culture-based to 37 weeks’ gestation (II-2B);
screening for vaginal and rectal GBS colonization of all • any woman with an infant previously infected
pregnant women at 35 to 37 weeks’ gestation. Updated with group B streptococcus (II-3B);
prophylaxis regimens for women with a penicillin allergy • any woman with documented group B
were provided, including cefazolin if not at high risk for streptococcus bacteriuria (regardless of
anaphylaxis, clindamycin or erythromycin if high risk for level of colony-forming units) in the current
anaphylaxis and GBS susceptible, or vancomycin if GBS pregnancy. (II-2A)
resistant or susceptibility unknown. Clindamycin can only 3. Manage all women who are < 37 weeks’ gestation
be utilized for erythromycin-resistant isolates if inducible and in labour or with rupture of membranes with
intravenous group B streptococcus antibiotic
clindamycin resistance has been excluded. Intrapartum
prophylaxis for a minimum of 48 hours, unless there
antibiotic GBS prophylaxis for GBS-colonized women
has been a negative vaginal/rectal swab culture or
undergoing planned Caesarean delivery before the onset
rapid nucleic acid-based test within the previous 5
of labour with intact membranes was not recommended.57
weeks. (II-3A)
A further update by the CDC in 2010 has included a 4. Treat all women with intrapartum fever and
change in the recommended dose for penicillin G for signs of chorioamnionitis with broad spectrum
prophylaxis (acceptable dose range of 2.5 to 3.0 million intravenous antibiotics targeting chorioamnionitis
units for doses subsequent to the initial dose), changes to and including coverage for group B streptococcus,
prophylaxis regimens for women with penicillin allergy regardless of group B streptococcus status and
(removal of erythromycin as an acceptable alternative gestational age. (II-2A)
PRACTICAL ASPECTS OF THE 190 women enrolled had results of the standard screen at
SCREENING METHODS 35 to 37 weeks available for comparison.12 The sensitivity
and specificity of the standard 35- to 37-week screen were
A vaginal/rectal (not vaginal/perianal) swab is taken at 35 84.3% (95% CI 71.4% to 93.0%) and 93.2% (95% CI
to 37 weeks’ gestation to screen women and detect GBS 86.5% to 97.2%), respectively, whereas the sensitivity and
colonization of the genital tract. This is done by using specificity of the rapid PCR were 90.7% (95% CI 79.7% to
a single swab first in the vagina then in the rectum and 96.9%) and 97.6% (95% CI 93.1% to 99.5%), respectively.
transporting it at room temperature to the laboratory The median reporting time for the rapid PCR test was 99
in a non-nutritive transport medium; Amies or Stuart’s minutes (range 50 to 255). Results were available more
medium is recommended.59 These specimens should be than 4 hours before delivery in 81% of cases.12
labelled clearly to inform the laboratory of the need to
perform specific GBS culturing. In addition, if the woman The advantage of PCR screening is the rapid, real-time result;
is allergic to penicillin and is at a high risk for anaphylaxis, the disadvantages are the lack of antibiotic susceptibility
this should be stated and a request made to perform data, potentially false-negative results related to rupture of
susceptibility testing (see Table 2).60,61 The laboratory membranes, and the fact that there is insufficient time for use
can then culture the organism in selective broth media to of selective enrichment broth for at least 4 hours prior to PCR
maximize the isolation of GBS. Self-sampling for GBS in the intrapartum setting. The 2010 CDC guideline suggests
at 35 to 37 weeks’ gestation, with appropriate instruction that a useful intrapartum screening test should be simple, have
in the clinical examination room or washroom, has been a turn-around time of < 30 minutes, and have a sensitivity and
shown to be accurate and acceptable when compared with specificity of ≥ 90%.13 This technique would be reserved for
physician sampling in a Canadian population.62 hospitals that had diagnostic laboratory capabilities of real-
time PCR testing, validated PCR performance, and appropriate
Recommendation quality controls. A study comparing the estimated direct
5. Request antibiotic susceptibility testing on group B costs (including screening test costs and hospital costs) and
streptococcus-positive urine and vaginal/rectal consequences of intrapartum PCR screening for early-onset
swab cultures in women who are thought to have a GBS disease (Xpert GBS test) with antenatal lower vagina
significant risk of anaphylaxis from penicillin. (II-1A) culture screening demonstrated a higher detection rate of GBS
colonization with PCR (16.7% versus 11.7%). The average total
Antenatal GBS cultures at 35 to 37 weeks’ gestation have cost per delivery was US$1759 ± 1209 for antenatal screening
been shown in a recent systematic review to have acceptable in 2009 and US$1754 ± 842 for intrapartum screening in 2010
positive and negative predictive values for colonization (P = 0.9).65 With improved techniques, therefore, in some
at delivery (mean positive predictive value 69%, mean institutions GBS screening may be replaced by intrapartum
negative predictive value 94%).63 A preferable method may PCR assessment.
be a rapid accurate test to detect the presence of GBS
at the actual time of delivery. The use of a polymerase ANTIBIOTIC CHOICES
chain reaction has been shown to have a sensitivity of
97% and a negative predictive value of 98.8%.64 The one Since GBS appears to be uniformly susceptible to the
negative PCR in the 33 women evaluated was in a woman penicillins, it is recommended that IV penicillin G be
with ruptured membranes prior to testing. In a Canadian used instead of IV ampicillin because of penicillin G’s
single-centre study evaluating the use of rapid PCR (IDI- narrow spectrum of action, which diminishes the risk of
Strep B assay) in the labour and delivery suite, 85% of the selective pressure on other organisms and decreases the
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group B streptococcal disease: a multistate surveillance analysis. The
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1997;90:901–6. policies based on 1996 group B streptococcal disease consensus
guidelines. The Active Bacterial Core Surveillance Team. Obstet Gynecol
34. Puopolo KM, Madoff LC, Eichenwald EC. Early-onset group 2000;95:377–82.
B streptococcal disease in the era of maternal screening. Pediatr
2005;115:1240–6. 53. Van Dyke MK, Phares CR, Lynfield R, Thomas AR, Arnold KE,
Craig AS, et al. Evaluation of universal antenatal screening for group B
35. Shah V, Ohlsson A; Canadian Task Force on Preventive Health Care. streptococcus. New Engl J Med 2009;360:2626–36.
Prevention of early-onset group B Streptococcal (GBS) infection in the
54. Ohlsson A, Shah VS. Intrapartum antibiotics for known maternal
newborn: systematic review and recommendations. CTFPHC Technical
Group B streptococcal colonization. Cochrane Database Syst Rev
Report 01-6. London, ON: Canadian Task Force; 2001.
2009;(3):CD007467. DOI: 10.1002/14651858.CD007467.pub2.
36. Regan JA, Klebanoff MA, Nugent RP, Eschenbach DA, Blackwelder WC,
55. Heath PT. An update on vaccination against group B streptococcus.
Lou Y, et al. Colonization with group B streptococci in pregnancy
Expert Rev Vaccines 2011;10:685–94.
and adverse outcome. VIP Study Group. Am J Obstet Gynecol
1996;174:1354–60. 56. Schrag SJ, Zell ER, Lynfield R, Roome A, Arnold KE, Craig AS, et al.
A population-based comparison of strategies to prevent early-onset group
37. Feikin DR, Thorsen P, Zywicki S, Arpi M, Westergaard JG, Schuchat A.
B streptococcal disease in neonates. N Engl J Med 2002;347:233–9.
Association between colonization with group B streptococci during
pregnancy and preterm delivery among Danish women. Am J Obstet 57. Centers for Disease Control and Prevention. Prevention of
Gynecol 2001;184:427–33. perinatal group B streptococcal disease. Mor Mortal Wkly Rep
2002;51(RR-11):1–22.
38. Krohn MA, Hillier SL, Baker CJ. Maternal peripartum complications
associated with vaginal group B streptococcal colonization. J Infect Dis 58. Yancey MK, Duff P. An analysis of the cost-effectiveness of selected
1999;179:1410–5. protocols for the prevention of neonatal group B streptococcal infection.
Obstet Gynecol 2003;83:367–71.
39. Rouse DJ, Goldenberg RL, Cliver SP, Cutter GR, Mennemeyer ST,
Fargason CA. Strategies for the prevention of early-onset neonatal 59. Fenton LJ, Harper MH. Evaluation of colistin and nalidixic acid in
group B streptococcal sepsis: a decision analysis. Obstet Gynecol Todd-Hewitt broth for selective isolation of group B streptococci. J Clin
1994;83:483–94. Microbiol 1979;9:167–9.
40. Allen VM, Yudin M; Society of Obstetricians and Gynaecologists 60. Bland ML, Vermillion ST, Soper DE. Antibiotic resistance patterns for
of Canada Infectious Diseases Committee. Management of group B group B streptococci in late third-trimester rectovaginal cultures. Am J
streptococcal bacteriuria in pregnancy. SOGC Clinical Practice Guideline, Obstet Gynecol 2001;184:1125–6.
No. 276, May 2012. J Obstet Gynaecol Can 2012;34:482–6. 61. Silverman NS, Morgan M, Nichols WS. Antibiotic resistance patterns
41. Baker CJ, Edwards MS. Group B streptococcal infections: perinatal of group B streptococcus in antenatal genital cultures. J Reprod Med
impact and prevention methods. Ann N Y Acad Sci 1988;549:193–202. 2000;45:979–82.
62. Price D, Shaw E, Howard M, Zazulak J, Waters H, Kaczorowski J.
42. Gardner SE, Yow MD, Leeds LJ, Thompson PK, Mason EO, Clark DJ.
Self-sampling for group B streptococcus in women 35 to 37 weeks
Failure of penicillin to eradicate group B streptococcal colonization in
pregnant is accurate and acceptable: a randomized cross-over trial.
pregnant women: a couple study. Am J Obstet Gynecol 1979;135:1062–5.
J Obstet Gynaecol Can 2006;28:1083–8.
43. Smaill F. Intrapartum antibiotics for group B streptococcal colonisation.
63. Valkenburg-van den burg AW, Houtman-Roelofsen RL, Oostvogel PM,
Cochrane Database Syst Rev 2000;(2):CD000115.
Dekker FW, Dörr PJ, Sprij AJ. Timing of group B streptococcus screening
44. US National Institutes of Health. Group B streptococcal vaccines. in pregnancy: a systematic review. Gynecol Obstet Invest 2010;69:174–83.
Available at: http://clinicaltrials.gov/ct2/home. Accessed on July 16,
64. Bergeron MG, Ke D, Menard C, Picard FJ, Gagnon M, Bernier M, et al.
2012.
Rapid detection of group B streptococci in pregnant women at delivery.
45. Boyer KM, Gotoff SP. Strategies for chemoprophylaxis of GBS early N Engl J Med 2000;343:175–9.
onset infections. Antibiot Chemother 1985;35:267–80.
65. El Helali N, Giovangrandi Y, Guyot K, Chevet K, Gutmann L,
46. Allen UD, Navas L, King SM. Effectiveness of intrapartum penicillin Durand-Zaleski I. Cost and effectiveness of intrapartum group B
prophylaxis in preventing early-onset group B streptococcal infection: streptococcus polymerase chain reaction screening for term deliveries.
results of a meta-analysis. CMAJ 1993;149:1659–65. Obstet Gynecol 2012;119:822–9.
66. Amstey MS, Gibbs RS. Is penicillin G a better choice than ampicillin for 71. Hannah ME, Ohlsson A, Wang EE, Matlow A, Foster GA,
prophylaxis of neonatal group B streptococcal infections? Obstet Gynecol Willan AR, et al. Maternal colonization with group B streptococcus
1994;84:1058–9. and prelabor rupture of membranes at term: the role of induction
of labor. Term PROM Study Group. Am J Obstet Gynecol
67. Johnson JR, Columbo DF, Gardner D, Cho E, Fan-Havard P, Shellhaas CS.
1997;177:780–5.
Optimal dosing of penicillin G in the third trimester for the prophylaxis
against group B streptococcus. Am J Obstet Gynecol 2001;185:850–3.
72. KJ Barrington; Canadian Paediatric Society, Fetus and Newborn
68. Pichichero ME. A review of evidence supporting the American Academy
Committee. Position statement: management of the infant at increased
of Pediatrics recommendation for prescribing cephalosporin antibiotics for
risk for sepsis. Paediatr Child Health 2007;12:893–8. Available at:
penicillin-allergic patients. Pediatrics 2005:115:1048–57.
http://www.cps.ca/en/documents/position/management-infant-sepsis.
69. Mitchell TF, Pearlman MD, Chapman RL, Bhatt-Mehta V, Faiz RG. Accessed on June 6, 2013.
Maternal and transplacental pharmacokinetics of cefazolin. Obstet Gynecol
2001;98:1075–9. 73. Woolf SH, Battista RN, Angerson GM, Logan AG, Eel W. Canadian
70. Stoll BJ, Hansen N, Fanaroff AA, Wright LL, Carlo WA, Ehrenkranz RA, et Task Force on Preventive Health Care. New grades for
al. Changes in pathogens causing early-onset sepsis in very-low-birth-weight recommendations from the Canadian Task Force on Preventive Health
infants. N Engl J Med 2002;347:240–7. Care. CMAJ 2003;169:207–8.
This document reflects emerging clinical and scientific advances on the date issued and is subject to change. The information
should not be construed as dictating an exclusive course of treatment or procedure to be followed. Local institutions can dictate
amendments to these opinions. They should be well documented if modified at the local level. None of these contents may be
reproduced in any form without prior written permission of the SOGC.
Key to evidence statements and grading of recommendations, using the ranking of the Canadian Task Force on
Preventive Health Care
Quality of evidence assessment* Classification of recommendations†
I: Evidence obtained from at least one properly randomized A. There is good evidence to recommend the clinical preventive action
controlled trial
II-1: Evidence from well-designed controlled trials without B. There is fair evidence to recommend the clinical preventive action
randomization
II-2: Evidence from well-designed cohort (prospective or C. The existing evidence is conflicting and does not allow to make a
retrospective) or case–control studies, preferably from recommendation for or against use of the clinical preventive action;
more than one centre or research group however, other factors may influence decision-making
II-3: Evidence obtained from comparisons between times or D. There is fair evidence to recommend against the clinical preventive action
places with or without the intervention. Dramatic results in
uncontrolled experiments (such as the results of treatment with E. There is good evidence to recommend against the clinical preventive
penicillin in the 1940s) could also be included in this category action
III: Opinions of respected authorities, based on clinical experience, L. There is insufficient evidence (in quantity or quality) to make
descriptive studies, or reports of expert committees a recommendation; however, other factors may influence
decision-making
*The quality of evidence reported in these guidelines has been adapted from The Evaluation of Evidence criteria described in the Canadian Task Force on
Preventive Health Care.
†Recommendations included in these guidelines have been adapted from the Classification of Recommendations criteria described in the Canadian Task Force
on Preventive Health Care.
Woolf SH, Battista RN, Angerson GM, Logan AG, Eel W. Canadian Task Force on Preventive Health Care. New grades for recommendations from the
Canadian Task Force on Preventive Health Care. CMAJ 2003;169:207–8.
RECOMMENDATIONS
Vaginal brachytherapy
3. Vaginal brachytherapy alone in the treatment of women with Stage I Low-Risk Endometrial Cancers
intermediate- to high-risk endometrial cancer has been shown to 1. As risk for recurrent disease is low in this patient group, no further
have outcomes in local control and overall survival that are similar treatment should be given after definitive surgery. Regular follow-
to those of pelvic radiotherapy in a well-defined intermediate- to up should be performed to monitor for signs and symptoms of
high-risk group. (I) recurrences. (II-1B)
4. Vaginal brachytherapy has the same outcome as external beam
radiotherapy with respect to overall survival in the defined Advanced Stage (II to IV) Endometrial Cancer
intermediate- to high-risk group. (I)
2. Treatment of these patients should be tailored according to
disease distribution and local treatment practices. (II-2C)
Chemotherapy
5. Chemotherapy has not been well studied in stage I intermediate-
to high-risk endometrial cancers. There is no strong evidence
for or against chemotherapy in this population at present. The
benefits of chemotherapy in addition to adjuvant radiotherapy
specifically in surgically stage I patients with high-risk features are
not clearly defined. (III)
Violaine Marcoux, MD, Ville Mont-Royal QC 4. Emergency cases such as a “crash” Caesarean section will
require a modified approach that is centre- and situation-
Chantal Menard, RN, Ottawa ON
dependent. (III)
Frank Potestio, MD, Thunder Bay ON
5. The SOGC endorses the adoption of the surgical safety checklist
David Rittenberg, MD, Halifax NS
in obstetrics and gynaecology. (III)
Sukhbir S. Singh, MD, Ottawa ON
Vyta Senikas, MD, Ottawa ON Recommendations
Disclosure statements have been received from all members of 1. The surgical safety checklist should be adopted by all surgical
the committee. care providers and their respective institutions to improve patient
safety. (II-1A)
2. Surgeons should be familiar with, advocate for the use of, and
Abstract participate in all 3 parts of the surgical safety checklist. (II-1A)
Objective: To provide guidance on the implementation of a surgical 3. The surgical safety checklist may be modified and adapted for
safety checklist in the practice of obstetrics and gynaecology. use in surgical obstetrics cases. (II-2A)
Outcomes: Outcomes evaluated include the impact of the surgical
safety checklist on surgical morbidity and mortality.
Evidence: Medline databases were searched for articles on subjects J Obstet Gynaecol Can 2013;35(1):82–83
related to “surgical safety checklist” published in English from
January 2001 to January 2011. Results were restricted to
systematic reviews, randomized control trials/controlled clinical
trials, and observational studies. Searches were updated on a Key Words: Patient safety, surgical safety checklist
regular basis and incorporated in the guideline to January 2012.
This document reflects emerging clinical and scientific advances on the date issued and is subject to change. The information
should not be construed as dictating an exclusive course of treatment or procedure to be followed. Local institutions can dictate
amendments to these opinions. They should be well documented if modified at the local level. None of these contents may be
reproduced in any form without prior written permission of the SOGC.
Key to evidence statements and grading of recommendations, using the ranking of the Canadian Task Force on
Preventive Health Care
Quality of evidence assessment* Classification of recommendations†
I: Evidence obtained from at least one properly randomized A. There is good evidence to recommend the clinical preventive action
controlled trial
II-1: Evidence from well-designed controlled trials without B. There is fair evidence to recommend the clinical preventive action
randomization
II-2: Evidence from well-designed cohort (prospective or C. The existing evidence is conflicting and does not allow to make a
retrospective) or case–control studies, preferably from recommendation for or against use of the clinical preventive action;
more than one centre or research group however, other factors may influence decision-making
II-3: Evidence obtained from comparisons between times or D. There is fair evidence to recommend against the clinical preventive action
places with or without the intervention. Dramatic results in
uncontrolled experiments (such as the results of treatment with E. There is good evidence to recommend against the clinical preventive
penicillin in the 1940s) could also be included in this category action
III: Opinions of respected authorities, based on clinical experience, L. There is insufficient evidence (in quantity or quality) to make
descriptive studies, or reports of expert committees a recommendation; however, other factors may influence
decision-making
*The quality of evidence reported in these guidelines has been adapted from The Evaluation of Evidence criteria described in the Canadian Task Force on
Preventive Health Care.
†Recommendations included in these guidelines have been adapted from the Classification of Recommendations criteria described in the Canadian Task Force
on Preventive Health Care.
Woolf SH, Battista RN, Angerson GM, Logan AG, Eel W. Canadian Task Force on Preventive Health Care. New grades for recommendations from the
Canadian Task Force on Preventive Health Care. CMAJ 2003;169:207–8.
This document reflects emerging clinical and scientific advances on the date issued and is subject to change. The information
should not be construed as dictating an exclusive course of treatment or procedure to be followed. Local institutions can dictate
amendments to these opinions. They should be well documented if modified at the local level. None of these contents may be
reproduced in any form without prior written permission of the SOGC.
Key to evidence statements and grading of recommendations, using the ranking of the Canadian Task Force on
Preventive Health Care
Quality of evidence assessment* Classification of recommendations†
I: Evidence obtained from at least one properly randomized A. There is good evidence to recommend the clinical preventive action
controlled trial
II-1: Evidence from well-designed controlled trials without B. There is fair evidence to recommend the clinical preventive action
randomization
II-2: Evidence from well-designed cohort (prospective or C. The existing evidence is conflicting and does not allow to make a
retrospective) or case–control studies, preferably from recommendation for or against use of the clinical preventive action;
more than one centre or research group however, other factors may influence decision-making
II-3: Evidence obtained from comparisons between times or D. There is fair evidence to recommend against the clinical preventive action
places with or without the intervention. Dramatic results in
uncontrolled experiments (such as the results of treatment with E. There is good evidence to recommend against the clinical preventive
penicillin in the 1940s) could also be included in this category action
III: Opinions of respected authorities, based on clinical experience, L. There is insufficient evidence (in quantity or quality) to make
descriptive studies, or reports of expert committees a recommendation; however, other factors may influence
decision-making
*The quality of evidence reported in these guidelines has been adapted from The Evaluation of Evidence criteria described in the Canadian Task Force on
Preventive Health Care.
†Recommendations included in these guidelines have been adapted from the Classification of Recommendations criteria described in the Canadian Task Force
on Preventive Health Care.
Woolf SH, Battista RN, Angerson GM, Logan AG, Eel W. Canadian Task Force on Preventive Health Care. New grades for recommendations from the
Canadian Task Force on Preventive Health Care. CMAJ 2003;169:207–8.
Vyta Senikas, MD, Ottawa ON 3. Vaginal erosions can be treated with removal of the pessary and
optional vaginal estrogen supplementation. (II-2)
David H.L. Wilkie, MD, Vancouver BC
4. Satisfaction rates with pessary use are very high. (II-2)
Disclosure statements have been received from all contributors.
Scott Farrell is Vice-President Medical and a major stakeholder Recommendation
of EastMed Inc. (Halifax, NS), the company marketing Uresta. 1. Pessaries should be considered in all women presenting with
Roxana Geoffrion is a shareholder of EastMed Inc. symptomatic prolapse and/or urinary stress incontinence. (II-1A)
This document reflects emerging clinical and scientific advances on the date issued and is subject to change. The information
should not be construed as dictating an exclusive course of treatment or procedure to be followed. Local institutions can dictate
amendments to these opinions. They should be well documented if modified at the local level. None of these contents may be
reproduced in any form without prior written permission of the SOGC.
Table 1. Key to evidence statements and grading of recommendations, using the ranking of the Canadian Task Force
on Preventive Health Care
Quality of evidence assessment* Classification of recommendations†
I: Evidence obtained from at least one properly randomized A. There is good evidence to recommend the clinical preventive action
controlled trial
II-1: Evidence from well-designed controlled trials without B. There is fair evidence to recommend the clinical preventive action
randomization
II-2: Evidence from well-designed cohort (prospective or C. The existing evidence is conflicting and does not allow to make a
retrospective) or case–control studies, preferably from recommendation for or against use of the clinical preventive action;
more than one centre or research group however, other factors may influence decision-making
II-3: Evidence obtained from comparisons between times or D. There is fair evidence to recommend against the clinical preventive action
places with or without the intervention. Dramatic results in
uncontrolled experiments (such as the results of treatment with E. There is good evidence to recommend against the clinical preventive
penicillin in the 1940s) could also be included in this category action
III: Opinions of respected authorities, based on clinical experience, L. There is insufficient evidence (in quantity or quality) to make
descriptive studies, or reports of expert committees a recommendation; however, other factors may influence
decision-making
*The quality of evidence reported in these guidelines has been adapted from The Evaluation of Evidence criteria described in the Canadian Task Force on
Preventive Health Care.54
†Recommendations included in these guidelines have been adapted from the Classification of Recommendations criteria described in the Canadian Task Force
on Preventive Health Care.54
Pessaries are made primarily of medical grade silicone; Pessaries can be used for diagnostic or therapeutic purposes.
only the largest sizes are made of surgical steel with a Pessaries are often used to relieve symptoms of prolapse6
covering of silicone. This has the advantage of making and of urinary stress incontinence. They are cost-effective in
them inert and less likely to have an odour or cause an the treatment of prolapse.7 Women choosing pessary for the
allergic reaction.3 Pessaries used for the treatment of treatment of prolapse are as likely to be satisfied and to have
prolapse can be classified as support pessaries or space- improved pelvic floor function as those selecting surgery.8
Figures 1 to 9 are reproduced with permission from CooperSurgical Inc., Trumbull CT, and Figure 10 is reproduced with permission from
EastMed Inc., Halifax NS
allow the escape of vaginal secretions. Open and covered Urinary Incontinence
ring pessaries are best used in POP-Q (pelvic organ prolapse Some pessaries have been specifically designed to treat urinary
quantification) stage I and II prolapse (mild to moderate stress incontinence. These include the ring pessary with
prolapse), although they often work well with a more support and knob (Figure 7), the incontinence ring (Figure 8),
advanced degree of prolapse if there is an adequate perineal the incontinence dish (Figure 9) and the Uresta device (Figure
body to ensure the pessary is retained.3 It has the advantage 10). They appear to stabilize the urethra and increase urethral
of ease of insertion and removal, and comfort. resistance.5 Initial successful fitting varies between 60% and
92%29,30 with an incontinence ring. Continued use drops to
If the pessary fails to remain in position or there continues to 55% by 6 months.31 By 1 year, the overall continuation may be
be protrusion, a stiffer pessary such as a Shaatz or a Gellhorn, as low as 16%, but this finding was from a study in which an
or a space-occupying pessary such as a cube or a donut may incontinence ring pessary with diaphragm was used, and most
be used. Cube pessaries have been successfully used in severe women discontinued use because of lack of efficacy.32 In a
prolapse. However, they may be more prone to erosion, and retrospective chart review33 of 100 women successfully fitted
they require frequent removal, nightly in some cases. Patients with pessaries, 59% were continent or mostly continent at
can learn to remove and re-insert a cube pessary. 11 months. Reasons for discontinuation included persistent
incontinence, pessary falling out, or pain and bleeding. One
Successful use of a pessary is dependent on both adequate crossover study showed that the incontinence ring was more
fit and patient satisfaction. effective than no treatment for the management of stress
urinary incontinence, significantly decreasing the number of
The most common reasons women choose to use a pessary
incontinence episodes and improving quality of life.34 Eighty
are to improve lower urinary tract symptoms secondary
percent of women saw an improvement of their incontinence,
to pelvic organ prolapse, such as bulging, and to improve
and 20% were dry.
activity and general health.22 Pessary use can also alleviate
other symptoms, including difficulty with bladder emptying, Using the new Uresta device, continuation rates at
urinary urgency symptoms, and defecatory symptoms.15,16 1 year were 50%.35 In that case series (n = 32), continence
Contrary to common belief, sexual activity is not a predictor was obtained by 31% of women, and incontinence was
for discontinued pessary use15,23; in fact, pessary use may improved in a further 34%.35
enhance sexual activity and satisfaction.17,24 Table 2 shows
There is insufficient evidence to state that pessaries are more
the change in symptoms after pessary fitting.
effective in treating urinary incontinence than other devices
Predictors for unsuccessful fitting include a short vagina or other treatments,36 including pelvic floor exercises.37
(< 6 cm),18,25 a wide introitus (> 4-finger breadth),18,25 the
Pregnancy
presence of a rectocele,26 previous vaginal surgery,14,16,17,25,27,28
Women who develop prolapse3,38,39 during pregnancy or
and coexisting stress urinary incontinence.27
who develop urinary retention because of an incarcerated
Predictors of discontinuation include posterior wall uterus40 can be fitted with a pessary, although not always
prolapse,14,16 younger age (< 65 years old),15 urinary successfully.41 By 18 weeks, when the uterus lifts out of
incontinence, and discomfort. However, in one study,
15 28 the pelvis, symptoms often resolve, and pessary use can
women who had previously undergone pelvic reconstructive be discontinued. The use of an incontinence pessary in
surgery were more likely to continue pessary use.27 pregnancy has not yet been described.
In small cohort studies, pessaries placed around the cervix, fall out. It is necessary to ensure that patients are able to
such as the Arabin pessary,42 have been shown to have some void and that they are given appropriate education before
benefit in preventing preterm birth in women with cervical leaving the clinic with their new pessary (Appendix). A
incompetence.43,44 Multiple randomized clinical trials, some post-void residual can be done to rule out the possibility of
international and multicentre, are ongoing.45 An RCT by obstruction. Dental floss can be attached to aid in removal
Goya et al.,46 published in 2012, found that the use of the of difficult pessaries.
Arabin pessary was associated with a significant reduction
of premature birth (< 34 weeks) from 27% to 6% in women An incontinence ring is fitted by assessing the distance
identified as having a short cervix (< 25 mm) on ultrasound between the posterior cul-de-sac and the mid urethra.
at 22 weeks, as well as with a decrease in premature rupture Because the incontinence ring is more flexible, it will
of membrane (9% to 2%) and a decrease in composite adapt to the configuration of the vagina. The health care
neonatal severe outcomes from 16% to 3%, mostly for provider must ensure that the knob is centred underneath
sepsis and respiratory distress syndrome. However, until the the mid-urethra and that the proximal ring is placed in the
results of this trial are reproduced, the use of pessary for posterior cul-de-sac and not in front of the cervix in the
prevention of premature birth cannot be recommended, as anterior fornix.50
its safety for this indication remains to be established.47 A ring pessary with incontinence knob is placed like a
regular ring, but once it is opened, the knob will be facing
GUIDELINES FOR FITTING the sidewall: it must therefore be rotated one quarter turn
to place the knob under the mid-urethra.50
Successful fitting and continued use is dependent on
adequate patient education (Appendix). It is imperative If the vaginal introitus is more than the width of 3 or 4
that the woman and/or her caregiver commit to proper fingers, a space-occupying pessary is the most likely to be
care of the pessary.48 successful. A Shaatz pessary is fitted similarly, with the
convex portion placed anteriorly. A Gellhorn pessary is fitted
As part of the history, health care providers should by folding of the disc as above when possible with the stem
inquire about symptoms of prolapse, bladder and bowel folded down for ease of insertion. The stem will be directed
dysfunction, and sexual activity. This is followed by a caudally (pointing out), and it should be possible to pass a
comprehensive examination: assessing vaginal mucosal finger between the disc and the vaginal side wall. Because of
health; assessing the degree and compartment of prolapse, its shape, a cube pessary need not be as large as the width of
including genital hiatus and vaginal length; and measuring the vagina (as measured with the examining fingers spread
pelvic floor strength. It is common but not essential49 to apart), but approximately one half that width. Insertion
begin vaginal estrogen therapy in postmenopausal women simply involves compressing the edge that is introduced
to improve the health of the vaginal epithelium.3,4 into the vaginal opening, and pushing it up and back. Donut
The approximate size of pessary required is determined pessaries also require compression for insertion.
by assessing the width of the vaginal canal by separating Follow-up Pessary Care
the 2 examining fingers at the vault in a sagittal plane Following a successful fitting, the woman is seen again
and estimating their separation distance. A ring pessary is within 2 to 4 weeks to see if she is satisfied or whether
usually fitted initially, as it is easy to use and tends to be another size or style is required. If possible, instruction
more comfortable. The pessary is folded, and the leading on removal and care should be given.3 Although there are
edge is lubricated. It is inserted by directing it towards the no clear guidelines for pessary care, women who are able
sacrum, and it is unfolded above the pelvic floor, with the to perform self-care are advised to remove the pessary
anterior edge just behind the symphysis. There should once a week and to wash it with water or mild soapy water.
be a finger’s breadth between the pessary (edge) and the Women who are not able to perform self-care should be
symphysis anteriorly and between the side of the pessary followed at 3-month intervals. Maintenance of pessary
and the lateral vaginal wall. The ring pessary should be care by a health care professional rather than the patient
turned one quarter turn in either direction following is often required with Gellhorn, cube, or donut pessaries.
placement to ensure the foldable edge is not placed in
front of the introitus, thus potentially limiting spontaneous Some pessaries may be difficult to remove. The Gellhorn
expulsion. Once the pessary has been fitted, the patient pessary is easier to remove when the health care professional
should ambulate in the clinic and perform activities such uses a ring or packing self-closing forceps on the base of
as squatting and Valsalva manoeuvre to ensure it will not the stem to apply outwards traction, and then uses one
finger to break the suction and fold the round disc along occur without local estrogen.17 For ongoing problems,
the stem. A cube pessary requires removal and cleaning more frequent visits and a change in pessary type or size
more often than every 3 months, because a greater amount may be required. Vaginal cancer is a rare association with
of discharge is usually trapped within the suction cups neglected pessary use but should be considered with non-
(although the cube is available with drainage holes). The healing ulcers.Vaginal discharge is a common complaint
frequency of cleaning required for a cube pessary will vary of pessary users. It can be caused by a physiologic
among patients, from as often as every few days to every response to friction of the pessary on the vaginal mucosa,
few weeks. bacterial vaginosis, or yeast. Bacterial vaginosis can cause
malodorous vaginal discharge, which can be problematic
Once removed, the pessary should be washed using plain but is not related to the appearance of an ulcer.17 Alnaif
soap and water. The perforations of the Gellhorn and and Drutz showed that in matched women, pessary users
Shaatz pessaries are best cleansed using a cytobrush or had a 32% rate of diagnosed bacterial vaginosis compared
a small cotton swab. The vaginal epithelium should be with 10% in non-users.52 The use of estrogen cream did
inspected for erosions or ulcerations, and special attention not appear to have a protective effect. More frequent
should be paid to the posterior and lateral fornices of the pessary removal can often alleviate this problem. The use
vagina. This is best accomplished using a large cotton swab of Trimo-San cream (Cooper Surgical) or Replens may
to displace the cervix to the contralateral direction. decrease the odour and discharge.3 Antibiotic treatment
with oral or vaginal metronizadole is also effective. Often
If no complications arise and the patient is able to
simple reassurance that the problem is physiologic may
perform self-care, the interval between visits can be
be sufficient. Yeast can be treated in conventional ways.
increased to 6 months or 1 year.30 Women can be sexually
Often it is recommended to keep the pessary removed
active with the ring or Shaatz pessary in place. A cube,
during treatment, although there is no evidence that this
donut, or Gellhorn pessary must generally be removed
makes a difference.
before intercourse.
If a pessary is repeatedly dislodged, women often
COMPLICATIONS discontinue use. This is best averted by preventing
constipation and avoiding straining in general.
Published complication rates vary, which likely reflects
a difference in reporting. In a study by Hanson et al. Major complications are uncommon with pessary use.
88.5% of 1216 women did not develop complications.17 In case reports documenting complications including
Common complications included erosions (8.9%) and vesicovaginal fistulae, bowel fistulae, incarcerated pessaries
vaginal infections (2.5%).17 This is in contrast to the study etc.,53 91% were related to neglected pessaries. This stresses
by Bai et al., in which 73% of women had complications, the importance of continued and diligent follow-up.
including bleeding, erosions, or foul odour.51 Despite this
relatively high rate, over 70% reported being satisfied with CONCLUSION
the pessary and wanted to continue its use,51 suggesting
that these complications are minor. Pessaries have a high success rate and minimal complication
rate for the treatment of both incontinence and prolapse.
Local pressure from the pessary can lead to focal When successfully fitted, they are associated with high
devascularisation and cause erosions. Reported rates patient satisfaction. They should therefore be considered
range from 2% to 9%.8,10 Erosions may present as vaginal as first-line treatment for all women presenting with pelvic
bleeding, odour, or increased discharge, which is typically prolapse and/or stress urinary incontinence.
brown. A strong odour is usually present upon removal
of the pessary. When such strong odour is detected Summary Statements
during routine pessary care, careful examination of the 1. Most women can be successfully fitted with a pessary
vagina should be performed, often facilitated by the use when they present with prolapse. (II-2)
of large swabs to push the cervix and sidewalls apart. 2. Complications of pessary use are usually minor,
If neglected, erosions can progress to ulcers or a fistula. and vaginal discharge is the most common
Other causes of vaginal bleeding cannot be excluded in complaint. (II-3)
pessary users, and endometrial or ulcer biopsy may be 3. Vaginal erosions can be treated with removal
indicated if they persist. Therapy consists of pessary of the pessary and optional vaginal estrogen
removal for a period of 2 to 4 weeks and local estrogen supplementation. (II-2)
use (tablet or cream). Resolution of erosions may also 4. Satisfaction rates with pessary use are very high. (II-2)
16. Fernando RJ, Thakar R, Sultan AH, Shah SM, Jones PW. Effect of vaginal
Recommendation pessaries on symptoms associated with pelvic organ prolapse. Obstet
1. Pessaries should be considered in all women Gynecol 2006;108(1):93–9.
presenting with symptomatic prolapse and/or 17. Hanson LA, Schulz JA, Flood CG, Cooley B, Tam F. Vaginal pessaries in
urinary stress incontinence. (II-1A) managing women with pelvic organ prolapse and urinary incontinence:
patient characteristics and factors contributing to success. Int Urogynecol J
Pelvic Floor Dysfunct 2006;17(2):155–9.
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Obstet 2011;284(2):391–5.
1. Swift SE. The distribution of pelvic organ support in a population of 19. Cundiff GW, Amundsen CL, Bent AE, Coates KW, Schaffer JI, Strohbehn
female subjects seen for routine gynecologic health care. Am J Obstet K, et al. The PESSRI study: symptom relief outcomes of
Gynecol 2000;183(2):277–85. a randomized crossover trial of the ring and Gellhorn pessaries.
2. Braekken IH, Majida M, Engh ME, Bø K. Can pelvic floor muscle Am J Obstet Gynecol 2007;196(4):405–8.
training reverse pelvic organ prolapse and reduce prolapse symptoms? 20. Lone F, Thakar R, Sultan AH, Karamalis G. A 5-year prospective study
An assessor-blinded, randomized, controlled trial. Am J Obstet Gynecol of vaginal pessary use for pelvic organ prolapse. Int J Gynaecol Obstet
2010;203(2):170–7. 2011;114(1):56–9.
3. Schulz JA, Kwon E. Pelvic organ prolapse: pessary treatment. 21. Cundiff GW, Weidner AC, Visco AG, Bump RC, Addison WA. A survey of
In: Baessler K, Schussler B, Burgio KL, Moore KH, Norton PA, pessary use by members of the American urogynecologic society. Obstet
Stanton SL, eds. Pelvic floor reeducation: principles and practice. Gynecol 2000;95(6 Pt 1):931–5.
London UK: Springer-Verlag London Limited; 2009:271–7.
22. Komesu YM, Rogers RG, Rode MA, Craig EC, Schrader RM,
4. Trowbridge ER, Fenner DE. Practicalities and pitfalls of pessaries in older Gallegos KA, et al. Patient-selected goal attainment for pessary wearers:
women. Clin Obstet Gynecol 2007;50(3):709–19. what is the clinical relevance? Am J Obstet Gynecol 2008;198(5):577–5.
5. Komesu YM, Ketai LH, Rogers RG, Eberhardt SC, Pohl J. Restoration 23. Brincat C, Kenton K, Pat FM, Brubaker L. Sexual activity
of continence by pessaries: magnetic resonance imaging assessment of predicts continued pessary use. Am J Obstet Gynecol 2004;191(1):198–200.
mechanism of action. Am J Obstet Gynecol 2008;198(5):563–6.
24. Kuhn A, Bapst D, Stadlmayr W, Vits K, Mueller MD. Sexual and organ
6. Patel M, Mellen C, O’Sullivan DM, LaSala CA. Impact of pessary use on function in patients with symptomatic prolapse: are pessaries helpful? Fertil
prolapse symptoms, quality of life, and body image. Am J Obstet Gynecol Steril 2009;91(5):1914–8.
2010;202(5):499e1–499e4. 25. Clemons JL, Aguilar VC, Tillinghast TA, Jackson ND, Myers DL.
7. Hullfish KL, Trowbridge ER, Stukenborg GJ. Treatment strategies for Risk factors associated with an unsuccessful pessary fitting trial in women
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Floor Dysfunct 2011;22(5):507–15. 26. Yamada T, Matsubara S. Rectocoele, but not cystocoele, may predict
8. Abdool Z, Thakar R, Sultan AH, Oliver RS. Prospective evaluation of unsuccessful pessary fitting. J Obstet Gynaecol 2011;31(5):441–2.
outcome of vaginal pessaries versus surgery in women with symptomatic 27. Nguyen JN, Jones CR. Pessary treatment of pelvic relaxation: factors
pelvic organ prolapse. Int Urogynecol J Pelvic Floor Dysfunct affecting successful fitting and continued use. J Wound Ostomy Continence
2011;22(3):273–8. Nurs 2005;32(4):255–61.
9. Liapis A, Bakas P, Georgantopoulou C, Creatsas G. The use of the pessary 28. Mutone MF, Terry C, Hale DS, Benson JT. Factors which influence the
test in preoperative assessment of women with severe genital prolapse. Eur short-term success of pessary management of pelvic organ prolapse.
J Obstet Gynecol Reprod Biol 2011;155(1):110–3. Am J Obstet Gynecol 2005;193(1):89–94.
10. Lazarou G, Scotti RJ, Mikhail MS, Zhou HS, Powers K. Pessary reduction 29. Noblett KL, McKinney A, Lane FL. Effects of the incontinence dish
and postoperative cure of retention in women with anterior vaginal wall pessary on urethral support and urodynamic parameters. Am J Obstet
prolapse. Int Urogynecol J Pelvic Floor Dysfunct 2004;15(3):175–8. Gynecol 2008;198(5):592–5.
11. Liang CC, Chang YL, Chang SD, Lo TS, Soong YK. Pessary test to predict 30. Nager CW, Richter HE, Nygaard I, Paraiso MF, Wu JM, Kenton K, et al.
postoperative urinary incontinence in women undergoing hysterectomy for Incontinence pessaries: size, POPQ measures, and successful fitting.
prolapse. Obstet Gynecol 2004;104(4):795–800. Int Urogynecol J Pelvic Floor Dysfunct 2009;20(9):1023–8.
12. Srikrishna S, Robinson D, Cardozo L. Ringing the changes in evaluation 31. Donnelly MJ, Powell-Morgan S, Olsen AL, Nygaard IE. Vaginal pessaries
of urogenital prolapse. [Erratum appears in Int Urogynecol J Pelvic Floor for the management of stress and mixed urinary incontinence.
Dysfunct 2011 Jul;22(7):901]. Int Urogynecol J Pelvic Floor Dysfunct Int Urogynecol J Pelvic Floor Dysfunct 2004;15(5):302–7.
2011;22(2):171–5. 32. Robert M, Mainprize TC. Long-term assessment of the incontinence ring
13. Ellstrom Engh AM, Ekeryd A, Magnusson A, Olsson I, Otterlind L, pessary for the treatment of stress incontinence. Int Urogynecol J Pelvic
Tobiasson G. Can de novo stress incontinence after anterior wall repair be Floor Dysfunct 2002;13(5):326–9.
predicted? Acta Obstet Gynecol Scand 2011;90(5):488–93. 33. Farrell SA, Singh B, Aldakhil L. Continence pessaries in the management of
14. Maito JM, Quam ZA, Craig E, Danner KA, Rogers RG. Predictors of urinary incontinence in women. J Obstet Gynaecol Can 2004;26(2):113–7.
successful pessary fitting and continued use in a nurse-midwifery pessary 34. Harvey MA. The treatment of stress urinary incontinence using an
clinic. J Midwifery Womens Health 2006;51(2):78–84. incontinence ring: a randomized, cross-over trial treatment of stress urinary.
Neurourol Urodyn 2009;28: 817–8.
15. Clemons JL, Aguilar VC, Tillinghast TA, Jackson ND, Myers DL. Patient
satisfaction and changes in prolapse and urinary symptoms in women who 35. Farrell SA, Baydock S, Amir B, Fanning C. Effectiveness of a new
were fitted successfully with a pessary for pelvic organ prolapse. self-positioning pessary for the management of urinary incontinence in
Am J Obstet Gynecol 2004;190(4):1025–9. women. Am J Obstet Gynecol 2007;196(5):474–8.
36. Lipp A, Shaw C, Glavind K. Mechanical devices for urinary incontinence 46. Goya M, Pratcorona L, Merced C, Rodo C, Valle L, Romero A,
in women. [Update of Cochrane Database Syst Rev. 2006;3:CD001756; et al. Pesario Cervical para Evitar Prematuridad (PECEP) Trial
PMID: 16855977]. Cochrane Database Syst Rev 2011;7(CD001756). Group. Cervical pessary in pregnant women with a short cervix
(PECEP): an open-label randomised controlled trial. Lancet
37. Richter HE, Burgio KL, Brubaker L, Nygaard IE, Ye W, Weidner A,
2012;279(9828):1800–6.
et al. Continence pessary compared with behavioral therapy or combined
therapy for stress incontinence: a randomized controlled trial. Obstet 47. Jorde A, Kastli K, Hamann B, Pockrandt H. Changes in the vaginal flora
Gynecol 2010;115(3):609–17. caused by supporting pessary treatment in pregnancy [article in German].
38. Ng YW, Paramasivan A, Ahmed AKS. Uterine prolapse in pregnancy: Zentralbl Gynakol 1983;105(13):855–62.
a case report and review of literature. Internet Journal of Gynecology 48. Wu V, Farrell SA, Baskett TF, Flowerdew G. A simplified protocol for
and Obstetrics 2010; 13(2). pessary management. Obstet Gynecol 1997;90(6):990–4.
39. De Vita D, Giordano S. Two successful natural pregnancies in a patient
49. Ramsay S, Bouchard F, Tu LM. Long term outcomes of pessary use in
with severe uterine prolapse: a case report. J Med Case Rep 2011;5:459.
women with pelvic organ prolapse. Neurourol Urodyn 2011;30(6):1105–6.
40. Yohannes P, Schaefer J. Urinary retention during the second trimester of
pregnancy: a rare cause. Urology 2002;59(6):946i–946iii. 50. Farrell SA. Pessaries for the management of stress urinary incontinence.
J Obstet Gynaecol Can 2001;23(12):1184–9.
41. Brown HL. Cervical prolapse complicating pregnancy. J Natl Med Assoc
1997;89(5):346–8. 51. Bai SW, Yoon BS, Kwon JY, Shin JS, Kim SK, Park KH, et al. Survey of
the characteristics and satisfaction degree of the patients using a pessary.
42. Quaas L, Hillemanns HG, Du BA, Schillinger H. The
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Arabin-cerclage pessary—alternative to surgery [article in German].
Geburtshilfe Frauenheilkd 1990;50(5):429–433. 52. Alnaif B, Drutz HP. Bacterial vaginosis increases in pessary users.
43. Dharan VB, Ludmir J. Alternative treatment for a short cervix: the cervical Int Urogynecol J Pelvic Floor Dysfunct 2000;11(4):219–22.
pessary. Semin Perinatol 2009;33(5):338–42. 53. Arias BE, Ridgeway B, Barber MD. Complications of neglected vaginal
44. Abdel-Aleem H, Shaaban OM, Abdel-Aleem MA. Cervical pessaries: case presentation and literature review. Int Urogynecol J Pelvic
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2010;(9):CD007873.
54. Woolf SH, Battista RN, Angerson GM, Logan AG, Eel W. Canadian
45. Hegeman MA, Bekedam DJ, Bloemenkamp KW, Kwee A, Papatsonis DN, Task Force on Preventive Health Care. New grades for
van der Post JA, et al. Pessaries in multiple pregnancy as a prevention of recommendations from the Canadian Task Force on Preventive Health
preterm birth: the ProTwin Trial. BMC Pregnancy Childbirth 2009;9:44. Care. CMAJ 2003;169:207–8.
Date: Size: Type:
Problem Suggestions
• Pessary falls out Reinsert your pessary if you are able to. Go to your scheduled appointment, and bring your
pessary with you.
• You have pelvic pain If you feel that your pessary is the cause of the pain, remove it and bring it with you to your next
appointment. If you are unable to remove your pessary, contact the clinic.
• Vaginal odour and/or discharge Some odour and discharge is normal. If the odour is very foul, remove the pessary if you can,
and go to your scheduled appointment. If you are unable to remove your pessary, contact the
clinic.
• Vaginal bleeding This may be a sign that the pessary is irritating your vaginal lining. Remove the pessary if you
can, and go to your scheduled appointment. If you are unable to remove your pessary, contact
the clinic.
• Leaking urine If you feel that the pessary is making your leakage worse, remove it. Go to your scheduled
appointment. If you are unable to remove your pessary, contact the clinic.
If you are having urgent problems, phone the Pessary Clinic at:
This material is designed for information purposes only. It should not be used in place of medical advice, instruction, and/or treatment.
If you have specific questions, please consult your doctor or appropriate health care professional.
APPENDIX. Continued
Cleaning
Use warm tap water and mild soap (for example, Sunlight dish detergent). Make sure that you rinse the pessary well. Store it in a clean,
dry place. Do not boil or disinfect the pessary. Remember that your hands, and the pessary, must be clean before insertion.
Sex
The pessary may be left in or may be removed before intercourse, depending on your comfort level. This is a trial and error process.
Some styles must be removed before intercourse.
Bowel movements
Most women wearing a pessary have no trouble or interference when having bowel movements. Women who tend to be constipated
may have some problems. It is important that you keep your stools soft and regular. Some women may find it necessary to remove their
pessary before they have a bowel movement.
This material is designed for information purposes only. It should not be used in place of medical advice, instruction, and/or treatment.
If you have specific questions, please consult your doctor or appropriate health care professional.
Janice Kwon, MD, Vancouver BC 1. In low-risk disease, there is no evidence that lymphadenectomy
improves survival in grade 1 adenocarcinoma. (I)
Michel Préfontaine, MD, London ON
2. Endometrial cancer requires a coordinated multidisciplinary team
Isabelle Germain, MD, Montreal QC approach for management. (III)
Robert Pearcey, MD, Edmonton AB 3. The purpose of lymphadenectomy is to guide adjuvant therapy
David D’Souza, MD, London ON that may affect survival in high-risk populations or prevent
treatments that may result in unnecessary toxicity. (III)
Mary Senterman, MD, Ottawa ON
Paul Hoskins, MA, Vancouver BC
Disclosure statements have been received from all contributors. J Obstet Gynaecol Can 2013;35(4):370–371
The literature searches and bibliographic support for this
guideline were undertaken by Becky Skidmore, Medical
Research Analyst, Society of Obstetricians and Gynaecologists Key Words: Endometrial cancer, lymphadenectomy, surgical
of Canada. staging, sentinel nodes for endometrial cancer
This document reflects emerging clinical and scientific advances on the date issued and is subject to change. The information
should not be construed as dictating an exclusive course of treatment or procedure to be followed. Local institutions can dictate
amendments to these opinions. They should be well documented if modified at the local level. None of these contents may be
reproduced in any form without prior written permission of the SOGC.
Key to evidence statements and grading of recommendations, using the ranking of the Canadian Task Force on
Preventive Health Care
Quality of evidence assessment* Classification of recommendations†
I: Evidence obtained from at least one properly randomized A. There is good evidence to recommend the clinical preventive action
controlled trial
II-1: Evidence from well-designed controlled trials without B. There is fair evidence to recommend the clinical preventive action
randomization
II-2: Evidence from well-designed cohort (prospective or C. The existing evidence is conflicting and does not allow to make a
retrospective) or case–control studies, preferably from recommendation for or against use of the clinical preventive action;
more than one centre or research group however, other factors may influence decision-making
II-3: Evidence obtained from comparisons between times or D. There is fair evidence to recommend against the clinical preventive action
places with or without the intervention. Dramatic results in
uncontrolled experiments (such as the results of treatment with E. There is good evidence to recommend against the clinical preventive
penicillin in the 1940s) could also be included in this category action
III: Opinions of respected authorities, based on clinical experience, L. There is insufficient evidence (in quantity or quality) to make
descriptive studies, or reports of expert committees a recommendation; however, other factors may influence
decision-making
*The quality of evidence reported in these guidelines has been adapted from The Evaluation of Evidence criteria described in the Canadian Task Force on
Preventive Health Care.
†Recommendations included in these guidelines have been adapted from the Classification of Recommendations criteria described in the Canadian Task Force
on Preventive Health Care.
Woolf SH, Battista RN, Angerson GM, Logan AG, Eel W. Canadian Task Force on Preventive Health Care. New grades for recommendations from the
Canadian Task Force on Preventive Health Care. CMAJ 2003;169:207–8.
Extent of lymph node evaluation which is often required postoperatively. The survival benefit of
lymphadenectomy in this specific group of patients has not been
4. Decisions regarding adjuvant therapy in endometrial cancer are
studied. (II-2B)
dependent on both histopathologic risk factors for recurrences
post-hysterectomy and the status of retroperitoneal lymph nodes 4. Patients with high-risk histological subtypes of endometrial cancer
when lymphadenectomy is performed. (III) such as clear cell and papillary serous adenocarcinomas should
receive full staging surgery that includes pelvic and/or para-aortic
RECOMMENDATIONS lymphadenectomy and omentectomy. (II-2B)
Toxoplasmosis in Pregnancy:
Prevention, Screening, and Treatment
Objective: To review the prevention, diagnosis, and management of
This clinical practice guideline has been prepared by the toxoplasmosis in pregnancy.
Infectious Disease Committee, reviewed by the Family
Outcomes: Outcomes evaluated include the effect of screening
Practice Advisory Committee and the Maternal Fetal
on diagnosis of congenital toxoplasmosis and the efficacy of
Medicine Committee, and approved by the Executive and
prophylaxis and treatment.
Council of the Society of Obstetricians and Gynaecologists
of Canada. Evidence: The Cochrane Library and Medline were searched for
articles published in English from 1990 to the present related to
PRINCIPAL AUTHORS
toxoplasmosis and pregnancy. Additional articles were identified
Caroline Paquet, RM, Trois-Rivières QC through references of these articles.
Mark H. Yudin, MD, Toronto ON Values: The quality of evidence is rated and recommendations made
according to guidelines developed by the Canadian Task Force on
INFECTIOUS DISEASE COMMITTEE
Preventive Health Care (Table).
Mark H. Yudin, MD (Chair), Toronto ON
Benefits, harms, and costs: Guideline implementation should assist
Victoria M. Allen, MD, Halifax NS the practitioner in developing an approach to screening for and
Céline Bouchard, MD, Quebec QC treatment of toxoplasmosis in pregnancy. Patients will benefit from
appropriate management of this condition.
Marc Boucher, MD, Montreal QC
Sponsor: The Society of Obstetricians and Gynaecologists of
Sheila Caddy, MD, Edmonton AB Canada.
Eliana Castillo, MD, Calgary AB
Recommendations
Deborah M. Money, MD, Vancouver BC
01. Routine universal screening should not be performed for
Kellie E. Murphy, MD, Toronto ON pregnant women at low risk. Serologic screening should be
Gina Ogilvie, MD, Vancouver BC offered only to pregnant women considered to be at risk for
primary Toxoplasma gondii infection. (II-3E)
Caroline Paquet, RM, Trois-Rivières QC
02. Suspected recent infection in a pregnant woman should be
Julie van Schalkwyk, MD, Vancouver BC confirmed before intervention by having samples tested at a
Vyta Senikas, MD, Ottawa ON toxoplasmosis reference laboratory, using tests that are as
accurate as possible and correctly interpreted. (II-2B)
Disclosure statements have been received from all members of
the committee. 03. If acute infection is suspected, repeat testing should be
performed within 2 to 3 weeks, and consideration given to
starting therapy with spiramycin immediately, without waiting for
Abstract the repeat test results. (II-2B)
04. Amniocentesis should be offered to identify Toxoplasma gondii
Background: One of the major consequences of pregnant women in the amniotic fluid by polymerase chain reaction (a) if maternal
becoming infected by Toxoplasma gondii is vertical transmission primary infection is diagnosed, (b) if serologic testing cannot
to the fetus. Although rare, congenital toxoplasmosis can cause
severe neurological or ocular disease (leading to blindness),
as well as cardiac and cerebral anomalies. Prenatal care must
include education about prevention of toxoplasmosis. The low J Obstet Gynaecol Can 2013;35(1):78–79
prevalence of the disease in the Canadian population and
limitations in diagnosis and therapy limit the effectiveness of
Key Words: Toxoplasmosis, pregnancy, congenital, prenatal,
screening strategies. Therefore, routine screening is not currently disease transmission, mass screening, counselling
recommended.
This document reflects emerging clinical and scientific advances on the date issued and is subject to change. The information
should not be construed as dictating an exclusive course of treatment or procedure to be followed. Local institutions can dictate
amendments to these opinions. They should be well documented if modified at the local level. None of these contents may be
reproduced in any form without prior written permission of the SOGC.
Key to evidence statements and grading of recommendations, using the ranking of the Canadian Task Force on
Preventive Health Care
Quality of evidence assessment* Classification of recommendations†
I: Evidence obtained from at least one properly randomized A. There is good evidence to recommend the clinical preventive action
controlled trial
II-1: Evidence from well-designed controlled trials without B. There is fair evidence to recommend the clinical preventive action
randomization
II-2: Evidence from well-designed cohort (prospective or C. The existing evidence is conflicting and does not allow to make a
retrospective) or case–control studies, preferably from recommendation for or against use of the clinical preventive action;
more than one centre or research group however, other factors may influence decision-making
II-3: Evidence obtained from comparisons between times or D. There is fair evidence to recommend against the clinical preventive action
places with or without the intervention. Dramatic results in
uncontrolled experiments (such as the results of treatment with E. There is good evidence to recommend against the clinical preventive
penicillin in the 1940s) could also be included in this category action
III: Opinions of respected authorities, based on clinical experience, L. There is insufficient evidence (in quantity or quality) to make
descriptive studies, or reports of expert committees a recommendation; however, other factors may influence
decision-making
*The quality of evidence reported in these guidelines has been adapted from The Evaluation of Evidence criteria described in the Canadian Task Force on
Preventive Health Care.
†Recommendations included in these guidelines have been adapted from the Classification of Recommendations criteria described in the Canadian Task Force
on Preventive Health Care.
Woolf SH, Battista RN, Angerson GM, Logan AG, Eel W. Canadian Task Force on Preventive Health Care. New grades for recommendations from the
Canadian Task Force on Preventive Health Care. CMAJ 2003;169:207–8.
confirm or exclude acute infection, or (c) in the presence 09. A combination of pyrimethamine, sulfadiazine, and folinic acid
of abnormal ultrasound findings (intracranial calcification, should be offered as treatment for women in whom fetal infection
microcephaly, hydrocephalus, ascites, hepatosplenomegaly, or has been confirmed or is highly suspected (usually by a positive
severe intrauterine growth restriction). (II-2B) amniotic fluid polymerase chain reaction). (I-B)
05. Amniocentesis should not be offered for the identification of 10. Anti-toxoplasma treatment in immunocompetent pregnant women
Toxoplasma gondii infection at less than 18 weeks’ gestation and with previous infection with Toxoplasma gondii should not be
should be offered no less than 4 weeks after suspected acute necessary. (I-E)
maternal infection to lower the occurrence of false-negative
11. Women who are immunosuppressed or HIV-positive should
results. (II-2D)
be offered screening because of the risk of reactivation and
06. Toxoplasma gondii infection should be suspected and screening toxoplasmosis encephalitis. (I-A)
should be offered to pregnant women with ultrasound findings
12. A non-pregnant woman who has been diagnosed with an acute
consistent with possible TORCH (toxoplasmosis, rubella,
Toxoplasma gondii infection should be counselled to wait 6
cytomegalovirus, herpes, and other) infection, including but not
months before attempting to become pregnant. Each case should
limited to intracranial calcification, microcephaly, hydrocephalus,
be considered separately in consultation with an expert. (III-B)
ascites, hepatosplenomegaly, or severe intrauterine growth
restriction. (II-2B) 13. Information on prevention of Toxoplasma gondii infection in
pregnancy should be made available to all women who are
07. Each case involving a pregnant woman suspected of having
pregnant or planning a pregnancy. (III-C)
an acute Toxoplasma gondii infection acquired during gestation
should be discussed with an expert in the management of
toxoplasmosis. (III-B)
08. If maternal infection has been confirmed but the fetus is not The full version of this document
yet known to be infected, spiramycin should be offered for fetal is available online at
prophylaxis (to prevent spread of organisms across the placenta http://www.sogc.org and http://www.jogc.com.
from mother to fetus). (I-B)
SOGC GENETICS COMMITTEE Outcomes: The use of this genetic information may allow improved
risk-benefit assessment and management at the annual
R. Douglas Wilson, MD (Chair), Calgary AB gynaecological examination.
François Audibert, MD, Montreal QC Evidence: Studies published in English up to and including May
2010 were retrieved through searches of PubMed and the
Jo-Ann Brock, MD, Halifax NS
Cochrane Library, using appropriate controlled vocabulary
June Carroll, MD, Toronto ON (gynaecological diagnosis, genetic inheritance) and key words
(genetic risk, genetic mutation, inheritance, family history, uterus,
Lola Cartier, MSc, Montreal QC ovary, endometrial, vagina, colon, gastric, renal, breast, cardiac,
Valérie A. Désilets, MD, Montreal QC thrombophilia, diabetes, epilepsy, leiomyomata uteri). Other
literature sources were identified through searching the web
Alain Gagnon, MD, Vancouver BC sites of health technology assessment and health technology
Jo-Ann Johnson, MD, Calgary AB assessment-related agencies, clinical practice guideline
collections, clinical trial registries, and national and international
Sylvie Langlois, MD, Vancouver BC medical specialty societies.
Lynn Murphy-Kaulbeck, MD, Moncton NB Values: The levels of evidence are not adequate for evidence-based
recommendations to be made.
Nanette Okun, MD, Toronto ON
Benefits, harms, and costs: This committee opinion will enhance
Melanie Pastuck, RN, Calgary AB
the use of new genetic knowledge and its application to the annual
Vyta Senikas, MD, Ottawa ON gynaecological care of women. Risk management and diagnostic
opportunities for genetic gynaecological conditions will be
Disclosure statements have been received from all members of improved. A more complete understanding of genetic conditions
the committee. may increase anxiety and psychological stress for women and
their families.
Sponsors: Society of Obstetricians and Gynaecologists of Canada.
Recommendations
The levels of evidence are not adequate for evidence-based
Key Words: Genetic risk, genetic mutation, gynaecology, recommendations to be made.
inheritance, family history, uterus, ovary, endometrial, vagina,
colon, gastric, renal, breast, cardiac, thrombophilia, diabetes,
epilepsy, uterine leiomyomata uteri, uterine leiomyomas
J Obstet Gynaecol Can 2012;34(3):276–284
This document reflects the emerging clinical and scientific advancement on the date issued and is subject to change. The
information should not be construed as dictating an exclusive course of treatment or procedure to be followed. Local institutions
can dictate amendments to these opinions. They should be well documented if modified at the local level. None of these contents
may be reproduced in any form without prior written permission of the SOGC.
INTRODUCTION care, patients with congenital heart disease now live longer,
frequently reaching child-bearing age. Chromosomal
Table 2. Estimated 22q11 deletion frequency in women with epilepsy and fetal antiepileptic drug exposure.
congenital heart disease The majority of defects are identified in the central nervous,
Estimated deletion orofacial, cardiovascular, and urogenital systems. Congenital
Cardiac defect frequency, % anomaly screening in pregnancy should include a detailed
Interrupted aortic arch 50 to 89 ultrasound to identify structural defects in the fetus from
VSDs 10 18 to 20 weeks, and possibly maternal serum alpha fetoprotein
With normal aortic arch* 3 screening for open neural tube defects specifically. Joint
With aortic arch anomaly† 45 SOGC-Motherisk guidelines indicate that women with
Truncus arteriosus 34 to 41 epilepsy should supplement their diets with 5 mg of folic
Tetralogy of Fallot 8 to 35 acid daily and a multivitamin to minimize the teratogenic
Isolated aortic arch anomalies 24 component of the antiepileptic drugs.7 Monotherapy for
Double-outlet right ventricle <5
epilepsy should be reviewed with the patient and her other
Transposition of the great arteries <1
physicians as a treatment option minimizing teratogenic risks.
VSD: ventricular septal defect.
Uterine Leiomyomas
*Left-sided aortic arch with normal branching pattern.
Uterine leiomyomas are the most common benign
†Includes right aortic arch and/or abnormal branching pattern, cervical
location, and/or discontinuous branch pulmonary arteries. neoplasia developing within the uterus. It is not known
Table adapted with permission from Pierpont ME, Basson CT, Benson W, whether a leiomyoma actually transforms into a malignant
Gelb BD, Giglia TM, Goldmuntz E, et al.3 leiomyosarcoma, but the incidence of leiomyosarcoma is
extremely low in premenopausal women when compared
with the incidence in older postmenopausal women in
whom they account for < 1% of uterine malignancies.8,9
Genetic factors are now being identified. Somatic Table 3. Genes associated with congenital heart
mutations and, less frequently, molecular alterations in defects
the X chromosome must occur for the initiation and Chromosome
subsequent development of a myoma. The high prevalence Condition location
of leiomyomas suggests that they result from stable Congenital heart defects
mutations. Very specific genetic risks have been identified Familial congenital heart disease 5q
for HLRCC,10 which is inherited in an autosomal dominant (ASD, atrioventricular block)
fashion. Affected individuals demonstrate an increased D-TGA, DORV 2q
risk for leiomyomas of the skin and uterus, as well as D-TGA 12q
renal cancers. As leiomyomas have a prevalence of 30% Tetralogy of Fallot 8q
in the female population (although this varies according 5q
to ethnicity), it is important for clinicians, gynaecologists, 20p
and other caregivers to be aware that HLRCC-associated Atrioventricular septal defect 3p
kidney tumours are often biologically aggressive. Although ASD/VSD 8p
screening for this mutation or for renal tumour in all women Xq
with leiomyomas is not recommended, clinicians should Heterotaxy 2q
have a high index of suspicion when women present with 3p
hematuria suggestive of a renal tumour.
1q
Thrombophilias Syndromes
Thrombophilias can be inherited or acquired.11–14 The DiGeorge syndrome 22q11
most common inherited disorders are mutations of factor Holt-Oram syndrome 12q24
V Leiden, prothrombin gene (G20210A mutation), and Alagille syndrome (PPS) 20p12
MTHFR mutation or homozygosity to MTHFR C677T, but Char syndrome (PDA) 6p12
the complete list of inherited disorders includes deficiencies Noonan syndrome 12q24
in protein S, C, and Z or antithrombin III, homozygosity 12p1.21
to 4G/4G mutation in PAI-1 gene, and polymorphisms 2p21
in thromobomodulin gene. People of Caucasian heritage CHARGE association 8q12
have a higher rate of genetic thrombophilias than other Ellis-van Creveld syndrome 4p16
ethnic groups. Marfan syndrome 15q21.1
Table 4. Estimated number and lifetime risk of women Mayer-Rokitansky-Kuster-Hauser syndrome.19 A 2006
who would develop or die of various types of cancer report of a cohort of 106 consecutive women with the
in 2007 MRKH syndrome reviewed other congenital anomalies
Lifetime risk of Lifetime risk of associated with MRKH syndrome.18 Hypoplastic vagina
Type of cancer developing, 1 in dying of, 1 in was present in 61 women. Laterally displaced Mullerian
Breast 008 034 remnants were present in 92 women, and 26% of the
Lung 017 030 remnants had a cavity with endometrial mucosa. Ovaries
Colorectal 018 045 were extrapelvic in 16%. Urinary tract abnormalities were
Endometrial 038 196 present in 30%, with unilateral renal agenesis (18%),
Skin 077 500 pelvic kidney (11%), and horseshoe kidney (2%) being
Ovarian 068 095 the most common anomalies. The recognition of this
Cervical 135 385 wide variability of anatomical presentations is important
Data from Adams Hillard PJ and Berek JS,20 Jemal A, Siegel R, Ward E, for appropriate surveillance, diagnosis, and treatment of
Murray T, Xu J, Thun MJ,21 American Cancer Society.22 gynaecological problems in women with MRKH syndrome.
A renal ultrasound is recommended to assess urinary tract
anomalies, particularly before abdominal or pelvic surgery.
thrombophilia group, most studies are observational with RISK ASSESSMENT FOR CANCER AND
small, heterogeneous groups. A single RCT15 is available in HEREDITARY CANCER SYNDROMES
which 160 women with at least 1 fetal loss after 10 weeks (BACKGROUND, PERSONAL, FAMILY)
and heterozygosity for a single thrombophilia mutation Recent estimates of lifetime risk of a woman developing
(factor V Leiden, prothrombin G20210A mutation, protein or dying from various types of cancer are shown in
S) were randomized to enoxparin 40 mg or low-dose ASA Table 4.20–22 Breast cancer occurs most frequently. It has a
100 mg daily. The enoxparin group had an increased live lifetime presentation risk of 1 in 8 and a death risk of 1 in
birth rate (86% vs. 29%), higher birth weight, and lower 34 compared with cervical cancer, which has a presentation
intrauterine growth restriction rates (10% vs. 30%) than risk of 1 in 135 and a death risk of 1 in 385.
the low-dose ASA group. Other thrombophilia treatment
protocols are available.16,17 Referral to a treatment centre Despite these risks, a recent publication23 reported that a
with expertise in the topic should be considered before financially stable and well-educated population of women
anticoagulant treatment is initiated before or during had very little knowledge or understanding of hereditary
pregnancy. cancer risks. Cancers studied in this population included
hereditary breast cancer, Lynch syndrome, and p16-related
Pre-conception discussion with a woman with a melanoma. Although approximately 11% were identified
thrombophilia and a past history of poor pregnancy as being at high-risk for at least 1 of the 3 syndromes
outcome should include increased fetal surveillance (breast cancer 88.5%, Lynch syndrome 6.1%, p16-related
starting at 24 weeks, with serial ultrasound (every 4 weeks) melanoma 3.8%), < 3% had ever had genetic counselling
for fetal growth, umbilical artery Doppler, non-stress test or testing.
and/or biophysical profile used as clinically required, and
consideration of delivery by 39 weeks.11 The discovery of genes responsible for hereditary cancer
syndrome has led to specific recommendations for genetic
Contraception with estrogen-containing products is testing for mutations in BRCA1 and BRCA2, responsible
contraindicated unless long-term anticoagulation is used. for hereditary breast and ovarian cancer, and the mismatch-
Progestin-only products do not increase thromboembolic repair genes responsible for the hereditary nonpolyposis
risks. Estrogen-containing hormone therapy may colon cancer also known as Lynch syndrome.24 A 2007
increase the risk of stroke and thromboembolic disease. commentary25 emphasized the need for more public
Surgery on a woman with factor V Leiden requires education. A 2005 US Preventive Services Task Force
thromboprophylaxis according to published protocols to recommendation26 indicates that women whose family
decrease her thrombotic risk.18 history (first and second degree relatives) is indicative of
an increased risk for deleterious mutations in BRCA10r
Congenital Mullerian Anomalies BRCA2 genes should be referred for genetic counselling
Women with agenesis of the uterus and vagina but normal and evaluation for these mutations. These women would
ovarian function and secondary sexual characteristics have benefit from obtaining information that would allow
informed choice about testing and further prophylactic syndrome (AD), Peutz-Jeghers syndrome (AD), and partial
treatment and risk-reduction surgery. This counselling androgen insensitivity syndrome (X-linked recessive).
should be done within a genetic oncology program by
trained health care providers. There is increasing evidence For women with BRCA1 or BRCA2 mutations who have
to consider the benefits of chemoprevention or intensive not undergone risk-reduction mastectomy, intensive breast
screening in improving health outcomes in women who test screening with both annual mammogram and annual breast
positive for deleterious BRCA1 or BRCA2 mutations.27,28 MRI beginning at age 25 years could be considered. American
However, there is fair evidence that risk-reduction surgery Cancer Society guidelines29 for breast cancer screening with
for these women significantly decreases breast and ovarian MRI as an adjunct to mammography recommend that an
cancer incidence. In 2007, the American Cancer Society annual MRI could also be used not only for the high-risk
issued guidelines29 for offering screening breast MRI BRCA mutation carrier and first degree relative cohort but
in women with a lifetime risk of breast cancer of 20% also for screening other high-risk breast cancer groups,
to ≥ 25% (based on models of family history) using an such as women with a history of therapeutic radiation (e.g.,
annual breast MRI examination beginning at age 30. A for Hodgkin’s disease) to the chest between the ages of 10
more recent study30 indicates that although family history and 30 years, women with Li-Fraumeni syndrome and first
is a strong predictor of risk, it is not always required, as degree relatives, and women with Cowden or Bannayan-
a cohort of women with apparently sporadic (no first or Riley-Ruvalcaba syndrome and first degree relatives.
second degree relatives with breast or ovarian cancer) and In 2010, the Public Health Agency of Canada produced
early onset breast cancer had a 9.5% incidence BRCA1 or a “Decision Aid for Breast Cancer Screening in Canada.”
BRCA2 mutation. It provides information on mammography to assist
For women with BRCA1 or BRCA2 mutations, the risk women aged ≥ 40 in making decisions about screening.
of breast cancer is up to 87% by the age of 70. Clinicians The document recommends that women aged 50 to
should ensure that women at risk are given tools to help 69 years who are at average risk should have screening
them make the difficult decision about prophylactic mammograms every 2 years.32
salpingo-oophorectomy or bilateral mastectomy and the Endometrial cancers can also be a component of an
increased lifetime risks for BRCA-associated gynaecologic inherited cancer susceptibility syndrome. For example,
(ovarian, fallopian tube, and primary peritoneal) cancers.31 endometrial cancer is associated with HNPCC/Lynch
Recent reviews27,28 of ovarian cancer prevention in patients syndrome. HNPCC is likely the most common hereditary
with BRCA1 or BRCA2 germline mutations indicate cancer syndrome, causing about 1 in 20 cases of colorectal
that although chemoprevention (tamoxifen, raloxifene) cancer.33 The mutation confers a lifetime risk of about
and screening (twice yearly vaginal ultrasound and 80% that a carrier will develop CRC. Men with these
serum CA-125) both have a role, neither is efficacious mutations appear to have a greater risk of developing CRC
enough to eliminate the need for risk reducing salpingo- than women. The mutation confers a 30% to 60% lifetime
oophorectomy in women with an inherited predisposition risk for endometrial cancer in female carriers. This is an
to ovarian cancer; therefore, risk reducing salpingo- inherited autosomal dominant mutation, and there are 4
oophorectomy will remain an important component of known genes: hMLH1, hMSH2, hMSH6, PMS2.
gynaecologic cancer risk reduction.
Decision models for Lynch/HNPCC34 have compared
Although BRCA1 and BRCA2 account for the largest 3 management strategies: (1) annual gynaecological
proportion of genetic susceptibility to breast cancer, other examination alone; (2) annual examination with screening
rare disorders make up approximately 10% to 20% of the (ultrasound, endometrial biopsy, CA 125); and (3) hyster
genetic susceptibility. These include ataxia-telangiectasia ectomy with bilateral salpingo-oophorectomy. The third
(AR), oculocutaneous telangiectasia, cerebellar ataxia, option may be considered for appropriately counselled
variable immunodeficiency, lymphoid and epithelial cancers, women with Lynch/HPNCC to prevent gynaecologic
Li-Fraumeni syndrome (AD), childhood bone or soft- cancers and their associated morbidities. The same
tissue sarcomas, early onset breast cancer, acute leukemias, research group has reported that this surgical approach is
brain tumours, carcinoma of the lung or pancreas, cost effective.35
melanoma, Cowden disease (AD), mucocutaneous
lesions, thyroid, breast, hamartomatous polyps of the GI Recommendations for presymptomatic women with
tract, macrocephaly, uterine leiomyomas), and very rare documented HPNCC/Lynch mutations include
syndromes such as Gorlin syndrome (AD), Muir-Torre colonoscopic screening starting at age 25 and continuing as
Table 5. Routine cancer screening clinical approach (American Congress of Obstetricians and Gynecologists,
The Society of Obstetricians and Gynaecologists of Canada, and The Society of Gynecologic Oncologists of
Canada)
Topic Guideline
Breast Cancer ACOG: Mammography should be performed every 1 to 2 years beginning at age 40 years and yearly beginning at
age 50 years. All women should have an annual clinical breast examination as part of the physical examination.
Despite a lack of definitive data for or against breast self-examination, it has the potential to detect palpable breast
cancer and can be recommended.
SOGC/GOC: Age 40 to 49, clinical breast examination by trained professional every 2 years; age 50 to 69, clinical
breast examination by trained professional and mammogram every 2 years; > age 70, personal plan discussed with
trained professional
Colorectal Cancer ACOG: Beginning at age 50 years, 1 of 5 screening options should be selected:
1. Yearly patient-collected FOBT or FIT,* or
2. Flexible sigmoidoscopy every 5 years, or
3. Yearly patient-collected FOBT or FIT* plus flexible sigmoidoscopy every 5 years, or
4. Double-contrast barium enema every 5 years, or
5. Colonoscopy every 10 years
SOGC/GOC: Women at low risk > age 50 fecal occult blood every 2 years; Women at high risk (first degree relative
affected with CRC, FAP, HNPCC, history of inflammatory bowel disease, benign polyps in colon or rectum) should
discuss surveillance such as colonoscopy with trained gastrointestinal professional
Ovarian Cancer ACOG and SOGC/GOC: Currently, there are no effective techniques for the routine screening of asymptomatic,
women at low risk for ovarian cancer. It appears that the best way to detect early ovarian cancer is for both the patient
and her clinician to have a high index of suspicion of the diagnosis in the symptomatic woman, and both should be
aware of the symptoms commonly associated with ovarian cancer. Persistent symptoms such as an increase in
abdominal size, abdominal bloating, fatigue, abdominal pain, indigestion, inability to eat normally, urinary frequency,
pelvic pain, constipation, back pain, urinary incontinence of recent onset, or unexplained weight loss should be
evaluated, with ovarian cancer included in the differential diagnosis.
Research in progress: combining CA125 and transvaginal ultrasound in a small study detected 34/38 ovarian cancers
with 50% in stage I or II.
FIT: fecal immunochemical testing; FOBT: fecal occult blood testing; CA125 blood test for cancer screening.
*Both FOBT and FIT require 2 or 3 samples of stool collected by the patient at home and returned for analysis. A single stool sample for FOBT or FIT obtained
by digital rectal examination is not adequate for the detection of CRC.
Table adapted from Adams Hillard PJ and Berek JS,20 Canadian Cancer Society.46,47
Table 6. Primary and preventive care: periodic assessments in women who have
a family history
Periodic assessment Leading causes of death
Age range (consider family history/risk) (genetic disease) Rank
13 to 18 years genetic testing/counselling malignant neoplasms 2
congenital conditions 6
19 to 39 years genetic testing/counselling malignant neoplasms 1
cardiovascular risk cardiac 3
diabetes 8
40 to 64 years CRC screening malignant neoplasms 1
lipid/cholesterol profile cardiac 2
diabetes diabetes 6
breast cancer
thyroid (TSH)
≥ 65 years as above cardiac 1
malignant neoplasms 2
Alzheimer’s disease 5
diabetes 7
TSH: thyroid stimulating hormone
Table adapted from ACOG Committee Opinion No. 452.48
frequently as once per year.36 Gynaecological surveillance 11. Sibai BM, How HY, Stella CL. Thrombophilia in pregnancy: whom to
screen, when to treat. OBG Management 2007;19:50–64.
should start at age 30 (17% of endometrial cancers and 42%
12. James AJ, Brancazio LR. Factor V Leiden thrombophilia. Female Patient
of ovarian cancers in these patients cohort are diagnosed
2007; 32:14–6.
by age 40). Women with Lynch syndrome do not have an
13. Gibson CS, MacLennan AH, Janssen NG, Kist WJ, Hague WM, Haan
increased risk for breast cancer, so they may benefit from EA, et al.; South Australian Cerebral Palsy Research Group. Associations
estrogen-replacement therapy after oophorectomy to between fetal inherited thrombophilia and adverse pregnancy outcomes.
prevent or minimize the potential sequelae of surgically Am J Obstet Gynecol 2006;194:947–53.
induced menopause. 14. Spector EB, Grody WW, Matteson CJ, Palomaki G, Bellissino DB,
Wolff DJ, et al. Technical standards and guidelines: venous
Other genetic gastrointestinal cancers, including thromboembolism (Factor V Leiden and prothrombin 20210G>A
testing): a disease-specific supplement to the standards and guidelines for
hamartomatous polyposis syndromes, gastric cancer, and clinical genetics laboratories. Genet Med 2005;7:444–53.
CRC/familial adenomatous polyposis, are described in the 15. Gris JC, Mercier E, Quéré I, Lavigne-Lissalde G, Cochery-Nouvellon E,
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women with one fetal loss and a constitutional thrombophilic disorder.
Table 5 summarizes general approaches for cancer Blood 2004;103:3695–9.
screening of breast, colon and ovary20,46,47 considering both 16. Qaseem A, Snow V, Barry P, Hornbake ER, Rodnick JE, Tobolic T,
Canadian and American sources. et al. Joint American Academy of Family Physicians/American College
of Physicians Panel on Deep Venous Thrombosis/Pulmonary Embolism.
Table 6 summarizes the primary and preventive care Current diagnosis of venous thromboembolism in primary care: a clinical
practice guideline from the American Academy of Family Physicians and
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Founder and recurrent CDH1 mutations in families withy hereditary
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The hamartomatous polyposis syndromes are a heterogeneous group of disorders that share an autosomal-dominant pattern of inheritance and
are characterized by hamartomatous polyps of the gastrointestinal tract.37 These syndromes include juvenile polyposis syndrome, Peutz-Jeghers
syndrome, and PTEN hamartoma tumour syndrome. The frequency and location of the polyps vary considerably, as does the predisposition
for the development of gastrointestinal and other malignancies. In addition, there are non-malignant manifestations, such as bleeding,
intussusception, and bowel obstruction. Surveillance guidelines for these rare syndromes were published in 2007.37
Gastric cancer is the second most common cause of cancer death worldwide. A germline mutation in the epithelial cadherin (CDH1) has an
increased risk for diffuse gastric cancer and lobular breast cancer. A recent publication indicates the presence of a founder mutation from
Newfoundland pedigrees.38 Published guidelines39,40 recommend providing genetic counselling to the family and beginning screening in the late
teens or early 20s. The timing of prophylactic gastrectomy is an individual decision.
Colorectal cancer is the second leading cause of cancer death in North America. CRC evolves in an adenoma to carcinoma sequence during
which a series of somatic alterations accumulate in the DNA of the tumour tissue.40 About 75% of these molecular changes are sporadic
events, but the remaining 25% arise in individuals with a family history of colon cancer. HNPCC (etiology for 1 in 20 CRC) has been discussed
previously. The other hereditary cancer (much rarer with 100 to thousands of polyps) is FAP, which is an autosomal dominant syndrome with
germline mutations. Clinical onset is at a young age (12 to 15 years) with hundreds of adenomatous polyps in the colon and increased risk for
gastric polyps, duodenal cancer, thyroid cancer, and desmoids tumours. There is an attenuated variety, AFAP, that has fewer than 100 adenomas
with a proximal predominance and a later age of onset (55 years).40
Cancer genetic risk assessment for hereditary colon cancer would include HNPCC and FAP.41 A recent mutation was identified specifically in
the Ashkenazi Jewish population. A 2002 statement from American College of Medical Genetics and the American Society of human Genetics
presents guidelines for screening and tumour analysis.40 Identification of this colorectal family history should allow discussion with the patient
about counselling, possible testing and referral to a hereditary cancer program through medical or provincial cancer agencies.41 Recently
published results42,43 from a 2003 survey indicate only 23.5% of Canadians at risk for colon cancer reported receiving screening, but this dropped
to 17.6% when only up-to-date screening was considered. Canadian recommendations44 are that screening involves geographic availability and
patient discussion with the screening options of fecal occult blood testing every 2 years; flexible sigmoidoscopy every 5 years; double contrast
barium enema every 5 years; colonoscopy every 10 years. The use of colonoscopy as a screening test for CRC has indentified increased
numbers of patients with polyps requiring follow-up. A recent review45 reports that most patients do not require intensive surveillance, as patients
with 1 or 2 small (< 1 cm) adenomas can safely repeat colonoscopy after 5 to 10 years.
J Obstet Gynaecol Can 2012;34(4):382–391 04. Prophylactic antibiotics should be administered 15 to 60 minutes
prior to skin incision. No additional doses are recommended. (I-A)
05. If an open abdominal procedure is lengthy (e.g., > 3 hours), or if
Key Words: Antibiotics, prophylaxis, hysterectomy, hysteroscopy, the estimated blood loss is > 1500 mL, an additional dose of the
gynaecologic surgery prophylactic antibiotic may be given 3 to 4 hours after the initial
dose. (III-C)
This document reflects emerging clinical and scientific advances on the date issued and is subject to change. The information
should not be construed as dictating an exclusive course of treatment or procedure to be followed. Local institutions can dictate
amendments to these opinions. They should be well documented if modified at the local level. None of these contents may be
reproduced in any form without prior written permission of the SOGC.
06. Antibiotic prophylaxis is not recommended for laparoscopic The presence of antibiotic resistant organisms is a reality
procedures that involve no direct access from the abdominal
in Canadian health care facilities.1 These organisms include
cavity to the uterine cavity or vagina. (l-E)
methicillin resistant Staphylococcus aureus, vancomycin
07. All women undergoing surgery for pelvic organ prolapse and/or
stress urinary incontinence should receive a single dose of first- resistant Enterococcus, and extended-spectrum beta-
generation cephalosporin. (III-B) lactamase-producing organisms.
08. Antibiotic prophylaxis is not recommended for hysteroscopic
surgery. (II-2D) Both morbidity and mortality are increased in infections
09. All women undergoing an induced (therapeutic) surgical abortion involving these organisms, as they may be more virulent and
should receive prophylactic antibiotics to reduce the risk of post- are more difficult to treat because therapeutic options are
abortal infection. (I-A) limited. Antibiotic resistance development results mainly
10. Prophylactic antibiotics are not suggested to reduce infectious from the inappropriate use of antibiotics. Incomplete
morbidity following surgery for a missed or incomplete
abortion. (I-E)
courses of antibiotic therapies and the unnecessary use
of broader spectrum regimens play a role.2 Adherence
11. Antibiotic prophylaxis is not recommended for insertion of an
intrauterine device. (I-E) However, health care professionals to treatment and prophylaxis guidelines likely assists in
could consider screening for sexually transmitted infections in reducing infection and antibiotic resistance. Physician
high-risk populations. (III-C) adherence to antibiotic prophylaxis guidelines is variable
12. There is insufficient evidence to support the use of antibiotic and frequently at odds with published guidelines.3,4
prophylaxis for an endometrial biopsy. (III-L)
13. The best method to prevent infection after hysterosalpingography In addition to antibiotic prophylaxis, all factors that
is unknown. Women with dilated tubes found at the time of affect infectious risk reduction in our specialty must
hysterosalpingography are at highest risk, and prophylactic
antibiotics (e.g., doxycycline) should be given. (II-3B) be reviewed. Sterile surgical fields must be ensured, and
14. Antibiotic prophylaxis is not recommended for urodynamic
ongoing quality assessment of sterilization technique, air
studies in women at low risk, unless the incidence of urinary ventilation, and postoperative wound care are needed.
tract infection post-urodynamics is > 10%. (1-E) Consistent infection control surveillance and reporting of
15. In patients with morbid obesity (BMI > 35 kg/m2), doubling the infectious complications track ability to minimize these
antibiotic dose may be considered. (III-B)
morbidities and possibly to identify clusters of infection
16. Administration of antibiotics solely to prevent endocarditis is and the emergence of antibiotic resistant organisms. This
not recommended for patients who undergo a genitourinary
procedure. (III-E)
will dictate changes to operative routines to respond to
evolving microbial diversity that seems inevitable.
INTRODUCTION
PRINCIPLES OF ANTIBIOTIC PROPHYLAXIS
Table 1. Key to evidence statements and grading of recommendations, using the ranking of the Canadian Task Force
on Preventive Health Care
Quality of evidence assessment* Classification of recommendations†
I: Evidence obtained from at least one properly randomized A. There is good evidence to recommend the clinical preventive action
controlled trial
II-1: Evidence from well-designed controlled trials without B. There is fair evidence to recommend the clinical preventive action
randomization
II-2: Evidence from well–designed cohort (prospective or C. The existing evidence is conflicting and does not allow to make a
retrospective) or case–control studies, preferably from recommendation for or against use of the clinical preventive action;
more than one centre or research group however, other factors may influence decision-making
II-3: Evidence obtained from comparisons between times or D. There is fair evidence to recommend against the clinical preventive action
places with or without the intervention. Dramatic results in
uncontrolled experiments (such as the results of treatment with E. There is good evidence to recommend against the clinical preventive
penicillin in the 1940s) could also be included in this category action
III: Opinions of respected authorities, based on clinical experience, L. There is insufficient evidence (in quantity or quality) to make
descriptive studies, or reports of expert committees a recommendation; however, other factors may influence
decision-making
*The quality of evidence reported in these guidelines has been adapted from The Evaluation of Evidence criteria described in the Canadian Task Force on
Preventive Health Care.56
†Recommendations included in these guidelines have been adapted from the Classification of Recommendations criteria described in the Canadian Task Force
on Preventive Health Care.56
during surgery and for a few hours (at most) after the SURGICAL PROCEDURES
incision is closed.5
Vaginal Hysterectomy
Wound infections—surgical site infections—in the form A hysterectomy is considered a “class II or clean-
of cellulitis, abscess, or dehiscence can occur following contaminated” wound (Table 2).5 The method of
laparotomy. Pelvic infections, such as an abscess or infected hysterectomy may modify the inherent risk of postoperative
hematoma, are a risk with any surgical procedure that infection. A Cochrane review suggested that vaginal
enters the abdominal cavity. Cuff cellulitis is a specific risk hysterectomy results in fewer unspecified infections or
for hysterectomy. Endometritis can result from Caesarean febrile episodes (OR 0.42; 95% CI 0.21 to 0.83) than
section or surgical abortion. Urinary tract infections abdominal hysterectomy.9
can occur as a result of any procedure that involves
There is no meta-analysis or systematic review regarding
catheterization of the bladder.
antibiotic prophylaxis for vaginal hysterectomy. A review
A 1999 guideline published by the United States Centers by Duff and Park10 included 20 studies, the majority of
for Disease Control and Prevention lists the specific and which were prospective randomized trials (18/20) and
stringent criteria that must be met for diagnosis of a many of which were double-blinded (13/20). Without
surgical site infection.5 Accurate surveillance for surgical prophylaxis, the incidence of febrile morbidity averaged
site infection monitoring requires follow-up for 30 days 40% to 50% but was reduced to 5% to 20% with
postoperatively, and the trend towards early discharge from prophylactic antibiotics.10 The type, dose, and duration of
antibiotics used were highly variable, but a first-generation
hospital makes surveillance a challenge. It is estimated
cephalosporin was used in the majority of studies.
that up to 84% of surgical site infections occur following
discharge from hospital.5 A randomized trial comparing amoxicillin-clavulanic acid
with cefazolin (n = 178) showed no difference in infection
If prophylactic antibiotics are to be given, they should be
rates.11 Another trial comparing use of cefuroxime,
administered shortly before or at bacterial inoculation.6,7
metronidazole, or both showed an increased morbidity
This should be done 15 to 60 minutes before skin incision.
when metronidazole was added.12
The majority of studies suggest that a single dose is
effective but that for lengthy procedures (> 3 hours) the Treating bacterial vaginosis with metronidazole rectally
dose should be repeated at intervals 1 or 2 times the half- for at least 4 days prior to vaginal hysterectomy appears to
life of the drug. It has also been suggested that with large reduce the incidence of vaginal cuff infection (n = 59; 0 vs.
blood loss (> 1500 mL), a second dose should be given.8 27%) but may be impractical given the possibility of surgery
Table 2. Centers for Disease Control and Prevention surgical wound classification
Class I/Clean: An uninfected operative wound in which no inflammation is encountered and the respiratory, alimentary,
genital, or uninfected urinary tract is not entered. In addition, clean wounds are primarily closed and, if
necessary, drained with closed drainage. Operative incisional wounds that follow nonpenetrating (blunt)
trauma should be included in this category if they meet the criteria.
Class II/Clean-Contaminated: An operative wound in which the respiratory, alimentary, genital, or urinary tracts are entered under controlled
conditions and without unusual contamination. Specifically, operations involving the biliary tract, appendix,
vagina, and oropharynx are included in this category, provided no evidence of infection or major break in
technique is encountered.
Class III/Contaminated: Open, fresh, accidental wounds. In addition, operations with major breaks in sterile technique (e.g., open
cardiac massage) or gross spillage from the gastrointestinal tract, and incisions in which acute, nonpurulent
inflammation is encountered are included in this category.
Class IV/Dirty-Infected: Old traumatic wounds with retained devitalized tissue and those that involve existing clinical infection or
perforated viscera. This definition suggests that the organisms causing postoperative infection were present
in the operative field before the operation.
Centers for Disease Control and Prevention. Guideline for Prevention of Surgical Site Infection, 1999.5
3. The choice of antibiotic for hysterectomy should significant difference in the occurrence of bacteremia (16%
be a single dose of a first-generation cephalosporin. vs. 2%); however, the authors comment that the majority
If patients are allergic to cephalosporin, then of organisms were of dubious clinical significance and
clindamycin, erythromycin, or metronidazole should that contamination could not be excluded in 7 of 10 cases.
be used. (I-A) No significant difference was found for women treated
4. Prophylactic antibiotics should be administered 15 for presumed infection (11.4% vs. 9%), but no objective
to 60 minutes prior to skin incision. No additional measures were used.25 A case series of 568 women
doses are recommended. (I-A) suggests that the infection risk is low (< 1%).26 There are
5. If an open abdominal procedure is lengthy (e.g., > 3 no studies addressing prophylactic antibiotics in the setting
hours), or if the estimated blood loss is > 1500 mL, of hysteroscopic myomectomy.
an additional dose of the prophylactic antibiotic may
be given 3 to 4 hours after the initial dose. (III-C) Recommendation
6. Antibiotic prophylaxis is not recommended for 8. Antibiotic prophylaxis is not recommended for
laparoscopic procedures that involve no direct hysteroscopic surgery. (II-2D)
access from the abdominal cavity to the uterine
Induced (Therapeutic) Abortion
cavity or vagina. (I-E)
A meta-analysis that included 12 randomized clinical trials,
Surgery for Pelvic Organ Prolapse and/or demonstrated that prophylactic antibiotics significantly
Stress Urinary Incontinence reduced post-abortal infection (at < 16 weeks), compared
A randomized double-bind, placebo-controlled trial with placebo.27 The relative risk of upper genital tract
enrolled 449 patients to receive nitrofurantoin monohydrate infection following surgical abortion was 0.58 (95% CI
monocrystals or placebo preoperatively. Procedures 0.47 to 0.71) with antibiotics. The benefit was seen in
included surgery for pelvic organ prolapse and/or stress women considered to be at high risk and in those at low
incontinence with suprapubic catheterization. Positive urine risk for infection; thus, the authors conclude that universal
prophylaxis should be given and that no more placebo-
cultures were significantly reduced (46% vs. 61%), as was
controlled trials should be performed. The most appropriate
symptomatic urinary tract infection (7.2% vs. 19.8%).22
antibiotic regimen, however, is yet to be determined, as
There are no studies assessing prophylactic antibiotics prior
no comparative or superiority trials have been conducted.
to these surgeries without use of a suprapubic catheter.
The largest trial to date (n = 1074), which had the most
There are also no studies regarding isolated sub-urethral
statistically significant reduction in postoperative infection
sling procedures (e.g., transvaginal or transobturator tapes),
rates (RR 0.12; 95% CI 0.08 to 0.38), used doxycycline 100
but given the very poor outcomes associated with mesh
mg orally before the procedure followed by 200 mg after
infection, administration of a single preoperative dose of a
the procedure.28 Other regimens that have been effective
first-generation cephalosporin is common practice.
in a randomized trial include metronidazole 400 mg
Recommendation orally 1 hour before the procedure and then repeated 4
7. All women undergoing surgery for pelvic organ and 8 hours after the procedure (RR 0.19; 95% CI 0.10
prolapse and/or stress urinary incontinence to 0.83)29 and doxycycline 400 mg orally 10 to 12 hours
should receive a single dose of first-generation before the procedure (RR 0.33; 95% CI 0.22 to 0.73)30
cephalosporin. (III-B) A cost-effectiveness study looking at universal screening
for sexually transmitted infections versus prophylactic
Hysteroscopic Surgery azithromycin (1 g) showed that prophylactic treatment
A Cochrane review of prophylactic antibiotics for provided a significant cost savings.31 Disadvantages of not
transcervical intrauterine procedures did not identify screening include the lack of case identification and the
any randomized trials that met their criteria.23 A inability to complete therapy or conduct contact tracing.
pseudorandomized study that used centre-specific Some authors have questioned whether the presence of BV
antibiotic prophylaxis analyzed 631 infertile women who influences the rate of postoperative infection after induced
underwent office hysteroscopy. Two hundred sixty-six abortion. In a double-blind placebo-controlled trial,
women received amoxicillin-clavulanate and doxycycline treatment using 2% vaginal clindamycin for at least 3 days
2 hours pre-procedure. There was no difference in post- preoperatively did not decrease the risk of postoperative
procedural infection (1 in the antibiotic group).24 A infection in patients with or without documented BV.
randomized trial of amoxicillin and clavulanate versus The only statistically significant difference was seen when
placebo for hysteroscopic ablation (n = 116) found a the authors combined the women who had intermediate
flora with those who had BV (RR = 4.2 in untreated high risk for sexually transmitted infections, it would be
group; 95% CI 1.2 to 15.9).32 Another randomized reasonable to consider screening before IUD placement.
blinded trial found that giving a single 2 g metronidazole
suppository preoperatively to women who had confirmed Recommendation
bacterial vaginosis33 did not make a significant difference 11. Antibiotic prophylaxis is not recommended for
(RR = 0.53; P = 0.055). Screening and treating for bacterial insertion of an intrauterine device. (I-E) However,
vaginosis prior to surgery also may be impractical, and the health care professionals could consider screening
cost-effectiveness is not known. for sexually transmitted infections in high-risk
populations. (III-C)
Recommendation
9. All women undergoing an induced (therapeutic) Endometrial Biopsy
surgical abortion should receive prophylactic There are no studies that assess the use of prophylactic
antibiotics to reduce the risk of post-abortal antibiotics given before an endometrial biopsy procedure,
infection. (I-A) and this is not considered standard of care.
Missed or Incomplete Abortion Recommendation
There are two randomized placebo-controlled trials that
12. There is insufficient evidence to support the
assess the effectiveness of prophylactic antibiotics to
use of antibiotic prophylaxis for an endometrial
reduce infectious morbidity following uterine evacuation
biopsy. (III-L)
for incomplete abortion. One trial involving 240 women
used a preoperative intravenous dose of doxycycline or Hysterosalpingography
placebo.34 Chlamydia and gonorrhea rates were low (3% There are many options for preventing infection that may
to 6%) in this population. No difference in postoperative occur as a result of HSG:
infectious morbidity rates occurred up to 2 weeks post-
procedure. A second study of 300 women investigated 1. Universal screening for STIs could be carried out, and
the use of 200 mg oral doxycycline at 30 to 60 minutes patients treated as necessary.
pre-procedure. Again, no significant difference between
groups was found.35 A 2007 Cochrane Review on this topic 2. Only patients at high risk (determined by history)
concluded there is not enough evidence to recommend could be screened.
routine antibiotic prophylaxis for incomplete abortion at
the time of evacuation of the uterus.36 3. All patients could receive prophylactic antibiotics.
Table 3. Cardiac conditions associated with the highest risk of adverse outcome
from endocarditis
Prosthetic cardiac valve or prosthetic material used for cardiac valve repair
Previous infective endocarditis
Congenital heart disease (CHD)
Unrepaired cyanotic CHD (including palliative shunts and conduits)
Completely repaired CHD with prosthetic material < 6 months after procedure
Repaired CHD with residual defects at/near site of prosthetic material
Cardiac transplant recipient with cardiac valvulopathy
Adapted from Wilson W, Taubert KA, Gewitz M, Lockhart PB, Baddour LM, Levison M, et al. Prevention of Infective
Endocarditis: Guidelines From the American Heart Association: A Guideline From the American Heart Association
Rheumatic Fever, Endocarditis, and Kawasaki Disease Committee, Council on Cardiovascular Disease in the
Young, and the Council on Clinical Cardiology, Council on Cardiovascular Surgery and Anesthesia, and the Quality
of Care and Outcomes Research Interdisciplinary Working Group. Circulation 2007;116:1736–54.54
Used with permission of Wolters Kluwer Health.
the 1997 American Heart Assocation guideline. The 2007 the utility of prophylactic antibiotics is either unclear or not
guideline identifies 4 conditions that are at highest risk of studied. Appropriate antibiotics used at the correct dose
adverse outcome (Table 3). For patients with the conditions and time and with the appropriate frequency will reduce
listed in Table 3 who have an established gastrointestinal or infectious postoperative complications and minimize the
genitourinary infection, or for those who receive antibiotic development of antibiotic resistant organisms.
therapy for another reason (e.g., to prevent wound
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This document reflects emerging clinical and scientific advances on the date issued and is subject to change. The information
should not be construed as dictating an exclusive course of treatment or procedure to be followed. Local institutions can dictate
amendments to these opinions. They should be well documented if modified at the local level. None of these contents may be
reproduced in any form without prior written permission of the SOGC.
Ensuring a Healthy Mother, Child, and Family 11. HIV-positive women who are considering pregnancy should
be counselled on the possibility of legal action if they do not
Recommendations
permit antiretroviral therapy to be given to their baby after
01. Reproductive health counselling, including contraception and birth. (III-B)
pregnancy planning, should be offered to all reproductive-aged
HIV-positive individuals soon after HIV diagnosis and on an 12. Ethical considerations, including those related to the health
ongoing basis. (II-3A) status of HIV-positive individuals or couples, should be
discussed during pre-conception counselling. (III-B)
02. Men and women should be counselled on all relevant aspects
of pregnancy planning, such as maintaining a healthy diet and
lifestyle, the risk of genetic disease occurrence, and integrated Antiretroviral and Other Drugs in
prenatal screening, as outlined in current Canadian practice Pregnancy Planning
guidelines irrespective of their known HIV status. (III-A) Recommendations
03. Women with no risk factors should start taking folic acid (in the
13. Clinicians should review all medications that HIV-positive
form of vitamin supplements) 1 mg a day for 3 months before
men and women may be using, including antidepressants,
becoming pregnant and for at least the first 3 months of their
pain medications, over-the-counter medications, and hepatitis
pregnancy. (II-3A)
treatment, to ensure that they are safe during conception and
04. Women should be encouraged to give up smoking, drinking pregnancy. (II-3A)
alcohol, and using recreational drugs, and should be referred for
support if required. (III-A) 14. All HIV-positive men and women who require combination
antiretroviral therapy for their own health during the pre-
05. Both prospective parents should be tested for other sexually conception period should be advised to continue their current
transmitted infections, even if they have conceived in the past regimens, but women should not take any drugs that are
and have no symptoms of infection. (III-A) potentially teratogenic or considered toxic in pregnancy,
substituting other drugs when necessary or possible. The
Psychosocial/Mental Health Issues Related most efficacious regimen that is safe in pregnancy should
to HIV Pregnancy Planning and Fertility be selected. (II-3A)
All individuals or couples planning pregnancy are potentially 15. HIV-positive women who do not require combination
susceptible to psychosocial and mental health problems. An
antiretroviral therapy for their own health need to consider
additional burden may be placed on the HIV-positive individual or
starting treatment before becoming pregnant or no later than late
couple because of stigma associated with the condition and the risks
in the first trimester of pregnancy. The most efficacious regimen
of HIV transmission.
that is safe in pregnancy should be selected. (II-3A)
Recommendations
16. HIV-positive men and women who require treatment should be
06. Counselling should be performed by a knowledgeable health encouraged to initiate combination antiretroviral therapy during
care professional or trained peer counsellor in a supportive, non- the pre-conception period to reduce HIV plasma viral load, which
judgemental manner that takes into account sexual diversity and can reduce the risk of HIV transmission to their HIV-negative
ethnocultural or religious beliefs and practices. (III-A) partner or reduce the risk of superinfection of their HIV-positive
07. Counselling should include a discussion of the potential risk for partner. (II-3B)
both horizontal (between partners) and vertical (from mother to
17. All decisions about the use of combination antiretroviral
child) transmission and how that might affect the mental health
therapy and other drugs during pregnancy should be made
of one or both parents. (III-A)
in consultation with experts such as HIV specialists and
08. HIV-positive people who intend to conceive should be made pharmacists. (III-A)
aware of the potential stigma and discrimination they may
face from others who are less informed about how HIV is Scenario-Based Recommendations for the
transmitted, horizontally and vertically. In addition, HIV-positive Prevention of Horizontal HIV Transmission
women who are not breastfeeding should be made aware that
they may face disapproval from people who are not aware of The recommended option may not always be the most practical or
their HIV status. (II-3A) preferred option for the patient, given availability of services, cost,
cultural beliefs, or personal risk evaluation. Physicians and other
09. Further counselling may be suggested to help couples and
health care providers should provide non-judgemental support of the
individuals cope more effectively with fear, stigma, and other
patient’s decision.
psychosocial issues, such as postpartum depression. (II-3A)
Recommendations Recommendations
10. All HIV-positive individuals should be counselled on the possible 18. For serodiscordant couples in which the woman is HIV positive,
legal ramifications of non-disclosure of their HIV status to their it is preferable to attempt home insemination with the partner’s
sexual partner(s). (III-A) sperm during ovulation for 3 to 6 months before considering
other methods. (III-A)
19. If home insemination is unsuccessful, couples should be
ABBREVIATIONS referred to a gynaecologist for consultation and then to a
cART combined antiretroviral therapy fertility specialist for a complete fertility work-up and appropriate
treatment when necessary, including counselling on all assisted
ICS intracytoplasmic sperm injection reproductive technologies if pregnancy is not achieved in 6 to 12
IUI intrauterine insemination months. (III-A)
Key to evidence statements and grading of recommendations, using the ranking of the Canadian Task Force on
Preventive Health Care
Quality of evidence assessment* Classification of recommendations†
I: Evidence obtained from at least one properly randomized A. There is good evidence to recommend the clinical preventive action
controlled trial
II-1: Evidence from well-designed controlled trials without B. There is fair evidence to recommend the clinical preventive action
randomization
II-2: Evidence from well-designed cohort (prospective or C. The existing evidence is conflicting and does not allow to make a
retrospective) or case–control studies, preferably from recommendation for or against use of the clinical preventive action;
more than one centre or research group however, other factors may influence decision-making
II-3: Evidence obtained from comparisons between times or D. There is fair evidence to recommend against the clinical preventive action
places with or without the intervention. Dramatic results in
uncontrolled experiments (such as the results of treatment with E. There is good evidence to recommend against the clinical preventive
penicillin in the 1940s) could also be included in this category action
III: Opinions of respected authorities, based on clinical experience, L. There is insufficient evidence (in quantity or quality) to make
descriptive studies, or reports of expert committees a recommendation; however, other factors may influence
decision-making
*The quality of evidence reported in these guidelines has been adapted from The Evaluation of Evidence criteria described in the Canadian Task Force on
Preventive Health Care.80
†Recommendations included in these guidelines have been adapted from the Classification of Recommendations criteria described in the Canadian Task Force
on Preventive Health Care.80
HIV-Positive Single Woman or HIV-Positive Woman HIV-Positive Man and HIV-Positive Woman
in a Same-Sex Relationship
It is common for seroconcordant couples to attempt natural conception,
Recommendation especially if both partners have fully suppressed viral loads.
Seroconcordant couples may wish to consider intrauterine insemination
20. Single HIV-positive women or HIV-positive women in a same-
with sperm washing to reduce the potential risk of super-infection or
sex relationship should be referred to a fertility specialist and
transmission of drug-resistant strains of HIV between partners.
should consider the option of intrauterine insemination with
HIV-negative donor sperm. This option is preferred over home Recommendations
insemination with donor sperm because the cost of sperm is high 25. Timed natural conception is recommended for seroconcordant
and intrauterine insemination performed in a fertility clinic has couples who are taking combination antiretroviral therapy and
a higher success rate than home insemination. If sperm from a who have fully suppressed HIV plasma viral loads. (II-3A)
known donor is used for intrauterine insemination, regulations
26. Seroconcordant couples should be counselled on the risks
applicable to the donation of sperm must be followed. (III-A)
and benefits of timed natural conception (including HIV
superinfection and transmission of drug-resistant strains of
HIV-Positive Man and HIV-Negative Woman HIV). (II-3A)
Recommendations 27. If timed natural conception is unsuccessful, couples should
21. Serodiscordant couples in which the man is HIV positive be referred to a gynaecologist for consultation and then to a
fertility specialist for a complete fertility work-up and appropriate
should be referred to a fertility specialist and should consider
treatment when necessary, including counselling on all assisted
the preferred option of sperm washing with intrauterine
reproductive technologies. (III-A)
insemination. (II-2A)
22. If intrauterine insemination is unsuccessful, couples should Infertility Investigations and Treatment
consider in vitro fertilization or intracytoplasmic sperm injection
with either sperm washing or the use of donor sperm. (II-3A) Historically, fertility clinics in Canada have been reluctant to provide
fertility investigation and treatment to HIV-positive people. Fertility
23. HIV-positive men who do not require combination experts concur that this has likely been due to a lack of information
antiretroviral therapy for their own health should be about HIV and its successful treatment coupled with a concern that
encouraged to initiate combination antiretroviral therapy serving HIV-positive people could deter HIV-negative individuals
during the pre-conception period to reduce HIV plasma viral from accessing services. In 2010, the American Association of
load, which can reduce the risk of HIV transmission to their Reproductive Medicine released a statement in which it endorsed the
HIV-negative partner. (II-3B) provision of fertility services to all HIV-positive individuals.
Recommendations
HIV-Positive Single Man or Male Same-Sex Couple
28. HIV-positive people should be counselled about fertility problems
Recommendation that occur in the general population, including genetic disorders
24. HIV-positive single men or men in same-sex relationships who and advancing maternal age. (III-A)
have an HIV-negative or HIV-positive surrogate should be 29. Infertility investigations and treatment should be offered to HIV-
referred to a fertility specialist. (III-A) positive people if required. (III-A)
30. All decisions about combination antiretroviral therapy during the through a registry created by the Canadian Perinatal
pre-conception period and during pregnancy should consider
the health of the HIV-positive person and reduction of the
HIV Surveillance Program of the Public Health Agency
risk of horizontal and vertical transmission of HIV. Decisions of Canada. Their 2009 annual report indicates that 180
about combination antiretroviral therapy should be made in children were born to HIV-positive women in Canada
consultation with an HIV specialist. (III-A)
that year. In the 4 preceding years, the number of children
HIV Infection Control in Fertility Clinics
born to HIV-positive women was as follows: 238 (2008),
208 (2007), 194 (2006), and 189 (2005).5 Furthermore,
Recommendations
pregnancy planning has been identified as a key area of
31. Fertility laboratories should follow Canadian Standards
Association guidelines for infection control when handling HIV-
importance to people with HIV in Canada.6 Nevertheless,
positive materials. (III-A) the reproductive health concerns and services available and
32. Potentially infectious materials should be stored in segregated provided to people living with HIV have received minimal
containers and incubators to reduce the risk of HIV attention.
contamination. (III-A)
33. Bio-containment straws for specimen storage should be used to A gap exists between the desires and intentions of people
further reduce the risk of cross-contamination of samples. (III-A) living with HIV to have children and their need for support
in doing so and the resources, relevant research, and
INTRODUCTION support networks necessary for them to do so successfully
and in a medically safe manner. Issues to consider in
Demand for HIV Pregnancy Planning and
pregnancy planning when at least one partner has HIV
Fertility Services in Canada
T
are not just the prevention of vertical transmission but
he natural history of human immunodeficiency virus
also the prevention of horizontal transmission and the
infection has changed significantly in the last decade
management of potential infertility issues. In 2006,
with advances made in medical treatment, most specifically
Ogilvie et al.7 conducted a research study to examine the
with the introduction of highly successful combination
antiretroviral therapy.1 As a result, individuals living with fertility intentions of women living with HIV in British
HIV are now experiencing an improved quality of life and Columbia. Of the 182 women analyzed in the study, 25.8%
a prolonged life expectancy.1–3 In countries with greater expressed intentions to have children regardless of their
resources, the mortality caused by HIV has significantly clinical HIV status.7 Most recently, Loutfy et al.8 completed
decreased and approaches general population norms. A a cross-sectional study designed to assess fertility desires,
recent study indicated that HIV-positive individuals within intentions, and actions. This study surveyed 490 HIV-
7 years of their diagnosis have the same life expectancy positive women of reproductive age (18 to 52) living in
as the general population.2 While the overall current life Ontario. Sixty-one percent were born outside Canada, 52%
expectancy of someone infected with HIV is difficult to lived in Toronto, 47% were of African ethnicity, 74% were
predict (as successful treatment has been widely prescribed currently on cART, and the median age was 38. Sixty-nine
only since 1996), present projections estimate that an percent wanted to give birth, and 57% intended to give
individual living with HIV today will live at least 30 to 40 birth in the future. This study found that the significant
years from the time of infection.3 predictors of fertility intentions were younger age (age
< 40), African ethnicity, living in Toronto, and a lower
Another significant change in the field of HIV in the past number of lifetime births (P = 0.02).8 In 2005, Oladapo et
2 decades is that the rate of HIV infection in women al. conducted a study determining the fertility desires and
has been steadily on the rise. By the end of 2007, it was intentions of people living with HIV who were receiving
estimated that approximately 65 000 Canadians were living care at a suburban specialist clinic in Sagamu, Nigeria.9
with HIV and that 10 114 were women.4 This represents a
Of the 147 participants, 63.3% expressed a desire for
23% increase from 2002. Similarly, women now account for
child-bearing, even though 50.4% of them already had 2
more than one quarter of new positive HIV test reports.4
or more children. Of those who wanted to have children,
The use of cART, possible Caesarean section (as indicated 71.5% of men and 93.8% of women intended to have 2
by current guidelines on pregnancy and HIV), and or more children in the near future.9 In 2009, Nattabi et
abstaining from breastfeeding have reduced the chance al. conducted a systematic review of 29 studies of factors
of vertical transmission of HIV to < 1%. These factors influencing fertility desires and intentions among people
have likely led to the increasing number of pregnancies living with HIV and found that fertility desires were
in HIV-positive women over the past decade.5 In Canada, influenced by a variety of demographic, health, stigma-
all pregnancies to HIV-positive mothers are reported associated, cultural, and psychosocial factors.10
In all of the aforementioned studies, it was concluded that HIV-positive women of reproductive age found that 56%
the desire and intention of HIV-positive individuals to of their most recent pregnancies were unintended.15 One
have children were high and that clinical HIV status did not of the goals of these guidelines is to encourage health
seem to be a predictor of fertility intentions. Specialized care providers to discuss pregnancy planning, including
counselling, services, and support will be required to meet contraception, with their patients as early as possible after
the needs of this group. diagnosis to reduce the incidence of unintended pregnancy
and to reduce the risk of both vertical and horizontal
Access to HIV Pregnancy Planning and
transmission of HIV.
Fertility Services in Canada
Despite the fact that many HIV-positive individuals and
couples wish to have children, there is a scarcity of HIV or HIV/AIDS AND HUMAN RIGHTS
fertility clinics in North America offering advice to HIV-
The World Health Organization states that “all couples
positive individuals and couples on the management of
and individuals have the right to decide freely and
HIV during pregnancy planning, timing of ovulation to
responsibly the number and spacing of their children and
allow fertilization, sperm washing (a procedure designed to
to have access to the information, education and means to
remove viral particles from the sperm, reducing the chance
do so.”16 This includes people living with HIV or AIDS.
of horizontal transmission), management of individuals or
The human rights of those infected with and affected
couples affected by infertility issues, and fertility treatments
by HIV are frequently violated, and this can affect their
including intrauterine insemination and in vitro fertilization.
intentions and desires with respect to having children.
In Europe, HIV-positive couples have had access to There is a need to integrate these guiding principles into
reproductive assistance since the 1980s, and at least 5 all aspects of HIV pregnancy planning, fertility care,
European countries have national programs to assist people treatment and support for people living with HIV in
living with HIV in their pregnancy planning.11 As of 2003, Canada. Recommendations for care must be evidence-
less than 5% of fertility clinics in the United States offered based, and their implementation must be flexible and
reproductive care to HIV-serodiscordant couples.12 In ethnoculturally sensitive, and must also take into account
Canada, services and treatment protocols differ depending diverse and intersecting local/population needs and the
on the clinic or centre, and therefore so do the costs. It social determinants of health.17
is important to note that in most jurisdictions in Canada
sperm washing, IUI, IVF, and ICSI are not covered by SCOPE OF DOCUMENT
provincial medical services plans, so costs are charged
directly to the patient. This guideline does not address the management of HIV
during pregnancy or HIV testing during pregnancy, because
A 2010 study by Yudin et al. showed that while over 70% of
this information is available elsewhere.18 Similarly, as there
clinics surveyed were willing to see people living with HIV
are guidelines dealing with fertility and infertility issues in
in consultation, substantially fewer had actually seen any
the general population, these issues are not addressed in
people living with HIV within the previous 12 months.13
this document.19 The postpartum period and infant feeding
Services offered also varied by region, with clinics located
options for people with HIV are outside of the scope of
in only 5 provinces offering fertility treatments to people
this document.
living with HIV. Some important procedures were also less
commonly available to people living with HIV. In particular,
sperm washing was available in only 26% of clinics in ENSURING A HEALTHY MOTHER,
4 provinces, a service gap noted in the Newmeyer et al. CHILD, AND FAMILY
study that described the barriers to services experienced by
Although management of HIV in pregnancy planning entails
people living with HIV.14
many special considerations, it is important to remember
In addition to a deficiency in assisted reproductive services, that most general recommendations for pregnancy planning
there remains a scarcity of pregnancy planning, prenatal also apply to HIV-positive individuals and couples.
and postnatal care, and counselling programs for HIV-
positive individuals and couples in Canada. The Public Health Agency of Canada is an important
source of information to ensure a healthy mother, child,
Unintended Pregnancy and family. Eating Well with Canada’s Food Guide provides
As is the case in the general population, many pregnancies women with the information they need to eat well during
in people with HIV are unintended. An Ontario study of pregnancy and includes specific advice for all women
of child-bearing age. Detailed recommendations for for choosing to become parents and may worry that they
pregnancy and breastfeeding are available for health will feel guilty about conceiving or breastfeeding, or that
professionals. The Public Health Agency of Canada has family members, friends, or community members may
described alcohol use in pregnancy as “an important public disapprove and withdraw support. As with legal and ethical
health and social issue for Canadians,” recognizing the issues, little information is available on this subject, and
increasing societal awareness of the significant personal recommendations for psychosocial counselling have been
and social costs associated with fetal alcohol spectrum based on expert consensus.
disorder.20 In addition to specific guidelines for alcohol use The transition to parenthood is often a time of great joy,
and nutrition during pregnancy, the agency has produced but it is also life-altering and can result in considerable stress
The Sensible Guide to a Healthy Pregnancy, which includes and anxiety.23–25 When one or both prospective parents have
guidance on general nutrition, folic acid, alcohol, physical HIV, the stress can be greatly increased. Even in 2009, the
activity, smoking and oral health.21 stigma and marginalization associated with HIV continued
to place a significant psychological burden on those who
In addition, SOGC has published numerous guidelines were affected.26,27 A 2007 study showed that health care
addressing most of these topics.22 professionals play a large role in the systemic discrimination
against people living with HIV who wish to have children.28
Recommendations
Thus the environment in which HIV-positive parents live is
1. Reproductive health counselling, including one that can easily cause psychological distress.
contraception and pregnancy planning, should
be offered to all reproductive-aged HIV-positive Although the mental health needs of pregnant women
individuals soon after HIV diagnosis and on an have been studied,29–31 less is known about the specific
ongoing basis. (II-3A) mental health needs of HIV-positive pregnant women. A
2. Men and women should be counselled on all large 2004 American study examined minority women who
relevant aspects of pregnancy planning, such as were pregnant and HIV- positive in 4 regions of the United
maintaining a healthy diet and lifestyle, the risk States.32 They found that depressive symptoms were severe
of genetic disease occurrence, and integrated and that social isolation, perceived stress, and ineffective
coping strategies were among the factors associated with
prenatal screening, as outlined in current Canadian
depression. On the other hand, the presence of a supportive
practice guidelines irrespective of their known
partner was associated with fewer depressive symptoms.
HIV status. (III-A)
This type of research might enable the development of
3. Women with no risk factors should start taking appropriate interventions that will decrease the risk of
folic acid (in the form of vitamin supplements) psychological morbidity for HIV-positive women during
1 mg a day for 3 months before becoming the pregnancy planning and antenatal periods.
pregnant and for at least the first 3 months of their
pregnancy. (II-3A) An earlier, longitudinal study by Larrabee et al.,33 in Texas
4. Women should be encouraged to give up smoking, followed 21 HIV-positive and 21 HIV-negative women
drinking alcohol, and using recreational drugs, and from the antenatal period until 6 months postpartum using
should be referred for support if required. (III-A) the Medical Outcome Survey–Short Form to assess overall
5. Both prospective parents should be tested for other quality of life. Overall, HIV-positive women reported
sexually transmitted infections, even if they have increased health distress and a more difficult transition during
conceived in the past and have no symptoms of the antenatal period than did HIV-negative control subjects. A
infection. (III-A) similar difference was found at 6 months postpartum, but not
during the perinatal period. Once again, seropositivity appears
to be associated with poorer mental health during pregnancy.
PSYCHOSOCIAL/MENTAL HEALTH
ISSUES RELATED TO HIV PREGNANCY There are few published studies about the mental health
PLANNING AND FERTILITY concerns of fathers, and even fewer about the mental
health of HIV-positive fathers.34,35 However, it is known
All individuals or couples planning pregnancy must consider that a father’s behaviour during the early postnatal
the implications of psychosocial and mental health issues. An weeks can significantly affect the mental health status of
additional burden is placed on the HIV-positive individual or new mothers,35 particularly with respect to postpartum
couple because of the stigma and discrimination associated depression, which has a prevalence rate of about 10%.36,37
with the condition and the risks of transmission. People As more and more people with HIV are living longer,
living with HIV considering pregnancy may be concerned healthier lives when they have access to medication, this
that they will experience stigma and discrimination simply will become an increasingly important area of research.
prenatal care and conception counselling. Ideally, doctors and vertical HIV transmission, thus leading to a greater
and other health care providers should be involved from number of people living with HIV having or planning to
pre-conception when women are HIV-positive, so routine have children.1–5,7–10 These breakthroughs affect both men
prevention measures can be planned in addition to cART and women by reducing viral load to decrease the risk of
to decrease transmission rates. horizontal HIV transmission and, for women, the risk of
vertical transmission. It is well accepted that cART during
A 1996 paper published by Williams et al. reviewed the
pregnancy should take into consideration the health of
modest data available on reproductive decision-making in
both mother and child and that, with some exceptions,
HIV-positive women and found that awareness of their HIV
cART is generally safe in pregnancy. The selection of
infection was not associated with pregnancy termination
cART in pregnancy should consider drugs that are
or subsequent pregnancy prevention.44 This confirms the
effective in and tolerable to the mother and that are of
fact that HIV-positive women are having and will continue
least toxicity to the fetus and newborn. Specifically, the
to have children, so health professionals must be prepared
mother should be treated not only to prevent vertical HIV
to guide them in this process. There are ethical concerns
transmission but also to ensure optimal therapy for herself.
associated with all pregnancies and with conception and
assisted reproductive interventions, and these are addressed Both the Canadian consensus guidelines for the care of
in SOGC guidelines.22 Ethical considerations common HIV-positive pregnant women, Putting Recommendations
in HIV infection, such as the health of the prospective into Practice, and the United States Department of Health
parents and their financial ability to care for a child, are and Human Services guidelines recommend that women
reasonable and should be discussed with HIV-positive who are not already on cART for their own health before
individuals and couples. Many health care providers cite becoming pregnant can delay the initiation of therapy until
“ethical” considerations when refusing to provide care. after the first trimester. Delaying treatment until the second
These are often “perceived” ethical considerations, such as trimester is intended to reduce any theoretic teratogenic
concern that a child or partner will be infected with HIV, effects of cART, which may be greater in the first trimester.
or they are based on stereotypes associated with a history Fertility clinics generally require an HIV-positive woman to
of drug use. These perceptions generally arise from lack be on a successful cART regimen before she seeks fertility
of information or failure to review and/or accept current services, regardless of whether or not she requires cART
scientific evidence on HIV transmission risk reduction. for her own health. This is supported by recently presented
Refusal to provide HIV transmission risk-reduction conference abstract findings of the French cohort, which
services for people planning pregnancy is itself unethical show that initiation of cART before conception or early
and contrary to the human right to non-discrimination and in the first trimester led to the lowest vertical transmission
the right to choose the number and spacing of children.45 rate of 0% to 0.6 %.46
Recommendations There is seldom discussion about the benefit of starting
10. All HIV-positive individuals should be counselled cART during the pre-conception period for men and
on the possible legal ramifications of non- women who do not require cART for their own health.
disclosure of their HIV status to their sexual Treatment before conception is a horizontal risk-reduction
partner(s). (III-A) issue—as reduction in viral plasma load often correlates
11. HIV-positive women who are considering to reduction of viral load in semen and vaginal fluid—and
pregnancy should be counselled on the possibility should be discussed with the patient in all scenarios to
of legal action if they do not permit antiretroviral reduce risk to his or her HIV-negative partner or reduce
therapy to be given to their baby after birth. (III-B) the risk of superinfection to his or her HIV-positive
12. Ethical considerations, including those related to partner.47–49
the health status of HIV-positive individuals or
couples, should be discussed during pre-conception There are currently several ongoing studies looking
counselling. (III-B) at the efficacy of HIV pre-exposure prophylaxis in
preventing HIV transmission to a non-infected partner in
a serodiscordant couple during conception. The United
COMBINATION ANTIRETROVIRAL AND
States Centers for Disease Control and Prevention
OTHER DRUGS IN PREGNANCY PLANNING
published an interim guidance document for the use of
A substantial body of evidence has shown that potent pre-exposure prophylaxis in men who have sex with men.50
cART not only prolongs the lives of people living with HIV This document is primarily based on the results of the
but also significantly reduces the risk of both horizontal investigators for the Pre-Exposure Prophylaxis Initiative
study,51 which has shown pre-exposure prophylaxis to be 17. All decisions about the use of combination anti
efficacious in this population. Currently, the Centers for retroviral therapy and other drugs during pregnancy
Disease Control and Prevention cautions against the use of should be made in consultation with experts such as
pre-exposure prophylaxis by women for HIV prevention, HIV specialists and pharmacists. (III-A)
as the FEM-PrEP Project (a study of pre-exposure
prophylaxis for HIV prevention among heterosexual
women)52 was stopped early because it was highly unlikely OPTIONS FOR REDUCING RISK OF HORIZONTAL
HIV TRANSMISSION DURING CONCEPTION
to be able to demonstrate the effectiveness of Truvada
(emtricitabine and tenofovir disoproxil fumarate) in HIV-positive couples and individuals who wish to conceive
preventing HIV infection in women. a child need to consider the risk of horizontal HIV
There are many non-cART medications that people living transmission during conception. That risk depends on
with HIV may be using to treat concurrent conditions, a number of variables, including the HIV serostatus of
including but not limited to hepatitis C and depression, each partner (i.e., HIV-positive woman and HIV-negative
and adverse events from cART. Clinicians should review man or HIV-positive man and HIV-negative woman) and
all prescribed, over-the-counter, and complementary the plasma viral load and level of drug-resistant virus of
therapies, as well as street drugs used by HIV-positive each prospective parent. Couples and individuals should be
individuals before conception. Most notably, treatment counselled thoroughly about all horizontal HIV transmission
for hepatitis C is considered to be teratogenic when used risk-reduction methods before conception so they can make
by either male or female partners. Hepatitis C treatment an informed choice about which conception method is
should be stopped at least 6 months before couples most appropriate to their particular situation. Furthermore,
attempt to conceive. prospective parents should be informed about the rate of
success, availability, and cost of each conception option.
Recommendations
Timed Natural Conception
13. Clinicians should review all medications that
HIV-positive men and women may be using, Natural conception has only recently been seen as an option
including antidepressants, pain medications, over- for people living with HIV. Although not for everyone,
the-counter medications, and hepatitis treatment, natural conception is suitable in some circumstances,
to ensure that they are safe during conception and and the nature of each individual case must be evaluated.
pregnancy. (II-3A) Prospective parents must have a frank discussion about
14. All HIV-positive men and women who require the risks of horizontal HIV transmission to make an
combination antiretroviral therapy for their own informed decision about this option. The relative risk of
health during the pre-conception period should horizontal HIV transmission involved in natural conception
be advised to continue their current regimens, but is dependent on the plasma viral load of the HIV-positive
women should not take any drugs that are potentially partner, the frequency of intercourse, the presence of
teratogenic or considered toxic in pregnancy, concurrent sexually transmitted infections, and which
substituting other drugs when necessary or possible. partner is infected.41,52,53 People living with HIV who do not
The most efficacious regimen that is safe in have access to or who cannot afford assisted conception
pregnancy should be selected. (II-3A) services may be more likely to attempt natural conception.
15. HIV-positive women who do not require combina Additionally, people living with HIV who fear stigma will be
tion antiretroviral therapy for their own health need associated with the use of assisted conception services may
to consider starting treatment before becoming be more likely to consider natural conception. More research
pregnant or no later than late in the first trimester of is needed to determine the factors considered when couples
pregnancy. The most efficacious regimen that is safe decide to conceive naturally. In the case of an HIV-positive
in pregnancy should be selected. (II-3A) man who is not taking cART, the risk of HIV transmission
16. HIV-positive men and women who require to his uninfected female partner is quoted as 0.1% to 0.3%
treatment should be encouraged to initiate per act of intercourse.54 This assumes that the couple is in a
combination antiretroviral therapy during the pre- stable relationship and that they are not participating in any
conception period to reduce HIV plasma viral load, other form of high-risk activity.54 Without the intervention
which can reduce the risk of HIV transmission to of cART, the risk of transmission from an HIV-positive
their HIV-negative partner or reduce the risk of woman to her uninfected male partner is reported to
superinfection of their HIV-positive partner. (II-3B) be 0.03% to 0.09%.54 In general, plasma viral load may
be concordant with the viral load of genital secretions.
However, people living with HIV and their uninfected HIV-negative and for seroconcordant couples when
partners should be counselled that this is not always the superinfection is a concern. Semen is centrifuged to
case. cART further reduces the risk when long-term viral separate live sperm (which do not carry HIV) from seminal
suppression is achieved. Normally, the viral load in semen is plasma and non-germinal cells (which may carry HIV) and
lower than that in blood; however, this is greatly influenced then inseminated into the female partner at the time of
by the use of cART, known to have optimal penetration of ovulation. This practice is well supported by the literature,
the genital tract, as well as the absence of coexisting sexually which is extensive.12,61–75 In technical terms, sperm washing
transmitted infections and the absence of drug resistance.55–57 involves centrifuging ejaculated semen in a 40% to 80%
It is possible to achieve an undetectable viral load in genital colloidal silica density gradient to separate progressively
secretions with the long-term use of cART; however, assays motile HIV-free sperm from non-sperm components
to detect genital fluid viral load are not readily available.58 and seminal plasma, which remain in the supernatant.
The sperm pellet at the bottom is re-suspended in a fresh
In early 2008, the Swiss Federal Commission for HIV/AIDS medium and centrifuged twice before the preparation of
issued a controversial statement authored by Vernazza et
a final swim-up. There is no consensus among researchers
al.,41 known as the Swiss Statement, claiming that an HIV-
about the need to test washed sperm for detectable HIV
infected person on antiretroviral therapy with completely
RNA before the sample is used. A nucleic-acid-based
suppressed viremia (effective ART) is not sexually infectious
sequence amplification (NASBA; Biomerieux, Basingstoke,
and cannot transmit HIV through sexual contact provided
UK) or similar commercial assay can be used; however,
that “the HIV-positive individual takes anti-retroviral therapy
these assays are not commercially available in Canada. The
consistently and as prescribed and is regularly followed by his/
risk of the sample having detectable HIV is 3% to 6%. This
her doctor; viral load is undetectable (i.e., < 40 copies/mL)
is because centrifugation fails to remove all of the seminal
and has been so for at least 6 months; and the
plasma and leukocytes in a small proportion of cases. The
HIV-positive individual does not have any sexually
number of washes is limited because repeated centrifuging
transmitted infections.” Thus, although there remains a slight
leads to loss of sperm quality and quantity. A double-tube
risk of transmisson,59,60 some serodiscordant couples opt to
technique has been proposed to increase yield and reduce
proceed with timed unprotected intercourse—only during
the need for post-wash HIV testing. Unfortunately, this
ovulation—to reduce the number of exposures to HIV
technique has not been adopted by the majority of centres
by the uninfected partner and to increase the probability
offering sperm washing, because it is not currently available
of conception. Women should be directed to health care
commercially. According to studies published to date, there
providers and the websites of relevant health care agencies
have been no reported cases of infection of the female
for information about timing ovulation. Ovulation timing
kits are available over the counter at most pharmacies. partner when sperm washing is carried out following the
reported published protocols in more than 3000 cycles of
Home Insemination sperm washing combined with intrauterine insemination,
Home insemination is a particularly popular option for in vitro fertilization and intracytoplasmic sperm injection.12
conception for HIV-positive women with HIV-negative The results of a multicentre retrospective analysis of 1036
partners and for same-sex female couples and single serodiscordant couples from 8 European centres offering
HIV-positive women with access to donor sperm. The sperm washing reported 2840 IUI cycles, 107 IVF cycles,
procedure involves collecting sperm from a partner or 394 ICSI cycles, and 49 frozen embryo transfers. At least
donor in a sterile container or a condom. The sperm is 6 months post-treatment there was careful HIV follow-
drawn into a needle-less syringe and then inserted into the up of the HIV-negative women. All tests recorded on the
vagina as close to the cervix as possible. Optimal results women were negative (7.1% lost to follow-up), giving a
are achieved when insemination is done during ovulation. calculated probability of contamination equal to zero
This is a particularly attractive method, as it is very low (95% CI 0 to 0.09). Clinical pregnancy rates recorded with
cost and does not require the assistance of a fertility all forms of treatment were comparable to those found in
specialist. If home insemination is unsuccessful after 3 to cycles carried out in HIV-negative couples.76
6 months, HIV-positive women should be advised to seek
the assistance of a fertility specialist. IUI, IVF, and ICSI
IUI, IVF, and ICSI are fertility techniques that can reduce
Sperm Washing the risk of HIV transmission to the uninfected partner.
Sperm washing is a well-established, effective, and safe IUI is most commonly used and is combined with sperm
risk-reduction fertility option for serodiscordant couples washing if the male partner is HIV positive. This process
in which the man is HIV-positive and the woman is involves placing prepared sperm directly into the uterus
during ovulation. For couples who wish to further reduce couple. Sperm donation by HIV-positive men is restricted
the risk of horizontal HIV transmission or for those who by Canadian law; however, it may be possible through the
have infertility issues, sperm washing can be combined Donor Semen Special Access Program when the recipient
with ovulation induction, IVF, or ICSI. is known to the donor. Further information is available
from Assisted Human Reproduction Canada and fertility
IVF refers to the procedure whereby oocytes are exposed specialists. HIV-positive individuals and couples who
to spermatozoa outside the uterus, and a fertilized embryo require sperm donation, egg donation, or a surrogate are
is returned to the uterus for the gestation period. likely to require legal advice and contracts.
Some studies have shown that because ICSI involves Adoption
fertilization with only one sperm, the risk of possible HIV Adoption is a legal and social process. It involves the
transmission in serodiscordant couples should be lower transferring of rights over a child from birth parents
than with traditional assisted reproductive technology to adoptive parents. In Canada, adoption is regulated
methods. This is because in traditional IUI women receive provincially, so requirements vary depending upon
millions of spermatozoa, and in classic IVF the oocytes geographical location. They may also differ depending
are exposed to thousands of spermatozoa.77 upon whether the adoption is undertaken privately or
through the public system, or is international.79 No current
Both IVF and ICSI are very expensive, costing up to data are available on the success rate of adoption in Canada
$15 000 per cycle, making these procedures inaccessible to if one or both prospective parents are HIV positive. In
many people living with HIV. the United States, Lambda Legal has successfully assisted
A 2003 meta-analysis assessing the efficacy of assisted same-sex couples and people living with HIV to adopt
children.
reproductive technologies in serodiscordant couples
found they were less successful in the group in which the
female partner was infected, with an overall pregnancy rate SCENARIO-BASED RECOMMENDATIONS FOR THE
per assisted reproductive technology attempt of 6.7%. PREVENTION OF HORIZONTAL HIV TRANSMISSION
No pregnancies resulted from the IUI attempts, while 2 The scenario-based recommendations are intended to
pregnancies resulted from the IVF and ICSI attempts.66 guide health care providers during the pre-conception
A 2007 study examining the safety and effectiveness of counselling process. All options, including risks and
assisted reproduction (IUI, IVF, and ICSI) using sperm benefits, should be presented to prospective parents
washing for HIV-1 serodiscordant couples in which the to facilitate informed decision making. Although the
male partner was infected showed pregnancy resulting in recommendations are based on expert opinion of the
580 of 3315 cycles. Throughout the period of treatment, all safest and most practical option for most individuals
couples were required to use condoms during intercourse. and couples, they may not always be the most practical
IUI was the most frequently used procedure, representing or preferred option for some patients, depending on
84% of procedure use. Out of the 580 pregnancies, there availability of services, cost, cultural beliefs, and personal
were 112 miscarriages, 8 extra-uterine pregnancies, 2 preference. In these cases, physicians and other health care
pregnancy terminations and 1 intrauterine death. Overall, providers should provide non-judgemental support of the
no transmission of HIV to the female partner was decision of the patient(s) involved.
observed with complete follow-up information in 967 out
of 1036 cases.67 HIV-Positive Woman and HIV-Negative Man
HIV serodiscordant couples in which the woman is HIV
Sperm Donation, Egg Donation, and Surrogacy positive and the man is HIV negative should be counselled
Sperm donation, egg donation, and surrogacy are on the risks and benefits of timed natural conception, home
discussed in depth in a joint policy statement on ethical insemination, IUI, IVF, ICSI, the option of a gestational
issues in assisted reproduction prepared by the Society carrier or true surrogate, and adoption.
of Obstetricians and Gynaecologists of Canada and the
Recommendations
Canadian Fertility and Andrology Society.19 However, these
policies do not directly address the issues of people living 18. For serodiscordant couples in which the woman
with HIV.78 Sperm donation is available to the uninfected is HIV positive, it is preferable to attempt home
partners of HIV-positive men and to HIV-positive women. insemination with the partner’s sperm during
Surrogacy is not currently an option in Canada for HIV- ovulation for 3 to 6 months before considering
positive single men or HIV-positive men in a same-sex other methods. (III-A)
19. If home insemination is unsuccessful, couples 23. HIV-positive men who do not require combination
should be referred to a gynaecologist for antiretroviral therapy for their own health
consultation and then to a fertility specialist for should be encouraged to initiate combination
a complete fertility work-up and appropriate antiretroviral therapy during the pre-conception
treatment when necessary, including counselling on period to reduce HIV plasma viral load, which
all assisted reproductive technologies if pregnancy can reduce the risk of HIV transmission to their
is not achieved in 6 to 12 months. (III-A) HIV-negative partner. (II-3B)
HIV-Positive Single Woman or HIV-Positive HIV-Positive Single Man or Male Same-Sex Couple
Woman in a Same-Sex Relationship
HIV-positive single women or HIV-positive women in a Recommendation
same-sex relationship should be counselled on the risks 24. HIV-positive single men or men in same-sex
and benefits of home insemination with donor sperm relationships who have an HIV-negative or
(known donor or purchased sperm), IUI with donor HIV-positive surrogate should be referred to a
sperm, IVF with donor sperm, ICSI with donor sperm, fertility specialist. (III-A)
and the option of a gestational carrier or true surrogate
HIV-Positive Man and HIV-Positive Woman
with donor sperm, and adoption.
Heterosexual couples in which both partners are HIV
Recommendation positive should be counselled on the risks and benefits
20. Single HIV-positive women or HIV-positive of timed natural conception, IUI with sperm washing,
women in a same-sex relationship should be IVF with sperm washing, ICSI with sperm washing, and
referred to a fertility specialist and should adoption.
consider the option of intrauterine insemination
Recommendations
with HIV-negative donor sperm. This option is
preferred over home insemination with donor 25. Timed natural conception is recommended
sperm because the cost of sperm is high and for seroconcordant couples who are taking
intrauterine insemination performed in a fertility combination antiretroviral therapy and who have
clinic has a higher success rate than home fully suppressed HIV plasma viral loads. (II-3A)
insemination. If sperm from a known donor is 26. Seroconcordant couples should be counselled on
used for intrauterine insemination, regulations the risks and benefits of timed natural conception
applicable to the donation of sperm must be (including HIV superinfection and transmission of
followed. (III-A) drug-resistant strains of HIV). (II-3A)
27. If timed natural conception is unsuccessful,
couples should be referred to a gynaecologist
HIV-Positive Man and HIV-Negative Woman
for consultation and then to a fertility specialist
HIV serodiscordant couples in which the male partner
for a complete fertility work-up and appropriate
is HIV positive should be counselled on the risks and
treatment when necessary, including counselling on
benefits of timed natural conception, home insemination,
all assisted reproductive technologies. (III-A)
IUI with sperm washing or donor sperm, IVF with sperm
washing or donor sperm, ICSI with sperm washing or
donor sperm, and adoption. FERTILITY ISSUES IN THE CONTEXT OF HIV AND
HIV INFECTION CONTROL IN FERTILITY CLINICS
Recommendations
Infertility Investigations and Treatment
21. Serodiscordant couples in which the man is Historically, fertility clinics in Canada have been reluctant
HIV positive should be referred to a fertility to provide fertility investigation and treatment to people
specialist and should consider the preferred living with HIV. Fertility experts concur that this has likely
option of sperm washing with intrauterine been due to lack of information about HIV and concern
insemination. (II-2A) that serving people living with HIV could deter HIV-
22. If intrauterine insemination is unsuccessful, negative individuals from accessing services. However, it
couples should consider in vitro fertilization or is common practice in many fertility clinics across Canada
intracytoplasmic sperm injection with either sperm to offer investigation, treatment, and storage of potentially
washing or the use of donor sperm. (II-3A) infected specimens to people with other infectious diseases
risk of HIV contamination. (III-A) 7. Ogilvie GS, Palepu A, Remple VP, Maan E, Heath K, MacDonald G,
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80. Woolf SH, Battista RN, Angerson GM, Logan AG, Eel W. Canadian
65. Bagasra O, Farzadegan H, Seshamma T, Oakes JW, Saah A, Pomerantz RJ. Task Force on Preventive Health Care. New grades for recommendations
Detection of HIV-1 proviral DNA in sperm from HIV-1-infected men. from the Canadian Task Force on Preventive Health Care. CMAJ
AIDS 1994;8(12):1669–74. 2003;169:207–8.
Tracy Pressey, MD, Vancouver BC Modified Robson criteria should be used to enable comparison of
Caesarean section rates and indications. (III-B)
Anne Roggensack, MD, Calgary AB
Frank Sanderson, MD, Saint John NB
Vyta Senikas, MD, Ottawa ON
Disclosure statements have been received from all authors and
members of the committee.
This document reflects emerging clinical and scientific advances on the date issued and is subject to change. The information
should not be construed as dictating an exclusive course of treatment or procedure to be followed. Local institutions can dictate
amendments to these opinions. They should be well documented if modified at the local level. None of these contents may be
reproduced in any form without prior written permission of the SOGC.
Table 1. Key to evidence statements and grading of recommendations, using the ranking of the Canadian Task Force
on Preventive Health Care
Quality of evidence assessment* Classification of recommendations†
I: Evidence obtained from at least one properly randomized A. There is good evidence to recommend the clinical preventive action
controlled trial
II-1: Evidence from well-designed controlled trials without B. There is fair evidence to recommend the clinical preventive action
randomization
II-2: Evidence from well-designed cohort (prospective or C. The existing evidence is conflicting and does not allow to make a
retrospective) or case–control studies, preferably from recommendation for or against use of the clinical preventive action;
more than one centre or research group however, other factors may influence decision-making
II-3: Evidence obtained from comparisons between times or D. There is fair evidence to recommend against the clinical preventive action
places with or without the intervention. Dramatic results in
uncontrolled experiments (such as the results of treatment with E. There is good evidence to recommend against the clinical preventive
penicillin in the 1940s) could also be included in this category action
III: Opinions of respected authorities, based on clinical experience, L. There is insufficient evidence (in quantity or quality) to make
descriptive studies, or reports of expert committees a recommendation; however, other factors may influence
decision-making
*The quality of evidence reported in these guidelines has been adapted from The Evaluation of Evidence criteria described in the Canadian Task Force on
Preventive Health Care.14
†Recommendations included in these guidelines have been adapted from the Classification of Recommendations criteria described in the Canadian Task Force
on Preventive Health Care.14
TRENDS IN CAESAREAN SECTION RATES 3. Be easily derived from current obstetric databases.
2. Canadian Institute for Health Information. Health indicators interactive 7. Brennan DJ, Robson MS. Murphy M, O’Herlihy C. Comparative analysis
tool: Caesarean section rates; 1997–2009. Ottawa: CIHI. Available at: of international cesarean delivery rates using 10-group classification
http://www.cihi.ca/hirpt/?language=en&healthIndicatorSelection=Csec. identifies significant variation in spontaneous labor. Am J Obstet Gynecol
Accessed August 8, 2012. 2009;201(3):308.e1–8.
8. McCarthy FP, Rigg L, Cady L, Cullinane F. A new way of looking at 12. Perinatal Services BC. Examining cesarean delivery rates in
Caesarean section births. Aust N Z J Obstet Gynaecol 2007;47(4):316–20. British Columbia using the Robson ten classification. Part
1: understanding the ten groups. A Perinatal Services BC
9. Nesheim BI, Eskild A, Gjessing L. Does allocation of low risk parturient surveillance special report. Perinatal Services BC: December
women to a separate maternity unit decrease the risk of emergency 2011;1(4). Available at: http://www.perinatalservicesbc.ca/NR/
cesarean section? Acta Obstet Gynecol Scand 2010;89(6):813–6. rdonlyres/3CE464BF-3538–4A78-BA51–451987FDD2EF/0/
SurveillanceSpecialReportRobsonTenClassificationDec2011.pdf.
10. Betrán AP, Gulmezoglu AM, Robson M, Merialdi M, Souza JP, Wojdyla D,
Accessed August 8, 2012.
et al. WHO global survey on maternal and perinatal health in Latin
America: classifying caesarean sections. Reprod Health 2009;6:18. 13. Torloni MR, Betran AP, Souza JP, Widmer M, Allen T, Gulmezoglu M,
et al. Classifications for cesarean section: a systematic review. PLoS One.
11. The Maternal Newborn Services Task Force, Child Health Network
2011;6(1):e14566.
for the Greater Toronto Area. The birthing review project. Application of
the Robson classification of cesarean sections. In focus: Robson groups 14. Woolf SH, Battista RN, Angerson GM, Logan AG, Eel W. Canadian
1 & 2. Toronto: Child Health Network for the Greater Toronto Area; April Task Force on Preventive Health Care. New grades for
2010. Available at: http://www.childhealthnetwork.com/documents/ recommendations from the Canadian Task Force on Preventive Health
CHN-BirthingReview-Phase1-Apri12010.pdf. Accessed August 8, 2012. Care. CMAJ 2003;169:207–8.
Delayed Child-Bearing
Abstract
This Committee Opinion has been prepared by the Genetics
Committee, reviewed by the Reproductive Endocrinology Objective: To provide an overview of delayed child-bearing and to
and Infertility Committee, and approved by the Executive describe the implications for women and health care providers.
and Council of the Society of Obstetricians and Options: Delayed child-bearing, which has increased greatly in
Gynaecologists of Canada. recent decades, is associated with an increased risk of infertility,
PRINCIPAL AUTHOR pregnancy complications, and adverse pregnancy outcome. This
guideline provides information that will optimize the counselling and
Jo-Ann Johnson, MD, Calgary AB care of Canadian women with respect to their reproductive choices.
Suzanne Tough, PhD, Calgary AB Outcomes: Maternal age is the most important determinant of fertility,
and obstetric and perinatal risks increase with maternal age.
SOGC GENETICS COMMITTEE
Many women are unaware of the success rates or limitations of
R. Douglas Wilson, MD (Chair), Calgary AB assisted reproductive technology and of the increased medical
risks of delayed child-bearing, including multiple births, preterm
François Audibert, MD, Montreal QC
delivery, stillbirth, and Caesarean section. This guideline provides
Claire Blight, RN, Dartmouth NS a framework to address these issues.
Jo-Ann Brock, MD, Halifax NS Evidence: Studies published between 2000 and August 2010 were
retrieved through searches of PubMed and the Cochrane Library
Lola Cartier, MSc, CCGC, Montreal QC using appropriate key words (delayed child-bearing, deferred
Valérie A. Désilets, MD, Montreal QC pregnancy, maternal age, assisted reproductive technology,
infertility, and multiple births) and MeSH terms (maternal age,
Alain Gagnon, MD, Vancouver BC reproductive behaviour, fertility). The Internet was also searched
using similar key words, and national and international medical
Sylvie Langlois, MD, Vancouver BC
specialty societies were searched for clinical practice guidelines
Lynn Murphy-Kaulbeck, MD, Moncton NB and position statements. Data were extracted based on the aims,
sample, authors, year, and results.
Nanette Okun, MD, Toronto ON
Values: The quality of evidence was rated using the criteria described
The literature searches and bibliographic support for this in the Report of the Canadian Task Force on Preventive Health
guideline were undertaken by Becky Skidmore, Medical Care (Table 1).
Research Analyst, Society of Obstetricians and Gynaecologists
of Canada. Sponsor: The Society of Obstetricians and Gynaecologists of
Canada.
Disclosure statements have been received from all members of
the committee.
Recommendations
1. Women who delay child-bearing are at increased risk of infertility.
Prospective parents, especially women, should know that their
fecundity and fertility begin to decline significantly after 32 years of
age. Prospective parents should know that assisted reproductive
technologies cannot guarantee a live birth or completely
J Obstet Gynaecol Can 2012;34(1):80–93 compensate for age-related decline in fertility. (II-2A)
2. A fertility evaluation should be initiated after 6 months of
unprotected intercourse without conception in women 35 to 37
years of age, and earlier in women > 37 years of age. (II-2A)
Key Words: Maternal age, delayed child-bearing, reproductive 3. Prospective parents should be informed that semen quality and
technology, oocyte donation, late maternal age male fertility deteriorate with advancing age and that the risk of
genetic disorders in offspring increases. (II-2A)
This document reflects emerging clinical and scientific advances on the date issued and is subject to change. The information
should not be construed as dictating an exclusive course of treatment or procedure to be followed. Local institutions can dictate
amendments to these opinions. They should be well documented if modified at the local level. None of these contents may be
reproduced in any form without prior written permission of the SOGC.
4. Women ≥ 35 years of age should be offered screening for fetal maternal age and the use of reproductive assistance.4,5
aneuploidy and undergo a detailed second trimester ultrasound
examination to look for significant fetal birth defects (particularly
These pregnancy complications include ectopic pregnancy,
cardiac defects). (II-1A) spontaneous abortion, fetal chromosomal abnormalities,
5. Delayed child-bearing is associated with increased obstetrical and certain congenital anomalies, placenta previa, gestational
perinatal complications. Care providers need to be aware of these diabetes, preeclampsia, multiple births, PTD, and Caesarean
complications and adjust obstetrical management protocols to section. These in turn are associated with an increased risk
ensure optimal maternal and perinatal outcomes. (II-2A)
of preterm birth and perinatal and maternal mortality and
6. All adults of reproductive age should be aware of the obstetrical
and perinatal risks of advanced maternal age so they can make
morbidity.6–10 Infants born preterm, especially multiples,
informed decisions about the timing of child-bearing. (II-2A) are at increased risk of morbidity, mortality, and long-term
7. Strategies to improve informed decision-making by prospective disability.
parents should be designed, implemented, and evaluated. These
strategies should provide opportunity for adults to understand the If the trend towards delayed child-bearing continues, society
potential medical, social, and economic consequences of child- can anticipate increased demand for reproductive assistance
bearing throughout the reproductive years. (III-B)
and associated increases in the need for more sophisticated
8. Barriers to healthy reproduction, including workplace policies,
should be reviewed to optimize the likelihood of healthy
prenatal, postpartum, and early development care. While a
pregnancies. (III-C) short delay in age at parenting poses little absolute risk for
the individual woman, small shifts in population distribution
INTRODUCTION curves affect large numbers of women, which has important
implications for the health care system.
T here is a growing trend in Canada for child-bearing
to occur later in women’s lives. Not only are more
women aged > 30 years giving birth, but the proportion of
The SOGC hopes to alert care providers to the implications
of this emerging public health issue and supports the
first births occurring among women aged > 30 has been urgent need for better public information to enable more
increasing steadily over the past 20 years.1 Currently, 11% informed reproductive choices.
of first births occur in women aged ≥ 35 years.1 This trend
towards delayed child-bearing is also occurring in Western DEFINITION OF DELAYED CHILD-BEARING
Europe, Australia, New Zealand, and the United States.2
Fertility declines with increasing maternal age, especially
Many of the reasons why women are choosing to postpone
after the mid-30s. For this reason, delayed child-bearing
child-bearing reflect the availability of safe, effective, and
is traditionally defined as pregnancy occurring in women
reversible contraception, which has allowed women the
aged ≥ 35 years. This population has been referred to
reproductive autonomy to decide if and when they will
as advanced maternal age or late maternal age. In recent
have children. Biologically, the optimum period for child-
years, advances in ART have challenged the traditional
bearing is between 20 and 35 years of age. After 35 years
age-related boundaries of reproduction, enabling even
of age, fecundity decreases, and the chance of miscarriage,
spontaneous abortion, pregnancy complications, and postmenopausal women to conceive and give birth.11
adverse pregnancy outcomes (including PTD and multiple Before ART, the oldest naturally conceived pregnancy
birth) increases.3 As women age, many opt for fertility was in a 57-year-old woman.12 With use of ART and
treatment to improve their chance of conception. The donor oocytes, the birth rate in older mothers has risen
effectiveness of various reproductive technologies declines dramatically, and in one case, a 70-year-old woman has
steadily after the age of 35, while the risk of pregnancy given birth. These women are defined as “very advanced
complications and adverse outcome increases with both maternal age” (44 years of age or older), “mature” gravida,
or “extremely elderly” gravida.
Table 1. Key to evidence statements and grading of recommendations, using the ranking of the Canadian Task Force
on Preventive Health Care
Quality of evidence assessment* Classification of recommendations†
I: Evidence obtained from at least one properly randomized A. There is good evidence to recommend the clinical preventive action
controlled trial
II-1: Evidence from well-designed controlled trials without B. There is fair evidence to recommend the clinical preventive action
randomization
II-2: Evidence from well–designed cohort (prospective or C. The existing evidence is conflicting and does not allow to make a
retrospective) or case–control studies, preferably from recommendation for or against use of the clinical preventive action;
more than one centre or research group however, other factors may influence decision-making
II-3: Evidence obtained from comparisons between times or D. There is fair evidence to recommend against the clinical preventive action
places with or without the intervention. Dramatic results in
uncontrolled experiments (such as the results of treatment with E. There is good evidence to recommend against the clinical preventive
penicillin in the 1940s) could also be included in this category action
III: Opinions of respected authorities, based on clinical experience, L. There is insufficient evidence (in quantity or quality) to make
descriptive studies, or reports of expert committees a recommendation; however, other factors may influence
decision-making
*The quality of evidence reported in these guidelines has been adapted from The Evaluation of Evidence criteria described in the Canadian Task Force on
Preventive Health Care.101
†Recommendations included in these guidelines have been adapted from the Classification of Recommendations criteria described in the Canadian Task Force
on Preventive Health Care.101
the fertility rate of 30- to 34-year-old women exceeded the relationship factors (e.g., partner’s interest in and suitability
rate for women aged 25 to 29 years.13 Over the same time for parenting) ranked as the 2 most important factors
period, the proportion of live births to women between the influencing readiness for child-bearing.16
ages of 35 to 39 and 40 to 44 years also increased, from 4.7%
to 14.8%, and from 0.6% to 2.8% respectively.14 A false sense of security is associated with advances in
ART, and most women are unaware that technology cannot
As women delay child-bearing and age at first birth compensate completely for the effects of reproductive
increases, the total number of births to each woman aging, except potentially through oocyte donation. A recent
decreases, and the size, composition, and future growth survey of 360 Canadian undergraduate women assessing
of the population is affected. The postponement of first their understanding of reproductive aging found that while
births has been associated with smaller family sizes and most were aware of the drop in fertility with age, they
increased childlessness, all of which contribute to the overall significantly overestimated the likelihood of pregnancy at
decline in fertility rate as experienced in Canada and other all ages and were not aware of the steep rate of fertility
countries, including Spain, Sweden, the United Kingdom, decline with age. These women also overestimated the
and Australia. In Canada the fertility rate (average number chance of pregnancy loss at all ages, but they did not
of children per woman) of 1.66 (2007) is well below the identify a woman’s age as the strongest risk factor for this
replacement level of 2.1 children per woman.15 event.17
A number of factors have been proposed in the demographic Delayed child-bearing is associated with an increased risk
and sociological literature to explain the phenomenon of of infertility, maternal comorbidity, pregnancy and birth
delayed child-bearing, including safe, effective contraception, complications, and increased maternal and fetal morbidity
changes in societal expectations of women in post-secondary and mortality. Women who start their families in their 20s
education and the workforce, and an increased population and complete them by age 35 face significantly reduced risks.
of women 35 to 44 years of age.12
MATERNAL AGE-RELATED SUBFERTILITY
Indeed, maternal education has been identified as one of
the strongest predictors of use of contraception, timing of Advancing maternal age is associated with a longer
child-bearing, and the total number of children a woman average time to achieve conception.18 Fecundability (i.e.,
will bear. In a study by Tough et al., financial security and the probability of achieving a pregnancy in one menstrual
35 70
30 60
15 30
10 20
5 10
0 0
22 24 26 28 30 32 34 36 38 40 42 44 46
Age of Woman
Reproductive Ageing: Guidelines for First Line Physicians for Investigation of Infertility Problems
(Canadian Fertility and Andrology Society;2004). Used with permission.
cycle) begins to decline significantly in the early 30s (about In addition to ovarian factors, older women have an
age 32), and typically subfecundability becomes more increased probability of underlying medical pathology that
evident by age 37.19 adversely affects fertility, such as endometriosis, fibroids,
tubal disease, and polyps. These and other pathologies
The influence of female age on fertility has been clearly
increase the likelihood of a history of ovarian surgery,
established by a number of observational studies that have
radiation, or chemotherapy, which are threats to fertility.
consistently demonstrated a decline in pregnancy rates
Older women are more likely to be obese, to have a chronic
with advancing maternal age (Figure 1).7,20–22 Furthermore,
medical condition, and to have lifestyle issues, including
cycles that result in pregnancy are less likely to progress decreased coital frequency, all of which may affect fertility.
to live births because of higher rates of aneuploidy and
spontaneous abortion among older women.19
INCREASED USE OF
The progressive decrease in the number and quality of REPRODUCTIVE TECHNOLOGY
oocytes from fetal life until menopause is the cause of the
age-related decline in female fertility. The oocyte pool peaks Women who delay child-bearing fall into 3 broad categories:
while the female fetus is in utero, reaching approximately (1) those who conceive without intervention, (2) those who
6 to 7 million at 20 weeks of gestation.23 Subsequently, still have fertilizable oocytes and conceive through use
progressive atresia occurs so that the number of remaining of ART, and (3) those who conceive after egg donation.
oocytes is approximately 1 to 2 million at birth and Women who are < 37 years of age should be supported
250 000 at the onset of puberty. During the reproductive with expectant management for up to 6 months, after which
years, there is continued atresia, which occurs at an a referral should be offered. For women aged ≥ 37, referral
accelerated rate after the age of 37 in the average woman.18 to a specialist is recommended without waiting 6 months
The average age of menopause is 51, at which time for “spontaneous” conception, because ovarian reserve
approximately 1000 oocytes remain. can further deplete during the waiting period. For women
in categories 2 and 3, active treatment options may be
As the number of oocytes declines, so too does the quality, initiated after appropriate investigations (which are beyond
eventually reaching a threshold below which pregnancy is no the scope of this guideline); these include controlled
longer possible. The decrease in quality is primarily due to ovarian hyperstimulation with IUI, in vitro fertilization,
an increased prevalence of aneuploid oocytes.18 Autosomal and oocyte donation. While IUI and IVF can accelerate
trisomy is the most frequent finding and is thought to be the time to conception, they cannot compensate for the
associated with age-related changes in the meiotic spindle that natural decline of fertility due to age. With increasing
predispose to non-disjunction.24 Chromosomally abnormal maternal age, the chance of a woman progressing from
embryos account for the lower chances of pregnancy and the beginning of ART treatment to pregnancy and live
the higher rates of spontaneous abortion. birth using her own eggs decreases at every stage of ART
Figure 2. Percentages of transfers that resulted in live births for ART cycles
using fresh embryos from own and donor eggs, by ART patient’s age, 2006
70
60 Donor eggs
40
30
Own eggs
20
10
0
<25 26 28 30 32 34 36 38 40 42 44 46 >47
treatment (Figure 2).3 The live birth rate per cycle of IVF pregnancies. Children of a multiple birth are at increased
for example has been shown to drop from approximately risk of neonatal mortality, developmental disabilities, and
31% at age 35 to < 5% at age 42.25 significant and lifelong special needs. Since the majority
of multiple births are premature and consequently require
The only effective option for older women (> 40) with additional medical attention before discharge, the effect
decreased ovarian reserve is oocyte donation.25 In contrast on obstetric and neonatal intensive care resources and
to IVF with non-donor eggs, the success of IVF with the health care system has been dramatic. Caring for
donor eggs does not vary significantly according to the multiples rather than singletons, has been associated with
recipient’s age up to age 50, after which declining rates of significant physical, economic, and psychological stress for
implantation, clinical pregnancy, and delivery are seen.26,27 families.7,32–37
In the largest study of delivery outcomes among recipients
of donated eggs, (17 339 ART recipient cycles) no effect of Recommendations
recipient age was observed between ages 25 and 45 years; 1. Women who delay child-bearing are at increased
however, older recipient age was associated with statistically risk of infertility. Prospective parents, especially
reduced rates of implantation, clinical pregnancy, and women, should know that their fecundity and
delivery.27 This effect first appeared when women were in fertility begin to decline significantly after 32 years
their late 40s and became more pronounced at age 50.27 of age. Prospective parents should know that
Pregnancy loss rates among recipients ≥ 45 years versus assisted reproductive technologies cannot guarantee
younger recipients were also slightly higher (3%).27 Age- a live birth or completely compensate for age-
related uterine factors are proposed to play a role in these related decline in fertility. (II-2A)
outcomes, with reduced uterine blood flow affecting 2. A fertility evaluation should be initiated after
uterine receptivity to both implantation and pregnancy 6 months of unprotected intercourse without
maintenance.27–30 conception in women 35 to 37 years of age, and
earlier in women > 37 years of age. (II-2A)
The risk of multiple births is substantially elevated in
ART pregnancies. In Canada, the incidence of twin ADVANCED PATERNAL AGE
births increased by 35%, and triplets and higher order
multiple births by over 250%, between 1974 and 1990.31 While the reproductive consequences of advanced paternal
Multiple gestations are at greater risk of pregnancy loss, age (≥ 40 years of age at the time of conception)38 are not
preterm birth, and maternal complications than singleton as well-defined as the risks of advanced maternal age, the
Table 2. Risk of Down syndrome and other chromosome abnormalities in live births by maternal age
Risk Risk Risk
Maternal Total Maternal Total Maternal Total
age Down chromosome age Down chromosome age Down chromosome
(at term) syndrome abnormalities (at term) syndrome abnormalities (at term) syndrome abnormalities
25 1 in 1250 1 in 476 32 1 in 637 1 in 323 39 1 in 125 1 in 81
26 1 in 1190 1 in 476 33 1 in 535 1 in 286 40 1 in 94 1 in 63
27 1 in 1111 1 in 455 34 1 in 441 1 in 224 41 1 in 70 1 in 49
28 1 in 1031 1 in 435 35 1 in 356 1 in 179 42 1 in 52 1 in 39
29 1 in 935 1 in 417 36 1 in 281 1 in 149 43 1 in 40 1 in 31
30 1 in 840 1 in 385 37 1 in 217 1 in 123 44 1 in 30 1 in 21
31 1 in 741 1 in 385 38 1 in 166 1 in 105 ≥ 45 ≥ 1 in 24 ≥ 1 in 19
Source: Hecht CA, Hook EB.1996
Reproduced from BC Prenatal Genetic Screening Program, Provincial Health Services Authority.
spontaneously conceived pregnancies. The use of sperm ≥ 40 years of age compared with women 20 to 24 years of
from subfertile men and the ICSI procedure itself are age.52 The risks of clubfoot and diaphragmatic hernia also
thought to increase the risk of chromosomal abnormalities increased as maternal age increased. Overall, the additional
in children conceived using this method.46,47 Couples age-related risk of non-chromosomal malformations was
undergoing IVF-ICSI for male-factor infertility should approximately 1% in women ≥ 35 years of age.
receive information and be offered genetic counselling about
the increased risk of de novo chromosomal abnormalities Recommendation
(mainly sex chromosomal anomalies) associated with their 4. Women ≥ 35 years of age should be offered
condition. Prenatal diagnosis by chorionic villus sampling screening for fetal aneuploidy and undergo a
or amniocentesis should be offered to these couples if they detailed second trimester ultrasound examination to
conceive.47 look for significant fetal birth defects (particularly
Preimplantation genetic diagnosis with transfer of cardiac defects). (II-1A)
chromosomally normal embryos has been suggested as
a way to increase rates of implantation and reduce risks IMPACT OF MATERNAL AGE
of spontaneous abortion in older women and to avoid ON PREGNANCY OUTCOME
chromosomally abnormal births. However, despite the
high number of aneuploid embryos that are selected out A large body of literature exists describing the impact
using this procedure, preimplantation genetic diagnosis of advanced maternal age on pregnancy outcome. When
for aneuploidy screening selection has not been found to compared with younger women, women > 35 years
be effective in improving pregnancy outcomes for women are at increased risk of spontaneous abortion, ectopic
35 to 41 years of age, and it is currently not recommended pregnancy, placenta previa,8,52,53 pre-gestational diabetes,
solely for advanced maternal age.48,49 eclampsia,8,53,54 and pregnancy-induced hypertension,8 as
well as Caesarean section8,52,55 and induction of labour. 8,55,56
Gene Abnormalities Perinatal and neonatal death and stillbirth also increase
The effect of advanced maternal age on single gene disorders with increasing maternal age.55 Some of these obstetrical
and epigenetic events, other than in the clinical area of complications appear to be related to the aging process
assisted reproduction, is not well known. Epidemiologic alone, while others are related to coexisting factors such
studies have suggested a correlation between autism and as multiple gestation, higher parity, and underlying chronic
advanced maternal and paternal age, but larger studies are medical conditions (hypertension, diabetes mellitus and
needed to understand this association.50 other chronic diseases) that become more prevalent with
increasing age.8,52,55,56
Congenital Malformations
The risk of certain non-chromosomal birth defects has In September 2011, the Canadian Institute of Health
been shown to increase with maternal age. In a study of Information published the results of a 3-year study (2006 to
> 1 million singleton infants born after 20 weeks of 2009)57 which determined that advanced maternal age was
gestation who did not have a chromosomal abnormality, associated with an increased risk of pregnancy complications
advanced maternal age (35 to 40 years) was associated and other adverse outcomes. The study linked the birth
with an increased risk for all types of heart defects records and mothers’ hospital records of > 1 million
(OR 1.12; 95% CI 1.03 to 1.22), tricuspid atresia (OR 1.24; hospital live births. Findings included the following:
95% CI 1.02 to 1.50), right outflow tract defects
(OR 1.28; 95% CI 1.10 to 1.49), hypospadias second degree • Women > 40 were at least 3 times more likely to
or higher (OR 1.85; 95% CI 1.33 to 2.58), male genital develop gestational diabetes and placenta previa than
defects excluding hypospadias (OR 1.25; 95% CI 1.08 to younger women
1.45), and craniosynostosis (OR 1.65; 95% CI 1.18 to 2.30).51
• More than 50% of first time mothers > 40 years of
Hollier et al., prospectively catalogued malformations age were delivered by Caesarean section compared
detected at birth or in the newborn nursery over a 6-year with 25% of women 20 to 24 years
period for 102 728 pregnancies, including abortions,
stillbirths, and live births.46 After excluding infants with • The incidence of chromosome disorders was 4-fold
chromosomal abnormalities, the incidence of structurally higher, and the rates of preterm birth and SGA were
malformed infants increased progressively with maternal age. 20% and 7% higher in women ≥ 35 years than in
The OR for cardiac defects was 3.95 in infants of women women 20 to 34 years.
These data are consistent with the literature reviewed result, pregnant women ≥ 35 years of age have 2-to 3-fold
in these guidelines and provide additional support to higher rates of hospitalization, Caesarean section, and
the recommendations. They also further highlight the pregnancy-related complications than younger women.61–67
importance of increasing public awareness of this Lifestyle factors, such as smoking and alcohol use during
potentially preventable cause of maternal and neonatal pregnancy have been associated with an increased risk of
morbidity. LBW, perinatal morbidity, and stillbirth in all age groups,
The paper also suggests that the additional cost to the system and the risks are further elevated in older women.68–70
associated with in-hospital births among older women (≥ 35 Hypertension
years) compared with younger women was $ 61.1 million Although the maternal and fetal morbidity and mortality
over the 3 years. The main cost drivers of maternity care related to hypertensive disorders during pregnancy can be
are labour and delivery complications and/or interventions, reduced with careful monitoring and timely intervention,
Caesarean section, PTD, and length of hospital stay, all of these disorders are associated with an increased incidence
which were higher in older than in younger women. This
of preterm birth, SGA infants, and Caesarean section. The
costing information has important implications for policy,
incidence of chronic hypertension is 2- to 4-fold greater in
planning, and provision of care in Canada.
women ≥ 35 years of age than in women 30 to 34 years of
Spontaneous Abortion age.71 Rates of preeclampsia in the general obstetric population
Older women have a higher rate of spontaneous abortion. are 3% to 4%. They increase to 5% to 10% in women over 40,
These losses are both aneuploid and euploid, and most and up to 35 % percent in women > 50 years of age.72
occur between 6 and 14 weeks’ gestation. In a large study
from Denmark, the calculated risk of spontaneous loss in Diabetes
women > 35 years of age was more than double that in Pre-existing diabetes is associated with increased risks of
women < 30 years of age (25% vs. 12%), and was > 90% congenital anomalies and perinatal morbidity and mortality,
in women ≥ 45 years of age.58 The influence of maternal while the major complication of gestational diabetes is fetal
age on the spontaneous abortion rate was independent of macrosomia and its sequelae.73 The prevalence of diabetes
parity and history of previous abortion, although these increases with maternal age. The incidence of both pre-
characteristics were also risk factors for pregnancy loss. existing diabetes mellitus and gestational diabetes is 3- to
Chromosomally abnormal embryos (mainly autosomal 6-fold higher in women ≥ 40 years of age than in women
trisomies) account for the majority of spontaneous aged 20 to 29.53,65,73 The incidence of gestational diabetes
abortions in older women. In a recent study of over is also 3- to 4-fold higher in older women (7% to 12 % in
2000 IVF pregnancies in which fetal cardiac activity was women > 40; 20% in women > 50) compared with the 3%
documented by transvaginal ultrasound, the pregnancy loss incidence in the general obstetric population.
rate was significantly higher in older women, increasing
from 5% in women < 30 years of age to 13% and 22% in Placental Abnormalities
women aged 35 to 39, and ≥ 40 years, respectively.59,60 The prevalence of placental problems, such as placental
abruption, placenta previa, and placenta accreta, is higher
Ectopic Pregnancy among older women.12,74 Multiparity accounts for a significant
Ectopic pregnancy is a major source of maternal mortality proportion of the excess risk in these disorders. For example,
and morbidity in early pregnancy. Maternal age ≥ 35 years
there is no significant correlation between maternal age
is associated with a risk of ectopic pregnancy 4- to 8-fold
and abruption when parity and hypertension are taken into
greater than that of younger women.60 This is due to an
account. Maternal age is, however, an independent risk factor
accumulation of risk factors over time, such as multiple
sexual partners, pelvic infection, and tubal pathology. for placenta previa. Nulliparous women ≥ 40 years of age
have a 10-fold increased risk of placenta previa compared
Coexisting Medical Conditions with nulliparous women aged 20 to 29 years, although the
The 2 most common medical problems complicating absolute risk is small (0.25% vs. 0.03%).74
pregnancy are hypertension (pre-existing and gestational)
and diabetes mellitus (pre-gestational and gestational), Placenta accreta occurs in approximately 1 of 2500
and the risk of both of these complications increases deliveries, and the incidence is as high as 10% in women
with maternal age. The prevalence of medical and surgical with placenta previa. Advanced maternal age and previous
illnesses, such as cancer and cardiovascular, renal, and Caesarean section are independent risk factors for placenta
autoimmune disease, increases with advancing age. As a accreta.74
Figure 3. Hazard (risk) of stillbirth for singleton births without congenital anomalies by gestational
age, 2001–2002
<20 years
2.50 20-24 years
25-29 years
2.25
30-34 years
35-39 years
2.00
≥40 years
Hazard of fetal death per 1,000 ongoing pregnancies
1.75
1.50
1.25
1.00
0.75
0.50
0.25
0.00
20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42
Gestation (Weeks)
Reprinted from Am J Obstet Gynecol 2006;195(3), Reddy UM, Ko CW, Willinger M., Maternal age and the risk of stillbirth throughout
pregnancy in the United States, 764–70, Copyright 2006, with permission from Elsevier.
Perinatal Morbidity diseases, the rates of PTD < 32 weeks for women 20 to
Preterm and LBW infants are at increased risk of death, 29, 40 to 44, and ≥ 45 years of age were 1.01, 1.80, and
morbidity, and long-term disability. These disabilities include 2.24%, respectively.
developmental disorders (e.g., cerebral palsy and blindness),
respiratory problems, learning problems (e.g., lower IQ and Tough et al. compared birth weight and PTD rates in
lower academic achievement), and behavioural problems women aged ≥ 35 with those < 35 years.72 Among older
(e.g., attention deficit hyperactivity disorder).75–77 mothers, the risk of LBW delivery was significantly higher
in every weight category (< 2500 g, < 1500 g, < 1250 g,
Advanced maternal age has been associated with an < 1000 g) (OR 1.1 to 1.6), as was the rate of PTD (< 37,
increased risk of LBW (< 2500 g) and PTD. A large < 35, < 32, and < 30 weeks of gestation) (OR 1.1 to 1.3).
prospective study from Sweden compared birth outcomes During the study period, delayed child-bearing accounted
in healthy nulliparous women delivering singletons at 35
for 78% of the increase in the rate of LBW and 36% of
to 40 years of age with those in women who were 20 to
the increase in the rate of PTD in the population. Maternal
24 years of age.78 After adjusting for smoking, history of
age was not related to changes in SGA, suggesting that the
infertility, and other medical conditions, older maternal
age was associated with a significantly higher risk of age effect was through pregnancy complications that led to
LBW and PTD: very LBW, < 1500 g (OR 1.9); moderate PTD and LBW.
LBW, 1500 to 2499 g) (OR 1.7); very preterm birth ≤ 32 In 2005, Joseph et al.56 published the results of a large
weeks (OR 1.7); moderately preterm birth 33 to 36 weeks population-based study of all singleton births (n = 157
(OR 1.2); and SGA infant < 2 SD for GA (OR 1.7).
445) in the province of Nova Scotia during 1988 to 1995.
A subsequent prospective population-based study, also The risk of very preterm (< 32 weeks) and preterm
from Sweden, evaluated pregnancy outcome in over 32 000 (< 37 weeks) birth and SGA (3rd and 10th percentile)
women ≥ 40 years of age and confirmed an increased increased with advanced maternal age, showing a statistically
risk of PTD.51 After adjustment for confounders such as significant excess risk for women ≥ 35 compared with 20
multiple gestation, smoking, parity, and maternal medical to 24 year olds.56
Perinatal Mortality overall twin birth rate increased 70% between 1980 and
Most large studies worldwide have reported that women 2004, from 18.9 per 1000 to 32.1 per 1000 births, but it was
≥ 35 years of age are at greater risk of perinatal mortality essentially unchanged between 2004 and 2006, indicating a
than younger women, with relative risks of 1.2 to 4.5.79 possible slowing of the upward trend. The rate of triplet
This excess perinatal mortality in older women is present and higher order multiple births (quadruplets, quintuplets
even after controlling for risk factors such as hypertension, and other higher order multiples per 100 000 live births),
diabetes, antepartum bleeding, smoking, and multiple which climbed more than 400% during the 1980s and
gestation, and is mostly due to unexplained stillbirths.47,79–85 1990s, also declined (by 21%) over the same period from
the all-time high in 1998 (193.5 per 100 000 total births).87
In a study of over 5 million singleton pregnancies in the
This is likely due in part to changes in practices in IVF
United States, Reddy et al. reported the risk of stillbirth
clinics across the country.
was 3.73, 6.41, and 8.65 per 1000 ongoing pregnancies in
women < age 35, 35 to 39 years, and ≥ 40 years of age There is a high risk of an adverse outcome for multiple
respectively, with the risk increasing sharply at 40 weeks of births, and > 12% of twins and 30% of triplets are born
gestation (Figure 3).83 at < 32 weeks, compared with 2% of singletons. The
perinatal mortality rate is significantly higher among twins
Bahtiyar et al.85 analyzed > 6 million singleton pregnancies (29.8 per 1000) and triplets (59.6 per 1000) than among
in the United States to determine the influence of maternal singletons (6.0 per 1000).86,87
age on stillbirth risk. After women with congenital anomalies
and medical complications were excluded, older women Caesarean Section
were compared with a group of 25- to 29-year-old women Women ≥ 35 years of age are more likely than younger
with the lowest stillbirth risk. The odds of stillbirth at term women to be delivered by Caesarean section.25,50 The
increased significantly with advancing maternal age: 30 to Caesarean section rate in women 40 to 45 approximates
34 years, OR 1.24, (95% CI 1.13 to 1.36), 35 to 39 years, 50%, and this increases to approximately 80% in women
OR 1.45, (95% CI 1.21 to 1.74), and 40 to 44 years, OR 3.04 aged 50 to 63 years, although the rate in the general
(95% CI 1.58 to 5.86).85 Of note, the risk of stillbirth for obstetric population is about 25%.55,68,87
women 40 to 44 years of age at 39 weeks was comparable to
The reasons for the high rate of Caesarean section
the risk for women 25 to 29 years old at 42 weeks. The authors
in older women include an increased prevalence of
concluded that advanced maternal age is an independent
medical complications, fetal malposition, cephalopelvic
predictor of stillbirth and that antenatal testing in women
disproportion, induction of labour, a failed trial of labour,
≥ 40 years of age should begin at 38 weeks’ gestation. They
also suggested delivery by 39 weeks in women > 40 years of and uterine rupture.88–93
age, since the cumulative risk of stillbirth in women 40 to 44 In a study by Smith et al., a linear increase in ORs for
years of age at 39 weeks is the same as the risk in a 25- to Caesarean section with advancing maternal age (≥ 16 years)
29-year-old at 42 weeks’ gestation.85 was demonstrated (adjusted OR for a 5-year increase in age:
These data suggest that women ≥ 40 years of age should be 1.49; 95% CI 1.48 to 1.50).91 During the study period (1980
considered biologically “post-term” at 39 weeks’ gestation, to 2005), the proportion of women aged 30 to 34 years
and fetal monitoring (twice-weekly fetal assessment) increased 3-fold, the proportion of women aged 35 to 40 years
should be initiated at 38 weeks in this age group. increased 7-fold, and the proportion of women aged > 40
years increased more than 10-fold. The authors used these
Multiple Pregnancy data in a calculation model to determine the contribution
Advancing maternal age is associated with an increased of advanced maternal age to the overall Caesarean section
prevalence of twin pregnancy, related to both a higher rate rate and concluded that if the maternal age distribution had
of naturally conceived twins and a higher use of ART in stayed at the 1980 level, 38% of the additional Caesarean
older women.86 Data from the Centers for Disease Control sections would not have been performed.
and Prevention87 show that between 1980 and 2006, twin
birth rates rose 27% for mothers < age 20 years compared There is also a lower threshold among both women and
with 80% for women aged 30 to 39, and 190% for mothers physicians for performing a Caesarean section in older
aged ≥ 40 years. In 2006, 20% of births to women aged women, and maternal request for Caesarean section is more
45 to 54 years were twins, compared with about 2% of common among older women.88 There is a continuous
births to women aged 20 to 24 years. These data mainly negative relationship between age and uterine function
reflect the increased use of ART in older women.86 The throughout the child-bearing years.90
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Practice Points
• Pre-conceptional counselling is recommended for all couples when one or both partners are of advanced reproductive age.
• Pre-conceptional counselling and education at a government and public health level are required in order to inform younger women and men
about the possible consequences of delaying child-bearing before they make the decision whether or not to do so.
• When women ≥ 35 years become pregnant, an early ultrasound to document location, number, and viability of the pregnancy should be
undertaken.
• Prenatal screening for chromosome abnormalities and a second trimester ultrasound should be offered as is standard of care for all women.
Practice Points
Women ≥ 35 years should
• Have a thorough history and physical examination.
• Have prenatal bloodwork that includes baseline liver and kidney function, as well as mammogram (> 40 years) and cardiology consultation >
45 years.
• Be monitored closely for hypertensive disorders of pregnancy and preeclampsia, and all should undergo screening for gestational diabetes.
• Have careful placental localization with ultrasound at the time of the second trimester scan, to be followed up at 28 weeks’ gestation if low
lying or previa.
A third trimester scan to document fetal growth and placental location should be considered.
The cumulative risk of stillbirth in women of 40 to 44 years of age at 39 weeks’ gestation is nearly identical to the risk in those of 25 to 29 years of
age at 42 weeks’ gestation.
Therefore, a strategy of antenatal testing beginning at 38 gestational weeks with delivery by the completion of the 39th week for women > 40
years of age should be considered.
T
Committee and approved by the Executive of the Society of
risomies 21, 18, and 13 are the most frequently
Obstetricians and Gynaecologists of Canada.
occurring fetal aneuploidies, although all have been
PRINCIPAL AUTHORS
observed at term. Eighty percent of fetuses with trisomy
Lola Cartier, MSc, CCGC, Montreal QC
18 or 13 and 30% with trisomy 21 die in utero between 12
Lynn Murphy-Kaulbeck, MD, Moncton NB and 40 weeks of gestation.
GENETics COMMITTEE
R. Douglas Wilson, MD (Chair), Calgary AB Trisomy 21, or Down syndrome, is the most common
François Audibert, MD, Montreal QC viable chromosomal anomaly, with an incidence of
Jo-Ann Brock, MD, Halifax NS
1/770 live births. Individuals with trisomy 21 may have
physical abnormalities such as a cardiac defect, early onset
June Carroll, MD, Toronto ON
Alzheimer disease, and/or increased rates of leukemia, and
Lola Cartier, MSc, CCGC, Montreal QC
all will have some degree of developmental delay. The 18-
Alain Gagnon, MD, Vancouver BC
to 20-week ultrasound examination will show no abnormal
Jo-Ann Johnson, MD, Calgary AB findings in 50% of fetuses with trisomy 21.
Sylvie Langlois, MD, Vancouver BC
Lynn Murphy-Kaulbeck, MD, Moncton NB The risk of having an affected fetus increases with maternal
Nanette Okun, MD, Toronto ON
age. However, as most pregnancies occur in young women,
Melanie Pastuck, RN, Cochrane AB
most fetuses with trisomy 21 occur in younger mothers.
Disclosure statements have been received from all members of
the committee. SCREENING
This document reflects emerging clinical and scientific advances on the date issued and is subject to change. The information
should not be construed as dictating an exclusive course of treatment or procedure to be followed. Local institutions can dictate
amendments to these opinions. They should be well documented if modified at the local level. None of these contents may be
reproduced in any form without prior written permission of the SOGC.
It is important to ensure that these screening tests are •• The higher the sensitivity of the screening test, the more
offered within the context of an organized program, likely it is to identify individuals with the condition.
ensuring laboratory tests and ultrasound operators have
appropriate validation to meet quality assurance standards. •• Sensitivity is the probability that an individual who has
the condition will test positive; it is not the risk for
Screening is intended to identify women in the general trisomy 21 after a positive screening test result.
pregnancy population who are at increased risk of having
a child with an anomaly. Health care professionals should Specificity
discuss the screening tests with all pregnant women. •• Specificity refers to the probability that an individual
Information pamphlets can also be helpful in explaining the who does not have the condition will test negative.
purpose and limitations of screening tests, but health care •• The higher the specificity of the screening test, the
providers should be aware that some women may not have more likely it is to correctly identify individuals who do
sufficient English or French to understand them. Health not have the condition.
care providers must be satisfied that patients understand the
screening available and that screening is entirely voluntary, •• Specificity measures the test’s ability to identify only
and that they are making an informed decision about whether individuals who have the condition.
to have testing. The decision should be documented.
Positive Predictive Value
Screening Methods •• Positive predictive value is the probability that an
Screening can be divided into two broad categories: individual has the condition given a positive screening
result.
1. Maternal serum sampling: measure of maternal
biochemical markers in the first and/or second •• Positive predictive value is determined/assessed on
trimester of pregnancy. This can be done with or the basis of test sensitivity and specificity, and the
without ultrasound screening. prevalence of the condition.
•• Counsel your patient that a positive screen will baby and that her child could still be born with an
mean that her risk is above a pre-determined cut- aneuploidy or another genetic or developmental
off (set by regional programs), not that her fetus is condition not detected through screening. Inform your
necessarily affected. Some patients may have difficulty patient that if the screening test is positive she is eligible
understanding the difference between a screening test for diagnostic testing.
and a diagnostic test.
–– This testing would be done by amniocentesis, which
•• Counsel your patient that her risk is specific and carries a procedural risk of 1/100 to 1/175 for loss
personalized. For example, a risk of 1:100 means that of the pregnancy or by chorionic villus sampling,
for one woman carrying an affected fetus, there are 99 which carries a procedural risk of 1/100 for loss of
women carrying a fetus that is not affected. Prenatal the pregnancy.2,3
aneuploidy screening using age and nuchal translucency
measurement in the first trimester is appropriate –– Ensure your patient is aware that diagnostic testing
for screening in multiple gestations. For multiple is entirely voluntary.
gestations, it is important to check with the screening –– Ensure your patient knows that she has the option
centre close to you, as availability of maternal serum of continuing or terminating the pregnancy if
screening varies from centre to centre. the test shows that her fetus has an aneuploidy or
•• When screening is offered, discuss options and another significant chromosomal anomaly. It is a
the invasive prenatal testing that may need to be common misconception that screening is offered
considered after screening. only to patients who would terminate a pregnancy
if an anomaly were found. It is important to tell
•• Tell your patient that if screening is negative, no patients who may choose to continue the pregnancy
further testing is indicated other than routine second that their fetus will be given the best care possible.
trimester ultrasound. Remind her that there is a risk to In the case of chromosomal anomalies that have an
invasive procedures. Inform the patient that negative extremely poor prognosis, this may include referring
screening does not guarantee the birth of a healthy the patient to a neonatologist to discuss palliative
care. For the care of a fetus with Down syndrome Positive Screen
this should include A positive screen for trisomy 21 is anxiety provoking and
needs to be discussed with the patient in an environment
○ Ensuring that the fetus receives necessary testing that allows proper explanation and discussion of options.
and monitoring, such as fetal echocardiogram Allow sufficient time for the woman and her partner to ask
and increased surveillance. questions.
○ Informing the patient of the support available The first point of counselling should be that there are a
for parents choosing to raise a child with Down number of reasons why a screen may be positive. A positive
syndrome, including the Canadian Down screen is not a diagnosis of a chromosome anomaly: it is a
Syndrome Society. positive screen as established by a predetermined cut-off,
and further investigation and possibly invasive testing will
–– Be aware that undecided patients may pursue or be required. It may be necessary to discuss with the patient
decline screening and testing at any point in the the false-positive rate of the tests used.
screening process. Counselling should include a discussion of risk. Patients
often find it easier to understand risks when they are
POST-SCREENING COUNSELLING explained as percentages. For example, a risk of 1/100 is
a 1% risk of the fetus having the condition whereas a risk
A screening program should include a reliable laboratory of 1/200 is a risk of 0.5%. Stated another way, a risk of
that can provide a report of results within a working week. 1/200 means that there is a 99.5% chance that the fetus
Screening results should be reported to the patient as does not have trisomy 21 or that if 200 women have this
soon as possible after results have been reported to the same result, 1 of them will have a fetus with trisomy 21 and
practitioner. Ideally, screening results should be discussed 199 will not. An explanation of a negative screen and the
in person. percentage of risk may also be helpful.
Counselling should include the information that if invasive •• A positive screen does not warrant further genetic
testing does reveal a fetus has trisomy 21 or any other testing other than amniocentesis or chorionic villus
chromosomal anomaly, pregnancy termination may be one sampling unless there are other indications for more in-
option. It should be made clear to the patient that the offer depth testing on the basis of previous pregnancy history
of invasive testing is not contingent upon her terminating or family history.
the pregnancy if her baby has a chromosomal anomaly. It
•• Chromosome analysis is specific; no other genetic testing
is important for women to understand that if a diagnosis
is done unless indicated.
of Down syndrome or other anomaly is made, further
consultation and support will be available to help her decide •• The pregnancy loss risk associated with amniocentesis is
whether to continue or terminate the pregnancy. Women 1:175 to 1:100.
and families may require more information about what
trisomy 21 is and about the possible health implications •• If she has a fetus diagnosed with a chromosomal
and long-term outcomes for people with this condition. anomaly, she has the option of continuing or
A request for consultation at a genetics service can be terminating the pregnancy.
helpful. Also, diagnosing trisomy 21 or other non-lethal •• If she chooses to continue her pregnancy, special tests,
chromosomal anomaly prenatally ensures that the fetus such as a fetal echocardiogram, will be performed as
receives the most appropriate prenatal and neonatal care, necessary, and routine obstetrical care will be adjusted
including testing and monitoring that may be necessary, because there is an increased risk for adverse outcome
such as fetal echocardiogram and increased antenatal and with a trisomy 21 affected pregnancy.
intrapartum surveillance.
•• This is a difficult and very personal decision and she will
Women should be made aware that although invasive be supported whatever she chooses to do. Acknowledge
testing is being offered, it is not mandatory following a that a positive screen is anxiety provoking and support
positive screen. They should be reassured that they will still the woman in her decision making.
receive the best possible care they if they choose not to
have diagnostic testing. BIBLIOGRAPHY
TIPS FOR COUNSELLING PATIENTS Chitayat D, Langlois S, Wilson RD; SOGC Genetics Committee; CCMG
WITH A POSITIVE SCREENING RESULT Prenatal Diagnosis Committee. Prenatal screening for fetal aneuploidy in
singleton pregnancies. SOGC Clinical Practice Guideline no. 261, July 2011.
J Obstet Gynaecol Can 2011;33:736–50.
Tell your patient that
Audibert F, Gagnon A. SOGC Genetics Committee; CCMG Prenatal Diagnosis
•• A positive screen does not mean her baby is affected. Committee. Prenatal screening for fetal aneuploidy in twin pregnancies.
SOGC Clinical Practice Guideline no. 262, July 2011. J Obstet Gynaecol Can
2011;33:754–67.
•• Her risk for having an affected fetus has been adjusted
from her age-only related risk and that her risk is higher Chodirker BN, Cadrin C, Davies GAL, Summers AM, Wilson RD, Winsor EJT,
et al.; SOGC Genetics Committee; CCMG Prenatal Diagnosis Committee.
than the pre-determined cut-off, which results in a Canadian guidelines for prenatal diagnosis: techniques of prenatal diagnosis.
positive screen. SOGC Clinical Practice Guideline, no. 105, July 2001. J Obstet Gynaecol Can
2001;23:616–24.
•• False positives do occur. Summers AM, Langlois S, Wyatt P, Wilson RD; SOGC Genetics Committee;
CCMG Committee on Prenatal Diagnosis; SOGC Diagnostic Imaging
•• She is eligible for diagnostic invasive testing, but this is Committee. Prenatal screening for fetal aneuploidy. Joint SOGC-CCMG
her choice, and she can decline the procedure. Clinical Practice Guideline no. 187, February 2007. J Obstet Gynaecol Can
2007;29:146–61.
•• If she has diagnostic testing following a positive Van den Hof MC, Wilson DR; SOGC Diagnostic Imaging Committee;
screening result, it will diagnose Down syndrome and SOGC Genetics Committee. Fetal soft markers in obstetric ultrasound.
SOGC Clinical Practice Guideline no. 162, June 2005. J Obstet Gynaecol Can
that other chromosome anomalies may be diagnosed. 2005;27:592–612.
•• The identification of a chromosomal anomaly Wilson RD, Langlois S, Johnson J; SOGC Genetics Committee; CCMG
Prenatal Diagnosis Committee. Mid-trimester amniocentesis fetal loss rate.
may require further investigation of the parents’ SOGC Committee Opinion, No. 194, July 2007. J Obstet Gynaecol Can
chromosomes before a firm diagnosis can be made. 2007;29:586–90.
This document reflects emerging clinical and scientific advances on the date issued and is subject to change. The information
should not be construed as dictating an exclusive course of treatment or procedure to be followed. Local institutions can dictate
amendments to these opinions. They should be well documented if modified at the local level. None of these contents may be
reproduced in any form without prior written permission of the SOGC.
Table 1. Key to evidence statements and grading of recommendations, using the ranking of the Canadian Task Force
on Preventive Health Care
Quality of evidence assessment* Classification of recommendations†
I: Evidence obtained from at least one properly randomized A. There is good evidence to recommend the clinical preventive action
controlled trial
II-1: Evidence from well-designed controlled trials without B. There is fair evidence to recommend the clinical preventive action
randomization
II-2: Evidence from well-designed cohort (prospective or C. The existing evidence is conflicting and does not allow to make a
retrospective) or case–control studies, preferably from recommendation for or against use of the clinical preventive action;
more than one centre or research group however, other factors may influence decision-making
II-3: Evidence obtained from comparisons between times or D. There is fair evidence to recommend against the clinical preventive action
places with or without the intervention. Dramatic results in
uncontrolled experiments (such as the results of treatment with E. There is good evidence to recommend against the clinical preventive
penicillin in the 1940s) could also be included in this category action
III: Opinions of respected authorities, based on clinical experience, L. There is insufficient evidence (in quantity or quality) to make
descriptive studies, or reports of expert committees a recommendation; however, other factors may influence
decision-making
*The quality of evidence reported in these guidelines has been adapted from The Evaluation of Evidence criteria described in the Canadian Task Force on
Preventive Health Care.82
†Recommendations included in these guidelines have been adapted from the Classification of Recommendations criteria described in the Canadian Task Force
on Preventive Health Care.82
04. Trospium, immediate and extended release, may be offered as adverse effects. It is, however, associated with improved
treatment for overactive bladder syndrome as it is associated subjective outcomes. (I-A) To decrease side effects, switching
with significant clinical improvement at 12 weeks. (I-A) Trospium to a lower dose or using an extended release formulation or a
is an adequate anticholinergic choice for overactive bladder transdermal delivery mechanism should be considered. (I-A)
syndrome patients with pre-existing cognitive impairment (II-B)
09. Education on treatment efficacy, realistic expectations,
and for overactive bladder syndrome patients taking concurrent
and length of treatment should be offered to patients upon
CYP450 inhibitors. (III-B)
initiation of anticholinergic therapy, as continuation rates for
05. Solifenacin may be offered as treatment for overactive bladder anticholinergic therapy are low. (III-B)
syndrome, as it is associated with significant objective clinical
10. Oral or transdermal estrogen supplementation should not be
improvement at 12 weeks. (I-A) Solifenacin may be an
recommended for treatment of overactive bladder syndrome as
adequate anticholinergic choice for elderly overactive bladder
its effects are comparable to placebo. (I-E) Vaginal estrogen can
syndrome patients or patients with pre-existing cognitive
be suggested for subjective improvements in overactive bladder
dysfunction. (I-B)
syndrome symptoms. (III-B)
06. Darifenacin may be offered as treatment for overactive bladder
11. Intravesical botulinum toxin injection and sacral nerve
syndrome, as it is associated with significant objective clinical
and posterior tibial nerve stimulation are clinically effective
improvement at 12 weeks. (I-A) Darifenacin is an adequate
options for patients with overactive bladder syndrome
anticholinergic choice for overactive bladder syndrome patients
unresponsive to conservative options, anticholinergics, or
with pre-existing cardiac concerns or cognitive dysfunction. (I-B)
vaginal estrogen. (I-A)
07. Overactive bladder syndrome patients should be offered a
choice between bladder training, functional electric stimulation,
and anticholinergic therapy, as there is no difference in cure INTRODUCTION
O
rates. Combination therapy does not have a clear advantage
over one therapy alone. (I-A) veractive bladder syndrome comprises symptoms
08. The choice of anticholinergic therapy should be guided by related to abnormal urinary bladder storage. It is
individual patient comorbidities, as objective efficacy of defined as urinary urgency, usually accompanied by frequency
anticholinergic drugs is similar. (I-A) Dose escalation does not
and nocturia, with or without urgency urinary incontinence,
improve objective parameters and causes more anticholinergic
in the absence of urinary tract infection or other obvious
pathology.1 It can be associated with detrusor overactivity
ABBREVIATIONS on urodynamic studies.1 The prevalence of OAB is reported
CNS central nervous system at 11.8% to 17% in women and significantly increases with
CYP450 cytochrome p450 age.2–5 Most women with OAB (96%) report leakage of
ER extended release urine with an overall prevalence of urgency incontinence of
IR immediate release 12%.2 OAB has a greater impact on quality of life than stress
OAB overactive bladder syndrome urinary incontinence6,7 and is responsible for several medical
XR extended release comorbidities. Up to 67% of women with OAB report a
negative effect on daily living.4 Significant comorbidities (Detrol or Detrol LA), trospium chloride (Trosec IR and
associated with OAB include depression,8 falls and fractures,9 XR), solifenacin (VESIcare), darifenacin (Enablex), and
and increased admissions to hospitals and nursing homes.10 fesoterodine (Toviaz).
hydrophilic properties.18 Smaller molecules, neutral in charge Oxybutynin (Ditropan, Ditropan XL)
and lipophilic, are more likely to cross the blood–brain barrier Oxybutynin oral preparations have established clinical
and cause central nervous system side effects. These can be efficacy when compared with placebo.20 Oxybutynin IR is
immediate (confusion, delirium, headache, blurred vision, also more cost-effective.21 However, it is associated with
dizziness and hallucinations) or delayed (memory loss).19,20 significant anticholinergic adverse events in up to 80% of
Specific patient factors such as increased permeability of the patients22 and with discontinuation rates of up to 33%.23
blood–brain barrier in older adults, and comorbid diseases Shortly after treatment initiation, oxybutynin may cause
predisposing to adverse CNS effects, as well as the intake of cognitive impairment, and long-term trials of cognitive
other drugs with anticholinergic effects may render individual function while on this anticholinergic are lacking.24–26
patients particularly susceptible to antimuscarinic adverse
CNS events.20 Non-selective molecules with some M2 Two transdermal preparations, a patch (Oxytrol) and a gel
receptor affinity may lead to an increase in heart rate.19 Some (Gelnique 10%), have been developed to improve on the side-
molecules acting on potassium channels within the heart effect profile of oral oxybutynin.27–29 Both preparations have
may cause small increases in the QT interval.19 Tolterodine superior clinical efficacy to placebo, with fewer side effects
and solifenacin have led to small increases in the QT interval; than oral oxybutynin.27–30 Application site reactions (pruritus
on the other hand, darifenacin, fesoterodine, and trospium and erythema) are more common with the transdermal
have not.19 These small recordable changes in heart function preparations (14% for the patch and 5% for the gel).27–29
do not seem to cause clinically adverse outcomes.19 Most
anticholinergics are metabolized by the CYP450 system in Recommendation
the liver with the exception of trospium, which undergoes 2. Oral oxybutynin, immediate and extended release,
minimal hepatic metabolism. Therefore, other medications as well as transdermal oxybutynin, may be offered
or dietary components affecting the CYP450 mechanism as treatment for overactive bladder syndrome, as
may interact with anticholinergic drugs.19 they are associated with significant objective
clinical improvement at 12 weeks. (I-A)
Clinical Efficacy: Anticholinergics Oxybutynin immediate release has superior cost-
Compared With Placebo effectiveness but more side effects than other
A Cochrane Review of 5 of 6 anticholinergic drugs currently anticholinergics. (I-A) Adverse events associated
on the market concluded that anticholinergics lead to with transdermal oxybutynin are fewer than with oral
statistically significant improvements in OAB symptoms.20 oxybutynin. (I-A)
The number needed to treat for clinical improvement or
cure was 7. On average, patients on anticholinergics had 4 Tolterodine (Detrol, Detrol LA,)
fewer leakage episodes and 5 fewer voids per week when Both IR and ER tolterodine are associated with
compared with patients on placebo. As anticholinergics are improvements in health-related quality of life and objective
not curative in most instances, clinical success depends on OAB parameters in the results of several randomized
ongoing use; thus a recommendation was made for future placebo controlled trials with 12-week duration of follow-
trials to include long-term, patient-centred outcomes. up.30–32 Greater effects are noted in patients with moderate
to severe OAB symptoms at baseline.33 Dry mouth is a The incidence of constipation is 7% to 8%.43 Solifenacin
common side effect that occurs in one third of patients does not appear to affect cognitive function, as shown in a
on tolterodine,34 but it does not increase the number of pilot randomized trial of healthy elderly volunteers.50
treatment discontinuations.35 Tolterodine does not seem to
cause any cardiovascular or CNS adverse effects.35 Recommendation
5. Solifenacin may be offered as treatment for
Recommendation overactive bladder syndrome, as it is associated
3. Tolterodine, immediate and extended release, may with significant objective clinical improvement at
be offered as treatment for overactive bladder 12 weeks. (I-A) Solifenacin may be an adequate
syndrome, as it is associated with significant anticholinergic choice for elderly overactive bladder
objective clinical improvement at 12 weeks. (I-A) syndrome patients or patients with pre-existing
cognitive dysfunction. (I-B)
Trospium (Trosec IR and XR)
Trospium, both IR and XR, was associated with improved Darifenacin (Enablex)
OAB symptoms in reports from several randomized The safety and clinical efficacy of darifenacin compared with
placebo controlled trials with 12-week duration of follow- placebo is shown by three randomized double-blind placebo-
up.20,36,37 Adverse effects are more common than with controlled multicentre phase III trials with 12-week duration
placebo but do not affect discontinuation rates. The XR of follow-up.51–53 The most common side effects are dry
formulation significantly improves OAB symptoms and mouth and constipation, but discontinuations are rare (0.6%
condition-specific quality of life.38,39 to 2.1% vs. 0.3% in the placebo group).54 Specifically, women
over 65 have a significant improvement in condition-specific
Trospium has low penetration into the CNS and thus fewer quality of life compared with those on placebo.55
CNS side effects.36,37,40 In addition, it offers benefits for the
bladder and does not affect cognitive function even when Because of its M3 receptor selectivity, darifenacin does not
used concurrently with a cholinesterase inhibitor for the affect heart rate.56 Moreover, darifenacin does not affect
treatment of Alzheimer’s disease.41 Trospium undergoes memory or other cognitive functions.57
minimal hepatic metabolism. Therefore patients who
Recommendation
receive concurrent medications that inhibit the CYP450
hepatic metabolism are good candidates for therapy with 6. Darifenacin may be offered as treatment for
trospium.40 Trospium is primarily excreted intact in the urine; overactive bladder syndrome, as it is associated
however, medications competing for renal elimination, such with significant objective clinical improvement
as digoxin, have not shown significant interactions.42 at 12 weeks. (I-A) Darifenacin is an adequate
anticholinergic choice for overactive bladder
Recommendation syndrome patients with pre-existing cardiac
4. Trospium, immediate and extended release, may concerns or cognitive dysfunction. (I-B)
be offered as treatment for overactive bladder
syndrome as it is associated with significant clinical Clinical Efficacy: Anticholinergics
improvement at 12 weeks. (I-A) Trospium is an Compared With Non-Drug Therapies
adequate anticholinergic choice for overactive A Cochrane Review compared the effects of various
bladder syndrome patients with pre-existing anticholinergic drugs with those of non-pharmacologic
cognitive impairment (II-B) and for overactive therapies, consisting mainly of bladder training, pelvic
bladder syndrome patients taking concurrent floor muscle exercises, and electrostimulation.58 Thirteen
CYP450 inhibitors. (III-B) trials, with a total of 1770 participants, were analyzed.
Follow-up was up to 24 weeks after initiation of treatment.
Solifenacin (VESIcare) Tolterodine and oxybutynin had similar cure rates and
Several double-blind placebo-controlled randomized subjective improvement for OAB when compared with
controlled trials with 12-week follow-up support the bladder training alone. Objective improvement was better in
safety and clinical efficacy of solifenacin compared with the anticholinergic group than in the bladder training group.
placebo.43–46 Solifenacin also significantly improves the quality When oxybutynin was compared with a more comprehensive
of life in patients with OAB symptoms up to 1 year.46–48 behavioural intervention consisting of pelvic floor muscle
At 1 year, discontinuation rates are low.46 The incidence of exercises, biofeedback, and bladder training, the overall
dry mouth in patients on solifenacin is significantly lower effect subjectively and objectively favoured the behavioural
than in patients on oxybutynin (35 vs. 83%, P < 0. 001).49 intervention (RR 2.42; 95% CI 1.00 to 5.85).
Oxybutynin or trospium compared with functional effects in terms of objective measures of improvement.
electrostimulation yielded no statistically significant Extended release preparations of both oxybutynin and
difference in cure rates or subjective or objective measures tolterodine, including the extended release oxybutynin
of improvement.58,59 patch, were associated with less dry mouth than immediate
release preparations.61
Oxybutynin or tolterodine and bladder training compared
with bladder training alone showed a subjective advantage Several other comparative randomized controlled trials
of the combination treatment. Tolterodine and bladder comparing anticholinergics have been published since the
training or pelvic floor muscle exercises compared with most recent Cochrane Review update. One trial compared
tolterodine alone did not show any statistically significant solifenacin 5 mg and 10 mg daily with tolterodine extended
difference in subjective improvement.58 release 4 mg daily.62 Subjective cure was significantly more
common in the solifenacin group (59% vs. 49%, P = 0.006).
Since the most recent Cochrane update of this review, Objective measures of improvement and withdrawals
an additional randomized controlled trial was published because of side effects were not significantly different
comparing darifenacin with darifenacin and a behavioural between the groups. Another trial comparing darifenacin
modification program consisting of patient education 15 mg and 30 mg daily with oxybutynin 5 mg 3 times daily
given in a primary physician’s office (timed voiding, dietary showed comparable efficacy and improved tolerability
modifications, Kegel exercises).60 There were no significant of darifenacin.63 The other trials compared fesoterodine
differences between treatment groups in efficacy or health- 4 mg and 8 mg daily with tolterodine extended release 4
related quality of life variables.60 mg daily.64,65 Fesoterodine was superior to tolterodine on
several objective measures of improvement such as urge
Recommendation
incontinence episodes, severe urgency with incontinence,
7. Overactive bladder syndrome patients should mean voided volume, and number of continent days
be offered a choice between bladder training, per week. Diary dry rates were significantly better in the
functional electric stimulation, and anticholinergic fesoterodine group than in the tolterodine group (64% vs.
therapy, as there is no difference in cure rates. 57%; P = 0.015).64,65
Combination therapy does not have a clear
advantage over one therapy alone. (I-A) Recommendation
be monitored for drug interactions or polypharmacy of voids amongst women treated with local estrogen.72 A small
drugs with anticholinergic effect (e.g., antidepressants, trial showed modest benefit from vaginal estriol ovules in
antipsychotics, anxiolytics), as the overall anticholinergic prevention of symptoms of urgency and frequency after
load is associated with confusion, falls, and fractures.66 tension-free vaginal tape placement.72
Anticholinergics are category C drugs in pregnancy, to be
used only if the benefits clearly outweigh the risk. Oral estriol or a subcutaneous estradiol implant were not
significantly better than placebo for OAB symptoms.73,74
Adherence and Continuation Rates
Patient adherence to a prescribed anticholinergic treatment Recommendation
plan has been shown to be low. In a study of oxybutynin 10. Oral or transdermal estrogen supplementation
and tolterodine ER and IR prescriptions in 1117 adult should not be recommended for treatment of
patients, only 13.2% persisted with treatment for at least overactive bladder syndrome as its effects are
1 year, with a median time to discontinuation of 31 days.67 comparable to placebo. (I-E) Vaginal estrogen
Adherence was significantly better but still suboptimal for can be suggested for subjective improvements in
the extended release formulations.67 In another trial of overactive bladder syndrome symptoms. (III-B)
patients on immediate release oxybutynin, at 2-year follow-
up, 67% of respondents had stopped drug therapy, most PHARMACOTHERAPEUTIC
within 2 months of initiation.68 Reasons for discontinuation INTERVENTIONS: OTHER DRUG OPTIONS
were adverse effects (24%) and symptomatic improvement
or cure (53%).68 White ethnicity, previous hospitalization There is a long list of medications with anticholinergic
length, starting with tolterodine or oxybutynin extended- effects, few of which have been studied as treatment
release, and previous use of topical drugs or antipsychotics specifically for overactive bladder. Tricyclic antidepressants
were associated with increased adherence to anticholinergics such as imipramine and amitryptyline have been used for
during a 6-month period.69 Previous depression or overactive bladder. With a dual activity as an anticholinergic
urinary tract infection diagnosis and polypharmacy (to relax the detrusor) and an alpha agonist (to contract
significantly increased the odds of early discontinuation.69 the urethral sphincter), they have adequate biologic
Patient counselling about efficacy of treatment, realistic plausibility for the treatment of urinary urge incontinence.
expectations, and length of treatment was recommended to Unfortunately, their anticholinergic activity is weaker
improve long-term adherence to anticholinergic therapy.70 than that of modern bladder anticholinergics.75 There
is minimal evidence to support the use of imipramine
Recommendation for urinary incontinence in the elderly.75 There are no
9. Education on treatment efficacy, realistic randomized controlled trials to compare tricyclics with
expectations, and length of treatment should be modern anticholinergics used to treat overactive bladder.75
offered to patients upon initiation of anticholinergic
therapy, as continuation rates for anticholinergic
REFRACTORY OAB
therapy are low. (III-B)
Options for OAB symptoms resistant to anticholinergic
PHARMACOTHERAPEUTIC therapy are limited and costly. These options include but
INTERVENTIONS: ESTROGENS are not limited to local bladder therapies such as botulinum
toxin type A detrusor injections, central neurostimulation,
The lower urinary tract (urethra and trigone) derives from and peripheral neurostimulation (e.g., tibial nerve).
the cloaca, which shares an embryological origin with the
lower vaginal canal. Therefore, the trigonal squamous Botulinum toxin for OAB (100 to 300 units injected into the
epithelium differs from the transitional epithelium and detrusor muscle) has been shown, in several randomized
undergoes squamous metaplasia. The urethral mucosa is controlled trials, to reduce number of voids and urgency
continuous with the squamous epithelium of the vestibule. and incontinence episodes per day and to improve
Both areas are hormonally sensitive.71 A Cochrane Review maximum cystometric capacity and condition-specific
examined the effect of estrogen supplementation on urinary quality of life.76 Generally, around 80% of patients treated
incontinence in postmenopausal women.72 Heterogeneous with botulinum toxin experienced improvement, with
evidence derived from trials investigating other conditions some patients requiring reinjection for recurrence of OAB
such as stress urinary incontinence and using greater than symptoms.76 Overall patient satisfaction with botulinum
low dose vaginal estrogen of different types, showed that toxin was high.76 The most common complication related
there were 1 to 2 fewer voids in 24 hours and nocturnal to intravesical botulinum toxin was transient urinary
retention. Up to 43% of patients needed clean intermittent 2. Lawrence JM, Lukacz ES, Nager CW, Hsu J-W, Luber KM. Prevalence and
co-occurrence of pelvic floor disorders in community-dwelling women.
self-catheterization, and the incidence of retention was Obstet Gynecol 2008;111(3):678–85.
reported to be dose-dependent.76
3. Irwin DE, Milsom I, Hunskaar S, Reilly K, Kopp Z, Herschorn S, et al.
Population-based survey of urinary incontinence, overactive bladder, and
There are also data from randomized controlled trials to other lower urinary tract symptoms in five countries: results of the EPIC
support the use of sacral nerve stimulation. Good clinical study. Eur Urol 2006;50(6):1306–15.
response, with improvement on several objective measures 4. Milsom I, Abrams P, Cardozo L, Roberts RG, Thuroff J, Wein AJ.
of OAB severity, was reported in 64% 88% of patients, How widespread are the symptoms of overactive bladder and how
and clinical success seems to persist in the long term. are they managed? A population-based prevalence study. Br J Urol Int
2001;87(9):760–6.
Subjective outcomes are also favourable.76 However, lead
migration, pain, and infection result in a 33% reoperation 5. Stewart WF, Van Rooyen JB, Cundiff GW, Abrams P, Herzog AR,
Corey R, et al. Prevalence and burden of overactive bladder in the
rate to treat these complications.77 United States. World J Urol 2003; 20(6):327–36.
Another form of neurostimulation, tibial nerve 6. Bartoli S, Aguzzi G, Tarricone R. Impact on quality of life of urinary
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stimulation, is gaining acceptance. Two double-blind Urology 2010;75(3):491–500.
randomized sham-controlled trials showed significant 7. Kelleher CJ, Cardozo LD, Khullar V, Salvatore S. A new questionnaire
objective and subjective improvements in OAB when to assess the quality of life of urinary incontinent women. Br J Obstet
compared with placebo.78,79 Treatment benefit was Gynaecol 1997;104(12):1374–9.
sustained at 12 months.80 A randomized controlled trial 8. Zorn BH, Montgomery H, Pieper K, Gray M, Steers WD. Urinary
of tibial nerve stimulation versus tolterodine showed incontinence and depression. J Urol 1999;162:82–4.
similar objective improvement and superior subjective 9. Brown JS, Vittinghoff E, Wyman JF, Stone KL, Nevitt MC, Ensrud KE,
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Study of Osteoporotic Fractures Research Group: Collaboration. J Am
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10. Thom DH, Haan MN, Van Den Eeden SK. Medically recognized urinary
11. Intravesical botulinum toxin injection and sacral
incontinence and risks of hospitalization, nursing home admission and
nerve and posterior tibial nerve stimulation mortality. Age Ageing 1997;26(5)367–74.
are clinically effective options for patients with 11. Robert M, Ross S; SOGC Urogynaecology Committee. Conservative
overactive bladder syndrome unresponsive to management of urinary incontinence. J Obstet Gynaecol Can
conservative options, anticholinergics, or vaginal 2006;28(12):1113–8.
estrogen. (I-A) 12. Andersson KE, Chapple C, Wein A. The basis for drug treatment of the
overactive bladder. World J Urol 2001;19:294–8.
13. Braverman AS, Ruggieri MR, Pontari MA. The M2 muscarinic receptor
CONCLUSION subtype mediates cholinergic bladder contractions in patients with
neurogenic bladder dysfunction. J Urol 2001;165(Suppl):36.
Overactive bladder syndrome is a common bothersome
14. Andersson KE. Antimuscarinics for treatment of overactive bladder.
condition. Options for therapy include behavioural, Lancet Neurol 2004;3:46–53.
pharmacologic, and surgical interventions. Pharmacotherapy
15. Jensen D. Uninhibited neurogenic bladder treated with prazosin. Scand J
for OAB includes anticholinergics and local vaginal estrogen. Urol Nephrol 1981;15:229–33.
Anticholinergics have been shown to offer some symptomatic 16. Tyagi S, Tyagi P, Van-le S, Yoshimura N, Chancellor MB, de Miguel F.
improvement over placebo, with a strong placebo therapeutic Qualitative and quantitative expression profile of muscarinic receptors in
effect noted. Anticholinergics are similar to behavioural human urothelium and detrusor. J Urol 2006;176(4 Pt 1):1673–8.
therapy and electrical stimulation in clinical efficacy. They 17. Giglio D, Tobin G. Muscarinic receptor subtypes in the lower urinary
have significant side effects that need to be carefully tract. Pharmacology 2009;83(5):259–69.
considered along with individual patient comorbidities. 18. Robinson D, Cardozo L. New drug treatments for urinary incontinence.
Newer formulations, particularly those administered Maturitas 2010;65:340–7.
transdermally, have been shown to have a better side-effect 19. Ellsworth P, Kirshenbaum E. Update on the pharmacologic management
of overactive bladder: the present and the future. Urol Nursing
profile. Long-term effects of anticholinergics and patient- 2010;30(1):29–53.
centred outcomes should be the focus of future studies.
20. Nabi G, Cody JD, Ellis G, Hay-Smith J, Herbison GP. Anticholinergic
drugs versus placebo for overactive bladder syndrome in adults.
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68. Salvatore S, Khullar V, Cardozo L, Milani R, Athanasiou S, Kelleher C. 82. Woolf SH, Battista RN, Angerson GM, Logan AG, Eel W. Canadian
Long-term prospective randomized study comparing two different Task Force on Preventive Health Care. New grades for
regimens of oxybutynin as a treatment for detrusor overactivity. recommendations from the Canadian Task Force on Preventive Health
Eur J Obstet Gynecol Reprod Biol 2005;119:237–41. Care. CMAJ 2003;169:207–8.
Alon Shrim, MD, Montreal QC Methods: The maternal and fetal outcomes in varicella zoster
infection were reviewed, as well as the benefit of the different
Gideon Koren, MD, Toronto ON treatment modalities in altering maternal and fetal sequelae.
Mark H. Yudin, MD, Toronto ON Evidence: Medline was searched for articles and clinical guidelines
Dan Farine, MD, Toronto ON published in English between January 1970 and November 2010.
MATERNAL FETAL MEDICINE COMMITTEE Values: The quality of evidence was rated using the criteria described
in the Report of the Canadian Task Force on Preventive Health
Robert Gagnon, MD (Co-Chair), Verdun QC
Care. Recommendations for practice were ranked according to
Lynda Hudon, MD (Co-Chair), Montreal QC the method described in that report (Table).
Melanie Basso, RN, Vancouver BC
Recommendations
Hayley Bos, MD, London ON
1. Varicella immunization is recommended for all non-immune
Joan Crane, MD, St. John’s NL women as part of pre-pregnancy and postpartum care. (II-3B)
Gregory Davies, MD, Kingston ON 2. Varicella vaccination should not be administered in pregnancy.
Marie-France Delisle, MD, Vancouver BC However, termination of pregnancy should not be advised
because of inadvertent vaccination during pregnancy. (II-3D)
Savas Menticoglou, MD, Winnipeg MB
William Mundle, MD, Windsor ON 3. The antenatal varicella immunity status of all pregnant women
should be documented by history of previous infection, varicella
Annie Ouellet, MD, Sherbrooke QC vaccination, or varicella zoster immunoglobulin G serology. (III-C)
Tracy Pressey, MD, Vancouver BC 4. All non-immune pregnant women should be informed of the risk
Christy Pylypjuk, MD, Saskatoon SK of varicella infection to themselves and their fetuses. They should
be instructed to seek medical help following any contact with a
Anne Roggensack, MD, Calgary AB
person who may have been contagious. (II-3B)
Frank Sanderson, MD, Saint John NB
5. In the case of a possible exposure to varicella in a pregnant
Vyta Senikas, MD, Ottawa ON woman with unknown immune status, serum testing should be
Disclosure statements have been received from all members of performed. If the serum results are negative or unavailable within
the committee. 96 hours from exposure, varicella zoster immunoglobulin should
be administered. (III-C)
6. Women who develop varicella infection in pregnancy need to be
made aware of the potential adverse maternal and fetal sequelae,
J Obstet Gynaecol Can 2012;34(3):287–292 the risk of transmission to the fetus, and the options available for
prenatal diagnosis. (II-3C)
7. Detailed ultrasound and appropriate follow-up is recommended for
Key Words: Chickenpox, varicella, diagnosis, pregnancy all women who develop varicella in pregnancy to screen for fetal
consequences of infection. (III-B)
This document reflects emerging clinical and scientific advances on the date issued and is subject to change. The information
should not be construed as dictating an exclusive course of treatment or procedure to be followed. Local institutions can dictate
amendments to these opinions. They should be well documented if modified at the local level. None of these contents may be
reproduced in any form without prior written permission of the SOGC.
8. Women with significant (e.g., pneumonitis) varicella infection POSSIBLE SEQUELAE OF VARICELLA
in pregnancy should be treated with oral antiviral agents (e.g., INFECTION IN PREGNANCY: MATERNAL
acyclovir 800 mg 5 times daily). In cases of progression to varicella
pneumonitis, maternal admission to hospital should be seriously
considered. Intravenous acyclovir can be considered for severe
The mortality rate for chickenpox increases with age. Thus in
complications in pregnancy (oral forms have poor bioavailability). early adulthood it is associated with mortality rate that is 15
The dose is usually 10 to 15 mg/kg of BW or 500 mg/m2 IV every times higher than the childhood mortality rate.6 According
8 h for 5 to 10 days for varicella pneumonitis, and it should be
started within 24 to 72 h of the onset of rash. (III-C)
to the Centers for Disease Control and Prevention, the case
fatality rate increases from 2.7 per 100 000 persons aged
9. Neonatal health care providers should be informed of peripartum
varicella exposure in order to optimize early neonatal care with 15 to 19 years, to 25.2 per 100 000 persons aged 30 to 39.7
varicella zoster immunoglobulin and immunization. (III-C) Varicella Mortality rates are higher in pregnant women than in non-
zoster immunoglobulin should be administered to neonates pregnant adults, and death usually results from respiratory
whenever the onset of maternal disease is between 5 days before
and 2 days after delivery. (III-C)
disease. It is estimated that 5% to 10% of pregnant women
with varicella infection develop pneumonitis.8 Risk factors
for the development of varicella pneumonitis in pregnancy
INTRODUCTION include cigarette smoking and > 100 skin lesions.9 Most of
V
the complications of adult chickenpox, such as pneumonitis
aricella zoster virus is a highly contagious DNA virus
occur on day 4 or later.10 In one prospective study,11 12 out
of the herpes family. It is transmitted by respiratory
droplets and by direct personal contact with vesicular fluid. 21 pregnant patients who were diagnosed with varicella
The primary infection is characterized by fever, malaise, and pneumonitis and treated with acyclovir in the second or third
a pruritic rash that develops into crops of maculopapules, trimester of pregnancy required intubation and mechanical
which become vesicular and crust over before healing. The ventilation. The strongest correlate with maternal death was
incubation period lasts 10 to 21 days, and the disease is onset of disease in the third trimester, with no deaths among
infectious 48 hours before the rash appears and continues the second-trimester subjects.
to be infectious until the vesicles crust over.1
POSSIBLE SEQUELAE OF VARICELLA
Chickenpox (or primary VZV infection) is a common INFECTION IN PREGNANCY: FETAL
childhood disease. In this population it usually causes
mild infection, and mortality rates in the United States Fetal effects of varicella can manifest as either congenital
are as low as 0.4 per 1 million population.2 It is estimated varicella syndrome (embryopathy) or neonatal varicella (no
that > 90% of the antenatal population are seropositive embryopathy, but chickenpox infection within the first 10
for VZV IgG antibody3 and therefore almost invariably days of life). Since the first described cases in 1947, the
immune to infection. Because of this high frequency overall number of neonates that have been reported to
of immunity, contact with chickenpox among pregnant have congenital varicella syndrome is as low as 41 per year
women rarely results in primary maternal VZV infection, in the United States, 4 per year in Canada, and 7 per year
which is estimated to complicate up to 2 to 3 of every 1000 in the United Kingdom and Germany.12,13 Maternal varicella
pregnancies.4 Therefore in Canada, with about 350 000 during the first half of pregnancy may cause congenital
pregnancies per year,5 700 to 1050 cases of chickenpox in malformations or deformations by transplacental infection.
pregnant women are expected to occur annually. Some of these manifestations include chorioretinitis, cerebral
cortical atrophy, hydronephrosis, and cutaneous and bony
Following the primary infection, the virus may remain leg defects, often presenting as a partial limb reduction.14
dormant in sensory nerve root ganglia but can be Rates of infection are approximately 0.4% before 13 weeks
reactivated to cause a vesicular erythematous skin rash and 2% between 13 and 20 weeks.4,15 In a systematic review
in a dermatomal distribution known as herpes zoster or by the Motherisk program (Canadian data), with all available
shingles. As shingles in pregnancy is not associated with cohort studies, the risk was 0.7% in the first trimester, 2%
viremia and does not appear to cause fetal sequelae, it is in the second, and 0% in the third trimester.16 In most of
not discussed in these guidelines. the cohorts, there was no clinical evidence of congenital
varicella embryopathy after 20 weeks’ gestation.17 Yet, Tan
and Koren reviewed the literature and identified 9 case
reports of fetal varicella syndrome occurring in weeks 21 to
ABBREVIATIONS 28 of gestation.12 In 8 out of these 9 cases there were serious
IgG immunoglobulin G adverse effects in the central nervous system, an incidence
VZIG varicella zoster immunoglobulin as high as the rates of central nervous system involvement
VZV varicella zoster virus in earlier trimesters.13
Key to evidence statements and grading of recommendations, using the ranking of the Canadian Task Force on
Preventive Health Care
Quality of evidence assessment* Classification of recommendations†
I: Evidence obtained from at least one properly randomized A. There is good evidence to recommend the clinical preventive action
controlled trial
II-1: Evidence from well-designed controlled trials without B. There is fair evidence to recommend the clinical preventive action
randomization
II-2: Evidence from well–designed cohort (prospective or C. The existing evidence is conflicting and does not allow to make a
retrospective) or case–control studies, preferably from recommendation for or against use of the clinical preventive action;
more than one centre or research group however, other factors may influence decision-making
II-3: Evidence obtained from comparisons between times or D. There is fair evidence to recommend against the clinical preventive action
places with or without the intervention. Dramatic results in
uncontrolled experiments (such as the results of treatment with E. There is good evidence to recommend against the clinical preventive
penicillin in the 1940s) could also be included in this category action
III: Opinions of respected authorities, based on clinical experience, L. There is insufficient evidence (in quantity or quality) to make
descriptive studies, or reports of expert committees a recommendation; however, other factors may influence
decision-making
*The quality of evidence reported in these guidelines has been adapted from The Evaluation of Evidence criteria described in the Canadian Task Force on
Preventive Health Care.36
†Recommendations included in these guidelines have been adapted from the Classification of Recommendations criteria described in the Canadian Task Force
on Preventive Health Care.36
Persons with continuous exposure to household members The value of VZIG in averting fetal varicella is primarily
who have varicella are at greatest risk for infection.7 in its ability to prevent maternal infection, but it may have
some effect in decreasing the risk of fetal infection even
Vaccine in those women who go on to develop varicella. In a
An attenuated live-virus vaccine (Varivax) was approved study of 1373 women who had varicella during pregnancy,
for use in 1995.26 Two doses, given 4 to 8 weeks apart, 9 cases of congenital varicella syndrome were identified, all
are recommended for adolescents ≥ 13 years of age occurring after maternal varicella during the first 20 weeks
and for adults with no history of varicella. This results of gestation. However, no cases of congenital varicella
in 97% seroconversion.27 The vaccine, however, is not syndrome were reported in any of the 97 women in whom
recommended for pregnant women or for those within a varicella occurred after post-exposure prophylaxis with
month of pregnancy. Nevertheless, a pregnancy registry anti-VZIG.4,30,31
listing 362 vaccine-exposed pregnancies has reported no
case of congenital varicella syndrome or other congenital The most frequent adverse reaction following VZIG
malformation.28 Therefore, termination of pregnancy administration is local discomfort at the injection site, with
should not be recommended because of inadvertent pain, redness, and swelling occurring in approximately
vaccination during pregnancy. 1% of people.32 Less frequent adverse events include
gastrointestinal symptoms, malaise, headache, rash, and
Varicella Zoster Immunoglobulin respiratory symptoms, which occur in approximately 0.2%
As prevention is the most effective strategy for the of recipients. Severe events, such as angioneurotic edema
reduction of maternal complications associated with and anaphylactic shock, are rare (occurring in < 0.1% of
varicella infections, immunoglobulin prophylaxis is an recipients). Obstetrical care providers need to be aware
important objective for susceptible, exposed pregnant of the availability of testing and therapy in their local
women.23 environment. As both testing and therapy are time sensitive,
it is important to know the turnover time for the test in local
VZIG has been shown to lower varicella infection rates laboratories, and how to arrange VZIG administration. As
if administered within 72 to 96 hours after exposure.4 VZIG is a blood product, patient consent is required.
The effectiveness of VZIG when given beyond the
96 hours after initial exposure has not been evaluated.
TREATMENT
Protection is estimated to extend through 3 weeks, which
corresponds with the half-life of the immunoglobulin. Acyclovir
The principal indication for the use of VZIG in Acyclovir is a synthetic nucleoside analogue that inhibits
pregnant women is reduction of the maternal risks of replication of human herpes viruses, including VZV.
varicella infection-related complications associated with Acyclovir crosses the placenta readily and can be found
adult disease.4 If the mother does not acquire varicella in fetal tissues, cord blood as well as in the amniotic fluid.
infection, this eliminates risk for the neonate, but this It may inhibit viral replication during maternal viremia,
has not been studied as an end point because of the limiting transplacental passage of the virus.33,34
low frequency of cases. The dose is 125 units per
10 kg given intramuscularly, with a maximum dose of Safety
625 units. VZIG is recommended7 for all susceptible Data published since acyclovir became available do not
pregnant women.29 indicate increased adverse effects related to its use in
pregnancy.35
To determine if an exposed pregnant woman is susceptible,
a history of varicella infection should be taken, and, if this Efficacy
is positive, the woman can be assumed to be immune. If When compared with placebo, oral acyclovir reduces the
the history is negative and no varicella antibody testing was duration of fever and symptoms of varicella infection in
done in early pregnancy, antibody testing with enzyme- immunocompromised children and immunocompetent
linked immunosorbent assay or fluorescent antibody to adults if commenced within 24 hours of development
membrane antigen should, if possible, precede use of of the rash.24,25 In instances of serious, viral-mediated
VZIG. However, in settings where pregnant women might complications (e.g., pneumonitis), the American Academy
be tested too late and/or results may not be available of Pediatrics states that intravenous acyclovir should be
quickly, using VZIG before antibody testing results are considered.7 It is not given as prophylaxis to exposed
available might be practical. women during pregnancy.
Recommendations REFERENCES
1. Varicella immunization is recommended for all 1. Tyring SK. Natural history of varicella zoster virus. Semin Dermatol
non-immune women as part of pre-pregnancy and 1992;11:211–7.
postpartum care. (II-3B) 2. Nguyen HQ, Jumaan AO, Seward JF. Decline in mortality due to varicella
2. Varicella vaccination should not be administered after implementation of varicella vaccination in the United States. N Engl
in pregnancy. However, termination of pregnancy J Med 2005; 352:450–8.
should not be advised because of inadvertent 3. Glantz JC, Mushlin AI. Cost-effectiveness of routine antenatal varicella
vaccination during pregnancy. (II-3D) screening. Obstet Gynecol 1998;91:519–28.
3. The antenatal varicella immunity status of all 4. Enders G, Miller E, Cradock-Watson J, Bolley I, Ridehalgh M.
Consequences of varicella and herpes zoster in pregnancy: prospective
pregnant women should be documented by history study of 1739 cases. Lancet 1994; 343(8912):1548–51.
of previous infection, varicella vaccination, or
5. Statistics Canada. Births and birth rate, by province and territory.
varicella zoster immunoglobulin G serology. (III-C) Available at: http://www40.statcan.gc.ca/101/cst01/dem004a-eng.htm.
4. All non-immune pregnant women should be Accessed December 28, 2011.
informed of the risk of varicella infection to 6. Rouse DJ, Gardner M, Allen SJ, Goldenberg RL. Management of the
themselves and their fetuses. They should be presumed susceptible varicella (chickenpox)-exposed gravida: a cost-
instructed to seek medical help following any effectiveness/cost-benefit analysis. Obstet Gynecol 1996;87:932–6.
contact with a person who may have been 7. Centers for Disease Control and Prevention. Prevention of varicella:
contagious. (II-3B) recommendations of the Advisory Committee on Immunization Practices
(ACIP). MMWR Recomm Rep 1996;45(RR-11):1–36.
5. In the case of a possible exposure to varicella in
8. Paryani SG, Arvin AM. Intrauterine infection with varicella-zoster virus
a pregnant woman with unknown immune status, after maternal varicella. N Engl J Med 1986;314(24):1542–6.
serum testing should be performed. If the serum
9. Harger JH, Ernest JM, Thurnau GR, Moawad A, Momirova V, Landon
results are negative or unavailable within 96 hours MB, et al. Risk factors and outcome of varicella-zoster virus pneumonia in
from exposure, varicella zoster immunoglobulin pregnant women. J Infect Dis 2002;185:422–7.
should be administered. (III-C) 10. Grose C. Varicella infection during pregnancy. Herpes 1999;6:33–7.
6. Women who develop varicella infection in 11. Smego RA Jr, Asperilla MO. Use of acyclovir for varicella pneumonia
pregnancy need to be made aware of the potential during pregnancy. Obstet Gynecol 1991;78:1112–6.
adverse maternal and fetal sequelae, the risk of 12. Tan MP, Koren G. Chickenpox in pregnancy: revisited. Reprod Toxicol
transmission to the fetus, and the options available 2006;21:410–20.
for prenatal diagnosis. (II-3C) 13. Koren G. Congenital varicella syndrome in the third trimester. Lancet
7. Detailed ultrasound and appropriate follow-up is 2005;366(9497):1591–2.
recommended to all women who develop varicella 14. Andrews JI. Diagnosis of fetal infections. Curr Opin Obstet Gynecol
in pregnancy to screen for fetal consequences for 2004;16:163–6.
infection. (III-B) 15. Pastuszak AL, Levy M, Schick B, Zuber C, Feldkamp M, Gladstone J,
8. Women with significant (e.g., pneumonitis) varicella et al. Outcome after maternal varicella infection in the first 20 weeks of
pregnancy. N Engl J Med 1994;330(13):901–5.
infection in pregnancy should be treated with oral
antiviral agents (e.g., acyclovir 800 mg 5 times daily). 16. Koren G. Risk of varicella infection during late pregnancy. Can Fam
Physician 2003;49:1445–6.
In cases of progression to varicella pneumonitis,
maternal admission to hospital should be seriously 17. Chiang CP, Chiu CH, Huang YC, Lin TY. Two cases of disseminated
cutaneous herpes zoster in infants after intrauterine exposure to varicella-
considered. Intravenous acyclovir can be considered zoster virus. Pediatr Infect Dis J 1995;14:395–7.
for severe complications in pregnancy (oral forms
18. Degani S. Sonographic findings in fetal viral infections: a systematic
have poor bioavailability). The dose is usually 10 to review. Obstet Gynecol Surv 2006;61:329–36.
15 mg/kg of BW or 500 mg/m2 IV every 8 h for 5 to 19. Skibsted L. Abnormal fetal ultrasound findings after maternal chickenpox
10 days for varicella pneumonitis, and it should be infection [article in Danish]. Ugeskr Laeger 2000;162(18):2546–9.
started within 24 to 72 h of the onset of rash. (III-C) 20. Pretorius DH, Hayward I, Jones KL, Stamm E. Sonographic evaluation
9. Neonatal health care providers should be informed of pregnancies with maternal varicella infection. J Ultrasound Med
of peripartum varicella exposure in order to 1992;11:459–63.
optimize early neonatal care with varicella zoster 21. Meyers JD. Congenital varicella in term infants: risk reconsidered. J Infect
immunoglobulin and immunization. (III-C) Varicella Dis 1974;129:215–7.
zoster immunoglobulin should be administered to 22. Royal College of Obstetricians and Gynecologists. Chickenpox in
neonates whenever the onset of maternal disease is pregnancy. RCOG Green-top Guideline no. 13, September 2007.
Available at: http://www.rcog.org.uk/womens-health/guidelines.
between 5 days before and 2 days after delivery. (III-C) Accessed December 26, 2011.
23. Maupin RT. Obstetric infectious disease emergencies. Clin Obstet Gynecol with polymerase chain reaction of amniotic fluid in 107 cases. Am J
2002;45(2):393–404. Obstet Gynecol 1997;177:894–8.
24. Wallace MR, Bowler WA, Murray NB, Brodine SK, Oldfield EC III. 31. Enders G Miller E. Varicella and herpes zoster in pregnancy and the
Treatment of adult varicella with oral acyclovir. A randomized, placebo- newborn. In: Arvin AM, Gershon AA, eds. Varicella-zoster virus:
controlled trial. Ann Intern Med 1992;117:358–63. virology and clinical management. Cambridge: Cambridge University
25. Nyerges G, Meszner Z, Gyarmati E, Kerpel-Fronius S. Acyclovir prevents Press;2000:317–47.
dissemination of varicella in immunocompromised children. J Infect Dis
32. Koren G, Money D, Boucher M, Aoki F, Petric M, Innocencion G, et
1988;157:309–13.
al. Serum concentrations, efficacy, and safety of a new, intravenously
26. ACOG practice bulletin. Perinatal viral and parasitic infections. Number administered varicella zoster immune globulin in pregnant women. J Clin
20, September 2000. (Replaces educational bulletin number 177, February Pharmacol 2002;42:267–74.
1993). American College of Obstetrics and Gynecologists. Int J Gynaecol
Obstet 2002;76:95–107. 33. Henderson GI, Hu ZQ, Johnson RF, Perez AB, Yang Y, Schenker
S. Acyclovir transport by the human placenta. J Lab Clin Med
27. ACOG Committee Opinion. Immunization during pregnancy. Obstet 1992;120:885–92.
Gynecol 2003;101:207–12.
34. Landsberger EJ, Hager WD, Grossman JH III. Successful management
28. Shields KE, Galil K, Seward J, Sharrar RG, Cordero JF, Slater E. Varicella
of varicella pneumonia complicating pregnancy. A report of three cases. J
vaccine exposure during pregnancy: data from the first 5 years of the
Reprod Med 1986;31:311–4.
pregnancy registry. Obstet Gynecol 2001;98:14–9.
29. Gruslin A, Steben M, Halperin S, Money DM, Yudin MH; SOGC 35. Spangler JG, Kirk JK, Knudson MP. Uses and safety of acyclovir in
Infectious Diseases Committee. Immunization in pregnancy. SOGC pregnancy. J Fam Pract 1994;38:186–91
Clinical Practice Guideline no. 236, November 2009. J Obstet Gynaecol
36. Woolf SH, Battista RN, Angerson GM, Logan AG, Eel W. Canadian
Can 2009;31:1085–101.
Task Force on Preventive Health Care. New grades for recommendations
30. Mouly F, Mirlesse V, Meritet JF, Rozenberg F, Poissonier MH, from the Canadian Task Force on Preventive Health Care. CMAJ
Lebon P, et al. Prenatal diagnosis of fetal varicella-zoster virus infection 2003;169:207–8.
This document reflects emerging clinical and scientific advances on the date issued, and is subject to change. The information
should not be construed as dictating an exclusive course of treatment or procedure to be followed. Local institutions can dictate
amendments to these opinions. They should be well documented if modified at the local level. None of these contents may be
reproduced in any form without prior written permission of the SOGC.
3. Ovarian reserve testing may be considered for women ≥ 35 first-time mothers who are > 30 years of age increased
years of age or for women < 35 years of age with risk factors
for decreased ovarian reserve, such as a single ovary, previous
steadily from 11% in 1987 to 26% in 2005.1 During the
ovarian surgery, poor response to follicle-stimulating hormone, same period, there was a significant rise in first-time
previous exposure to chemotherapy or radiation, or unexplained mothers > 35 years of age, from 4% in 1987 to 11% in
infertility. (III-B) 2005, and a corresponding decrease in the group who are
4. Ovarian reserve testing prior to assisted reproductive technology < 25 years.1 Similar trends have been seen in other parts
treatment may be used for counselling but has a poor predictive
value for non-pregnancy and should be used to exclude women
of the world.3
from treatment only if levels are significantly abnormal. (II-2A)
Ovarian function declines as women approach their later
5. Pregnancy rates for controlled ovarian hyperstimulation are low for
women > 40 years of age. Women > 40 years should consider IVF
reproductive years until menopause, and increasing age is
if they do not conceive within 1 to 2 cycles of controlled ovarian associated with lowered fecundity and infertility. Women
hyperstimulation. (II-2B) experience a decline in natural fertility that begins in the
6. The only effective treatment for ovarian aging is oocyte donation. mid-30s, and they will often reach sterility many years
A woman with decreased ovarian reserve should be offered before the complete cessation of menses.4 Although ART
oocyte donation as an option, as pregnancy rates associated with
this treatment are significantly higher than those associated with
may aid some couples who present with fertility issues, it
controlled ovarian hyperstimulation or in vitro fertilization with a will not compensate for the decline in natural fertility that
woman’s own eggs. (II-2B) occurs with delayed child-bearing.5 ART is also invasive,
7. Women should be informed that the risk of spontaneous expensive, and not covered by most provincial health
pregnancy loss and chromosomal abnormalities increases with plans for this indication. In addition, complications of
age. Women should be counselled about and offered appropriate
prenatal screening once pregnancy is established. (II-2A)
pregnancy increase for both the mother and the offspring
with advanced maternal age.6
8. Pre-conception counselling regarding the risks of pregnancy
with advanced maternal age, promotion of optimal health and
weight, and screening for concurrent medical conditions such as
Women and their health care providers should be aware of
hypertension and diabetes should be considered for women the effects of age on reproductive potential.
> age 40. (III-B)
9. Advanced paternal age appears to be associated with an OVARIAN AGING
increased risk of spontaneous abortion and increased frequency
of some autosomal dominant conditions, autism spectrum
disorders, and schizophrenia. Men > age 40 and their partners
The loss of oocytes from the ovaries is a continual process
should be counselled about these potential risks when they are that begins in utero. The ovaries in the female fetus contain
seeking pregnancy, although the risks remain small. (II-2C) 6 to 7 million oocytes at approximately 20 weeks’ gestation.
At birth, 1 to 2 million oocytes remain, and only 300 000 to
J Obstet Gynaecol Can 2011;33(11):1165–1175
500 000 are present at the onset of puberty.7 This process
continues until menopause, when only a few hundred
oocytes remain.8 During the reproductive years, 400 to
INTRODUCTION 500 oocytes will be ovulated; the majority of oocytes are
S
lost through apoptosis, or programmed cell death. Earlier
ocial trends in Canada and around the world have led
research suggested that a more accelerated process of
to women delaying child-bearing into their 30s and, in
decline occurs in the last 10 to 15 years before menopause,
some cases, their 40s. The average age of women giving
beginning around the age of 38 years.9 However, more
birth has increased from 27 to 29.3 over the last 20 years.1
recent data suggest that oocyte loss occurs at the same
In 2006, the fertility rate for women aged 30 to 34 was the
rate through the reproductive lifetime, with the slope of
highest of any age group, surpassing that of the previous
decline remaining fairly consistent until menopause.10
highest group, women aged 25 to 29.2 The percentage of
As the ovarian follicular pool decreases, women will
experience infertility, sterility, cycle shortening, menstrual
irregularity, and finally menopause (Figure 1).10 In
ABBREVIATIONS
Western countries, the mean age of menopause is 51, and
AFC antral follicle count
1% will experience premature ovarian failure before age
AMH antimüllerian hormone
40.11 There appears to be a fixed interval through these
ART assisted reproductive technology
stages of ovarian function. Women who experience an
COH controlled ovarian hyperstimulation earlier menopause will have an earlier loss of fertility12;
FSH follicle-stimulating hormone therefore, approximately 10% of women will have
IUI intrauterine insemination decreased ovarian function in their early to mid-30s.13
Key to evidence statements and grading of recommendations, using the ranking of the Canadian Task Force on
Preventive Health Care
Quality of evidence assessment* Classification of recommendations†
I: Evidence obtained from at least one properly randomized A. There is good evidence to recommend the clinical preventive action
controlled trial
II-1: Evidence from well-designed controlled trials without B. There is fair evidence to recommend the clinical preventive action
randomization
II-2: Evidence from well–designed cohort (prospective or C. The existing evidence is conflicting and does not allow to make a
retrospective) or case–control studies, preferably from recommendation for or against use of the clinical preventive action;
more than one centre or research group however, other factors may influence decision-making
II-3: Evidence obtained from comparisons between times or D. There is fair evidence to recommend against the clinical preventive action
places with or without the intervention. Dramatic results in
uncontrolled experiments (such as the results of treatment with E. There is good evidence to recommend against the clinical preventive
penicillin in the 1940s) could also be included in this category action
III: Opinions of respected authorities, based on clinical experience, L. There is insufficient evidence (in quantity or quality) to make
descriptive studies, or reports of expert committees a recommendation; however, other factors may influence
decision-making
*The quality of evidence reported in these guidelines has been adapted from The Evaluation of Evidence criteria described in the Canadian Task Force on
Preventive Health Care.95
†Recommendations included in these guidelines have been adapted from the Classification of Recommendations criteria described in the Canadian Task Force
on Preventive Health Care.95
Child-bearing usually ends 10 years before menopause, 30.12 Markers of ovarian reserve may be useful to predict
and this time period is consistent regardless of the age an earlier menopause or menopause transition for women
of menopause.14,15 Cycle irregularity will usually occur who do not yet have clinical signs or symptoms of ovarian
6 to 7 years before menopause,14 regardless of the age aging but who may already have decreased fertility.
of menopause, coinciding with approximately 10 000
follicles remaining.8 When menopause occurs, there are often a few hundred
follicles remaining. There is still ovarian activity and
As the total number of remaining follicles decreases, there is estrogen production during the first year after menopause.14
a corresponding decrease in the available follicular cohort. Although the mean age of menopause in Western countries
As a consequence of a smaller follicular cohort, there is a is 51, there is a significant range, from 40 to 60 years of
decline in inhibin-B, which is produced by the granulosa age. Sibling and twin studies have shown a significant
cells in the early follicular phase.16 There is an inverse genetic component to the age of menopause.19 Smoking
correlation between FSH and inhibin-B, which is likely due has been associated with a decreased follicular pool and
to a loss in negative feedback; the rise in FSH during the earlier menopause.14
early follicular phase is one of the earliest signs of ovarian
aging.17 This initial stage may not be clinically apparent, Oocyte quality also appears to be affected by age. Studies on
or present only as infertility, because ovarian hormone IVF oocytes have shown that the rate of oocyte aneuploidy
production remains constant, and women continue to increases with age.20 The rate is low in women < age 35
ovulate and have regular cycles. The first clinical signs of (10%), but increases to 30% at the age of 40, to 40% at the
ovarian aging may be shortening of menstrual cycles, which age of 43, and to 100% in women > age 45.20 These were
is due to a shorter follicular phase. More rapid follicular gonadotropin stimulated oocytes, and therefore may not
development leads to earlier recruitment of a dominant reflect the rate of aneuploidy in oocytes from a dominant
follicle.18 As this transition continues, women will notice follicle recruited during a non-stimulated or natural cycle;
that their cycles lengthen and become more irregular as however, this correlates with the increase in chromosomally
they enter the menopause transition and ovulation is less abnormal pregnancies and spontaneous abortions with age.
consistent.8 Once women start to notice clinical signs of The decline in oocyte quality may be in the formation and
ovarian aging such as cycle shortening or irregularity, their function of the spindles, which appear to be more diffuse.21
fertility may already be greatly diminished. One review This may result in chromosomes being less tightly arranged
article found that women who were sterile after age 35 had and may therefore lead to meiotic errors. Data also suggest
already demonstrated lower fecundity before the age of that the selection process may deteriorate with age, allowing
Number of follicles
fertility Menopause
105 Irregular
cycles
100
104
75
103 50
25
10 2
0 10 20 30 40 50 60
Age (years)
Figure 2. Natural fertility by age poorer quality oocytes the opportunity to develop into the
dominant follicle, or to be selected during an IVF cycle.
600 The selection of the available follicular cohort may be less
discriminating, allowing follicles to mature which should
500 have undergone atresia.22 Other proposed mechanisms
include cumulative damage to the oocyte with age and
400 decreasing quality of granulosa cells.23
Rate per 1000 wives
300
FEMALE ADVANCED REPRODUCTIVE
AGE AND INFERTILITY
200
Population studies have consistently noted that the decline
100 in birth rates begins when women reach the age of 35
(Figure 2).4 On average, women will deliver their last child at
0
20 25 30 35 40 45 50 age 41, with a range of 23 to 51.24 Natural population studies
Age of wife may not take into account non-reproductive factors, such as
The ten populations (in descending order at age 20 to 24) are desire to prevent pregnancy, coital frequency, aging partners,
Hutterites, marriages 1921–30 ( ); Geneva bourgeoisie, husbands and other medical conditions that may affect live birth rates.
born 1600–49 ( ); Canada, marriages 1700–30 ( ); Normandy,
marriages 1760–90 ( ); Hutterites, marriages before 1921 ( ); In addition, conditions such as fibroids and endometriosis
Tunis, marriages of Europeans 1840-59 ( ); Normandy, marriages are more frequent in later reproductive years. These studies
1674–1742 ( ); Norway, marriages 1874–76 ( ); Iran, village therefore may not offer a full reflection of a woman’s
marriages, 1940–50 ( ); Geneva bourgeoisie, husbands born
before 1600 ( ). maximum fertility potential. Natural fertility studies of
patients who had recently discontinued contraception have
Menken J, Trussell J, Larsen U. Age and infertility. Science 1986;
shown that younger women have a higher fecundity rate,
233(4771):1389–1394.4 Reprinted with permission from AAAS. and therefore conceive sooner than older women.25
The incidence of infertility and sterility increases as the Age-associated infertility appears to be primarily related
age of the female partner increases. Although the true to ovarian aging and the diminishing ovarian follicle
incidence of sterility is difficult to determine because of count. The uterine endometrium has the capacity to
non-reproductive factors such as voluntary childlessness, maintain a pregnancy throughout a woman’s reproductive
population studies can provide some insight. In one study years and, with newer technologies such as egg donation,
of 7 populations in which contraception use is rare and in even beyond the natural reproductive years. Age does
which there is a low incidence of premarital conceptions, not affect the endometrium’s response to hormonal
the percentage of women who remained childless was stimulation.34 Pregnancy rates from donor egg cycles
higher in those who married later.4 Only 6% of women also confirm that the age of the recipient does not affect
who married in their early 20s remained childless, while pregnancy rates.33
64% of women who were not married until their 40s
remained childless. Studies in the Hutterite population Recommendations
confirm an increase in infertility with age, escalating from 1. Women in their 20s and 30s should be counselled
11% after age 34 to 33% by age 40 and to 87% by age 45.26 about the age-related risk of infertility when other
reproductive health issues, such as sexual health
Although social changes have led to women delaying or contraception, are addressed as part of their
their reproduction, concomitant advances in reproductive primary well-woman care. Reproductive-age women
sciences have led to increased options for fertility treatment should be aware that natural fertility and assisted
and ART. Unfortunately, this may give women false optimism reproductive technology success (except with egg
that they can delay pregnancy while pursing their education donation) is significantly lower for women in their
and careers with the expectation that ART will help them to late 30s and 40s. (II-2A)
conceive if they have difficulty conceiving later. However, 2. Because of the decline in fertility and the increased
success rates for ART treatment for women using their own time to conception that occurs after the age of
eggs are directly linked to the age of the women,27 and many 35, women > 35 years of age should be referred
women may not realize that older women are successful for infertility work-up after 6 months of trying to
using ART to achieve pregnancy later in life only with donor conceive. (III-B)
eggs. Computer models have demonstrated that the current
ART success rates cannot compensate for the loss in natural ASSESSMENT OF OVARIAN AGING
fertility that occurs in a women who has delayed child-
bearing from 30 to 35 years of age.5 Ovarian aging will have begun before women notice any
clinical changes to their menstrual cycles; therefore, they are
Studies on donor insemination confirm an age-related often unaware that they may be at greater risk of infertility.
decline in pregnancy rates. Most of the earlier donor Ovarian reserve testing has been explored as a means to
insemination studies were performed in couples with severe determine a woman’s fertility potential and provide an
male factor infertility. These studies are thought to be a assessment of ovarian aging. Although chronological age
good reflection of female fertility because non-reproductive alone serves as a good marker of ovarian reserve, some
factors such as coital frequency are removed. A negative women will experience a decline in their natural fertility
effect on pregnancy rates is seen in women > age 30, and sooner than average, while some older women may
is even more pronounced for women > age 35.28–31 One maintain above average ovarian function. Identification of
study of almost 3000 cycles showed cumulative pregnancy these two groups, in which ovarian reserve is inconsistent
rates of 62% for women < 30 years of age, and 44% for with chronological age, may be useful for counselling and
women aged ≥ 30 years after 12 cycles. Younger women planning treatment.35
often conceive quickly, and more cycles of treatment were
often needed for women aged ≥ 35 years.29,31 Many tests of ovarian reserve have been tried. However,
testing has mainly been performed on infertile populations,
Pregnancy rates collected from ART treatment cycles show with little data on the distribution in the normal fertile
the significant impact of female age on success. The 2007 population. Ovarian reserve testing cannot be used to
Canadian live birth rate after IVF was 37.4% for women predict infertility or time to infertility; therefore, its
< 35 years of age, 26.5% for women aged 35 to 39 years, and application to the general population as a screening tool
11.4% for women aged ≥ 40 years.32 ART reports from the is untested. Most studies have used these tests to try to
United States show similar age-related success rates.33 Age is predict a woman’s ovarian response and prognosis with
the most significant prognostic factor for IVF success. fertility treatment and IVF. Overall, markers of ovarian
reserve have been shown to correlate with egg quantity and The clomiphene challenge test is performed by
response to ovarian stimulation, but not with egg quality. administering 100 mg of clomiphene daily from day 5 to day
9 of the cycle. FSH is measured on day 3 and on day 10. If
The most commonly used test of ovarian reserve is the an adequate response to clomiphene is generated, the rise
cycle day 3 or basal FSH level. An elevated basal FSH level in FSH will be suppressed by the release of estradiol and
(> 14 IU/L) is the first sign of ovarian aging that can be inhibin-B by developing follicles. Systematic reviews have
detected in women, and usually occurs in women aged not shown a benefit to the clomiphene challenge test over
35 to 40.36 Physiologically, the follicular pool is reduced basal FSH or AFC.35 Inhibin-B and basal estradiol have not
to approximately 10% of the levels present at puberty.9 been shown to be more useful predictors of poor response
The rise in basal FSH is due to a loss in ovarian feedback or pregnancy than basal FSH.35 However, basal estradiol
(inhibin-A and B) as the available follicular cohort levels are often screened in conjunction with FSH and can
diminishes. Basal FSH levels are easy to obtain, and no confirm correct timing in the menstrual cycle. An elevated
special skills are required to perform the test or interpret estradiol level may also falsely suppress FSH levels.
the results; therefore, it is easily accessible. However, basal
FSH levels have been shown to be predictive for poor Ovarian reserve tests performed before ART treatment is
response to ovarian stimulation and for non-pregnancy begun may be useful for counselling, but they have a poor
only when the levels are extremely elevated.35 Although predictive power for pregnancy.12 AFC and AMH have been
a high threshold may improve the usefulness of the test shown to be useful for prediction of poor ovarian response
in predicting a poorer prognosis, only a small number with IVF.12 Although significantly abnormal results are
of women will have abnormal tests at this threshold. In associated with lower pregnancy rates (< 5%), only about
addition, it has been associated with a false positive rate of 3% of women will have results in this category.35 In general,
5%.35 Elevated basal FSH levels are also less predictive of ovarian reserve testing is useful for predicting egg quantity
pregnancy for women < age 35.37,38 and ovarian response to stimulation but has little value for
the prediction of egg quality. Therefore, although these tests
An ovarian antral follicle count can be performed early may be useful for counselling before ART treatment, testing
in the menstrual cycle. Antral follicles between 2 mm and should not be used to exclude women from ART treatment,
10 mm can be identified by transvaginal ultrasound and abnormal tests do not preclude the possibility of
performed by an experienced sonographer using a vaginal pregnancy. These test results can be used to obtain individual
transducer with a minimum frequency of 7 MHz.39 Antral prognostic information to help to guide the choice of
follicles are sensitive to FSH and are considered to be treatment and best use of resources.
representative of the available follicle pool. The number
of antral follicles seems to correlate with the number Ovarian reserve testing may be considered in women > age
of primordial follicles in the ovary, with a decline in 35 to screen for age-related infertility, although its results
primordial follicles being reflected in a lower number of may be useful only for counselling and to aid women in
antral follicles.24 In later reproductive years, the proportion their decision-making process. Testing in women < 35
of antral follicles to total follicles may increase as the years may be considered if they have risk factors for
ovary allows a higher proportion of follicles to be selected. decreased ovarian reserve, such as a single ovary, previous
This may reflect a loosening of the selection process.14 ovarian surgery, poor response to FSH, previous exposure
The decline in AFC may not be as steep as the decline to chemotherapy or radiation, or unexplained infertility.42
in fertility. Although decline in AFC is correlated with Although markers of ovarian reserve are not good
both the menopause transition and ovarian response to predictors of pregnancy rate with ART for women < 35,38
stimulation, it is not a good predictor of pregnancy.35 identification of these women may prompt shorter delay
to infertility investigations and treatment.
Antimüllerian hormone is produced by the granulosa cells
of pre-antral and small antral follicles but not dominant
Recommendations
follicles.12 AMH levels decrease with decreasing AFC,
which in turn is a marker of the primordial follicle count. 3. Ovarian reserve testing may be considered for
Levels remain consistent throughout the menstrual cycle40 women ≥ 35 years of age or for women < 35 years
and become undetectable in women after menopause.41 of age with risk factors for decreased ovarian reserve,
Although AMH provides moderate value in prediction such as a single ovary, previous ovarian surgery,
of ovarian response in IVF, it is a poor predictor of poor response to follicle-stimulating hormone,
pregnancy.35 Currently, AMH testing is not widely available previous exposure to chemotherapy or radiation,
across Canada. or unexplained infertility. (III-B)
4. Ovarian reserve testing prior to assisted Assisted Human Reproduction Act regulates all reproductive
reproductive technology treatment may be used for technologies, including the use of donor gametes.
counselling but has a poor predictive value for non- Specifically, the Act prohibits the sale of eggs, sperm,
pregnancy and should be used to exclude women or surrogacy services.48 Compensation to donors for
from treatment only if levels are significantly receiptable expenses such as medications and parking are
abnormal. (II-2A) allowed,49 although the specific regulations are not yet
available. Many countries, including the United States,
TREATMENT OF AGE-RELATED INFERTILITY rely on paid, often anonymous, egg donors to ensure an
adequate supply to meet the significant demand for this
Fertility treatment for age-related infertility is aimed at treatment option. However, as this practice is prohibited
increasing monthly fecundity and decreasing the time to in Canada, Canadian women must rely on altruistic
conception. Women may be offered controlled ovarian egg donors, usually family members, close friends, or
hyperstimulation with clomiphene citrate or gonadotropins, colleagues. Unfortunately, many women will not know an
or IVF to improve their chances of pregnancy and appropriate donor, so egg donation may not be an option
decrease time to pregnancy. Both treatments are intended for them. Other women turn to reproductive tourism and
to increase the number of mature oocytes each month to seek treatment in the United States or Europe.
balance decreasing oocyte quality, but they do not address
the underlying issue of oocyte quantity or quality. The only Pregnancy rates with oocyte donation are based on the
effective treatment for age-related infertility and declining age of the donor, not the recipient.33,50 Pregnancies and
oocyte quality is oocyte donation. live births have been reported in women into their 60s51;
however, the use of donor eggs for women after the age of
In reality, pregnancy and live birth rates with COH in 50 is controversial. There are increased rates of obstetrical
older women are low. In one retrospective review of more and maternal complications with increasing maternal age,
than 4000 treatment cycles using clomiphene citrate and including maternal death, hypertension, prematurity, fetal
intrauterine insemination, pregnancy rates were 7% for and neonatal death, and operative delivery.52–55 At least one
women aged 38 to 40, 4% for women 41 to 42, and 1% for death immediately after delivery has been reported in a
women > 42.43 A small study of 130 cycles of COH with 50-year-old woman who conceived with oocyte donation.56
gonadotropins and IUI found a live birth rate of 6% for However, many of these studies show these risks are
women aged 38 to 39, and 2% for women > 40.44 All live already increased in women > age 40, and treatment is
births happened within the first or second cycles. Older offered to women between the ages of 40 and 50 without
women may consider 1 to 2 cycles of COH if they do not significant debate. Many clinicians feel the natural age of
want to try IVF as a first-line treatment, but they should menopause is an appropriate maximum age for offering
move on to IVF quickly if they are unsuccessful within the oocyte donation, although others argue this is an arbitrary
first couple of cycles.45 cut-off point.57 In Canada, there are no regulations that
set an age limit for oocyte donation, although many clinics
Although chance of success diminishes with age, IVF have set the age of menopause as the maximum age for
still offers higher pregnancy and live birth rates than this treatment.
COH, although significantly lower rates than oocyte
donation. In 2007, live birth rates were 11.4% per cycle Recommendations
for women aged > 40 in Canada.32 One study of women
5. Pregnancy rates for controlled ovarian
aged > 40 undergoing IVF, showed that for women aged
hyperstimulation are low for women > 40 years
≥ 42, live birth rates drop to below 5%.46 In this study,
of age. Women > 40 should consider IVF if they
no live births were reported in 54 cycles for women
do not conceive within 1 to 2 cycles of controlled
aged ≥ 45. A separate study found a significant drop in
ovarian hyperstimulation. (II-2B)
IVF live birth rates in women aged ≥ 43 and over. Live
6. The only effective treatment for ovarian aging
birth rates were 7.4% for women 40 to 42 years of age,
is oocyte donation. A woman with decreased
and only 1.1% for women ≥ 43 years. Miscarriage rates
ovarian reserve should be offered oocyte donation
were 43.1% in the younger age group and 65.2% in the
as an option, as pregnancy rates associated
older age group.47
with this treatment are significantly higher
Oocyte donation offers women with an intact uterus than those associated with controlled ovarian
the opportunity to carry a pregnancy despite declining hyperstimulation or in vitro fertilization with a
ovarian function or menopause. In Canada, the 2004 woman’s own eggs. (II-2B)
found a relative risk 1.6 for fathers > 40 to 44 years of age, 5. Leridon H. Can assisted reproduction technology compensate for the
natural decline in fertility with age? A model assessment. Hum Reprod
and an Israeli cohort study found an OR 5.75 for fathers 2004;19:1548–53.
aged 40 to 49.88,89 A large US study found an association
6. Gilbert WM, Nesbitt TS, Danielsen B. Childbearing beyond age 40:
between autism and both maternal and paternal age, with pregnancy outcome in 24,032 cases. Obstet Gynecol 1999;93(1):9–14.
a relative risk of 1.3 for every 10-year increase in paternal 7. Baker TG. A quantitative and cytological study of germ cells in human
age.90 The link between paternal age and schizophrenia was ovaries. Proc R Soc Lond B Biol Sci 1963;158:417–33.
initially felt to be constitutional: people with this condition 8. Richardson SJ, Senikas V, Nelson JF. Follicular depletion during the
tend to marry and reproduce later in life. A cohort of menopausal transition: evidence for accelerated loss and ultimate
almost 90 000 children in Jerusalem was linked to the exhaustion. J Clin Endocrinol Metab 1987; 65:1231–7.
Israeli Psychiatric Registry. The relative risk for offspring 9. Faddy MJ, Gosden RG, Gougeon A, Richardson SJ, Nelson JF.
with schizophrenia was 2.0 for fathers aged 45 to 49, and Accelerated disappearance of ovarian follicles in mid-life: implications for
forecasting menopause. Hum Reprod 1992;7:1342–6.
3.0 for fathers > age 50.91 This finding has been seen
10. Hansen KR, Knowlton NS, Thyer AC, Charleston JS, Soules MR,
across other studies in other ethnic populations, including Klein NA. A new model of reproductive aging: the decline in ovarian
populations in Denmark, Sweden, and Japan.92–94 non-growing follicle number from birth to menopause. Hum Reprod
2008;23:699–708.
The American College of Medical Genetics does not 11. Nikolaou D, Templeton A. Early ovarian ageing: a hypothesis. Detection
recommend additional prenatal testing solely on the basis and clinical relevance. Hum Reprod 2003;18:1137–9.
of advanced paternal age (defined as ≥ 40), although 12. Broekmans FJ, Soules MR, Fauser BC. Ovarian aging: mechanisms and
prenatal counselling about the potential risks of advanced clinical consequences. Endocr Rev 2009;30:465–93.
paternal age should be undertaken.78 13. Johnson NP, Bagrie EM, Coomarasamy A, Bhattacharya S, Shelling AN,
Jessop S, et al. Ovarian reserve tests for predicting fertility outcomes
for assisted reproductive technology: the International Systematic
Recommendation Collaboration of Ovarian Reserve Evaluation protocol for a systematic
9. Advanced paternal age appears to be associated review of ovarian reserve test accuracy. BJOG 2006;113:1472–80.
with an increased risk of spontaneous abortion 14. te Velde ER, Pearson PL. The variability of female reproductive ageing.
and increased frequency of some autosomal Hum Reprod Update 2002;8:141–54.
dominant conditions, autism spectrum disorders, 15. Stein ZA. A woman’s age: childbearing and child rearing. Am J Epidemiol
1985; 121:327–42.
and schizophrenia. Men > age 40 and their partners
16. Klein NA, Battaglia DE, Miller PB, Branigan EF, Giudice LC, Soules MR.
should be counselled about these potential risks
Ovarian follicular development and the follicular fluid hormones and
when they are seeking pregnancy, although the risks growth factors in normal women of advanced reproductive age. J Clin
remain small. (II-2C) Endocrinol Metab 1996;81:1946–51.
17. Klein NA, Battaglia DE, Fujimoto VY, Davis GS, Bremner WJ,
Soules MR. Reproductive aging: accelerated ovarian follicular
CONCLUSIONS development associated with a monotropic follicle-stimulating hormone
rise in normal older women. J Clin Endocrinol Metab 1996;81:1038–45.
Female reproductive aging is a common cause of infertility
18. Klein NA, Harper AJ, Houmard BS, Sluss PM, Soules MR. Is the
in women in their late 30s and 40s. Health care providers short follicular phase in older women secondary to advanced or
should counsel women about the realities of the biological accelerated dominant follicle development? J Clin Endocrinol Metab
clock and ensure they have realistic expectations about 2002;87:5746–50.
natural and assisted fertility rates if they choose to delay 19. de Bruin JP, Bovenhuis H, van Noord PA, Pearson PL, van Arendonk JA,
child-bearing into their later reproductive years. te Velde ER, et al. The role of genetic factors in age at natural
menopause. Hum Reprod 2001;16:2014–8.
20. Pellestor F, Andreo B, Arnal F, Humeau C, Demaille J. Maternal aging and
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This document reflects emerging clinical and scientific advances on the date issued, and is subject to change. The information
should not be construed as dictating an exclusive course of treatment or procedure to be followed. Local institutions can dictate
amendments to these opinions. They should be well documented if modified at the local level. None of these contents may be
reproduced in any form without prior written permission of the SOGC.
Key to evidence statements and grading of recommendations, using the ranking of the Canadian Task Force
on Preventive Health Care
I: Evidence obtained from at least one properly randomized A. There is good evidence to recommend the clinical preventive
controlled trial action
II-1: Evidence from well-designed controlled trials without B. There is fair evidence to recommend the clinical preventive
randomization action
II-2: Evidence from well-designed cohort (prospective or C. The existing evidence is conflicting and does not allow to
retrospective) or case–control studies, preferably from more make a recommendation for or against use of the clinical
than one centre or research group preventive action; however, other factors may influence
decision-making
II-3: Evidence obtained from comparisons between times or
places with or without the intervention. Dramatic results in D. There is fair evidence to recommend against the clinical
uncontrolled experiments (such as the results of treatment preventive action
with penicillin in the 1940s) could also be included in this E. There is good evidence to recommend against the clinical
category preventive action
III: Opinions of respected authorities, based on clinical L. There is insufficient evidence (in quantity or quality) to make
experience, descriptive studies, or reports of expert a recommendation; however, other factors may influence
committees decision-making
*The quality of evidence reported in these guidelines has been adapted from The Evaluation of Evidence criteria described in the Canadian Task Force on
Preventive Health Care.71
†Recommendations included in these guidelines have been adapted from the Classification of Recommendations criteria described in the The Canadian Task
Force on Preventive Health Care.71
no evidence to recommend routine investigations for It is unknown how many women who have endometrial
asymptomatic endometrial thickening.18 Despite this cancer are diagnosed in the absence of bleeding. Diagnosis of
recommendation, clinicians are concerned when the cancer in asymptomatic women has been estimated by
ultrasound report states that endometrial cancer cannot be Smith-Bindman to be 5% to 10% of all cases.30 It is also
ruled out because of endometrial thickening found in an unknown if diagnosing endometrial cancer before a woman
asymptomatic postmenopausal woman. Goldstein, in bleeds would improve overall survival.
2010,19 recommended postmenopausal asymptomatic
endometrial thickening be evaluated on a case-by-case In 1981 Koss et al.2 initiated a screening study of 1280
basis. The clinician must consider risk factors for asymptomatic women aged 45 and older via endometrial
endometrial cancer including obesity, polycystic ovary sampling in a New York Medical Center. Carcinoma was
syndrome, and diabetes mellitus in their decision making. found in only 8 patients (6/1000).
Goldstein19 emphasized that it is inappropriate to
investigate every asymptomatic patient with thickened In 1997 Korhonen et al.31 published their results of patho-
endometrium > 5 mm. logic findings for endometrial biopsy in 2964
perimenopausal and postmenopausal women who were
ENDOMETRIAL CANCER AND RISK FACTORS
candidates for hormone therapy. Endometrial biopsy
Endometrial cancer is the most common gynaecologic findings were 68.7% atrophic, 23.5% proliferative, 0.5%
malignancy.20 The incidence in Canada is 19/100 000 women. secretory, 0% hyperplastic, and < 0.07% malignant. Of the
The Canadian Cancer Society estimated that in 2009 there biopsy samples, 6.6 % were insufficient for classification,
would be 4400 cases of endometrial cancer and 720 deaths reflecting the low incidence of pathology in the general
due to the disease in Canada.16 Approximately 80% of population.
endometrial cancers occur in postmenopausal women.21
Ninety percent of women with endometrial cancer present A necropsy study found an occult incidence of endometrial
with bleeding.22 Most women (72%) have stage I cancer cancer of 22 to 31/10 000 women (0.22% to 0.31%).32
when diagnosis is made,22 and the survival rate depends on These studies indicate a background incidence of endometrial
the stage, grade, and type of cancer. Five-year survival rates cancer of 0.6 to 6/1000 women (0.2% to 0.6%).2,32
for localized, regional, and metastatic endometrial cancer
are 95%, 67%, and 23%, respectively, and the overall 5-year SIGNIFICANCE OF ASYMPTOMATIC
survival rate is 86%.20 ENDOMETRIAL THICKENING
Individual risk factors are obesity, high-fat diet, reproductive
factors such as nulliparity and polycystic ovary syndrome, In a menstruating woman the endometrium changes with
early menarche, and late menopause.23 Tamoxifen use also the phase of the menstrual cycle. It ranges from 3 mm after
increases the risk of developing endometrial cancer by menses to a thickness of 15 mm in the luteal phase. In the
2.3 per 1000 women.24 first year after the last menstrual period the normal
endometrium is often thicker than it will be several years
Women with hereditary nonpolyposis colorectal cancer
after menopause, reflecting fluctuating levels of estrogen.
syndrome have an estimated cumulative incidence of
endometrial cancer ranging from 20% to 60% by the age of
70 years. The mean age of developing cancer is 47 in carriers Descriptions of the endometrium on ultrasound examination
versus 60 years in those with non-inherited endometrial include global thickening, heterogeneity, thickening, focal
cancer.25 No studies have yet shown the benefit of screening areas of thickening, fluid collections, increased vascularity,
for endometrial cancer in female carriers of hereditary and myometrial associated findings such as myometrial
nonpolyposis colorectal cancer syndrome.26 cysts, and submucosal fibroids. After menopause, endometrial
thickening may reflect proliferative endometrium, cystic
The incidence of endometrial cancer is lower in Black hyperplasia, complex hyperplasia, atypical hyperplasia, or
women. However, the overall mortality due to the disease is carcinoma of the endometrium. Ultrasound evidence of
higher among this group.27 thickened endometrium may also indicate structural
A Swedish longitudinal evaluation of postmenopausal abnormalities such as a uterine septum, submucous myomas,
women found that a history of bleeding incurs a 64-fold polyps, or adenomyosis. Ultrasound technology, by identi-
increased risk of endometrial cancer.28,29 For any woman fying vascular flow, now allows differentiation of polyps
presenting with postmenopausal bleeding there is approxi- from other abnormalities.33 Increased vascularity and fluid
mately a 10% risk of endometrial carcinoma.29 If the accumulation in association with endometrial thickening
woman is on hormone therapy and bleeds, the risk is 1%.29 are cause for greater concern than other findings.34
SCREENING STUDIES OF ASYMPTOMATIC WOMEN yielding 5 abnormal results (1 endometrial cancer). The
sensitivity was 17% for 6 mm and 33% using 5 mm as a
The purpose of performing ultrasound in non-bleeding
threshold. The positive predictive value was 2%. The nega-
postmenopausal women may be to investigate abdominal
tive predictive value at < 6 mm was 99%.
pain or masses or to delineate the adnexae when pelvic
examination is inadequate. Screening studies have been Smith-Bindman et al.30 calculated a 6.7% risk of
undertaken to assess whether ultrasound can detect endometrial cancer if the endometrium was > 11 mm, and a
endometrial cancer in large populations of asymptomatic 0.002 % risk if the endometrium was thin (< 11 mm). This
women.3,35,36 theoretical risk was calculated on the basis of a review of
published and unpublished data and an estimate of 15% of
The American Cancer Society concluded that there was total cases of endometrial cancer occurring in women who
insufficient evidence to recommend any routine screening have no bleeding. The risk is also related to age, with
for endometrial cancer with TVUS or endometrial biopsy.37 women > 70 years, with a thicker endometrium having a
Screening asymptomatic women will result in unnecessary higher risk (9.3% with 11 mm endometrium).
additional examinations because of low specificity. Most
cases of endometrial cancer are diagnosed as a result of Gambacciani et al.1 undertook a retrospective review of
symptoms reported by patients, and a high proportion 850 postmenopausal women who were investigated with
of these cases are diagnosed at an early stage, with high rates outpatient hysteroscopy for various causes of thickening.
of survival. The authors focused on the 148 asymptomatic postmenopausal
women with endometrium > 4 to 5 mm, and found 1 case
In 1995, Ciatto and colleagues35 performed TVUS on of adenocarcinoma (0.7%) (endometrium 16 mm) and
2025 women to evaluate the feasibility of using this modality 9 cases of hyperplasia (6.1%). In this study 24/27 cases of
to screen for endometrial carcinoma solely on the basis of adenocarcinoma presented with bleeding, 2/27 had an
endometrial thickness. In this study, 117 women (5.8%) abnormal Papanicolaou smear, and 1/27 (3.7%) had thickened
showed abnormal thickness of > 4 mm. Of these, 98 underwent endometrium. One hundred forty-seven hysteroscopies
endometrial biopsy, but 32 had impassable cervical stenosis. were performed for benign pathology; the false positive rate
It was decided that evaluation of the endometrium by dila- was 93.2%.
tation and curettage was not warranted. These women
Gerber et al.38 in a retrospective analysis discovered
underwent repeat transvaginal ultrasound examination.
16 patients (13%) had endometrial cancer when an
The positive predictive value was 3.3%, with 3 endometrial
endometrial thickening of 10 mm was used as a cut-off in
carcinomas found out of 66 biopsies.
the investigation of 123 asymptomatic women; 21 of the
A 1999 study by Vuento et al.3 focused on the feasibility of women (17%) had hyperplasia. Asymptomatic women
TVUS to screen for endometrial cancer in asymptomatic without symptoms had no prognostic advantage over the
postmenopausal women using multiple criteria, one of symptomatic women if bleeding had occurred for < 8 weeks.
which was endometrial thickness. In this study, 291 of 1074 Duration of postmenopausal bleeding was correlated with
women (29%) had an abnormal thickness > 4 mm, uterine increasing tumour stage and reduced survival time.
artery pulsatility index < 1.0, or fluid accumulation in the Endometrial screening often resulted in unnecessary opera-
endometrial cavity. However, after biopsy, only 23 women tions with increased morbidity and cost.
were found to have endometrial pathology, and only 3 were Archer et al.12 attempted to obtain endometrial samples in
found to have endometrial cancer. Endometrial fluid was 801 asymptomatic perimenopausal and postmenopausal
found in 12%. Another case of carcinoma was found women prior to enrolment in a multicentre hormone
2.5 years later in a patient who had refused biopsy. The replacement therapy study. Of the samples, 75% contained
authors concluded that TVUS, while sensitive for detecting sufficient tissue for diagnosis. One endometrial cancer was
early endometrial cancer, has a low specificity that precludes diagnosed, illustrating the low incidence of disease in
its utility as a screening modality. Doppler ultrasound did asymptomatic women and the low incidence of disease in
not improve detection of abnormal endometrial pathology. asymptomatic women. The endometrium was atrophic in
A study by Fleischer et al.36 of 1926 women who underwent 46.9%, proliferative in 16.7%, secretory in 6.8%, and
ultrasound examination as part of the workup for an osteo- hyperplastic in 5.2%.
porosis prevention trial found that 93 women had an Tsuda et al.39 screened 1400 asymptomatic postmenopausal
endometrium > 6 mm. When endometrial aspiration of Japanese women and found a prevalence of endometrial
42 of these women was undertaken, there were abnormal disease of 2.3% in asymptomatic and 21% in symptomatic
findings in only 1 case. A further 1750 of 1833 women with women. At a cut-off of 3 mm in non-bleeding women,
endometrial thickness of < 6 mm underwent sampling, sensitivity was 90%, specificity 84%, and positive predictive
value 12%. With an endometrial thickness < 3 mm, the Ovarian Cancer Screening Trial in 1271 women. Thickness
probability that endometrial disease would be missed was ranged from 1 to 32 mm (median 3 mm). Frequency of
0.003. thicker endometrium was independently associated with
A review of the literature therefore does not indicate that increasing BMI and current use of HT.
routine screening via transvaginal ultrasound for endometrial The time from menopause is a factor in investigating the
cancer is recommended. There is a baseline incidence of significance of the findings. Tsuda et al.11 found histologic
thickening (³ 4.5 mm) of up to 17%, with a low incidence findings of a proliferative endometrium in 28% of women
of cancer < 1%.1,12,36–38 < 5 years post-menopause and in 4.8% in women ³ 5 years
post-menopause. Andolf and colleagues41 found only an
WOMEN WITH RISK FACTORS insignificant trend towards decreasing endometrial thickness
Increased lifetime estrogen exposure has been associated with time after menopause.
with an increased risk of endometrial cancer. Early menarche,
ENDOMETRIAL THICKENING IN WOMEN ON HT
late menopause, obesity, and unopposed estrogen use have
been linked to an increased risk. Should endometrial thick- Hänggi et al.10 compared TVUS with histological findings
ening on ultrasound be more aggressively investigated in in endometrial evaluation of postmenopausal women
women with risk factors? using hormone therapy to evaluate the safety of 3 hormone
A regression analysis by Maatela et al.40 of endometrial therapy regimens versus no therapy. Patients on oral
thickening in asymptomatic postmenopausal women found micronized 17b-estradiol/oral sequential dydrogesterone
an increased risk of pathological findings in the presence of were compared with those using transdermal
obesity (BMI > 26) and late menopause. 17b-estradiol/oral sequential dydrogesterone, or oral
In a 1993 study of ultrasonic thickness of the endometrium in tibolone. If endometrial thickness was < 5 mm, endometrial
300 asymptomatic postmenopausal women, Andolf et al.41 biopsy sample was either inactive/atrophic or insufficient
found that endometrial thickness correlated significantly for diagnosis. Hyperplastic or malignant change was not
with BMI. In the same study, Andolf and colleagues found a reported. After 24 months, endometrial thickness was
non-significant trend towards a higher prevalence of predis- increased both in the oral and the transdermal
posing factors (hypertension, nulliparity, diabetes) in women 17b-estradiol/dydrogesterone groups. The tibolone group
with a thick endometrium. showed no difference from the control group.
The Women’s Health Initiative data, however, showed that In the Postmenopausal Estrogen and Progestin Interven-
the interactions of age, race/ethnicity, BMI, hypertension, tions Trial, 448 participants underwent both TVUS and
smoking status, pack-years of smoking, prior use of unopposed endometrial biopsy over 4 years.45 They were randomized
estrogen, or prior use of estrogen and progesterone had no to placebo or to cyclic or sequential HT. Langer et al.45
significant effect on the observed incidence rate of endometrial found that at a threshold value of 5 mm for endometrial
cancer.42 There was a insignificant decrease in the number thickness, TVUS had 90% sensitivity and 48% specificity.
of endometrial cancer cases in women taking HT rather No cancer or atypical hyperplasia was found in 261 women
than placebo (13 fewer cases per 10 000). with endometrial thickness of < 5 mm. Two cases of atypical
hyperplasia and 1 case of cancer were found in 307 women
Martinez-Rubio and Alcazar43 prospectively compared the
prevalence of abnormal endometrium in 187 postmenopausal with endometrial thickness ³ 5 mm. The majority of serious
asymptomatic, normotensive women and 182 asymptomatic disease cases were found in women with endometrial
postmenopausal women receiving anti-hypertensive drugs. thickness > 10 mm. Eight cases of complex hyperplasia,
The endometrium was assessed via office endometrial 3 cases of atypical hyperplasia, and 1 case of adenocarcinoma
biopsy and TVUS when the definition of abnormal were found in the study population. Using this threshold,
ultrasound was > 5 mm. Women taking antihypertensive more than one half of the women would undergo a biopsy,
medications were significantly more likely than while only 4% had serious disease.
normotensive women to have endometrial thickness > 5 mm Gull et al.46 evaluated a random sample of 1000 women
(26.9% vs. 12.8%; P 0.001), heterogeneous endometrial between the ages of 45 and 80 who underwent screening
polyps (23.1 vs. 12.8%; P < 0.001), and endometrial polyps ultrasound in Sweden; 559 were postmenopausal. The cur-
(17.6 vs. 9.6%; P < 0.001). These results were independent rent use of HT was associated with increasing endometrial
of body mass index. thickness.
Sit et al.44 evaluated asymptomatic thickening as an estrogen Kurtay et al.47 assessed the effects of hormone therapy on
biomarker as a part of the Prostate, Lung, Colorectal and endometrial thickness in asymptomatic postmenopausal
women between 1997 and 2001. Three hundred seven Antunes et al.53 sought to determine factors associated with
women received oral equine HT, oral equine estrogen, oral malignancy in endometrial polyps in their 2007 study. A
17b-estradiol, or oral tibolone. All women on estrogen also retrospective chart review of 475 surgical patients of any
received a progestin. Patients with endometrial thickness age who underwent hysteroscopy for endometrial polyp
> 7 mm underwent a biopsy. Patients taking tibolone did removal were included in the study. Overall, 78.53% of the
not have a statistically significant increased thickness of polyps were benign, 13.47% had simple or complex hyper-
endometrium compared with those in the other arms of the plasia, and 2.74% were malignant. Statistical subanalysis
study. The authors suggested that tibolone closely mimics showed that women over 60 years of age were 3.28 times
the natural atrophic state of the postmenopausal more likely than their younger counterparts to have malig-
endometrium and could be considered as an alternative to nant endometrial polyps. Women over 60 with
HT. postmenopausal bleeding were 5.31 times more likely than
asymptomatic younger women to have malignant polyps.
In a 10-year (1991 to 2001) study undertaken in by Mossa et al.,48
The authors did not find a significant difference in the
the threshold of endometrial thickness was investigated in
prevalence of malignant polyps associated with arterial
587 women on HT. An increased endometrial thickness
hypertension, diabetes mellitus, obesity, HT, or tamoxifen
and increased incidence of bleeding was found in the HT
use. Antunes et al.53 concluded that older women with
group. However, no difference in the prevalence of
postmenopausal bleeding are at greatest risk for malignancy
endometrial cancer was found between the HT and control
and should have hysteroscopic resection of the polyps.
groups. The authors recommended that women with bleeding
on HT undergo hysteroscopy and biopsy only if In 2009, Ferrazzi et al.54 sought to elucidate the risk of
endometrial thickness is > 8 mm. malignancy in endometrial polyps in a large sample of
asymptomatic and symptomatic postmenopausal women.
STUDIES IN WOMEN WITH ENDOMETRIAL POLYPS A total of 1155 asymptomatic women and 770 bleeding
The estimated prevalence of polyps in women with women who had undergone polypectomy were included in
postmenopausal bleeding ranges from 13% to 50%.49 Several the retrospective clinical chart review study. The authors
studies have also shown that polyps are highly prevalent in found only one case of a cancerous polyp in the asymptomatic
asymptomatic postmenopausal women.49–52 The molecular group. The polyp in this case was large, with a mean diameter
and pathological etiology of endometrial polyps is evolving. of 40 mm. There was a significantly (P < 0. 001) higher
Most lesions are benign, but some may be pre-malignant prevalence of malignant polyps in the symptomatic group.
(simple or complex hyperplasia with cytological atypia) or The authors concluded that women with incidentally found
malignant.53 Malignant pathology is identified in 0.5% to polyps do not require polypectomy unless the polyps have a
4.8% of polyps found in postmenopausal women.53,54 How- large diameter.
ever, polyps are a known risk factor for the subsequent In 2009, Gregoriou et al.56 published a retrospective analysis of
development of endometrial cancer.49–53 516 cases of women who underwent hysteroscopic
Fernández-Parra et al.55 conducted a retrospective chart polypectomy to determine risk factors for malignancy. The
review to determine the incidence of malignant polyps in final pathology report after polyp resection was compared
postmenopausal women. Of 1870 hysteroscopies conducted at with each patient chart. The majority of polyps were benign
the study centre, 653 had confirmed polyps. The majority of (96.9%), and a small percentage were premalignant (1.2%)
women had postmenopausal bleeding, and only 117 women or malignant (1.9%). Obesity (BMI > 30) (P = 0.001),
were asymptomatic. No cases of cancer in a polyp were diabetes mellitus (P = 0.04), menopause (P = 0.005), and
found in asymptomatic women. age > 60 years (P = 0.001) were all significant risk factors
for the development of malignant polyps. Gregoriou et al.56
In a Norwegian study of 411 pre- and postmenopausal suggested that all clinical parameters must be considered to
patients, pathological analysis of hysteroscopically resected assess the risk of the malignancy potential of a polyp in a
endometrial polyps was conducted.49 Thirty-one percent of postmenopausal woman.
study participants were symptomatic in postmenopause,
and 18.5% were asymptomatic in postmenopause. In the Baiocchi et al.57 also conducted a large-scale retrospective
group of postmenopausal women with symptoms, 5.5% of study to determine the clinical factors associated with
polyps were malignant or had atypical hyperplasia com- malignant polyps. Inclusion criteria for this study were
pared with 2.6% in women with no symptoms. The authors diagnosis of an endometrial polyp or endometrial
concluded that hysteroscopic resection of both symptom- postmenopausal thickening of ³ 5 mm. In total, 1242 cases
atic and asymptomatic polyps should be performed since were included in this study run from January 1995 to
the natural course of malignant polyps is still unknown. December 2006. The majority of patients (95.2%) had
benign polyps. Hyperplastic polyps with atypia occurred in dilatation and curettage revealed endometrial atrophy in all
1.3% of patients and cancer in 3.5%. Postmenopausal status, 4 cases in the anastrozole group, and there were 14 polyps,
age > 60, and hypertension were all significantly correlated 8 hyperplasias, and 7 atrophies in the tamoxifen group.
with cancer in the polyp. Other clinical factors such as dia- Women on long-term tamoxifen therapy are thought to
betes mellitus, HT, tamoxifen, and bleeding symptoms have higher risk of developing endometrial cancer. Berlière
were not significantly different between the benign and et al.61 enrolled 575 women with estrogen receptor-positive
cancerous polyp groups. In fact, the 2 most important factors breast cancer into a prospective study of endometrial
appear to be advanced age and postmenopausal status. pathology. Prior to tamoxifen treatment, all women had
Baiocci et al.57 concluded that older menopausal patients TVUS, and if endometrial thickness was > 5 mm,
with hypertension are at the greatest risk of developing a hysteroscopy was performed to remove polyps or lesions.
malignant polyp. However, in both the Gregoriou et al.56 In the study by Berlière et al.,61 women who had lesions
and Baiocci et al.57 studies the incidence of cancer in polyps before initiating tamoxifen therapy were found at 2-year
was low (1.9% and 3.5% respectively). follow-up to be at significantly higher risk (P < 0.001) of
developing atypical lesions. The lesions in the women who
IMPLICATIONS OF TAMOXIFEN
FOR ENDOMETRIAL THICKENING had lesions originally were also more severe than any devel-
oped in the women who were initially lesion-free. The
Women taking tamoxifen have a greater risk of endometrial authors concluded that women with initial lesions may be at
cancer. This risk is augmented further if those women were greater risk for the oncologic effects of tamoxifen on their
previously taking estrogen replacement therapy.58 endometrium.
Routine endometrial biopsy is not necessary in asymptomatic Garuti et al.62 also conducted a prospective study of estrogen-
women who are taking tamoxifen.24 Endometrial thickening positive breast cancer patients who were being prescribed
can be confused with stromal hypertrophy in these women. tamoxifen adjuvant therapy. The authors enrolled 99
However, any abnormal bleeding should be evaluated. asymptomatic patients and evaluated the endometrium using
Endometrial cancers that occur in these women are similar hysteroscopy if their endometrial thickness was > 4 mm.
to endometrial cancers occurring in the general population Thirty-four women had thickness > 4 mm, 10 had polyps, 4 had
with respect to stage, grade, and histology. Prognosis tends simple hyperplasia, and 3 had complex hyperplasia. Thus,
to be good. To date there have been no published studies 18.6% of the patients had asymptomatic endometrial
evaluating the effect of endometrial cancer screening pathology before tamoxifen treatment. Garuti et al.62 sug-
modalities on mortality among women taking tamoxifen for gested routine endometrial screening for all women before
the treatment or prevention of breast cancer. initiation of tamoxifen therapy since subclinical
Fishman et al.59 found that endometrial thickness increased endometrial pathology is prevalent in this group of women.
with increasing duration of tamoxifen use at a rate of The most recent American College of Obstetricians and
0.75 mm/yr. The mean endometrial thickness after 5 years Gynecologists guideline for tamoxifen use and endometrial
of tamoxifen use was 12 mm (range 6 to 21 mm). After cancer risk has several recommendations for
discontinuation of tamoxifen treatment the endometrium postmenopausal women.24 Women may be stratified into
decreased by 1.27 mm/yr. 2 risk groups based on whether they have initial endometrial
Gerber et al.60 investigated the effect on the endometrium lesions. Women with initial lesions are at higher risk for
in women with breast cancer when they switched from developing endometrial cancers on tamoxifen therapy.
tamoxifen to an aromatase inhibitor, anastrozole. A total of Routine endometrial screening is not recommended for
226 postmenopausal women who had received tamoxifen women taking tamoxifen because of the costs incurred and
20 mg/d for ³ 12 months, £ 48 months and had developed risk of unnecessary further investigation. Instead, women
abnormal vaginal bleeding and/or asymptomatic endometrial should be educated regarding the symptoms of endometrial
thickness >10 mm underwent hysteroscopy and dilatation cancer and instructed to consult their doctor if they develop
and curettage. One hundred seventy-one were randomized any spotting or postmenopausal bleeding. If a woman
to continue tamoxifen (88) or changed to anastrozole (83). develops endometrial hyperplasia, the use of tamoxifen
Patients were monitored for £ 42 months via TVUS at should be re-assessed.
6-monthly intervals. There was no difference in recurrent
COMPLICATIONS OF INVESTIGATION
vaginal bleeding between groups: 4/83 on tamoxifen and
9/88 on anastrozole. Mean endometrial thickness for Endometrial biopsy may result in pain, bleeding, infection,
patients who switched to anastrozole was significantly less and uterine perforation, and office-based endometrial
than for those on tamoxifen. Repeat hysteroscopy and biopsy has false negative rates of 5% to 15%.63 Dilatation
and curettage has false negative rates of 2% to 6%.46 ultrasound screening for asymptomatic women is not rec-
Endometrial sampling may be limited or impossible ommended. Current evidence suggests that certain subsets
because of virginal status, cervical stenosis, small introitus, of women at high risk of developing endometrial cancer
pain, or anatomical abnormalities such as fibroids who have endometrial thickening on ultrasound and other
aberrating the canal. The finding of insufficient tissue in the positive findings (increased vascularity, inhomogeneity of
face of endometrial thickening prompts further investigations endometrium, particulate fluid, excessively thickened
such as hysterosonogram, office hysteroscopy, dilatation endometrium > 11 mm) should be referred to gynaecologists
and curettage, and diagnostic and therapeutic hysteroscopy for further investigations. Women with risk factors for
under general anaesthetic.63–66 Each of these procedures has endometrial cancer and endometrial thickening such as
its own complications, including untimely hysterectomy. In tamoxifen use, obesity, hypertension, and late menopause
a study designed to compare blind biopsy, hysteroscopy should be triaged on an individual basis. Polyps found in
with biopsy, and ultrasound in 683 women who were asymptomatic postmenopausal women need not be removed
experiencing bleeding, discomfort and distress was routinely. However, factors such as polyp size and
reported in 16% of women who had hysteroscopy and in histopathology, and patient age must be incorporated into
10% who had blind biopsy.67 the decision for polypectomy. Investigations for asymp-
No major complications were reported in the Shushan et al.68 tomatic endometrial thickening are not risk free, and serious
study of 300 women who underwent hysteroscopic polyp complications such as bowel injury and uterine perforation
removal. Minor complications reported in the study have been reported in the literature. Thus, adoption of these
included bradycardia during general anaesthetic and post- recommendations may reduce anxiety, pain and risk of
operative hemorrhage that was treated conservatively with procedural complication to the postmenopausal patient.
uterine tamponade for 8 hours. Two of the 300 patients
Recommendations
were readmitted to hospital with postoperative fever and
treated with antibiotic combination therapy for pelvic 1. Transvaginal ultrasound should not be used as screening
inflammatory disease. Lev-Sagie et al.69 reported a compli- for endometrial cancer. (II-1E)
cation rate of 3.6% in a retrospective study of women who
underwent hysteroscopy after incidental finding of 2. Endometrial sampling in a postmenopausal woman with-
endometrial polyp on ultrasound examination. The out bleeding should not be routinely performed. (II-1E)
complications reported in the study were uterine perforation
in 2 women and complication of general anaesthetic due to 3. Indications for tissue sampling of the endometrium in
difficult intubation. Ferrazzi et al.54 reported a particularly bleeding postmenopausal women with an endometrial
low rate of complications in the literature. Only the minor thickness of greater than 4 to 5 mm should not be extrap-
complications of cervical tears and false passages were olated to asymptomatic women. (II-2E)
reported in 0.6% and 0.3% of asymptomatic patients
respectively. False passage complications were reported in 4. A woman who has endometrial thickening and other positive
0.8% of symptomatic patients in the Ferrazzi et al. study.54 findings on ultrasound, such as increased vascularity,
In the 2007 Lieng et al.70 study, 92.2% of hysteroscopies inhomogeneity of endometrium, particulate fluid, or
performed to remove endometrial polyps were complication- thickened endometrium over 11 mm, should be referred
free. The complications that did occur included uterine per- to a gynaecologist for further investigations. (II-1A)
foration, creation of false passage, moderate bleeding,
endometritis, failed procedure, and uterine perforation 5. Decisions about further investigations should be made
including bowel injury. Thus, some of the complications of on a case-by-case basis in asymptomatic women with
hysteroscopy carry significant morbidity and possible increased endometrial thickening and risk factors for
mortality. endometrial cancer such as obesity, hypertension, and
late menopause. (II-1B)
CONCLUSION
6. In asymptomatic women on tamoxifen, a routine ultrasound
Asymptomatic endometrial thickening found on ultrasound for endometrial thickening should not be performed. (II-2E)
examination in postmenopausal women often poses a clinical
management dilemma. Although the prevalence of endometrial 7. Not all postmenopausal women who have asymptomatic
cancer is relatively low in women with no bleeding, the disease endometrial polyps require surgery. Women found to
has the best outcome when it is found at an early stage. The have asymptomatic polyps on ultrasound should be
disease is usually diagnosed at an early stage when triaged for intervention according to size of the polyp,
postmenopausal women present with bleeding. Routine age, and other risk factors. (II-1A)
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T
Kathi Wilson, RM, Ilderton ON
he role of obstetrical care providers in Canada is to
Grace Yeung, MD, London ON
promote and apply best practices in caring for the
FAMILY PHYSICIANS ADVISORY COMMITTEE
pregnant woman in order to minimize risk and maximize
William Ehman, MD (Chair), Nanaimo BC positive outcomes for both mother and infant. Pregnant
Anne Biringer, MD, Toronto ON women often seek input from their caregivers on the topic
Andrée Gagnon, MD, Blainville QC of maternity leave to plan cessation of work. In Canada, the
Lisa Graves, MD, Sudbury ON importance of child care in the first year of life is recognized
Jonathan Hey, MD, Saskatoon SK with benefit programs that provide financial support to
Jill Konkin, MD, Edmonton AB families. In addition, many employers have extended these
Francine Léger, MD, Montreal QC benefits through insurance plans or collective agreements
Cindy Marshall, MD, Lower Sackville NS to promote healthy beginnings.
Disclosure statements have been received from all members of
the committees. CESSATION OF WORK AND PARENTAL BENEFITS
This document reflects emerging clinical and scientific advances on the date issued, and is subject to change. The information
should not be construed as dictating an exclusive course of treatment or procedure to be followed. Local institutions can dictate
amendments to these opinions. They should be well documented if modified at the local level. None of these contents may be
reproduced in any form without prior written permission of the SOGC.
before the expected due date and “within 17 weeks of When complications arise in the antepartum period, physicians
the actual or expected week of birth.” 1 The employment can recommend a medical absence from the workplace if they
insurance program provides parental benefits to either feel it is in the best interests of the patient.
parent for up to 35 weeks. The benefits can be claimed
concurrently or consecutively but must be claimed within Even in uncomplicated pregnancies a health-related leave may
the 52 weeks following the birth. In addition, many be required to optimize maternal and fetal health, although
employers will supplement benefits so that parents receive there is no conclusive evidence of improved outcomes.3
up to 95% of their salary. Health care providers should initiate a discussion early in the
Quebec is the only province that has a program that pregnancy to educate women about the difference between
health-related and illness-related leaves of absence. This
provides financial benefits for women with uncomplicated
provides an opportunity to advise women about the possible
pregnancies whose work or work environment may pose a
medical complications that would support an illness-related
threat to them or their unborn child.2
leave of absence and to inform them that issues such as
Currently, a woman with an uncomplicated pregnancy is discomfort, poor sleep, fatigue, and musculoskeletal pain are
deemed to be unfit for work and to qualify for benefits at an unfortunate but normal part of a healthy pregnancy.
the onset of labour.
When a patient requests a medical leave of absence for
Women who experience complications of pregnancy or an uncomplicated pregnancy, the physician is not required
other illness-related problems and who are deemed unable to support this demand. The patient should also be made
to continue working are eligible for sickness benefits rather aware that it is not a recommended practice for care
than maternal benefits. providers to advocate an illness-related leave for women
with uncomplicated pregnancy without justification.
Healthy women with uncomplicated pregnancies often
ask their care providers to support a period of absence However, physicians can and should support a health-
from work before delivery, because they want to prepare related leave to enable a woman to prepare for the eventual
for labour; however, such a leave of absence would be delivery, although she may not receive benefits for the
considered a health-related rather an illness-related leave. entire period of the leave. If care providers do support
There are few guidelines or standards governing the timing a health-related leave, the woman should be advised that
or duration of health-related maternity leave. In addition, it cannot be defined as an illness-related medical leave
there is no conclusive evidence for the ideal length of and that she would not, therefore, be entitled to receive
health-related prenatal maternity leave, and there are no any medical benefits. In effect, this health-related leave to
data suggesting that such a leave of absence improves prepare for childbirth would be voluntary. A woman would
outcomes. This leads to uncertainty for care providers, receive employment insurance benefits if this leave began
resulting in inconsistent practices. within 8 weeks of her expected due date.
The timing of cessation of work before delivery is unique The issue of benefits is beyond the scope of maternity
for each pregnancy and should be discussed between care providers. If a physician does recommend a leave of
patient and care provider. The SOGC Clinical Practice absence, he or she should advise the patient that she may
or may not be entitled to employee benefits for the entire
Obstetrics Committee has reviewed and endorses the
period. Women should be aware of the maternity benefits
document published by the Alberta Perinatal Health
they are entitled to through their employer or government
Program: Health-Related Maternity Leave in the Uncomplicated
agency, and should be advised that a recommendation to
Pregnancy and Birth.3 This document summarizes current
take health-related leave in preparation for delivery does
evidence regarding work-related risks and presents a
not guarantee benefits.
summary of current practices and recommendations for
health-related maternity leave in the antepartum and the
postpartum period. It supports the federal definition, RECOMMENDATIONS FOR
stating that women with uncomplicated pregnancies are OBSTETRICAL CARE PROVIDERS
deemed unfit to work no later than at the onset of labour. 1. Understand the difference between a health-related and
The document also expands this definition by stating that an illness-related leave of absence.
for uncomplicated singleton pregnancies, health-related
maternity leave may be required for 2 to 6 weeks before the 2. Initiate a routine discussion early in pregnancy about
estimated date of birth. the issues that can present in an uncomplicated
This clinical practice guideline has been prepared by MATERNAL FETAL MEDICINE COMMITTEE
the Guidelines Consensus Group, reviewed by the Robert Gagnon, MD (Co-Chair), Montreal QC
Maternal Fetal Medicine Committee, and approved by the
Executive and Council of the Society of Obstetricians Lynda Hudon, MD (Co-Chair), Montreal QC
and Gynaecologists of Canada. This document has been Melanie Basso, RN, Vancouver BC
reveiwed by the Fetus and Newborn Committee of the Hayley Bos, MD, London ON
Canadian Paediatric Society.
Joan M. Crane, MD, St. John’s NL
PRINCIPAL AUTHORS
Gregory Davies, MD, Kingston ON
Laura Magee, MD, Vancouver BC
Marie-France Delisle, MD, Vancouver BC
Diane Sawchuck, RN, PhD, Vancouver BC
Savas Menticoglou, MD, Winnipeg MB
Anne Synnes, MD, Vancouver BC
William Mundle, MD, Windsor ON
Peter von Dadelszen, MBChB, Vancouver BC
Annie Ouellet, MD, Sherbrooke QC
THE MAGNESIUM SULPHATE FOR FETAL
NEUROPROTECTION CONSENSUS COMMITTEE Tracy Pressey, MD, Vancouver BC
Melanie Basso, RN, Vancouver BC Christy Pylypjuk, MD, Saskatoon SK
Joan M. Crane, MD, St. John’s NL Anne Roggensack, MD, Calgary AB
Lex Doyle, MD, Victoria, Australia Frank L. Sanderson, MD, Saint John NB
William Ehman, MD, Nanaimo BC Disclosure statements have been received from all members of
the committees.
Robert Gagnon, MD, Montreal QC
The literature searches and bibliographic support for this
William Grobman, MD, Chicago IL
guideline were undertaken by Becky Skidmore, Medical
Michael Helewa, MD, Winnipeg MB Research Analyst, Society of Obstetricians and Gynaecologists
KS Joseph, MD, Vancouver BC of Canada.
M. Jocelyne Martel, MD, Saskatoon SK
Steven Miller, MD, Vancouver BC
Nan Okun, MD, Toronto ON Abstract
Dwight Rouse, MD, Providence RI Objective: To provide guidelines for the use of antenatal magnesium
Vyta Senikas, MD, Ottawa ON sulphate (MgSO4) for fetal neuroprotection of the preterm infant.
Rebecca Sherlock, MD, Vancouver BC Options: Antenatal MgSO4 administration should be considered for
Amanda Skoll, MD, Vancouver BC fetal neuroprotection when women present at ≤ 31+6 weeks
Graeme Smith, MD, Kingston ON with imminent preterm birth, defined as a high likelihood of birth
because of active labour with cervical dilatation ≥ 4 cm, with
Brenda Wagner, MD, Richmond BC
or without preterm pre-labour rupture of membranes, and/or
Sandrine Wavrant, MD, Montreal QC planned preterm birth for fetal or maternal indications.
R. Douglas Wilson, MD, Calgary AB There are no other known fetal neuroprotective agents.
Jennifer Hutcheon, PhD, Vancouver BC
Outcomes: The outcomes measured are the incidence of cerebral
palsy (CP) and neonatal death.
Evidence: Published literature was retrieved through searches of
PubMed or Medline, CINAHL, and the Cochrane Library in May
Key Words: Magnesium sulphate, preterm birth, cerebral palsy, 2010, using appropriate controlled vocabulary and key words
death, neuroprotection (magnesium sulphate, cerebral palsy, preterm birth). Results
were restricted to systematic reviews, randomized controlled
This document reflects emerging clinical and scientific advances on the date issued, and is subject to change. The information
should not be construed as dictating an exclusive course of treatment or procedure to be followed. Local institutions can dictate
amendments to these opinions. They should be well documented if modified at the local level. None of these contents may be
reproduced in any form without prior written permission of the SOGC.
trials, and relevant observational studies. There were no date Summary Statement
or language restrictions. Searches were updated on a regular 1. “Imminent preterm birth” is defined as a high likelihood of birth
basis and incorporated in the guideline to August 2010. Grey due to one or both of the following conditions (II-2):
(unpublished) literature was identified through searching the • Active labour with ≥ 4 cm of cervical dilation, with or without
websites of health technology assessment and health technology PPROM.
assessment-related agencies, clinical practice guideline
• Planned preterm birth for fetal or maternal indications.
collections, clinical trial registries, and national and international
medical specialty societies. Recommendations
Values: The quality of evidence was rated using the criteria described 1. For women with imminent preterm birth (≤ 31+6 weeks), antenatal
in the Report of the Canadian Task Force on Preventive Health magnesium sulphate administration should be considered for fetal
Care (Table 1). neuroprotection. (I-A)
2. Although there is controversy about upper gestational age,
Benefits, harms, and costs: Antenatal magnesium sulphate for fetal
antenatal magnesium sulphate for fetal neuroprotection should be
neuroprotection reduces the risk of “death or CP” (RR 0.85;
considered from viability to ≤ 31+6 weeks. (II-1B)
95% CI 0.74 to 0.98; 4 trials, 4446 infants), “death or moderate-
3. If antenatal magnesium sulphate has been started for fetal
severe CP” (RR 0.85; 95% CI 0.73 to 0.99; 3 trials, 4250 infants),
neuroprotection, tocolysis should be discontinued. (III-A)
“any CP” (RR 0.71; 95% CI 0.55 to 0.91; 4, trials, 4446 infants),
4. Magnesium sulphate should be discontinued if delivery is no
“moderate-to-severe CP” (RR 0.60; 95% CI 0.43 to 0.84; 3
longer imminent or a maximum of 24 hours of therapy has been
trials, 4250 infants), and “substantial gross motor dysfunction”
administered. (II-2B)
(inability to walk without assistance) (RR 0.60; 95% CI 0.43
5. For women with imminent preterm birth, antenatal magnesium
to 0.83; 3 trials, 4287 women) at 2 years of age. Results were
sulphate for fetal neuroprotection should be administered as
consistent between trials and across the meta-analyses. There
a 4g IV loading dose, over 30 minutes, followed by a 1g/hr
is no anticipated significant increase in health care-related costs, maintenance infusion until birth. (II-2B)
because women eligible to receive antenatal MgSO4 will be
6. For planned preterm birth for fetal or maternal indications,
judged to have imminent preterm birth.
magnesium sulphate should be started, ideally within 4 hours
Validation: Australian National Clinical Practice Guidelines were before birth, as a 4g IV loading dose, over 30 minutes, followed by
published in March 2010 by the Antenatal Magnesium Sulphate a 1g/hr maintenance infusion until birth. (II-2B)
for Neuroprotection Guideline Development Panel. Antenatal 7. There is insufficient evidence that a repeat course of antenatal
MgSO4 was recommended for fetal neuroprotection in the magnesium sulphate for fetal neuroprotection should be
same dosage as recommended in these guidelines. However, administered. (III-L)
MgSO4 was recommended only at < 30 weeks’ gestation, based 8. Delivery should not be delayed in order to administer antenatal
on 2 considerations. First, no one gestational age subgroup magnesium sulphate for fetal neuroprotection if there are maternal
was considered to show a clear benefit. Second, in the face of and/or fetal indications for emergency delivery. (III-E)
uncertainty, the committee felt it was prudent to limit the impact 9. When magnesium sulphate is given for fetal neuroprotection,
of their clinical practice guidelines on resource allocation. Also maternity care providers should use existing protocols to monitor
in March 2010, the American College of Obstetricians and women who are receiving magnesium sulphate for preeclampsia/
Gynecologists issued a Committee Opinion on MgSO4 for fetal eclampsia. (III-A)
neuroprotection. It stated that, “the available evidence suggests 10. Indications for fetal heart rate monitoring in women receiving
that magnesium sulphate given before anticipated early preterm antenatal magnesium sulphate for neuroprotection should follow
birth reduces the risk of cerebral palsy in surviving infants.” No the fetal surveillance recommendations of the SOGC 2007 Fetal
Health Surveillance: Antepartum and Intrapartum Consensus
official opinion was given on a gestational age cut-off, but it was
Guideline. (III-A)
recommended that physicians develop specific guidelines around
the issues of inclusion criteria, dosage, concurrent tocolysis, and 11. Since magnesium sulphate has the potential to alter the
neonate’s neurological evaluation, causing hypotonia or apnea,
monitoring in accordance with one of the larger trials.
health care providers caring for the neonate should have an
Sponsors: Canadian Institutes of Health Research (CIHR). increased awareness of this effect. (III-C)
BACKGROUND
ABBREVIATIONS
APH antepartum hemorrhage The Importance of Preterm Birth
CP
IQR
cerebral palsy
interquartile range T he Canadian preterm birth rate overall reached
8.2 % of live births in 2004, with births at < 32 weeks
representing 1.2 % of live births in Canada.1 The survival
IUGR intrauterine growth restriction
of infants born preterm has improved with interventions
NNT number needed to treat
such as antenatal corticosteroids and surfactant. However,
PPROM preterm pre-labour rupture of membranes
survival has been associated with substantial risk of medical
PTL preterm labour
and neurodevelopmental impairment.
Table 1. Key to evidence statements and grading of recommendations, using the ranking of the Canadian Task Force
on Preventive Health Care
Quality of evidence assessment* Classification of recommendations†
I: Evidence obtained from at least one properly randomized A. There is good evidence to recommend the clinical preventive action
controlled trial
II-1: Evidence from well-designed controlled trials without B. There is fair evidence to recommend the clinical preventive action
randomization
II-2: Evidence from well–designed cohort (prospective or C. The existing evidence is conflicting and does not allow to make a
retrospective) or case–control studies, preferably from recommendation for or against use of the clinical preventive action;
more than one centre or research group however, other factors may influence decision-making
II-3: Evidence obtained from comparisons between times or D. There is fair evidence to recommend against the clinical preventive action
places with or without the intervention. Dramatic results in
uncontrolled experiments (such as the results of treatment with E. There is good evidence to recommend against the clinical preventive
penicillin in the 1940s) could also be included in this category action
III: Opinions of respected authorities, based on clinical experience, L. There is insufficient evidence (in quantity or quality) to make
descriptive studies, or reports of expert committees a recommendation; however, other factors may influence
decision-making
* The quality of evidence reported in these guidelines has been adapted from The Evaluation of Evidence criteria described in the Canadian Task Force on
Preventive Health Care.47
† Recommendations included in these guidelines have been adapted from the Classification of Recommendations criteria described in the The Canadian Task
Force on Preventive Health Care.47
Two identified patterns of injury appear to underlie the 3. Ataxic (problems with balance and depth perception)
central nervous system complications of preterm infants: 4. Mixed
(1) intraventricular hemorrhage and (2) white matter injury.
Severe intraventricular hemorrhage (grades 3 and 4) is reliably The most common pattern is spasticity plus athetoid move-
detected by ultrasound and occurs primarily among babies ments.5 CP can be reliably diagnosed by the age of 2 years.
who are born at or before 28 weeks’ gestation. Although the
incidence of severe intraventricular hemorrhage is highest The prevalence of CP is 2 to 2.5 per 1000 live births.6 The risk
at 24 to 25 weeks, severe intraventricular hemorrhage is still of CP is highest at earlier gestational ages. Compared with
a relevant problem up to 28 weeks, because there are more infants born at term, infants born preterm have a CP risk
births at 26 to 28 weeks than at 24 to 25 weeks. MRI is that is approximately 3-fold higher at 34 to 36 weeks,7 8-fold7
required for reliable detection of white matter injury, which to 14-fold8 higher at 30 to 33 weeks, 46-fold higher at 28 to
has a peak prevalence at 28 weeks. Its severity is associated 30 weeks,8 and as high as 30-fold4 to 80-fold8 higher at < 28
with adverse motor and cognitive outcomes.2 weeks.9 The gestational age-related risk is associated, in part,
with very low birth weight (i.e., < 1500 g) and intraventricular
Clinically, the most frequent adverse neurological outcomes hemorrhage.10–12 Multiples are also at heightened CP risk.13
associated with preterm birth are cerebral palsy and cognitive
impairment. Other adverse outcomes include blindness, Temporal trends in the prevalence of CP among infants
deafness, developmental delay, and/or other neurological born very preterm are a matter of controversy. Rates have
impairment. More than 50% of very preterm babies suffer been reported to be both falling14,15 and rising,10,16 possibly
from learning or motor disabilities or school difficulties, because perinatal mortality rates are decreasing, so that the
compared with about 20% of normal birthweight controls.3 rate of “death or CP” among infants born at < 30 weeks
has appeared to be stable.6
The Importance of Cerebral Palsy
Cerebral palsy is a symptom complex of non-progressive What is agreed upon, however, is that the economic
motor impairment syndromes secondary to brain injury or burden associated with CP is enormous. The US Centers
anomalies arising in early development.4 The typical signs of for Disease Control and Prevention estimate that lifetime
CP include spasticity, movement disorders, muscle weakness, health care, productivity, and social costs for a person with
ataxia, and rigidity. There are 4 main types of cerebral palsy: CP are US$921 000 (2003).17
1. Spastic (increased muscle tone) There is no known cure for CP, which makes effective
2. Athetoid or dyskinetic (slow, uncontrolled movements) preventive measures of primary importance. To date, no
Table 2. Inclusion criteria in the randomized controlled trials of magnesium sulphate for fetal neuroprotection
Inclusion criteria*
Multiple Delivery
Women, pregnancy, Gestational likely within PTL, Chorioam- Pre- Severe
Study n % age, weeks 24 hours % PPROM nionitis eclampsia IUGR APH
Neuroprotective intent
ACTOMgSO4 1062 17 < 30 Yes 63 9% 14% 15% 9% 14%
Crowther et al.
200335
PREMAG Marrett 564 22 < 33 Yes 85 61% 11% Excluded Excluded 19%
et al. 200636
MAGnet 57 4 25 to 33+6 NA 100† If Excluded Excluded NA NA
Mittendorf et al. associated
2002— with PTL
neuroprotective
intent arm37
BEAM Rouse 2241 9 24 to 31+6 NA 10 87% NA Excluded Included NA
et al. 200838 by % NA
Other primary intent
MAGnet Mittendorf 92 15 25to 33+6 NA 100 If Yes‡ Excluded NA Yes‡
et al. 2002, tocolytic associated
arm37 with PTL
MAGPIE 200641 10 4 < 37 NA NA NA NA 100% NA NA
141 (but subgroup analyses
were possible for lower
gestational age categories)
LD: loading dose; NA: not available
* indications for at least 90% of study population listed.
† With cervical dilatation > 4 cm and therefore not eligible for tocolysis.
‡ 71.1% had PPROM and 50.8% had chorioamnionitis, but the results were not presented according to whether women were in the tocolytic or neuroprotective intent arms.
antenatal interventions have been identified that effectively vasodilation, reduction in inflammatory cytokines and/or
decrease CP risk among preterm infants. oxygen free radicals, and/or inhibition of calcium influx
into cells.28,29 Animal studies have shown a neuroprotective
Magnesium Sulphate for Neuroprotection effect.30,31
In two studies published in the 1980s, preterm infants
born to women with preeclampsia had a lower incidence From 2002 to 2008, 5 randomized controlled trials (6145
of adverse CNS outcomes than gestational age-matched babies) studied magnesium sulphate for fetal neuroprotection
neonates born to mothers without preeclampsia.18,19 In (Table 2). In 2009, a milestone was reached with the
1995, a seminal case–control study20 was conducted with publication of 3 meta-analyses, all of which concluded that
data derived from the California Cerebral Palsy project.21 magnesium sulphate for fetal neuroprotection decreases
It demonstrated an association between antenatal the risk of childhood CP.32–34 Four trials used magnesium
magnesium sulphate administration prior to preterm sulphate specifically for fetal neuroprotection among women
birth and fewer cases of CP among infants born < 1500 likely to deliver within 24 hours.35–38 The fifth trial26 evaluated
g.20 It has been proposed that use of magnesium sulphate the effectiveness of magnesium sulphate for eclampsia
for eclampsia treatment and prophylaxis may underlie the prevention in women with preeclampsia. Of the 4 trials
potential association between antenatal administration with neuroprotective intent, one also included a tocolytic
of magnesium sulphate and CP,20,22 but the findings arm.37 Three of these 4 trials enrolled primarily women with
of subsequent observational studies investigating the preterm labour (with or without PPROM),35–37 whereas the
association have been inconsistent.23–25 Although the fourth focused on women with PPROM.38 Children were
effectiveness of magnesium sulphate for prevention and followed-up to the age of 2 years for CP assessment, and 3
treatment of maternal eclampsia is well proven, there trials undertook cognitive testing.26,35,38
remains a lack of understanding of how it may act as
a neuroprotective agent.26,27 Magnesium acts in many Study quality was good.32 Importantly, 4 of the 5 trials
intracellular processes, and its actions include cerebral (and all neuroprotective intent trials) described an adequate
Table 3a. Magnesium sulphate versus placebo: perinatal outcomes in neuroprotection trials only
RR (95%CI) Trials, n, Infants, n
Costantine Conde-Agudelo Costantine Conde-Agudelo
Doyle et al.34 and Weiner33 and Romero32 Doyle et al.34 and Weiner33 and Romero32
Primary outcomes
Death or CP 0.85 0.86 Not presented 4 trials, 4 trials, Not presented
(0.74 to 0.98) (0.75 to 0.99) 4446 infants 4314 infants
Death or moderate- 0.85 Not presented Not presented 3 trials, Not presented
severe CP (0.73 to 0.99) 4250 infants
Death or substantial 0.84 Not presented Not presented 3 trials, Not presented Not presented
gross motor dysfunction (0.71 to 1.00) 4387 infants
Death 0.95 0.95 0.95 4 trials, 4 trials, 4 trials,
(0.80 to 1.12) (0.80 to 1.13) (0.80 to 1.12) 4446 infants 4324 infants 4446 infants
CP 0.71 0.71 0.71 4 trials, 4 trials, 4 trials,
(0.55 to 0.91) (0.55 to 0.91) (0.55 to 0.91) 4446 infants 4314 infants 4446 infants
Moderate-severe CP Not presented 0.60 Not presented Not presented 3 trials, Not presented
(0.43 to 0.84) 4250 infants
Substantial gross motor 0.60 Not presented Not presented 3 trials; Not presented Not presented
dysfunction (0.43 to 0.83) 4387 infants
Any neurological 1.03 Not presented Not presented 1 trial, Not presented Not presented
impairment (0.87 to 1.21) 1255 infants
Other neonatal CNS outcomes
IVH 0.96 Not presented Not presented 4 trials to Not presented Not presented
(0.86 to 1.07) 4446 infants
Severe IVH 0.83 Not presented Not presented 2 trials; Not presented Not presented
(grade 3 or 4) (0.62 to 1.13) 3699 infants
PVL 0.93 Not presented Not presented 4 trials to Not presented Not presented
(0.68 to 1.28) 4446 infants
Other infant/child neurodevelopmental outcomes
Developmental delay or 1.00 Not presented Not presented 3 trials, Not presented Not presented
intellectual impairment (0.91 to 1.09) 4387 infants
Major neurological 1.14 Not presented 1.09 1 trial, Not presented 2 trials,
disability (0.86 to 1.51) (0.83 to 1.43) 1255 infants 2060 infants
Blindness 0.97 Not presented 0.97 2 trials, Not presented 2 trials,
(0.14 to 6.90) (0.14 to 6.90) 1943 infants 1943 infants
Deafness 0.51 Not presented 0.51 2 trials, Not presented 2 trials,
(0.05 to 4.96) (0.05 to 4.96) 1943 infants 1943 infants
CNS: central nervous system; IVH: intraventricular hemorrhage; PVL: periventricular leukomalacia.
method of allocation concealment.26,35,36,38 All but the • Active labour with ≥ 4 cm of cervical dilation,
tocolytic arm of Mittendorf et al.37 described double- • with or without PPROM.
masking of outcome assessment.
• Planned preterm birth for fetal or maternal
Magnesium Sulphate Use in Obstetrics • indications.
Magnesium sulphate is widely available and commonly used
in Canadian obstetric practice for eclampsia prophylaxis
and treatment.26,27,39 Magnesium sulphate is no longer Recommendation
recommended for tocolysis, because it is ineffective.34
1. For women with imminent preterm birth
This document summarizes the relevant evidence and (≤ 31+6 weeks), antenatal magnesium sulphate
provides practice recommendations related to the use of administration should be considered for fetal
antenatal magnesium sulphate for fetal neuroprotection neuroprotection. (I-A)
among women with imminent preterm birth.
Summary Statement Table 3a presents the results of the 3 relevant meta-
1. “Imminent preterm birth” is defined as a high analyses of neuroprotective trials,32–34 and shows that
likelihood of birth due to one or both of the antenatal magnesi um sulphate reduced the risk of
following conditions (II-2): “death or CP,” “death or moderate-severe CP,” “any CP,”
Table 3b. Magnesium sulphate versus placebo: perinatal outcomes in all trials of antenatal magnesium sulphate
Doyle et al.34 Costantine and Weiner33 Conde-Agudelo and Romero32
Trials, n Trials, n Trials, n
RR (95% CI) Infants, n RR (95% CI) Infants n RR (95% CI) Infants n
Primary outcomes
Death or CP 0.94 5 trials, 0.92 5 trials, 0.92 5 trials,
(0.78 to 1.12) 6145 infants (0.83 to 1.03) 5225 infants (0.83 to 1.02) 5357 infants
Death or moderate- Not presented Not presented 0.85 3 trials, Not presented Not presented
severe CP (0.73 to 0.99) 4250 infants
Death or substantial 0.92 4 trials, Not presented Not presented Not presented Not presented
gross motor dysfunction (0.75 to 1.12) 5980 infants
Death 1.01 5 trials, 0.95 4 trials, 1.01 5 trials,
(0.82 to 1.23) 6145 infants (0.80 to 1.13) 4324 infants (0.89 to 1.14) 5357 infants
CP 0.69 5 trials, 0.71 4 trials, 0.69 5 trials,
(0.54 to 0.87) 6145 infants (0.55 to 0.91) 4314 infants (0.55 to 0.88) 5357 infants
Moderate-severe CP Not presented Not presented 0.60 3 trials, 0.64 3 trials,
(0.43 to 0.84) 4250 infants (0.44 to 0.92) 4387 infants
Substantial gross motor 0.60 4 trials, Not presented Not presented 0.60 3 trials,
dysfunction (0.43 to 0.83) 4387 infants (0.43 to 0.83) 4387 infants
Any neurological 1.01 2 trials, Not presented Not presented 1.02 2 trials,
impairment ( 0.86 to 1.19 ) 2848 infants (0.86 to 1.20) 2060 infants
Other neonatal CNS outcomes
IVH 0.96 4 trials, Not presented Not presented 0.96 5 trials,
(0.86 to 1.08) 4552 infants (0.86 to 1.08)) 4552 infants
Severe IVH (grade 3/4) 0.83 2 trials, Not presented Not presented 0.83 4 trials,
(0.62 to 1.13) 3699 infants (0.61 to 1.11) 3864 infants
PVL 0.93 4 trials, Not presented Not presented 0.93 5 trials,
(0.68 to 1.28) 4552 infants (0.68 to 1.28) 4552 infants
Other infant/child neurodevelopmental outcomes
Developmental delay or 0.99 4 trials, Not presented Not presented Not presented Not presented
intellectual impairment (0.91 to 1.09) 5980 infants
Major neurological 1.07 2 trials, Not presented Not presented 1.09 2 trials,
disability (0.82 to 1.40) 2848 infants (0.83 to 1.43) 2060 infants
Blindness 0.74 3 trials, Not presented Not presented 0.97 2 trials,
(0.17 to 3.30) 3536 infants (0.14 to 6.90) 1943 infants
Deafness 0.79 3 trials, Not presented Not presented 0.51 2 trials,
(0.24 to 2.56) 3536 infants (0.05 to 4.96) 1943 infants
CNS: central nervous system; IVH: intraventricular hemorrhage; PVL: periventricular leukomalacia.
“moderate-severe CP,” and “substantial gross motor of a placebo arm, that crossover was allowed, and that 3
dysfunction” (inability to walk without assistance) at 2 of the 8 neonatal deaths in the magnesium sulphate arm
years of age. The direction of effect was the same for were related to congenital anomalies (n = 1) or twin-to-
death or substantial gross motor dysfunction, but this did twin transfusion (n = 2).
not reach statistical significance. Results were consistent
between trials and across the meta-analyses. Use of
When the tocolytic arm of the MAGnet Trial40 and
magnesium sulphate was not associated with an increase
in pediatric death. The tocolytic arm of one study37 was results of the preeclampsia prophylaxis trial (MAGPIE)41
stopped early because of an increase in pediatric mortality; were included in the meta-analyses, antenatal magnesium
although this is consistent with the effects of magnesium sulphate was shown to reduce the risk of death or moderate-
sulphate administered as a tocolytic in other studies,34 severe CP, any CP, moderate-severe CP, and substantial
there were other quality issues with the Mittendorf et gross motor dysfunction; the outcome of death or CP no
al. tocolytic arm. These included the confounding effect longer reached statistical significance (Table 3b). Although
of multiple births (i.e., more in the magnesium sulphate such analyses support the use of magnesium sulphate to
arm), the low quality score (Jahad score of 2/8 when the decrease CP, the results of the neuroprotective intent trials
other neuroprotective intent trials scored 7–8/8), the lack suggest a change in clinical practice.
Table 4a. Subgroup analyses by gestational age at randomization: neuroprotective trials only35–38
RR (95% CI) NNT to prevent harm
Weeks Death or CP CP Death or CP CP Trials, n, infants, n
< 34 0.85 (0.74 to 0.98) 0.71 (0.55 to 0.91) 43 53 5 trials, 6145 infants
< 32 0.86 (0.74 to 1.00) 0.68 (0.52 to 0.91) 43 50 3 trials, 3981 infants
< 30* 0.87 (0.74 to 1.03) 0.69 (0.48 to 0.99) 36 53† 3 trials, 2475 infants
< 28* 0.95 (0.74 to 1.22) 0.45 (0.23 to 0.87) 91 30 1 trial, 938 infants
* Includes the < 28 week subgroup of Rouse et al.38 which had women as the denominator.
† Inclusion of only the Crowther et al.35 trial and exclusion of the BEAM data (Rouse et al.38) give an NNT of 24.
This also includes the < 30 week subgroup data provided by the MAGPIE trial.
† In the Cochrane review,34 the < 30 week subgroup did not include the BEAM trial data for < 28 week38 and the NNT was 50.
A more useful post hoc analysis would be to examine CP risk considerations, including the accuracy of gestational age
reduction within gestational age strata (32 to 33 weeks, 30 determination and resource allocation.
to 31 weeks, 28 to 29 weeks, and < 28 weeks) to identify the
gestational age at which babies may be most likely to benefit. Table 2 presents the baseline characteristics of women who
In the BEAM trial,38 analyses were stratified by gestational were enrolled in the relevant randomized controlled trials.
age (< 28 vs. 28 to 31 weeks). Although it appeared as if In 3 of the 4 neuroprotective intent trials, most women
the decrease in CP was confined to the < 28-week subgroup, had preterm labour with anticipated delivery within 24
the test for interaction by gestational age was actually not hours. This is not equivalent to threatened preterm labour
significant. This should be interpreted as revealing no for which tocolysis is an option in the hope/expectation
difference in magnesium effect on CP rate by gestational of being able to arrest labour; this must be emphasized
age up to 31+6 weeks. In MAGPIE,41 which was not a to prevent potential overuse of magnesium sulphate for
neuroprotective intent trial and which underreported CP, neuroprotection in patients who are not truly in labour. The
CP risk was similar at < 30 weeks (RR 1.04; 95% CI 0.06 to other major indications for very preterm delivery (APH or
16.06) and at 30 to 33 weeks (RR 0.95; 95% CI 0.71 to 1.27). IUGR) were present in a minority of women enrolled in the
relevant trials. Although many women also had PPROM,
In summary, CP risk is highest at earlier gestational ages, only the BEAM trial38 enrolled women with PPROM
but these very preterm infants are fewer in number. Use without associated preterm labour. In this guideline,
of magnesium sulphate at gestational ages closer to 34 these women are not included as eligible for magnesium
weeks has the potential to substantially increase overuse of sulphate for neuroprotection. First, in the BEAM trial, re-
magnesium sulphate for women with threatened preterm treatment with magnesium was administered for 59.1%
birth who do not deliver in the subsequent 24 to 48 hours. of women. Second, women with PPROM who are not in
Therefore, consensus was reached to recommend an upper labour are not necessarily in a delivery suite and receiving
gestational age cut-off of < 32 weeks (i.e., ≤ 31+6 weeks) one-to-one nursing care; administration of magnesium
to strike a balance between appropriate use of magnesium for neuroprotective intent could have significant hospital
sulphate at earlier gestational ages and potential overuse resource implications for these women.
of magnesium sulphate at later gestational ages, when
neurological morbidity is lower. Institutions may choose All trials excluded women with the usual contraindications to
different thresholds (< 34 weeks) according to other magnesium sulphate (i.e., hypersensitivity to the drug, hepatic
Table 5. Inclusion and exclusion criteria for antenatal much lower, at 6.5 g (IQR of 4.5 to 14.0 g),35 when women
magnesium sulphate administration in randomized were enrolled primarily for preterm labour, reflecting a very
controlled trials short median time from enrolment to delivery.
Inclusion criteria Exclusion criteria
Singleton and multiple Magnesium sulphate already
There have been no direct comparisons of different dosing
pregnancies administered for preeclampsia/ regimens of magnesium sulphate for neuroprotection.
eclampsia A loading dose of 4 g IV with a maintenance infusion of
Nulliparous and parous < 12 hours since discontinuation 1 g/hr has been recommended to (1) resemble current
of previous magnesium sulphate clinical practice and hospital protocols for magnesium
infusion
sulphate for eclampsia prophylaxis and treatment, and
Anticipated vaginal or Magnesium sulphate
Caesarean delivery contraindicated
(2) minimize concerns about maternal safety, particularly as
Any reason for anticipated Fetus unlikely to benefit
higher dosing regimens have not been associated with greater
preterm birth neuroprotection. Trials that administered maintenance
infusions treated for a maximum of 24 hours antenatally.
YES NO
CLINICAL TIPS
• MgSO4 may be administered before tocolytic drugs have been cleared from the maternal
circulation. If nifedipine has been used for tocolysis or hypertension, there is NO
contraindication to the use of MgSO4 for fetal neuroprotection.
• Delivery should NOT be delayed in order to administer antenatal MgSO4 for fetal
neuroprotection if there are maternal and/or fetal indications for urgent delivery.
• Monitoring of serum Mg levels is NOT required.
“Imminent preterm birth” is defined as a high likelihood of birth, due to one or both of the following conditions: active
labour with ≥4 cm of cervical dilation, with or without PPROM; planned preterm birth for fetal or maternal indications.
maternal urine output should not be required to the same observed but are more frequent when magnesium sulphate
degree (i.e., no requirement for Foley catheter) when is prepared in the delivery suite rather than by a central
magnesium sulphate is given with neuroprotective intent. pharmacy.
Magnesium sulphate produces peripheral vasodilation Because of their underlying condition, women with
when infused intravenously. In neuroprotective intent imminent preterm birth require continuous fetal heart rate
trials, dose-related effects were common, particularly monitoring, in accordance with the SOGC fetal health
flushing, problems at the injection site, sweating, and surveillance guidelines.42
nausea and vomiting (Table 7). Serious maternal side effects Recommendations
were uncommon, with only maternal hypotension and
tachycardia reaching statistical significance. Few women 10. Indications for fetal heart rate monitoring in
discontinued magnesium sulphate because of side effects. women receiving antenatal magnesium sulphate for
Neither maternal death nor cardiorespiratory arrest was neuroprotection should follow the fetal surveillance
reported in the magnesium sulphate arm of these trials. recommendations of the SOGC’s 2007 Fetal Health
Surveillance: Antepartum and Intrapartum Consensus
Monitoring of maternal serum magnesium levels is not Guideline. (III-A)
required when magnesium sulphate is administered solely 11. Since magnesium sulphate has the potential to
for fetal neuroprotection. Maternal adverse effects are alter the neonate’s neurological evaluation, causing
dose-related, with respiratory or cardiac arrest associated hypotonia or apnea, health care providers caring for
with levels in excess of 5 mmol/L. Levels of this magnitude the neonate should have an increased awareness of
are not anticipated when magnesium contraindications are this effect. (III-C)
Table 6. Magnesium sulphate dosing in the randomized controlled trials of magnesium sulphate for fetal
neuroprotection
Intervention: MgSO4
Women who Median (IQR) dose
Study Women, n Loading dose received the LD, % Maintenance dose received (g)
Neuroprotective intent
ACTOMgSO4 1062 4g IV over 20 mins 90% 1g/hr IV for 24 hr or 6.5 (4.5, 14)
Crowther et al. 200335 until delivery, whichever
comes first
PREMAG Marrett et al. 564 4g IV over 30 mins 99% None given 4 g IV over 30 mins
200636
MAGnet Mittendorf et al. 57 4g IV bolus Not reported Neuroprotective arm: Not reported
2002—neuroprotective none
intent arm37 (Tocolysis arm: 2–3g/hr)
BEAM Rouse et al. 200838 2241 6g IV over > 90%† 2 g/hr IV for a maximum 31.5 (29.0, 44.6)
20–30 mins* of 12 hr or until delivery†
Other primary intent
MAGnet Mittendorf et al. 92 4g IV “bolus” Not known 2–3 g/hr Not reported
2002—tocolytic arm37
MAGPIE 200641 10 141 4g IV over 96% 1g/hr IV (or 5g/4hrs IM) 18 (9, 29)‡
10 to15 mins for 24 hours
LD: loading dose; NA: not available.
* 71.5% of women were eligible for re-treatment. 59.1% of women were re-treated and were on magnesium sulphate at delivery.
† Based on the fact that 91% of women were on magnesium sulphate for at least three hours.
‡ Estimated as value uncertain from published data.33
The relevant randomized controlled trials34 raise no concerns Few newborn subjects with in utero exposure to magnesium
about short-term neonatal adverse effects of antenatal sulphate remote from delivery were included in the
exposure, and no additional neonatal assessment or care relevant trials. There is no clear rationale for any additional
is required. Neonates with hypermagnesemia may present assessment of these newborns.
with symptoms of apnea or hypoventilation, weakness,
There should be an ongoing registry of children exposed
hypotonia, absent or reduced deep tendon reflexes, and
to antenatal magnesium sulphate for neuroprotection. This
stupor or coma. This symptom complex has been described
would allow evaluation of the following:
in the neonates of mothers administered large doses of IV
magnesium sulphate for eclampsia with neonatal serum 1. Effects on delivery room resuscitation, especially in
levels > 4.5 mEq/L.43 However, antenatal magnesium sul- units with ventilation-avoidance protocols
phate administered specifically for fetal neuroprotection did 2. Anticipated reduction in CP
not affect the incidence of Apgar score < 7 at 5 minutes 3. Effect on the high prevalence of school age morbidities
(RR 1.03; 95% CI 0.90 to 1.18; 3 trials, 4387 infants), among infants born preterm.
neonatal hypotonia (RR 1.02; 95% CI 0.77 to 1.36; 1 trial,
2444 infants), or the need for ongoing ventilatory support SPECIAL CONSIDERATIONS REGARDING
(RR 0.94; 95% CI 0.89 to 1.00; 3 trials; 4387 women). None THE USE OF MAGNESIUM SULPHATE
of the main trial publications reported on the need for active FOR FETAL NEUROPROTECTION
resuscitation at birth,34 but a subanalysis of the BEAM trial Transport
found no correlation between cord blood magnesium levels
When maternal transport is being considered, magnesium
and the need for bag-mask ventilation, intubation, or chest
administration should be decided on in consultation with
compressions.44 It is unknown whether magnesium sulphate
the receiving centre, on a case-by-case basis.
exposure would affect the need for ventilation in neonatal
intensive care units using protocols to minimize ventilation. Drug Interactions
Antenatal corticosteroids should be administered for fetal
The relevant randomized controlled trials35–38 demonstrated lung maturation.
no other differences in neonatal morbidity, including
seizures, respiratory distress syndrome, bronchopulmonary When tocolysis has been employed to attempt to arrest
dysplasia, or necrotizing enterocolitis. preterm labour, magnesium sulphate can be used once
tocolysis has been discontinued because delivery is for fetal neuroprotection (excellent evidence) in the same
considered imminent. If nifedipine has been used for dosage as recommended in these guidelines. However,
tocolysis or hypertension, there is no contraindication to magnesium was recommended only at < 30 weeks’ gestation
the use of magnesium sulphate for fetal neuroprotection. (good evidence) on the basis of two considerations. First,
Although case reports have described neuromuscular no one gestational age subgroup (of the < 34, < 33, < 32,
blockade with concomitant use of magnesium sulphate and and < 30 week categories considered) was considered to
nifedipine or other calcium channel blockers, a controlled
show a clear benefit, although the < 28 week subgroup of
study and synthesis of the literature failed to demonstrate
Rouse et al.38 was not included, because the committee felt
an increased risk.42
that the predominance of PPROM in that study population
Potential Obstetrical Adverse Outcomes limited generalizability to the target population of women
In the Conde-Agudelo and Romero meta-analysis,32 mag- with imminent preterm labour (which the committee
nesium sulphate given with neuroprotective intent was not defined as planned or definitely expected within 24 hours).
associated with a difference in Caesarean section (822 [42.9%] Second, in the face of uncertainty, the committee felt it
in the magnesium arm vs. 834 [42.8%] for placebo; RR 1.0; was prudent to limit the impact of their clinical practice
95% CI 0.9 to 1.1; 3 trials, 3867 women) or severe
guidelines on resource allocation.
postpartum hemorrhage (28 [3.4%] in the magnesium
arm vs. 26 [3.2%] for placebo; RR 1.1; 95% CI 0.6 to 1.8; Also in March 2010, the American College of Obstetricians
2 trials, 1626 women). None of the trials reported on length and Gynecologists issued a committee opinion on magnesium
of labour or augmentation of labour. sulphate for fetal neuroprotection. It stated that “the
available evidence suggests that magnesium sulphate given
CLINICAL PRACTICE GUIDELINES before anticipated early preterm birth reduces the risk of
AND COMMITTEE OPINION cerebral palsy in surviving infants.” No official opinion was
Australian National Clinical Practice Guidelines45 were given on a gestational age cut-off, but it was recommended
published in March 2010 by the Antenatal Magnesium that physicians develop specific guidelines around the issues
Sulphate for Neuroprotection Guideline Development of inclusion criteria, dosage, concurrent tocolysis, and
Panel. They recommended antenatal magnesium sulphate monitoring in accordance with one of the larger trials.46
40. Mittendorf R, Covert R, Boman J, Khoshnood B, Lee KS, Siegler M. Is Bethesda MD. Correlation of cord blood magnesium level with neonatal
tocolytic magnesium sulphate associated with increased total paediatric resuscitation requirements in preterm infants. Presented at: Pediatric
mortality? Lancet 1997;350(9090):1517–8. Academic Societies Meeting; May 2010; Vancouver BC.
41. The Magpie Trial: a randomised trial comparing magnesium sulphate with
placebo for pre-eclampsia. Outcome for children at 18 months. BJOG 45. The Antenatal Magnesium Sulphate for Neuroprotection Guideline
2007;114:289–99. Development Panel. Antenatal magnesium sulphate prior to preterm birth
for neuroprotection of the fetus, infant and child: national clinical practice
guidelines. The Australian Research Centre for Health of Women and
42. Liston R, Sawchuck D, Young D; SOGC Fetal Health Surveillance
Babies, The University of Adelaide; 2010.
Consensus Committee. Fetal health surveillance: antepartum and
intrapartum consensus guideline. SOGC clinical practice guideline no. 197,
September 2007. J Obstet Gynaecol Can 2007;29(Suppl 4):S1-S58. 46. Magee LA, Miremadi S, Li J, Cheng C, Ensom MH, Carleton B, et al.
Therapy with both magnesium sulfate and nifedipine does not increase
the risk of serious magnesium-related maternal side effects in women with
43. Volpe JJ. Neurology of the newborn. 4th ed. Philadelphia: W.B. Saunders;
preeclampsia. Am J Obstet Gynecol 2005;193:153–63.
2001.
47. Woolf SH, Battista RN, Angerson GM, Logan AG, Eel W. Canadian
44. Johnson L; for the Eunice Kennedy Shriver, National Institute of Child Task Force on Preventive Health Care. New grades for recommendations
Health and Human Development Maternal Fetal Medicine Units Network, from the Canadian Task Force on Preventive Health Care. CMAJ
2003;169:207–8.
This document reflects emerging clinical and scientific advances on the date issued and is subject to change. The information
should not be construed as dictating an exclusive course of treatment or procedure to be followed. Local institutions can dictate
amendments to these opinions. They should be well documented if modified at the local level. None of these contents may be
reproduced in any form without prior written permission of the SOGC.
S
Health Care. Recommendations for practice were ranked
according to the method described in that report (Table 1). ubstance use during pregnancy is common. In national
Benefits, harms, and costs: This guideline is intended to increase
prevalence surveys, 14% of Canadian women reported
the knowledge and comfort level of health care providers using alcohol during their last pregnancy, and 17% reported
caring for pregnant women who have substance use disorders. smoking during pregnancy.1,2 The prevalence of illicit drug
Improved access to health care and assistance with appropriate use among Canadian women of childbearing age is less but
addiction care leads to reduced health care costs and decreased
maternal and neonatal morbidity and mortality. not insignificant. In United States population surveys ~5%
Recommendations
of pregnant women reported illicit drug use during the
preceding month.3 Marijuana remains the most commonly
1. All pregnant women and women of childbearing age should be
screened periodically for alcohol, tobacco, and prescription and used illegal drug, followed by cocaine. Women report
illicit drug use. (III-A) higher rates than men of prescription drug use, including
2. When testing for substance use is clinically indicated, urine drug pain relievers (23.1%), opioid analgesics (2.1%), sleeping
screening is the preferred method. (II-2A) Informed consent pills (1.7%), tranquilizers (1.1%), and antidepressants
should be obtained from the woman before maternal drug
(2.1%).2
toxicology testing is ordered. (III-B)
3. Policies and legal requirements with respect to drug testing of
newborns may vary by jurisdiction, and caregivers should be
The use of alcohol and drugs by pregnant women can result
familiar with the regulations in their region. (III-A) in significant maternal, fetal, and neonatal morbidity.4–17 In
general, pregnant women with substance use disorders are
less likely to seek prenatal care, and they have higher rates
of infectious diseases such as HIV, hepatitis, and other
ABBREVIATIONS sexually transmitted infections.17–19
HCV hepatitis C virus
MMT methadone maintenance therapy
There are numerous direct and indirect costs of perinatal
NAS neonatal abstinence syndrome
substance exposure. In 2002, the overall social cost of
substance abuse in Canada, including burden on health
NRT nicotine replacement therapy
care, law enforcement, and loss of productivity due to
UDS urine drug screening
premature death and ill health, totalled ~$40 billion.20 Data
Table 1. Key to evidence statements and grading of recommendations, using the ranking of the Canadian Task Force
on Preventive Health Care
Quality of evidence assessment* Classification of recommendations†
I: Evidence obtained from at least one properly randomized A. There is good evidence to recommend the clinical preventive action
controlled trial
II-1: Evidence from well-designed controlled trials without B. There is fair evidence to recommend the clinical preventive action
randomization
II-2: Evidence from well–designed cohort (prospective or C. The existing evidence is conflicting and does not allow to make a
retrospective) or case–control studies, preferably from recommendation for or against use of the clinical preventive action;
more than one centre or research group however, other factors may influence decision-making
II-3: Evidence obtained from comparisons between times or D. There is fair evidence to recommend against the clinical preventive action
places with or without the intervention. Dramatic results in
uncontrolled experiments (such as the results of treatment with E. There is good evidence to recommend against the clinical preventive
penicillin in the 1940s) could also be included in this category action
III: Opinions of respected authorities, based on clinical experience, L. There is insufficient evidence (in quantity or quality) to make
descriptive studies, or reports of expert committees a recommendation; however, other factors may influence
decision-making
*The quality of evidence reported in these guidelines has been adapted from The Evaluation of Evidence criteria described in the Canadian Task Force on
Preventive Health Care.161
†Recommendations included in these guidelines have been adapted from the Classification of Recommendations criteria described in the The Canadian Task
Force on Preventive Health Care.161
(Figure 1).33,34 The ALPHA tool incorporates the CAGE Table 2. Definitions of substance-related disorders
questionnaire to screen for maternal recreational drug Substance
use, as well as validated questions to identify associated use disorder Definition
psychosocial risk factors such as family violence or Substance A pattern of substance use, leading to
postpartum depression (Appendix).35,36 If the woman dependence clinically significant impairment or distress, as
manifested by ≥ 3 of the following, occurring at
acknowledges substance use, a more complete assessment
any time in the same 12-month period:
is then recommended to determine if there is a history of
1. tolerance
substance abuse or dependence (Figure 2).
2. withdrawal
3. substance taken in larger amounts or over a
Role of Toxicology Testing longer period than was intended
Drug toxicology testing is not recommended for universal
4. persistent desire or unsuccessful efforts to
screening (i.e., routine testing of all women) because it has cut down or control substance use
numerous limitations (Figure 3), and it should be considered 5. a great deal of time spent in activities
only after a comprehensive assessment if there is a clinical necessary to obtain the substance (e.g.,
indication.37 If a woman is concerned about providing visiting multiple doctors or driving long
distances), use the substance (e.g., chain-
a sample or is reluctant to do so, clinicians should focus smoking), or recover from its effects
on developing a trusting relationship before suggesting
6. important social, occupational, or
toxicology testing. Vulnerable women may feel threatened recreational activities given up or reduced
if clinicians wish to gather detailed information through because of substance use
drug testing and psychosocial histories. 7. continued use despite knowledge of harm
Substance abuse A pattern of substance use leading to
Urine, hair, and meconium samples are sensitive biological clinically significant impairment or distress, as
manifested by ≥ 1 of the following, occurring
markers of substance use. Urine drug screening can detect within a 12-month period:
only recent substance exposure, while neonatal hair and
1. recurrent substance use resulting in a
meconium testing can document intrauterine use because failure to fulfill major role obligations at work,
meconium and hair form in the second and third trimester, school, or home
respectively.38–41 By itself, a single positive test result cannot 2. recurrent substance use in situations in
be used to diagnose substance dependence. Although which it is physically hazardous
child protection agencies sometimes request hair analyses, 3. recurrent substance-related legal problems
neither hair nor meconium is appropriate for routine 4. persistent or recurrent social or interpersonal
clinical use because of the high costs and propensity for problems caused or exacerbated by the
effects of the substance
false positive results.
Tolerance Characterized by a need for markedly
increased amounts of the substance to
UDS has several clinical indications. Evidence shows that achieve desired effect or diminished effect with
the addition of urine drug testing to the structured maternal continued use of the same amount of
the substance
interview can increase the detection of problematic
substance use in pregnancy.42,43 Detection can facilitate
early intervention, including treatment of maternal and
neonatal withdrawal and counselling and referral for long- this should be documented, and testing should not be
term outpatient treatment. For example, an unexpected performed. Neonatal toxicology testing may be performed
positive UDS result for opioids may prompt an assessment without consent of the parent(s) if the person requesting
for opioid dependence and observation of the neonate for this testing has a legislative right to make decisions for
signs of withdrawal. Ongoing outpatient monitoring with the infant to be tested. However, the mother should be
UDS is also used to advocate on behalf of patients with informed that the neonate is being tested.34 Once consent
child protection services and to monitor compliance with is obtained, any drug toxicology testing to be performed
prescribed medications (e.g., opioids).34,38 In addition, it can must be ordered by the physician responsible for maternal
be performed on maternal request. and/or neonatal care.
2. When testing for substance use is clinically indicated, use, treatment of withdrawal symptoms, counselling and/
urine drug screening is the preferred method. (II-2A) or pharmacotherapy. Pregnancy may motivate women to
Informed consent should be obtained from the woman abstain from or reduce drug use, given the potential effects
before maternal drug toxicology testing is ordered. on fetal outcomes.
(III-B)
Pregnant substance-using women are also at increased
3. Policies and legal requirements with respect to drug risk of infectious diseases. Injection drug use remains the
testing of newborns may vary by jurisdiction, and most dominant mode of hepatitis C virus acquisition.
caregivers should be familiar with the regulations in Approximately, 70% to 80% of HCV-infected patients
their region. (III-A) report a history of current or past injection drug use.59
HCV-negative women should be advised about ways to
Components of office management prevent exposure to HCV. Women should be told not to
share materials to prepare, inject, or inhale drugs, and that
Obstetrical care providers need to establish rapport they should not engage in higher risk sexual behaviours
with substance-using pregnant women through good (e.g., unprotected sex with multiple sexual partners or
communication and a willingness to be flexible in providing unprotected sex with HCV-positive partners). Pregnant
prenatal care and ongoing support. These women face a HCV-infected women have a 5% chance of transmitting
number of barriers to receiving optimal prenatal care the virus to their infants.60 There are no ways to decrease
(Figure 4).45–48 Flexibility with respect to patient scheduling the risk of vertical transmission. Furthermore, mode of
and understanding late arrivals and missed appointments delivery and breastfeeding do not affect mother-to-infant
are key to engaging these women for prenatal care. Women transmission. Procedures that promote mixing of maternal
are likely to seek and commit to prenatal care if health care and fetal blood, such as use of scalp electrodes, should be
providers are welcoming and non-judgemental, and if they avoided, if possible. Serology testing of infants at 12 to 18
acknowledge the women’s courage and persistence in the months of age is recommended to determine HCV status.
face of very difficult personal circumstances. Studies have
shown that comprehensive care provided at one site is cost- The prevalence of sexually transmitted infections is also
effective and produces better outcomes for both mother higher among pregnant women with a history of substance
and child.9,19,49–58 abuse related to high-risk sexual behaviours.61,62 Screening
for Chlamydia, gonorrhea, syphilis, hepatitis, and HIV
It is also important to address women’s substance use should be repeated throughout pregnancy if historical
because pregnancy is an ideal time for women to make a factors warrant it.63
change. Harm reduction is defined as a program or policy
designed to reduce the drug-related harm without requiring There are numerous adverse effects associated with
the cessation of drug use.30 The philosophy of care for prenatal drug exposure (Table 4). These effects may also
women with problematic substance use in pregnancy is be linked to other factors such as inadequate prenatal care,
harm reduction. Components of this philosophy include poor social circumstances, and concomitant use of other
encouragement of abstinence or reduction of use, safe substances.64,65 Therefore, long-term studies are difficult to
T-ACE
T How many drinks does it take to make you feel high? (Tolerance)
A Have people annoyed you by criticizing your drinking?
C Have you felt you ought to cut down on your drinking?
E Have you ever had a drink first thing in the morning to steady your nerves or get rid
of a hangover? (Eye-opener)
Scoring: T: 2 points if > 3 drinks; A,C,E: 1 point for each yes answer
A total of 2 or more points indicates patient is likely to have an alcohol problem.
TWEAK
T Tolerance
W Have friends or relatives complained about your drinking? (Worried)
E Eye-opener
A Has a friend or family member ever told you about things you said or did while you
were drinking that you could not remember? (Amnesia or black-out)
K Cut-down
Scoring: T: 2 points if > 3 drinks; W, E, A, K: 1 point for each yes answer
A total of score of 3 or more points indicates patient is at-risk drinking
Complete drug history: name of drug, amount, frequency, duration, route(s), last use,
injection drug use, sharing needles/paraphernalia, withdrawal symptoms
Stage of change with respect to substance use
• Consequences of drug use: medical, social, personal
• Previous treatment programs, mutual aid groups (e.g., AA)
Medical history: HIV, Hepatitis B and C, STIs
• Chronic medical conditions (e.g., chronic pain), medications
Psychiatric history: eating disorders, sexual/physical abuse, mood and
anxiety disorders
Obstetrical history: cycle regularity, LMP, past obstetrical outcomes and
complications
Social history: family situation (partner and number of children), custody status,
housing situation, legal status (current charges and court dates), finances, nutrition,
child protection agency involvement, child safety concerns
FIFE: feelings, impressions/ideas, functioning, expectations about pregnancy
and drug use
interpret because effects may be due to these confounders frequency of antenatal testing will be determined by the
and environmental deprivation rather than the drug itself. presence or absence of these complications.66
In addition to routine care, patients should be given
counselling regarding the drug-specific fetal, neonatal, and There are two phases to the management of substance
maternal effects of substance use. use disorders. The first addresses treatment of withdrawal
syndromes. Pregnant women who are dependent on alcohol,
Antenatal fetal surveillance should be based on obstetrical opioids, or high-dose benzodiazepines (> 50 mg daily
indications rather than solely on substance use. Substance diazepam equivalent) may require medical detoxification
use during pregnancy has been associated with obstetrical under the supervision of a physician (Table 5).30 Women
complications such as preterm labour, placental abruption, who are in withdrawal from other substances, such as
and intrauterine growth restriction (Table 4), and these cocaine or marijuana, may also benefit from a supportive
adverse effects may lead to an increased risk of perinatal admission to a non-medical withdrawal management
morbidity and mortality. Therefore, the method and centre, if available.
• Women can avoid detection of substances in urine samples through simple measures such as abstaining
for 1–3 days before testing, drinking lots of water to lower the concentration of the drug in the urine, or
substituting samples of another person’s urine for their own
• Alcohol is very hard to detect with laboratory testing (blood and urine sampling) because of its short half-life
• The amount of drug in a hair sample correlates with degree of drug use (which is not the case with urine
drug testing); however, a positive finding is not diagnostic of addiction
• Hair analysis can have false-positive results due to passive exposure to smoked drugs in environment
• A false positive result can have serious legal and emotional consequences for the mother
• Personal factors: shame, stigma, guilt, lack of family support, substance using male partner, fear of losing
children, concomitant psychosocial issues (e.g., transportation, child care)
• Systemic factors: lack of appropriate treatment services for pregnant women, negative attitudes of health
care providers
The second phase focuses on relapse prevention by health (e.g., food and housing). The cornerstone of care
encouraging substance abuse treatment and development of problematic substance use in pregnant women is harm
of a supportive network. Brief interventions can range reduction. Components of this include encouragement
from simple physician advice to motivation counselling of abstinence or reduction of use, safe use, treatment of
sessions consisting of goal setting, problem solving with withdrawal, counselling, and/or pharmacotherapy.
respect to triggers, and information on potential harms.
These interventions are effective in reducing alcohol Any health care provider who has a clinical suspicion based
use among pregnant women.67,68 Currently, there are no on history and/or physical examination that a child is or
research data on the effectiveness of similar interventions may be in need of protection because of abuse or neglect
for illicit substance use in pregnancy. However, systematic must make a report to child protection services.81 Health
reviews have shown that outpatient psychotherapy for care professionals should be aware of province-specific
cannabis dependence is moderately effective at reducing legislation with respect to child welfare and reporting
substance use in non-pregnant patients.69,70 Therefore, responsibilities. Clinicians are not required to report until
physician counselling may also be of benefit to pregnant birth, because unborn babies do not have any legal rights,
women. Pharmacological maintenance options are available but antenatal self-reporting is encouraged to increase
for management of nicotine and opioid dependence. maternal self-determination, dignity, and stability and
Evidence suggests that enhanced treatment programs for the establishment of a treatment plan. However, if other
opioid dependence that combine methadone maintenance children present in the home are deemed to be at risk,
therapy, group psychotherapy, and obstetrical care result earlier referral to child protection is indicated to ensure
in less overall illicit substance use, improved prenatal care, the safety of these children. Health care professionals
and lower rates of obstetrical complications.19,52,71–73 Evaluation should advocate on behalf of women involved with
of comorbid conditions should include screening for child protection agencies and should encourage a positive
depression, anxiety, and other mental health disorders, relationship between mothers and workers. A history of
domestic violence and abuse, and psychosocial support substance dependence is not incompatible with ability to
system. Most women in substance abuse treatment parent.
programs report a past history of trauma (including physical
and sexual abuse), and approximately 25% have been Recommendations
diagnosed with posttraumatic stress disorder.74–76 Partner 4. Health care providers should employ a flexible
involvement in prenatal care and addiction treatment approach to the care of women who have substance
is critical to recovery.56 A partner’s active drug use has use problems, and they should encourage the use of
been linked to delayed treatment time for women seeking all available community resources. (II-2B)
care.77,78 Similarly, women with fewer social supports are less
likely to seek and to remain in treatment.79,80 Appropriate 5. Women should be counselled about the risks of
referrals may include counselling to deal with pre-existing periconception, antepartum, and postpartum drug
trauma and assistance with other social determinants of use. (III-B)
nicotine DEPENDENCE Pharmacotherapy
Controlled trials have failed to demonstrate that nicotine
Smoking Cessation Counselling replacement therapy increases smoking cessation
Smoking cessation interventions are effective in reducing the rates, although it may reduce the number of cigarettes
number of women smoking during pregnancy regardless of smoked.90,91 NRT (gum, lozenge, or patch), combined
intensity or provider delivering the intervention.82–87 Lower with cognitive behavioural therapy, results in higher quit
rates of preterm delivery and low birth weight infants are rates during pregnancy than counselling alone.92 The
additional benefits of smoking cessation interventions. safety of NRT is unknown since the link between NRT
A variety of interventions have been studied ranging and congenital anomalies and poor perinatal outcomes is
from simple advice to cognitive behavioural strategies for uncertain.90,92–96 However, women may be offered NRT if
quitting smoking. Women also often received pregnancy- they continue to smoke despite counselling and after an
specific self-help materials and telephone counselling to informed discussion regarding the benefits and risks during
support smoking cessation. pregnancy.82,83,97,98 Intermittent dosage NRT preparations
such as nicotine gum or nasal spray may be preferable to
These interventions are estimated to be highly cost-effective the patch, which gives a continuous dose of nicotine. The
with savings of US$3 in health-related costs for every lowest effective dose of NRT is advised. If the patch is
US$1 spent on smoking cessation for pregnant women.88 used, the patient may consider removing it at night. NRT
However, brief interventions are ineffective in preventing should be discontinued if the woman continues to smoke
postpartum relapse to smoking.89 at the same rate.
Buproprion and varenicline are effective in non-pregnant a full opioid agonist that has an increasing effect with higher
populations. There are limited safety data on the use doses. There are numerous benefits of methadone use
of these medications during pregnancy.82,83,97 To date, during pregnancy, including improved prenatal care,12,107–109
bupropion has not been associated with malformations longer gestation,50,110 higher birth weight,111,112 and increased
during pregnancy.83,97,99 Preliminary evidence from a small rates of infants discharged home in the care of their
study suggests that bupropion is effective for smoking mothers.4,12,18,49,101,108,113–118 Although infants of methadone-
cessation during pregnancy.100 Further research is needed on treated women tend to be smaller (lower birth weight,
the safety and efficacy of bupropion and varenicline before length, and head circumference) than drug-free controls,
they can be recommended for routine use in pregnancy. studies have shown a catch-up of growth by 12 months of
age.118,119 Urgent consultation with an addiction medicine
Recommendation specialist should be sought to facilitate rapid access to MMT
6. Smoking cessation counselling should be considered during pregnancy. Close monitoring of methadone dosing
as a first-line intervention for pregnant smokers. (I-A) during pregnancy is recommended, especially during the
Nicotine replacement therapy and/or pharmacotherapy third trimester when methadone metabolism and clearance
can be considered if counselling is not successful. (I-A) are increased and dose augmentation is required.120,121
Pregnant women should receive the methadone dose
OPIOID DEPENDENCE that is required for their opioid dependence, because
the literature reports inconsistent results regarding the
Opioid Detoxification association between maternal methadone dose and severity
Opioid detoxification is defined as medication-assisted of neonatal withdrawal. Prenatal discussion with the
withdrawal for opioid-dependent patients. There is good methadone prescribing physician is recommended to plan
evidence that detoxification in the second and third trimesters for intrapartum methadone dosing.
of pregnancy is not linked to increased adverse perinatal
events. Recent studies have failed to show any significant Any regular, daily antenatal opioid exposure (e.g., morphine,
increased rates of obstetrical complications following opioid codeine, oxycodone, methadone, or buprenorphine) can
detoxification.91,93,94,101 Regardless, opioid detoxification is produce neonatal withdrawal, also known as neonatal
not advisable during pregnancy primarily because of the abstinence syndrome. Estimates show that up to 96%
high rate of relapse.102–106 Opioid detoxification should be of infants display withdrawal symptoms, and a smaller
performed only after the first trimester and with informed proportion require pharmacotherapy.4,68,116,117,120,121 NAS
consent based on a discussion of the potential risks and bene- is characterized by respiratory, gastrointestinal, central
fits. Methadone maintenance treatment is associated with nervous system, and autonomic symptoms (Table 6). Onset
longer adherence to treatment and decreased risk of relapse of withdrawal symptoms is dependent on the opiate’s half-
to opioid use; therefore, the standard of care for pregnant life; the longer the half-life, the later the onset of withdrawal.
opioid-dependent women is opiate substitution therapy. Heroin-exposed infants may demonstrate symptoms within
24 hours of birth. In comparison, methadone-maintained
Methadone Maintenance Treatment infants have a delayed presentation at more than 24 hours,
Currently, methadone maintenance treatment is the standard usually within 48 to 72 hours after birth and at up to
of care for opioid dependence in pregnancy. Methadone is 4 weeks of age.122 The length of monitoring is based on
the specific drug exposure. Treated neonatal withdrawal Table 6. Neonatal abstinence syndrome
has not been associated with any long-term complications. System Symptoms and signs
Respiratory Respiratory distress
A variety of standards of practice have been documented
Central nervous system Increased tone, tremors, seizure
in Canadian hospitals with variability by region and
Gastrointestinal Poor feeding, vomiting, regurgitation,
practitioner. Little research is available to validate current diarrhea
practices. Several scoring scales have been developed Autonomic Sweating
for evaluation of NAS and response to therapy. The
Finnegan scoring tool (also known as the Finnegan
Neonatal Abstinence Scoring System) is the method
most commonly used by Canadian hospitals.123 Non-
pharmacologic therapy is the standard of care for all
opioid-exposed infants.124 For a smaller subset of infants, during pregnancy. The availability of buprenorphine during
pharmacotherapy may be needed to treat severe symptoms. pregnancy is limited through Health Canada’s Special
Opioid agonist medications are the most effective agents Access Program.
for treatment of NAS.122,125 Options include morphine,
methadone, and diluted tincture of opium (contains small OPIOIDS FOR CHRONIC NON-CANCER PAIN
amount of alcohol). Morphine is the most frequently used
medication.122,123 Phenobarbital may be used as an adjunct Pregnant women with a history of chronic pain need to be
to treat infants who are not well-controlled using an opioid managed according to evidence-based recommendations
alone. One half of Canadian hospitals care for substance- for chronic non-cancer pain.134,135 The goal of therapy is
exposed infants in the neonatal care unit or special care to use the lowest effective dose of scheduled controlled-
nursery. The other half provide care for asymptomatic release opioids.134 Most women who use opioids for chronic
infants with the mother as part of rooming-in. One non-cancer pain are not psychologically dependent on these
retrospective cohort study demonstrated that rooming- medications. Risk factors for dependence on prescription
in, under the care of supportive nursing and medical opioids include past history of drug dependence and
staff, was associated with decreased rates and length of psychiatric comorbid conditions such as posttraumatic
morphine treatment, decreased need for admission to an stress disorder and eating disorders. Regular opioid use
NICU, decreased mean neonatal length of stay in hospital, for pain management during pregnancy is associated
and increased likelihood of discharge in the custody of with neonatal withdrawal.136,137 Methadone is the first-line
the mother.126 Additional large-scale prospective studies treatment for chronic non-cancer pain and concurrent
are required to determine the optimal management of opioid dependence.
neonatal withdrawal.
Recommendations
Buprenorphine 7. Methadone maintenance treatment should be standard
Buprenorphine represents an alternative opioid replacement of care for opioid-dependent women during pregnancy.
treatment. Buprenorphine is a partial agonist with a ceiling (II-IA) Other slow-release opioid preparations may be
effect. It has typical opioid effects with less sedation than considered if methadone is not available. (II-2B)
methadone and a threshold after which a higher dose has no
further effect, thereby reducing the risk of overdose on this 8. Opioid detoxification should be reserved for selected
medication.127 The main rationale for buprenorphine use women because of the high risk of relapse to opioids.
for treating opioid dependence during pregnancy is reports (II-2B)
of reduced incidence and severity of NAS128–131; however,
there are limited data regarding the long-term effects of 9. Opiate-dependent women should be informed that
in utero exposure to buprenorphine.132,133 Buprenorphine neonates exposed to heroin, prescription opioids,
should be prescribed by a physician who has experience with methadone, or buprenorphine during pregnancy are
substitution treatment for opioid dependence. The only monitored closely for symptoms and signs of neonatal
preparation of buprenorphine readily available in Canada withdrawal (neonatal abstinence syndrome). (II-2B)
is Suboxone, which is a combination of buprenorphine Hospitals providing obstetric care should develop a
and naloxone. There is limited information on the safety protocol for assessment and management of neonates
of this medication in pregnancy; therefore, the use of exposed to opiates during pregnancy. (III-B)
buprenorphine as a single agent (Subutex) is recommended
PERIPARTUM PAIN MANAGEMENT can cause fetal distress.144 On the basis of gestational age
and viability, the fetus should be monitored throughout
Women with substance use disorders, especially those treatment. Similarly, during neonatal resuscitation, naloxone
with opioid dependence, face numerous peripartum should not be administered to a newborn of an opioid-
pain management challenges, including increased pain dependent mother because of the risk of precipitating
sensitivity, inadequate analgesia, difficult intravenous acute withdrawal and seizures.
access, and anxiety about suffering pain due to their history
of addiction.138–142 Inappropriate pain management is more POSTPARTUM CARE
likely than provision of opioid analgesics for treatment of
acute pain to lead to a relapse. Women on MMT should Substance-using women require additional supports from
be continued on the same dose of methadone, although health care professionals in the postpartum period. More
this is ineffective for acute pain management.138,142 Opioids frequents visits may be required to deal with their complex
have been found to be safe and effective even in opioid- medical and psychosocial needs. Areas to review include
dependent women; however, these women may require the following:
higher doses and more frequent analgesics for pain
relief.138,142,143 Epidural analgesia is an ideal choice for pain • Support of breastfeeding, as appropriate (see
management for opioid-dependent women. Agonist- paragraph below for more details)
antagonist medications (e.g., butorphanol, nalbuphine,
and pentazocine) should not be used in opioid-dependent • Follow-up of other medical problems such as liver
individuals because of the risk of precipitating acute disease and sexually transmitted infections
withdrawal. For more complicated cases (e.g., poor venous
access, contraindications to epidural), referral to an • Discussion of contraceptive needs
anaesthesiologist should be arranged antenatally to discuss,
in advance, alternatives for pain management. • Surveillance and appropriate referral for treatment of
postpartum mood and anxiety disorders
Recommendation
10. Antenatal planning for intrapartum and postpartum • Assessment of substance use and encouragement to
analgesia may be offered for all women in consultation continue attending drug treatment programs
with appropriate health care providers. (III-B)
• Support with child protection services involvement
MANAGEMENT OF OPIOID OVERDOSE
• Assistance with referrals for ongoing primary care and
Education about prevention of opioid overdose should social services
also be provided routinely. This includes advising patients
that they could overdose if they suddenly stop or markedly BREASTFEEDING
reduce their opioid medication and then resume their usual
dose. They are also at risk of overdose if they combine Although there are numerous benefits of breastfeeding,
opioids with other sedatives, such as benzodiazepines. alcohol and illicit substances that are commonly abused
They should be warned never to give or sell their opioid (e.g., marijuana, cocaine, amphetamines) have been detected
medication to anyone else, because others may lack in breast milk.145–148 There have been reports documenting
tolerance to opioids. Finally, they should be advised neonatal effects due to breast milk exposure; therefore, the
to contact a physician immediately at the first signs of decision to breastfeed should be made on an individual basis
overdose (“nodding off,” slurred speech, drowsiness). after discussing the potential risks and benefits.146,147149,150
Breastfeeding may be delayed after maternal use of any of
Acute opioid overdose during pregnancy can be managed these agents and any neonatal exposure to any fumes in
with respiratory support and the use of naloxone, a short- the environment. Women who are regular substance users
acting opioid antagonist, as a last resort after an airway has should be encouraged to remain abstinent while nursing
been established. The dose of naloxone should be based on and counselled regarding the increased risks for neonatal effects.
response to treatment and duration of action of ingested
opioid. Naloxone may be required on a continuous basis All opiates have been documented in breast milk in
until the effects of the opioid have diminished. Care should small amounts and are unlikely to be of any clinical
be taken to prevent acute withdrawal symptoms, which significance.106,121,151–157 Specifically, the presentation
and treatment of neonatal withdrawal is not affected by 8. Makarechian N, Agro K, Devlin J, Trepanier E, Koren G, Einarson TR.
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and intrauterine growth retardation: new insights based on maternal hair
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such as drowsiness, apnea, and bradycardia have been consequences of prenatal exposure to nicotine. J Am Acad Child Adolesc
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Appendix
MATERNAL FACTORS
Prenatal care (late onset) (WA) Low
First prenatal visit in third trimester? (check records) Some
High
Prenatal education (refusal or quit) (CA) Low
What are your plans for prenatal classes? Some
High
Feelings toward pregnancy after 20 weeks (CA, WA) Low
How did you feel when you just found out you were pregnant? Some
How do you feel about it now? High
Relationship with parents in childhood (CA) Low
How did you get along with your parents? Some
Did you feel loved by your parents? High
Self esteem (CA, WA) Low
What concerns do you have about becoming/being a mother? Some
High
History of psychiatric/emotional problems (CA, WA, PD) Low
Have you ever had emotional problems? Some
Have you ever seen a psychiatrist or therapist? High
Depression in this pregnancy (PD) Low
How has your mood been during this pregnancy? Some
High
FAMILY VIOLENCE
Woman or partner experienced or witnessed abuse
(physical, emotional, sexual) (CA, WA)
What was your parents’ relationship like? Low
Did your father ever scare or hurt your mother? Some
Did your parents ever scare or hurt you? High
Were you ever sexually abused as a child?
FOLLOW UP PLAN
Supportive counselling by provider Homecare Legal advice
Additional prenatal appointments Parenting classes / parents’ support group Children’s Aid Society
Additional postpartum appointments Addiction treatment programs Other:
Additional well baby visits Smoking cessation resources Other:
Public Health referral Social Worker Other:
Prenatal education services Psychologist / Psychiatrist Other:
Nutritionist Psychotherapist / marital / family therapist
Community resources / mothers’ group Assaulted women’s helpline / shelter / counseling
COMMENTS:
© ALPHA Group, April, 2005; Department of Family & Community Medicine, University of Toronto
http://dfcm19.med.utoronto.ca/research/alpha
Used with permission.
This document reflects emerging clinical and scientific advances on the date issued and is subject to change. The information
should not be construed as dictating an exclusive course of treatment or procedure to be followed. Local institutions can dictate
amendments to these opinions. They should be well documented if modified at the local level. None of these contents may be
reproduced in any form without prior written permission of the SOGC.
Table 1. Key to evidence statements and grading of recommendations, using the ranking of the Canadian Task Force
on Preventive Health Care
Quality of evidence assessment* Classification of recommendations†
I: Evidence obtained from at least one properly randomized A. There is good evidence to recommend the clinical preventive action
controlled trial
II-1: Evidence from well-designed controlled trials without B. There is fair evidence to recommend the clinical preventive action
randomization
II-2: Evidence from well–designed cohort (prospective or C. The existing evidence is conflicting and does not allow to make a
retrospective) or case–control studies, preferably from recommendation for or against use of the clinical preventive action;
more than one centre or research group however, other factors may influence decision-making
II-3: Evidence obtained from comparisons between times or D. There is fair evidence to recommend against the clinical preventive action
places with or without the intervention. Dramatic results in
uncontrolled experiments (such as the results of treatment with E. There is good evidence to recommend against the clinical preventive
penicillin in the 1940s) could also be included in this category action
III: Opinions of respected authorities, based on clinical experience, L. There is insufficient evidence (in quantity or quality) to make
descriptive studies, or reports of expert committees a recommendation; however, other factors may influence
decision-making
*The quality of evidence reported in these guidelines has been adapted from The Evaluation of Evidence criteria described in the Canadian Task Force on
Preventive Health Care.36
†Recommendations included in these guidelines have been adapted from the Classification of Recommendations criteria described in the The Canadian Task
Force on Preventive Health Care.36
Elevate system from AMS and the Pinnaclesystem from Table 2. Commercial TVM kits available
Boston Scientific (both approved by the FDA). Their intent Company Device Implant material
is to lower rates of nerve and vascular injury associated American Medical Systems Apogee/ Intepro
with trocar placement, expedite operating time, and Inc., Minnetonka, MN Perigee polypropylene
potentially reduce rates of pelvic pain and dyspareunia. As InteXen porcine
dermis
no literature yet exists on their risks and effectiveness, they
Gynecare/Ethicon, Johnson & Prolift Gynemesh-PS
are not discussed in this update. Johnson, Somerville, NJ polypropylene
CR Bard Inc., Murray Hill, NJ Avaulta- Polypropylene
TVM PROCEDURE Plus +Porcine collagen
*Trocarless not included: see Recommendation 5.
Currently the vast majority of the published studies are In October 2008, the FDA released a statement regarding
limited to short-term follow-up (typically 3 to 12 months) potential serious complications associated with transvaginal
through either observational or retrospective studies.11-15,17-25 placement of surgical mesh in pelvic floor surgery.30
Initial rates of anatomical cure (typically defined as less On February 4, 2010, Health Canada issued important
than POP-Q stage II) in all compartments combined range safety information on surgical mesh for stress urinary
from 79% to 100%.11-15,17-23,26 These results are comparable incontinence and pelvic organ prolapse.31 It outlined the
to subjective satisfaction rates from the procedure. serious potential adverse events associated with transvaginal
meshes placed for pelvic organ prolapse or incontinence,
The only published randomized clinical trial in this area using minimally invasive procedures information from over
compared the Perigee system from AMS with traditional 1000 reports from 9 urogynaecologic surgical companies.
anterior colporrhaphy for anterior compartmental These included vaginal mesh exposure, infection, pain,
prolapse.27 Seventy-five patients were randomized to voiding dysfunction, pelvic floor dysfunction recurrence,
either traditional anterior colporrhaphy (n = 38) or a and visceral or vascular perforation. The Health Canada
Perigee procedure (n = 37). Anatomic failure was defined document31 made recommendations for obtaining
as recurrent POP-Q stage II prolapse or greater. Optimal specialized training to carry out these procedures, being
repair was achieved in 55% of the colporrhaphy group and vigilant for adverse events associated with the trocars
87% of the Perigee group (P = 0.005). Rates of dyspareunia and the mesh, obtaining informed consent for surgery by
and voiding symptoms were not different. Mesh exposure advising the patient of potentially uncorrectable sequelae
rate was 5% in the Perigee group, and all were managed as of mesh placement including pelvic pain and dyspareunia,
outpatients. Number needed to treat analysis was carried and reporting complications to appropriate bodies.
out and determined that 9 anterior colporrhaphy patients
would have recurrent anterior vaginal wall prolapse to Relatively new long-term sequelae of pelvic floor
prevent 1 mesh erosion. A summary of outcomes is shown reconstruction—vaginal scarring and mesh exposure—
in Table 4. were also addressed in this notification. These may reduce
patients’ quality of life through debilitating discomfort and trials with sufficient long-term follow-up comparing
dyspareunia. Several studies have investigated this issue TVM with accepted “gold-standard” procedures such
with conflicting results.12,13,19,27,32-34 as sacral colpopexy would allow accurate assessment of
success with appropriate subjective and objective outcome
DISCUSSION measures and complication rates. TVM procedures must
While numerous short-term observational and be more thoroughly evaluated before it is assumed they
retrospective studies are emerging that demonstrate the offer benefits over traditional repairs. The ethical issues
potential effectiveness of the TVM systems, there is a associated with the introduction of new surgical devices
need to demonstrate their longevity and safety profiles, are discussed in a commentary by Ross et al.35
particularly in comparison with traditional and established
procedures for pelvic floor repair. Appropriately designed The purported intent of the TVM systems is to further
and adequately powered prospective and randomized reduce the invasiveness and potential morbidity of the
Abdel-Fattah and Ramsay14 Prolift 76% 289 3 1.6 cystotomy 5.2 buttock pain 10 vaginal
AMS 24% 1.1 rectal injury 0.07 sepsis 0.06 bladder
0.06 vascular
Van Raalte et al.12 Prolift 350 6 – 6 dyspareunia 1
2 de novo SUI
Davila 25
AMS 298 9 – 1 pain 12
laparoscopic sacral colpopexy by delivering the mesh adequacy of training and ability to prevent complications.
vaginally as opposed to using an intraperitoneal approach Traditionally, advanced pelvic floor reconstructive surgery
and to eliminate the need for general anaesthesia and (such as laparoscopic sacral colpopexy, pubovaginal
concurrent hysterectomy. Comparison of these procedures slings, vaginal paravaginal repairs, and to a lesser extent
with traditional techniques by adequately trained pelvic colpocleisis) has been the domain of the trained pelvic
floor surgeons is the first step towards elucidating the floor reconstructive surgeon and, less commonly, the
effectiveness and appropriateness of the use of these general gynaecologist who feels competent to carry out
novel surgical techniques in our common urogynaecologic these procedures from experience or extra training. The
practices. The evolution of graft materials with interwoven role of the subspecialist has included mentoring and
absorbable mesh, such as monocryl, addition of barrier training of generalists interested in novel techniques. The
layers, such as bovine collagen, and xenografts, such as TVM systems assume familiarity with pelvic floor anatomy
porcine dermis or small intestinal submucosa further and surgical techniques not typically known to most
complicates the challenge of determining the best generalists. Familiarity with these procedures does require
materials and techniques for pelvic floor surgery. These surgical expertise, knowledge of pertinent anatomy, and
graft materials mimic to a certain extent the anatomical experience with the procedure itself. These elements would
considerations of the transvaginal mesh systems and facilitate the trained pelvic floor surgeon’s dissemination of
warrant further evaluation and comparison with TVM his or her knowledge and skill to the interested generalist.
systems as an alternate minimally invasive novel vaginal Adequate training programs would ensure that trainees
approach to pelvic floor repair. could perform competently and safely. Until adequate
effectiveness and safety evidence is available, the use of
The more than 1000 reports of mesh complication new TVM devices for prolapse repair should be considered
referenced in the FDA notification30 raise concerns about experimental and restricted to use in investigative trials.
3. Clark AL, Gregory T, Smith VJ, Edwards R. Epidemiologic evaluation 21. Fatton B, Amblard J, Debodinance P, Cosson M, Jacquetin B. Transvaginal
of reoperation for surgically treated pelvic organ prolapse and urinary repair of genital prolapse: preliminary results of a new tension-free vaginal
incontinence. Am J Obstet Gynecol 2003;189:1261–7. mesh (Prolift technique)—a case series multicentric study. Int Urogynecol
J Pelvic Floor Dysfunct 2007;18:743–52.
4. Cosson M, Debodinanace P, Boukerrou M, Chauvet MP, Lobry P, Crépin
G, et al. Mechanical properties of synthetic implants used in the repair of 22. Gauruder-Burmester A, Koutouzidou P, Rohne J, Gronewold M, Tunn
prolapse and urinary incontinence in women: which is the ideal material? R. Follow-up after polypropylene mesh repair of anterior and posterior
compartments in patients with recurrent prolapse. Int Urogynecol J Pelvic
Int Urogynecol J Pelvic Floor Dysfunct 2003;14:169–78.
Floor Dysfunct 2007;18:1059–64.
5. Birch C. The use of prosthetics in pelvic reconstructive surgery.
23. Shek KL, Dietz HP, Rane A, Balakrishnan S. Transobturator mesh
Best Pract Res Clin Obstet Gynaecol 2005;19:979–91.
for cystocele repair: a short to medium-term follow-up using 3D/4D
6. Nygaard IE, McCreery R, Brubaker L, Connolly A, Cundiff G, Weber ultrasound. Ultrasound Obstet Gynecol 2008;32(1):82–6.
AM, et al. Abdominal sacrocolpopexy: a comprehensive review. Obstet
24. Moore RD, Beyer RB, Miklos JR, Jacoby KJ, Freedman SF, McCammon
Gynecol 2004;104:805–23.
KM, et al. Prospective, multicenter trial evaluating the Perigee system
7. Nilsson CG, Palva K, Rezapour M, Falconer C. Eleven years prospective with polypropylene mesh for cystocele repair. Int Urogynecol J
follow-up of the tension-free vaginal tape procedure for treatment of 2006;18(Suppl 1):S068.
stress urinary incontinence. Int Urogynecol J Pelvic Floor Dysfunct
25. Davila GW. Introduction to the 2005 IUGA Grafts Roundtable.
2008;19:1043–7.
Int Urogynecol J 2006;17(Suppl 1):S4–5.
8. Paraiso MF, Walters MD, Rackley RR, Melek S, Hugney C. Laparoscopic 26. Elmer C, Altman D, Engh ME, Axelsen S, Vayrynen T, Falconer C.
and abdominal sacral colpopexies: a comparative cohort study. Am J Trocar-guided transvaginal mesh repair of pelvic organ prolapse.
Obstet Gynecol 2005;192:1752–8. Obstet Gynecol 2009; 113:117–26.
9. Altman D, Falconer C. Perioperative morbidity using transvaginal mesh 27. Nguyen JN, Burchette RJ. Outcome after anterior vaginal prolapse repair:
in pelvic organ prolapsed repair. Obstet Gynecol 2007;109(2 Pt 1):303–8. a randomized controlled trial. Obstet Gynecol 2008;111:891–8.
28. Araco F, Gravante G, Sorge R, Overton J, De Vita D, Primicerio M, et al. 32. Sentilhes L, Berthier A, Sergent F, Verspyck E, Descamps P, Marpeau
The influence of BMI, smoking, and age on vaginal erosions after L. Sexual function in women before and after transvaginal mesh repair
synthetic mesh repair of pelvic organ prolapses. A multicentre study. for pelvic organ prolapse. Int Urogynecol J Pelvic Floor Dysfunct
Acta Obstet Gynecol Scand 2009;88:772–80. 2008;19:763–72.
29. Collinet P, Belot F, Debodinance P, Ha Duc E, Lucot JP, Cosson M. 33. Lowman JK, Jones LA, Woodman PJ, Hale DS. Does the Prolift system
Transvaginal mesh technique for pelvic organ prolapsed repair: mesh cause dyspareunia? Am J Obstet Gynecol 2008;199:707.e1–6.
exposure management and risk factors. Int Urogynecol J Pelvic Floor 34. Altman D, Elmer C, Kiilholma P, Kinne I, Tegerstedt G, Falconer C.
Dysfunct 2006;17:315–20. Sexual dysfunction after trocar-guided transvaginal mesh repair of pelvic
30. Medical Devices Safety Alerts and Notices. Available at: http://www.fda.gov/ organ prolapse. Obstet Gynecol 2009;113:127–33.
MedicalDevices/Safety/AlertsandNotices/PublicHealthNotifications/ 35. Ross S, Robert M, Harvey M, Farrell S, Schulz J, Wilkie D, et al. Ethical
ucm061976.htm. Accessed November 25,2010. issues associated with the introduction of new surgical devices, or
31. Health Canada. Drugs & health products. Advisories, warnings & recalls. just because we can, doesn’t mean we should. J Obstet Gynaecol Can
Surgical Mesh - Complications Associated with Transvaginal Implantation 2008;30:508–13.
of Surgical Mesh for the Treatment of Stress Urinary Incontinence 36. Woolf SH, Battista RN, Angerson GM, Logan AG, Eel W. Canadian Task
and Pelvic Organ Prolapse - Notice to Hospitals. February 4, 2010. Force on Preventive Health Care. New grades for recommendations
Available at: http://www.hc-sc.gc.ca/dhp-mps/medeff/advisories-avis/ from the Canadian Task Force on Preventive Health Care. CMAJ
prof/_2010/surgical-mesh_nth-aah-eng.php. Accessed January 21, 2011. 2003;169:207–8.
These guidelines reflect emerging clinical and scientific advances as of the date issued and are subject to change. The information
should not be construed as dictating an exclusive course of treatment or procedure to be followed. Local institutions can dictate
amendments to these opinions. They should be well documented if modified at the local level. None of the contents may be
reproduced in any form without prior written permission of SOGC.
labour, ultrasound, cervix, incompetent cervix, transvaginal, empiric management of these women, including reduction of
transperineal, cervical length, fibronectin). Results were activity level, work, or travel, relocation, increased surveillance,
restricted to general and systematic reviews, randomized and administration of corticosteroids. (III)
controlled trials/controlled clinical trials, and observational
6. Transvaginal ultrasound appears to be safe in preterm premature
studies. There were no date or language restrictions. Grey
rupture of membranes, but its clinical predictive value is uncertain
(unpublished) literature was identified through searching
in this context. (II-2)
the websites of health technology assessment and health
technology assessment-related agencies, clinical practice 7. It is unclear whether ultrasonographic cervical length assessment
guideline collections, clinical trial registries, and national and has significant advantages over clinical examination alone after
international medical specialty societies. elective or emergency cervical cerclage placement, although
some signs, such as funnelling to the stitch, are associated with a
Values: The evidence and this guideline were reviewed by the high risk of preterm premature rupture of membranes. There is no
Diagnostic Imaging Committee and the Maternal Fetal Medicine consensus on the frequency or timing of ultrasonographic cervical
Committee of the Society of Obstetricians and Gynaecologists of length assessment post cerclage. (II-2)
Canada, and the recommendations were made according to the
guidelines developed by The Canadian Task Force on Preventive 8. It is unclear whether a policy of cervical length surveillance is
Health Care (Table 1). equivalent to clinical assessment of the need for elective cerclage
in those at risk of preterm delivery. (I)
Benefits, harms, and costs: Preterm birth is a leading cause of
perinatal morbidity and mortality. Use of the ultrasonographic 9. Ultrasonographic cervical length assessment and fetal fibronectin
technique reviewed in this guideline may help identify women appear to be similar in predictive ability, and the combination of
at risk of preterm birth and, in some circumstances, lead to both in a high-risk population may be of value. However, further
interventions that may reduce the rate of preterm birth. research is needed in this area. (II-2)
1. Cervical length in the general obstetrical population is relatively 2. Transvaginal ultrasonography is the preferred route for cervical
stable over the first 2 trimesters. The natural history of cervical assessment to identify women at increased risk of spontaneous
length change may be useful in identifying women at increased preterm birth and may be offered to women at increased risk of
risk of spontaneous preterm birth. Because there may be preterm birth. (II-2B)
different patterns or a delay in cervical length shortening, repeat 3. Transperineal ultrasonography may be offered to women at
assessment of cervical length may be useful. (II-2) increased risk of preterm birth if transvaginal ultrasonography is
2. There is no consensus on the optimal timing or frequency of either unacceptable or unavailable. (II-2B)
serial evaluations of cervical length. If repeat measurements are 4. Because of poor positive predictive values and sensitivities and lack
performed, they should be done at suitable intervals to minimize of proven effective interventions, routine transvaginal cervical length
the likelihood of observation error. (II-2) assessment is not recommended in women at low risk. (II-2E)
3. Transvaginal sonography can be used to assess the risk of 5. In women presenting with suspected preterm labour, transvaginal
preterm birth in women with a history of spontaneous preterm sonographic assessment of cervical length may be used to help
birth and to differentiate those at higher and lower risk of preterm in determining who is at high risk of preterm delivery and may
delivery. The gestational age of a prior preterm birth affects the be helpful in preventing unnecessary intervention. It is unclear
cervical length in a future pregnancy. (II–2) whether this information results in a reduced risk of preterm birth.
4. Cervical length measurement can be used to identify increased (II-2B)
risk of preterm birth in asymptomatic women at < 24 weeks who 6. In asymptomatic women with a history of spontaneous preterm
have other risk factors for preterm birth (previous excisional birth and an ultrasonographically diagnosed short cervical length
treatment for cervical dysplasia, uterine anomaly, or prior (< 25 mm) prior to 24 weeks of gestation, cervical cerclage should
multiple dilatation and evacuation procedures beyond 13 weeks’ be considered to reduce the risk of preterm birth. (I-B)
gestation). However, there is insufficient evidence to recommend
7. In all asymptomatic women who present with membranes at or
specific management strategies, such as cerclage, in these
protruding past the external cervical os, an emergency cerclage
women. (II-2)
should be considered to reduce the risk of preterm delivery. (I-B)
5. No specific randomized trials have evaluated any interventions
in asymptomatic women at > 24 weeks’ gestation who are at
increased risk of preterm birth (e.g., those who have a history of J Obstet Gynaecol Can 2011;33(5):486–499
prior spontaneous preterm birth, previous excisional treatment
for cervical dysplasia, uterine anomaly, or prior multiple dilatation
and evacuation procedures beyond 13 weeks’ gestation) and INTRODUCTION
who have a short cervical length. This information may help with
Table 1. Key to evidence statements and grading of recommendations, using the ranking of the Canadian Task Force
on Preventive Health Care
Quality of evidence assessment* Classification of recommendations†
I: Evidence obtained from at least one properly randomized A. There is good evidence to recommend the clinical preventive action
controlled trial
II-1: Evidence from well-designed controlled trials without B. There is fair evidence to recommend the clinical preventive action
randomization
II-2: Evidence from well–designed cohort (prospective or C. The existing evidence is conflicting and does not allow to make a
retrospective) or case–control studies, preferably from recommendation for or against use of the clinical preventive action;
more than one centre or research group however, other factors may influence decision-making
II-3: Evidence obtained from comparisons between times or D. There is fair evidence to recommend against the clinical preventive action
places with or without the intervention. Dramatic results in
uncontrolled experiments (such as the results of treatment with E. There is good evidence to recommend against the clinical preventive
penicillin in the 1940s) could also be included in this category action
III: Opinions of respected authorities, based on clinical experience, L. There is insufficient evidence (in quantity or quality) to make
descriptive studies, or reports of expert committees a recommendation; however, other factors may influence
decision-making
* The quality of evidence reported in these guidelines has been adapted from The Evaluation of Evidence criteria described in the Canadian Task Force on
Preventive Health Care.141
† Recommendations included in these guidelines have been adapted from the Classification of Recommendations criteria described in the The Canadian Task
Force on Preventive Health Care.141
and neonatal consequences.10–19 In order to address the demographic factors, but these have not been fully validated
prematurity problem, it is important to identify those at in large scale studies.30–42 Other screening strategies that have
increased risk. been suggested include measuring biochemical markers
such as fetal fibronectin and screening for infections.27,43–46
The following are risk factors for spontaneous preterm
birth: In the 1980s, an objective, ultrasound-based measurement
was developed to identify women at increased risk of preterm
• Reproductive history (previous spontaneous
birth. The risk of preterm birth was inversely correlated to
preterm birth and use of assisted reproductive
the length of the cervix as measured by ultrasound. This
technologies)8,20–22
observation has been confirmed in multiple studies using
• Antepartum bleeding, rupture of membranes,
different techniques; however, the most widely accepted and
cervical/uterine factors (cervical insufficiency, uterine
used technique is transvaginal ultrasound.34,47–57 A number of
anomalies,22 fibroids, and excisional cervical treatment
interventions based on this observation have been studied in
for cervical intraepithelial neoplasia)23–25
randomized trials. A recent meta-analysis58 has looked at its
• Fetal/intrauterine factors (multifetal gestation, fetal
efficacy in preventing preterm birth. Since the publication
anomaly, and polyhydramnios)
of the 2001 SOGC guideline,36 there have been numerous
• Infection (chorioamnionitis, bacteruria, periodontal
studies on imaging, natural history, and use of transvaginal
disease,26 current bacterial vaginosis with a prior
ultrasound in common clinical scenarios, as well as a number
preterm birth27)
of randomized trials looking at interventions for a short
• Demographic factors (low socioeconomic status, single
cervix. This updated guideline provides a comprehensive
marital status, low level of education, First Nations
review of studies of shortened cervical length diagnosed
ethnicity, or maternal age < 18 years or > 35 years)
on transvaginal ultrasound and is broader in scope than the
• Lifestyle issues (cigarette smoking, illicit drug use,
2001 guideline.36
stress, physical abuse28)
• Inadequate prenatal care, low pre-pregnancy weight
and poor weight gain in pregnancy.29 ULTRASONOGRAPHY COMPARED WITH DIGITAL
ASSESSMENT OF CERVICAL LENGTH
However, many women who deliver preterm do not have
any known risk factors.8,22 Digital assessment of the cervix has been commonly
used to diagnose premature labour or to evaluate women
Research has focused on combined risk scoring systems perceived to be at increased risk of preterm labour. Digital
that use multiple serum markers, ultrasound, and maternal assessment of cervical length is subjective, varies between
examiners, and underestimates true anatomic length. be obtained, TP ultrasonography can predict preterm birth
In one study, digital examinations before hysterectomy as accurately as TV ultrasonography.56,63 However, most
underestimated cervical length by approximately 14 mm, authors suggest that adequate images can be obtained more
whereas ultrasonography measured length accurately.59 frequently with TV than with TP technique,55,67,71,72 that TV
Investigations using transvaginal ultrasound measurement assessment is easier to obtain and more reproducible, and
as the standard confirmed that digital examination that TV correlates better with true cervical length than TP
underestimates cervical length.57,60 This underestimation assessment.69,71,72 Since the TV technique is more studied
may result from an inability to assess the cervix length and more likely to be obtainable, TP ultrasonography
digitally beyond the vaginal fornices unless there is 2 cm should be reserved for women at increased risk of preterm
or more of dilatation and the entire intracervical canal birth for whom vaginal assessment is unavailable or
is examined. The majority of studies have found that unacceptably invasive or uncomfortable.
ultrasound assessment of cervical length is superior to
Recommendations
clinical examination for the prediction of preterm birth.61–64
Therefore, ultrasound assessment of cervical length is more 2. Transvaginal ultrasonography is the preferred
reliable and more clinically predictive of preterm birth than route for cervical assessment to identify
manual examination of the cervix. women at increased risk of spontaneous
preterm birth and may be offered to women
at increased risk of preterm birth. (II-2B)
COMPARISON OF TRANSVAGINAL,
3. Transperineal ultrasonography may be offered
TRANSABDOMINAL, AND TRANSPERINEAL
to women at increased risk of preterm birth
ULTRASONOGRAPHIC CERVICAL
LENGTH ASSESSMENT
if transvaginal ultrasonography is either
unacceptable or unavailable. (II-2B)
Ultrasound assessment of the cervix was initially performed
transabdominally, but specific disadvantages led to a NORMAL CERVICAL LENGTH
preference for transvaginal ultrasound assessment. Both
TP and TV cervical assessments have been studied, with Cervical length is normally distributed and remains
most studies evaluating TV assessment.65,66 relatively constant in pregnancy until the third trimester.73–75
If there is any statistically significant reduction in length,
The patient’s bladder must be full for transabdominal it is not clinically significant (< 0.5 mm /week).73–77 Heath
ultrasonography to assess the cervix adequately, but et al.52 found a mean length of 38 mm at 23 weeks. Iams
this may spuriously lengthen the cervix by opposing et al.34 found a mean length of 35 mm at 24 weeks and of
the anterior and posterior lower uterine segments65 and 34 mm at 28 weeks. If funnelling is present, measurement
concealing cervical shortening or funnelling. In contrast, should exclude the funnel and be taken from the funnel tip
TV ultrasound is performed with the bladder empty.66 to the external os.47
Transabdominal ultrasound is significantly less likely
than the other 2 methods to provide adequate imaging CERVICAL CHANGE IN WOMEN WHO
and measurements.67 Visualization of the cervix by DELIVER PRETERM
transabdominal ultrasonography is hampered significantly
In women who deliver preterm or require cerclage, the rate
by maternal obesity, shadowing from fetal parts, and the
of cervical length change may be predictive of preterm
need for lower frequency transducers.
birth. The rate of cervical shortening is faster in women
Recommendations who deliver preterm than in those who deliver at term;
1. Transabdominal ultrasonography should however, the difference can be quite small.76–80 The range
not be used for cervical length assessment of cervical length decline in those who go on to preterm
to predict preterm birth. (II-2D) delivery, preterm labour, or pregnancy intervention varies
from 0.5 mm/week to 8 mm/week.76–80 In a cross-sectional,
TP ultrasonography has been found to be as accurate as longitudinal study, Yoshizato et al.81 examined cervical
transabdominal ultrasound for examining the cervix, and change in women whose cervix became short (< 25 mm)
one study found it was more acceptable to women than in either the early (< 26 weeks) or the late preterm period
TV scanning.55,67 Other studies, however, have found both (26 to 30 weeks). They found that “rapid CL shortening
TV and TP techniques acceptable to women.55,68–70 TP occurred between 16–20 and 21–25 weeks in the early
assessment is more accurate than digital examination for group and between 21–25 and 26–30 weeks in the late
predicting preterm birth, and, when adequate images can group”81 Intervention in terms of tocolytics or cerclage was
used in 19 of 20 in the early group, and 10 of 19 in the late perhaps even 2, to avoid observation error. The shorter
group. More interesting was that the longitudinal cervical the interval of time between measurements, the higher
length change (mm/week) in the late group was statistically the rate of observation error: either not enough time
the same as in controls between 16 and 25 weeks, and then has elapsed between assessments to detect change in
accelerated 3-fold in the next observation period. This study the cervical length, or a small observed change is really
suggests that cervical length may be stable for a period of observational error. The current evidence and the regional
time and then undergo a phase of rapid decline prior to differences in resources, access, and practice across the
the onset of symptoms.81 Hence, repeat evaluation of the country do not allow the development of a national
cervical length may be reasonable to screen for those who consensus surveillance protocol.
may be at increased risk of late preterm delivery.
Summary Statement
Summary Statement 2. There is no consensus on the optimal timing or
1. Cervical length in the general obstetrical population frequency of serial evaluations of cervical length.
is relatively stable over the first 2 trimesters. If repeat measurements are performed, they
The natural history of cervical length change should be done at suitable intervals to minimize
may be useful in identifying women at increased the likelihood of observation error. (II-2)
risk of spontaneous preterm birth. Because
there may be different patterns or a delay in
TRANSVAGINAL SONOGRAPHIC
cervical length shortening, repeat assessment
CERVICAL LENGTH ASSESSMENT IN
of cervical length may be useful. (II-2)
ASYMPTOMATIC WOMEN AT LOW RISK
weeks) had a 5.5-fold increased risk (44%) of delivery within The results suggest that it may be safe to use ultrasonographic
a week, and those with a cervical length of ≥ 15 mm had a cervical length assessment to prevent unnecessary use of
2% risk.104 In other studies, delivery occurred within 7 days tocolytics and steroids.108 However, the small sample size
of presentation in 37% of 43 women with cervical length of this study does not provide adequate power to assess
< 15 mm,102 and a cervical length of < 20 mm had a 93.7% uncommon outcomes such as preterm birth at < 34 weeks
and 87.5% positive predictive value for preterm birth in and to determine whether this approach could cause harm.
primiparous and multiparous women respectively.105 In all
these studies, the cervical length was an independent predictor A meta-analysis by Berghella et al.58 evaluated the efficacy
of preterm delivery.102–105 In 2010, Sotiriadis et al.106 published of cervical length measurements to prevent preterm birth
a meta-analysis on the use of cervical length measurements in by asking whether the knowledge of ultrasonographic
patients presenting with symptoms of preterm labour. They cervical length affected the rate of preterm birth.58 This
included prospective cohort and/or case–control studies was studied in 2 groups: those that presented in preterm
that evaluated transvaginal ultrasonographic assessment of labour and those with preterm rupture of membranes.
cervical length for the prediction of preterm birth in women Knowledge of TV ultrasonographic cervical length results
with a singleton pregnancy and intact membranes (studies was associated with a non-significant decrease in preterm
with < 20% premature rupture of membranes and multiples birth at < 37 weeks (22.3% and 34.7%, respectively;
were included, however). Studies involving the use of RR 0.59; 95% CI 0.26 to 1.32). Delivery occurred at a later
tocolytics and/or prophylactic steroid administration were gestational age in the knowledge than in the no-knowledge
also included. They used a weighted analysis to determine test group (mean difference 0.64 weeks; 95% CI 0.03 to 1.25).
performance. The cumulative data suggest that the cervical The authors concluded that there was insufficient evidence
length measurement in symptomatic women can be used to recommend routine screening of asymptomatic
to discriminate between those at higher and those at lower or symptomatic pregnant women with transvaginal
risk of preterm delivery, which may help to rationalize their ultrasound. However, it should be noted that the total
management; however, there was considerable heterogeneity number of women in the study was small (total N = 290
across the studies. Table 2 presents data from the study by in preterm labour, n = 92 in premature preterm rupture of
Sotiriadis et al.106 membranes). Also, the study did not determine whether
progesterone or cerclage was used, and it included clinical
On the basis of the weighted estimates, and using a presentations in which neither of those interventions
pooled prevalence of 11.1% for birth within 1 week of would likely be used.
presentation, Sotiriadis et al.106 calculated that the negative
predictive values of 15 mm, 20 mm, and 25 mm would be In summary, it appears that TV ultrasonography can be
94.8%, 96.3%, and 95.8%, respectively. used to stratify risk in women presenting with preterm
labour, and there is some evidence that suggests this can be
Use of Transvaginal Ultrasound to Stratify done safely and with some benefit.
Women Presenting With Preterm Labour
In a prospective cohort study among several hospitals using Recommendation
different protocols for threatened preterm labour, the use 5. In women presenting with suspected preterm
of ultrasound assessment of cervical length appeared to labour, transvaginal sonographic assessment of
shorten hospital stay without compromising patient care.107 cervical length may be used to help in determining
In a small (N = 41) trial,108 women with threatened preterm who is at high risk of preterm delivery and may
labour were randomized to a control group, who received be helpful in preventing unnecessary intervention.
tocolytics and steroids in keeping with the hospital’s It is unclear whether this information results
protocol, or to an assessment group who had cervical in a reduced risk of preterm birth. (II-2B)
length measured by transvaginal ultrasound. Women in the
assessment group who were found to have a cervical length Ultrasonographic Cervical Assessment in
of < 15 mm were given tocolytics and steroids. Those with Women With Suspected Preterm Premature
cervical length of ≥15 mm were not given tocolytics and Rupture of Membranes
steroids. No babies in the group considered to be at low Preterm premature rupture of membranes conveys an
risk of preterm birth were born prematurely without a increased risk of chorioamnionitis and preterm birth.27,28
full course of antenatal corticosteroid therapy, and babies In such circumstances, uterine contractions causing
in this group had significantly lower rates of exposure to cervical change are difficult to assess because the digital
steroids and tocolytics. cervical examination is associated with an increased risk
of infection and should be postponed until labour is double-blind, placebo-controlled trial of progesterone to
established. Several cohort studies have shown that the prevent preterm birth in patients with a history of preterm
cervical length measured by TV predicts latency to delivery birth,113 the use of progesterone when cervical length was
in preterm premature rupture of membranes.109,110 In < 28 mm was associated with a reduction in preterm birth
a much smaller study, cervical length measurements by prior to 32 weeks (0% vs. 29.6%, P = 0.014), fewer NICU
TP ultrasound did not correlate with latency duration to admissions (15.8% vs. 51.9%, P = 0.016), and shorter NICU
delivery.111 Transvaginal cervical length measurement in stays (1.1 vs. 16.5 days, P = 0.013). A recent randomized trial
a randomized trial was not found to increase the risk of compared cerclage and 17 α-hydroxyprogesterone for short
infection in patients with preterm premature rupture of cervix (< 25 mm) in a high-risk population and showed no
membranes. This study did not find that cervical length had difference in rates of preterm birth; however, this study
predictive value for latency. This is not consistent with the was small (N = 79) and underpowered, because recruitment
findings of another study.112 was halted at the midpoint of the study. In a sub-analysis
of that data set, it was shown that cerclage may be better if
Summary Statement the cervix is < 15 mm.114 In 2009, the United States Food
6. Transvaginal ultrasound appears to be safe in preterm and Drug Administration declined approval of this use of
premature rupture of membranes, but its clinical progesterone, because of concerns about possible adverse
predictive value is uncertain in this context. (II-2) effects, but in February 2011, intramuscular progesterone was
approved for the prevention of preterm birth.115 Although
The Use of Progesterone in Women With a Short
progesterone supplementation in women with a previous
Cervical Length by Ultrasonographic Assessment
preterm birth and a short cervix appears promising, more
Recent studies have evaluated the use of progesterone in
data are needed to better demonstrate benefit and a number
patients with a short cervix to prevent preterm delivery.
of studies are in progress.116 A committee consensus could
In a study by Fonseca et al.,83 250 women (24 to 34 weeks’
not be reached to recommend its use in this population.
gestation) who were determined to have a cervical length of
< 15 mm were randomized to either vaginal progesterone Ultrasonographic Cervical Length Assessment
(200 mg each night) or placebo. The primary outcome was and Cervical Cerclage
spontaneous delivery before 34 weeks. Delivery before 34 Several studies have evaluated the value of cervical cerclage
weeks of gestation was less frequent in the progesterone in women with ultrasonographically diagnosed short cervix.
group than in the placebo group (19.2% vs. 34.4%; RR 0.56; A prospective cohort study was the first to show benefits
95% CI 0.36 to 0.86). However, there was no statistically in those who had a cerclage versus those who had usual
significant reduction in neonatal morbidity (8.1% vs. care, with significantly lower rates of prematurity and
13.8%; RR 0.59; 95% CI 0.26 to 1.25; P = 0.17). There no fetal losses.84 Subsequently, 3 randomized trials had
were no serious adverse events associated with the use of disparate findings, although their patient populations were
progesterone.83 In a secondary analysis of a randomized, different.87,90,117 A meta-analysis of patient level data of
those 3 studies showed that in women with a history of value is therefore in doubt.123,124 O’Brien et al.126 empirically
spontaneous preterm birth and a cervical length < 25 mm suggest every 2 to 4 weeks post cerclage placement until
before 24 weeks’ gestation, placement of a cervical cerclage 28 weeks of gestation, whereas other authors suggest that
was associated with a significant decrease in preterm birth cervical length shortening after 28 weeks is most diagnostic
< 35 weeks of gestation (from 39% to 23%).86 A recent of preterm delivery.123,124 Although the assessment of the
National Institutes of Health-sponsored multicentre trial cervix may help identify those at increased risk of preterm
confirmed these findings, noting a significant reduction birth, it cannot predict when it will occur.
in preterm birth < 35 weeks and/or previable delivery in
women with a prior spontaneous preterm birth and mid- Summary Statement
trimester transvaginal cervical length < 25 mm, with findings 7. It is unclear whether ultrasonographic cervical
most pronounced when cervical length was < 15mm.118 length assessment has significant advantages
over clinical examination alone after elective or
In patients with membrane prolapse at or beyond the emergency cervical cerclage placement, although
external os of the cervix, there may be benefit to emergency some signs, such as funnelling to the stitch, are
cerclage compared with conservative management. Several associated with a high risk of preterm premature
retrospective studies119–122 suggest that pregnancy outcomes rupture of membranes. There is no consensus
are better with emergency cerclage, and a small randomized on the frequency or timing of ultrasonographic
trial82 also showed significant prolongation of pregnancy cervical length assessment post cerclage. (II-2)
and reduced preterm delivery rates.
Serial Ultrasonographic Cervical Length
Recommendations Assessment Compared With Clinical Assessment
6. In asymptomatic women with a history of of Need for Elective Cerclage Placement
spontaneous preterm birth and an ultrasonographi- Several authors have noted that if a policy of surveillance
cally diagnosed short cervical length (< 25 mm) prior is used in women at high risk, with urgent or emergency
to 24 weeks of gestation, cervical cerclage should be cerclage for those who develop a short cervix, approximately
considered to reduce the risk of preterm birth. (I-B) 60% of those patients would not have required cerclage. In
7. In all asymptomatic women who present with small studies, this approach of using cervical cerclage in
membranes at or protruding past the external only women with a short cervix had perinatal outcomes
cervical os, an emergency cerclage should be con- equivalent to those in women who had elective cerclage.117,127
sidered to reduce the risk of preterm delivery. (I-B) The CIRCLE trial128 was a randomized trial of either serial
Ultrasonographic Cervical Length Assessment
TV ultrasound measurements with cerclage when cervical
After Cervical Cerclage Placement length was < 20 mm or clinician-based assessment of
need for elective cerclage. Its findings, published in 2009,
There is limited information on the use of ultrasonographic were not consistent with those of earlier studies: the TV
cervical length assessment after cervical cerclage placement. ultrasound group was found to have significantly more
Studies involve a combination of both elective and interventions, including cerclage, hospitalization, and
emergency cerclage, which can confuse the results. It is progesterone use with no difference in outcomes.128
unclear whether ultrasound assessment is superior to clinical
examination in determining the need for cerclage.123 Cervical Summary Statement
length significantly increases post cerclage,124–126 but the 8. It is unclear whether a policy of cervical length surveillance
overall length post cerclage does not seem to predict preterm is equivalent to clinical assessment of the need for
birth.124,126 There is some evidence that absent or short elective cerclage in those at risk of preterm delivery. (I)
cervical length above the cerclage123,125 or the appearance of
funnelling to the level of the cerclage123,126 (at 24 to 28 weeks) ULTRASONOGRAPHIC CERVICAL LENGTH
increases the risk of preterm delivery. In particular, 2 studies COMBINED WITH FETAL FIBRONECTIN IN THE
have shown that funnelling down to the cerclage has a 50% PREDICTION OF PRETERM BIRTH
risk of preterm premature rupture of membranes.123,126
Progressive shortening may also indicate an increased risk Multiple studies have considered association between
of preterm birth, but the difference between women who ultrasonographic assessment of cervical length and
deliver preterm and those who deliver at term, is slight.123–126 the presence of fetal fibronectin. It appears they are
There is considerable disagreement about when to initiate, independently associated with an increased risk of preterm
how frequently to reassess, and when to stop performing birth although there is some overlap.42,50,129–132 Direct
transvaginal cervical length assessments after cerclage, and its comparison of these tests can be difficult. Depending
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This Clinical Practice Guideline has been prepared by the Jo-Ann Johnson, MD, Calgary AB
Diagnostic Imaging Committee, reviewed by the Genetics
Sylvie Langlois, MD, Vancouver BC
Committee and the Maternal Fetal Medicine Committee, and
approved by the Executive and Council of the Society of Lynn Murphy-Kaulbeck, MD, Moncton NB
Obstetricians and Gynaecologists of Canada. Nanette Okun, MD, Toronto ON
PRINCIPAL AUTHORS Melanie Pastuck, RN, Cochrane AB
Lucie Morin, MD, Outremont QC MATERNAL FETAL MEDICINE COMMITTEE
Kenneth Lim, MD, Vancouver BC Robert Gagnon, MD, Montreal QC
DIAGNOSTIC IMAGING COMMITTEE Lynda Hudon, MD (Co-Chair), Montreal QC
Lucie Morin, MD (Chair), Outremont QC Melanie Basso, RN, Vancouver BC
Kenneth Lim, MD (Co-Chair), Vancouver BC Hayley Bos, MD, London ON
Stephen Bly, MD, Ottawa ON Joan M. Crane, MD, St. John’s NL
Kimberly Butt, MD, Fredericton NB Gregory Davies, MD, Kingston ON
Yvonne M. Cargill, MD, Ottawa ON Marie-France Delisle, MD, Vancouver BC
Gregory Davies, MD, Kingston ON Savas Menticoglou, MD, Winnipeg MB
Nanette Denis, CRGS, Saskatoon SK William Mundle, MD, Windsor ON
Robert Gagnon, MD, Montreal QC Annie Ouellet, MD, Sherbrooke QC
Marja Anne Hietala-Coyle, RN, Halifax NS Tracy Pressey, MD, Vancouver BC
Annie Ouellet, MD, Sherbrooke QC Christy Pylypjuk, MD, Saskatoon SK
Shia Salem, MD, Toronto ON Anne Roggensack, MD, Calgary AB
Vyta Senikas, MD, Ottawa ON Frank Sanderson, MD, Saint John NB
SPECIAL CONTRIBUTOR Disclosure statements have been received from all members of
Jon Barrett, MD, Toronto ON the committees.
GENETICS COMMITTEE
R. Douglas Wilson, MD (Chair), Calgary AB
François Audibert, MD, Montreal QC
Abstract
Jo-Ann Brock, MD, Halifax NS
June Carroll, MD, Toronto ON Objective: To review the literature with respect to the use of
diagnostic ultrasound in the management of twin pregnancies.
Lola Cartier, MSc, Montreal QC
To make recommendations for the best use of ultrasound in twin
Alain Gagnon, MD, Vancouver BC pregnancies.
Outcomes: Reduction in perinatal mortality and morbidity and
short- and long-term neonatal morbidity in twin pregnancies.
Optimization of ultrasound use in twin pregnancies.
This document reflects emerging clinical and scientific advances on the date issued and is subject to change. The information
should not be construed as dictating an exclusive course of treatment or procedure to be followed. Local institutions can dictate
amendments to these opinions. They should be well documented if modified at the local level. None of these contents may be
reproduced in any form without prior written permission of the SOGC.
Evidence: Published literature was retrieved through searches of 7. Although many methods of evaluating the level of amniotic fluid in
PubMed and the Cochrane Library in 2008 and 2009 using twins (deepest vertical pocket, single pocket, amniotic fluid index)
appropriate controlled vocabulary (e.g., twin, ultrasound, cervix, have been described, there is not enough evidence to suggest
prematurity) and key words (e.g., acardiac, twin, reversed that one method is more predictive than the others of adverse
arterial perfusion, twin-to-twin transfusion syndrome, amniotic
pregnancy outcome. (II-3)
fluid). Results were restricted to systematic reviews, randomized
control trials/controlled clinical trials, and observational studies. 8. Referral to an appropriate high-risk pregnancy centre is indicated
There were no date restrictions. Studies were restricted to those when complications unique to twins are suspected on ultrasound.
with available English or French abstracts or text. Searches were (II-2) These complications include:
updated on a regular basis and incorporated into the guideline
to September 2009. Grey (unpublished) literature was identified 1. Twin-to-twin transfusion syndrome
through searching the websites of health technology assessment
2. Monoamniotic twins gestation
and health technology assessment-related agencies, clinical
practice guideline collections, clinical trial registries, and national 3. Conjoined twins
and international medical specialty societies.
4. Twin reversed arterial perfusion sequence
Values: The evidence collected was reviewed by the Diagnostic
Imaging Committee of the Society of Obstetricians and 5. Single fetal death in the second or third trimester
Gynaecologists of Canada, with input from members of the 6. Growth discordance in monochorionic twins.
Maternal Fetal Medicine Committee and the Genetics Committee
of the SOGC. The recommendations were made according to the Recommendations
guidelines developed by The Canadian Task Force on Preventive
Health Care (Table 1). 1. All patients who are suspected to have a twin pregnancy on first
trimester physical examination or who are at risk (e.g., pregnancies
Benefits, harms, and costs: The benefit expected from this guideline
resulting from assisted reproductive technologies) should have first
is facilitation and optimization of the use of ultrasound in twin
pregnancy. trimester ultrasound performed. (II-2A)
2. Every attempt should be made to determine and report amnionicity
Summary Statements
and chorionicity when a twin pregnancy is identified. (II-2A)
1. There are insufficient data to make recommendations on repeat
3. Although the accuracy in confirmation of gestational age at the first
anatomical assessments in twin pregnancies. Therefore, a
complete anatomical survey at each scan may not be needed and second trimester is comparable, dating should be done with
following a complete and normal assessment. (III) first trimester ultrasound. (II-2A)
2. There are insufficient data to recommend a routine preterm labour 4. Beyond the first trimester, it is suggested that a combination of
surveillance protocol in terms of frequency, timing, and optimal parameters rather than a single parameter should be used to
cervical length thresholds. (II-2) confirm gestational age. (II-2C)
3. Singleton growth curves currently provide the best predictors of 5. When twin pregnancy is the result of in vitro fertilization, accurate
adverse outcome in twins and may be used for evaluating growth
determination of gestational age should be made from the date of
abnormalities. (III)
embryo transfer. (II-1A)
4. It is suggested that growth discordance be defined using either
a difference (20 mm) in absolute measurement in abdominal 6. There is insufficient evidence to make a recommendation of which
circumference or a difference of 20% in ultrasound-derived fetus (when discordant for size) to use to date a twin pregnancy.
estimated fetal weight. (II-2) However, to avoid missing a situation of early intrauterine growth
restriction in one twin, most experts agree that the clinician may
5. Although there is insufficient evidence to recommend a specific
schedule for ultrasound assessment of twin gestation, most consider dating pregnancy using the larger fetus. (III-C)
experts recommend serial ultrasound assessment every 2 to 7. In twin pregnancies, aneuploidy screening using nuchal
3 weeks, starting at 16 weeks of gestation for monochorionic transluscency measurements should be offered. (II-2B)
pregnancies and every 3 to 4 weeks, starting from the anatomy
scan (18 to 22 weeks) for dichorionic pregnancies. (II-1) 8. Detailed ultrasound examination to screen for fetal anomalies
should be offered, preferably between 18 and 22 weeks’ gestation,
6. Umbilical artery Doppler may be useful in the surveillance of twin
gestations when there are complications involving the placental in all twin pregnancies. (II-2B)
circulation or fetal hemodynamic physiology. (II-2) 9. When ultrasound is used to screen for preterm birth in a twin
gestation, endovaginal ultrasound measurement of the cervical
length should be performed. (II-2A)
ABBREVIATIONS 10. Increased fetal surveillance should be considered when there is
AC abdominal circumference either growth restriction diagnosed in one twin or significant growth
CL cervical length discordance. (II-2A)
EFW estimated fetal weight 11. Umbilical artery Doppler should not be routinely offered in
IUGR intrauterine growth restriction uncomplicated twin pregnancies. (I-E)
NPV negative predictive value
12. For defining oligohydramnios and polyhydramnios, the
NT nuchal translucency ultrasonographer should use the deepest vertical pocket in either
PPV positive predictive value sac: oligohydramnios when < 2 cm and polyhydramnios when
TTTS twin-to-twin transfusion syndrome > 8 cm. (II-2B)
Table 1. Key to evidence statements and grading of recommendations, using the ranking of the Canadian Task Force
on Preventive Health Care
Quality of evidence assessment* Classification of recommendations†
I: Evidence obtained from at least one properly randomized A. There is good evidence to recommend the clinical preventive action
controlled trial
II-1: Evidence from well-designed controlled trials without B. There is fair evidence to recommend the clinical preventive action
randomization
II-2: Evidence from well–designed cohort (prospective or C. The existing evidence is conflicting and does not allow to make a
retrospective) or case–control studies, preferably from recommendation for or against use of the clinical preventive action;
more than one centre or research group however, other factors may influence decision-making
II-3: Evidence obtained from comparisons between times or D. There is fair evidence to recommend against the clinical preventive action
places with or without the intervention. Dramatic results in
uncontrolled experiments (such as the results of treatment with E. There is good evidence to recommend against the clinical preventive
penicillin in the 1940s) could also be included in this category action
III: Opinions of respected authorities, based on clinical experience, L. There is insufficient evidence (in quantity or quality) to make
descriptive studies, or reports of expert committees a recommendation; however, other factors may influence
decision-making
* The quality of evidence reported in these guidelines has been adapted from The Evaluation of Evidence criteria described in the Canadian Task Force on
Preventive Health Care.100
† Recommendations included in these guidelines have been adapted from the Classification of Recommendations criteria described in the The Canadian Task
Force on Preventive Health Care.100
all cases.9,12 Scardo et al.12 in their second trimester study (underestimate 1 day from IVF dating) with both first (11 to
found that the twin peak alone may not be sufficiently 14 weeks) and second (18 to 22 weeks) trimester ultrasound
accurate. With a composite of second trimester ultrasound estimates being very accurate in relation to conceptual age by
markers (number of placentas, fetal phenotype, membrane IVF.15,19 Hence, in twins, although there is expert consensus
thickness, and twin peak sign), the sensitivity for correct that first trimester ultrasound dating is preferable, second
identification of monochorionic pregnancies is reported trimester dating is also acceptable and accurate.
at 91.7% with 97.3% specificity.12 In the second trimester,
The best parameter or parameters to use for the most
the twin peak sign becomes more difficult to visualize,
accurate dating vary according to the gestational age. Many
and it disappears in about 7% of dichorionic pregnancies
studies show that singleton dating formulas work equally well
at 16 to 20 weeks. Therefore, the absence of the twin
with twins, hence studies in this area are usually a mixture of
peak sign in the second or third trimester cannot exclude
singletons and multiples.14–17 In the first trimester, crown–
dichorionicity.12,13
rump length provides appropriate gestational dating within
5 to 7 days.15–17 First trimester crown–rump length and
Recommendations
second trimester biparietal diameter provide gestational age
1. All patients who are suspected to have a twin with an error of plus or minus 7 days and are very similar in
pregnancy on first trimester physical examination accuracy.16 In the second trimester, different combinations
or who are at risk (e.g., pregnancies resulting from of each parameter demonstrate slight differences in
assisted reproductive technologies) should have first accuracy, with the best estimate using a combination of
trimester ultrasound performed. (II-2A) head circumference, abdominal circumference, and femur
2. Every attempt should be made to determine and length.14 Some centres use an average of all parameters,
report amnionicity and chorionicity when a twin equally weighted, or use mathematical formulas that give
pregnancy is identified. (II-2A) different significance to each parameter used. There are
more than 30 different formulas in the literature, using
different combinations of parameters.14 In general, about
DETERMINING GESTATIONAL 95% of gestational age estimates in the first and second
AGE IN TWIN PREGNANCIES
trimester will be within 5 to 7 days of the “true” gestational
The accurate confirmation of gestational age using age, regardless of the parameter or parameters used.14,16,17
ultrasound is essential to pregnancy management. It In twin pregnancies, modest size discordance is common.
necessitates determining whether there is a high probability Several studies have cited the need to use the larger twin for
that the measurements of the fetus are appropriate for the dating purposes to minimize the chance of missing a fetus
estimated gestational age. Early studies of the reliability that might present with IUGR.16,19 Some studies have based
of ultrasound to confirm gestational age used menstrual the estimated gestational age on the mean of the fetuses.14
dating in women with regular cycles; however, menstrual Salomon et al.20 recently suggested that if the inter-twin
dating is fraught with biological variability. More recently, crown–rump length discrepancy was less than the 95th
studies of this nature were done in IVF pregnancies, for percentile, according to their charts, the biometry of the
which conception date is known precisely, but it is unclear smaller fetus was the more correlative with the conception
whether this will work as well with natural conceptions. date of IVF pregnancies.20 However, the majority of
The literature on gestational age confirmation is also not centres, largely on the basis of expert opinion, use the
specific to multiple pregnancies, and in general these studies larger of the 2 fetuses to date a pregnancy, erring on the
were a mixture of singletons, twins, and triplets, with side of overestimation of gestational age and lessening the
the vast majority of subjects being singleton.14–17 Studies chance of missing IUGR in the smaller twin.
assessing the benefits of confirmation of gestational age
by ultrasound have been published,18 but with singleton not Therefore, there is no absolute consensus on the optimal
twin pregnancies. A comprehensive and critical review of method to determine gestational age in twin pregnancies.
this topic is well beyond the scope of this document. Most academic centres use the estimated gestational age
based on a known last menstrual period, corrected for a
The first trimester is generally considered to be the ideal time regular cycle length if the initial ultrasound falls within
to confirm or establish accurate gestational age dating, and it an accepted range of days. If the fetal biometry does not
is statistically superior to second trimester dating. However, agree, new gestational age estimates can be established with
in 2 dating studies using twins, the difference in accuracy an anticipated accuracy of 5 to 7 days. Further study in this
compared with IVF could be considered clinically insignificant area appears to be warranted.
Table 2. Risk of spontaneous preterm birth (< 32 to 33 weeks) given various CL thresholds
Author Prevalence N CL (mm) GA (weeks) Sensitivity Specitivity % PPV % NPV %
Goldenberg et al. 34
8.8% 147 ≤ 25 24 53.8 85.8 26.9 95.0
Skentou et al.35 7.8% 434 ≤ 25 22 to 24 35.3 91.8 26.7 94.3
Vayssiere et al.36
5.4% 251 ≤ 25 21 to 23 38 97 38 96
Sperling et al.37 6.0% 383 ≤ 20 23 21.4 96.4 27.8 95.4
Guzman et al.38 9.2% 131 ≤ 20 21 to 24 42.0 85 22.0 94
a surviving twin after the demise of the other twin. Summary Statement
Anomalies seen as consequence of such events 1. There are insufficient data to make recommendations
include microcephaly, periventricular leukomalacia, on repeat anatomical assessments in twin pregnancies.
hydrocephalus, intestinal atresia, renal dysplasia, and Therefore, a complete anatomical survey at each scan
limb amputation. may not be needed following a complete and normal
3. Defects or deformities from intrauterine crowding: assessment. (III)
foot deformities, hip dislocation, and skull
asymmetry Recommendation
8. Detailed ultrasound examination to screen for
Edwards et al.32 evaluated the accuracy of antenatal fetal anomalies should be offered, preferably
ultrasound in the detection of fetal anomalies in 245 twins between 18 and 22 weeks’ gestation, in all twin
managed in a specialized multiples clinic. The prevalence of pregnancies. (II-2B)
anomalies was 4.9%. In this study, antepartum ultrasound
detected 88% of anomalies; ultrasound for the detection
of congenital anomalies in twins therefore appears to be SCREENING FOR PRETERM BIRTH
effective.32
Preterm birth is a major cause of mortality and morbidity in
Twin pregnancies will be scanned multiple times during twin pregnancies. Sonographic assessment of the cervical
pregnancy, predominantly to assess fetal growth. There length can identify twins at significantly elevated risk of preterm
are no data to determine whether formal reassessment of delivery. A number of studies have shown that cervical length
fetal anatomy at each scan is of significant value in anomaly can help identify those twins that may be at either increased or
detection in twins. Only one study of singleton pregnancies33 reduced risk of early delivery. Most of these studies include both
found that routine repeat anatomy scanning in the early monochorionic and dichorionic pregnancies, and differentiation
third trimester resulted in further diagnosis of anomalies. on that basis is not known. Studies varied with respect to the
In the second trimester, a major anomaly was detected in cervical length threshold chosen, the gestational age at which the
0.36% of scanned fetuses, and anatomical reassessment in cervical length assessment was performed, and the definition of
the third trimester resulted in further diagnosis in 0.22% of preterm birth. Tables 2 and 3 show information from studies
the fetuses previous assessed as “normal.” The anomalies that were similar with respect to these 3 variables. None of the
detected were predominantly lesions that may develop studies included patients who had a cerclage, and all studies
late in pregnancy and that would not be detectable in the employed transvaginal ultrasound.
mid-second trimester. Given the number of ultrasound
examinations per twin pregnancy and the rising rates of The studies listed in Table 2 show that a finding of a
multiple gestations, the resource implications of a policy certain cervical length measured between 21 and 24 weeks
of repeated anatomical evaluation are significant. There
correlates highly with preterm birth at < 32 to 33 weeks.
are insufficient data to make a recommendation on how The results are fairly consistent in that the risk of preterm
often repeat anatomical survey should be done in twin birth is increased 3- to 5-fold from baseline prevalence.
pregnancies. The absolute PPV ranges from 22% to 38 %. Notably, the
negative predictive values are quite high and consistent
Ultrasound scanning for fetal anomalies in twins is clearly across these studies: 94% to 96%.
justifiable and best performed between 18 and 22 weeks’
gestation. A management plan necessitates knowledge of Table 3 shows studies that attempted to define a threshold
chorionicity and consideration of the risk to the unaffected at which the likelihood of delivery prior to 34 to 35 weeks
fetus. is low. The results are more variable than those shown in
However, application to clinical practice is less clear. The American Congress of Obstetricians and Gynecologists
The 95% confidence interval of inter- and intraobserver technical bulletin on assessment of growth51 suggests
variability (intraobserver repeatability coefficient of that centres should use growth tables derived from twin
approximately ± 6 mm and the interobserver limits of gestations. However, most studies of twin growth curves are
agreement was approximately ±10 mm)44 is quite large derived from a small sample size that includes pregnancies
relative to the reported rates of cervical change. Observed with adverse outcomes and do not take into account
changes may simply be observer variability unless the chorionicity, race, or gender. The argument in favour of using
interobservation interval is quite long. There is also no twin growth charts is that it likely prevents the over-diagnosis
proven intervention in this scenario. Thus, the optimal of IUGR in normally grown twins (which would result in
protocol for serial CL evaluation in twins is unclear. an increase in iatrogenic preterm delivery). A large cohort
study52 comparing the outcome of twins and singletons,
In women with signs and symptoms of preterm labour
taking into account chorionicity and fetal growth centiles,
between 23 and 33 weeks, CL was a better predictor of
demonstrated that twins with growth restriction (defined
preterm delivery than funnelling and digital examination.45
using singleton growth curves) were not protected from
Fuchs et al.46 found that among twin pregnancies that
perinatal loss; growth restricted monochorionic twins were,
presented in preterm labour, the longer the CL, the less
in fact, at increased risk of perinatal mortality. Therefore,
likely it was that delivery would occur within 1 week. At a
although it is suggested that the twin growth curve pattern
cervical length of > 25 mm, there were no deliveries (0/21)
starts to decelerate from 32 weeks’ gestation, IUGR twins
that occurred within a week, whereas when cervical lengths
were ≤ 15 mm, the rate of delivery was 44% (18 of 32). defined according to the singleton growth curve have worse
outcomes than those defined as appropriately grown using
Summary Statement the same curve. Thus, the literature still suggests that the
2. There are insufficient data to recommend a routine use of biometry charts from singletons in the follow-up of
preterm labour surveillance protocol in terms twin pregnancy provide good predictors of adverse perinatal
of frequency, timing, and optimal cervical length outcome.52 Further investigation in this area using twin
thresholds. (II-2) growth charts is warranted.
Determination of fetal growth discordance is important, respectively. The range of specificities for appropriate for
because studies have shown an association with increased gestational age was 68% to 91% versus 81% to 98% for AC
mortality and morbidity when there are significant and EFW, respectively.66 Studies that directly compared the
differences in birthweight.53–58 Therefore, detection of 2, showed them to be equally efficacious compared with
antenatal growth discordance by ultrasound is useful in estimated fetal weight formulas.66,67 Regardless of growth
identifying twins that may require increased surveillance to curves used, increased fetal surveillance is indicated when
prevent higher fetal/neonatal complications. Confounding abdominal circumference and/or EFW of one or both
factors in studies of twin growth discordance include twins is < 10th percentile or when growth discordance is
chorionicity, gestational age at delivery, and growth identified.19,70–72
restriction relative to expected birth weight, as well as
suboptimal sample size. Growth discordance has been Summary Statements
defined in several ways, with the most common being the 3. Singleton growth curves currently provide the best
difference in estimated fetal weight derived by ultrasound predictors of adverse outcome in twins and may be
biometry.59 Another method uses absolute differences used for evaluating growth abnormalities. (III)
in abdominal circumference.59 Both methods have their 4. It is suggested that growth discordance be defined
strengths and weaknesses. using either a difference (20 mm) in absolute
measurement in abdominal circumference or a
Birthweight discordance is defined by the following difference of 20% in ultrasound derived estimated
formula, using the larger of the twins as the denominator. fetal weight. (II-2)
2 weeks in uncomplicated monochorionic twin pregnancies, velocimetry over the use of ultrasound alone; therefore,
but there is little evidence beyond expert opinion to support routine use of Doppler velocimetry in twin gestations
this practice. Some centres advocate scanning dichorionic cannot be recommended at this time.
twins every 3 weeks in the third trimester, since the growth
rate slows down after 30 to 32 weeks. Of note, in uncomplicated monochorionic twins, uterine
artery waveform abnormalities may be common, and
Grobman and Parilla75 found that in twins (of all types) they reflect retrograde transmission of arterio-arterial
the positive predictive value of a sonogram for a growth interference patterns in the presence of large arterio-
abnormality at birth significantly decreased if the 20- to arterial anastomosis rather than fetal compromise.76,77
24-week sonogram was normal. Furthermore, in gestations
with normal growth at 20 to 24 weeks a mean of 10.3 (± 3.9) Summary Statement
weeks elapsed before a growth abnormality was subsequently 6. Umbilical artery Doppler may be useful in the
detected.75 This suggests that some routine growth scans surveillance of twin gestations when there are
may be of very limited benefit while increasing the false complications involving the placental circulation
positive rate. Increased surveillance is warranted when one or fetal hemodynamic physiology. (II-2)
or both fetuses show growth restriction or discordance. In
these circumstances, serial growth scans every 2 to 3 weeks
(or more frequently in monochorionic twins) and fetal Recommendation
surveillance testing are indicated as for singleton (Doppler, 11. Umbilical artery Doppler should not be routinely
non-stress test, and/or biophysical profile). offered in uncomplicated twin pregnancies. (I-E)
Summary Statements
5. Although there is insufficient evidence to recommend ASSESSMENT OF AMNIOTIC FLUID
a specific schedule for ultrasound assessment of twin Currently available evidence78–81 is insufficient to make a
gestation, most experts recommend serial ultrasound formal recommendation on the best method of amniotic
assessment every 2 to 3 weeks, starting at 16 weeks of fluid assessment in twins. Outcome-based studies are
gestation for monochorionic pregnancies and every
lacking. Identification of the inter-twin membrane is vital
3 to 4 weeks, starting from the anatomy scan
in order to determine the fluid space around each fetus.
(18 to 22 weeks) for dichorionic pregnancies. (II-1)
Accepted methods for fluid estimation include subjective
Recommendation assessment, deepest vertical pocket, modified amniotic
fluid index and 2-dimensional pockets. Another method
10. Increased fetal surveillance should be considered
is to ascertain the presence of fluid, caudal and rostral,
when there is either growth restriction diagnosed in
and determine to which fetus it belongs and subjectively
one twin or significant growth discordance. (II-2A)
estimate if normal. When amniotic fluid volume appears
reduced or increased, the vertical measurement of the
USE OF UMBILICAL ARTERY largest pocket in each sac is taken. The condition is
DOPPLER VELOCIMETRY IN TWINS
defined as oligohydramnios when the deepest vertical
Because inequality of the 2 fetal-placental circulations can pocket < 2 cm and as polyhydramnios when the deepest
cause inter-twin differences in growth, umbilical artery vertical pocket is > 8 cm. These definitions correspond
Doppler velocimetry may improve the detection of IUGR approximately to the 2.5th percentile and 95th percentile
or fetal growth discordance.65 The largest trial of Doppler across all gestational ages.82 This is also a common
assessment of twin pregnancy (n = 526) compared criterion used in defining TTTS, and for these reasons,
routine biometric ultrasound assessment to routine this may be the clinically useful method for assessing
assessment plus umbilical artery Doppler velocimetry in amniotic fluid in twins.83
a randomized fashion at 25, 30, and 35 weeks’ gestation.73
There were no differences between groups in any Summary Statements
antenatal, intrapartum, or neonatal outcome; there were 7. Although many methods of evaluating the level of
fewer unexplained fetal deaths in the Doppler group, amniotic fluid in twins (deepest vertical pocket, single
but this was not statistically significant. Unfortunately, pocket, amniotic fluid index) have been described,
this study was limited by insufficient power and because there is not enough evidence to suggest that one
monochorionic pregnancies were not analyzed separately. method is more predictive than the others of adverse
The available data do not show a clear benefit of Doppler pregnancy outcome. (II-3)
twin over time.92 Because of the complexity of these cases Summary Statement
and the possible management options, including expectant 8. Referral to an appropriate high-risk pregnancy centre
management,92,93 referral to a tertiary care unit is indicated. is indicated when complications unique to twins are
suspected on ultrasound. (II-2) These complications
Conjoined Twins include:
The incidence of conjoined twins varies between 1 in 50 000 1. Twin-to-twin transfusion syndrome
and 1 in 100 000 births.94,95 The diagnosis can be made by 2. Monoamniotic twins gestations
ultrasound examination in the first trimester. If the embryo 3. Conjoined twins
appears bifid, follow-up imaging should be performed to 4. Twin reversed arterial perfusion sequence
confirm the diagnosis. Other clues to the diagnosis include 5. Single fetal death in the second or third trimester
the inability to separate the fetal bodies and skin contours, lack 6. Growth discordance in monochorionic twins.
of a separating membrane between the twins, the presence
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74. Mongelli M, Ek S, Tambyrajia R. Screening for fetal growth restriction: of the pregnant patient. Philadelphia: Lippincott Williams & Wilkins;
a mathematical model of the effect of time interval and ultrasound error. 2000:149–72.
Obstet Gynecol 1998;92:908–12.
97. Samuels P. Ultrasound in the management of the twin gestation. Clin
75. Grobman WA, Parilla BV. Positive predictive value of suspected growth Obstet Gynecol 1988;31:110–22.
aberration in twin gestations. Am J Obstet Gynecol 1999;181:1139–41.
98. Prompeler HJ, Madjar H, Klosa W, du BA, Zahradnik HP, Schillinger H,
76. Gratacos E, Lewi L, Carreras E, Becker J, Higueras T, Deprest J, et al. et al. Twin pregnancies with single fetal death. Acta Obstet Gynecol Scand
Incidence and characteristics of umbilical artery intermittent absent 1994;73:205–8.
and/or reversed end-diastolic flow in complicated and uncomplicated
99. Landy HJ, Weingold AB. Management of a multiple gestation complicated
monochorionic twin pregnancies. Ultrasound Obstet Gynecol
by an antepartum fetal demise. Obstet Gynecol Surv 1989;44:171–6.
2004;23:456–60.
77. Wee LY, Taylor MJ, Vanderheyden T, Talbert D, Fisk NM. Transmitted 100. Woolf SH, Battista RN, Angerson GM, Logan AG, Eel W. Canadian
arterio-arterial anastomosis waveforms causing cyclically intermittent Task Force on Preventive Health Care. New grades for recommendations
absent/reversed end-diastolic umbilical artery flow in monochorionic from the Canadian Task Force on Preventive Health Care. CMAJ
twins. Placenta 2003;24:772–8. 2003;169:207–8.
This document reflects emerging clinical and scientific advances on the date issued and is subject to change. The information
should not be construed as dictating an exclusive course of treatment or procedure to be followed. Local institutions can dictate
amendments to these opinions. They should be well documented if modified at the local level. None of these contents may be
reproduced in any form without prior written permission of the SOGC.
Key to evidence statements and grading of recommendations, using the ranking of the Canadian Task Force
on Preventive Health Care
I: Evidence obtained from at least one properly randomized A. There is good evidence to recommend the clinical preventive
controlled trial action
II-1: Evidence from well-designed controlled trials without B. There is fair evidence to recommend the clinical preventive
randomization action
II-2: Evidence from well-designed cohort (prospective or C. The existing evidence is conflicting and does not allow to
retrospective) or case–control studies, preferably from more make a recommendation for or against use of the clinical
than one centre or research group preventive action; however, other factors may influence
decision-making
II-3: Evidence obtained from comparisons between times or
places with or without the intervention. Dramatic results in D. There is fair evidence to recommend against the clinical
uncontrolled experiments (such as the results of treatment preventive action
with penicillin in the 1940s) could also be included in this E. There is good evidence to recommend against the clinical
category preventive action
III: Opinions of respected authorities, based on clinical L. There is insufficient evidence (in quantity or quality) to make
experience, descriptive studies, or reports of expert a recommendation; however, other factors may influence
committees decision-making
*The quality of evidence reported in these guidelines has been adapted from The Evaluation of Evidence criteria described in the Canadian Task Force on
Preventive Health Care.1
†Recommendations included in these guidelines have been adapted from the Classification of Recommendations criteria described in the The Canadian Task
Force on Preventive Health Care.1
damaged peritoneum, Interceed transforms into a gel that through one of the laparoscopic ports. The slurry produces
covers the area and is postulated to prevent adhesion for- a gelatinous membrane coating on any surface on which it is
mation.17 The membrane may be cut as necessary, which deposited, and it is postulated that its adhesion-preventing
may allow for its use in both open and laparoscopic surgeries; effects may be similar to those produced when Seprafilm is
however, the product monograph specifies that it has been used at laparotomy. Although this slurry is being used by
approved only for use at laparotomy. It should be applied in Canadian and international surgical experts, there is insuffi-
a single layer between two adjacent tissues. Interceed is cient evidence to support its use in preventing adhesions,
completely absorbed within two weeks. Meticulous and this constitutes an off-label use of the product. Trials
hemostasis must be achieved before Interceed is applied; of benefits are presently underway.
when mixed with blood Interceed increases fibrin deposition
and may increase the formation of adhesions.18 The only study to examine the use of Seprafilm at
laparotomy versus no treatment31 concluded that it reduced
There have been numerous studies evaluating the use of the incidence, extent, and severity of postoperative
Interceed versus no treatment.19-28 When compared with no adhesions. However, the Cochrane database found that
treatment, Interceed was associated with a reduced suboptimal statistical analyses were used in this study, and
incicence of pelvic adhesion (OD 0.39; 95% CI 0.28 to the results should therefore be interpreted with caution.15
0.55) following laparotomy.15 Similar results were noted No studies have yet evaluated the incidence of small bowel
following laparoscopy, with a reduction noted in new obstruction or chronic pelvic pain or pregnancy rates fol-
formation (OD 0.31; 95% CI 0.23 to 0.79) and in lowing the use of Seprafilm.
reformation (OR 0.19; 95% CI 0.09 to 0.42) of adhesions.15
There are no data on its effects on the incidence of small Summary Statements
bowel obstruction, chronic pelvic pain, or pregnancy rates. 3. Polytetrafluoroethylene (Gore-Tex) barrier is more
Polytetrafluoroethylene (Gore-Tex) effective than no barrier or oxidized regenerated
Gore-Tex is a permanent, nonabsorbable membrane that cellulose in preventing adhesion formation. (I)
must be sutured into place. Particularly at laparoscopy, the 4. Oxidized regenerated cellulose (Interceed) adhesion
need to stabilize the membrane with sutures may result in barrier is associated with a reduced incidence of
surgical delays. pelvic adhesion formation at both laparoscopy and
There is evidence to suggest that, compared with no treat- laparotomy when complete hemostasis is achieved.
ment, Gore-Tex results in a reduction in the formation of Oxidized regenerated cellulose may increase the risk
new adhesions in patients undergoing a myomectomy (OR of adhesions if optimal hemostasis is not achieved. (II-2)
0.21; 95% CI 0.05 to 0.87).29 Gore-Tex has been reported to
have less adhesion reformation than Interceed in women 5. Chemically modified sodium hyaluronate/
undergoing adhesiolysis (OR 0.16; 95% CI 0.03 to 0.80).15,30 carboxymethylcellulose (Seprafilm) is effective in
Results should be interpreted with caution, as it is unclear if preventing adhesion formation, especially following
the surgeon was unblinded at the time of second look lapa- myomectomies. There is insufficient evidence on the
roscopy.15 Again, no studies have evaluated the incidence of effect of sodium hyaluronate/carboxymethylcellulose
small bowel obstruction and chronic pelvic pain or preg- on long-term clinical outcomes such as fertility,
nancy rates following the use of Gore-Tex. chronic pelvic pain, or small bowel obstruction. (II-2)
Chemically modified sodium hyaluronate/ 6. No adverse effects have been reported with the use
of oxidized regenerated cellulose,
carboxymethylcellulose (Seprafilm)
polytetrafluoroethylene, or sodium
Seprafilm is an absorbable synthetic membrane made up of hyaluronate/carboxymethylcellulose. (II-1)
two polysaccharides: sodium hyaluronate and
carboxymethylcellulose. Seprafilm is supplied within a Recommendation
plastic sleeve which must be removed before the Seprafilm 3. Surgeons could consider using an adhesion barrier for
is placed on the tissues. Within 24 to 48 hours, the mem- patients who are at high risk of forming clinically
brane becomes gelatinous, and it is absorbed within one significant adhesions (i.e., patients who have
week. At the present time, Seprafilm is indicated only for endometriosis or pelvic inflammatory disease or who are
use at laparotomy. undergoing a myomectomy). If there is a risk of ongoing
Some surgeons use Seprafilm at laparoscopy by creating a bleeding from the surgical site, oxidized regenerated
“slurry” (i.e., a thin mixture of Seprafilm mixed with normal cellulose (Interceed) should not be used as it may
saline) and then flushing this preparation via a catheter increase the risk of adhesions in this situation. (II-2B)
This document reflects emerging clinical and scientific advances on the date issued and is subject to change. The information
should not be construed as dictating an exclusive course of treatment or procedure to be followed. Local institutions can dictate
amendments to these opinions. They should be well documented if modified at the local level. None of these contents may be
reproduced in any form without prior written permission of the SOGC.
Table 1. Key to evidence statements and grading of recommendations, using the ranking of the Canadian Task Force
on Preventive Health Care
I: Evidence obtained from at least one properly randomized A. There is good evidence to recommend the clinical preventive
controlled trial action
II-1: Evidence from well-designed controlled trials without B. There is fair evidence to recommend the clinical preventive
randomization action
II-2: Evidence from well–designed cohort (prospective or C. The existing evidence is conflicting and does not allow to
retrospective) or case–control studies, preferably from more make a recommendation for or against use of the clinical
than one centre or research group preventive action; however, other factors may influence
decision-making
II-3: Evidence obtained from comparisons between times or
places with or without the intervention. Dramatic results in D. There is fair evidence to recommend against the clinical
uncontrolled experiments (such as the results of treatment preventive action
with penicillin in the 1940s) could also be included in this E. There is good evidence to recommend against the clinical
category preventive action
III: Opinions of respected authorities, based on clinical L. There is insufficient evidence (in quantity or quality) to make
experience, descriptive studies, or reports of expert a recommendation; however, other factors may influence
committees decision-making
*The quality of evidence reported in these guidelines has been adapted from The Evaluation of Evidence criteria described in the Canadian Task Force on
Preventive Health Care.40
†Recommendations included in these guidelines have been adapted from the Classification of Recommendations criteria described in the The Canadian Task
Force on Preventive Health Care.40
6. In patients with morbid obesity (BMI > 35), doubling the antibiotic methicillin resistant Staphylococcus aureus, vancomycin resistant
dose may be considered. (III-B)
Enterococcus, and extended-spectrum beta-lactamase-producing
7. Antibiotics should not be administered solely to prevent
endocarditis for patients who undergo an obstetrical procedure organisms.
of any kind. (III-E)
J Obstet Gynaecol Can 2010;32(9):878–884 Both morbidity and mortality are increased in infections
caused by these organisms, as they may be more virulent
INTRODUCTION and are more difficult to treat because therapeutic options
are limited. Antibiotic resistance development results
nfectious complications following obstetric surgical
I procedures are a significant source of morbidity and
mainly from the inappropriate use of antibiotics. Incomplete
courses of antibiotic therapies and the unnecessary use of
potential mortality. They include urinary tract infection, broader spectrum regimens play a role.2 Adherence to both
endometritis, wound infection, perineal infection, and sepsis, treatment and prophylaxis guidelines likely assists in reducing
which lead to prolonged hospital stays and increased health infection and antibiotic resistance. Physician adherence to
care costs. Much work has been done to study the effect of antibiotic prophylaxis guidelines is variable and usually at
prophylactic antibiotics in reducing infectious morbidity. A odds with published guidelines.3,4
plethora of antibiotic types, dosing schedules, and routes of
administration have been investigated. There is evidence to In addition to antibiotic prophylaxis, it is essential to review
support the use of prophylactic antibiotics for a number of all factors that affect infectious risk reduction in obstetrical
procedures in obstetrics. Unfortunately, few comparative care.5 Adherence to appropriate skin preparation procedure,
trials have been conducted, leaving the clinician with uncer- including hair clipping as opposed to shaving, and effective
tainty as to which regimen is superior. antisepsis of both patient and staff are required.6 Sterile
surgical fields must be ensured, and ongoing quality assess-
The presence of antibiotic resistant organisms is a reality in ment of sterilization technique, air ventilation, and postop-
Canadian health care facilities.1 These organisms include erative wound care is needed. Consistent infection control
surveillance and reporting of infectious complications track
ability to minimize these morbidities and possibly to
ABBREVIATIONS
identify clusters of infection and the emergence of antibiotic
CDC Centers for Disease Control and Prevention resistant organisms. This will dictate changes to operative
IE infective endocarditis routines to respond to evolving microbial diversity that
SSI surgical site infection seems inevitable.
PRINCIPLES OF ANTIBIOTIC PROPHYLAXIS repair of third or fourth degree perineal laceration, cervical
The purpose of antibiotic prophylaxis in surgical procedures cerclage, and postpartum dilatation and curettage. Recent
is not to sterilize tissues but to reduce the colonization pres- changes to endocarditis prophylaxis guidelines are also be
sure of microorganisms introduced at the time of operation reviewed.
to a level that the patient’s immune system is able to over- Caesarean Section
come.7 Prophylaxis does not prevent infection caused by The single most important risk factor for postpartum maternal
postoperative contamination. Prophylactic antibiotic use infection is Caesarean section.11 Women having Caesarean
differs from treatment with antibiotics5 in that the former is section have a 5- to 20-fold greater risk of infection than
intended to prevent infection, whereas the latter is intended women having vaginal delivery. Rates of wound infection
to resolve an established infection, typically requiring a longer and serious infectious complications can be as high as
course of therapy. Prophylaxis is intended for elective pro- 25%.12 There is no consistent application of definitions for
cedures when the incision will be closed in the operating SSI, and the practice of post-discharge surveillance varies
room. widely.13 A recent prospective study with proper application
Before an agent can be considered for use as a prophylactic of CDC definitions for surgical site infection with follow-
antibiotic, there must be evidence that it reduces postoperative up to 30 days post-Caesarean section identified a wound
infection. It must also be safe and inexpensive, and it must infection rate of 8.9%.14 It is likely that post- Caesarean
be effective against organisms likely to be encountered in wound infection rates are inaccurate, because up to 84% of
the surgical procedure. infections occur after discharge,7 when surveillance may be
The agent must be administered in a way that ensures that lacking.
serum and tissue levels are adequate before an incision is made Endomyometritis, urinary tract infection, wound infection,
and that therapeutic levels of the agent can be maintained in and sepsis may occur following Caesarean section. Numerous
serum and tissue during surgery and for a few hours (at most) studies have investigated the use of prophylactic antibiotics
after the incision is closed.7 to reduce these complications, the rates of which are all
Wound infections—surgical site infections—in the form of higher in the case of emergency Caesarean section, with or
cellulitis, abscess, or dehiscence can occur following without the presence of maternal fever and/or chorioamnionitis.
laparotomy. Pelvic infections, such as an abscess or infected A Cochrane review published in 2002 included 81 randomized
hematoma, are a risk with any surgical procedure that enters trials assessing antibiotic prophylaxis versus placebo or no
the abdominal cavity. Cuff cellulitis is a specific risk for hys- treatment for both elective and emergency Caesarean sections.
terectomy. Endometritis can result from Caesarean section The review included just over 2000 women in each arm.
or surgical abortion. Urinary tract infections can occur as a When antibiotics were given rather than placebo or no
result of any procedure that involves catheterization of the treatment, the relative risk of endometritis in both elec-
bladder. tive and emergency Caesarean sections was reduced
A 1999 guideline published by the US Centers for Disease (RR 0.38; 95% CI 0.22 to 0.64 and RR 0.39; 95% CI 0.34 to 0.46),
Control and Prevention lists the specific and stringent criteria as was the risk of wound infection (RR 0.36; 95% CI 0.26 to
that must be met for diagnosis of a surgical site infection.7 0.51 and RR 0.73; 95% CI 0.53 to 0.99).15
Accurate surveillance for SSI monitoring requires follow- There has been debate about the benefit of prophylactic
up for 30 days postoperatively, and the trend towards early antibiotics for a woman who has an elective Caesarean section
discharge from hospital makes surveillance a challenge. It is with intact membranes and without labour. A meta-analysis
estimated that up to 84% of surgical site infections occur of 4 studies found that antibiotic prophylaxis resulted in a
following discharge from hospital.7 decrease in postoperative fever (RR 0.25; 95% CI 0.14 to 0.44)
If prophylactic antibiotics are to be given, they should be and endometritis (RR 0.05; 95% CI 0.01 to 0.38).16
administered shortly prior to or at bacterial inoculation.8,9 Taken together, these data support the recommendation to
The majority of studies suggest that a single dose is effective, use prophylactic antibiotics for all women undergoing
but for lengthy procedures (> 3 hours) the dose should be Caesarean section.
repeated at intervals 1or 2 times the half-life of the drug. It Controversy also exists about whether prophylactic antibiotics
has also been suggested that with large blood loss (> 1500 mL), in Caesarean section should be given prior to skin incision
a second dose should be given.10 or at the time of the umbilical cord clamping. Traditionally,
prophylaxis has been delayed in an effort to avoid masking a
USE OF ANTIBIOTIC PROPHYLAXIS IN OBSTETRICS
neonatal infection and to prevent an unnecessary septic
Procedures reviewed in this section include Caesarean section, work-up. However, recent evidence may change this practice.
operative vaginal delivery, manual removal of placenta, A randomized trial compared maternal infectious and
neonatal outcomes in women randomized to receive of antibiotic prophylaxis after manual removal of the pla-
cefazolin 15 to 60 minutes before incision versus at cord centa and bases the recommendation on studies involving
clamp. Three hundred fifty-seven women were enrolled. Caesarean section and abortion and on observational
Overall maternal infectious morbidity was reduced in the studies of other intrauterine manipulations.23
pre-treatment group (RR 0.4; 95% CI 0.18 to 0.87); in
The effect of operator glove change before manual removal
particular, endometritis was reduced (RR 0.2; 95% CI 0.15 to 0.94).
of the placenta at Caesarean section was studied in a group
No increase in neonatal sepsis, investigation, or length of
of 228 women, with operators changing gloves in one half
stay was observed.17 A recent meta-analysis supports the
of the cases. No difference in post-Caesarean endometritis
use of prophylactic antibiotics prior to Caesarean incision
was noted between the 2 groups.24 However, the incidence
to prevent total infectious morbidity (RR 50; 95% CI 0.33
of endometritis was decreased when the placenta delivered
to 0.78, P = 0.002). Neonatal outcomes were not affected.18
spontaneously rather than being manually removed at Cae-
The most widely studied antibiotics for surgical prophylaxis
sarean section in a study of 333 women, all of whom
are cephalosporins. Cefazolin is a first-generation cephalosporin
received prophylactic antibiotics (15% vs. 26%, RR 0.6;
and is a Pregnancy Category B drug. When given intrave-
P = 0.01).25
nously, its half-life is 1.8 hours. It provides good coverage
for gram positive organisms and has modest gram negative Third or Fourth Degree Perineal Laceration
coverage. In a 1999 guideline, the US Centers for Disease
A 2005 Cochrane review26 on this subject found there were
Control and Prevention recommended its use at Caesarean
no randomized trials comparing prophylactic antibiotics
section.7 It is recommended that 1 to 2 grams should be
with placebo or no treatment in fourth degree perineal tears
administered intravenously not more than 30 minutes before
during vaginal birth. A well-designed randomized trial was
the skin is cut. An additional dose can be considered if
recommended. This was undertaken by Duggal et al.27 and
blood loss exceeds 1500 mL or at 4 hours if the procedure
published in 2008. This prospective trial followed 107 women
lasts more than 4 hours (i.e., up to 2 half-lives of the drug).19
post third or fourth degree laceration repair for 2 weeks; the
Trials have shown that broader spectrum antibiotics for women had been randomly assigned to receive a single
Caesarean section do reduce infectious morbidity. Superi- intravenous dose of cefotetan, cefoxitin, or placebo. Four
ority trials with cefazolin have not been conducted. Given of 49 (8%) who received antibiotics and 14 of 58 (24%) who
the potential for antibiotic resistance in both mother and received placebo developed perineal wound complication
neonate, recommendations for the use of broader spectrum (P = 0.037). This suggests a benefit to using prophylactic
antibiotics require further study.20 antibiotics to reduce morbidity following significant perineal
Operative Vaginal Delivery laceration.27
A 2004 Cochrane review investigated the use of prophylactic Elective and Emergency Cerclage, With or
antibiotics for operative vaginal delivery, with either forceps Without Exposed Membranes
or vacuum assisted deliveries, to determine if prophylaxis
There is insufficient evidence to support the use of prophy-
reduces the incidence of postpartum infections.21 The
lactic antibiotics with the placement of cervical cerclage in
review identified only one trial of 393 women, and only 2 of
any clinical setting. One study28 investigated the use of
9 outcomes deemed appropriate by the reviewers were
continuous low-dose antibiotics in women with a history
assessed in this study: endometritis and length of hospital
of second trimester pregnancy loss with the placement
stay. These did not differ between those who received
of cerclage at 14 to 24 weeks’ gestation on the basis of
prophylaxis and those who received no treatment. The
transvaginal sonographic findings of cervical funnelling.
review concluded there were insufficient data on which to
base recommendations for practice and that further Each of the 10 patients had a live birth, and pregnancy was
research is needed. No additional studies addressing this prolonged by a mean of 13.4 ± 4.2 weeks beyond the
issue have been published to date. previous pregnancy. There was no control group.28 In a second
retrospective study of 116 mid-trimester cerclage place-
Manual Removal of Placenta ments, antibiotic use was not associated with a decreased
There is limited information regarding the use of prophy- risk of delivery before 28 weeks’ gestation.29 Randomized
lactic antibiotics to reduce the development of postpartum clinical trials are needed to confirm the role of antibiotics in
endometritis following manual removal of the placenta. these high-risk pregnancies.
A Cochrane review, updated in April 2009, did not identify
Postpartum Dilatation and Curettage
any randomized controlled trials.22 The World Health
Organization suggests that prophylaxis should be offered No studies were identified that investigated the use of
but recognizes that there is no direct evidence of the value prophylactic antibiotics for postpartum dilatation and curettage.
Table 2. Cardiac conditions associated with the highest risk of adverse outcome from endocarditis
Prosthetic cardiac valve or prosthetic material used for cardiac valve repair
Previous infective endocarditis
Congenital heart disease (CHD)
Unrepaired cyanotic CHD (including palliative shunts and conduits)
Completely repaired CHD with prosthetic material < 6 months after procedure
Repaired CHD with residual defects at/near site of prosthetic material
Cardiac transplant recipient with cardiac valvulopathy
Adapted from Wilson W, Taubert KA, Gewitz M, Lockhart PB, Baddour LM, Levison M, et al. 38
Emergency or elective caesarean section Cefazolin IV 15–60 mins prior to skin incision 1–2 g IV I-A
(no labour, no rupture of membranes)
If penicillin allergic
Clindamycin OR 600 mg IV
erythromycin 500 mg IV
Operative vaginal delivery None recommended N/A II-1C
Manual removal placenta None recommended N/A III-L
Repair third or fourth degree laceration Cefotetan 1 g IV I-B
Cefoxitin 1 g IV I-B
Postpartum dilatation and curettage None recommended N/A No evidence
Cerclage None recommended N/A II-3C
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33. del Real GA, Rose ME, Ramirez-Atamoros MT, Hammel J, Gordon SM,
22. Chongsomchai C, Lumbiaganon P, Laopaiboon M. Prophylactic antibiotics Arroliga AC, Arroliga ME. Penicillin skin testing in patients with a history
for manual removal of retained placenta in vaginal delivery. Cochrane of beta-lactam allergy. Ann Allergy Asthma Immunol 2007;98:355–9.
Database Syst Rev 2006;(2):CD004904.
34. International Rheumatic Fever Study Group. Allergic reactions to
23. World Health Organisation (WHO). WHO guidelines for the management long-term benzathine penicillin propylaxis for rheumatic fever.
of postpartum hemorrhage and retained placenta. Geneva: WHO; 2009. Lancet 1991;337(8753):1308–10.
Available at: http://whqlibdoc.who.int/publications/2009/
35. Dash, CH. Penicillin allergy and the cephalosporins. J Antimicrob Chemother
9789241598514_eng.pdf. Accessed May 23, 2010.
1975;1:107.
24. Turrentine MA, Banks TA. Effect of changing gloves before placental 36. Daulat, S, Solensky, R, Earl, HS, Casey W, Gruchalla RS. Safety of
extraction on incidence of postcesarean endometritis. Infect Dis Obstet cephalosporin administration to patients with histories of penicillin allergy.
Gynecol 1996;4:16–9. J Allergy Clin Immunol 2004;113:1220.
25. Lasley DS, Eblen A, Yancey MK, Duff P. The effect of placental removal 37. Fonacier L, Hirschberg R, Gerson S. Adverse drug reactions to a cephalosporins
method on the incidence of postcesarean infections. Am J Obstet Gynecol in hospitalized patients with a history of penicillin allergy. Allergy Asthma
1997;176:1250–4. Proc 2005;26:135.
26. Buppasiri P, Lumbiganon P, Thinkhamrop J, Thinkhamrop B. Antibiotic 38. Wilson W, Taubert KA, Gewitz M, Lockhart PB, Baddour LM, Levison M, et al.;
prophylaxis for fourth degree perineal tear during vaginal birth. Cochrane American Heart Association Rheumatic Fever, Endocarditis, and Kawasaki
Database Syst Rev 2005;(4):CD005125. Disease Committee; American Heart Association Council on Cardiovascular
27. Duggal N, Mercado C, Daniels K, Bujor A, Caughey AB, El-Sayed YY. Disease in the Young; American Heart Association Council on Clinical
Antibiotic prophylaxis for prevention of postpartum perineal wound Cardiology; American Heart Association Council on Cardiovascular Surgery
complications: a randomized controlled trial. Obstet Gynecol and Anesthesia; Quality of Care and Outcomes Research Interdisciplinary
2008;111:1268–73. Working Group. Prevention of Infective Endocarditis: Guidelines From the
American Heart Association. Circulation 2007;116:1736–54.
28. Shiffman RL. Continuous low-dose antibiotics and cerclage for recurrent
39. Castillo E, Magee LA, von Dadelszen P, Money D, Blondel-Hill E,
second-trimester pregnancy loss. J Reprod Med 2000;45:323–6.
van Schalkwyk J. Our patients do not need endocarditis prophylaxis
29. Terkildsen MF, Parilla BV, Kumar P, Grobman WA. Factors associated for genitourinary tract prodecures: insights from the 2007 Amercian Heart
with success of emergent second-trimester cerclage. Obstet Gynecol Association guidelines. J Obstet Gynaecol Can 2008;30:796–9.
2003;101:565–9.
40. Woolf SH, Battista RN, Angerson GM, Logan AG, Eel W. Canadian Task
30. Heslehurst N, Simpson H, Ells LJ, Rankin J, Wilkinson J, Lang R, et al. Force on Preventive Health Care. New grades for recommendations from
The impact of maternal BMI status on pregnancy outcomes with the Canadian Task Force on Preventive Health Care. CMAJ 2003;169:207–8.
This document reflects emerging clinical and scientific advances on the date issued and is subject to change. The information
should not be construed as dictating an exclusive course of treatment or procedure to be followed. Local institutions can dictate
amendments to these opinions. They should be well documented if modified at the local level. None of these contents may be
reproduced in any form without prior written permission of the SOGC.
5. Following a diagnosis of fetal CMV infection, serial ultrasound probability of intrauterine transmission following primary
examinations should be performed every 2 to 4 weeks to detect
sonographic abnormalities, which may aid in determining the prognosis infection during pregnancy is 30% to 40%,1,8 compared
of the fetus, although it is important to be aware that the absence of with only 1% following secondary infection. 1,8 Ten to
sonographic findings does not guarantee a normal outcome. (II-2B)
fifteen percent of congenitally infected infants will have
6. Quantitative determination of CMV DNA in the amniotic fluid may
assist in predicting the fetal outcome. (II-3B)
symptoms at birth including intrauterine growth restriction,
microcephaly, hepatosplenomegaly, petechiae, jaundice,
7. Routine screening of pregnant women for CMV by serology testing
is currently not recommended. (III-B) chorioretinitis, thrombocytopenia, and anemia, and 20% to 30%
8. Serologic testing for CMV may be considered for women who develop of them will die, mostly of disseminated intravascular coag-
influenza-like illness during pregnancy or following detection of ulation, hepatic dysfunction, or bacterial superinfection.8–10
sonographic findings suggestive of CMV infection. (III-B)
Most of the congenitally infected infants (85–90%) have no
9. Seronegative health care and child care workers may be offered signs or symptoms at birth, but 5% to 15% of them will
serologic monitoring during pregnancy. Monitoring may also be
considered for seronegative pregnant women who have a young develop sequelae such as sensorineural hearing loss, delay of
child in day care. (III-B) psychomotor development, and visual impairment.11,12
J Obstet Gynaecol Can 2010;32(4):348–354
PRENATAL DIAGNOSIS
INTRODUCTION
The first step in the prenatal diagnosis of congenital CMV
Table 1. Key to evidence statements and grading of recommendations, using the ranking of the
Canadian Task Force on Preventive Health Care
I: Evidence obtained from at least one properly randomized A. There is good evidence to recommend the clinical preventive
controlled trial action
II-1: Evidence from well-designed controlled trials without B. There is fair evidence to recommend the clinical preventive
randomization action
II-2: Evidence from well-designed cohort (prospective or C. The existing evidence is conflicting and does not allow to
retrospective) or case–control studies, preferably from more make a recommendation for or against use of the clinical
than one centre or research group preventive action; however, other factors may influence
decision-making
II-3: Evidence obtained from comparisons between times or
places with or without the intervention. Dramatic results in D. There is fair evidence to recommend against the clinical
uncontrolled experiments (such as the results of treatment preventive action
with penicillin in the 1940s) could also be included in this E. There is good evidence to recommend against the clinical
category preventive action
III: Opinions of respected authorities, based on clinical L. There is insufficient evidence (in quantity or quality) to make
experience, descriptive studies, or reports of expert a recommendation; however, other factors may influence
committees decision-making
*The quality of evidence reported in these guidelines has been adapted from The Evaluation of Evidence criteria described in the Canadian Task Force on
Preventive Health Care.38
†Recommendations included in these guidelines have been adapted from the Classification of Recommendations criteria described in the The Canadian Task
Force on Preventive Health Care.38
infection. Avidity levels are reported as the avidity Table 2. Congenital CMV infection-sonographic finding
index, expressing the percentage of IgG bound to IUGR
the antigen following treatment with denaturing Cerebral ventriculomegaly
agents.13 Microcephaly
An avidity index > 60% is highly suggestive of past or Intracranial calcifications
secondary infection, while an avidity index < 30% is Ascites/pleural effusion
highly suggestive of a recent primary infection (duration Hydrop fetalis
< 3 months).17 Hence, serologic diagnosis of primary CMV Oligohydramnios/polyhydramnios
infection during pregnancy is documented by either Hyperechogenic bowel
seroconversion (the appearance of CMV-specific IgG Liver calcifications
antibody in a previously seronegative woman) or detection
of specific IgM antibody associated with low IgG avidity.
Women who have detectable specific IgG antibodies with-
out IgM antibodies before pregnancy and a significant rise sonographic findings of fetal CMV infection include fetal
of IgG antibody titre with or without the presence of spe- growth restriction, cerebral ventriculomegaly, ascites,
cific IgM antibodies and with high IgG avidity can be classi- intracranial calcifications, abnormality of amniotic fluid volume
fied as having recurrent infection.18 (usually oligohydramnios), microcephaly, hyperechogenic
Diagnosis of Fetal Infection bowel, hydrops fetalis, pleural effusion, and liver
calcifications19–21 (Table 2).
Since intrauterine transmission of the virus occurs in only
30% to 40% of pregnancies in women with primary infection Because of its high sensitivity and specificity, CMV isolation
and at a significantly lower rate in women with secondary from amniotic fluid has been recognized as the gold standard
infection, it is important in cases of proven maternal infection for prenatal diagnosis of fetal CMV infection.9,13,22 To achieve
to find out if the fetus is infected. the highest sensitivity, the amniocentesis should be per-
Ultrasonographic findings are helpful but not diagnostic formed until at least 7 weeks after the onset of maternal
because CMV has features in common with other infection and after 21 weeks of gestation because a detectable
intrauterine infections and with other fetal diseases. Moreover, quantity of the virus is not secreted to the amniotic fluid
these abnormalities are observed in less than 25% of until 5 to 7 weeks after fetal infection and replication of the
infected fetuses.19 The most frequently reported virus in the kidney.9,16,23 It has been repeatedly reported that
prenatal diagnosis procedures performed too close to the Prognostic Markers of CMV Disease
onset of maternal infection carry a substantial risk of false One of the major limitations of prenatal diagnosis of CMV
negative results.24–26 The diagnosis of fetal CMV infection is that positive results of amniotic fluid tests such as viral
should be based on the results of culture and PCR testing of isolation and PCR do not discriminate between infants who
amniotic fluid samples. CMV isolation can be done by con- will have symptoms at birth and those who will not.
ventional culture on fibroblasts or by the shell vial tech-
nique, which uses monoclonal antibodies to the major The severity of the sonographically detected abnormalities
immediate early protein p72 and enables detection of the may aid in determining the prognosis of the fetus, but the
virus 16 to 24 hours after amniotic fluid collection.23,27,28 absence of sonographic findings does not guarantee a normal
outcome. Once fetal infection is diagnosed, serial ultra-
Diagnosis of fetal infection by testing for fetal IgM is not sound examinations should be done every 2 to 4 weeks to
recommended not only because of the risk associated with look for signs of CMV infection (Table 2) that might help in
cordocentesis but also because many fetuses infected by predicting the outcome. The ultrasound follow-ups should
CMV do not develop specific IgM until late in pregnancy, be performed in a laboratory that is capable of diagnosing
resulting in poor sensitivity.5,25 the abnormalities outlined in Table 2, and preferably in a
referral centre.
Although it is accepted that amniocentesis in primary
maternal CMV infection is warranted because of the high Fetal MRI may improve the prognostic evaluation, espe-
risk of fetal infection, there is no consensus on whether to cially when brain abnormalities are detected by ultrasound.
perform amniotic fluid viral studies in cases of secondary However, the role of fetal MRI in providing useful information
infection, when the risk of fetal infection is low. However, in fetuses with CMV still needs to be determined.30,31
there are several cases of secondary infection with severe The clinical significance of the viral load in amniotic fluid as
sequelae described in the literature; therefore, amniocente- a prognostic factor has been investigated by several studies,
sis for prenatal diagnosis of fetal infection may be consid- which showed that the CMV DNA load values in amniotic
ered even in cases of secondary infection.3,29 fluid samples were significantly higher in the group of
symptomatic than in the group of asymptomatic fetuses.32 young children and careful hand washing after changing
However, a great number of values were found to overlap diapers and wiping secretions.33 Despite our assumption
between the two groups33,34; thus the role of quantitative that changing protective behaviours prevents child to
determination of CMV DNA in the amniotic fluid as a mother transmission of CMV during pregnancy, Adler et al.
prognostic factor of CMV disease still awaits confirmation. did not show any benefit for such intervention.34 However,
their data also demonstrated that intervention is more effective
PRENATAL TREATMENT AND PREVENTION OF during pregnancy than before pregnancy, because pregnant
CONGENITAL CMV INFECTION women are more motivated to adhere to recommendations
Despite advances in the diagnosis of fetal CMV infection, than non-pregnant women.35
there is no effective therapy, and the option of pregnancy The Question of Screening
termination is often raised once fetal infection is detected by
ultrasound or amniocentesis or once a fetus is determined or Screening for CMV by serology has been and still is a
suspected to be affected. debated issue. Routine serologic screening for pregnant
women has never been recommended by any public health
A recent multicentre prospective cohort study of 157 preg- authority.13 The screening, if done, should be performed at
nant women with confirmed primary CMV infection evalu- the beginning of pregnancy or even prior to a planned
ated the use of CMV-specific hyperimmune globulin for the pregnancy. If a woman is seronegative, repeated examinations
treatment and prevention of fetal CMV infection.32 during pregnancy should be done when there is clinical
Forty-five women had a primary infection more than 6 weeks suspicion. However, screening is usually done before
before enrolment, underwent amniocentesis, and had CMV pregnancy for diseases such as rubella and varicella against
detected in the amniotic fluid. Thirty-one of these women which immunization can be provided, whereas there is
elected to receive intravenous treatment with currently no effective and safe immunization against CMV.
CMV-hyperimmune globulin (200 U/kg of the mother’s Moreover, because effective prenatal treatment options are
body weight). Fourteen women declined treatment with not yet available, the choices when a women is carrying a
hyperimmune globulin, and 7 of them had infants who were baby with CMV infection or disease are limited to elective
symptomatic at delivery. In contrast, only 1 of the 31 treated termination of the pregnancy or expectant observation until
women had an infant with clinical CMV disease at birth delivery. Prenatal testing, however, offers an opportunity to
although 15 of them were carrying fetuses with educate women about behaviours, and precautionary measures
ultrasonographic evidence of CMV disease.32 In the preven- can be suggested to seronegative women.36 Moreover, routine
tion group, 37 received hyperimmune globulin, 6 (16%) of antibody testing, especially if done before pregnancy, may
whom had infants with congenital CMV infection, com- help to differentiate between primary and secondary infection
pared with 19 of 47 women (40%) who did not receive in cases of suspected CMV infection during pregnancy.29
hyperimmune globulin. No adverse effects of Naessens et al. evaluated a screening program for CMV in
hyperimmune globulin were observed.32 These results offer which serological testing was performed at the first prenatal
a potential measure to treat and prevent congenital CMV visit; they showed that such screening allows the detection
infection. However, this was not a randomized controlled of 82% of all congenital CMV infections.37 Nevertheless,
trial, and further study is necessary prior to widespread routine serologic testing of all pregnant women for CMV to
adoption of this strategy. identify those who have acquired primary infection during
Regarding postnatal therapy, there is some evidence sug- pregnancy is not currently recommended. Therefore,
gesting a limited beneficial role for ganciclovir treatment of serological testing for CMV should be used only in women
neonates with symptomatic congenital CMV infection. A who develop influenza-like symptoms during pregnancy or
few studies have demonstrated some hearing improvement following detection of sonographic findings that are suggestive
and less hearing deterioration in infants treated with of CMV infection and that cannot be explained by another
ganciclovir.33–35 cause (placental insufficiency in case of IUGR and
oligohydramnios and fetal anemia in case of ascites etc.).
The ultimate goal in prevention of congenital CMV infection
is to develop a vaccine, which would be administered to SUMMARY
seronegative women of childbearing age to prevent the
occurrence of primary CMV infection during pregnancy. Congenital CMV infection is the leading infectious cause of
Until an effective vaccine is available, recommendations for mental retardation and sensorineural deafness. Once pri-
seronegative pregnant women with respect to CMV infection mary maternal CMV infection has been diagnosed, fetal
include practising good personal hygiene such as avoiding infection can be accurately determined by amniocentesis.
intimate contact with salivary secretions and urine from Prenatal counselling in case of fetal infection is difficult
because of our limited ability to predict outcome. Because 8. Serologic testing for CMV may be considered for women
20% to 25% of infected fetuses will develop sequelae, ter- who develop influenza-like illness during pregnancy or
mination of pregnancy should be discussed as one of the following detection of sonographic findings suggestive
management options. Currently, routine serologic testing of of CMV infection. (III-B)
all pregnant women is not recommended, and use of sero- 9. Seronegative health care and child care workers may be
logic testing should be used only in pregnant women who offered serologic monitoring during pregnancy. Moni-
develop influenza-like illness or following detection of toring may also be considered for seronegative pregnant
sonographic findings suggestive of CMV infection. women who have a young child in day care. (III-B)
RECOMMENDATIONS
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Obesity in Pregnancy
Abstract
This Clinical Practice Guideline has been prepared by the Objective: To review the evidence and provide recommendations for
Maternal Fetal Medicine Committee, reviewed by the Clinical the counselling and management of obese parturients.
Practice Obstetrics Committee, and approved by the Executive
and Council of the Society of Obstetricians and Gynaecologists of Outcomes: Outcomes evaluated include the impact of maternal
Canada obesity on the provision of antenatal and intrapartum care,
maternal morbidity and mortality, and perinatal morbidity and
PRINCIPAL AUTHORS mortality.
Gregory A.L. Davies, MD, Kingston ON Evidence: Literature was retrieved through searches of Statistics
Cynthia Maxwell, MD, Toronto ON Canada, Medline, and The Cochrane Library on the impact of
obesity in pregnancy on antepartum and intrapartum care,
Lynne McLeod, MD, Halifax NS maternal morbidity and mortality, obstetrical anaesthesia, and
MATERNAL FETAL MEDICINE COMMITTEE perinatal morbidity and mortality. Results were restricted to
systematic reviews, randomized controlled trials/controlled clinical
Robert Gagnon, MD (Chair), Montreal QC
trials, and observational studies. There were no date or language
Melanie Basso, RN, Vancouver BC restrictions. Searches were updated on a regular basis and
Hayley Bos, MD, London ON incorporated in the guideline to April 2009. Grey (unpublished)
literature was identified through searching the websites of health
Marie-France Delisle, MD, Vancouver BC technology assessment and health technology
Dan Farine, MD, Toronto ON assessment-related agencies, clinical practice guideline
collections, clinical trial registries, and national and international
Lynda Hudon, MD, Montreal QC medical specialty societies.
Savas Menticoglou, MD, Winnipeg MB Values: The evidence obtained was reviewed and evaluated by the
William Mundle, MD, Windsor ON Maternal Fetal Medicine and Clinical Practice Obstetric
Committees of the SOGC under the leadership of the principal
Lynn Murphy-Kaulbeck, MD, Allison NB
authors, and recommendations were made according to
Annie Ouellet, MD, Sherbrooke QC guidelines developed by the Canadian Task Force on Preventive
Tracy Pressey, MD, Vancouver BC Health Care.
Anne Roggensack, MD, Calgary AB Benefits, Harms, and Costs: Implementation of the
recommendations in this guideline should increase recognition of
CLINICAL PRACTICE OBSTETRICS the issues clinicians need to be aware of when managing obese
Dean Leduc, MD (Chair), Ottawa ON women in pregnancy, improve communication and consultation
amongst the obstetrical care team, and encourage federal and
Charlotte Ballerman, MD, Edmonton AB provincial agencies to educate Canadians about the values of
Anne Biringer, MD, Toronto ON entering pregnancy with as healthy a weight as possible.
Louise Duperron, MD, Montreal QC Recommendations
Donna Jones, MD, Calgary AB 1. Periodic health examinations and other appointments for
gynaecologic care prior to pregnancy offer ideal opportunities to
Lily Shek-Yun Lee, MSN, Vancouver BC
raise the issue of weight loss before conception. Women should
Debra Shepherd, MD, Regina SK 2
be encouraged to enter pregnancy with a BMI < 30 kg/m , and
2
Kathleen Wilson, RM, Ilderton ON ideally < 25 kg/m . (III-B)
Disclosure statements have been received from all members of 2. BMI should be calculated from pre-pregnancy height and weight.
2
the committees. Those with a pre-pregnancy BMI > 30 kg/m are considered
obese. This information can be helpful in counselling women
about pregnancy risks associated with obesity. (II-2B)
Key Words: Obesity, pregnancy, obstetric anaesthesia, Caesarean 3. Obese pregnant women should receive counselling about weight
section, body mass index, ultrasound, decision to delivery interval gain, nutrition, and food choices. (II-2B)
This document reflects emerging clinical and scientific advances on the date issued and is subject to change. The information
should not be construed as dictating an exclusive course of treatment or procedure to be followed. Local institutions can dictate
amendments to these opinions. They should be well documented if modified at the local level. None of these contents may be
reproduced in any form without prior written permission of the SOGC.
Key to evidence statements and grading of recommendations, using the ranking of the
Canadian Task Force on Preventive Health Care
I: Evidence obtained from at least one properly randomized A. There is good evidence to recommend the clinical preventive
controlled trial action
II-1: Evidence from well-designed controlled trials without B. There is fair evidence to recommend the clinical preventive
randomization action
II-2: Evidence from well-designed cohort (prospective or C. The existing evidence is conflicting and does not allow to
retrospective) or case-control studies, preferably from more make a recommendation for or against use of the clinical
than one centre or research group preventive action; however, other factors may influence
decision-making
II-3: Evidence obtained from comparisons between times or
places with or without the intervention. Dramatic results in D. There is fair evidence to recommend against the clinical
uncontrolled experiments (such as the results of treatment preventive action
with penicillin in the 1940s) could also be included in this E. There is good evidence to recommend against the clinical
category preventive action
III: Opinions of respected authorities, based on clinical L. There is insufficient evidence (in quantity or quality) to make
experience, descriptive studies, or reports of expert a recommendation; however, other factors may influence
committees decision-making
*The quality of evidence reported in these guidelines has been adapted from The Evaluation of Evidence criteria described in the Canadian Task Force
on Preventive Health Care.79
†Recommendations included in these guidelines have been adapted from the Classification of Recommendations criteria described in the The Canadian
Task Force on Preventive Health Care.79
4. Obese women should be advised that they are at risk for medical the television and computer, a sedentary lifestyle, and poor
complications such as cardiac disease, pulmonary disease,
gestational hypertension, gestational diabetes, and obstructive nutrition.4 The lifestyle that leads to obesity has a direct
sleep apnea. Regular exercise during pregnancy may help to effect on indicators of health. Women who are overweight
reduce some of these risks. (II-2B)
or obese are significantly more likely to suffer from high
5. Obese women should be advised that their fetus is at an increased blood pressure, diabetes, and heart disease.3 Concordantly,
risk of congenital abnormalities, and appropriate screening should
be done. (II-2B) rates of obesity in pregnancy are increasing.5 This guideline
6. Obstetric care providers should take BMI into consideration when examines the impact of obesity on maternal, fetal, and neo-
arranging for fetal anatomic assessment in the second trimester. natal outcomes. Recommendations for the management of
Anatomic assessment at 20 to 22 weeks may be a better choice
for the obese pregnant patient. (II-2B) obese patients in pregnancy are quantified according to the
7. Obese pregnant women have an increased risk of Caesarean
evaluation of evidence guidelines developed by the
section, and the success of vaginal birth after Caesarean section Canadian Task Force on Preventive Health Care (Table 1).
is decreased. (II-2B)
8. Antenatal consultation with an anaesthesiologist should be DEFINING OBESITY
considered to review analgesic options and to ensure a plan is in
place should a regional anaesthetic be chosen. (III-B) The most clinically relevant definition of obesity is the body
9. The risk of venous thromboembolism for each obese woman mass index. BMI is weight in kilograms divided by height in
should be evaluated. In some clinical situations, consideration for
thromboprophylaxis should be individualized. (III-B) meters squared (kg/m2).6 Canadian guidelines for appropri-
J Obstet Gynaecol Can 2010;32(2):165–173
ate BMI are aligned with those of the World Health Organi-
zation and separated into six categories (Table 2).3
INTRODUCTION Studies of the non-pregnant population show that increas-
T he people of industrialized nations, including Canada, ing values of BMI are associated with an increased risk for
have experienced a dramatic increase in obesity in cardiovascular disease, diabetes, osteoarthritis, and cancer.3
recent times1 The proportion of overweight and obese The definition of obesity in pregnancy varies by author and
women in Canada rose from 34% in 1978 to 40% in 1992, includes women who are 110% to 120% of their ideal body
and in 2004 it was 53%.2,3 Of particular concern is the rapid weight or > 91 kg (200 lbs) or who have a BMI > 30 kg/m2.
increase in overweight and obesity in Canada’s adolescents, There is a paucity of information describing the prevalence
in whom rates have risen 100% since 1978.4 Rising rates of of overweight and obesity specifically in the pregnant popu-
obesity are associated with increasing time spent in front of lation. However, BMI data from the 2004 Canadian
pregnancy is increasing. According to Nova Scotia’s Atlee Underweight < 18.5 Increased
perinatal database, using a definition of obesity as > 90 kg, Normal weight 18.5 to 24.9 Least
the rate of obesity rose from 3.2% in 1988 to 10.2% Overweight 25.0 to 29.9 Increased
in 2002.7 Obese Class I 30.0 to 34.9 High
Most obstetrical caregivers in Canada record pre- Obese Class II 35.0 to 39.9 Very high
pregnancy weight in the antenatal record, although docu- Obese Class III ³ 40.0 Extremely high
mentation of maternal height is inconsistent.7 Recent
evidence from the United States suggests that many
obstetrician- gynaecologists use BMI data to screen for obe-
sity.8 The identification of women at risk is not routinely Table 3. Pregnancy weight gain based on BMI
followed by interventions. Suggested strategies include
behavioural weight loss treatments and specific counselling BMI range Suggested weight gain (kg)
regarding exercise, diet, and pregnancy weight gain.8 Underweight < 18.5 12.5 to 18
Normal weight 18.5 to 24.9 11.5 to 16
WEIGHT GAIN IN PREGNANCY Overweight 25.0 to 29.9 7 to 11.5
Women should set pregnancy weight gain goals based on Obese Class I 30.0 to 34.9 7
their pre-pregnancy BMI as shown in Table 3.9 Obese Class II 35.0 to 39.9 7
Obese Class III ³ 40.0 7
To achieve these goals women should be at the healthiest
weight possible when they enter pregnancy. During
well-woman checks and other health care interactions,
non-pregnant women of child-bearing age can be advised evaluation of fetal structures.14,15 The sonographer’s ability
of their BMI. An evaluation of dietary intake and exercise to evaluate fetal structures is largely dependent on maternal
habits can provide insight into women at risk.10 According size. Approximately 15% of normally visible structures will
to the joint guidelines on exercise in pregnancy by the be suboptimally seen in women with a BMI above the 90th
SOGC and the Canadian Society for Exercise Physiology, percentile.15 In women with a BMI above the 97.5th percen-
all pregnant women without contraindications should par- tile, only 63% of structures are well visualized. The ana-
ticipate in regular exercise.11 During prenatal visits women tomic structures commonly less well seen with increasing
can be questioned and advised about their diet and exercise BMI include the fetal heart, spine, kidneys, diaphragm, and
habits. Where available, nutritional counselling can be a umbilical cord.16 Repeat examinations 2 to 4 weeks later to
helpful adjunct for women not meeting the weight gain assess the fetal cardiac anatomy will reduce the number of
guidelines in Table 3.12 Pregnancy outcomes are related to suboptimally viewed fetuses; however, 12% to 20%
maternal weight gain.13 Fifty-two percent of a Canadian (depending on BMI class) will remain poorly visualized.15
cohort of women gained more than the recommended Obstetric care providers should take BMI into consider-
weight in pregnancy. Depending on pre-pregnancy BMI, ation when arranging for fetal anatomic assessment in the
these pregnancies were at increased risk of macrosomia second trimester. Anatomic assessment at 20 to 22 weeks
> 4000 g, augmentation of labour, gestational hypertension, may be a better choice for the obese pregnant patient.
and neonatal metabolic abnormalities. Regardless of BMI,
those women who gained the recommended amount of The challenge of fetal ultrasound in obese mothers is
weight in pregnancy had fewer adverse outcomes (Caesar- further complicated by evidence suggesting an increased
ean section, gestational hypertension, birth weight < 2500 g rate of fetal anomalies. Nuthalapaty and Rouse17 reviewed
or ³ 4000 g).13 17 studies published between 1978 and 2003 associating
maternal pre-pregnancy BMI with congenital anomalies.
IMPACT OF OBESITY ON OBSTETRIC OUTCOMES They reported a two-fold increase in neural tube defects in
the offspring of obese women. A dose-response was noted,
Ultrasound with heavier women having an even higher risk. Their
With the exception of women who are underweight, most report is supported by the findings of Anderson et al.18
women are best assessed at 18 to 22 weeks to allow better Alarmingly, the protective effects of periconceptional folic
acid do not appear to benefit the obese woman.19 It is increasing levels of exercise both during the pregnancy and
unknown whether an increased dose of folic acid would in the year prior to conception.24,25 Postulations on the pro-
reduce the risk to that of a lean woman. In their review, tective mechanisms of exercise against preeclampsia
Nuthalapaty and Rouse17 also found associations between include enhanced placental growth and vascularity, preven-
obesity and risk of other congenital malformations such as tion and reduction of oxidative stress, and correction of
heart defects, ventral wall defects, and orofacial clefts but vascular endothelial dysfunction.26
commented that these data were less consistent.
Ultrasound estimation of fetal weight is not superior to Gestational Diabetes
clinical estimation in the obese population.20 Although both It is well documented that rising rates of obesity in North
methods have an associated error of approximately 10%, in America are responsible for the concordant rise in type 2
the series reported by Field et al.,20 30% of obese women diabetes in the general population.27 Pre-gestational diabe-
had an ultrasound estimated fetal weight within 5 days of tes is more prevalent in obese women. Therefore, testing in
delivery that was > 10% different from the actual birth women with risk factors early in pregnancy is recom-
weight. mended.28 Obese women are also at increased risk of
developing gestational diabetes.29 In a cohort of 16 102
PREGNANCY COMPLICATIONS women, Weiss et al.23 found that in contrast to control sub-
jects (BMI < 30 kg/m2), the odds ratio for obese women
Spontaneous Abortion (BMI 30 to 34.9 kg/m2) to develop gestational diabetes is
The risk of spontaneous abortion is increased in obese 2.6 (95% CI 2.1 to 3.4) and for morbidly obese women
women. Using a retrospective case–control model and a (BMI ³ 35 kg/m2) is 4.0 (95% CI 3.1 to 5.2). Not surpris-
sample size of 4932, Lashen et al.21 identified an odds ratio ingly, obese women are also at increased risk of having a
for spontaneous abortion of 1.2 (95% CI 1.01 to 1.46) for macrosomic child. The likelihood of delivering an infant
obese women (BMI > 30 kg/m2). The authors also identi- weighing more than 4000 g was 1.7 times (95% CI 1.4 to
fied an increased risk of recurrent early miscarriages (more 2.0) greater for obese and 2.0 times (95% CI 1.5 to 2.3)
than 3 successive miscarriages < 12 weeks’ gestation) in the greater for morbidly obese patients. The odds of delivering
obese population, odds ratio 3.5 (95% CI 1.03 to 12.01).21 an infant weighing more than 4500 g was 2.0 times (95% CI
Similar risks have been identified in obese women undergo- 1.4 to 3.0) and 2.4 times (95% CI 1.5 to 3.8) greater for
ing in vitro fertilization therapy.22 obese and morbidly obese patients, respectively.22 Physical
activity is inexpensive and can significantly reduce the risk
Hypertensive Disorders of Pregnancy of gestational diabetes. Zhang et al.29 reported a significant
Robinson et al.7 reviewed pregnancy outcomes stratified by inverse relationship between the amount of weekly vigor-
maternal pre-pregnancy weight, comparing women whose ous activity and the risk for gestational diabetes. More rele-
weight was 55 to 75 kg with those whose weight was > 90 kg.7 vant to the obese population, they also reported a 34%
In this 15-year retrospective review (1988–2002), there were reduction in the development of gestational diabetes in
79 005 women between 55 and 75 kg, 9355 women between women who did not participate in vigorous exercise but
90 and 120 kg (moderate obesity) and a further 779 women who did participate in brisk walking compared with those
> 120 kg (severe obesity). Compared with the normal who participated in easy pace walking.28 At a Canadian cen-
weight group, the odds ratio of pregnancy induced hyper- tre, regular walking has been used in addition to diet and
tension for the moderate obesity group was 2.38 (95% CI insulin as part of therapy for gestational diabetes. Com-
2.24 to 2.52). The odds ratio for the severe obesity group pared with a non-exercising matched control group, those
was 3.00 (95% CI 2.49 to 3.62). Obesity also increased the who included walking 25 to 40 minutes 3 to 4 times per
likelihood that women would experience more severe week were able to significantly reduce fasting and 1-hour
forms of hypertensive complications. For the moderate postprandial glucose levels using less insulin over fewer
obesity group the odds ratio of severe pregnancy induced injections. The study design did not permit comment on
hypertension, including HELLP syndrome, was 1.56 (95% perinatal outcomes.30
CI 1.35 to 1.80) and for the severe obesity group was 2.34
(95% CI 1.59 to 3.46). Relative to non-obese women there INTRAPARTUM COMPLICATIONS AND MANAGEMENT
was 1 excess case of pregnancy induced hypertension for
every 10 moderately obese women and every 7 severely Macrosomia and Shoulder Dystocia
obese women.7 These findings have been confirmed by oth- Sheiner et al.31 analyzed pregnancy outcomes in a cohort of
ers.23 In contrast, retrospective cohorts show a 24% to 60% 126 080 deliveries. Patients with hypertension and diabetes
reduction in preeclampsia in nulliparous women who had were excluded. Obese women (BMI > 30 kg/m2) had an
increased risk of fetal macrosomia with an odds ratio of 1.4 Caesarean Section
(95% CI 1.2 to 1.7). Sheiner et al.31 did not find an increased The risk of Caesarean section is increased in the obese
risk for shoulder dystocia in the obese population. Jensen et parturient. Dietz et al.39 analyzed 24 423 nulliparous women
al.32 found similar results in their cohort. The use of antena- stratified by pre-pregnancy BMI and pregnancy complica-
tal ultrasound to detect fetal macrosomia is associated with tions. The Caesarean section rate was 14.3% for lean
increased obstetric interventions such as induction of women (BMI < 19.8 kg/m2) and 42.6% for very obese
labour and Caesarean section.33 Delpapa and women (BMI ³ 35 kg/m2). Among women without any
Mueller-Heubach33 reported 86 women with an estimated complications, the relative risk of Caesarean section was 1.4
fetal weight > 4000 g within 3 days of delivery. In 77%, the (95% CI 1.0 to 1.8) for overweight women (BMI 25 to
ultrasound estimate was greater than the actual birth 29.9 kg/m2), 1.5 (95% CI 1.1 to 2.1) for obese women (BMI
weight.33 The rate of Caesarean section is affected when 30 to 34.9 kg/m2), and 3.1 (95% CI 2.3 to 4.8) for very
sonographic examination indicates a macrosomic fetus.34 obese women (BMI ³ 35 kg/m2).39 Large cohorts from dif-
Parry et al.34 compared the rate of Caesarean section when fering jurisdictions show similar findings.22,40 The increase
fetal macrosomia was incorrectly predicted by antenatal in the rate of Caesarean section may be due, in part, to the
ultrasound with the rate of Caesarean section in pregnancies fact that overweight and obese nulliparous women progress
when antenatal ultrasound correctly predicted the fetal more slowly through the first stage of labour.41 When faced
weight not to be macrosomic. The estimated fetal weight with lack of descent in the second stage of labour, some
for the predicted macrosomic group was significantly practitioners may opt for Caesarean section rather than
greater than that of the non-macrosomic group: 42.3% ver- operative vaginal delivery because of concerns about fetal
sus 24.3%, RR 1.74, (95% CI, 1.09 to 2.78).34 Although fetal macrosomia and shoulder dystocia. This may explain the
macrosomia is a risk factor for shoulder dystocia, the abso- decreased operative vaginal delivery rate in some series.42
lute risk of a severe shoulder dystocia associated with
permanent impairment, or death, remains low.35 When the Obese women undergoing Caesarean section experience
sensitivity and specificity of ultrasound to predict a birth more complications, including blood loss > 1000 mL,
weight > 4500 g are included, it is estimated that 3695 increased operative time, increased postoperative wound
non-diabetic women would require Caesarean section to infection and endometritis, and need for vertical skin inci-
prevent a single case of permanent brachial plexus injury sion.43,44 Those obese women with diabetes who undergo
due to shoulder dystocia.35 Caesarean section have an odds ratio for postoperative
wound infection of 9.3 (95% CI 4.5 to 19.2), and those who
require a vertical skin incision have a 12% rate of wound
Fetal Monitoring
complication serious enough to require opening the inci-
External fetal monitoring is at times more difficult in the sion.43,45 Postoperative infections are even increased in
presence of maternal obesity given the challenge of trans- those obese women who have elective Caesarean section
ducing the fetal heart through the maternal pannus. There is with prophylactic antibiotics.46
no evidence to support the routine use of internal fetal
Hospitals should ensure that there is an operating room
monitoring in this population, but it may be more effective
table that can accommodate morbidly obese parturients.
in some women.
Similarly, hospitals and obstetrical caregivers should ensure
there are appropriate surgical instruments to adequately
Uterine Monitoring visualize and operate on obese patients who require
There is increasing evidence that uterine contractility in Caesarean section.
obese women, compared with normal weight women, may
be altered or impaired.36,37 It is unclear whether these alter- Vaginal Birth After Caesarean Section
ations in myometrial response may lead to abnormal labour In the absence of contraindications, women who have had
and the observed increase in risk of Caesarean delivery. their first child by Caesarean section are asked to consider
Monitoring contractions and ensuring adequate labour in vaginal birth in subsequent pregnancies.47 The success of
obese women poses a special challenge. Although most vaginal birth after Caesarean section is commonly quoted at
obstetric care providers rely on manual palpation and/or 80%.48 Obese women are less likely than their lean peers to
external tocometry, the use of an intrauterine pressure cath- be successful in delivering vaginally after previous Caesar-
eter may be advantageous in some cases. Newer techniques, ean section. In women with a BMI > 29 kg/m2 the success
such as electrohysterography, may prove superior to both rate is 54% to 68%.49,50 The rate of success is further
tocodynometry and intrauterine pressure assessment for reduced in even heavier women. Chauhan et al.51 found a
labour monitoring in this population.38 13% VBAC success rate in women > 300 lbs (136 kg). When
discussing VBAC, obstetric care providers should consider minutes and those delivered between 16 and 75 minutes
the longer time required to prepare for and commence Cae- after the decision to proceed to Caesarean section.57 There
sarean section in obese patients. This includes longer time are no published data from Canadian centres that indicate
for patient transport and set-up in an operating room, lon- whether obstetric providers can reliably meet this arbitrary
ger time for establishment of anaesthesia, and longer time standard. There are no published data that address decision
from incision to delivery of the fetus. Obese women would to delivery interval in obese patients.
benefit from knowing the success rates for women in their
BMI group when they make a decision about vaginal birth Thromboembolism
after Caesarean section. The risk of thromboembolism is increased in obese
parturients. Edwards et al.58 reported 683 obese women
Obstetric Anaesthesia (BMI > 29 kg/m2) who were matched to 660 women of
Rates of difficult or failed tracheal intubations are increased normal weight (BMI 19.8 to 26.0 kg/m2). The incidence of
thromboembolism was 2.5% in the obese women, and only
in obese parturients.52 A 6-year review of failed intubations
0.6% in the control subjects.58 The Royal College of Obste-
in obstetric patients in a United Kingdom region reported
tricians and Gynaecologists (RCOG) in the United King-
36 cases of failed intubation; the average BMI of these
dom recommends thromboprophylaxis for 3 to 5 days,
women was found to be 33.53 The equipment and expertise
using low molecular weight heparin after vaginal delivery
required to manage a difficult intubation should be readily
for women who are over age 35 and have a pre-pregnancy
available. In obese patients the risk of epidural failure is
or early pregnancy BMI > 30 kg/m2 or weight > 90 kg.59 In
increased. The initial failure rate for epidural catheter place-
addition, the RCOG recommends thromboprophylaxis
ment can be very high (42%),54 and multiple attempts at
before and for 3 to 5 days following Caesarean section for
catheter placement may be required. More than a single
women with a pre-pregnancy or early pregnancy BMI > 30
attempt is necessary for successful epidural placement in
kg/m2 or with a current weight > 80 kg. The RCOG also
approximately 75% of morbidly obese parturients. and
recommends considering thromboprophylaxis in
more than three attempts are needed in 14%.55 The use of
“extremely obese” women who are hospitalized
regional anaesthesia may require significant time and staff
antenatally.59,60 However, the Pregnancy and Thrombosis
resources, which may limit its use in some health care set-
Working Group in the United States does not concur with
tings. Techniques to improve the success of regional anaes-
the RCOG guidelines. This group recommends consider-
thesia in obese pregnant women, such as ultrasound guid-
ation of thromboprophylaxis for patients who are obese, on
ance, will require further investigation in obstetrics.56 Given
bed rest, or having surgery.61 There have been no random-
the increased risks of regional anaesthesia in this popula-
ized controlled trials regarding thromboprophylaxis when
tion, and dependent on the wishes of the patient, consider-
there are additional factors to consider in the obese
ation should be given to early epidural in labour. Obese
parturient. Therefore, the risk of venous thromboembolism
women have an increased risk for sleep apnea, which may
for each obese woman should be evaluated. Depending on
influence the choice of location for postoperative care for
the clinical situation, consideration for thromboprophylaxis
obese parturients.
should be individualized.
Caesarean Section and Decision to Delivery Interval PERINATAL OUTCOMES
The decision to delivery interval may be longer when an
The most prevalent risk factor for unexplained stillbirth is
emergent or urgent Caesarean section is required for an
pre-pregnancy obesity.62 The odds ratio for stillbirth is 2.79
obese parturient. Causes for this delay may include patient
transport and bed transfer, the establishment of adequate (95% CI 1.94 to 4.02) for morbidly obese women (BMI ³
analgesia, and the operative time from incision to delivery. 35 kg/m2).63 The mechanisms suggested for increased still-
The performance of emergent Caesarean section within birth risk in the obese woman include a decreased ability to
30 minutes is an arbitrary threshold rather than an evi- perceive a reduction in fetal movement, hyperlipidemia
dence-based standard. Thomas et al.57 reviewed 17 780 leading to atherosclerosis affecting placental blood flow,
emergency Caesarean sections performed in 2000 in Eng- and increased snoring and sleep apnea associated with oxy-
land and Wales. Only 22% of women were delivered within gen desaturation and hypoxia.57
30 minutes. Of the 4622 Caesarean sections performed for There is a growing body of literature demonstrating the in
immediate threat to the life of the mother or fetus only 46% utero environment is a predictor of future neonatal, child,
were achieved within 30 minutes. There was no difference and adult health.64 In the Growing Up Today Study, a
noted in the rate of 5-minute Apgar scores < 4 or < 7, or the cohort of over 14 000 adolescents in the United States, a
rate of stillbirth between those delivered less than 15 1 kg increment in birth weight in full-term infants was
associated with an approximately 50% increase in the risk of specialists.72 A limited but growing body of literature
being overweight at ages 9 to 14 years.65 This is especially regarding pregnancy outcomes in women who have
true for the offspring of women who experienced gesta- undergone obesity surgery suggests reassuring outcomes;
tional diabetes during the pregnancy.63 In the Hypertension however, there are reports of significant complications such
in Pregnancy Offspring Study, Himmelmann et al.66 as nutrient deficiency, severe fetal growth restriction, and
reported that neonates born to women who were hyperten- maternal bowel obstruction.73–78
sive during pregnancy appear to have a propensity to
impaired glucose tolerance in later childhood.66 Taittonen et SUMMARY
al.67 have also reported an increased risk of hypertension in It is critical that women be informed prior to pregnancy
the children of women who are hypertensive during pregnancy . about the need to be as healthy as possible before becoming
pregnant, which includes having a normal BMI, eating a bal-
THERAPY AND MANAGEMENT
anced diet, and participating in regular exercise. It is also
All women should be encouraged to participate in regular critical that provincial and federal authorities recognize the
physical exercise during their pregnancy.11 Joint recommen- impact on future populations and health care costs of preg-
dations by the SOGC and the Canadian Society for Exercise nancies complicated by obesity. A long-term national infor-
Physiology were published in 2003.11 It is recommended mation campaign is required to exploit women’s interest in
that women exercise four times weekly at moderate inten- having as healthy a pregnancy as possible by giving them the
sity. The actual effect of these recommendations is hard to information they need to become fit and have a normal
measure because of the difficulty of behavioural change BMI before they consider pregnancy. Only a national strat-
assessment; however, the rising obesity rate in the Canadian egy can change the complacency about pre-pregnancy
pregnant population and the maternal and neonatal weight and inform women about the significant increase in
sequelae described above are most disturbing. Heart rate risks for themselves and their children.
target zones for previously sedentary obese pregnant Recommendations
women have recently been developed, using a Canadian
population. Davenport et al. recommend target heart rate 1. Periodic health examinations and other appointments for
zones of 102 to 124 beats per minute in obese women gynaecologic care prior to pregnancy offer ideal oppor-
aged 20 to 29, and 101 to 120 beats per minute in those aged tunities to raise the issue of weight loss before concep-
30 to 39.68 tion. Women should be encouraged to enter pregnancy
with a BMI < 30 kg/m2, and ideally < 25 kg/m2. (III-B)
Nutritional counselling and dietary records may be helpful
in guiding overweight and obese women with respect to 2. BMI should be calculated from pre-pregnancy height and
adequate weight gain during pregnancy. Ideally these should weight. Those with a pre-pregnancy BMI > 30 kg/m2 are
be offered prior to pregnancy so that health status can be considered obese. This information can be helpful in
optimized before conception.69 The role of behavioural counselling women about pregnancy risks associated
therapy and caloric restriction in obese women to prevent with obesity. (II-2B)
excess weight gain has not been established. Randomized 3. Obese pregnant women should receive counselling about
controlled studies using behavioural intervention in normal weight gain, nutrition, and food choices. (II-2B)
weight and obese women with the goal of preventing excess
weight gain have been inconclusive.70 A systematic review 4. Obese women should be advised that they are at risk for
examining energy and protein restriction as preventive medical complications such as cardiac disease, pulmo-
strategies to avoid adverse perinatal outcomes concluded nary disease, gestational hypertension, gestational
these measures are unlikely to be beneficial and may pose diabetes, and obstructive sleep apnea. Regular exercise
harm to the developing fetus.71 during pregnancy may help to reduce some of these
risks. (II-2B)
The rate of unintended pregnancy increases following
5. Obese women should be advised that their fetus is at an
bariatric or gastric bypass surgery in morbidly obese
increased risk of congenital abnormalities, and appropri-
women. Although this therapy is not recommended during
ate screening should be done. (II-2B)
pregnancy, it may arise as a discussion point during
pre-pregnancy or postpartum visits. New evidence and sys- 6. Obstetric care providers should take BMI into consider-
tematic reviews suggest that weight loss surgery is more ation when arranging for fetal anatomic assessment in
effective than conventional treatments in morbid obesity the second trimester. Anatomic assessment at 20 to
(Table 2). Thus, women who meet the criteria may benefit 22 weeks may be a better choice for the obese pregnant
from counselling and consultation with obesity surgery patient. (II-2B)
7. Obese pregnant women have an increased risk of Caesar- 18. Anderson JL, Waller DK, Canfield MA, Shaw GM, Watkins ML, Werler MM.
Maternal obesity, gestational diabetes, and central nervous system birth defects.
ean section, and the success of vaginal birth after Caesar- Epidemiology 2005;16:87–92.
ean section is decreased. (II-2B)
19. Werler MM, Louik C, Shapiro S, Mitchell AA. Prepregnant weight in relation to
8. Antenatal consultation with an anaesthesiologist should risk of neural tube defects. JAMA 1996;275:1127–8.
be considered to review analgesic options and to ensure a 20. Field NT, Piper JM, Langer O. The effect of maternal obesity on the accuracy of
plan is in place should a regional anaesthetic be fetal weight estimation. Obstet Gynecol 1995;86:102–7.
chosen. (III-B) 21. Lashen H, Fear K, Sturdee DW. Obesity is associated with increased risk of first
trimester and recurrent miscarriage: matched case-control study. Hum Reprod
9. The risk of venous thromboembolism for each obese
2004;19:1644–6.
woman should be evaluated. In some clinical situations,
22. Bellver J, Rossal LP, Bosch E, Zuniga A, Corona JT, Melendez F, et al. Obesity
consideration for thromboprophylaxis should be indi-
and the risk of spontaneous abortion after oocyte donation. Fertil Steril
vidualized. (III-B) 2003;79:1136–40.
23. Weiss JL, Malone FD, Emig D, Ball RH, Nyberg DA, Comstock CH, et al.
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55. Jordan H, Perlow MD, Mark A, Morgan MD. Massive maternal obesity and
perioperative cesarean morbidity. Am J Obstet Gynecol 1994;170:560–5. 76. Weissman A, Hagay Z, Schacter M, Dreazen E. Severe maternal and fetal
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58. Edwards LE, Hellerstedt WL, Alton IR, Story M, Himes JH. Pregnancy 79. Woolf SH, Battista RN, Angerson GM, Logan AG, Eel W. Canadian Task Force
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Alaa Awadalla, MD, Winnipeg MB 1. Modern oral contraceptives offer highly effective contraception and
a range of non-contraceptive benefits. (I)
Carolyn Best, MD, Toronto ON
2. Venous thromboembolism, although rare, remains one of the
Sheila Dunn, MD, Toronto ON serious adverse consequences of hormonal contraception. Best
Madeleine Lemyre, MD, Quebec QC evidence indicates that venous thromboembolism rates in
non-users of reproductive age approximate 4–5/10 000 women
Violaine Marcoux, MD, Ville Mont-Royal QC
per year; rates in oral contraceptive users are in the range of
Chantal Menard, RN, Ottawa ON 9–10/10 000 women per year. For comparison, venous
Frank Potestio, MD, Thunder Bay ON thromboembolism rates in pregnancy approach 29/10 000 overall
and may reach 300–400/10 000 in the immediate postpartum
David Rittenberg, MD, Halifax NS period. (II-1)
Sukhbir Singh, MD, Ottawa ON
3. Research demonstrates that oral contraceptives with £ 35 µg
Vyta Senikas, MD, Ottawa ON of ethinyl estradiol carry a lower risk of venous thromboembolism
Disclosure statements have been received from all members of than oral contraceptives with 50 µg. (II-2) Although preliminary
the committee. data suggest a possible further reduction in venous
thromboembolism with oral contraceptives with < 35 µg ethinyl
The literature searches and bibliographic support for this guideline estradiol, robust data to support this conclusion are presently
were undertaken by Becky Skidmore, Medical Research Analyst, lacking.
Society of Obstetricians and Gynaecologists of Canada.
4. Recent contradictory evidence and the ensuing media coverage
of the venous thromboembolism risk attributed to the progestin
component of certain newer oral contraceptive products have led
Abstract to fear and confusion about the safety of oral contraceptives in
general and drospirenone-containing oral contraceptives in
Objective: To provide current and emerging evidence on oral particular. “Pill scares” of this nature have occurred in the past,
contraceptives and the risk of venous thromboembolism. with panic stopping of the pill, increased rates of unplanned
Evidence: Articles published in English from 2005 were retrieved pregnancy, and no subsequent decrease in venous
through searches of PubMed and Medline, using the following thromboembolism rates. (II-3)
terms: venous thromboembolism, VTE, contraception, oral 5. Two high quality research studies that addressed the venous
thromboembolism risk associated with various oral contraceptives
found comparable venous thromboembolism rates with
drospirenone-containing oral contraceptives and other approved
products. (II-1)
Key Words: Venous thromboembolism, VTE, contraception, 6. Two reports suggesting an increased risk of venous thromboembolism
oral contraceptives, hormonal contraception with drospirenone-containing oral contraceptives have significant
This document reflects emerging clinical and scientific advances on the date issued and is subject to change. The information should
not be construed as dictating an exclusive course of treatment or procedure to be followed. Local institutions can dictate
amendments to these opinions. They should be well documented if modified at the local level. None of these contents may be
reproduced in any form without prior written permission of the SOGC.
Key to evidence statements and grading of recommendations, using the ranking of the Canadian Task Force
on Preventive Health Care
I: Evidence obtained from at least one properly randomized A. There is good evidence to recommend the clinical preventive
controlled trial action
II-1: Evidence from well-designed controlled trials without B. There is fair evidence to recommend the clinical preventive
randomization action
II-2: Evidence from well-designed cohort (prospective or C. The existing evidence is conflicting and does not allow to
retrospective) or case–control studies, preferably from more make a recommendation for or against use of the clinical
than one centre or research group preventive action; however, other factors may influence
decision-making
II-3: Evidence obtained from comparisons between times or
places with or without the intervention. Dramatic results in D. There is fair evidence to recommend against the clinical
uncontrolled experiments (such as the results of treatment preventive action
with penicillin in the 1940s) could also be included in this E. There is good evidence to recommend against the clinical
category preventive action
III: Opinions of respected authorities, based on clinical L. There is insufficient evidence (in quantity or quality) to make
experience, descriptive studies, or reports of expert a recommendation; however, other factors may influence
committees decision-making
*The quality of evidence reported in these guidelines has been adapted from The Evaluation of Evidence criteria described in the Canadian Task Force on
Preventive Health Care.35
†Recommendations included in these guidelines have been adapted from the Classification of Recommendations criteria described in the The Canadian Task
Force on Preventive Health Care.35
methodological flaws that render their conclusions suspect. It seems VENOUS THROMBOEMBOLISM
likely that residual confounding could have distorted both the
results and the conclusions of these reports. (II-3) Risk Factors
J Obstet Gynaecol Can 2010;32(12):1192–1197
Venous thromboembolism is a rare but potentially serious
INTRODUCTION condition, usually involving a blood clot in the deep veins of
the legs or pelvis. If the clot breaks away into the circulation
odern oral contraceptives afford not only excellent
M contraception but also a variety of non-contraceptive
it may block blood flow to the lungs (pulmonary embolism)
with potentially fatal consequences. Known risk factors for
benefits, ranging from regulation and reduction of both VTE include advancing age,2 cigarette smoking,3 immobility
menstrual bleeding and dysmenorrhea to treatment of (such as that associated with travel or hospitalization),4
premenstrual syndrome, menstrual migraines, acne, and obesity,5 and pregnancy and the peripartum period.6,7
hirsutism. Long-term benefits include reduced rates of
Hormonal Effects on Venous
endometrial, ovarian, and colorectal cancer.1 Modern OCs
Thromboembolism
are well tolerated (serious side effects are rare), and adherence
to prescribed regimens is generally excellent. As a result, Hormonal contraceptives increase the risk of VTE above
OC users are able to prevent pregnancy and the considerable the background rate (from 5/10 000 woman years in non-
risks associated with being pregnant while enjoying the users8 to 9–10/10 000 woman years in OC users9).
non-contraceptive benefits of hormonal contraception. To keep the risks of VTE for OC users in perspective, it is
important to remember that the risk of VTE in pregnancy
may reach 29/10 000,9,10 and in the peripartum period the
risk has been reported to be as high as 300–400/10 000.6,7
Among the most widely used and effective contraceptive
methods, OCs reduce rates of unplanned pregnancies and
actually decrease the overall rate of VTE in the population
ABBREVIATIONS compared with rates in populations without access to effec-
FDA US Food and Drug Administration
tive contraception.11
OC oral contraceptives Older OCs, which contained higher levels of estrogen, carried
VTE venous thromboembolism a slightly greater risk than currently available OCs, most of
which contain < 50 µg of ethinyl estradiol. Sub-50 µg pills system continue to be studied and debated,20 but because
have a lower risk of VTE than pills with ³ 50 µg.12 Although, there were no compelling data demonstrating an increased
in theory, greater reductions in the dosage of estrogen risk, third generation pills remain on the market and are
might further decrease the risk of VTE, this benefit has not widely prescribed.21
been clearly established. A non-significant decrease in VTE Assessing Venous Thromboembolism Risks
was noted in the European Active Surveillance Study when of Oral Contraceptives
OCs containing 30µg ethinyl estradiol were compared with
those containing 20µg.9 Lidegaard et al.13 also reported that VTE remains one of the few serious side effects of OC use.
“a reduction in estrogen dose from 30–40 µg to 20 µg for Because VTE is so rare, valid information about the risks
OCs containing desogestrel or gestodene reduced the risk associated with a given pill cannot be adequately gleaned
of venous thromboembolism by 18%”; however, the valid- from pre-marketing research, which may involve only 1000
ity of the VTE diagnoses in the Danish National Patient to 3000 women. Information on serious but rare side effects
Registry (1 of 4 registries used by the Lidegaard et al. study) like VTE must come from post-marketing surveillance.
has been questioned.14 The current Canadian system requires that health care pro-
Many pills with ethinyl estradiol levels lower than 35 µg are viders voluntarily report unexpected or severe adverse
currently on the market, and although they may be associated reactions to drugs to Health Canada. Although such a system
with fewer estrogen-related nuisance side effects (such as can alert regulatory authorities to rare unexpected side
nausea or breast tenderness) in the first months of use, no effects of a medication, it cannot provide valid information
conclusive data exist to establish that they result in a lower about the rates of complications or inform consumers
about the comparative risks of available products. This is
risk of VTE. Pills with £ 20 µg of ethinyl estradiol have the
because newer products tend to be prescribed for women
potential to cause more breakthrough (unscheduled) bleeding,
who already have risk factors. For example, drospirenone-
and this may be a deterrent to consistent use for some
containing pills, which are effective in reducing acne and
women.15
hair growth, tend to be prescribed for women who are
Innovations in hormonal contraception in recent years have obese and who therefore already have an independent risk
largely involved the use of new progestins, and this has factor for a blood clot. Isolated reports of serious side
brought the progestin component of the OC under increasing effects of a specific OC may motivate health care providers
scrutiny. New progestins are, in part, responsible for some to be more vigilant in looking for and reporting similar
of the most desired non-contraceptive benefits, while main- cases (stimulated reporting). Numerators in adverse event
taining a low risk of serious side effects. reporting are therefore selectively biased towards certain
Third generation pills have been promoted as being less products, which may give a misleading impression of risk.
androgenic and as possibly having fewer adverse effects on Since denominators (the number of women using a particular
cardiovascular and metabolic parameters and therefore as product) and risk factors in the entire population of women
being safer than existing pills. Shortly after the introduction prescribed a specific type of OC are unknown, voluntary
of these third generation pills, reports of a possible increased reports of individual cases cannot provide valid information
risk of VTE began to appear, bringing the progestin com- on comparative risks for rare but serious side effects.
ponent of these pills under scrutiny. A phenomenon called Another suggested methodology is to try to obtain more
“stimulated reporting” occurred: physicians with patients comprehensive data by retrospectively searching large
on these new pills were more likely to send their patients for databases for use of specific products and establish links between
assessment of any leg pain and more likely to report any their use and complications like VTE. These techniques
VTE episodes to regulatory authorities because of height- may be useful if the original data set includes information
ened awareness of the possible risk. What followed was the on age, weight, duration of use, etc., which are important
“pill scare” in 1995, when regulatory authorities issued an independent risk factors that might influence risks for VTE.
alert about the possible increased risk of VTE with third In the absence of quality data on such variables, it is possible
generation pills. The abrupt rise in births and abortions16,17 that a risk apparently associated with a specific OC is
(each associated with an increased risk of VTE) that resulted actually associated with the characteristics of the women
from unplanned pregnancies indicated that many women who were taking that OC. Databases, especially those
stopped taking OCs because of this scare. The history of developed for administrative purposes, may lack adequate
this unfortunate episode is well-documented.18,19 Subsequent validation of discharge diagnoses. A 2010 study has shown
analysis and/or replication has shown systematic error in the that conditions signed out as VTEs in an administrative
epidemiological studies that examined VTE risks. The precise database are often found to be something else when testing
effects of different hormonal contraceptives on the hemostatic is completed.14 A valid comparison of VTE risk with
different OCs must consider the fact that the risk for VTE no statistically significant differences between drospirenone
is greatest in the first months of use and declines thereaf- and so-called second generation progestins. Duration of use
ter.9,22–24 This same effect was noted in the largest random- information was not available on all women, so it is not
ized clinical trial to examine VTE in menopausal women clear that all were new users. In addition, the risk estimates
receiving hormone therapy at the time of menopause.25 were not adjusted for important risk factors (such as obesity).
Comparisons of the VTE risks for different OCs must Despite this the authors concluded that second generation
account for duration of use and ensure that new users of OCs were safer than third generation as far as VTE was
one pill are truly being compared with new users of the concerned. The FDA has recently revised the product labelling
other pill. for a drospirenone-containing OC, and with respect to the
Dutch Mega Study notes that “The number of [drospirenone-
RECENT RESEARCH containing OC] cases (in the Dutch Mega Study) was very
Legitimate information on these rare risks is most likely to small (1.2% of all cases) making the risk estimates
come from research that uses a prospective approach with unreliable.”29
subjects who are all new users of various OCs. Careful follow-
The other study reporting increased rates of VTE with
up by active surveillance (regular patient contact) and
drospirenone-containing and other third generation OCs
validation of all suspected cases (through examination of
was a large Danish national cohort study.13 It consisted of a
the medical records) is critical.
retrospective examination of Danish women who had
The European Active Surveillance Study was conducted prescriptions for hormonal contraception and subsequent
by the manufacturer of a new drospirenone-containing hospital diagnostic codes for deep vein thrombosis between
OC with an independent advisory board and after approval 1995 and 2005 in a number of interrelated databases
by European regulatory authorities. This prospective non- maintained by the Danish national health service. This com-
interventional active surveillance study followed 59 674 new prehensive data set included 3.4 million woman years of
users of different OCs for a total of 142 475 woman years, hormonal contraceptive use. The investigators identified
with a loss to follow-up of only 2.4%. The study demonstrated 2045 hormonal contraceptive-related VTEs during this
that drospirenone-containing OCs were prescribed more time period. In keeping with prior reports, they found that
often to heavier women and that despite this there was no the risk of VTE decreased with duration of use and with
difference in VTE rates between users of this new pills containing lower estrogen dosages. In contrast to the
drospirenone- containing OC and other OCs. prospective studies reported above, they found that
Another large prospective study used a propensity (risk factor) drospirenone-containing OCs and other third generation
scoring system to match new users of different pills according OCs (those containing desogestrel, gestodene) carried an
to baseline VTE risk.26,27 This study matched new OC pre- increased risk of VTE compared with levonorgestrel-
scriptions (drospirenone-containing OCs vs. other OCs in a containing OCs. Several significant methodological weak-
2:1 ratio) and evaluated the medical records of all potential nesses have been identified since the publication of that
VTE episodes. No differences in VTE rates were found report.13 First, detailed information on confounders such as
between drospirenone-containing OCs and other OCs. obesity was not available for the analysis. This is important:
obesity rates in the Danish population have almost tripled
Recent publicity about class action litigation in the US and
in the past decade, and evidence from other research
Canada over complications related to drospirenone-
suggests that obese women are more likely to be prescribed
containing OCs has again raised questions about whether
drospirenone-containing OCs because of the perceived
VTE rates are higher with drospirenone-containing OCs.
beneficial effects on androgenic symptoms that affect many
Critical analysis of the 2 studies responsible for this adverse
obese women and on body weight (diuretic effect). In
publicity,13,28 however, suggests that the conclusions could
addition, the investigators had no information on OC use
have resulted from methodologic flaws and/or misinterpre-
before 1995. Therefore, they classified all levonorgestrel use
tation of findings, a view shared by the FDA.29
in 1995 as short-term use, but others have estimated that
The Dutch Mega Study,28 a retrospective case-control study, 60% of those levonorgestrel users should have been
was designed to evaluate environmental and genetic factors classified as long-term users.30 Supporting this premise was
influencing VTE and the effects of different OCs on VTE. the finding that the expected first year elevation of VTE risk
Controls were found in an unusual way: many were the was seen with all OCs except the levonorgestrel products.
partners of men who were seen in a thrombosis clinic, and
the remainder were recruited through random-digit dialling. More importantly, the incidence of VTE could not reliably
The authors showed hazard ratios for various OCs with be assessed in the Danish registry.14 Severinsen et al.14
wide and overlapping 95% confidence intervals indicating examined the medical records of patients with a diagnosis of
VTE in the same Danish registry used for the Lidegaard et al.13 Summary Statements
study and could confirm only 31% of diagnoses made 1. Modern oral contraceptives offer highly effective
through emergency room visits and only 71% of those contraception and a range of non-contraceptive
made in women admitted to the ward for diagnostic testing. benefits. (I)
The Danish database was designed as an administrative
database rather than as a medical research database, and the 2. Venous thromboembolism, although rare, remains one
of the serious adverse consequences of hormonal
diagnostic codes were primarily intended to capture costs
contraception. Best evidence indicates that venous
related to hospitalization. Many physicians were incorrectly
thromboembolism rates in non-users of reproductive
entering a diagnostic code for VTE rather than the intended
age approximate 4–5/10 000 women per year; rates
code of “admitted for evaluation of possible VTE.”14
in oral contraceptive users are in the range of
9–10/10 000 women per year. For comparison,
The increased rate ratio of VTEs with drospirenone- venous thromboembolism rates in pregnancy approach
containing OCs compared with levonorgestrel containing 29/10 000 overall and may reach 300–400/10 000
OCs was 1.64 (95% CI 1.27 to 2.10). With the potential in the immediate postpartum period. (II-1)
methodological issues identified above and with rate ratios 3. Research demonstrates that oral contraceptives with
that in epidemiological terms are very small (relative risks of £ 35 µg of ethinyl estradiol carry a lower risk of venous
£ 2), it is extremely difficult to exclude bias or residual con- thromboembolism than oral contraceptives with 50 µg.
founding as the explanation for the findings.30–33 Despite (II-2) Although preliminary data suggest a possible
the recent serious allegations about the validity of the VTE further reduction in venous thromboembolism with
diagnostic codes in the Danish database, the authors of this oral contraceptives with < 35 µg ethinyl estradiol,
research have yet to acknowledge the possibility that their robust data to support this conclusion are presently
data were invalid and their conclusions incorrect.34 The new lacking.
FDA-endorsed product labelling for a drospirenone- 4. Recent contradictory evidence and the ensuing media
containing OC addresses the Lidegaard et al. study and coverage of the venous thromboembolism risk
concludes, “The risk estimates may not be reliable because attributed to the progestin component of certain
the analysis may include women of varying risk levels.”29 newer oral contraceptive products have led to fear
and confusion about the safety of oral contraceptives
in general and drospirenone-containing oral
CONCLUSION
contraceptives in particular. “Pill scares” of this
nature have occurred in the past, with panic stopping
The highest quality scientific studies evaluating the risk of of the pill, increased rates of unplanned pregnancy,
VTE in OC users show a baseline risk of approximately and no subsequent decrease in venous
4–5/10 000 woman years in women who do not use thromboembolism rates. (II-3)
hormonal contraception. In the absence of reliable contra-
5. Two high quality research studies that addressed the
ception, women of reproductive age face risks of VTE
venous thromboembolism risk associated with
associated with pregnancy of up to 29/10 000 woman years,
various oral contraceptives found comparable venous
and in the immediate postpartum period this risk is as high
thromboembolism rates with
as 300–400/10 000 woman years. Prospective observa-
drospirenone-containing oral contraceptives and
tional studies have shown that all currently available OCs
other approved products. (II-1)
increase the risk of VTE to the range of 9–10/10 000
woman years of use and that this risk is highest in the first 6. Two reports suggesting an increased risk of venous
months of use, with a fall towards baseline risk thereafter. thromboembolism with drospirenone-containing oral
Modern OCs offer excellent contraceptive efficacy, and contraceptives have significant methodological flaws
adherence is good because of their many non-contraceptive that render their conclusions suspect. It seems likely
benefits. The occurrence of serious risks such as VTE, that residual confounding could have distorted both
including pulmonary embolism, are rare with contemporary the results and the conclusions of these reports. (II-3)
OCs, but individualized risk assessment should always be
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unertaken to identify women who would be better advised
1. ACOG Noncontraceptive uses of hormonal contraception. ACOG Practice
to use other forms of contraception. For most healthy Bulletin No. 110, Jan 2010. Obstet Gynecol 2010;115:206–18.
women of reproductive age, the benefits of OCs will 2. Silverstein MD, Heit JA, Mohr DN, Petterson TM, O’Fallon WM, Melton
outweigh the risks. L J 3rd. Trends in the incidence of deep vein thrombosis and pulmonary
embolism. A 25-year population-based study. Arch Intern Med 20. Hennessy S, Berlin JA, Kinman JL, Margolis DJ, Marcus SM, Strom BL.
1998;158:585–93. Risk of venous thromboembolism from oral contraceptives containing
3. Pomp ER, Rosendaal FR, Doggen CJM. Smoking increases the risk gestodene and desogestrel versus levonorgestrel: a meta-analysis and formal
of venous thrombosis and acts synergistically with oral contraceptive use. sensitivity analysis. Contraception 2001;64:125–33.
Am J Hematol 2008;83:97–102.
21. Spitzer WO. The 1995 pill scare revisited: anatomy of a non-epidemic.
4. Cannegieter SC, Doggen CMJ, van Houwelingen HC, Rosendaal FR.
Hum Reprod 1997;12:2347–57.
Travel-related venous thrombosis: results from a large population-based
case control study (MEGA Study). PLoS Med 2006;3(8):e307. 22. Suissa S, Blais L, Spitzer WO, Cusson J, Lewis M, Heineman L. First time
DOI:10.1371/journal.pmed. 0030307. use of newer oral contraceptives and the risk of venous thromboembolism.
5. Pomp ER, le Cessie S, Rosendaal FR, Doggen CJR. Risk of venous Contraception 1997;56:141–6.
thrombosis: obesity and its joint effect with oral contraceptive use and
prothrombotic mutations. Br J Haematol 2007;139:289–96. 23. Herings RM, Urquhart J, Leufkens HG. Venous thromboembolism among
new users of different oral contraceptives. Lancet 1999;354:127–8.
6. Ros HS, Lichtenstein P, Belloco R, Petersson G, Cnattingius S. Increased
risks of circulatory diseases in late pregnancy and puerperium. 24. Bloemenkamp KW, Rosendaal FR, Helmerhorst FM, Vandenbroucke JP.
Epidemiology 2001;12:456–60. Higher risk of venous thrombosis during early use of oral contraceptives in
7. Pomp ER, Lenselink AM, Rosendaal FR, Doggen CJM. Pregnancy, the women with inherited clotting defects. Arch Intern Med 2000;160:49–52.
postpartum period and prothrombotic defects: risk of venous thrombosis
in the MEGA study. J Thromb Haemost 2008;6:632–7. 25. Cushman M, Kuller LH, Prentice R, Rodabough RJ, Psaty BM, Stafford RS, et al.;
for the WHI Investigators. Estrogen plus progestin and the risk of venous
8. Heinemann LAJ, Dinger JC. Range of published estimates of venous
thromboembolism incidence in young women. Contraception thrombosis. JAMA 2004;292:1573–80.
2007;75:328–36.
26. Seeger JD, Loughlin J, Eng PM, Clifford CR, Cutone J, Walker AM. Risk
9. Dinger JC, Heinemann LAJ, Kuhl-Habich D. The safety of a of thromboembolism in women taking ethinyl estradiol/drospirenone and
drospirenone-containing oral contraceptive: final results from the European other oral contraceptives. Obstet Gynecol 2007;110:587–93.
Active Surveillance study on Oral Contraceptives based on 142,475
women-years of observation. Contraception 2007;75:344–54. 27. Eng PM, Seeger JD, Loughlin J, Clifford CR, Mentor S, Walker AM.
10. Heit JA, Kobbervig CE, James AH, Petterson TM, Bailey KR, Melton LJ 3rd. Supplementary data collection with case-cohort analysis to address potential
Trends in the incidence of venous thromboembolism during pregnancy confounding in a cohort study of thromboembolism in oral contraceptive
or postpartum: a 30-year population-based study. Ann Intern Med initiators matched on claims-based propensity scores. Pharmacoepidemiol
2005;143:697–706. Drug Saf 2008;17:297–305.
11. Ory HW. Mortality associated with fertility and fertility control: 1983. 28. Van Hylckama Vlieg A, Helmerhorst FM, Vandenbroucke JP, Doggen CJM,
Fam Plann Perspect 1983;15:57–63. Rosendaal FR. Effects of oestrogen dose and progestogen type on venous
thrombotic risk associated with oral contraceptives: results of the MEGA
12. Gerstman BB, Piper JM, Tomita DK, Ferguson WJ, Stadel BV, Lundin FE.
case-control study. BMJ 2009;339:b2921.
Oral contraceptive estrogen dose and the risk of deep venous thromboembolic
disease. Am J Epidemiol 1991;133:32–7. 29. Yasmin physician labeling. Available at:
13. Lidegaard Ø, Løkkegaard E, Svendsen AL, Agger C. Hormonal contraception http://www.yasmin-us.com/index.html. Accessed September 29, 2010.
and risk of venous thromboembolism: national follow-up study. BMJ 30. Shapiro S, Dinger J. Risk of VTE among users of oral contraceptives
2009;339: b2890. [reply to letter to editor]. J Fam Plann Reprod Health Care 2010:36:104–5.
14. Severinsen MT, Kristensen SR, Overvad K, Dethlefsen C, Tjønneland A,
31. Spitzer WO. Bias or causality: Interpreting recent evidence of oral
Johnsen SP. Venous thromboembolism discharge diagnoses in the Danish
contraceptive studies. Am J Obstet Gynecol 1998;179:S43–S50.
National Patient Registry should be used with caution. J Clin Epidemiol
2010;63:223–8. 32. Dinger J. Oral contraceptives and venous thromboembolism: old questions
15. Gallo MF, Nanda K, Grimes DA, Schulz KF. Twenty micrograms vs. revisited. J Fam Plann Reprod Health Care 2009;35:211–3.
> 20 microg estrogen oral contraceptives for contraception: systematic 33. Shapiro S. Causation, bias and confounding: a hitchhiker’s guide to the
review of randomized controlled trials. Contraception 2005;71:162–9. epidemiological galaxy. Part 3: principles of causality in epidemiological
16. Mills A. Combined oral contraception and the risk of venous thromboembolism. research: statistical stability, dose- and duration-response effects, internal
Hum Reprod 1997;12:2595–8. and external consistency, analogy and biological plausibility. J Fam Plann
Reprod Health Care 2008:34:261–4.
17. Goodyear-Smith A, Arroll B. Termination of pregnancy following panic-stopping
of oral contraceptives. Contraception 2002;66:163–7. 34. Lidegaard O. Risk of venous thromboembolism among users of oral
18. Spitzer WO. The aftermath of a pill scare: regression to reassurance. contraceptives: a review of two recently published studies. J Fam Plann
Hum Reprod Update 1999;5:736–45. Reprod Health Care 2010;36:103–4.
19. Lewis MA, MacRae KD, Kuhl-Habichl D, Bruppacher R, Heinemann LA, 35. Woolf SH, Battista RN, Angerson GM, Logan AG, Eel W. Canadian Task
Spitzer WO. The differential risk of oral contraceptives: the impact of full Force on Preventive Health Care. New grades for recommendations from
exposure history. Hum Reprod 1999;14:1493–9. the Canadian Task Force on Preventive Health Care. CMAJ 2003;169:207–8.
Benjamin Chee-Man Wong, MD, Calgary AB Validation: These guidelines have been reviewed and approved by
the Reproductive Endocrinology and Infertility Committee of the
CANADIAN FERTILITY AND ANDROLOGY SOCIETY SOGC.
Jason Min, MD (président), Ottawa (Ont.) Sponsor: The Society of Obstetricians and Gynaecologists of Canada.
Ken Cadesky, MD, Toronto (Ont.) Recommendations
Ellen Greenblatt, MD, Toronto (Ont.) 1. Weight loss, exercise, and lifestyle modifications have been
Jon Havelock, MD, Burnaby (C.-B.) proven effective in restoring ovulatory cycles and achieving
pregnancy in overweight women with PCOS and should be the
Jeff Roberts, MD, Burnaby (C.-B.) first-line option for these women. (II-3A) Morbidly obese women
Disclosure statements have been received from all members of should seek expert advice about pregnancy risk. (III-A)
the committee. 2. Clomiphene citrate has been proven effective in ovulation
induction for women with PCOS and should be considered the
first-line therapy. Patients should be informed that there is an
increased risk of multiple pregnancy with ovulation induction
Abstract using clomiphene citrate. (I-A)
Objective: To review current non-pharmacologic and pharmacologic 3. Metformin combined with clomiphene citrate may increase
options for ovulation induction in women with polycystic ovary ovulation rates and pregnancy rates but does not significantly
syndrome (PCOS). improve the live birth rate over that of clomiphene citrate
alone.(I-A) Metformin may be added to clomiphene citrate in
women with clomiphene resistance who are older and who have
visceral obesity. (I-A)
4. Gonadotropin should be considered second-line therapy for fertility
Key Words: Polycystic ovary syndrome, ovulation induction, in anovulatory women with PCOS. The treatment requires
infertility ultrasound and laboratory monitoring. High costs and the risk of
multiple pregnancy and ovarian hyperstimulation syndrome are
drawbacks of the treatment. (II-2A)
This document reflects emerging clinical and scientific advances on the date issued and is subject to change. The information
should not be construed as dictating an exclusive course of treatment or procedure to be followed. Local institutions can dictate
amendments to these opinions. They should be well documented if modified at the local level. None of these contents may be
reproduced in any form without prior written permission of the SOGC.
Key to evidence statements and grading of recommendations, using the ranking of the Canadian Task Force
on Preventive Health Care
I: Evidence obtained from at least one properly randomized A. There is good evidence to recommend the clinical preventive
controlled trial action
II-1: Evidence from well-designed controlled trials without B. There is fair evidence to recommend the clinical preventive
randomization action
II-2: Evidence from well–designed cohort (prospective or C. The existing evidence is conflicting and does not allow to
retrospective) or case–control studies, preferably from more make a recommendation for or against use of the clinical
than one centre or research group preventive action; however, other factors may influence
decision-making
II-3: Evidence obtained from comparisons between times or
places with or without the intervention. Dramatic results in D. There is fair evidence to recommend against the clinical
uncontrolled experiments (such as the results of treatment preventive action
with penicillin in the 1940s) could also be included in this E. There is good evidence to recommend against the clinical
category preventive action
III: Opinions of respected authorities, based on clinical L. There is insufficient evidence (in quantity or quality) to make
experience, descriptive studies, or reports of expert a recommendation; however, other factors may influence
committees decision-making
*The quality of evidence reported in these guidelines has been adapted from The Evaluation of Evidence criteria described in the Canadian Task Force on Preven-
tive Health Care.69
†Recommendations included in these guidelines have been adapted from the Classification of Recommendations criteria described in the The Canadian Task
Force on Preventive Health Care.69
ovaries. Intraovarian hyperandrogenism in turn inhibits receptor modulator that stimulates endogenous FSH pro-
follicular maturation.10 duction and secretion by interrupting estrogen feedback to
Weight loss through exercise and diet has been proven the hypothalamus and pituitary. PCOS patients can be sensitive
effective in restoring ovulatory cycles and achieving to ovulation induction medications because of a large number
pregnancy for many of these patients.11–13 In obese, of antral follicles. This places some women with PCOS at risk
anovulatory women with PCOS, weight loss of even 5% to 10% of overresponse with multiple follicular development and
of body weight often restores ovulatory cycles.7,9,14,15 Studies ovarian hyperstimulation; however, other women have a
also show that overweight women are less likely to respond poor response without development of a dominant follicle,
to pharmacologic ovulation induction methods.7,16 despite using higher doses of CC.
The starting dose of clomiphene citrate is 50 mg per day for
Obese women often report difficulty in achieving and
5 days, commencing between day 2 and 5 of menses.22 Menses
maintaining weight loss. The extent to which their obesity
may be induced with a progestin if required. If this dose
reflects an inherent metabolic disturbance, making it more
produces multiple follicular development, the dose can be
challenging for them to lose weight, remains a question.
lowered to 25 mg. If ovulation is not achieved using 50 mg per
The current recommendation is to reduce weight gradually
day, the dose can be increased in increments of 50 mg. The
to increase the chances of maintaining the weight loss.
manufacturer does not recommend exceeding 100 mg per
Preferential diet composition has been evaluated in 2 small
day23; however, many clinicians use doses up to 150 mg and
studies.17,18 These studies compared a high carbohydrate
some even up to 250 mg per day for 5 days,24 taking into
(55%), low protein (15%) hypocaloric diet with a low
account that alternatives treatments such as gonadotropins
carbohydrate (40%), high protein (30%) hypocaloric diet
are more costly and have greater risk (see below).
and found similar weight loss and decrease in circulating
androgen and insulin levels. Although the patient sample Cycle monitoring should be considered in at least the first
size was small, these 2 studies suggest that patients can cycle and when the treatment dose has to be increased
safely pursue either dietary composition, despite the need because of failure to ovulate. Common indications of an
for larger confirmatory studies. ovulatory response are a biphasic pattern on basal body
temperature charting and a serum progesterone measurement
Routine exercise is also very important in the reproductive
in the expected luteal phase of > 10 nmol/L if tested 6 to 8 days
health of women with PCOS. Exercise increases insulin
before the onset of menses.25 However, in some circumstances,
sensitivity and helps achieve and maintain weight loss.19 Other
detection of the pre-ovulatory LH surge with urinary kits, and
lifestyle factors such as excessive caffeine intake, alcohol
ovarian follicle and endometrial assessment with transvaginal
consumption, and smoking should also be addressed.8
ultrasound during the late follicular phase can be useful.
Once patients have achieved weight loss, they should be
If ovulation cannot be achieved with CC, the patient should
encouraged to maintain this in the long term and to have
be offered further options.
normal weight gain during pregnancy. Obesity contributes
to poor obstetric outcome (increased risk of spontaneous Although 60% to 85% of patients will ovulate on CC, only
abortion and preterm labour) and also increases maternal about one half will conceive.26,27 Approximately 50% of
complications, including gestational hypertension, gestational conceptions will occur on 50 mg, with another 20% to 25%
diabetes mellitus, thromboembolism, and wound infection.6 and 10% occurring on 100 mg and 150 mg, respectively.15,28
Long-term lifestyle modifications can decrease predisposition Lack of conception despite evidence of ovulation may be
to health conditions such as type 2 diabetes mellitus and due to anti-estrogenic effects of CC on the endometrium,
modify risk factors for cardiovascular disease.8 which may manifest as a thin endometrium on ultrasound.29
In one study, no pregnancies occurred when the
Recommendation endometrium was < 6 mm at midcycle,30 but others have
1. Weight loss, exercise, and lifestyle modifications have not found a similar association.31 Nevertheless, alternatives for
been proven effective in restoring ovulatory cycles and ovulation induction should be considered if the
achieving pregnancy in overweight women with PCOS periovulatory endometrium is persistently thin on CC therapy.
and should be the first-line option for these women. Similarly, if pregnancy does not occur within 6 ovulatory
(II-3A) Morbidly obese women should seek expert cycles, another ovulation induction method should be
advice about pregnancy risk. (III-A) considered.
Other drawbacks of CC include an increased rate of twin
CLOMIPHENE CITRATE
(7% to 9%) and triplet (0.3%) pregnancy, and side effects
Clomiphene citrate has been used as a first-line ovulation such as vasomotor hot flashes.32 Unusual visual symptoms
induction agent for over 40 years.20,21 It is a selective estrogen (visual blurring or persistent after-images) are also noted in
1% to 2% of patients taking CC, which are likely due to live birth rates with CC and metformin versus CC
anti-estrogenic effects of CC on the visual cortex.33 alone.41,46–48 Collectively, the combination of CC and
Although more studies are required, it is best to limit a metformin suggested an increase in live birth rate over CC
patient’s lifetime exposure to CC to 12 treatment cycles, as alone, but this increase was not statistically significant (OR
additional cycles may place the patient at increased risk of 1.74; 95% CI 0.79 to 3.86). The only trial adequately pow-
borderline ovarian tumours.34 ered to assess live birth rates was the large randomized-
controlled trial published by Legro et al. in 2007.46 This trial
Recommendation
included 626 patients and demonstrated that although the
2. Clomiphene citrate has been proven effective in ovulation live birth rate following up to 6 months of treatment with
induction for women with PCOS and should be considered metformin and CC was increased (26.8%), it was not signifi-
the first-line therapy. Patients should be informed that cantly different from that with CC alone (22.5%). Live birth
there is an increased risk of multiple pregnancy with rates using CC alone or with metformin were significantly
ovulation induction using clomiphene citrate. (I-A) higher than rates with metformin alone (7.2%).
INSULIN SENSITIZING AGENTS The evidence supports the use of clomiphene citrate over
metformin as first-line pharmacologic therapy following
The recognition of an association between PCOS and lifestyle modification in women with PCOS. However,
hyperinsulinemia has led to the use of insulin-sensitizing there may be a role for the addition of metformin to CC in
agents in ovulation induction. Metformin, the most widely women who are clomiphene-resistant. Siebert et al.49 exam-
studied agent used in PCOS, is a biguanide insulin-sensitizing ined 6 trials in which metformin was randomized with
agent that acts by inhibiting hepatic glucose production and either placebo or CC in clomiphene-resistant patients and
increasing peripheral glucose uptake.35 It does not stimulate found an overall statistically significant improvement in
secretion of insulin or cause hypoglycemia. ovulation with combination therapy (OR 6.82; 95% CI 3.59
Many earlier studies examining the use of metformin alone to 12.96). Further, a recent study also suggested that women
or in conjunction with CC in ovulation induction showed with PCOS who are older and have increased visceral obe-
promising results,36–42 but most of these studies had relatively sity may benefit from the additional use of metformin.50
small sample sizes. A meta-analysis of 13 randomized Patients on metformin often experience unpleasant side effects
controlled trials by Lord et al.43 in 2003 concluded that of nausea, bloating, cramps, and diarrhea, and they should
metformin is effective in achieving ovulation in women be counselled to start with 250 mg to 500 mg PO daily and
with PCOS, with odds ratios of 3.88 (95% CI 2.25 to 6.69) increase as tolerated to the optimal daily dose of 500 mg to
for metformin compared with placebo and 4.41 (95% CI 750 mg 3 times daily with food. Metformin can also be
2.37 to 8.22) for metformin and CC compared with CC dosed 850 mg PO twice daily or a long-acting formulation
alone. Pregnancy rates were not significantly better with (Glumetza) can be used to improve compliance.
metformin than with placebo (OR 2.76; 95% CI 0.85 to
8.98), but an improvement was seen with metformin plus Although some studies have shown that continuing
CC over CC alone (OR 4.4; CI 1.96 to 9.85).43 metformin in pregnancy may decrease the spontaneous
abortion rate,42,51–53 none of these are prospective, random-
A more recent meta-analysis published in April 200844 com- ized trials. Randomized controlled trials are needed in this
paring CC and metformin, both alone and in combination, area before sustained metformin treatment throughout
found that metformin alone increased the odds of ovulation pregnancy can be recommended.
compared with placebo (OR 2.94; 95% CI 1.43 to 6.02) but
did not result in a statistically significant difference in preg- Recommendation
nancy rates (OR 1.56; 95% CI 0.74 to 3.33). When CC and 3. Metformin combined with clomiphene citrate may
metformin were compared with CC alone, both ovulation increase ovulation rates and pregnancy rates but does not
and pregnancy rates were statistically increased to 4.39 significantly improve the live birth rate over that of
(95% CI 1.94 to 9.96) and 2.67 (95% CI 1.45 to 4.94), clomiphene citrate alone.(I-A) Metformin may be added
respectively. to clomiphene citrate in women with clomiphene resis-
This meta-analysis also included studies that reported live tance who are older and who have visceral obesity. (I-A)
birth rates. Ng et al.45 in 2001 compared metformin and
GONADOTROPINS
placebo in 20 women and found that women who received
metformin were less likely to achieve a live birth, although Use of intramuscular gonadotropins began in the 1960s.
this difference did not reach statistical significance (OR 0.44; These preparations, from the purified urine of
95% CI 0.03 to 5.88). Four of the included trials examined postmenopausal women, contained both FSH and LH.
Over the last decade, recombinant human FSH has been A Cochrane review published in 2007 examined 16 random-
the main preparation, and it can be self-administered subcu- ized controlled trials evaluating ovulation induction in
taneously.54 Gonadotropins are used when PCOS patients clomiphene-resistant PCOS with LOD. The dose at which
fail either to ovulate or to conceive with oral ovulation induc- clomiphene resistance was defined ranged from 100 mg to
ing medications. 200 mg in the various studies. Approximately 80% of
PCOS patients will become ovulatory after LOD. There
Daily injections of gonadotropins are combined with con-
was no difference found in the rates of miscarriage, ongoing
current blood and ultrasound monitoring with the aim of
pregnancy, or live birth between patients who underwent
monofollicular growth and development. However,
LOD and patients treated with gonadotropins for ovulation
because of the inherent nature of exogenous gonadotropin
induction. There were significantly fewer multiple pregnancies
treatment, multifollicular development is not uncommon,
in the LOD than in the gonadotropin treatment groups
despite careful dose adjustment and monitoring. Once the
(1% vs. 16%; OR 0.13; 95% CI 0.03 to 0.59).58 In one of the
dominant follicle has reached the appropriate size, hCG is
included trials, adjuvant therapy with CC or gonadotropins
administered to trigger ovulation.
was required to achieve equivalent pregnancy and live birth
Injectable gonadotropins are very expensive and require rates in patients remaining anovulatory 8 weeks after LOD
frequent monitoring, with serum estradiol and ultrasound or those who subsequently became anovulatory.59
assessments to minimize the risks from excessive follicular Despite this evidence that LOD may be equivalent to gon-
growth and development. Because of the high number of adotropins in achieving ovulation, the effects of LOD on
antral follicles in women with PCOS, it is not uncommon postoperative adhesion formation remain a concern,60
that treatment is cancelled to minimize the occurrence of although it has been shown that in women who respond to
multiple pregnancy and also of ovarian hyperstimulation this treatment, the rate of cessation of ovulation is low.61
syndrome.55 Pregnancy rates with gonadotropins are 20%
to 25% per cycle.54 Drawbacks to gonadotropin treatment, Recommendation
as mentioned earlier, are requirements for intensive moni- 5. Laparoscopic ovarian drilling may be considered in
toring, cost, multiple pregnancy, and ovarian women with clomiphene-resistant PCOS, particularly
hyperstimulation. Gonadotropins should be administered when there are other indications for laparoscopy. (I-A)
by physicians with specific training in reproductive medi- Surgical risks need to be considered in these patients.
cine and with ready access to ultrasound monitoring and (III-A)
rapid hormone testing.
AROMATASE INHIBITORS
Recommendation
Aromatase inhibitors have been used for the last decade as
4. Gonadotropin should be considered second-line therapy adjunctive treatments in breast cancer.62 They block the
for fertility in anovulatory women with PCOS. The treat- conversion of testosterone and androstenedione to
ment requires ultrasound and laboratory monitoring. estradiol and estrone, respectively, and hence inhibit the
High costs and the risk of multiple pregnancy and ovar- estrogen-negative feedback on the hypothalamic–pituitary
ian hyperstimulation syndrome are drawbacks of the axis. This leads to increased gonadotropin secretion, which in
treatment. (II-2A) turn leads to ovarian follicular growth and development.62
OVARIAN DRILLING
The use of aromatase inhibitors in ovulation induction was
first introduced in 2001.63 Ovulation and pregnancy rates
Surgical ovarian wedge resection by open laparotomy was with aromatase inhibitors such as letrozole and anastrozole
one of the first treatments for anovulation due to PCOS.56 appear to be promising, and these agents appear to have less
It was thought to induce ovulation by decreasing the ovarian anti-estrogen effect on the endometrium, but the evidence
theca and thus reducing androgen production. Because of on endometrial effects is conflicting, and most studies show
the operative morbidity of the procedure and the risk of equivalence with clomiphene citrate.62–65 In 2005, however,
postoperative adhesions,57 ovarian wedge resection by Health Canada and the manufacturing company of
laparotomy has largely been abandoned as more effective letrozole issued a “Physician Warning Letter” on the
medical therapies for ovulation induction have become off-label use of letrozole for fertility and the possibility of
available. With the popularity of minimally invasive surgery, embryotoxicity, fetotoxicity, and teratogenicity found in
laparoscopic ovarian drilling is thought to be less destructive rats.66 This followed preliminary research findings by Biljan
to the ovary and has a lower risk of adhesion formation. et al.67 comparing congenital malformations in babies con-
Laparoscopic ovarian drilling uses either cautery or laser to ceived with letrozole with or without gonadotropins with
create approximately 10 superficial perforations per ovary.58 those in babies born to a low-risk population of women
without known fertility treatments. These findings reported a who have increased visceral obesity as assessed by increased
higher incidence of both cardiac and bone abnormalities in waist-to-hip ratios, and in those who have failed to ovulate
the letrozole group.67 More recently, however, Tulandi et al.68 on clomiphene citrate alone. Laparoscopic ovarian drilling
retrospectively evaluated 911 newborns from letrozole and should be considered in women who are resistant to
CC pregnancies. They found a 2.4% incidence of congenital clomiphene citrate because of the lower risk of multifetal
malformations and chromosomal abnormalities in the gestation compared with gonadotropin therapy. Further trials
letrozole group versus 4.8% in the CC group.68 However, until are needed in the area of aromatase inhibitors if they are to
aromatase inhibitors have been approved for ovulation be used routinely for ovulation induction.
induction by Health Canada, they should be used with Clinicians should always consider a patient’s age and duration of
caution, and patients should be carefully counselled, given infertility as they progress through the different treatment
potential medico–legal implications. options available. If a patient does not become pregnant in a
timely manner, referral to a fertility clinic and appropriate
IN VITRO FERTILIZATION
uses of gonadotropins and IVF are effective options.
IVF, with or without intracytoplasmic sperm injection, is
the next treatment option for women with PCOS who fail REFERENCES
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of other indications for advanced reproductive technologies. Azziz R. Prevalence of the polycystic ovary syndrome in unselected black
and white women of the southeastern United States: a prospective study.
In IVF, gonadotropins are administered to achieve J Clin Endocrinol Metab 1998;83:3078–82.
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Obstet Gynecol Scand 1994;73:407–12. 2003;169:207–8.
Christy Pylypjuk, MD, Winnipeg MB Benefits, harms, and costs: This guideline is expected to facilitate
optimal and uniform care for pregnancies complicated by trauma.
Anne Roggensack, MD, Calgary, AB
Frank Sanderson, MD, Saint John, NB SUMMARY STATEMENT
Disclosure statements have been received from all contributors. Specific traumatic injuries
At this time, there is insufficient evidence to support the practice of
disabling air bags for pregnant women. (III)
Primary survey
Key words: Abruption, electrical, fall, fetal, injury, maternal, MVC, 1. Every female of reproductive age with significant injuries should
penetrating, perimortem, pregnancy. be considered pregnant until proven otherwise by a definitive
pregnancy test or ultrasound scan. (III-C)
This document reflects emerging clinical and scientific advances on the date issued and is subject to change. The information
should not be construed as dictating an exclusive course of treatment or procedure to be followed. Local institutions can dictate
amendments to these opinions. They should be well documented if modified at the local level. None of these contents may be
reproduced in any form without prior written permission of the SOGC.
Table 1. Key to evidence statements and grading of recommendations, using the ranking of the Canadian Task Force
on Preventive Health Care
Quality of evidence assessment* Classification of recommendations†
I: Evidence obtained from at least one properly randomized A. There is good evidence to recommend the clinical preventive action
controlled trial
II-1: Evidence from well-designed controlled trials without B. There is fair evidence to recommend the clinical preventive action
randomization
II-2: Evidence from well-designed cohort (prospective or C. The existing evidence is conflicting and does not allow to make a
retrospective) or case–control studies, preferably from recommendation for or against use of the clinical preventive action;
more than one centre or research group however, other factors may influence decision-making
II-3: Evidence obtained from comparisons between times or D. There is fair evidence to recommend against the clinical preventive action
places with or without the intervention. Dramatic results in
uncontrolled experiments (such as the results of treatment with E. There is good evidence to recommend against the clinical preventive
penicillin in the 1940s) could also be included in this category action
III: Opinions of respected authorities, based on clinical experience, L. There is insufficient evidence (in quantity or quality) to make
descriptive studies, or reports of expert committees a recommendation; however, other factors may influence
decision-making
*The quality of evidence reported in here has been adapted from The Evaluation of Evidence criteria described in the Canadian Task Force on Preventive Health
Care.133
†Recommendations included in these guidelines have been adapted from the Classification of Recommendations criteria described in the Canadian Task Force
on Preventive Health Care.133
2. A nasogastric tube should be inserted in a semiconscious or 11. When the severity of injury is undetermined or when the
unconscious injured pregnant woman to prevent aspiration of gestational age is uncertain, the patient should be evaluated in the
acidic gastric content. (III-C) trauma unit or emergency room to rule out major injuries. (III-C)
3. Oxygen supplementation should be given to maintain
Evaluation of a pregnant trauma patient in the emergency room
maternal oxygen saturation > 95% to ensure adequate fetal
oxygenation. (II-1B) 12. In cases of major trauma, the assessment, stabilization, and
care of the pregnant women is the first priority; then, if the
4. If needed, a thoracostomy tube should be inserted in an
fetus is viable (≥ 23 weeks), fetal heart rate auscultation and
injured pregnant woman 1 or 2 intercostal spaces higher than fetal monitoring can be initiated and an obstetrical consultation
usual. (III-C) obtained as soon as feasible. (II-3B)
5. Two large bore (14 to 16 gauge) intravenous lines should be 13. In pregnant women with a viable fetus (≥ 23 weeks) and
placed in a seriously injured pregnant woman. (III-C) suspected uterine contractions, placental abruption, or
6. Because of their adverse effect on uteroplacental perfusion, traumatic uterine rupture, urgent obstetrical consultation is
vasopressors in pregnant women should be used only recommended. (II-3B)
for intractable hypotension that is unresponsive to fluid 14. In cases of vaginal bleeding at or after 23 weeks, speculum or
resuscitation. (II-3B) digital vaginal examination should be deferred until placenta
7. After mid-pregnancy, the gravid uterus should be moved off previa is excluded by a prior or current ultrasound scan. (III-C)
the inferior vena cava to increase venous return and cardiac
output in the acutely injured pregnant woman. This may be Adjunctive tests for maternal assessment
achieved by manual displacement of the uterus or left lateral 15. Radiographic studies indicated for maternal evaluation
tilt. Care should be taken to secure the spinal cord when using including abdominal computed tomography should not be
left lateral tilt. (II-1B) deferred or delayed due to concerns regarding fetal exposure to
8. To avoid rhesus D (Rh) alloimmunization in Rh-negative radiation. (II-2B)
mothers, O-negative blood should be transfused when needed 16. Use of gadolinium-based contrast agents can be considered
until cross-matched blood becomes available. (I-A) when maternal benefit outweighs potential fetal risks. (III-C)
9. The abdominal portion of military anti-shock trousers should 17. In addition to the routine blood tests, a pregnant trauma patient
not be inflated on a pregnant woman because this may reduce should have a coagulation panel including fibrinogen. (III-C)
placental perfusion. (II-3B)
18. Focused abdominal sonography for trauma should be considered
Transfer to health care facility for detection of intraperitoneal bleeding in pregnant trauma
patients. (II-3B)
10. Transfer or transport to a maternity facility (triage of a labour
and delivery unit) is advocated when injuries are neither life- 19. Abdominal computed tomography may be considered as an
nor limb-threatening and the fetus is viable (≥ 23 weeks), and alternative to diagnostic peritoneal lavage or open lavage when
to the emergency room when the fetus is under 23 weeks’ intra-abdominal bleeding is suspected. (III-C)
gestational age or considered to be non-viable. When the
Fetal assessment
injury is major, the patient should be transferred or transported
to the trauma unit or emergency room, regardless of 20. All pregnant trauma patients with a viable pregnancy (≥ 23 weeks)
gestational age. (III-B) should undergo electronic fetal monitoring for at least 4 hours. (II-3B)
T
bleeding, sustained contractions (> 1/10 min), rupture of the
rauma during pregnancy is the leading cause of non-
membranes, atypical or abnormal fetal heart rate pattern, high
risk mechanism of injury, or serum fibrinogen < 200 mg/dL should obstetric maternal mortality, with 20% of maternal
be admitted for observation for 24 hours. (III-B) deaths directly attributable to injuries.1 Non-lethal
22. Anti-D immunoglobulin should be given to all rhesus D-negative injuries occur in 1 in every 12 pregnant women and are
pregnant trauma patients. (III-B) most commonly the result of an MVC or of domestic
23. In Rh-negative pregnant trauma patients, quantification of or intimate partner violence.1–3 Other common causes
maternal–fetal hemorrhage by tests such as Kleihauer-Betke of trauma in a pregnant patient are penetrating injuries
should be done to determine the need for additional doses of
anti-D immunoglobulin. (III-B) and falls.4–6 Health Canada reported maternal mortality
24. An urgent obstetrical ultrasound scan should be undertaken
as 6.1 per 100 000 live births during 1997–2000.7
when the gestational age is undetermined and need for delivery During that period 15 maternal deaths (an incidence of
is anticipated. (III-C) 1.5/100 000) were attributed to MVC. There was no other
25. All pregnant trauma patients with a viable pregnancy who are single diagnosis (pulmonary embolism, preeclampsia,
admitted for fetal monitoring for greater than 4 hours should have hemorrhage, etc.) with such a high mortality rate. A
an obstetrical ultrasound prior to discharge from hospital. (III-C)
Swedish national population-based study (1991–2001)
26. Fetal well-being should be carefully documented in cases
involving violence, especially for legal purposes. (III-C)
reported an MVC incidence of 207/100 000 pregnancies
that was associated with a maternal mortality of 1.4 per
Obstetrical complications of trauma 100 000 pregnancies and a perinatal mortality of 3.7 per
27. Management of suspected placental abruption should not be 100 000 pregnancies (an odds ratio of 3.55 compared
delayed pending confirmation by ultrasonography as ultrasound with the background risk).8 There was no significant
is not a sensitive tool for its diagnosis. (II-3D)
difference in fatal injury risk among pregnant and non-
Specific traumatic injuries pregnant women involved in an MVC.8 A report by
28. Tetanus vaccination is safe in pregnancy and should be given the National Trauma Data Bank (2001–2005) indicated
when indicated. (II-3B) that trauma-related mortality among pregnant women
29. Every woman who sustains trauma should be questioned is lower than that among non-pregnant women.9 This
specifically about domestic or intimate partner violence. (II-3B) difference has been attributed to protective hormonal
30. During prenatal visits, the caregiver should emphasize the and physiologic effects of pregnancy as well as a higher
importance of wearing seatbelts properly at all times. (II-2B)
likelihood of hospital admission of pregnant versus non-
Perimortem Caesarean section pregnant trauma victims.9,10
31. A Caesarean section should be performed for viable pregnancies
(≥ 23 weeks) no later than 4 minutes (when possible) following The management of a pregnant trauma patient warrants
maternal cardiac arrest to aid with maternal resuscitation and consideration of several issues specific to pregnancy
fetal salvage. (III-B) such as alterations in maternal physiology and anatomy,
exposure to radiation and other possible teratogens,
the need to assess fetal well-being, and conditions that
are unique to pregnancy and are related to trauma (Rh
ABBREVIATIONS
isoimmunization, placental abruption, and preterm
CNS central nervous system
labour). Optimization of outcome in severe trauma
CT computerized tomography cases mandates a multidisciplinary team approach
DPL diagnostic peritoneal lavage involving trauma surgeons, emergency medicine
ECG electrocardiogram physicians, obstetricians, neonatologists, nursing staff,
EFM electronic fetal monitoring and technicians. The obstetrician (or other obstetric care
ER emergency room provider) plays a major role in determining gestational
FAST focused abdominal sonography for trauma age, optimizing uteroplacental perfusion, assessing fetal
ICU intensive care unit well-being, providing information about the risks of
KB Kleihauer-Betke radiation exposure and use of medications, and deciding
L&D labour and delivery
upon and executing an emergency Caesarean section.
MAST military anti-shock trousers A systematic, evidence-based approach to the management
MFH maternal-fetal hemorrhage of maternal trauma is hereby provided to assist and
MVC motor vehicle collision guide physicians involved in such cases, either as primary
Rh rhesus D caregivers or consultants.
patient, O-negative blood should be transfused in order to to transfer patient care between different health facilities,
avoid Rh sensitization in Rh-negative women until type- but also where further care should be provided: in the
specific or cross-matched donor blood becomes available. trauma unit, ER, or community-designated emergency
care facility/personnel unit, in an ICU, or in the
Inflation of the abdominal portion of the MAST is maternity/L&D unit or community-designated maternity
contraindicated during pregnancy as it may lead to reduced facility/personnel unit. Although most injuries are not
placental perfusion and increased cardiac workload.26 categorized as life threatening, they may still be extensive
or mandate immediate intervention to prevent long-term
Recommendations consequences for the mother.
1. Every female of reproductive age with significant
injuries should be considered pregnant until Factors that should be taken into consideration are severity
proven otherwise by a definitive pregnancy test or of the injuries and gestational age. Maternal health should
ultrasound scan. (III-C) always take priority over interventions for the fetus. When
2. A nasogastric tube should be inserted in a major maternal trauma is evident or suspected, the patient
semiconscious or unconscious injured pregnant should be transferred without delay to the trauma unit or
woman to prevent aspiration of acidic gastric ER. The same applies for women with pregnancies of under
content. (III-C) 23 weeks’ gestation, when the fetus is considered non-
3. Oxygen supplementation should be given to viable and serious obstetric complications are uncommon.
maintain maternal oxygen saturation > 95% to Women over 23 weeks’ gestation without life- or limb-
ensure adequate fetal oxygenation. (II-1B) threatening injuries should be transported to a maternity or
4. If needed, a thoracostomy tube should be inserted L&D unit as soon as possible. However, the diagnosis of
in an injured pregnant woman 1 or 2 intercostal pregnancy is not always certain or obvious. Many seriously
spaces higher than usual. (III-C) injured trauma victims cannot communicate, and some are
5. Two large bore (14 to 16 gauge) intravenous lines unaware of their pregnancy status. Gestational age may be
should be placed in a seriously injured pregnant unobtainable or uncertain, complicating the process of
woman. (III-C) decision making. The primary care provider should try to
6. Because of their adverse effect on uteroplacental assess the gestational age by verbal communication with
perfusion, vasopressors in pregnant women should the patient or her companion or through documentation
be used only for intractable hypotension that is found in her possession. Fundal height may give a rough
unresponsive to fluid resuscitation. (II-3B) estimate of gestational age in most cases of a singleton
7. After mid-pregnancy, the gravid uterus should be gestation. Occasionally, injury-related distention of the
moved off the inferior vena cava to increase venous abdomen may interfere with the estimation of fundal
return and cardiac output in the acutely injured height.
pregnant woman. This may be achieved by manual Multiple systems for scoring the severity of trauma have
displacement of the uterus or left lateral tilt. Care been proposed in the literature,27 but most of them are
should be taken to secure the spinal cord when cumbersome and are not applicable for on-scene decision
using left lateral tilt. (II-1B) making. Severity assessment scoring systems frequently
8. To avoid rhesus D (Rh) alloimmunization in Rh- used in trauma and intensive care patients to predict
negative mothers, O-negative blood should be outcome are often not useful in pregnant women admitted
transfused when needed until cross-matched blood to a general ICU.28 The standard Injury Severity Score
becomes available. (I-A) assessment is also not accurate in predicting placental
9. The abdominal portion of military anti-shock abruption and fetal demise. Buchsbaum described simple
trousers should not be inflated on a pregnant and applicable criteria that essentially distinguish between
woman because this may reduce placental major maternal injuries that require further assessment in
perfusion. (II-3B) a trauma centre and minor injuries for which obstetrical
surveillance takes precedence.29 Buchsbaum used criteria
TRANSFER TO HEALTH CARE FACILITY such as hematuria, suspected internal bleeding, loss of
conscious, and fractures to delineate major trauma. We
Following successful initial maternal stabilization, suggest that these simple parameters should be considered
the primary care provider should organize further along with common sense when deciding upon patient
appropriate referral, consultation, and transfer of care transfer and transport arrangements for a pregnant woman
as required. The dilemma is not only whether and how after 23 weeks’ gestation.
after mid-pregnancy mortality and incidence of visceral Table 2. Estimated fetal radiation doses
injury with penetrating abdominal trauma are substantially during some common radio-diagnostic
lower than in the general population.35 However, injuries procedures
below the fourth intercostal space anteriorly, or the tip of Fetal dose
Examination (mrad)
the scapula posteriorly, should be carefully evaluated for
X-ray
potential thoraco-abdominal penetrating injuries. Risk factors
Upper gastrointestinal series 100
associated with maternal death include bruising injuries to
Cholecystography 100
the abdomen, pelvis, or lower back, pelvic fractures, intra-
Lumbar spine radiography 400
abdominal injuries, and penetrating trauma.34,36
Pelvic radiography 200
Clinical signs of peritoneal irritation are less evident in Hip and femur radiography 300
the pregnant woman; therefore, in cases of suspected Retrograde pyelography 600
abdominal injury, physical examination is less informative Abdominal radiography 250
in ruling out major organ damage and further Lumbar spine,
investigations should be conducted.37 The uterus should Anteroposterior 750
be assessed for fundal height, shape, hypertonus, and Lateral 91
on the abdomen may represent fetal body parts in cases of Intravenous pyelogram 480
Vaginal examination should be performed for cervical mrad: milli-rad (radiation absorbed dose)
with increased fetal radiation exposure depending on the 60 µmol/L, and even a value as low as 90 µmol/L may
body part being scanned, the gestational age, the number be abnormal. Alkaline phosphatase is secreted by the
and thickness of slices, and the equipment used. With placenta, thus levels that are twice the upper limit for
abdominal CT during the third trimester the fetal exposure non-pregnant patients are within the normal range during
is around 3.5 rads, which is still under the threshold for fetal pregnancy (up to 140 IU/L).58,59 In addition to the routine
damage.49 Use of gadolinium-based contrast agents has laboratory studies for trauma evaluation, it is advisable to
shown fetal toxicity in animal studies, though no adverse order a coagulation profile including fibrinogen.57
effects have been reported in human fetuses.50 Their use
can be considered when the maternal benefit outweighs Additional Investigations
potential fetal risks. Abdominal ultrasound
FAST is a useful aid for the detection of intraperitoneal
The carcinogenic effects of ionizing radiation exposure are fluid in pregnant trauma patients with suspected intra-
still in dispute. Some studies have suggested an increased abdominal injury. The sensitivity of FAST in detecting
risk with exposure to even a low dose of ionizing radiation intraperitoneal fluid in pregnant blunt trauma patients was
in utero, especially before 8 weeks.48,51–53 However, the 83% in a study that reviewed 127 pregnant trauma patients.60
lifetime cancer risk from prenatal exposure is considered This rate is similar to that in a previously published study
to be similar to that from exposure during childhood.48 of non-pregnant trauma patients.61,62 FAST is an easy and
Further, at an exposure level of < 5 rad, the additional rapid modality that has the added advantage of avoiding
lifetime risk was < 2% (< 0.6% during childhood), over fetal exposure to ionizing radiation, it should therefore
and above the background lifetime risk of around 40%.46 be part of the secondary survey in pregnant patients with
Other studies, including a large Ontario-based cohort, major trauma.
could not confirm an increased risk.54,55 Therefore, if
there is any carcinogenic potential of ionizing radiation Peritoneal lavage and laparotomy
exposure at levels usually used in diagnostic procedure, it DPL is a very rapid and sensitive test with sensitivity of
is thought to be quite low. However, careful consideration 96% to 100% for detection of traumatic intra-abdominal
of alternative forms of evaluation, accurate completion injury.63 The main disadvantages of this low cost, easily
of ionizing studies to avoid duplication, and limitation of interpretable test are that it does not provide information
the number of CT cuts or area studied may be beneficial about specific organ damage, and abdominal injuries
in limiting fetal exposure to radiation. that can be managed conservatively following CT would
require operative intervention based upon DPL. For these
Laboratory Tests
reasons, CT is the most widely used screening modality
In all trauma patients, laboratory tests are often ordered
for blunt abdominal trauma. CT identifies specific organ
by protocol, but in pregnant patients the clinician should
injury, evaluates the retroperitoneum as well and is less
be aware of alterations in the normal range of a few
invasive than DPL. Concerns over fetal exposure to
laboratory values. The white blood count is usually
radiation during pregnancy may lead to a more frequent
elevated and counts up to 20 × 109/L may represent the
use of DPL. The open lavage technique is preferable over
physiologic response to pregnancy. Leukocytosis should
a blind needle insertion in the pregnant patient in order
be correlated with clinical findings, other lab tests, and
to minimize uterine injury.64 When significant abdominal
imaging studies to confirm the suspicion of infection
blood is detected, an exploratory laparotomy with a
or inflammation. Fibrinogen values are often more than
midline incision should be performed.
4 g/L during pregnancy,56 therefore the normal values of
2.5 to 3 g/L for a non-pregnant patient may actually signify Recommendations
mild hypofibrinogenemia, and levels below 2 g/L may 15. Radiographic studies indicated for maternal
indicate disseminated intravascular coagulation, a frequent evaluation including abdominal computed
comorbidity of significant placental abruption.57 D-dimer tomography should not be deferred or delayed
measurement is a marker for venous thromboembolism. due to concerns regarding fetal exposure to
However, during pregnancy, the D-dimer is often positive radiation. (II-2B)
and therefore is of little value in the diagnosis or exclusion 16. Use of gadolinium-based contrast agents can
of venous thromboembolism. Normal range for the be considered when maternal benefit outweighs
partial pressure of CO2 is decreased during pregnancy potential fetal risks. (III-C)
to 27 to 32 mmHg, thus normal non-pregnant values of 17. In addition to the routine blood tests, a pregnant
40 mmHg may result from mild hypoventilation. Serum trauma patient should have a coagulation panel
creatinine levels are decreased during pregnancy to 50 to including fibrinogen. (III-C)
18. Focused abdominal sonography for trauma should expected consequence of maternal death.33,38 However, a
be considered for detection of intraperitoneal high Injury Severity Score, serious abdominal injury and
bleeding in pregnant trauma patients. (II-3B) hemorrhagic shock all increase the risk of fetal loss.33,38
19. Abdominal computed tomography may be Maternal trauma resulting in hypovolemic shock can
considered as an alternative to diagnostic peritoneal reduce uterine perfusion, a direct function of systemic
lavage or open lavage when intra-abdominal blood pressure.68 This can be further compounded by
bleeding is suspected. (III-C) visceral vasoconstriction. Placental abruption can further
reduce transplacental oxygenation. A combination
of these factors can lead to fetal hypoxemic injury.
FETAL ASSESSMENT
Compromised fetal perfusion and oxygenation usually
Assessment of a viable fetus (≥ 23 weeks gestational age) presents with abnormalities in the fetal heart rate pattern.
should be initiated immediately following, or in parallel An abnormality in the fetal heart rate pattern may also be
with the physical examination of the stabilized mother the first sign of maternal hemodynamic compromise.67
since it has been shown that most placental abruptions
Occasional uterine contractions are the most common
occur shortly after the insult.33 The objectives are:
finding with trauma during pregnancy, occurring in
•• identification of impending hypoxemic fetal injury 40% of cases,69 and resolving in 90% of cases with no
or death as a result of uteroplacental compromise or adverse fetal outcome.70 The intensity and frequency
placental abruption, of contractions are predictive of complications such
•• detection of trauma-related complications of as traumatic placental abruption and preterm labour.
pregnancy such as placental abruption, preterm Elevated basal uterine tone also raises the suspicions for
delivery and spontaneous rupture of the membranes, placental abruption.
•• evaluation of the degree of maternal–fetal hemorrhage Abnormal EFM tracings following trauma are not
and resultant fetal anemia, reliable in predicting adverse obstetrical outcome
•• delineation of fetal injuries, and (sensitivity of 62% and specificity of 49%).69,71 However,
•• identification of compensated maternal hypovolemia the combination of a normal tracing and physical
first manifested by decreased placental perfusion. examination has a negative predictive value of 100% in
excluding major adverse fetal outcome.33,69,72 Atypical or
Knowledge of the estimated gestational age is essential abnormal fetal heart rate patterns such as decelerations,
for appropriate interpretation of tests for fetal viability bradycardia, tachycardia or loss of variability mandate
and well-being. Along with clinical examination of fundal further testing, in utero resuscitation with supplemental
height and palpation for uterine contractions and tone, oxygen, IV fluids and left lateral decubitus positioning
in absence of certainty regarding the gestational age, an or delivery, depending on the severity of the abnormal
ultrasound examination should be undertaken. Electronic pattern, the presumed cause and gestational age. About
monitoring of the fetal heart rate should be initiated on 2.4% to 7.2% of maternal trauma patients require a
viable fetuses (≥ 23 weeks) as soon as possible. With Caesarean delivery shortly after trauma.34,38 Need for a
a confirmed pre-viable fetus, it may be sufficient to Caesarean section shortly after trauma is also a risk factor
demonstrate the presence of fetal cardiac activity. for maternal death.34
Monitoring of Fetal Heart Rate and Uterine Activity The duration of fetal monitoring following maternal
EFM allows assessment of fetal well-being and uterine trauma remains disputed. For many years it has been
activity, with abnormality of either being predictive of suggested that fetal monitoring should continue for at
potential obstetrical complications such as placental least 24 hours following the insult33,64,73,74 and some even
abruption, fetal hypoxic injury or fetal death. Rothenberger suggested a 48-hour period of close fetal monitoring.75
et al reported fetal loss in 61% of cases with major In a prospective study of pregnant trauma patients
maternal injuries and 27% with minor injuries, with no that had EFM for a minimum of 4 hours, the majority
effect on pregnancy outcome following insignificant demonstrated uterine activity during that period.70
maternal injuries.39 Hospital-based studies have suggested Contractions then abated in most patients. Patients were
a 5% to 19% risk of fetal death as opposed to a 1.3% risk discharged home if contractions ceased or were less
in population-based studies. This difference may result frequent than once every 15 minutes. These patients
from the fact that more serious injuries are more likely had pregnancy outcomes similar to that in an uninjured
to be assessed in a hospital.8,65–67 Fetal death may be an control group. The sensitivity of predicting placental
abruption by the frequency of uterine activity in the first alloimmunization in Rh-negative mothers. It has also been
4 hours after trauma was 100%. The study suggested suggested that a larger MFH may be predictive of other
that 4 hours of monitoring was a sensitive method of adverse obstetrical outcomes.80
predicting immediate post-traumatic adverse obstetrical
outcomes. Another retrospective study of 271 pregnant The Rh antigen is well developed by 6 weeks gestation81 and
patients, suggested monitoring for at least 24 hours as little as 0.001 mL of fetal blood can cause sensitization
only for a selected group of patients at high risk for of the Rh-negative mother. Even minor trauma in
fetal demise, preterm labour, and placental abruption.76 pregnancy may cause sensitizing MFH. Several studies
This high risk group consisted of patients involved in have demonstrated reduced Rh alloimmunization after
motorcycle, pedestrian or high velocity collisions, those routine administration of anti-D immune globulin G (IgG)
ejected from motor vehicles and patients demonstrating to Rh-negative mothers.81–83 Therefore, anti-D IgG should
maternal tachycardia, abnormal fetal heart rate pattern, be given to all Rh-negative pregnant trauma patients.84 A
and high injury severity scores. In a study of 317 patients single dose of 300 mg, administered within 72 hours of
with minor trauma (48% with falls), 14% had frequent injury, provides protection against sensitization for up
contractions requiring observation for 24 hours.77 to 30 mL of fetal blood in the maternal circulation.84–86
Delivery information was available in 80%. Only one case The feto-placental blood volume is estimated to be
of placental abruption occurred, remote from the trauma. 120 mL/kg of fetal weight. In most cases of traumatic
There were no other trauma-related adverse events. maternal–fetal hemorrhage, the estimated volume of
fetal blood in the maternal circulation is less than 15 mL
We suggest hospitalization and intermittent fetal heart and in more than 90% of cases it is less than 30 mL.70,78
rate and uterine activity monitoring by EFM for 24 hours Therefore, the vast majority of Rh-negative patients are
for patients with protected by one ampule.
•• uterine tenderness,
The KB test has been used to quantify MFH, so that Rh-
•• significant abdominal pain, negative women could receive appropriate Rh immune
•• vaginal bleeding, prophylaxis. If the KB test indicates transplacental
•• a contraction frequency of more than once per 10 hemorrhage in excess of 30 mL fetal blood, additional
minutes during a monitoring period of 4 hours, doses of anti-D IgG may be required. According to
the SOGC recommendations for prevention of Rh
•• rupture of the membranes, alloimmunization,84 KB test may be considered following
•• atypical or abnormal fetal heart rate pattern (fetal events potentially associated with placental trauma and
tachycardia, bradycardia or decelerations), disruption of the maternal–fetal interface (e.g., placental
•• high risk mechanism of injury (motorcycle, pedestrian, abruption, blunt trauma to the abdomen).
high speed crash), or
A novel approach for detecting MFH, using flow cytometry
•• serum fibrinogen < 200 mg/dL as a simpler, more objective, and more precise alternative
•• Monitoring for 4 hours is sufficient to rule out major to the KB method has been advocated.87,88 Another study
trauma-related complications in low risk patients has shown that both manual KB test and flow cytometry
without the above mentioned risk factors.69,72,78 have good sensitivity in detecting and quantifying fetal red
cells.89 Taking into consideration that flow cytometry is not
Prevention of Rh Alloimmunization and available in most medical facilities and its added value is
Evaluation of Maternal-fetal Hemorrhage still being investigated, we cannot recommend its routine
Traumatic placental injury can result in MFH. MFH occurs use at this time.
in 10% to 30% of pregnant trauma patients.79 Massive
MFH is a rare complication of trauma and is usually The universal use of KB testing for all pregnant
clinically evident, with fetal demise, abnormal fetal heart trauma patients, regardless of their Rh status had been
rate pattern (bradycardia or recurrent decelerations), or advocated by some,80,90 hypothesizing that the magnitude
abrupt fetal anemia and cardiac failure. The vast majority of of MFH reflects severity of injury and therefore would
post-traumatic transplacental hemorrhages are smaller and be predictive of trauma-related obstetrical complication
subclinical. The quantification of the amount of fetal blood such as preterm labour. In one study of maternal
cells in the maternal circulation enables the obstetric care trauma, of the 46 patients with a positive KB test, 44
provider to roughly estimate the degree of transplacental had contractions (of which 25 had preterm labour),
hemorrhage. This may be important in prevention of Rh and of the 25 patients with a negative KB test, none
had contractions or preterm labour.80 No information •• placental localization and exclusion of placenta previa
was available in this study regarding the incidence of •• assessment of amniotic fluid volume
preterm delivery. The authors concluded that KB test
•• cervical length assessment
accurately predicted the risk of preterm labour, and
clinical examination did not. However, it can be argued •• fetal well-being (biophysical profile)
that since all women with contractions had a positive •• detection of fetal anemia by peak systolic flow velocity
test, and those without contractions did not, presence of in the middle cerebral artery
uterine contractions can be used as a surrogate marker •• delineation of possible fetal injury, and
for occurrence of MFH. Therefore the utility of KB test
in rhesus-positive women is not clear. Another review •• confirmation of fetal demise.
suggested that KB test should be performed in all maternal Therefore, an obstetrical ultrasound examination is
trauma cases, although the basis for this recommendation recommended in all cases of significant maternal trauma
for rhesus-positive women was not apparent.90 Others that are admitted for monitoring for more than 4 hours.
have suggested the KB test is only useful in Rh-negative However, ultrasound should only be used to complement
women.69,91 A study comparing incidence of a positive EFM, the latter being more sensitive in predicting adverse
KB test in women with history of trauma and that in outcomes such as placental abruption or fetal hypoxic
a low risk population found no significant difference injury.69–72 In cases where severe MFH occurred, generally
(2.6% vs. 5.1%, respectively).92 Based on the evidence, there is no time for diagnostic tests such as KB test or
we suggest that KB testing should be done in all rhesus- middle cerebral artery Doppler. Fetal heart tracing is
negative pregnant trauma patients. Though EFM is more usually abnormal, and prompt delivery is recommended.
likely to be clinically useful in rhesus-positive women, KB Ultrasound needs to be done on an urgent basis only in
test can be considered as an optional test to determine the cases where fetal viability is in question, in all other cases, it
need for prolonged monitoring. Given the high incidence can be undertaken as a non-urgent follow-up examination
of a false-positive KB test, in rhesus-positive women, prior to discharge of the patient from the hospital. A
assessment of MFH by flow cytometry could be a useful reassuring biophysical profile should never be used as a
adjunct in differentiating true positive KB tests from the surrogate for EFM. After discharge from hospital, a follow-
false-positive ones. up obstetric ultrasound examination in 2 weeks should be
considered for all patients who needed hospital admission
The Role of Ultrasound for maternal or fetal factors (regardless of gestational age),
Ultrasonography is a rapid, non-invasive, valuable tool in this is to document normalcy after the traumatic event,
the assessment of pregnant trauma patients and it does especially of fetal intracranial anatomy and to assess fetal
not require transport of the patient from the trauma unit. growth in the interval.94
An obstetrical ultrasound scan should be done urgently
in cases where the gestational age cannot be determined Recommendations
with certainty and need for delivery is anticipated based 20. All pregnant trauma patients with a viable
on an atypical or abnormal fetal heart rate pattern or pregnancy (≥ 23 weeks) should undergo electronic
suspicion of placental abruption. However, it is not fetal monitoring for at least 4 hours. (II-3B)
sensitive in diagnosing placental abruption.70,72 Between 21. Pregnant trauma patients (≥ 23 weeks) with
50% and 80% of traumatic abruptions will be missed and adverse factors including uterine tenderness,
those detected by sonography are usually the clinically significant abdominal pain, vaginal bleeding,
apparent ones, which pose no diagnostic challenge.70,78 sustained contractions (> 1/10 min), rupture of the
The role of the biophysical profile in predicting adverse membranes, atypical or abnormal fetal heart rate
obstetrical outcome following trauma is yet to be studied.93 pattern, high risk mechanism of injury, or serum
However, in the setting of trauma, EFM is a more fibrinogen < 200 mg/dL should be admitted for
observation for 24 hours. (III-B)
sensitive tool not only to rule out a placental abruption
22. Anti-D immunoglobulin should be given to all
but also for assessment of fetal well-being as compared to
rhesus D-negative pregnant trauma patients. (III-B)
ultrasound.70,74,78 Nevertheless, ultrasound is an important
23. In Rh-negative pregnant trauma patients,
adjunctive to the physical examination and fetal assessment
quantification of maternal–fetal hemorrhage by
tests. Ultrasonography may assist in:
tests such as Kleihauer-Betke should be done to
•• determination of gestational age determine the need for additional doses of anti-D
•• demonstration of fetal cardiac rate and rhythm immunoglobulin. (III-B)
24. An urgent obstetrical ultrasound scan should be birth is preferable. Although placental abruption,
undertaken when the gestational age is undetermined particularly with greater than 50% placental separation,
and need for delivery is anticipated. (III-C) increases the risk of fetal death, it more often results in
25. All pregnant trauma patients with a viable preterm labour. Placental abruption is often associated
pregnancy who are admitted for fetal monitoring with a rapid cervical dilation and delivery, induction or
for greater than 4 hours should have an obstetrical augmentation of labour with a trial of vaginal birth may
ultrasound prior to discharge from hospital. (III-C) be reasonable in a hemodynamically stable mother at or
26. It is important to have careful documentation near term with a normal fetal heart rate pattern. However,
of fetal well-being in cases involving violence, in the presence of fetal or maternal compromise, prompt
especially for legal purposes. (III-C) delivery by Caesarean is often indicated. Maternal bleeding
and coagulation abnormalities should be aggressively
treated to optimize maternal and fetal outcome. Abruption
OBSTETRICAL COMPLICATIONS OF TRAUMA remote from term is challenging to manage. Deterioration
Placental Abruption in fetal condition or maternal hemodynamic instability is
Abruption of the placenta is a major complication of indications for immediate delivery, even at the expense of
maternal trauma, occurring in 5-50% of cases, depending prematurity.95
on the severity of injury.70,78 It is the most common cause Uterine Rupture
of fetal death in cases of blunt trauma. Resulting from the Post-trauma uterine rupture is rare (0.6% of all maternal
difference in physical properties of the relatively inelastic
injuries), but seen more frequently with a scarred uterus
placental tissue versus the elastic myometrium, significant
or with direct abdominal impact during the latter half
abruption of the highly vascular uteroplacental interface
of pregnancy.74 Most (75%) uterine ruptures involve
can mediate rapid maternal and in some cases fetal
the fundal area. The degree of rupture may vary from
exsanguination. Most abruptions occur within 2 to 6 hours
complete avulsion of the uterus to serosal hemorrhage
after the injury, and almost all of them with 24 hours of
and abrasions. Symptoms and signs suggestive of
injury.33,95 Abruption may follow even minor trauma and
uterine rupture include: maternal shock, abdominal
requires high index of suspicion to detect. The diagnosis
distension, irregular uterine contour, palpable fetal parts,
of abruption is based on clinical impression, laboratory
sudden abnormal fetal heart rate pattern, ascent of fetal
tests and fetal evaluation. Typical findings include
abdominal pain, uterine tenderness, uterine contractions presenting part and peritoneal irritation (abdominal
or hypertonicity, vaginal bleeding, preterm labour, or an rigidity, guarding and tenderness). Maternal mortality has
atypical or abnormal EFM tracing. Specific sonographic been described with traumatic uterine rupture and fetal
findings are uncommon; retroplacental hematoma is mortality is almost universal. It is the cause of MVC-
seen in 2% to 25% of abruptions. Treatment should related perinatal death in 17.5% of the cases.8 Suspected
never be delayed for ultrasound confirmation because uterine rupture with maternal and/or fetal comprise
ultrasonography is not reliable in diagnosing placental should prompt urgent laparotomy to control bleeding
abruption. In a study of 149 women with vaginal bleeding, and facilitate resuscitation.
the sensitivity, specificity, and positive and negative
Preterm Labour
predictive values of sonography in diagnosing placental
Traumatic injury during pregnancy can result in preterm
abruption were 24%, 96%, 88%, and 53%, respectively.96
labour through several mechanisms. Placental abruption
Some have suggested that traumatic abruption tends to
may culminate in preterm labour in 20% of cases.99 The
be occult without uterine tenderness or vaginal bleeding
extravasation of blood at the placental margin may lead
but with a higher incidence of coagulopathy.97 Abruption,
to decidual necrosis, which, in turn, could initiate the
occult or concealed, may lead to major maternal bleeding
production of prostaglandin, thereby leading to preterm
and consumption coagulopathy with thrombocytopenia,
labour.99 Traumatic injury to the uterus may also result in
prolonged coagulation tests and hypofibrinogenemia.57
destabilization of lysosomal enzymes which can initiate
Although severe placental abruption can be lethal to the prostaglandin production.68 Preterm premature rupture
fetus, a timely and prompt Caesarean section may result of membranes is also associated with preterm labour.
in considerable survival rates of up to 75%.34,98 Delay in Regardless of the mechanism, trauma (even with minor
recognition of non-reassuring fetal status, in such cases, injuries) is associated with a 2-fold higher risk of preterm
was accountable for 60% of potentially preventable delivery.100 The risk is higher with increasing injury severity
perinatal deaths. In cases of a non-viable fetus, vaginal and among those injured early in gestation.100 Signs of
preterm labour should be sought in every patient with a tip of the scapula posteriorly, may cause visceral injuries
viable fetus. EFM should be used to assess regularity and that are easily missed. At the same time that the gravid,
frequency of contractions. When regular contractions abdominal uterus provides protection to the abdominal
are noted, the fetal fibronectin test or cervical length viscera, it is susceptible, along with the fetus, to direct injury.
assessment to determine the risk for preterm labour According to Buchsbaum, the uterine musculature absorbs
should be considered. Rupture of the membranes, when a great amount of the projectile’s velocity and diminishes
suspected, should be ruled out by a speculum examination its ability to damage the viscera.29 Therefore, depending
including assessment with nitrazine paper and the ferning on the gestational age and the size of the uterus, the fetus
test. If risk of preterm delivery is high because of preterm is much more likely than the mother to sustain significant
labour or preterm premature rupture of membranes, injury (and to die) after a penetrating abdominal trauma. In
steroids (and any other indicated medications such as general, the fetus sustains injury in 60% to 70% of cases,
antibiotics and magnesium sulfate), transfer to a tertiary while visceral maternal injuries are seen only in 20% of
care centre, and neonatology consultation should be penetrating abdominal trauma.
considered based on gestational age and current location
of the patient. In many cases, iatrogenic preterm delivery Gunshot wounds produce transient shock waves and
may be indicated to improve fetal or maternal outcome. cavitations in displacement of kinetic energy to body
tissue, causing more damage and thus higher mortality
Direct Fetal Injury for both mother and fetus than low-velocity injuries:
Direct fetal injury is seen in less than 1% of blunt maternal 70% of abdominal gunshot wounds result in fetal injury,
trauma.101 Maternal soft tissues, uterus, and amniotic fluid and 40% to 65% of these fetuses die.104 Fetal mortality
serve to diminish the force delivered to the fetus. Direct generally results from premature delivery, maternal shock,
fetal injury from blunt abdominal trauma often involves uteroplacental injury, or direct fetal injury.105 A study
the fetal skull and brain. One possible mechanism involves of 321 pregnant trauma patients showed that 9% had
fracture of the maternal pelvis in late gestation with an
penetrating trauma, of which 73% were gunshot wounds.4
engaged fetal head resulting in fetal skull fracture.102 A
The risk of maternal death was not significantly higher
deceleration injury of an unengaged head can also occur.103
with penetrating trauma than with blunt trauma (7% vs.
Fetal injuries in other modes of maternal trauma are
2%); however, fetal mortality was significantly higher (75%
considered in the section below.
vs. 10%) with penetrating trauma.
Recommendation
Penetrating injuries in pregnant trauma patients are
27. Management of suspected placental abruption
managed in essentially the same way as in non-pregnant
should not be delayed pending confirmation by
patients. The standard of care is to prioritize the emergent
ultrasonography; ultrasound is not a sensitive tool
treatment of the gravid patient above that of her fetus.
for its diagnosis. (II-3B)
The hemodynamically stable patient should be assessed
by non-invasive diagnostic methods such as ultrasound
ADDITIONAL CONSIDERATIONS REGARDING and triple contrast CT scan. The same indications for
SPECIFIC TRAUMATIC INJURIES
surgical exploration apply as in the non-pregnant patient
Penetrating Trauma (positive findings on lavage, free air under the diaphragm
Penetrating trauma during pregnancy is becoming more before lavage, progressive abdominal distention with
common. Penetrating abdominal injuries are caused a declining hematocrit, or abdominal wall disruption
primarily by gunshot or stab wounds. As in non-pregnant or perforation). In cases of exploration, the decision
individuals, stab wounds tend to have a better prognosis to proceed with Caesarean section should be weighed
than gunshot wounds. The maternal bowel is less likely against the likelihood for fetal survival and long-term
to be involved with penetrating injuries after the second complications of prematurity and should be made in
trimester due to the protection provided by the large uterus. consultation with the trauma surgeon, neonatologist, and
The incidence of maternal visceral injury with penetrating pediatric surgeon. Factors that can influence the decision
abdominal trauma is only 15% to 40% compared with 80% to proceed with Caesarean section are gestational age,
to 90% in non-pregnant women.35 Although the visceral extent and severity of fetal injury, degree of uteroplacental
organs are displaced upwards and are less likely to be compromise, parameters of fetal well-being, and the
injured, upper abdominal stab wounds can result in more need for hysterectomy with extensive uterine injury.
complex bowel injury. Thoraco-abdominal penetrating A dead or injured fetus is not considered an indication
injuries, below the fourth intercostal space anteriorly, or the for exploration, as the fetus will usually spontaneously
abort or can be delivered vaginally. Tetanus vaccination seatbelts and air bag was the most beneficial, and could
is safe in pregnancy and should be given, when indicated, be lifesaving in severe MVC.117 Deployment of airbags
according to the usual protocol.106,107 has been associated with adverse events such as uterine
rupture, placental abruption, and fetal death that were
Domestic or Intimate Partner Violence attributed to the air bags.113,118,119 However, this is more
The incidence of domestic or intimate partner violence likely a reflection of the severity of traumatic force rather
increases during pregnancy and is clustered in the third than a causal association. At this point there are not
trimester.6,108 Domestic violence was reported by 6.6% enough data to make a recommendation about disabling
of pregnant women in Ontario.108 The most commonly
air bags during pregnancy. Furthermore, when the risk
struck body area was the abdomen (64%), a risk factor
of fetal death or injury is balanced against risks to the
for both maternal and fetal adverse outcome. Other
mother, the latter should take precedence, recognizing
studies have reported an even higher incidence of abuse
the fact that fetal well-being is dependent on maternal
during pregnancy (10–30%), with 5% resulting in fetal
well-being.
death.109,110 Every woman who sustains trauma, particularly
penetrating abdominal trauma, should be questioned Although organ damage, fractures, and hemorrhage can
specifically about domestic violence. Careful, detailed, occur in MVC, the most common mechanism of injury
and contemporaneous documentation is essential. Such is blunt trauma, which can cause both maternal and fetal
inquiry should occur in the absence of the partner. morbidity and mortality. The mechanism of trauma often
involves the uterus. A force applied to the uterus can
Motor Vehicle Collision
deform the shape of the uterus due to its elasticity, but
In the pregnant population, MVC is the leading cause
of maternal death, and after placental abruption, can have a smaller deforming effect on the less elastic
maternal death is the leading cause of fetal death.111,112 placenta. This can result in a shearing force that may
Of 351 maternal deaths from non-obstetric causes in separate the attached placenta from the uterus. Abrupt
a trauma centre registry, 72% resulted from MVC.113 changes in amniotic fluid pressure may further contribute
Documentation of the nature of the injury and of to placental separation. The end result of this kind of
maternal and fetal status is important for reasons that mechanism is placental abruption. One report suggested
include evaluating whether any subsequent adverse that up to 37% of life-threatening maternal injuries after
outcome should be attributed to the MVC. MVC are complicated by abruption, whereas in non–
life-threatening injuries, the incidence of abruption was
The outcome of MVC can range from no trauma at all only 1.6%.120 Uterine contractions may also result from
to severe multi-organ damage and death. The outcome blunt trauma and lead to preterm labour. Relatively
is related to various factors including the mechanism of minor injuries may be associated with a grave pregnancy
the collision itself, the acceleration-deceleration velocities outcome.121 Maternal–fetal hemorrhage may be a serious
of the vehicles involved, and the use of protective complication of blunt trauma. Exsanguination into
mechanisms, such as seat belts, air bags, and other safety maternal circulation can occasionally culminate in fetal
features. Wearing a seat belt in a motor vehicle during demise. Direct fetal intracranial injury is another, albeit
pregnancy is useful and effective in reducing the risk uncommon, mechanism of fetal injury.122 This type of
of adverse pregnancy outcomes including maternal injury may be attributed to a direct trauma to the fetal
death.113,114 Crosby and Costiloe reported a reduction in head but may also result from a massive maternal–fetal
the maternal death rate from 33% to 5% with the use hemorrhage and significant fetal hypotension with
of a two-point seatbelt, and that finding was reproduced subsequent hypoxic-ischemic intracranial injury.
by a more recent study.112,115 During prenatal visits, the
caregiver should emphasize the importance of wearing a Falls
properly adjusted and positioned seatbelt at all times and Falls are the cause in 3% to 31% of cases of maternal
refute any misconception about the use of seatbelts during trauma.69,123 Less than 10% of falls are associated with
pregnancy.116 Ejection from the vehicle increases the risk significant maternal or fetal complications.124 They are
to both the woman and the fetus. The lap belt should be more common in the latter half of pregnancy, particularly
positioned below the abdomen and not over the uterus. after 32 weeks.69,74 The increase in lumbar lordosis that is
The shoulder belt should be placed between the breasts. seen in pregnancy moves the centre of gravity forward
The belt should be comfortable, but not tight. Air bags and contributes to an increased incidence of falls.123
are a relatively newer modality in preventing and reducing Therefore, aggressive high-impact activity should be
injuries in MVC. In a simulated study, a combination of avoided in advanced pregnancy. Complications associated
heart tones can be demonstrated at initial assessment 18. Tsuei BJ. Assessment of the pregnant trauma patient. Injury
2006;37(5):367–73.
of a pregnant trauma patient after 23 weeks’ gestation,
19. American College of Surgeons Committee on Trauma. Trauma in
Caesarean section is likely to be futile in terms of fetal
women. In: Advanced trauma life support for doctors: student course
survival.34 manual.
8th edition. Chicago: American College of Surgeons; 2008:259–68.
Recommendation
20. Sperry JL, Minei JP, Frankel HL, West MA, Harbrecht BG, Moore EE,
31. A Caesarean section is recommended for viable et al. Early use of vasopressors after injury: caution before constriction.
pregnancies (≥ 23 weeks) no later than 4 minutes J Trauma 2008;64:9–14.
(when possible) following maternal cardiac 21. Atta E, Gardner M. Cardiopulmonary resuscitation in pregnancy. Obstet
arrest to aid with maternal resuscitation and fetal Gynecol Clin North Am 2007;34:585–97.
salvage. (III-B) 22. Pearlman M, Faro S. Obstetric septic shock: a pathophysiologic basis for
management. Clin Obstet Gynecol 1990;33:482–92.
23. Bamber JH, Dresner M. Aortocaval compression in pregnancy: the effect
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student to be guided through a pelvic examination by an medical students, and they must explain that they will be
expert teacher. assisting in the surgery.
If future generations of women are to have access to adequate As part of the surgical consent, patients should be informed
health care, medical students must be trained to competently that pelvic examinations will be performed by members of
examine female patients. The teaching of these examinations, the gynaecologic surgical team following the induction of
however, can pose ethical problems.3 Many women under- anaesthesia and before initiation of surgery. Verbal consent
going pelvic surgery may not be aware of the role medical for a medical student to be part of the surgical team and to
students play or of the importance of performing a pelvic perform an examination under anaesthesia should be
examination at the time of surgery.4 The sensitivity of this obtained and documented. Patient consent must be volun-
issue has been recognized within the medical community tary and not coerced. When possible, a discussion about the
for over 20 years,5 and medical societies have enacted teaching environment in the operating room should take
guidelines in response to these concerns.6,7 The controversy place with the patient in the office when she signs consent
about medical students’ performing pelvic examinations on for surgery.
anaesthetized women has been well documented.2,8,9 In summary, in out-patient clinics, in-patient settings, and
The most important consideration in this educational setting is birth units, medical students must introduce themselves
the need to establish that the patient has consented to a pelvic and identify themselves as medical students to the patient.
examination by a medical student before that examination is Verbal consent from the patient is required before a pelvic
performed.10 Patients have the right to refuse medical treat- examination is performed.
ment and participation in medical teaching exercises. In When pelvic examinations are to be performed during
fact, most patients are willing to participate in medical surgery while a patient is under anaesthesia, medical
education5,11–15 but want to be informed of medical student students must introduce themselves and identify them-
involvement in their care.4,14,15 Physicians and students selves as medical students to the patient before the surgery.
must be explicit about student participation during the Consent for the pelvic examination under anaesthesia by
consent process.16 Patient participation in medical education the gynaecologic surgical team, including the medical
in an academic or any teaching centre should be non- student, must be obtained.
discriminatory and respectful of patients’ rights and
Pelvic examinations under anaesthesia should not be the
autonomy.6 Race or socioeconomic status should not be the
primary means of teaching pelvic examinations to medical
basis for selection of patients for teaching. Pelvic examina-
students, and students must not be brought into the operating
tions under anaesthesia are not the primary means of
room solely to perform a pelvic examination on an
teaching pelvic examinations to medical students, and
anaesthetized patient.
students should not be brought into the operating room
solely to perform a pelvic examination on an anaesthetized ENSURING ADEQUATE SUPERVISION
patient.
Medical students must perform pelvic examinations only
OBTAINING INFORMED CONSENT TO PELVIC under the supervision of an appropriately qualified health
EXAMINATIONS PERFORMED BY MEDICAL STUDENTS care professional (i.e., nurse, resident, midwife, or
physician). Medical students may and should decline to
1. On Patients in Clinical Settings (in-patient
participate if they do not feel comfortable with the
wards, out-patient clinics, and birth units)
circumstances of the examination.
Medical students must introduce themselves to patients and
identify themselves as medical students. If a student will be SUMMARY
performing a pelvic examination, he or she must explain the The pelvic examination is an integral part of the gynaeco-
procedure that will be performed and seek the patient’s logical consultation and fundamental to planning any
permission to perform the examination. Patient consent gynaecological surgical intervention. Competently performing
must be voluntary and not coerced. the pelvic examination is an essential skill for all medical
2. On Patients Under Anaesthesia During Surgery professionals, but its sensitive nature makes it challenging
to teach and to learn. While educational tools such as didactic
All members of the gynaecologic surgical team (including teaching sessions and the use of standardized patients and
medical students, residents, and fellows) are expected to pelvic models have largely replaced the clinical patient as the
introduce themselves to the patient before her gynaecologic initial stage of teaching medical students how to perform a
surgery. Medical students must identify themselves as pelvic examination, the best means of consolidating that
knowledge is examining a patient in a clinical setting. 3. Coldicott Y, Pope C, Roberts C. The ethics of intimate examinations-
teaching tomorrow’s doctors. BMJ 2003;326(7380):97–101.
Indeed, our patients are our best teachers.
4. Wainberg S, Wrigley H, Fair J, Ross S. Teaching pelvic examinations under
In all settings, the patient’s consent must always be obtained anaesthesia: what do women think? J Obstet Gynaecol Can 2010;32:49–53.
by the medical student or a member of the gynaecologic 5. Bibby J, Boyd N, Redman CW, Luesley DM. Consent for vaginal examination
surgical team before the medical student performs a pelvic by students on anaesthetised patients. Lancet 1988;2(8620):1150.
examination. Medical students must introduce themselves 6. Professional responsibilities in obstetric-gynecologic education. ACOG
Committee Opinion 2007, No. 358. American College of Obstetricians
to all patients in whose care they are participating and identify and Gynecologists. Obstet Gynecol 2007;109:239–42. Available at:
their role as medical students. Specifically, patients who are http://www.acog.org/from_home/publications/ethics/c0358.pdf.
undergoing gynaecologic surgery should understand the Accessed February 15, 2010.
role of a pelvic examination during the procedure and that it 7. Gynaecological examinations: guidelines for specialist practice. London:
Royal College of Obstetricians and Gynaecologists Press; 2002.
may be performed by members of the gynaecologic surgical
team, including medical students. In all settings, consent 8. Ubel PA, Jepson C, Silver-Isenstadt A. Don’t ask, don’t tell: a change in
medical student attitudes after obstetrics/gynecology clerkships toward
must be given voluntarily and must not be coerced. seeking consent for pelvic examinations on an anesthetized patient.
Am J Obstet Gynecol 2003;188(2):575–9.
In order to maintain high standards of women’s health care
9. Hicks LK, Lin Y, Robertson DW, Robinson DL, Woodrow SI.
in Canada, all physicians must be trained to perform an Understanding the clinical dilemmas that shape medical students’
appropriate pelvic examination and to detect abnormal ethical development: questionnaire survey and focus group study.
pathology. Medical students are members of the medical BMJ 2001;322(7288):709–10.
team, and they should be involved in the full scope of 10. Wilson RF. Autonomy suspended: using female patients to teach intimate
patient care—communication, physical examination exams without their knowledge or consent. J Health Care Law Policy
2005;8:240–63.
including pelvic examinations, diagnosis, and therapy. During
their clinical rotations, medical students need to learn and 11. Lawton FG, Redman CW, Luesley DM. Patient consent for gynaecological
examination. Br J Hosp Med 1990;44(5):326,9.
perform pelvic examinations with adequate supervision to
ensure the safety and comfort of the patient and to optimize 12. Ubel PA, Silver-Isenstadt A. Are patients willing to participate in medical
education? J Clin Ethics 2000;11:230–5.
their learning experience.
13. Silver-Isenstadt A, Ubel PA. Erosion in medical students’ attitudes about
REFERENCES telling patients they are students. J Gen Intern Med 1999;14:481–7.
1. Siwe K, Wijma K, Stjernquist M, Wijma B. Medical students learning the 14. Wilson RF. Unauthorized practice: teaching pelvic examination on women
pelvic examination: comparison of outcome in terms of skills between under anesthesia. J Am Med Womens Assoc 2003;58:217–20; discussion 221–2.
a professional patient and a clinical patient model. Patient Educ Couns
15. Magrane D, Gannon J, Miller CT. Student doctors and women in labor:
2007;68(3):211–7.
attitudes and expectations. Obstet Gynecol 1996;88:298–302.
2. Wall LL, Brown D. Ethical issues arising from the performance of pelvic
examinations by medical students on anesthetized patients. Am J Obstet 16. O’Flynn N, Rymer J. Consent for teaching: the experience of women
Gynecol 2004;190(2):319–23. attending a gynaecology clinic. Med Educ 2003;37:1109–14.
Jane A. Schulz, MD, Edmonton AB 1. Urinalysis and midstream urine culture and sensitivity should be
performed with the first presentation of symptoms in order to
David Wilkie, MD, Vancouver BC
establish a correct diagnosis of recurrent urinary tract infection.
FAMILY PHYSICIANS ADVISORY COMMITTEE (III-L)
William Ehman, MD (Chair), Naniamo BC 2. Patients with persistent hematuria or persistent growth of bacteria
Sharon Domb, MD, Toronto ON aside from Escherichia coli should undergo cystoscopy and
imaging of the upper urinary tract. (III-L)
Andrée Gagnon, MD, Blainville QC
Owen Hughes, MD, Ottawa ON 3. Sexually active women suffering from recurrent urinary tract
infections and using spermicide should be encouraged to consider
Jill Konkin, MD, Edmonton AB an alternative form of contraception. (II-2B)
Joanna Lynch, MD, Winnipeg MB
4. Prophylaxis for recurrent urinary tract infection should not be
Cindy Marshall, MD, Lower Sackville NS undertaken until a negative culture 1 to 2 weeks after treatment
Disclosure statements have been received from all members of has confirmed eradication of the urinary tract infection. (III-L)
the committees. 5. Continuous daily antibiotic prophylaxis using cotrimoxazole,
The literature searches and bibliographic support for this guideline nitrofurantoin, cephalexin, trimethoprim, trimethoprim-
were undertaken by Becky Skidmore, Medical Research Analyst, sulfamethoxazole, or a quinolone during a 6- to 12-month period
Society of Obstetricians and Gynaecologists of Canada. should be offered to women with ³ 2 urinary tract infections in
6 months or ³ 3 urinary tract infections in 12 months. (I-A)
6. Women with recurrent urinary tract infection associated with
sexual intercourse should be offered post-coital prophylaxis as
Key Words: Recurrent urinary tract infection, prophylaxis, an alternative to continuous therapy in order to minimize cost
treatment, antibiotic, prevention and side effects. (I-A)
This document reflects emerging clinical and scientific advances on the date issued and is subject to change. The information should
not be construed as dictating an exclusive course of treatment or procedure to be followed. Local institutions can dictate
amendments to these opinions. They should be well documented if modified at the local level. None of these contents may be
reproduced in any form without prior written permission of the SOGC.
Table 1. Key to evidence statements and grading of recommendations, using the ranking of the Canadian Task Force
on Preventive Health Care
I: Evidence obtained from at least one properly randomized A. There is good evidence to recommend the clinical preventive
controlled trial action
II-1: Evidence from well-designed controlled trials without B. There is fair evidence to recommend the clinical preventive
randomization action
II-2: Evidence from well–designed cohort (prospective or C. The existing evidence is conflicting and does not allow to
retrospective) or case–control studies, preferably from more make a recommendation for or against use of the clinical
than one centre or research group preventive action; however, other factors may influence
decision-making
II-3: Evidence obtained from comparisons between times or
places with or without the intervention. Dramatic results in D. There is fair evidence to recommend against the clinical
uncontrolled experiments (such as the results of treatment preventive action
with penicillin in the 1940s) could also be included in this E. There is good evidence to recommend against the clinical
category preventive action
III: Opinions of respected authorities, based on clinical L. There is insufficient evidence (in quantity or quality) to make
experience, descriptive studies, or reports of expert a recommendation; however, other factors may influence
committees decision-making
*The quality of evidence reported in these guidelines has been adapted from The Evaluation of Evidence criteria described in the Canadian Task Force on
Preventive Health Care.82
†Recommendations included in these guidelines have been adapted from the Classification of Recommendations criteria described in the The Canadian Task
Force on Preventive Health Care.82
PRESENTATION
Classic symptoms of acute lower UTI include dysuria, uri-
ABBREVIATIONS
nary frequency, and suprapubic pain plus or minus
E. coli Escherichia coli
hematuria. Differential diagnoses include vaginitis, acute
HPF high-power field
urethritis, interstitial cystitis, and pelvic inflammatory dis-
TMP-SMX trimethoprim-sulfamethoxazole
ease. Other organisms that may be involved and mimic
UTI urinary tract infection acute cystitis include Chlamydia, Neisseria gonorrhea, Candida,
factors, such as family history and obesity. Most women do and other countries.28 The prevalence of resistance to
not require extensive urologic investigations.8,22 However, nitrofurantoin among E. coli is < 5%, although non-E. coli
women who suffer infection with organisms that are not uropathogens are often resistant. Resistance to the
common causes of UTI, such as Proteus, Pseudomonas, fluoroquinolones remains < 5% in most studies of
Enterobacter, and Klebsiella may have structural abnormalities uropathogenic strains.
or renal calculi. They would benefit from imaging studies of Three-day regimens are recommended because they are
the upper urinary tract and cystoscopy.7 Women who have associated with better compliance, lower cost, and lower
persistent hematuria after resolution of their infection also frequency of adverse reactions than 7- to 10-day regimens.29
require a complete urologic workup.8 Several studies and clinical experience have confirmed the
Although empiric therapy based on symptoms is generally effectiveness of 3-day regimens of trimethoprim, trimethoprim-
accurate and cost-effective, women who are felt to be in the sulfamethoxazole, or a fluoroquinolone for treatment of
early stages of a problem with recurrent UTI should have acute uncomplicated cystitis, and these agents are generally
documented cultures.23 Urine culture not only serves as the recommended for empiric therapy.29 In comparison, 3-day
gold standard for diagnostic accuracy but also provides regimens with beta-lactams are less effective than ³ 5 days
specific information about the uropathogen and its antibi- of therapy.29 Nitrofurantoin is a safe and generally effective
otic susceptibilities.6 The standard definition of a UTI on agent, but it should be administered for a minimum of
culture is > 100 000 colony forming units per HPF. This 7 days. Single-dose regimens are somewhat less effective
value has excellent specificity but a sensitivity of only 50%.7 than 3- to 7-day regimens, even with fluoroquinolones.27,29
In women with symptoms of a UTI > 1000 colony forming First-line treatment suggested by the Infectious Disease
units per HPF is considered sufficient to document infec- Society of America in 1999 was TMP-SMX in a 3-day
tion without compromising specificity. The sensitivity to regimen.29 Given the increasing prevalence of TMP-SMX
detect infection is 80% and the specificity 90%.7 When a resistance among uropathogens, it is important to examine
“clean-catch” or midstream technique is used to obtain a risk factors predicting in vitro resistance. These are diabetes,
urine sample, the rates of contamination with vaginal flora recent hospitalization, antibiotic use in the past 3 to 6 months
are approximately 30%.24 The presence of > 20 epithelial (for any reason), and recent TMP-SMX use.30
cells per HPF on urinalysis suggests contamination by Fluoroquinolones (norfloxacin, ciprofloxacin, ofloxacin,
vaginal secretions.23 fleroxacin) are generally not recommended as first-line
Because bacteria reduce urinary nitrates to nitrites, the use treatment because of their greater expense and concerns
of urine dipstick analysis can be helpful. A positive result regarding the promotion of quinolone resistance. However,
usually indicates infection, with a specificity of 92% to fluoroquinolones can become a reasonable first-line treat-
100% and a sensitivity of 19% to 48%.25 A negative result ment for women who have or are suspected of having
does not rule out infection if the patient is symptomatic. antimicrobial resistance or of being allergic to or not tolerating
Some bacteria such as Staphylococcus saprophyticus lack the more conventional therapy, and for women in areas where
enzymes to reduce nitrates. If urine has not been present in resistance to TMP-SMX is > 15% to 20%.29 Other reason-
the bladder for at least 4 hours, there may not have been able empiric choices for mild cystitis include a 7-day course
sufficient time for the reaction to occur.25 of nitrofurantoin or a single-dose of fosfomycin.29 In 2007,
Gupta et al. demonstrated the equivalent efficacy of a 5-day
Leukocyte esterase is produced by neutrophils and indicates
course of nitrofurantoin and a 3-day course of TMP-SMX.31
pyuria, which is associated with UTI. Organisms other than
uropathogens can produce leukocyte esterase. Therefore, this Recurrent cystitis that occurs during or within the first week
is a sensitive (72% to 97%) but not specific (41% to 86%) following treatment suggests possible relapse and should be
test for UTI in women. Blood on dipstick can help to con- managed with a pre-treatment urine culture, antimicrobial
firm infection, but this can be associated with other clinical susceptibility testing, and treatment with a fluoroquinolone
circumstances and therefore is more sensitive (68% to 92%) for 7 days.8
than specific (42% to 46%) for UTI.25
PREVENTION OF RECURRENT
TREATMENT OF ACUTE URINARY TRACT INFECTIONS URINARY TRACT INFECTIONS
of urination, delayed voiding habits, douching, use of hot Table 2. Antimicrobial prophylaxis regimens for women
tubs, bubble baths, BMI, frequent use of pantyhose or with recurrent urinary tract infections
tights, use of tight clothing, type of clothing, bicycle riding,
Oral regimens
and the volume of fluid consumed.32,33 However, behavioural
approaches are unlikely to be harmful.34 Continuous prophylaxis
TMP-SMX 40/200 mg daily
Antimicrobial Strategy TMP-SMX 40/200 mg 3´/week
There are as many options for prevention and management TMP 100 mg daily
of recurrent UTI as there are studies on the issue Nitrofurantoin 50–100 mg daily
monohydrate/macrocrystals
(Table 2).8,10,33,35–39 A Cochrane review,35 of 19 trials (Macrobid)
including 1120 patients, showed that antibiotics are better Nitrofurantoin macrocrystal 50–100 mg daily
than placebo in reducing the number of clinical and (Macrodantin)
microbiological recurrences in pre- and postmenopausal Cephalexin 125–250 mg daily
women with recurrent UTI. Seven trials including 257 Cefaclor 250 mg daily
patients showed a relative risk of having a clinical UTI of Norfloxacin 200 mg daily
0.15 (95% CI 0.08 to 0.28) favouring antibiotic over pla- Ciprofloxacin 125 mg daily
cebo. The number needed to treat to prevent one symptom- Cinoxacin 250–500 mg daily
atic recurrent UTI was 2.2. Antibiotics in this review were Post-coital prophylaxis
fluoroquinolones (norfloxacin, ciprofloxacin, pefloxacin), (single dose)
cephalosporins (cephalexin, cefaclor), trimethoprim, TMP-SMX 40/200 mg
sulfamethoxazole, and nitrofurantoin. No antibiotic was TMP-SMX 80/400 mg
superior. Choice of antibiotic should rely on community Nitrofurantoin macrocrystal 50–100 mg
patterns of resistance, adverse events, and local costs. Three (Macrodantin)
main management strategies generally considered are con- Cephalexin 125–250 mg
tinuous antimicrobial prophylaxis, post-coital prophylaxis, Cinoxacin 250 mg
and patient-administered self-treatment.36 For patients with Ciprofloxacin 125 mg
£ 2 UTIs per year, the acute self-treatment may be useful. Norfloxacin 200 mg
such as TMP-SMX and norfloxacin decrease the rate of The mechanism of action is thought to be the reappearance
recovery of aerobic Gram-negative uropathogens such as of vaginal lactobacilli which, unlike placebo, decrease the
E. coli from the fecal reservoir.44 Nitrofurantoin in contrast, vaginal pH. This results from maturation and thickening of
decreases the recurrence rate by intermittently sterilizing the the vaginal epithelium with increased cellular glycogen, a
urine and possibly by inhibiting bacterial attachment.36,45,46 main substrate for lactobacilli.52,53 This process prevents
overgrowth and colonization of Enterobacteriaceae in the
Adverse Events
vagina.54 It can take at least 12 weeks for the vaginal ring to
In a 2004 Cochrane Review,35 the rates of adverse events be effective in reducing the occurrence of UTIs.53
were higher in the antibiotic group than in the placebo
Studies have provided insufficient evidence for recom-
group. The relative risk for severe side effects requiring
mending a particular type or form of vaginal estrogen.50,51
withdrawal of treatment was 1.58 (95% CI 0.47 to 5.28)
Creams are cheaper and possibly more efficient but could
and for mild side effects the relative risk was 1.78 (95% CI
be more difficult to apply for some women and can produce
1.06 to 3.00). The most frequently reported adverse events
some adverse effects (e.g., itching, burning, occasional
were nausea and vaginal and oral candidiasis. Nitrofuran-
spotting). Estradiol vaginal tablets may have fewer side
toin required the highest number of withdrawals, followed
effects but are more expensive. The vaginal ring is also
by cephalexin and weekly pefloxacin.35 Several adverse effects
more expensive and may require a trained professional to
have been described with the use of nitrofurantoin,
place it correctly.51
including aplastic anemia, polyneuritis, acute cholestatic
and hepatocellular reactions, and pulmonary toxicity.47 A recent Cochrane review51 did not show a significant
Chronic pulmonary toxicity is uncommon and may develop difference in the number of women with UTI at the end of
after 1 month to 6 years of therapy. Patients who are treatment period between oral estrogens and placebo. It
long-term users of nitrofurantoin should be checked seems that the route of administration may be more impor-
regularly for any complications. tant than the compound itself.50 The studies comparing
vaginal estrogens to antibiotics were inconclusive because
Most authorities advocate an antibiotic prophylaxis duration
of their heterogeneity.51,55,56
of 6 to 12 months, although in certain cases this has been
extended to 2 to 5 years.48 However, as no study has looked Cranberries
at prophylaxis for more than 1 year, no conclusion can be Cranberries (particularly in the form of cranberry juice)
made about the optimal duration. have been touted as an effective home remedy for the pre-
In the two studies that had a follow-up assessment at up vention and treatment of UTIs for several decades. So far,
to 6 months after the prophylaxis period,44,49 there was no definite mechanism of action has been established. The
no difference in the microbiological recurrences between main suggestion is that cranberries prevent bacteria
the antibiotic group and the placebo group. There were (particularly E. coli) from adhering to uroepithelial cells.57,58
no studies that assessed clinical recurrences after prophy- Without adhesion, the bacteria cannot infect the mucosal
laxis. However, it appears that most women revert to the surface of the urinary tract.
previous pattern of recurrent infections once prophylaxis A recent Cochrane review59 of 10 studies with a total of
is stopped. 1049 subjects showed some evidence that cranberry juice
Estrogen Use in Postmenopausal Women and derivatives may decrease the number of symptomatic
UTIs over a period of 12 months, particularly for women
Evidence from two small RCTs shows that in with recurrent UTIs. A meta-analysis of the results of
postmenopausal women with recurrent UTI, vaginal 4 RCTs found that cranberry products significantly reduced
estrogens reduce the number of UTIs.50,51 Raz and Stamm the incidence of UTIs (RR 0.66; 95% CI 0.47 to 0.92)
reported a significant reduction in UTI among compared with placebo or control.60–63 Further, there is no
postmenopausal women using 0.5 mg of estriol cream clear evidence of the amount and concentration that must
vaginally every night for 2-weeks and then twice a week be consumed and over what period for the intervention to
for 8-months compared with those using a placebo (0.5 vs. be most effective. No published trials have been
5.9 episodes per patient-year, P < 0.001).52 Eriksen has undertaken that compare cranberry with established
shown a similar beneficial prophylactic effect with the use interventions (e.g., antibacterials) for preventing UTIs.59
of an estradiol-releasing vaginal ring (Estring, Pharmacia &
Upjohn) compared with a placebo vaginal ring.53 After Other Potential Strategies
36 weeks of the study, the cumulative likelihood of remaining Antibiotics are usually effective in treating acute infections
free of UTI was 45% in the Estring group compared with and are the primary means of prophylaxis for recurrent UTI
approximately 20% in the placebo group (P < 0.008).53 patients; however, their value is being lessened by the
emergence of increasing numbers of drug-resistant bacte- be effective, and agents of choice are nitrofurantoin (50 mg)
ria. Consequently, it is important that alternative prevention and cephalexin (250 mg).34,36,80,81
strategies be developed.
Recommendations
Acupuncture
Recommendations were made according to the guidelines
Two small RCTs evaluated the role of acupuncture developed by the Canadian Task Force on Preventive
compared with sham acupuncture or no treatment in the Health Care (Table 1).
prophylaxis of recurrent UTIs.64,65 During a 6-month
period, both studies demonstrated that acupuncture could 1. Urinalysis and midstream urine culture and sensitivity
play a significant role in preventing recurrent UTIs. should be performed with the first presentation of
Authors concluded that it seems a worthwhile alternative to symptoms in order to establish a correct diagnosis of
antibiotic strategy. recurrent urinary tract infection. (III-L)
12. Pregnant women at risk of recurrent urinary tract infec- 21. Minardi D, Parri G, d’Anzeo G, Fabiani A, El Asmar Z, Muzzonigro G.
tion should be offered continuous or post-coital prophy- Perineal ultrasound evaluation of dysfunctional voiding in women with
recurrent urinary tract infections. J Urol 2008;179:947–51.
laxis with nitrofurantoin or cephalexin, except during the
22. Car J, Sheikh A. Recurrent urinary tract infection in women. BMJ
last 4 weeks of pregnancy. (II-1B) 2003:327:1204.
23. Car J. Urinary tract infections in women: diagnosis and management in
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51. Perrotta C, Aznar M, Mejia R, Albert X, Ng CW. Oestrogens for preventing Scand J Prim Health Care 1994;12:239–43.
recurrent urinary tract infection in postmenopausal women. Cochrane 70. Falagas ME, Betsi GI, Tokas T, Athanasiou S. Probiotics for prevention
Database Syst Rev 2008;(2):CD005131. of recurrent urinary tract infections in women. Drugs 2006;66:1253–61.
52. Raz R, Stamm WE. A controlled trial of intravaginal estriol in postmenopausal
71. Grischke EM, Rüttgers H. Treatment of bacterial infections of the female
women with recurrent urinary tract infections. New Engl J Med 1993;329:753–6.
urinary tract by immunization of the patiets. Urol Int 1987;42:338–41.
53. Eriksen BC. A randomized, open, parallel-group study on the preventive
effect of an estradiol-releasing vaginal ring (Estring) on recurrent urinary 72. Uehling DT, Hopkins WJ, Beierle LM, Kryger JV, Heisey DM. Vaginal
tract infections in postmenopausal women. Am J Obstet Gynecol mucosal immunization for recurrent urinary tract infection: extended phase II
1999;180:1072–9. clinical trial. J Infect Dis 2001;183 (Suppl 1): S81–3.
54. Raz R. Hormone replacement therapy or prophylaxis in postmenopausal 73. Hopkins WJ, Uehling DT. Vaccine development for the prevention
women with recurrent urinary tract infection. J Infect Dis of urinary tract infections. Curr Infect Dis Rep 2002;4:509–13.
2001;183(Suppl 1):S74–6.
74. Sundén F, Håkansson L, Ljunggren E, Wullt B. Bacterial interference—is
55. Raz R, Colodner R, Rohana Y, Battino S, Rottensterich E, Wasser I, et al. deliberate colonization with Escherichia coli 83972 an alternative treatment
Effectiveness of estriol-containing vaginal pessaries and nitrofurantoin for patients with recurrent urinary tract infection? Int J Antimicrob Agents
macrocrystal therapy in the prevention of recurrent urinary tract infection 2006;28(Suppl 1):S26–9.
in postmenopausal women. Clin Infect Dis 2003;36:1362–8.
75. Lipovac M, Kurz C, Reithmayr F, Verhoeven HC, Huber JC, Imhof M.
56. Xu R, Wu Y, Hu Y. Prevention and treatment of recurrent urinary system Prevention of recurrent bacterial urinary tract infections by intravesical
infection with estrogen cream in postmenopausal women. Zhonghua Fu instillation of hyaluronic acid. Int J Gynaecol Obstet 2007;96:192–5.
Chan Ke Za Zhi 2001;36:531–3.
76. Constantinides C, Manousakas T, Nikolopoulos P, Stanitsas A, Haritopoulos
57. Schmidt DR, Sobota AE. An examination of the antiadherence activity
K, Giannopoulos A. Prevention of recurrent bacterial cystitis by intravesical
of cranberry juice on urinary and non-urinary bacterial isolates. Microbios
administration of hyaluronic acid: a pilot study. BJU Int 2004;93:1262–6.
1988;55:173–81.
58. Zafriri D, Ofek I, Adar R, Pocino M, Sharon N. Inhibitory activity of 77. Eden CS, Fretr R, Hagberg L, Hull R, Hull S, Leffler H, et al. Inhibition of
craberry juice on adherence of type 1 and type P fimbriated Escherichia coli experimental ascending urinary tract infection by an epithelial cell-surface
to eucaryotic cells. Antimicrob Agents Chemother 1989;33:92–8. receptor analogue. Nature 1982;298(5874):560–2.
59. Jepson JP, Craig JC. Cranberries for preventing urinary tract infections. 78. Zopf D, Roth S. Oligosaccharides anti-infectives agents. Lancet
Cochrane Database Syst Rev 2008;(1):CD 001321. 1996;347(9007):1017–21.
60. Kontiokari T, Sundqvist K, Nuutinen M, Pokka T, Koskela M, Uhari M. 79. Romero R, Oyarzun E, Mazor M, Sirtori M, Hobbins JC, Bracken M.
Randomised trial of cranberry-lingonberry juice and Lactobacillus GG drink Meta-analysis of the relationship between asymptomatic bacteriuria and
for the prevention of urinary tract infections in women. BMJ preterm delivery/low birth weight. Obstet Gynecol 1989;73:576–82.
2001;322(7302):1571–3.
80. Pfau A, Sacks TG. Effective prophylaxis for recurrent urinary tract infections
61. McMurdo ME, Bissett LY, Price RJ, Phillips G, Crombie IK. Does during pregnancy. Clin Infect Dis 1992;14:810–4.
ingestion of cranberry juice reduce symptomatic urinary tract infections
in older people in hospital? A double-blind, placebo-controlled trial. 81. Ovalle A, Levancini M. Urinary tract infections in pregnancy.
Age Ageing 2005;34:256–61. Curr Opin Urol 2001:11:55–9.
62. Stothers L. A randomized trial to evaluate effectiveness and cost effectiveness 82. Woolf SH, Battista RN, Angerson GM, Logan AG, Eel W. Canadian Task
of naturopathic cranberry products as prophylaxis against urinary tract Force on Preventive Health Care. New grades for recommendations from
infection in women. Can J Urol 2002;9:1558–62. the Canadian Task Force on Preventive Health Care. CMAJ 2003;169:207–8.
This document reflects emerging clinical and scientific advances on the date issued, and is subject to change. The information
should not be construed as dictating an exclusive course of treatment or procedure to be followed. Local institutions can dictate
amendments to these opinions. They should be well documented if modified at the local level. None of these contents may be
reproduced in any form without prior written permission of the SOGC.
Key to evidence statements and grading of recommendations, using the ranking of the Canadian Task Force
on Preventive Health Care
I: Evidence obtained from at least one properly randomized A. There is good evidence to recommend the clinical preventive
controlled trial action
II-1: Evidence from well-designed controlled trials without B. There is fair evidence to recommend the clinical preventive
randomization action
II-2: Evidence from well–designed cohort (prospective or C. The existing evidence is conflicting and does not allow to
retrospective) or case–control studies, preferably from more make a recommendation for or against use of the clinical
than one centre or research group preventive action; however, other factors may influence
decision-making
II-3: Evidence obtained from comparisons between times or
places with or without the intervention. Dramatic results in D. There is fair evidence to recommend against the clinical
uncontrolled experiments (such as the results of treatment preventive action
with penicillin in the 1940s) could also be included in this E. There is good evidence to recommend against the clinical
category preventive action
III: Opinions of respected authorities, based on clinical L. There is insufficient evidence (in quantity or quality) to make
experience, descriptive studies, or reports of expert a recommendation; however, other factors may influence
committees decision-making
*The quality of evidence reported in these guidelines has been adapted from The Evaluation of Evidence criteria described in the Canadian Task Force on
Preventive Health Care.20
†Recommendations included in these guidelines have been adapted from the Classification of Recommendations criteria described in the The Canadian Task
Force on Preventive Health Care.20
to relax the urethral sphincter, timed toileting, and double voiding. 3. An intraoperative or postoperative complication of
Intermittent self-catheterization may also be used. (III-C)
surgery (e.g., fistula).
9. Complete inability to void with or without overflow incontinence
may be managed by intermittent self-catheterization or 4. Surgery was inappropriate therapy or an inappropriate
urethrolysis. (III-C)
procedure used.
10. Fistulae should be managed by an experienced physician. (III-C)
5. Pre-existing or de novo overactive bladder causing
J Obstet Gynaecol Can 2010;32(9):893–898
urgency incontinence.
INTRODUCTION 6. Urinary tract infection causing urgency incontinence.
areful investigation and patient selection before 7. Voiding dysfunction causing urgency/frequency or
C primary pelvic surgery for prolapse and/or urinary overflow incontinence.
incontinence will minimize the incidence of immediate or Long-term Progressive Causes of Urinary
delayed failure.1 Conservative (i.e., non-surgical) or surgical Incontinence
intervention may be required when prior surgery has failed, 1. Deficiency of pelvic floor support either through
although non-surgical options should first be considered.2 genetic predisposition or other medical condition.
Patients who complain of either de novo or recurrent
urinary incontinence following reconstructive pelvic floor 2. Predisposing medical conditions (e.g., chronic
or incontinence surgery must undergo a thorough evalua- obstructive pulmonary disease, obesity, chronic
constipation).
tion to identify the cause of this incontinence. The causes of
incontinence for most of these patients will fall into one 3. Urogenital aging and estrogen deficiency.
of the following categories.
ASSESSMENT
Early Causes of Urinary Incontinence
Although some recurrent urinary incontinence may fit into
1. Surgical correction of stress incontinence either the category outlined in the 2003 SOGC guideline, “The
unsuccessful or not sustained. Evaluation of Stress Incontinence Prior to Primary
2. Latent (occult) stress incontinence not recognized Surgery,”1 specialized evaluation, including urodynamics,
preoperatively in a patient with pelvic organ prolapse. will permit accurate diagnosis and measurement of
urodynamic variables that may significantly affect the The majority of surgical procedures used to treat stress
management plan. Should a patient meet all the criteria on incontinence are designed to restore normal anatomic rela-
the following list, then assessment may proceed as suggested tionships and re-establish extrinsic urethral support.
in the guideline1 without multichannel urodynamics. Although the exact mechanism responsible for the restora-
• No more than one prior surgery for incontinence tion of continence that results from successful surgery is
• Symptoms of pure stress urinary incontinence uncertain3; the only consistent postoperative urodynamic
• No symptoms of overactive bladder finding is enhanced pressure transmission to the urethra.
This urodynamic change is probably a consequence of
• No symptoms of voiding dysfunction such as urinary
better transmission of intra-abdominal pressure to the
hesitancy, slow or interrupted stream, straining to void,
newly supported urethra. It is also speculated that support
or incomplete bladder emptying
of the mid-urethra results in some degree of kinking of the
• Hypermobile urethra urethra when the proximal urethra and bladder descend
• Post-void residual urine volume < 100 mL during increased intra-abdominal pressure.4 Using this
• Normal urinalysis model, it is evident that in order for surgery to correct stress
If any of the above requirements are not met, then a more incontinence, it must stabilize the urethra at an appropriate
thorough evaluation is required, using multichannel anatomic level to allow pressure transmission to the
urodynamics, and referral to a subspecialist may be indicated. urethra. If this stability is not established at the time of the
In all cases, the assessment must be designed to identify one operation or if it cannot be maintained over time, the
or a combination of the following predisposing conditions. surgery may fail.
1. Compromise to the urethral sphincter mechanism
Repeated surgery may cause significant trauma to the urethra
2. Detrusor overactivity (overactive bladder) resulting in a poorly vascularized, scarred, rigid “drainpipe
3. Voiding dysfunction urethra” that has no sphincteric function (intrinsic
sphincter deficiency).5 In this condition, the urethra is a
4. Urogenital fistula poorly coapted conduit through which urine may leak with
5. Persistent or de novo pelvic prolapse minimal increases in intra-abdominal pressure or on a
nearly continuous basis. Urethroscopy will reveal a smooth
Recommendation
rigid tube which does not coapt. The urethrovesical junction is
1. Thorough evaluation of each patient should be per- open and can be visualized from any point along the
formed to determine the underlying etiology of recurrent urethra. Videocystourethrography will confirm a urethra
urinary incontinence and to guide management. (II-3B) which is immobile and open. Intrinsic sphincter deficiency
Investigation of Urethral Sphincter Function (ISD) may result after prior retropubic urethropexy
(e.g., Burch procedure) or needle suspension (e.g., Pereyra
Extrinsic support of the urethra is critical to continence, and procedure), or less frequently after prior anterior
it is provided laterally by connective tissue attachment to colporrhaphy.6 The likelihood of ISD increases as the
the pelvic side walls and posteriorly by the levator ani mus- number of prior surgeries increases.6
cles. Urethral mobility should be assessed to evaluate
extrinsic support. However, continence is maintained only Urethrovesical junction mobility can be assessed by Q-tip
if extrinsic support is complemented by normal intrinsic ure- test,7 inspection and palpation of the distal anterior vaginal
thral function, which consists of the following: wall during Valsalva manoeuvre, ultrasound examination,
1. Healthy urethral mucosa videocystourethrography, and urethroscopy. If recurrent
hypermobility is found, it may be assumed that surgery has
2. A normal vascular plexus failed either to establish or to maintain urethral support. If
3. Normal smooth muscle sphincter function the urethra is maintained in an elevated retropubic position,
then it can be assumed that the goal of surgery has been
4. Normal external striated sphincter function achieved and that failure is the result of ISD. A patient with
Such factors as lack of estrogen, aging tissues, ISD will require subspecialized evaluation and manage-
devascularization, denervation, or disruption of muscular ment, including multichannel urodynamics. Urodynamic
sphincters can result in marked impairment of intrinsic ure- variables consistent with ISD include a maximum urethral
thral sphincter function. These problems may also arise closure pressure less than 20 cm of water or a leak point
from prior trauma, surgery, or pelvic radiation. Some pressure less than 60 cm of water.6 The choice of any subse-
patients may have a combination of recurrent quent surgical procedure will be determined by the degree
hypermobility and deficiency of intrinsic urethral function. of urethral fixation by scar, the patient’s medical condition,
and the degree to which detrusor and urethral function has retropubic sling procedure, use of an artificial sphincter,
been compromised by denervation caused by previous urinary diversion, or chronic catheterization. (III-C)
surgical procedures.8
OVERACTIVE BLADDER
MANAGEMENT OF RECURRENT STRESS INCONTINENCE
Overactive bladder, a symptom complex consisting of
Any decision to proceed with a specific treatment must urgency, frequency, nocturia, and urgency incontinence, is
include an assessment of the severity of the patient’s caused by a failure of bladder inhibition and, if unrecog-
symptoms, and a trial of conservative management must nized prior to surgery, may cause persistent incontinence
be considered (as described in the SOGC guideline following surgery. De novo overactive bladder may develop
“Conservative Management of Urinary Incontinence”).2 following surgery for stress incontinence,13 particularly if
Conventional retropubic urethropexy (Burch procedure)9 extensive vaginal dissection has been performed or as a sec-
has a higher rate of failure in cases of suspected ISD where ondary result after outlet obstruction. Patients will usually
maximum urethral closure pressure is less than 20 cm of present with urinary urgency, frequency, nocturia, with or
water. Tension-free vaginal tape has shown success rates of without urge incontinence. Cystoscopy may identify blad-
74% to 82% when performed as a repeat procedure, der pathology responsible for the urinary symptoms, such
depending on the degree of ISD present.8 Some data indi- as suture or mesh penetrating the bladder or urethra.
cate that transobturator tape may not be as effective as Although a simple cystometrogram will identify most cases
tension-free vaginal tape in cases where there is an element of overactive bladder, multichannel subtracted cystometry
of ISD,10 particularly if the maximum urethral closure is indicated if the diagnosis is uncertain.
pressure is less than 40 cm of water,11 with success rates of
The management of overactive bladder is medical or behav-
only approximately 50%. Patients with significant ISD,
ioural. Medical therapy typically uses anticholinergic/
such as a fixed drainpipe urethra, may also have persistent
antimuscarinic medications.14 Behavioural therapy includes
incontinence even if undergoing a urethral sling as the
prompted voiding, bladder training, caffeine reduction, or
repeat surgical technique. Referral to a subspecialist for a
biofeedback, with or without electrostimulation.2 In some
retropubic sling procedure with or without lysis of bladder
instances, overactive bladder is a result of outlet obstruc-
neck and paraurethral scar may provide continence under
tion, (discussed in the next section), and urethrolysis may
these circumstances. The risk of failure and urinary reten-
provide improvement.15
tion may be increased. Periurethral bulking agents may also
be injected.12 Consideration may be given to other Some patients may have mixed urinary incontinence.
“end-stage” options, such as placement of an artificial Although surgery is not contraindicated in cases of mixed
sphincter, urinary diversion, or chronic catheterization. urinary incontinence,16 conservative management options
Patients with recurrent stress incontinence who opt for for both the stress and urgency incontinence should be
surgical treatment should be managed according to the used, and benefits maximized before further surgery is
following recommendations. undertaken.
Recommendations Recommendation
2. Conservative management options should be used as the 7. Overactive bladder should be treated using medical
first line of therapy. (III-C) and/or behavioural therapy. (II-2B)
3. Patients with a hypermobile urethra, without evidence of
VOIDING DYSFUNCTION
intrinsic sphincter deficiency, may be managed with a
retropubic urethropexy (e.g., Burch procedure) or a sling Voiding dysfunction as a consequence of pelvic surgery
procedure (e.g., mid-urethral sling, pubovaginal sling). may develop for several reasons. In general, voiding dys-
(II-2B) function is due to either urethral obstruction or detrusor
4. Patients with evidence of intrinsic sphincter deficiency underactivity. A patient with subclinical preoperative dys-
may be managed with a sling procedure (e.g., mid-ure- functional voiding may not be able to empty her bladder
thral sling, pubovaginal sling). (II-3B) after surgical stabilization of the urethrovesical junction.17
Excessive elevation of the urethra in patients with a normal
5. In cases of surgical treatment of intrinsic sphincter defi- preoperative voiding mechanism may partially obstruct uri-
ciency, retropubic tension-free vaginal tape should be nary outflow, causing voiding dysfunction. Mild degrees of
considered rather than transobturator tape. (I-B) incomplete emptying will appear as urinary frequency, hesi-
6. Patients with significantly decreased urethral mobility tancy, and nocturia. More severe voiding compromise is
may be managed with periurethral bulking injections, a manifested in urinary retention, bladder distension and
overflow incontinence, recurrent urinary tract infections, tomography with intravenous contrast (CT urogram) is
and possible upper tract decompensation. Simple indicated to identify possible upper tract damage.
uroflowmetry including measurement of peak flow rate and Urogenital fistula is a surgical problem that must be cor-
post-void residual volume is sufficient to screen for voiding rected.19 The choice of procedure will depend on the sever-
dysfunction.1 Post-void residual levels can be measured by ity and location of the fistula. Fistula and stress inconti-
catheterization, ultrasound examination, or contrast radiog- nence can co-exist. If surgery is undertaken, it should cor-
raphy. An intermittent voiding pattern on uroflowmetry, a rect all incontinence and pelvic floor prolapse disorders,
decreased peak flow rate (< 15 mL/second), or a high either concomitantly or in stages, depending on individual
post-void residual volume (> 150 mL) should prompt more circumstances.
sophisticated voiding studies, which may include voiding
cystometry (simultaneous measurement of intravesical and Recommendations
abdominal pressures during voiding), urine flow rate, 10. Fistulae should be managed by an experienced physi-
electromyogram, and urethral sphincter activity.15 cian. (III-C)
Treatment should be individualized, and options include REFERENCES
timed toileting, double voiding, intermittent 1. Farrell SA, Epp A, Flood C, Lojoie F, MacMillan B, Mainprize T, Robert M.
catheterization, or urethrolysis. There are limited data on The evaluation of stress incontinence prior to primary surgery. SOGC
the use of urethral relaxants (e.g., benzodiazepines, lioresal, Guideline No. 127, Apr. 2003. J Obstet Gynaecol Can 2003;25:313–8.
alpha-blockers). Detrusor stimulation using bethanecol is 2. Robert M, Ross S, Farrell SA, Easton WA, Epp A, Girouard L, et al.
Conservative management of urinary incontinence. SOGC Clinical Practice
typically ineffective.18 Occasionally, voiding may be Guideline No. 186, December 2006. J Obstet Gynaecol Can
improved by use of a pessary or surgery to correct a high 2006;28:1113–25.
cystocoele if present. If detrusor hypotonia is the cause, 3. Nager CW, Schulz JA, Stanton SL, Monga A. Correlation of urethral
closure pressure, leak-point pressure and incontinence severity measures.
then sacral nerve stimulation can be used. Additional Int Urogynecol J Pelvic Floor Dysfunct 2001;12:395–400.
anti-incontinence operations for stress incontinence should 4. Lo TS, Wang AC, Horng SG, Liang CC, Soong YK. Ultrasonographic and
be planned cautiously in patients with marked postopera- urodynamic evaluation after tension free vagina tape procedure (TVT).
tive voiding dysfunction.15 Acta Obstet Gynecol Scand 2001;80:65–70.
5. GM Ghoniem, AN Elgamasy, R Elsergany, DS Kapoor. Grades of intrinsic
Recommendations sphincteric deficiency (ISD) associated with female stress urinary incontinence.
Int Urogynecol J Pelvic Floor Dysfunct 2002;13:99–05.
8. Urinary frequency with moderate elevation of post-void 6. McGuire EJ, Fitzpatrick CC, Wan J, Bloom D, Sanvordenker J, Ritchey M.
residual volume may be managed with conservative mea- Clinical assessment of urethral sphincter function. J Urol 1993;150:1452–4.
sures such as drugs to relax the urethral sphincter, timed 7. Karram MM, Bhatia NW. The Q-tip test: standardization of the technique
and its interpretation in women with urinary incontinence. Obstet Gynecol
toileting, and double voiding. Intermittent 1988;71:807–11.
self-catheterization may also be used. (III-C) 8. Rezapour M, Falconer C, Ulmsten U. Tension-free vaginal tape (TVT)
in stress incontinent women with intrinsic sphincter deficiency (ISD)—
9. Complete inability to void with or without overflow a long-term follow-up. Int Urogynecol J Pelvic Floor Dysfunct 2001;
incontinence may be managed by intermittent Suppl 2:S12–14.
self-catheterization or urethrolysis. (III-C) 9. Sand PK, Bowen LW, Panganiban R, Ostergard DR. The low pressure
urethra as a factor in failed retropubic urethropexy. Obstet Gynecol
1987;69:399–402.
UROGENITAL FISTULA
10. Schierlitz L, Dwyer PL, Rosamilia A. Effectiveness of tension-free vaginal
Urogenital fistula following incontinence surgery is a rare tape compared with transobturator tape in women with stress urinary
incontinence and intrinsic sphincter deficiency. Obstet Gynecol
complication. A fistula may exist between the vagina and 2008;112:1253–61.
the urethra, the bladder, the ureter, or a combination of 11. Guerette NL, Bena JF, Davila GW. Transobturator slings for stress
these organs. Methylene blue solution may be instilled into incontinence: using urodynamic parameters to predict outcomes.
the bladder followed by speculum examination or place- Int Urogynecol J Pelvic Floor Dysfunct 2008;19:97–102.
ment of tampons in the vagina. Direct visualization of dye 12. Herschorn S. Current status of injectable agents for female stress urinary
or staining of the tampon will confirm the presence of a incontinence. Can J Urol 2001;8:1281–9.
vesicovaginal fistula. Cystourethroscopy should permit the 13. Bombieri L, Freeman RM, Perkins EP, Williams MP. Why do women have
voiding dysfunction and de novo detrusor instability after colposuspension?
identification of a fistula in either the urethra or the bladder,
BJOG 2002;109:402–12.
as well as assessment of the precise size, location, and num-
14. JG Ouslander. Management of overactive bladder. N Engl J Med
ber of fistulae. Injection of intravenous indigo carmine fol- 2004;350:786–99.
lowed by speculum examination or the tampon test may
15. Carr L, Webster G. Voiding dysfunction following incontinence surgery:
identify a ureterovaginal fistula if a vesicovaginal fistula has diagnosis and treatment with retropubic or vaginal urethrolysis.
been ruled out. Intravenous pyelography or computed J Urol 1997;157:821–3.
16. Rezapour M, Falconer C, Ulmsten U. Tension-free vaginal tape (TVT) management protocols and the effect of bethanecol.
in women with mixed urinary incontinence—a long-term follow-up. Int Urogynecol J Pelvic Floor Dysfunct 1990;1:132–5.
Int Urogynecol J Pelvic Floor Dysfunct 2001;Suppl 2:S15–18.
19. Miller EA, Webster GD. Current management of vesicovaginal fistulae.
17. Minassian VA, Al-Badr A, Drutz HP, Lovatsis D. Tension-free vaginal
Curr Opin Urol 2001;11:417–21.
tape, Burch, and slings: are there predictors for early postoperative voiding
dysfunction? Int Urogynecol J Pelvic Floor Dysfunct 2004;15:183–7.
20. Woolf SH, Battista RN, Angerson GM, Logan AG, Eel W. Canadian Task
18. Farrell SA, Webster RD, Higgins LM, Steeves RA. Duration of postoperative Force on Preventive Health Care. New grades for recommendations from
catheterization: a randomized, double-blind trial comparing two catheter the Canadian Task Force on Preventive Health Care. CMAJ 2003;169:207–8.
Supracervical Hysterectomy
Evidence: The Cochrane Library, Medline, and Embase were
This guideline has been reviewed by the Clinical Practice searched for articles published in English from January 1950 to
Gynaecology Committee and approved by the Executive and March 2008 specifically comparing VH and SCH with TAH in the
Council of the Society of Obstetricians and Gynaecologists of prevention of sexual dysfunction, urinary dysfunction, and peri-
Canada. and postoperative complications. Results were restricted to
systematic reviews, randomized control trials/controlled clinical
PRINCIPAL AUTHORS trials, and observational studies. Additional publications were
Sari Kives MD, Toronto ON identified from the bibliographies of these articles. Randomized
controlled trials were considered evidence of the highest quality,
Guylaine Lefebvre MD, Toronto ON
followed by cohort studies.
CLINICAL GYNAECOLOGY COMMITTEE
Grey (unpublished) literature was identified through searching the
Wendy Wolfman (Co-Chair), MD, Toronto ON websites of health technology assessment and health technology
Nicholas Leyland (Co-Chair), MD, Toronto ON assessment-related agencies, clinical practice guideline
collections, clinical trial registries, and national and international
Catherine Allaire, MD, Vancouver BC medical specialty societies.
Alaa Awadalla, MD, Winnipeg MB Values: The quality of evidence was rated using the criteria
Carolyn Best, MD, Hamilton ON described in the Report of the Canadian Task Force on Preventive
Health Care (Table).
Nathalie Leroux, MD, Montreal QC
Recommendations
Frank Potestio, MD, Thunder Bay ON
1. Vaginal hysterectomy is generally considered the first choice of
David Rittenberg, MD, Halifax NS surgical approach for most benign indications for hysterectomy, as
Renée Soucy, MD, Chandler QC it is associated with lower rates of morbidity, fewer postoperative
complications, and a faster recovery time than abdominal
Sukhbir Singh, MD, Ottawa ON
hysterectomy. (I-A)
Disclosure statements have been received from all members of
2. Women contemplating a vaginal, laparoscopic, or abdominal
the committee.
hysterectomy for the management of benign uterine disease
should be reassured that hysterectomy is usually associated with
improved quality of life, including improved sexual function,
Abstract whether or not the cervix is removed. (I-B)
Objective: This guideline reviews the evidence relating to the 3. Supracervical hysterectomy should not be recommended as a
potential benefits of the vaginal hysterectomy (VH) and superior technique to total abdominal hysterectomy for the
supracervical hysterectomy (SCH) versus total abdominal prevention of postoperative lower urinary tract symptoms. (I-B)
hysterectomy (TAH) with respect to postoperative sexual function,
urinary function, and peri- and postoperative complications. 4. Although supracervical hysterectomy may be associated with less
Laparoscopic options are not included in this guideline. blood loss and a shorter surgical time, these parameters have not
been found to be clinically significant, and supracervical
Options: Women considering hysterectomy for benign disease can hysterectomy should not be recommended as a superior
be given the option of retaining the cervix or proceeding with a technique to total abdominal hysterectomy for the prevention of
total hysterectomy. peri- and postoperative complications. (I-B)
Outcomes: The outcomes measured are postoperative sexual 5. Women considering a supracervical hysterectomy should be
function and urinary function, and peri- and postoperative counselled that they may continue experiencing cyclic vaginal
complications. bleeding following the surgery. (I-B)
6. Women must be advised that they require routine cytological
screening following a supracervical hysterectomy. (II-B)
7. Women who require a hysterectomy and who have a current or
significant history of abnormal cervical cytological results should
be counselled on the advantages of vaginal hysterectomy or total
abdominal hysterectomy over supracervical hysterectomy. (I-B)
Key Words: Hysterectomy, vaginal, supracervical, perioperative J Obstet Gynaecol Can 2010;32(1):62–68
complications, postoperative complications
This document reflects emerging clinical and scientific advances on the date issued and is subject to change. The information
should not be construed as dictating an exclusive course of treatment or procedure to be followed. Local institutions can dictate
amendments to these opinions. They should be well documented if modified at the local level. None of these contents may be
reproduced in any form without prior written permission of the SOGC.
Key to evidence statements and grading of recommendations, using the ranking of the
Canadian Task Force on Preventive Health Care
I: Evidence obtained from at least one properly randomized A. There is good evidence to recommend the clinical preventive
controlled trial action
II-1: Evidence from well-designed controlled trials without B. There is fair evidence to recommend the clinical preventive
randomization action
II-2: Evidence from well-designed cohort (prospective or C. The existing evidence is conflicting and does not allow to
retrospective) or case-control studies, preferably from more make a recommendation for or against use of the clinical
than one centre or research group preventive action; however, other factors may influence
decision-making
II-3: Evidence obtained from comparisons between times or
places with or without the intervention. Dramatic results in D. There is fair evidence to recommend against the clinical
uncontrolled experiments (such as the results of treatment preventive action
with penicillin in the 1940s) could also be included in this E. There is good evidence to recommend against the clinical
category preventive action
III: Opinions of respected authorities, based on clinical L. There is insufficient evidence (in quantity or quality) to make
experience, descriptive studies, or reports of expert a recommendation; however, other factors may influence
committees decision-making
*The quality of evidence reported in these guidelines has been adapted from The Evaluation of Evidence criteria described in the Canadian Task Force
on Preventive Health Care.26
†Recommendations included in these guidelines have been adapted from the Classification of Recommendations criteria described in the The Canadian
Task Force on Preventive Health Care.26
States, the number of SCHs appears to be increasing simul- study was significantly longer than the other 3 trials, and its
taneously with a decrease in TAH.9 With the advent of min- findings suggest that these results persist beyond 1 year.
imally invasive surgical options, the laparoscopic SCH may
The study by Thakar et al.11 of 279 women (146 TAH and
be favoured over a total laparoscopic hysterectomy because
133 SCH) was the only double-blind RCT. Each woman
it is perceived to be technically easier laparoscopically to
was followed for 1 year. A short-form, previously validated
leave the cervix behind. The superiority of SCH over TAH
36-question health survey (SF-36) and psychological out-
still remains largely theoretical and is not supported by a
come measure (GHQ: general health questionnaire) were
review of evidence.
used preoperatively and at 6 and 12 months postoperatively
(0–100 scale). No statistical difference was found between
RATIONALE FOR GUIDELINE DEVELOPMENT
TAH and SCH on the SF-36 and GHQ before and after
This guideline provides a consolidation of a systematic surgery. The frequency of intercourse, desire for inter-
review of the evidence supporting or opposing the use of course, orgasm, and initiation of intercourse did not differ
SCH rather than TAH, and the consensus on whether or significantly between the groups. In addition, most aspects
not SCH offers our patients an advantage in the prevention of quality of life improved in both randomization groups.
of sexual dysfunction, urinary dysfunction, and peri- and All aspects of mental health improved following hysterec-
postoperative complications. tomy. There was also a significant increase in the frequency
of intercourse in both groups after surgery (P = 0.01). Deep
SEXUAL FUNCTION AND QUALITY OF LIFE
dyspareunia was reduced significantly in both groups
(46.2% to 6.6% SCH and 39.3% to 14.3% TAH) at
Four RCTs were identified that specifically address sexual 12 months (P < 0.001), but there was no statistical differ-
function and/or quality of life after total versus ence between groups.
supracervical hysterectomy.10–13 All 4 trials used objective, Zobbe et al.13 conducted a randomized trial of 319 women
previously validated questionnaires to assess sexual func- (158 TAH and 161 SCH). Each woman was followed for 1
tion and/or quality of life,10,11 psychological well-being,11,12 year. At the 12-month follow-up, there was no statistical
and pain.12 These 4 trials included only women undergoing difference between the 2 intervention groups regarding fre-
a hysterectomy for benign indications. Exclusion criteria quency of sexual desire, intercourse, masturbation, and
varied, but postmenopausal women were excluded in 3 of orgasm, as well as quality of orgasm, vaginal lubrication, or
the 4 trials.10–12 Oophorectomy was the only concomitant satisfaction with sexual life (P > 0.05). Dyspareunia
procedure permitted in all 4 trials. Thakar et al.11 also decreased significantly in both groups (89 women pre sur-
excluded women with comorbidities, including a body gery and 22 post surgery P = 0.009). A multivariate logistic
weight > 100 kg, previous pelvic surgery, and known regression analysis identified preoperative satisfaction with
endometriosis. Follow-up varied, ranging from a minimum sexual life, good relationship with partner, chronic disease,
of 7 months to a maximum of 24 months after surgery. One and use of hormone therapy as significant predictors of
study also tested subjects 2 to 3 weeks prior to surgery.12 All postoperative satisfaction with sexual life.
trials stated the method of randomization and included an
intention-to-treat analysis. Adequate follow-up of > 80% Flory et al.12 conducted a randomized trial of 63 women
was obtained in all 4 trials. All 4 trials were graded as good (32 LAVH and 31 LSCH). Each woman was followed for
because either the outcome was blinded,11 or the outcome 7 months. Two control groups of women who did not
was considered to be as objective as possible for a qualita- undergo hysterectomy were included. There were no
tive measure.10–13 differences among the 4 groups in sexual functioning over-
all (P > 0.05). There was significant improvement in sex
Kupperman et al.10 conducted a randomized trial of 135 drive, arousal, and sexual behaviour in the LAVH group,
women (67 TAH and 68 SCH). Each woman was followed and significant improvement in sexual behaviour and sexual
for 2 years. Baseline sexual functioning and quality of life function in the LSCH group (P < 0.01). No significant
variables were measured at randomization and again, with a difference in pain variables among the 4 groups was found
telephone interview, at 1, 3, 9, and 15 months, and with (P > 0.05). Chronic pain in the abdomen and intensity of
clinic-based interviews every 6 months. At 2 years, both pain during gynaecologic examination was alleviated in
groups reported few problems with sexual functioning both hysterectomy groups (P < 0.01). An overall postopera-
(mean score 82, SD 26 for SCH and 80, SD 26 for TAH). In tive improvement in depressive and psychological
addition, both randomization groups demonstrated symptoms was also demonstrated in both hysterectomy
substantial improvement in most measures of sexual func- groups (P < 0.001). Similarly, no statistical difference in
tioning and health-related quality of life at 2 years. This adverse psychological effects was demonstrated among the
4 groups (P > 0.05). While the laparoscopic approach to the Overall urinary frequency decreased and double/triple
surgery is more modern, the findings about sexual function (repetitive emptying) voiding increased in both groups at 1
specifically are consistent, regardless of the approach to year following hysterectomy (OR not provided). A
surgery. multivariate logistic regression analysis identified preopera-
Recommendation tive incontinence, duration of surgery, and size of uterus, as
the most important variables predicting urinary inconti-
2. Women contemplating a vaginal, laparoscopic, or nence at 1 year after surgery.
abdominal hysterectomy for the management of benign
uterine disease should be reassured that hysterectomy is Learman et al.17 conducted a randomized trial of 135
usually associated with improved quality of life, includ- women (67 TAH and 68 SCH). Each woman was followed
ing improved sexual function, whether or not the cervix for 2 years. There was no differential improvement in uri-
is removed. (I-B) nary symptoms overall according to randomization group
(P > 0.05). There was a statistically significant reduction of
URINARY DYSFUNCTION urgency incontinence, urinary urgency, sensation of incom-
Two RCTs specifically addressed urinary dysfunction after plete emptying, frequent urination, and stress incontinence
TAH compared with SCH.14,15 Three RCTs addressed uri- in the TAH group. There was a statistically significant
nary dysfunction as part of a larger study that also looked at reduction of urinary urgency, sensation of incomplete emp-
peri- and postoperative morbidity.16–18 All of these trials tying, and frequent urination in the SCH group (P < 0.05).
included only women undergoing a hysterectomy for
Recommendation
benign indications. Only 1 trial was reported as a
double-blind controlled trial.16 Two were multicentre trials, 3. Supracervical hysterectomy should not be recommended
but investigators were not blinded to the treatment assign- as a superior technique to total abdominal hysterectomy
ment.14,17 All 3 trials used standardized questionnaires in for the prevention of postoperative lower urinary tract
addition to cystometrography to assess urinary function.14,16,17 symptoms. (I-B)
The study by Thakar et al.11 of 279 women (146 TAH and
133 SCH) was the only double-blind RCT. Each woman PERIOPERATIVE AND POSTOPERATIVE MORBIDITY
was followed for 1 year. Urinary function was assessed by
use of twin-channel subtracted cystometrography and Three RCTs specifically addressed perioperative or postop-
uroflowmetry, as well as by the women’s response to sub- erative complications of TAH compared with SCH.16–18 All
jective standardized questionnaire. Urinary frequency, 3 trials used objective measures abstracted from operative
stress urinary incontinence, urgency, urgency incontinence, reports, pathology reports, and discharge summaries to esti-
poor stream, interrupted stream, and incomplete emptying mate the intraoperative and postoperative complication
did not differ significantly between groups. (P > 0.05). In rates. All 3 trials included only women undergoing hysterec-
both groups, significantly fewer women had stress inconti- tomy for benign indications. Only 1 trial was reported as a
nence (subjective and by urodynamic testing), urgency, double-blind controlled trial.16 Two were multicentre trials,
urinary frequency, nocturia, interrupted stream, and incom- but investigators were not blinded to the treatment assign-
plete emptying at 1 year after surgery (P < 0.05). ment.15,17 Repeat hospitalizations were ascertained by
cross-referencing abstracted data with diagnosis- related
Gimbel et al.18 conducted an RCT of 319 women (158 TAH group codes on readmission to hospitals affiliated with each
and 161 SCH). Each woman was followed for 1 year. A clinical centre and by assessing patients’ reports of hospital-
non-validated questionnaire was administered at random- ization every 3 months.17
ization and at 2, 6, and 12 months after surgery. The com-
parison of the 2 hysterectomy techniques showed a lower Learman et al.17 conducted a randomized trial of 135
rate of all urinary incontinence in the TAH group (OR 0.46, women (67 TAH and 68 SCH). Each woman was followed
95% CI 0.23 to 0.95; P = 0.03) than in the SCH at 12 for 2 years. There were no statistically significant differ-
months. Although there was no significant difference ences in procedure time, estimated blood loss, febrile
found between the method of operation, and the 3 catego- events, length of stay, and surgical complications between
ries of urinary incontinence were examined individually, the the 2 randomized groups (P > 0.05). The rate of hospital
TAH did show a larger reduction in SUI and MUI than the readmission was somewhat greater in the SCH group, but
SCH group, resulting in the demonstrated overall reduc- the difference was not statistically significant (relative haz-
tion. No other differences between the women in the TAH ard 1.99, 95% CI 0.58 to 6.8; P > 0.5). Five percent of the
and SCH groups regarding lower urinary tract symptoms SCH group experienced postoperative cyclical vaginal
were observed at the 12-month follow-up. (P > 0.05). bleeding.
Gimbel et al.18 conducted an RCT of 318 women (158 TAH incidence of cervical cancer of 0.3% at 10 years. Both cases
and 161 SCH). Each woman was followed for 1 year after of cervical cancer occurred in women over the age of 50.19
hysterectomy. SCH had a shorter median operation time Oats et al. looked at 1515 women treated for cervical cancer
(70 minutes; range 34–165 vs. 85 minutes; range 35–255, P between 1946 and 1972 and found a 3.6% incidence of cer-
< 0.001 ) and women who underwent this procedure had vical cancer in the stump.20 The incidence of cervical cancer
less median perioperative blood loss than those who under- is very low in both studies, but in view of the persistent risk,
went TAH (250 mL, range 10–2500 vs. 400 mL, range all women must continue to undergo routine cytological
25–4500; P < 0.001). Postoperative complications were screening following a SCH.
grouped into 4 categories according to severity and showed Recommendation
no difference between the 2 hysterectomy methods (OR
1.02, CI 0.55 to 1.88; P = 0.95). The overall complication 6. Women must be advised that they require routine
rate was 41%. Twenty percent of the SCH group had cycli- cytological screening following a supracervical hysterec-
cal vaginal bleeding postoperatively. tomy. (II-B)
In the double-blind RCT of 279 women (146 TAH and There are no data to suggest that screening is less adequate
133 SCH) by Thakar et al.,11 each woman was followed for or less frequent following the removal of the corpus. A ret-
1 year. SCH had a shorter duration of surgery (59 minutes, rospective cohort study on cervical screening in the US
range 39.6–80.2 vs. 71.1 minutes, range 47.7–84.5; P < demonstrated no difference in screening between women
0.001), and women who underwent this procedure had less after SCH and women who had not undergone hysterec-
estimated blood loss (320.1 mL, range 49.1–591.1 vs. 422.6 mL, tomy.21 Women with supracervical hysterectomies had the
range 120.8–724.4; P = 0.004) and a shorter hospital stay same rate of testing—approximately one test every 2.5
than those who underwent TAH (5.2 days, range 4.3–6.3 vs. years—as their non-exposed counterparts (mean differ-
6.0 days, range 1.3–10.7; P = 0.04). Immediate postopera- ence: –0.03 tests/year, P = 0.62). Additionally, a retrospec-
tive complications were greater in the TAH group: 9.8% tive cohort study by Hannoun-Levi et al. identified 77
(13) versus 27.4% (40) (P < 0.001), but delayed complica- patients with an infiltrating carcinoma of the cervical stump
tions after discharge were greater in the SCH group: 10.5% and demonstrated similar treatment results in patients with
(10) versus 6.2% (9) (P < 0.001). No visceral damage was carcinoma of the cervical stump and in patients with carci-
sustained in either group. The majority of the immediate noma of the intact uterus.22 The advantages of removing the
postoperative complications were pyrexia, retention of cervix when it is potentially diseased should be presented to
urine, and vault hematoma. Seven percent of the SCH patients who are having a hysterectomy and who have a cur-
group experienced cyclical vaginal bleeding. rent or significant history of abnormal cervical cytological
results. In the study by Learman et al.,17 3 TAH patients had
Recommendation
high-grade dysplasia in the cervical specimens despite the
4. Although supracervical hysterectomy may be associated requirement for up-to-date Papanicolaou smears and the
with less blood loss and a shorter surgical time, these exclusion from the study of women with a previous history
parameters have not been found to be clinically signifi- of cervical dysplasia. This may reflect limitations in the sen-
cant, and supracervical hysterectomy should not be rec- sitivity of cervical cancer screening tests. It is also important
ommended as a superior technique to total abdominal to discuss the need for ongoing surveillance of the vaginal
hysterectomy for the prevention of peri- and postopera- vault in women who have a total hysterectomy performed
tive complications. (I-B) in the presence of cervical dysplasia.
5. Women considering a supracervical hysterectomy should Recommendation
be counselled that they may continue experiencing cyclic
7. Women who require a hysterectomy and who have a cur-
vaginal bleeding following the surgery. (I-B)
rent or significant history of abnormal cervical cytologi-
ADVERSE EFFECTS cal results should be counselled on the advantages of
vaginal hysterectomy or total abdominal hysterectomy
Potential Harm of Leaving the Cervix at the Time of over supracervical hysterectomy. (I-B)
Hysterectomy Vaginal bleeding
Cervical cancer Most surgeons routinely attempt to ablate the endocervical
We identified 2 papers that specified the incidence of cervi- canal after removal of the corpus at the time of SCH.
cal cancer following a SCH. A case–control study of 1104 Persistent cyclical vaginal bleeding still occurs in up to 25%
women who underwent SCH in Denmark between 1978 women with a retained cervix following SCH. In a
and 1988 revealed 2 cases of cervical cancer, for an overall retrospective cohort by Van Der Stege et al., 25% of women
experienced regular vaginal bleeding following SCH.23 The 3 RCTs15–17 specifically addressing urinary dysfunction
Three RCTs16–18 described cyclical vaginal bleeding in 5% do not support the suggestion that removal of the uterine
to 20% of women following SCH. The problem of cyclical cervix at hysterectomy is more detrimental to urinary func-
vaginal bleeding exceeded acceptability in 2 women in the tion. Overall, SCH is not associated with any significant
study by Gimbel et al.,18 and each had her cervical stump improvement in urinary function when compared with
removed at 3 months after SCH. In the study by Learman et TAH; rather, women in both intervention groups had an
al.,17 persistent vaginal bleeding led to a trachelectomy in improvement in urinary symptoms, specifically SUI and
one SCH patient 15 months after hysterectomy. urgency.
The 4 RCTs specifically addressing sexual dysfunction do 6. Cohen MM, Young W. Costs of hysterectomy: does surgical approach make
not support the suggestion that removal of the uterine cer- a difference? J Womens Health 1998 Sep;7(7):885–92.
vix at hysterectomy is detrimental to sexual satisfaction.10–13 7. Kilkku P, Grönroos M, Hirvonen T, Rauramo L. Supravaginal uterine
amputation vs. hysterectomy. Effects on libido and orgasm. Acta Obstet
In fact, regardless of operative technique used, sexual func- Gynecol Scand 1983;62(2):147–52.
tion and frequency of intercourse often improved, as did
8. Vervest HA, Kiewiet de Jonge M, Vervest TM, Barents JW, Haspels AA.
quality of life, mental health, intensity and frequency of Micturition symptoms and urinary incontinence after non-radical
pain, and frequency of dyspareunia. hysterectomy. Acta Obstet Gynecol Scand 1988;67(2):141–6.
9. Sills ES, Saini J, Steiner CA, McGee M 3rd, Gretz HF 3rd. Abdominal Research Group. A randomized comparison of total or supracervical
hysterectomy practice patterns in the United States. Int J Gynaecol Obstet hysterectomy: surgical complications and clinical outcomes. Obstet Gynecol
1998 Dec;63(3):277–83. 2003 Sep;102(3):453–62.
10. Kuppermann M, Summitt RL Jr, Varner RE, McNeeley SG, 18. Gimbel H, Zobbe V, Andersen BM, Filtenborg T, Gluud C, Tabor A.
Goodman-Gruen D, Learman LA, et al. and Total or Supracervical Randomised controlled trial of total compared with subtotal hysterectomy
Hysterectomy Research Group. Sexual functioning after total compared with one-year follow up results. BJOG 2003 Dec;110(12):1088–98.
with supracervical hysterectomy: a randomized trial. Obstet Gynecol 2005
Jun;105(6):1309–18. 19. Storm HH, Clemmensen IH, Manders T, Brinton LA. Supravaginal uterine
amputation in Denmark 1978–1988 and risk of cancer. Gynecol Oncol 1992
11. Thakar R, Ayers S, Georgakapolou A, Clarkson P, Stanton S, Manyonda I. May;45(2):198–201.
Hysterectomy improves quality of life and decreases psychiatric symptoms:
a prospective and randomised comparison of total versus subtotal 20. Oats JJ. Carcinoma of the cervical stump. Br J Obstet Gynaecol 1976
hysterectomy. BJOG 2004 Oct;111(10):1115–20. Nov;83(11):896–9.
12. Flory N, Bissonnette F, Amsel RT, Binik YM. The psychosocial outcomes 21. Eaker ED, Vierkant RA, Konitzer KA, Remington PL. Cervical cancer
of total and subtotal hysterectomy: a randomized controlled trial. J Sex Med screening among women with and without hysterectomies. Obstet Gynecol
2006 May;3(3):483–91. 1998 Apr;91(4):551–5.
13. Zobbe V, Gimbel H, Andersen BM, Filtenborg T, Jakobsen K, Sørensen 22. Hannoun-Lévi JM, Peiffert D, Hoffstetter S, Luporsi E, Bey P, Pernot M.
HC, et al. Sexuality after total vs. subtotal hysterectomy. Acta Obstet Carcinoma of the cervical stump: retrospective analysis of 77 cases.
Gynecol Scand 2004 Feb;83(2):191–6. Radiother Oncol 1997 May;43(2):147–53.
14. Lalos O, Bjerle P. Bladder wall mechanics and micturition before and after 23. van der Stege JG, van Beek JJ. Problems related to the cervical stump at
subtotal and total hysterectomy. Eur J Obstet Gynecol Reprod Biol 1986 follow-up in laparoscopic supracervical hysterectomy. JSLS 1999
Mar;21(3):143–50. Jan-Mar;3(1):5–7.
15. Gimbel H, Zobbe V, Andersen BJ, Sørensen HC, Toftager-Larsen K, 24. Showstack J, Kuppermann M, Lin F, Vittinghoff E, Varner RE, Summitt
Sidenius K, et al. Lower urinary tract symptoms after total and subtotal RL Jr, et al. Resource use for total and supracervical hysterectomies: results
hysterectomy: results of a randomized controlled trial. Int Urogynecol J of a randomized trial. Obstet Gynecol 2004 May;103(5 Pt 1):834–41.
Pelvic Floor Dysfunct 2005 Jul-Aug;16(4):257–6. 25. ACOG Committee Opinion No. 388 November 2007: supracervical
16. Thakar R, Ayers S, Clarkson P, Stanton S, Manyonda I. Outcomes after hysterectomy. Obstet Gynecol 2007 Nov;110(5):1215–7.
total versus subtotal abdominal hysterectomy. N Engl J Med 2002 Oct
26. Woolf SH, Battista RN, Angerson GM, Logan AG, Eel W. Canadian Task
24;347(17):1318–25. Force on Preventive Health Care. New grades for recommendations from
17. Learman LA, Summitt RL Jr, Varner RE, McNeeley SG, Goodman-Gruen the Canadian Task Force on Preventive Health Care. CMAJ
D, Richter HE, et al. and Total or Supracervical Hysterectomy (TOSH) 2003;169(3):207–8.
Kathleen Wilson, RM, Ilderton ON 5. Ergonovine can be used for prevention of PPH but may be
considered second choice to oxytocin owing to the greater risk of
Disclosure statements have been received from all members of the maternal adverse effects and of the need for manual removal of a
committee. retained placenta. Ergonovine is contraindicated in patients with
hypertension. (I-A)
Evidence: Medline, PubMed, the Cochrane Database of Systematic 8. Ergonovine, 0.2 mg IM, and misoprostol, 600 to 800 mg given by
Reviews, ACP Journal Club, and BMJ Clinical Evidence were the oral, sublingual, or rectal route, may be offered as alternatives
searched for relevant articles, with concentration on randomized in vaginal deliveries when oxytocin is not available. (II-1B)
controlled trials (RCTs), systematic reviews, and clinical practice 9. Whenever possible, delaying cord clamping by at least 60 seconds
guidelines published between 1995 and 2007. Each article was is preferred to clamping earlier in premature newborns (< 37 weeks’
screened for relevance and the full text acquired if determined to gestation) since there is less intraventricular hemorrhage and less
need for transfusion in those with late clamping. (I-A)
10. For term newborns, the possible increased risk of neonatal
Key Words: Prevention, hemorrhage, obstetrics, obstetric jaundice requiring phototherapy must be weighed against the
hemorrhage
This document reflects emerging clinical and scientific advances on the date issued and is subject to change. The information
should not be construed as dictating an exclusive course of treatment or procedure to be followed. Local institutions can dictate
amendments to these opinions. They should be well documented if modified at the local level. None of these contents may be
reproduced in any form without prior written permission of the SOGC.
Table 1. Key to evidence statements and grading of recommendations, using the ranking of the
Canadian Task Force on Preventive Health Care
I: Evidence obtained from at least one properly randomized A. There is good evidence to recommend the clinical preventive
controlled trial action
II-1: Evidence from well-designed controlled trials without B. There is fair evidence to recommend the clinical preventive
randomization action
II-2: Evidence from well-designed cohort (prospective or C. The existing evidence is conflicting and does not allow to
retrospective) or case-control studies, preferably from more make a recommendation for or against use of the clinical
than one centre or research group preventive action; however, other factors may influence
decision-making
II-3: Evidence obtained from comparisons between times or
places with or without the intervention. Dramatic results in D. There is fair evidence to recommend against the clinical
uncontrolled experiments (such as the results of treatment preventive action
with penicillin in the 1940s) could also be included in this E. There is good evidence to recommend against the clinical
category preventive action
III: Opinions of respected authorities, based on clinical L. There is insufficient evidence (in quantity or quality) to make
experience, descriptive studies, or reports of expert a recommendation; however, other factors may influence
committees decision-making
*The quality of evidence reported in these guidelines has been adapted from The Evaluation of Evidence criteria described in the Canadian Task Force
on Preventive Health Care.54
†Recommendations included in these guidelines have been adapted from the Classification of Recommendations criteria described in the The Canadian
Task Force on Preventive Health Care.54
physiological benefit of greater hemoglobin and iron levels up to management of intractable PPH unresponsive to medical
6 months of age conferred by delayed cord clamping. (I-C) therapy. (III-B)
11. There is no evidence that, in an uncomplicated delivery without Recommendations were quantified using the evaluation of
bleeding, interventions to accelerate delivery of the placenta evidence guidelines developed by the Canadian Task Force on
before the traditional 30 to 45 minutes will reduce the risk of PPH. Preventive Health Care (Table 1).
(II-2C)
12. Placental cord drainage cannot be recommended as a routine J Obstet Gynaecol Can 2009;31(10):980–993
practice since the evidence for a reduction in the duration of the
third stage of labour is limited to women who did not receive
oxytocin as part of the management of the third stage. There is no
INTRODUCTION
evidence that this intervention prevents PPH. (II-1C)
ostpartum hemorrhage is the leading cause of maternal
13. Intraumbilical cord injection of misoprostol (800 mg) or oxytocin
(10 to 30 IU) can be considered as an alternative intervention
before manual removal of the placenta. (II-2C)
P death worldwide, with an estimated mortality rate of
140 000 per year, or 1 maternal death every 4 minutes.1 PPH
Treatment of PPH occurs in 5% of all deliveries and is responsible for a major
14. For blood loss estimation, clinicians should use clinical markers part of maternal mortality.2,3 The majority of these deaths
(signs and symptoms) rather than a visual estimation. (III-B)
occur within 4 hours of delivery, which indicates that they
15. Management of ongoing PPH requires a multidisciplinary
approach that involves maintaining hemodynamic stability while are a consequence of the third stage of labour.4,5 Nonfatal
simultaneously identifying and treating the cause of blood loss. (III-C) PPH results in further interventions, iron deficiency ane-
16. All obstetric units should have a regularly checked PPH mia, pituitary infarction (Sheehan’s syndrome) with associ-
emergency equipment tray containing appropriate equipment. (II-2B)
ated poor lactation, exposure to blood products,
17. Evidence for the benefit of recombinant activated factor VII has
been gathered from very few cases of massive PPH. Therefore coagulopathy, and organ damage with associated
this agent cannot be recommended as part of routine practice. (II-3L) hypotension and shock.
18. Uterine tamponade can be an efficient and effective intervention to
temporarily control active PPH due to uterine atony that has not Since all parturient women are at risk for PPH, care provid-
responded to medical therapy. (III-L) ers need to possess the knowledge and skills to practise
19. Surgical techniques such as ligation of the internal iliac artery, active management of the third stage of labour to prevent
compression sutures, and hysterectomy should be used for the
PPH and to recognize, assess, and treat excessive blood
loss.
ABBREVIATIONS
AMTSL active management of the third stage of labour DEFINITION OF PPH
PPH postpartum hemorrhage
Primary PPH is defined as excessive bleeding that occurs in
RCT randomized controlled trial
the first 24 hours after delivery.
Table 2. Signs and symptoms of shock resulting from The most common and important cause of PPH is uterine
blood loss atony. The primary protective mechanism for immediate
hemostasis after delivery is myometrial contraction causing
Degree of shock Blood loss Signs and symptoms
occlusion of uterine blood vessels, the so-called living liga-
Mild < 20% Diaphoresis tures of the uterus. Thus blood flow from the vascular
Increased capillary refilling space to the uterine cavity via the myometrium is impeded.
Cool extremities
Anxiety
Maternity care providers should recognize the risk factors
Moderate 20% to 40% Above plus for PPH due to the 4 Ts, as listed in Table 3, and take appro-
Tachycardia
Tachypnea priate action.
Postural hypotension
Oliguria PREVENTION OF PPH
Severe > 40% Above plus
Hypotension AMTSL involves interventions to assist in expulsion of the
Agitation/confusion
Hemodynamic instability
placenta with the intention to prevent or decrease blood
loss. Interventions include use of uterotonics, clamping of
the umbilical cord, and controlled traction of the cord. In
Traditionally the definition of PPH has been blood loss in contrast, with expectant, or physiological, management,
excess of 500 mL after vaginal delivery and in excess of spontaneous delivery of the placenta is allowed, with subse-
1000 mL after abdominal delivery. For clinical purposes, quent intervention, if necessary, that involves uterine
any blood loss that has the potential to produce massage and use of uterotonics.
hemodynamic instability should be considered PPH. The
amount of blood loss required to cause hemodynamic insta- Prendiville and colleagues’ meta-analysis8 demonstrated the
bility will depend on the pre-existing condition of the benefits of AMTSL to prevent and reduce PPH after vagi-
woman. Hemodynamic compromise is more likely to occur nal delivery for women at low risk of PPH. Studies included
in conditions such as anemia (e.g., iron deficiency, in the meta-analysis had design methods that involved rou-
thalassemia) or volume-contracted states (e.g., dehydration, tine use of uterotonics after delivery of the newborn and
gestational hypertension with proteinuria). before delivery of the placenta, early cord clamping, and
controlled cord traction. The primary goal of these inter-
Hypovolemic Shock6 ventions was to assist placental delivery, thereby allowing
Excessive bleeding, or hemorrhage, results in net loss of the uterus to contract and reduce blood flow across the
intravascular volume and decreased oxygen delivery to tis- myometrium.
sues and organs. Physiological compensatory mechanisms The meta-analysis concluded that active compared with
such as reflex tachycardia, peripheral vasoconstriction, and expectant management significantly reduced the risk in all
increased myocardial contractility help to maintain tissue areas, including mild PPH (estimated blood loss > 500 mL;
perfusion. Increasing blood loss results in circulatory col- OR 0.38; 95% CI 0.32 to 0.46), severe PPH (estimated
lapse, end-organ damage, and eventual death. blood loss > 1000 mL; OR 0.32; 95% CI 0.21 to 0.50), low
Ideally, care providers should be able to assess the amount postpartum hemoglobin level (< 9 g/dL; OR 0.38; 95% CI
of blood loss in order to estimate the volume of fluid that 0.27 to 0.53), need for transfusion (OR 0.33; 95% CI 0.21 to
needs to be replaced. However, research has shown that cli- 0.52), and need for additional uterotonic medication (OR
nicians often underestimate the actual loss.7 The signs and 0.17; 95% CI 0.14 to 0.21). There was no difference in the
symptoms listed in Table 2 should be used at the bedside to incidence of retained placenta or management of this
evaluate the amount of blood loss since, in general, the complication by manual or surgical removal. There was
degree of shock parallels the amount of blood loss that significantly more nausea and hypertension in the actively
results in these clinical markers.6 managed group given ergonovine (OR 1.83; 95% CI 1.51
to 2.23).
Etiology of PPH
A review of the data resulted in a joint statement in 2004 by
In regard to the underlying causes of PPH, it may be helpful the International Confederation of Midwives and Interna-
to think in terms of the 4 Ts: tional Federation of Gynaecologists and Obstetricians
• Tone: uterine atony, distended bladder endorsing the need for all deliveries to be attended by a
• Tissue: retained placenta and clots caregiver trained in AMTSL, which should include routine
• Trauma: vaginal, cervical, or uterine injury use of uterotonics, controlled cord traction, and uterine
• Thrombin: coagulopathy (pre-existing or acquired) massage.9 Delaying cord clamping by 1 to 3 minutes was
favoured over early cord clamping to reduce anemia in the 1. Active management should be offered to all women
newborn. by skilled care providers.
A similar review of the literature in 2006 by the World 2. Skilled attendants should offer uterotonics (oxytocin
Health Organization10 highlighted the most common cause preferred over ergonovine, misoprostol, and
of PPH as uterine atony and the fact that most women with carboprost) to prevent PPH.
PPH have no identifiable risk factors. The review resulted
in several recommendations to minimize maternal morbid- 3. Early cord clamping is recommended only when the
ity and mortality rates. newborn needs to be resuscitated.
4. Despite the lack of evidence to support cord traction, groups receiving ergonovine. Five trials showed little evi-
this practice should be continued as part of active dence of a synergistic effect of adding oxytocin to
management. ergonovine versus ergonovine alone.
One double-blind randomized controlled trial14 compared
Uterotonics
the efficacy of 10 IU of oxytocin in saline solution with
During the third stage of labour the muscles of the uterus saline solution alone in cephalic vaginal deliveries in
contract downward, causing constriction of the blood ves- low-risk women. The oxytocin group had a lower mean
sels that pass through the uterine wall to the placental sur- blood loss (407 vs. 527 mL), a lower incidence of blood loss
face and stopping the flow of blood. This action also causes > 800 mL (8.8% vs. 5.2%), and a lower rate of use of addi-
the placenta to separate from the uterine wall. The absence tional ergonovine (3.5% vs. 2.3%). Another double-blind
of uterine contractions, clinically defined as atony, may RCT15 found no difference in the incidence of PPH among
result in excessive blood loss. Uterotonics promote uterine women with low-risk vaginal deliveries given an IV bolus of
contractions to prevent atony and speed delivery of the oxytocin (20 IU in 500 mL of crystalloid) before or after
placenta. delivery of the placenta.
The uterotonic agents include oxytocin, ergonovine, The use of a slow IV bolus in management of the third stage
carbetocin, misoprostol, and Syntometrine (a combination of labour has been adopted as standard practice although
of ergonovine and oxytocin, unavailable in Canada). there is little supporting evidence in the literature. The
Oxytocin and ergonovine Dublin trial16 was the only study in Prendiville and
The 1997 Abu Dhabi study11 included in Prendiville and colleagues’meta-analysis8 in which a uterotonic
colleagues’meta-analysis8 randomly allocated low-risk (Syntometrine) was administered IV; the result was a lower
women who delivered vaginally to receive either 10 IU of incidence of PPH but more retained placentas.
oxytocin IM with delivery of the anterior shoulder followed There has been concern about the safety of such rapid
by controlled cord traction upon signs of placental separa- administration of oxytocin in the third stage, although
tion or minimal intervention. The results revealed a benefit 99 women given 10 IU in an IV push after vaginal delivery
for the oxytocin group: a lower incidence of blood loss did not have significant hemodynamic effects. The study,
> 500 mL (OR 0.50; CI 0.34 to 0.73) and > 1000 mL (OR however, was underpowered to demonstrate a reduction in
0.22; CI 0.08 to 0.57), fewer retained placentas (OR 0.31; CI the incidence of PPH.17
0.15 to 0.63), and less need for additional uterotonics (OR
For women undergoing elective Caesarean section, recent
0.44; CI 0.24 to 0.78).
studies have demonstrated adverse maternal effects of an
A 2004 Cochrane Review12 compared the efficacy of oxytocin IV bolus. One double-blind RCT found
Syntometrine and oxytocin alone, both administered IM, in hemodynamic changes in 30 patients given 5 IU IV over 30
AMTSL. The results showed a small benefit for seconds compared with women who received the same
Syntometrine in preventing blood loss > 500 mL (OR 0.82; dose over 5 minutes.18 In another double-blind RCT, 40
95% CI 0.71 to 0.95) but no difference in preventing losses patients given 10 IU of oxytocin as an IV bolus manifested
> 1000 mL. The group receiving Syntometrine were more electrocardiographic changes consistent with myocardial
likely to have elevated diastolic blood pressure (OR 2.40; ischemia when compared with pregnant women who
95% CI 1.58 to 3.64), nausea (OR 4.07; 95% CI 3.43 to received 0.2 mg of ergonovine and nonpregnant women;
4.84), and vomiting (OR 4.92; 95% CI 4.03 to 6.00). The the effect was transient, with onset at 1 minute and resolu-
authors favoured oxytocin alone on the basis of the lower tion by 5 minutes after exposure to oxytocin.19 These stud-
incidence of maternal side effects. ies suggest a potential maternal effect of the rapid adminis-
A 2008 meta-analysis13 included 14 studies assessing the tration (within 30 seconds) of oxytocin, and it may be
benefits of oxytocin in AMTSL for vaginal deliveries. Seven dose-related.
trials comparing oxytocin and no uterotonics found a lower Oxytocin given as part of AMTSL has been shown to
incidence of blood loss > 500 mL (RR 0.50; 95% CI 0.43 to reduce the need for manual removal of a retained placenta
0.59) and less need for therapeutic oxytocin (RR 0.5; 95% compared with expectant management.8,13 The greater need
CI 0.39 to 0.64) in the groups receiving oxytocin. Six trials for manual removal noted in the Dublin trial16 was attrib-
found no difference between the results with oxytocin and uted to the use of Syntometrine as an IV bolus. A 2001
ergonovine except that the groups receiving oxytocin had Cochrane review13 of prophylactic IM oxytocin use during
fewer manual removals of the placenta (RR 0.57; 95% CI the third stage of labour demonstrated a significantly
0.41 to 0.79) and a tendency to a lower incidence of raised reduced need for manual removal of the placenta compared
blood pressure (RR 0.53; 95% CI 0.19 to 1.52) than the with ergometrine use (RR 0.57; 95% CI 0.41 to 0.79).
• The effects have a slower onset but longer duration 25% to 60% of the fetal–placental circulation is found in the
with rectal and vaginal routes than with oral and placental circulation.33,34 Early cord clamping in term new-
sublingual routes. borns results in a decrease of 20 to 40 mL/kg of blood,
• Pyrexia is more common when the dose exceeds which is equivalent to 30 to 35 mg of iron. A delay in clamp-
600 mg. ing, causing increased neonatal blood volume, may lead to
There have been 3 systematic reviews of the use of complications such as respiratory distress, neonatal
misoprostol for the prevention of PPH.27–29 The WHO jaundice, and polycythemia.
multicentre trial30 and the Cochrane review27 suggested that Prendiville and colleagues’ meta-analysis espousing the
the observed lesser efficacy of misoprostol compared with benefit of AMTSL8 included studies that applied early cord
injectable uterotonics may be due to the later achievement clamping, controlled traction, and uterotonics before deliv-
of peak plasma levels with oral and sublingual administra- ery of the placenta. In these studies, early cord clamping was
tion of misoprostol: 30 minutes versus 1 to 2 minutes for included as part of controlled traction and was not inde-
IM or IV administration of oxytocin. All of the reviews con- pendently studied to demonstrate a benefit.
cluded that misoprostol was not as effective as oxytocin for
A 2004 Cochrane Review by Rabe et al.35 and a prospective
the prevention of PPH and that maternal pyrexia was a sig-
study by Ibrahim et al.36 demonstrated that delaying cord
nificant adverse effect.
clamping by 30 to 120 seconds resulted in less need for
A 2007 study comparing 800 mg of misoprostol adminis- transfusion because of anemia (RR 2.01; 95% CI 1.24 to
tered rectally with 10 IU of oxytocin administered IM in a 3.27) and less intraventricular hemorrhage (RR 1.74; 95%
developing country found these 2 agents to be equally effec- CI 1.08 to 2.81) in nonresuscitated premature infants (< 37
tive in minimizing blood loss during the third stage of weeks’ gestation).
labour.31 There was more pyrexia in the misoprostol group,
A systematic review and meta-analysis comparing cord
however.
clamping done early (less than 1 minute after delivery of the
The systematic review by Joy and colleagues29 compared the infant) and late (at least 2 minutes after delivery) showed
efficacy of misoprostol with that of oxytocin, other that late clamping conferred physiological benefit to the
uterotonic agents, and placebo in preventing PPH in the newborn that extended up to 6 months into infancy.37
third stage of labour. Compared with placebo, misoprostol Advantages included prevention of anemia over the first 3
was associated with a decreased need for additional months of life and enhanced iron stores (weighted mean
uterotonics (OR 0.64; 95% CI 0.46 to 0.90) and an difference 19.90; 95% CI 7.67 to 32.13) and ferritin concen-
increased risk of shivering and pyrexia. Oxytocin was supe- tration (weighted mean difference 17.89; 95% CI 16.58 to
rior to misoprostol in preventing blood loss and the need 19.21) for up to 6 months. There was no increase in respira-
for additional agents, and the patients had less shivering and tory distress, defined as tachypnea or grunting. Neonates
pyrexia. The authors proposed that misoprostol is a reason- were at increased risk of asymptomatic polycythemia (RR
able agent for management of the third stage of labour 3.82; 95% CI 1.11 to 13.21). There was no significant differ-
when other agents are not available for reasons of cost, stor- ence between the early and late groups in bilirubin levels
age, or difficulty of administration. and proportions of infants receiving phototherapy.
There have been no studies to determine the benefit of a A 2008 Cochrane review included 11 RCTs that compared
combination of oxytocin and misoprostol compared with the effect on maternal and neonatal outcomes of cord
either agent alone. clamping done early (up to 60 seconds after delivery) and
Recommendation late (beyond 60 seconds after delivery).38 The results
showed no difference in the incidence of PPH but an
8. Ergonovine, 0.2 mg IM, and misoprostol, 600 to
increased incidence of neonatal jaundice requiring
800 mg given by the oral, sublingual, or rectal route,
phototherapy, higher newborn hemoglobin levels up to 6
may be offered as alternatives in vaginal deliveries
months of age, and higher ferritin levels at 6 months of age
when oxytocin is not available. (II-1B) after late clamping.
Management of the Placenta Recommendations
Timing of cord clamping 9. Whenever possible, delaying cord clamping by at least
Clamping of the umbilical cord is a necessary part of the 60 seconds is preferred to clamping earlier in premature
third stage of labour. Its timing varies widely throughout newborns (< 37 weeks’ gestation) since there is less
the world, early clamping being the predominant practice in intraventricular hemorrhage and less need for transfu-
Western countries.32 Physiological studies have shown that sion in those with late clamping. (I-A)
10. For term newborns, the possible increased risk of neo- drainage group versus 8.57 and 6.20 minutes in the traction
natal jaundice requiring phototherapy must be weighed group in primigravid (P < 0.05) and multigravid (P < 0.05)
against the physiological benefit of greater hemoglobin women, respectively. There was no significant difference
and iron levels up to 6 months of age conferred by between the groups in the incidence of blood loss > 500 mL
delayed cord clamping. (I-C) and the need for transfusion (P > 0.05), and none of the
Timing of placental delivery women had a retained placenta.
Placental delivery is essential to allow the uterus to contract The limited number of studies makes it difficult to recom-
and thus reduce blood loss in the third stage of labour. This mend a change in practice to support routine cord drainage,
process is completed within 5 minutes in 50% of deliveries but this intervention does appear to reduce the length of the
and by 15 minutes in 90%. Failure of the placenta to be third stage of labour and the risk of a retained placenta.
delivered in such a timely manner is a well-known risk fac- More research is required to determine if the length of the
tor of PPH.39,40 third stage is reduced with routine drainage after the use of
The traditional definition of retained placenta includes fail- uterotonics and if this intervention reduces the risk of PPH.
ure of placental delivery within 30 to 45 minutes and a
Recommendation
requirement of intervention to assist with delivery. One
study published in 2006 concluded that the risk of PPH 12. Placental cord drainage cannot be recommended as a
increases if the placenta has not been delivered by 10 min- routine practice since the evidence for a reduction in the
utes, although research is needed to determine if the risk of duration of the third stage of labour is limited to women
PPH can be reduced by intervening at this stage.41 who did not receive oxytocin as part of the management
Recommendation of the third stage. There is no evidence that this interven-
tion prevents PPH. (II-1C)
11. There is no evidence that, in an uncomplicated delivery
without bleeding, interventions to accelerate delivery of Injection of the umbilical vein
the placenta before the traditional 30 to 45 minutes will
Injection of the umbilical vein has been proposed to assist
reduce the risk of PPH. (II-2C)
in uterine contractions and dehiscence of the placenta from
Placental cord drainage the uterine wall to effect delivery. If successful, this inter-
Drainage of cord blood has been proposed to assist with vention would avoid manual removal of the placenta, an
delivery of the placenta. invasive procedure with potential complications, including
A 2005 Cochrane review42 included only 2 studies address- hemorrhage, infection, and trauma. A 2001 Cochrane
ing this intervention, which makes it difficult to draw con- Review44 assessed if injection of various agents would
clusions. The selection criteria for the review were low-risk reduce the need for manual removal of a retained placenta.
vaginal deliveries in which a cord clamped within 30 sec- The authors derived the following conclusions.
onds of delivery and separated was unclamped, which • Saline versus expectant management: no difference
allowed the blood from the placenta to drain freely. The (RR 0.97; 95% CI 0.83 to 1.14).
measured outcomes included incidence of retained placenta • Saline plus oxytocin versus expectant management:
(at 30 to 45 minutes), manual removal of the placenta, PPH, nonsignificant reduction in the incidence of manual
length of the third stage of labour, need for blood transfu- removal (RR 0.86; 95% CI 0.72 to 1.01) with the use of
sion, decrease in maternal hemoglobin level, and maternal saline plus oxytocin.
pain. The outcomes reported were a decreased incidence of • Saline plus oxytocin versus saline: significantly lower
retained placenta at 30 minutes (RR 0.28; 95% CI 0.10 to incidence of manual removal of the placenta (RR 0.79;
0.73) and a shorter third stage (weighted mean difference 95% CI 0.69 to 0.91) (number needed to treat: 8; 95%
–5.46; 95% CI –8.02 to –2.90) after cord drainage. A major CI 5 to 20) with the use of saline plus oxytocin.
confounding factor was the lack of use of uterotonics and • Saline plus oxytocin versus plasma expander:
the varied definition of a prolonged third stage: from 30 to nonsignificantly greater incidence of manual removal of
45 minutes. the placenta (RR 1.34; 95% CI 0.97 to 1.85) with the
Sharma et al.43 randomly assigned 958 women to either pla- use of saline plus oxytocin.
cental cord drainage or controlled traction after administra- • Saline plus prostaglandin versus saline: significantly
tion of 0.2 mg of ergonovine with delivery of the anterior lower incidence of manual removal of the placenta (RR
shoulder and immediate cord clamping. Measured out- 0.05; 95% CI 0.00 to 0.73) with the use of saline plus
comes were PPH and length of the third stage. The third prostaglandin but no difference in the incidence of
stage had a mean duration of 3.24 and 3.20 minutes in the blood loss, fever, pain, and oxytocin augmentation.
Figure 1. Pipingas technique for injection of the intraumbilical vein if the placenta has not separated or
delivered within 45 minutes after delivery of the baby
• Prepare a syringe of misoprostol (800 mg) or oxytocin (50 IU) dissolved in 30 mL of normal saline.
• Insert a size 10 nasogastric suction catheter along the umbilical vein. If resistance is felt, retract the catheter 1 to 2 cm
and advance it further, if possible. If the catheter cannot be advanced further without force, inject the solution in this
position.
• If most of the catheter has been inserted when resistance is felt, indicating that it has reached the placenta, retract it 3 to
4 cm to ensure that the tip is in the umbilical vein and not in a placental branch.
• Connect the syringe to the catheter and inject the solution. Clamp the catheter in situ and record the time of the injection.
• Allow 30 minutes for the placenta to deliver before undertaking further intervention.
• Saline plus prostaglandin versus saline plus oxytocin: large volume of blood.43 Clinical signs and symptoms
no difference (RR 0.10; 95% CI 0.01 to 1.59). (Table 2) are useful bedside indicators of ongoing blood
This review suggests that umbilical vein injection of loss and will assist clinicians in management. A previously
uterotonics assists with the third stage of labour but pro- established plan of action is of great value when preventive
vides no convincing evidence of the benefit; the last 3 con- measures have failed. This plan should include aggressive
clusions were based on the results of a single small trial. The fluid resuscitation, control of bleeding to minimize loss, and
authors conclude that umbilical vein injection of oxytocin access to a surgical room and support personnel (Table 4).
may reduce the need for manual removal of a retained pla- The initial goal of management is to determine the cause of
centa, but further investigation is required. There is an blood loss while instituting resuscitative measures. Evalua-
ongoing systematic review to determine if routine injection tion of uterine tone and a complete inspection of the lower
of the umbilical vein with a uterotonic within 15 minutes of genital tract are required. The goal of resuscitative measures
birth will affect perinatal and maternal outcomes.45 is to maintain hemodynamic stability and oxygen perfusion
of the tissues. An IV infusion of crystalloid solution should
An RCT compared the effect of intraumbilical vein injec-
be instituted, using large-bore tubing, along with oxygen
tion of Syntocinon (synthetic oxytocin; 50 IU in 30 mL of
supplementation. The “ABCs” should be observed and
normal saline), misoprostol (800 mg in 30 mL of normal vital signs, oxygen saturation, and urinary output moni-
saline), or normal saline (30 mL) on the need for manual tored. A visual assessment of clotting can be done at the
removal of the placenta in a prolonged third stage of labour bedside while blood is sent for analysis and matching for
in 87 low-risk women at term.46 The Pipingas technique transfusion.
(Figure 1) was used for injection. All the women had
AMTSL with either oxytocin or Syntometrine with delivery PPH emergencies often occur unexpectedly and, depending
of the anterior shoulder, early cord clamping, and cord trac- on the volume of deliveries in each institution, may be infre-
tion when signs of placental separation were observed. The quent. When a situation does not resolve with the usual
women whose third stage exceeded 30 minutes were ran- interventions, there is a need for more equipment that may
domly assigned to intervention at 45 minutes with 1 of the 3 not be readily available when needed. For these reasons,
injections. The trial was stopped when the misoprostol every obstetric unit should have a readily available tray with
group had many fewer instances of manual removal of the all of the necessary equipment. Since clinicians may rarely
placenta (9 of 21 women) compared with the Syntocinon apply these interventions, this equipment should be accom-
group (16 of 20 women) and the saline group (7 of 13 panied by appropriate diagrams illustrating the relevant
women). anatomy and technique. A previously prepared PPH tray in
a large Canadian birthing centre was used in 1 in 250 Caesarean
Recommendation sections and 1 in 1000 vaginal deliveries.47
13. Intraumbilical cord injection of misoprostol (800 mg) or Recommendations
oxytocin (10 to 30 IU) can be considered as an alternative 14. For blood loss estimation, clinicians should use clinical
intervention before manual removal of the placenta. markers (signs and symptoms) rather than a visual
(II-2C) estimation. (III-B)
Call for help Uterus soft and relaxed Uterine atony Uterine massage Nonsurgical uterine Compression sutures Artery ligation
compression • B-Lynch
(uterine, hypogastric)
Resuscitation
• Bimanual uterine
Uterotonic drugs • Vertical compression
• Assess the “ABC” compression Hysterectomy
• Cho square
• Oxygen by mask • External aortic (subtotal or total)
compression Uterine artery
• IV line
embolization
• Crystalloid, isotonic • Uterine packing
fluid replacement • Balloon (condom)
• Monitor BP, P, R tamponade
• Empty bladder, monitor Placenta not separated Retained Whole placenta in uterus Placenta still retained Placenta still retained
urine output or partially separated placenta • Uterotonics
(placenta accreta)
(with or without
Laboratory tests hemorrhage) • Controlled cord Manual removal
traction Partial or complete
• Complete blood count removal of placenta
• Intraumbilical vein
• Coagulation screen through laparotomy
injection
• Blood grouping
and cross Hysterectomy
Incomplete separation Hysterectomy
• Manual vacuum
aspiration
• Manual exploration
• Gentle curettage
Excess bleeding or Low genital ® Repair tears in
shock shortly after birth, tract trauma perineum, vagina and
uterus contracted cervix
Uterine rupture ® Laparotomy:
• Primary repair
• Hysterectomy
Uterine fundus not felt Uterine ® Correct inversion in If nonsurgical correction Surgery
abdominally OR visible inversion theatre under general fails, ensure that uterus
vaginally anaesthesia remains contracted by
continued oxytocin Correction via
infusion laparotomy
Hysterectomy
Clotting Clotting disorder
• Treat accordingly with
989
Active Management of the Third Stage of Labour: Prevention and Treatment of Postpartum Hemorrhage
SOGC CLINICAL PRACTICE GUIDELINE
16. All obstetric units should have a regularly checked PPH Recommendation
emergency equipment tray containing appropriate
equipment. (II-2B) 17. Evidence for the benefit of recombinant activated fac-
tor VII has been gathered from very few cases of massive
Uterine Massage and Additional Uterotonic
PPH. Therefore this agent cannot be recommended as
Administration part of routine practice. (II-3L)
Since the most common cause of PPH is uterine atony, the
clinician’s initial efforts should be directed at preventing Tamponade
ongoing blood loss by performing the initial basic The quickest method of tamponade is with bimanual com-
maneuvres of uterine massage and administering additional pression of the uterus. One hand is placed over the uterus
uterotonics, which include the following. externally; the other is placed in the vagina to apply pressure
on the lower segment. Consistent compression with the 2
1. Oxytocin hands results in external compression of the uterus to
• 10 IU IM. Consider ability of the medication to reduce blood flow. This can be continued until further mea-
reach a uterus with poor tissue perfusion. sures are taken or assistance arrives.
• 5 IU IV push
• 20 to 40 IU in 250 mL of normal saline, infused IV In the case of uterine atony, the following can be placed
at an hourly rate of 500 to 1000 mL. inside the uterus to provide direct compression of the uter-
ine wall and thus decrease blood loss.
2. 15-methyl prostaglandin (carboprost tromethamine
[Hemabate]) • Bakri SOS tamponade balloon catheter
• 250 mg IM or intramyometrially • Sengstaken Blakemore esophageal catheter
• Can be repeated every 15 minutes to a maximum of • Foley catheter filled with 60 to 80 mL of sterile
2 mg (8 doses). solution
• Asthma is a relative contraindication. • Rusch hydrostatic urologic balloon
3. Carbetocin • Hydrostatic condom catheter
• Uterine packing
• 100 mg IM or IV over 1 minute
All the above have been reported to be successful for the
• Shown to reduce bleeding due to uterine atony in
temporary control of active bleeding. The insertion tech-
Caesarean sections but not low-risk vaginal
nique for a balloon device is relatively simple and requires
deliveries.
the operator to ensure that the entire balloon is positioned
4. Misoprostol (off-label use not approved for PPH by past the cervical canal. Once inserted, the balloon is filled
Health Canada) with sterile solution until there is no further bleeding. After
• 400 to 800 mg. Onset of effects is faster with oral or successful tamponade, continued oxytocin infusion may be
sublingual than with rectal administration. required to maintain uterine tone. Prophylactic antibiotic
• 800 to 1000 mg. Effects are longer lasting with rectal therapy should be considered. The balloon can be left in
than with oral administration. place for 8 to 48 hours and then gradually deflated and
• Higher incidence of pyrexia with oral than with removed.
rectal administration.
Uterine packing requires greater skill and experience to
5. Ergonovine properly pack the uterus with enough gauze to control
• 0.25 mg IM or IV, can be repeated every 2 hours bleeding while avoiding trauma to the uterine wall. Other
• Contraindicated in women with hypertension and disadvantages include risk of infection, unrecognized bleed-
those taking certain drugs (e.g., proteases for HIV ing with blood soaking the packing material, and the possi-
infection). ble need for another surgical procedure to remove the
6. Recombinant activated factor VII material.
• Has been used in women with massive PPH but in a Recommendation
limited number of studies, all without
randomization. 18. Uterine tamponade can be an efficient and effective
• A review by Franchini et al.48 suggests a potential intervention to temporarily control active PPH due to
role, although further research is required to uterine atony that has not responded to medical
determine this agent’s role and benefit. therapy. (III-L)
Reproduced from B-Lynch et al52 with permission of the Royal College of Obstetricians and Gynaecologists.
Reproduced from Cho et al53 with permission of the Royal College of Obstetricians and Gynaecologists.
Ligation of the internal iliac artery was used to control 8. Prendiville WJ, Elbourne D, McDonald S. Active versus expectant
management in the third stage of labour. Cochrane Database Syst Rev
intraoperative bleeding from cervical cancer before being 2000;(3):CD000007.
applied to obstetric cases.50 A retrospective study found this 9. International Confederation of Midwives, International Federation of
technique to be useful for preventing PPH in women at Gynaecologists and Obstetricians. Joint statement: management of the
third stage of labour to prevent post-partum haemorrhage. J Midwifery
high risk of hemorrhage and for treating PPH due to uterine Womens Health 2004;49:76–77.
atony or genital tract injury.51 The timing of this interven-
10. World Health Organization. Recommendations for the Prevention of
tion is important: it must be done without delay, before Postpartum Haemorrhage. Geneva: WHO; 2007.
excessive blood loss has occurred. Surgical skill is required 11. Khan GQ, John IS, Wani S, Doherty T, Sibai BM. Controlled cord traction
to avoid failure and complications such as damage to other versus minimal intervention techniques in delivery of the placenta: a
vascular structures and the ureters. randomized controlled trial. Am J Obstet Gynecol 1997;177(4):770–4.
12. McDonald S, Abbott JM, Higgins SP. Prophylactic ergometrine–oxytocin
Uterine compression sutures, described by B-Lynch52 (Fig- versus oxytocin for the third stage of labour. Cochrane Database Syst Rev
ure 2) and Cho53 (Figure 3), have the benefit of preserving 2004;(1):CD000201.
the uterus. Both techniques involve external compression 13. Cotter A, Ness A, Tolosa J. Prophylactic oxytocin for the third stage of
of the uterus to control bleeding, followed by application of labour. Cochrane Database Syst Rev 2001;(4):CD001808.
sutures into and over the uterus. The sutures are tied down 14. Nordstrom L, Fogelstam K, Fridman G, Larsson A, Rydhstroem H.
to maintain uterine compression and control further bleed- Routine oxytocin in the third stage of labour: a placebo controlled
ing. A hysterotomy at the lower segment is required to randomised trial. Br J Obstet Gynaecol 1997;104:781–6.
ensure that there are no retained products that would pre- 15. Jackson KW Jr, Allbert JR, Schemmer GK, Elliot M, Humphrey A, Taylor J.
A randomized controlled trial comparing oxytocin administration before
vent compression of the uterus and subsequent failure of
and after placental delivery in the prevention of postpartum hemorrhage.
pregnancy. Am J Obstet Gynecol. 2001 Oct;185(4):873–7.
Peripartum hysterectomy is indicated when massive hemor- 16. Begley C. A comparison of ‘active’ and ‘physiological’ management of the
third stage of labour. Midwifery 1990;6:3–17.
rhage has not responded to previous interventions and
requires a surgical intervention familiar to surgeons. Indica- 17. Davies GA, Tessier JL, Woodman MC, Lipson A, Hahn PM. Maternal
hemodynamics after oxytocin bolus compared with infusion in the third
tions include abnormal placentation (previa, accreta), atony, stage of labor: a randomized controlled trial. Obstet Gynecol
trauma, rupture, and sepsis. The disadvantage of 2005;105:294–9.
peripartum hysterectomy is the loss of fertility in women 18. Thomas JS, Koh SH, Cooper GM. Hemodynamic effects of oxytocin given
who wish to continue childbearing. as IV bolus or infusion on women undergoing caesarean section. Br J
Anaesth 2007;98;116–9.
Recommendation
19. Svanström MC, Biber B, Hanes M, Johansson G, Näslund U, Balfors EM.
19. Surgical techniques such as ligation of the internal iliac Signs of myocardial ischemia after injection of oxytocin: a randomized
double-blind comparison of oxytocin and methylergometrine during
artery, compression sutures, and hysterectomy should be caesarean section. Br J Anaesth 2008;100:683–9.
used for the management of intractable PPH unrespon-
20. Dansereau J, Joshi AK, Helewa ME, Doran TA, Lange IR, Luther ER, et al.
sive to medical therapy. (III-B) Double-blind comparison of carbetocin versus oxytocin in prevention of
uterine atony after cesarean section. Am J Obstet Gynecol 1999;180(3 Pt
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25. El-Refaey H, O’Brien P, Morafa W, Walder J, Rodeck C. Misoprostol for spontaneous vaginal delivery as part of the management of the third stage
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26. Hofmeyr GJ, Walraven G, Gülmezoglu AM, Maholwana B, Alfirevic Z, 43. Sharma JB, Pundir P, Malhotra M, Arora R. Evaluation of placental drainage
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27. Gülmezoglu AM, Forna F, Villar J, Hofmeyr GJ. Prostaglandins for 44. Carroli G, Bergel E. Umbilical vein injection for management of retained
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45. Nardin JM, Carroli G, Weeks a.d., Mori R. Umbilical vein injection for the
28. Villar J, Gülmezoglu AM, Hofmeyr GJ, Forna F. Systematic review of routine management of third stage of labour [Protocol]. Cochrane Database
randomized controlled trials of misoprostol to prevent postpartum Syst Rev 2006;(4):CD006176.
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46. Rogers MS, Yuen PM, Wong S. Avoiding manual removal of placenta:
29. Joy SD, Sanchez-Ramos L, Kaunitz AM. Misoprostol use during the third evaluation of intra-umbilical injection of uterotonics using the Pipingas
stage of labor. Int J Gynaecol Obstet 2003;82:143–52. technique for management of adherent placenta. Acta Obstet Gynecol
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48. Franchini M, Lippi G, Franchi M. The use of recombinant activated factor
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50. Kelly HA. Ligation of both internal iliac arteries for hemorrhage in
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51. Joshi V, Otiv SR, Majumder R, Nikam YA, Shrivastava M. Internal iliac
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37. Hutton EK, Hassan ES. Late vs early clamping of the umbilical cord in
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JAMA 2007;297:1241–52. bleeding during cesarean delivery. Obstet Gynecol 2000;96(1):129–31.
38. McDonald SJ, Middleton P. Effect of timing of umbilical cord clamping of 54. Woolf SH, Battista RN, Angerson GM, Logan AG, Eel W. Canadian Task
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Rev 2008;(2):CD004074. the Canadian Task Force on Preventive Health Care. CMAJ
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39. Dombrowski MP, Bottoms SF, Saleh AA, Hurd WW, Romero R. Third
stage of labor: analysis of duration and clinical practice. Am J Obstet 55. Mathai M, Gulmezoglu AM. Postpartum haemorrhage and retained
Gynecol 1995;172:1279–84. placenta. WHO guideline. Geneva: World Health Organization;2009.
Dean C. Leduc, MD (Chair), Ottawa ON 2. If there is a difference of greater than 5 days between gestational
age dated using the last menstrual period and first trimester
Charlotte Ballermann, MD, Edmonton AB ultrasound, the estimated date of delivery should be adjusted as
Anne Biringer, MD, Toronto ON per the first trimester ultrasound. (I-A)
Martina Delaney, MD, St. John’s NL 3. If there is a difference of greater than 10 days between gestational
age dated using the last menstrual period and second trimester
Loraine Dontigny, MD, Lasalle QC ultrasound, the estimated date of delivery should be adjusted as
Thomas P. Gleason, MD, Edmonton AB per the second trimester ultrasound. (I-A)
Lily Shek-Yn Lee, RN, Vancouver BC 4. When there has been both a first and second trimester ultrasound,
gestational age should be determined by the earliest ultrasound. (I-A)
Marie-Jocelyne Martel, MD, Saskatoon SK
5. Women should be offered the option of membrane sweeping
Valérin Morin, MD, Cap-Rouge QC
commencing at 38 to 41 weeks, following a discussion of risks and
Joshua Nathan Polsky, MD, Windsor ON benefits. (I-A)
Carol Rowntree, MD, Sundre AB 6. Women should be offered induction at 41+0 to 42+0 weeks, as the
Debra-Jo Shepherd, MD, Regina SK present evidence reveals a decrease in perinatal mortality without
increased risk of Caesarean section. (I-A)
Kathi Wilson, RM, Ilderton ON
7. Antenatal testing used in the monitoring of the 41- to 42-week
Disclosure statements have been received from all members of the pregnancy should include at least a non-stress test and an
committee. assessment of amniotic fluid volume. (I-A)
8. Each obstetrical department should establish guidelines dependent
on local resources for scheduling of labour induction. (I-A)
Abstract
J Obstet Gynaecol Can 2008;30(9):800–810
Objective: To provide evidence-based guidelines for the
management of pregnancy at 41+0 to 42+0 weeks.
INTRODUCTION
Outcomes: Reduction of perinatal mortality associated with
Caesarean section at 41+0 to 42+0 weeks of pregnancy.
he World Health Organization defines a post-term
Evidence: The Medline database, the Cochrane Library, and the
American College of Obstetricians and Gynecologists and the
T pregnancy as one that has extended to or beyond 42
Royal College of Obstetricians and Gynecologists, were searched weeks (294 days) of gestation.1 In 1997, the SOGC pub-
lished clinical practice guidelines recommending that
Key Words: Labour, induction, postdates pregnancy, post-term women with an uncomplicated pregnancy who reach 41 to
pregnancy
42 weeks’ gestation should be offered elective delivery.2
This document reflects emerging clinical and scientific advances on the date issued and is subject to change. The information
should not be construed as dictating an exclusive course of treatment or procedure to be followed. Local institutions can dictate
amendments to these opinions. They should be well documented if modified at the local level. None of these contents may be
reproduced in any form without prior written permission of the SOGC.
Sue-A-Quan et al. undertook a Canadian study to examine low pH according to the gestational age-dependent defini-
trends over time in the rates of induction in post-term tion of < mean-2 SDs showed no linear association with
pregnancies.3 The proportion of births occurring at 41 gestational age but a significant increase after 42 weeks (OR
weeks’ gestation increased significantly from 11.9% in 1980 1.24; 95% CI 1.05–1.47). The odds ratio for pH < 7.10
to 16.3% in 1995, and the proportion of births occurring at among infants born after 41 weeks 3 days was also signifi-
42 weeks or more decreased significantly from 7.1% in 1980 cant at 1.48 (95% CI 1.26–1.72).
to 2.9% in 1995. The authors reported that the rate of The RCT is the most reliable form of scientific evidence, as
labour induction increased significantly between 1980 and it is the best known design for eliminating biases that can
1995 among women delivering at 41 or more weeks’ gesta- compromise the validity of research. Controversy about the
tion, which indicates that the guidelines are, for the most management of and the risks associated with the post-term
part, being followed. The stillbirth rate was also examined in pregnancy led to the performance of many RCTs designed
the study by Sue-A-Quan and colleagues. Interestingly, the to determine if induction before or at the start of the
stillbirth rate among deliveries at 41 or more weeks’ gesta- post-term period versus expectant management results in
tion decreased significantly from 2.8/1000 total births in any difference in maternal or perinatal outcomes.
1980 to 0.9/1000 total births in 1995 (P < 0.001). This document updates the 1997 SOGC Guideline.2 Its rec-
Concern about increased risk to the post-term (³ 42 weeks) ommendations refer only to otherwise uncomplicated preg-
fetus has existed since the early to mid 1900s.4 Increased nancies at 41 to 42 weeks’ gestation. This guideline reviews
PMRs for the post-term fetus have been reported in the following:
descriptive studies.4,5 However, these studies did not 1. Interventions to decrease the incidence of pregnancy
exclude all high-risk pregnancies or fetuses with congenital beyond 41+0 weeks.
anomalies. Older descriptive studies that did correct for 2 . The evidence for induction of labour versus antenatal
congenital anomalies did not find any difference in PMRs surveillance in an uncomplicated pregnancy at 41+0 to
for post-term infants.6,7 More recent database studies have 42+0 weeks.
demonstrated an increasing risk of stillbirth with advancing
gestational age.8–11 However, a Canadian database study did 3. The role of antenatal fetal surveillance in the
not demonstrate an increased post-term PMR.12 Other uncomplicated pregnancy at 41+0 to 42+0 weeks.
obstetrical and perinatal complications that were found to Sources of information include Medline, the Cochrane
be higher in post-term pregnancies in these non- Library, and guidelines from the American College of
randomized studies include fetal distress, non-progression, Obstetricians and Gynecologists and the Royal College of
operative delivery (both operative vaginal and Caesarean), Obstetricians and Gynaecologists. The quality of evidence
macrosomia, shoulder dystocia, low Apgar scores, and was evaluated and recommendations were made according
meconium aspiration.12–14 A linear decline of umbilical to guidelines developed by the Canadian Task Force on
artery pH from term has also been described.15 Kitlinski Preventive Health Care (Table).16
et al.15 collected data on singleton pregnancies planned for
vaginal delivery after 37 completed weeks. They defined INTERVENTIONS TO REDUCE PREGNANCY
acidemia as a pH < 7.10 and a gestational age-dependent DURATION BEYOND 41+0 WEEKS
acidemia as a pH < mean-2 SDs. Their data show that the
mean umbilical cord arterial blood pH at birth decreases lin- Accurate Pregnancy Dating
early with gestational age. The odds ratio trend curve for Error is associated with pregnancy dating by LMP alone. If
the gestational age is underestimated, prematurity may be
misdiagnosed, and unnecessary obstetric interventions per-
ABBREVIATIONS
formed. However, overestimation of gestational age is
CI confidence interval more likely, increasing the risks of unnecessary induction of
CRL crown–rump length labour.
EDC estimated date of conception Dating gestational age with LMP alone assumes both accu-
LMP last menstrual period rate recall of the LMP and ovulation on the 14th day of the
NST non-stress test menstrual cycle. Error in estimating LMP is due to inaccu-
OR odds ratio rate patient recall, maternal preference of date of LMP, and
PMR perinatal mortality rate random error.17 The duration of the follicular phase is vari-
RCT randomized controlled trial able, ranging from 7 to 21 days. Sixty-eight percent of
RR relative risk women originally dated at greater than 42+0 weeks by LMP
Key to evidence statements and grading of recommendations, using the ranking of the
Canadian Task Force on Preventive Health Care
I: Evidence obtained from at least one properly randomized A. There is good evidence to recommend the clinical preventive
controlled trial action
II-1: Evidence from well-designed controlled trials without B. There is fair evidence to recommend the clinical preventive
randomization action
II-2: Evidence from well-designed cohort (prospective or C. The existing evidence is conflicting and does not allow to
retrospective) or case-control studies, preferably from more make a recommendation for or against use of the clinical
than one centre or research group preventive action; however, other factors may influence
decision-making
II-3: Evidence obtained from comparisons between times or
places with or without the intervention. Dramatic results in D. There is fair evidence to recommend against the clinical
uncontrolled experiments (such as the results of treatment preventive action
with penicillin in the 1940s) could also be included in this E. There is good evidence to recommend against the clinical
category preventive action
III: Opinions of respected authorities, based on clinical L. There is insufficient evidence (in quantity or quality) to make
experience, descriptive studies, or reports of expert a recommendation; however, other factors may influence
committees decision-making
*The quality of evidence reported in these guidelines has been adapted from The Evaluation of Evidence criteria described in the Canadian Task Force
on Preventive Health Care.16
†Recommendations included in these guidelines have been adapted from the Classification of Recommendations criteria described in the The Canadian
Task Force on Preventive Health Care.16
were actually less advanced in gestational age when basal ultrasound for dating significantly decreases the incidence
body temperature was used to determine the ovulation of birth after 41+0 and 42+0 weeks of gestation. Different
date.18 algorithms for combining LMP and CRL estimates were
compared. The lowest rates for delivery at > 41+0 or
Delayed ovulation is an important cause of perceived pro- > 42+0 weeks were seen with using early ultrasound alone
longed pregnancy.19 Most pregnancies induced after 41+0 for pregnancy dating (11.2% and 1.9%, respectively) and
weeks are found not to be > 41+0 when ultrasound rather changing the EDC if the discrepancy was > 3 days between
than LMP is used to date the pregnancy.20 LMP and CRL (11.7% and 1.9%). These data are compared
Ultrasound biometry in the second trimester ultrasound is with the results of using LMP alone (20.9% and 6.4%) or
accurate for dating ± 10 days and is routinely used in the changing the EDC if the discrepancy was > 14 days (16.9%
diagnosis of congenital anomalies. Biometry is most accu- and 3.5%).27
rate if two or more parameters, such as biparietal diameter, Bukowski et al.28 studied 3588 pregnancies in women with
abdominal circumference, and femur length, are used to known LMP who had a first trimester ultrasound as part of
estimate gestational age.21 Pregnancies noted to be term by the FASTER trial. When pregnancies were dated by the
second trimester ultrasound dating, but pregnancies CRL rather than the LMP, pregnancies reaching ³ 41+0
post-term by LMP estimate do not have an increased risk of were less frequent. The number of pregnancies at ³ 41+0
adverse fetal outcome.22 Induction of labour for post-term weeks (8.2% vs. 22.1%; [P < 0.001, RR 0.37; 95% CI
pregnancy is decreased when gestational age is estimated 0.33–0.4]), and at ³ 42+0 weeks (1.6% vs. 12.7% [P <
using second trimester biometry versus LMP alone.23–25 0.001, RR 0.13; 95% CI 0.1–0.2]) at birth was significantly
When pregnancies are dated from a second trimester ultra- reduced when gestational age was determined by CRL,
sound, delivery past 41+0 weeks occurs in 16.3%, com- compared with determination of gestational age by LMP.28
pared with 6.7% dated from a first trimester ultrasound.26
Bennett et al.29 conducted an RCT of routine first trimester
Gestational age is most accurately determined by first tri- ultrasound and the rate of post-term induction in a low-risk
mester CRL, with an error estimated to be ± 5 days. In addi- obstetric population. Two hundred eighteen women were
tion to accurate pregnancy dating, first trimester ultrasound randomized to first trimester ultrasound (EDC changed if
allows for early diagnosis of missed abortion, ectopic preg- > 5 days different from LMP) or second trimester
nancy, multiple gestations, and limited assessment of fetal ultrasound (changed if > 10 days different from LMP dates)
anatomy. A study involving 44 623 births in a Canadian ter- to determine the gestational age. Routine use of first
tiary centre demonstrated that the use of first trimester trimester ultrasound demonstrated a statistically and
clinically significant reduction in induction of labour for Theoretical risks of membrane sweeping include
pregnancy ³ 41+0 from 13% to 5% (P = 0.04, RR 0.37; chorioamnionitis, premature rupture of membranes, and
95% CI 0.14–0.96). There was no difference between the bleeding from an undiagnosed placenta previa. However, in
two groups in induction of labour for other indications, review of clinical trials, there was no increased incidence of
mode of delivery, or neonatal outcomes.29 There are no fetal infection or neonatal morbidity related to the proce-
studies investigating the cost-effectiveness of using first tri- dure. A small study did not find any increased colonization
mester ultrasound to decrease induction of labour between with group B streptococcus during membrane sweeping.36
41+0 and 42+0 weeks. Maternal morbidity is related mainly to significant discom-
fort or pain during procedure, bleeding, and contractions
Routine first trimester ultrasound reduces error in estimat-
not leading to labour within 24 hours.37,38
ing gestational age and induction of labour between 41+0
and 42+0 weeks.30 Other benefits of early ultrasound In an RCT investigating indicated induction of labour at 39
include measurement of nuchal translucency,31 visualiza- weeks in conjunction with membrane sweeping, the benefi-
tion of other markers of aneuploidy,32 and early diagnosis of cial effect of membrane sweeping was limited to nulliparous
some anatomical anomalies.33 women with unfavourable Bishop scores. In this patient
Recommendations group, both the induction-to-labour interval and oxytocin
use were decreased, and there was an increased rate of nor-
1. First trimester ultrasound should be offered, ideally mal vaginal delivery.39 Weekly membrane stripping preced-
between 11 and 14 weeks, to all women, as it is a more ing induction of labour has similar effects.40 However, the
accurate assessment of gestational age than last need for an intervention (sweeping membranes) at 38 weeks
menstrual period with fewer pregnancies prolonged past to routinely shorten pregnancy has been widely questioned
41+0 weeks. (I-A) in the literature. The results of membrane sweeping are not
2. If there is a difference of greater than 5 days between ges- predictable and should not be used alone for induction if
tational age dated using the last menstrual period and the indication for induction is urgent.
first trimester ultrasound, the estimated date of delivery In several small trials, membrane stripping has been an
should be adjusted as per the first trimester ultrasound. (I-A) effective outpatient method to reduce the number of
3. If there is a difference of greater than 10 days between patients with pregnancies exceeding 41+0.41–44 Again,
gestational age dated using the last menstrual period and membrane sweeping is generally most efficacious in
second trimester ultrasound, the estimated date of deliv- nulliparous women with unfavourable Bishop scores. In a
ery should be adjusted as per the second trimester ultra- study by Berghella et al.,45 patients were randomized to
sound. (I-A) weekly sweeping of membranes or gentle exams starting at
38 weeks. Time to delivery was significantly decreased with
4. When there has been both a first and second trimester
membrane stripping, and there were fewer pregnancies
ultrasound, gestational age should be determined by the
reaching past 41+0 weeks.45 Not all studies have noted a
earliest ultrasound. (I-A)
reduction in the need for post-term induction.46 A
well-designed Canadian study enrolled patients at 38 to 40
Sweeping of Fetal Membranes
weeks, and did not find any differences between a single
Sweeping (or stripping) of membranes off the lower uterine
membrane sweeping and routine examination with respect
segment has been reported since the 19th century and is
to onset of after 41 weeks or need for induction of labour.47
believed to stimulate the onset of labour. During a vaginal
Multiple episodes of membrane sweeping may be more effi-
examination, the fetal membranes are separated from the
cacious. There are no trials comparing single and multiple
cervix and lower uterine segment as far as possible, sweep-
sweepings of the membranes.
ing a finger inserted through the cervical os 360º if possible.
This procedure necessitates a sufficiently dilated cervix, A recently published RCT by de Miranda et al.48 random-
usually representing a favourable Bishop score. When the ized 750 low-risk pregnant women from the Netherlands at
cervix is closed, some clinicians attempt to stretch the cer- 41 weeks’ gestational age to routine monitoring or mem-
vix open or perform cervical massage. There are no trials brane sweeping every two days until spontaneous labour or
comparing these different techniques. Sweeping results in 42 weeks’ gestational age. Sweeping was defined as separat-
the release of endogenous prostaglandins, softening the cer- ing the lower membranes as much as possible from their
vix and augmenting oxytocin-induced uterine contrac- cervical attachment, with three circumferential passes of the
tions.34 Plasma prostaglandin concentrations after sweep- examining fingers. If the cervix was closed, cervical massage
ing are 10% of those achieved in labour, thus possibly was performed. Analysis was by intention-to-treat. Serial
improving labour outcomes.35 sweeping of the membranes decreased the risk of
pregnancy reaching 42+0 weeks (87/375 [23%] versus trial was a Canadian multi-centre trial enrolling 3407
149/367 [41%]); RR 0.57 [95% CI 0.46–0.71], NNT 6 [95% women.60 The remainder of the trials had sample sizes
CI 4–12]).48 Benefits were noted in both nulliparous and ranging from 22 to 440.49–59,61–64,66–68
multiparous patients. Uncomplicated vaginal bleeding was
reported more frequently in the sweeping group (111/364 The Canadian trial randomized women at 41 or more
vs. 16/345, RR 6.58 [95% CI 3.98–10.87]). As well, 68% of weeks’ gestation to induction or to serial antenatal monitor-
treated women reported sweeping as “somewhat” to “very ing, with delivery indicated for non-reassuring fetal status,
painful.” Of note, 88% of all women randomized to sweep- the development of obstetrical complications, or the attain-
ing reported that they would chose sweeping in the next ment of 44 weeks’ gestation.60 Those assigned to the induc-
pregnancy, despite the discomfort. Obstetric outcomes and tion group were to have labour induced within four days
neonatal morbidity were similar between groups.48 after randomization. The primary outcome of the study was
perinatal mortality and neonatal morbidity. The sample size
A recent Cochrane review assessed 22 trials involving was based on finding a reduction in the incidence of an
sweeping membranes. Sweeping of the membranes at term Apgar score less than 7 at five minutes. The secondary out-
(38–41 weeks) reduced the frequency of pregnancies con- come was the rate of Caesarean section. The authors con-
tinuing after 41+0 weeks (RR 0.59; 95% CI 0.46–0.74) and cluded that there was no difference in the risk of perinatal
after 42+0 weeks (RR 0.28; 95% CI 0.15–0.50). Eight mortality or neonatal morbidity between the two manage-
women would need to undergo sweeping of membranes to ment schemes. There were two stillbirths in the monitored
prevent one induction of labour.38 group and none in the induction group. The two groups did
Recommendation not differ significantly in the rate of neonatal morbidity.
The frequency of fetal distress was lower in the induction
5. Women should be offered the option of membrane
group (10.3% vs. 12.8%, P = 0.017). The incidence of
sweeping commencing at 38 to 41 weeks, following a dis-
meconium staining of the amniotic fluid was significantly
cussion of risks and benefits. (I-A)
lower in the induction group (25% vs. 28.7%, P = 0.009).
LABOUR INDUCTION VERSUS EXPECTANT There was a statistically significant higher rate of Caesarean
MANAGEMENT AT 41 WEEKS section among women who were monitored than among
those induced (24.5% vs. 21.25%, P = 0.03; OR 1.22; 95%
Nineteen trials randomizing women with uncomplicated CI 1.02–1.45), and this difference was due to a lower rate of
pregnancies at 41 or more weeks’ gestation to induction or this procedure for fetal distress. There were limitations in
expectant management with surveillance were identi- this study’s methods. Prostaglandin E2 gel was not used in
fied.49–67 A recently published trial randomized women at the monitoring group, as the authors felt there was insuffi-
41 weeks and two days of gestation to induction or expec- cient evidence to use this preparation in the presence of
tant management; however, the authors do not specify if the fetal compromise, and they speculated that most of the
pregnancies are uncomplicated.68 Two of these trials are women in this group requiring induction would have evi-
reported as abstracts only.50,66 A trial in a Spanish journal dence of fetal compromise. They acknowledge that this
was identified through the Cochrane Collaboration and was could account for the difference in the rate of Caesarean
not reviewed for this document.65 Nine trials began enrol- section. Also, this trial was not blinded, which introduces
ment at 41+0 weeks53,55,56,60–63,66,67 (two of these recruited at the potential for bias toward a higher Caesarean rate, as
41 weeks but did not randomize until 42 weeks);53,62 one pregnancies are likely to be considered higher risk as they
trial at 41+2 weeks68; five trials at 41+3 weeks;49,50,52,54,64 became further post-term. The authors conclude that
two trials at 42+0 weeks;51,57 and two trials at 42+1 labour induction in post-term pregnancies decreases the
weeks.58,59 Dating was by various methods (menstrual cycle Caesarean rate but leads to no difference in the incidence of
history, positive pregnancy tests, physical examination, and perinatal mortality and morbidity.
ultrasound) in each of the trials. Five trials did not use ultra-
sound assessment.49,54,57,59,63 It was unclear from one of the As the authors of the Canadian trial point out, the perinatal
trials published only as an abstract if ultrasound was used.66 mortality rate in their study was low at 0.6 per 1000. They
All trials reported perinatal mortality and delivery mode. reported that to detect a reduction of 50% in the perinatal
Perinatal morbidities and other maternal outcomes were mortality rate by inducing women with post-term preg-
reported in variable detail. As the incidence of substantive nancy, approximately 30 000 women would need to be
outcomes, such as perinatal mortality and morbidity associ- enrolled. Such a trial does not exist and for logistical reasons
ated with post-term pregnancy are low, a large sample size is likely not to be carried out. In the absence of such a trial,
would be required to detect a statistically significant differ- clinical practice relies on information from smaller trials
ence between these two management methods. The largest and from systematic reviews.
Three meta-analyses addressing labour induction versus required Caesarean section secondary to fetal heart rate
expectant management of pregnancies at 41 weeks and abnormalities at a significantly lower rate than those expec-
beyond have been published.69–71 tantly managed (6.2% vs. 8.0%; OR 0.77; 95% CI
0.61–0.96). Those whose labour was induced were less
In 1993, Hannah69 published a review of the literature on
likely to have meconium staining of amniotic fluid (22.4%
post-term pregnancy. Included in this review was a
vs. 27.75; OR 0.75; 95% CI 0.66–0.84). Women whose
meta-analysis of 11 randomized or quasi randomized trials
labour was induced had a lower rate of perinatal mortality;
in which a policy of routine induction at 41 weeks was com-
however, this difference was not statistically significant
pared with expectant management with serial fetal surveil-
(0.09% vs. 0.33%; OR 0.41; 95% CI 0.14–1.18). Other neo-
lance. A total of 5057 women were included in these trials.
natal outcomes showed no significant differences and
Methods of fetal surveillance and induction varied between
included meconium below the vocal cords, meconium aspi-
the studies. Ten studies reported on probability of Caesar-
ration, NICU admissions, and Apgar scores < 7 at 5 min-
ean and the results showed that inducing labour at ³ 41 utes. The authors concluded that labour induction in
weeks resulted in a significantly lower Caesarean section women at 41 weeks’ gestation with otherwise uncompli-
rate (OR 0.85; 95% CI 0.74–0.97). Inducing labour at ³ 41 cated pregnancies lowers the Caesarean rate without com-
weeks resulted in a lower rate of fetal distress, as defined by promising perinatal outcomes. As the authors state, none of
different authors, than expectant management (OR 0.81; these 16 trials had adequate statistical power to assess the
95% CI 0.68–0.97) and a lower rate of meconium staining perinatal mortality rate. Even when combined in a
of amniotic fluid (OR 0.79; 95% CI 0.69–0.90). Labour meta-analysis, the statistical power for assessing this out-
induction at ³ 41 weeks resulted in a lower rate of come remained low. They calculated that 16 000 women
macrosomia (usually defined as birth weight < 4000 g) than would need to be enrolled to detect a 50% reduction in the
expectant management (OR 0.80; 95% CI 0.69–0.92). PMR rate of 3 per 1000 with routine labour induction, com-
Inducing labour at ³ 41 weeks resulted in a lower rate of pared with expectant management at a power of 80% and
fetal or neonatal death (excluding lethal congenital anoma- allowing for a type I error of 5%. To detect an even smaller
lies) than expectant management (OR 0.23; 95% CI reduction in the PMR that would be clinically relevant,
0.06–0.90). The reduction in perinatal death was largely due would require even more participants.
to a reduction in fetal death (OR 0.14; 95% CI 0.02–0.98).
The Cochrane Collaboration published a review in 2006
There was no difference in other measures of neonatal mor-
whose objective was to evaluate the benefits and harms of a
bidity, such as small for gestational age, Apgar score < 7 at
policy of labour induction at term or post-term, compared
one minute, Apgar score < 7 at five minutes, shoulder
with awaiting spontaneous labour or later induction of
dystocia, cord prolapse, neonatal seizures, birth trauma,
labour.71 Eligible trials were RCTs enrolling women at low
admission to NICU, and meconium aspiration syndrome.
risk. This review included three trials65–67 not in the
The author concludes that the induction of labour groups
meta-analysis by Sanchez-Ramos et al. and excluded three
are less likely to undergo delivery by Caesarean, to have an
trials included in that review for methodological rea-
operative vaginal delivery, or to have fetal distress,
sons.51,52,58 The review included 19 trials involving 7984
macrosomic babies, or babies who die during the perinatal
women undergoing induction of at various times from 38 to
period. She states that women who reach 41 weeks should
> 42 weeks’ gestation. The review grouped the trials by ges-
be appropriately counselled about the higher risks to them-
tational age of induction at (1) 37 to 40 weeks, (2) 41 com-
selves and to their babies if they pursue expectant manage-
pleted weeks, and (3) 42 completed weeks, and compared
ment, and she suggests that a policy of labour induction is to
this with waiting until a later date for induction. Subgroup
be preferred.
analyses were also done according to the condition of the
A meta-analysis published in 2003 compared routine labour cervix. In this document, results from the 41-week and the
induction with expectant management for patients at 41 42-week groups from 16 trials are reviewed.49,50,53–57,59–67
weeks.70 Trials consisting of uncomplicated, singleton, live The primary outcome was perinatal mortality, which was
pregnancies were included. The primary outcomes assessed defined as intrauterine deaths plus newborn deaths in the
were perinatal mortality and Caesarean section. Sixteen tri- first week of life. Secondary infant and maternal outcomes
als enrolling 6588 subjects were included in the review.49–64 were also assessed. Eleven trials intervened at or during the
The trials differed in methods of antenatal fetal surveillance 41st completed week49,50,54–56,60,61,63,64,66,67 and five trials at
and means of labour induction. The meta-analysis showed or after 42 completed weeks.53,57,59,62,65 The relative risk of
that women who underwent labour induction had a signifi- perinatal death in the 41st week group was 0.25 with 95%
cantly lower rate of Caesarean section (20.1% vs. 22%; OR CI 0.05 to 1.18 (0/2835 vs. 6/2808), not statistically signifi-
0.88; 95% CI 0.78–0.99). Those whose labour was induced cant. When the 41- and 42-week groups were analyzed
together, the RR was 0.30 with 95% CI 0.09 to 0.99 (1/2986 that the pros and cons should be discussed so that women
vs. 9/2953), statistically significant. Labour induction sig- can make an informed decision. There does not seem to be
nificantly reduced the risk of meconium aspiration syn- any increased risk of Caesarean or assisted vaginal delivery
drome in the 41-week group (RR 0.29; 95% CI 0.12–0.68). with such a policy. The authors state that if a woman
In the 42-week group, fewer babies in the induction group chooses to await spontaneous labour, regular fetal
had meconium aspiration syndrome, but the difference was monitoring would be prudent as longitudinal
not statistically significant (RR 0.66; 95% CI 0.24–1.81). epidemiological studies suggest that there is an increased
There was no difference in neonatal intensive care admis- risk of perinatal death with increasing gestational age.
sions. There was no evidence of an increased risk of Caesar-
ean section for women induced at 41 and 42 weeks, respec- The evidence suggests that the rate of Caesarean section is
tively (RR 0.92; 95% CI 0.76–1.12; RR 0.97; 95% CI either reduced or not increased when women are induced,
0.72–1.31). There was no evidence of a statistically signifi- compared with those expectantly managed.65,30,66 The three
cant difference in the risk of assisted vaginal delivery for meta-analyses have different conclusions regarding the policy
women induced at 41 and 42 completed weeks, respectively of labour induction on PMR. The Hannah review69 demon-
(RR 1.05; 95% CI 0.94–1.17; RR 0.95; 95% CI 0.65–1.38). strated a statistically significant lower PMR with induction
Obstetric outcomes were also analyzed according to cervi- at 41 weeks or more. The meta-analysis by Sanchez-Ramos
cal status. This subgroup analysis was limited by the small et al. showed a lower PMR in the induced group, but it was
number of trials reporting cervical status. No differences not statistically significant.70 The most recent Cochrane
between a policy of labour induction and expectant man- review demonstrated a lower perinatal mortality rate for
agement were identified for Caesarean section or assisted induction at 41 weeks and beyond.71 In this review, when
the group induced at or during the 41st week was analyzed,
vaginal birth in these analyses. The reviewers did not pro-
the induced group had a lower PMR, but it did not reach
duce a point estimate because of significant heterogeneity
statistical significance. However, even when these studies
for these outcomes. The authors conclude in their discus-
are combined in a meta-analysis, there is still low statistical
sion that routine labour induction at 41 completed weeks or
power to assess this outcome. When the groups induced at
later, compared with waiting for the onset of labour for at
or during the 41st and at or during the 42nd week were
least one week is associated with fewer perinatal deaths and
combined, the PMR was lower in those induced, just reach-
meconium aspiration syndrome. The absolute number of
ing statistical significance. If anything, it appears induction
perinatal deaths was small in the induction group (1/3285,
during the 41st week may decrease the PMR, but there are
0.03%) and in the expectant management group (11/3238,
inadequate numbers of enrolled women to answer this
0.33%). In this review, there was one stillbirth reported
question definitively. Given that induction does not
among the seven trials since 1992. Excluding congenital
increase the risk of Caesarean and that uncertainty remains
anomalies, there were no deaths in the labour induction
regarding whether induction at 41 to 42 weeks decreases the
group and nine deaths in the expectant management group. PMR, it would seem reasonable to offer women induction
Regarding Caesarean rates, the authors acknowledge that in this gestational age range.
the data are difficult to interpret because of heterogeneity
among trials. This review also analyzed the data excluding A 2002 commentary on routine labour induction at 41
the multicentre trial by Hannah et al., which did not use weeks’ gestation noted that aggregate data to that point
prostaglandins in the expectantly managed group,60 and showed that not all of the seven perinatal deaths in the
reported that there did not seem to be a difference in Cae- expectantly managed groups occurred in women who
sarean rates.” The authors state that the effect on Caesarean received contemporary fetal testing, and it is questionable
section is unclear, but the rate is not increased. With respect whether all causes were related to pregnancy duration.72
to fetal monitoring in the expectant arms, most trials The stillbirth rate within the following week for women
included twice weekly non-stress tests and amniotic fluid who remain undelivered at 41 weeks 0 days is about 0.1%
index assessments, and the authors speculate that in centres (1.04–1.27 per 1000).72 Concern has been expressed that
that can offer these services, expectant management could obstetricians have responded to the previous SOGC guide-
be safely practised. In conclusion, the authors state that they line by booking induction by one week past the expected
think the results are valid and indicate beneficial outcomes due date.72 A proportion of women will labour spontane-
with a policy of labour induction at 41 completed weeks. ously between 41 and 42 weeks. Provided there are no indi-
They acknowledge that the risk of the primary outcome cations for delivery earlier, that fetal surveillance is
(perinatal death) is small but that such a policy is associated employed and is reassuring, and if the patient chooses,
with fewer perinatal deaths. They state that labour induc- induction at the latter end of this gestational age spectrum
tion should be offered to women at low risk at 41 weeks and will maximize the chances of spontaneous labour. Each
obstetrics department should establish guidelines depend- women at low risk who began twice weekly testing at 41
ent on their local resources for scheduling of labour weeks’ gestation with an NST and amniotic fluid volume
inductions. assessment. The control population consisted of 59 women
Recommendation at low risk delivered between 39 and 41 weeks’ gestation,
who were referred for routine testing at term. The outcome
6. Women should be offered induction at 41+0 to 42+0 parameters studied were abnormal NST, oligohydramnios,
weeks, as the present evidence reveals a decrease in Caesarean section for fetal distress, Apgar score £ 6 at five
perinatal mortality without increased risk of Caesarean minutes, NICU admissions, and perinatal deaths. When the
section. (I-A) study group delivering at 41 to 42 weeks were compared
with the control group, the former had a statistically signifi-
FETAL SURVEILLANCE IN THE cant increase in the incidence of abnormal NSTs,
41 TO 42 WEEK PREGNANCY
oligohydramnios, Caesarean section for fetal distress, and
Options for fetal surveillance include fetal movement admissions to the neonatal unit. When the study group who
counting, non-stress test, biophysical profile or modified were delivered between 41 and 42 weeks were compared
biophysical profile (non-stress test plus amniotic fluid vol- with those delivered after 42 weeks, the only significant dif-
ume estimation), and contraction stress test. In each of the ference was that the former had more abnormal NSTs.
aforementioned randomized trials of labour induction, Bochner et al.75 compared neonatal outcomes of patients
compared with expectant management of the post-term with antenatal fetal testing starting at 41 weeks’ gestation
patient, some form of antenatal test of fetal well-being was with patients who delivered between 41 and 42 weeks with-
used at varying frequencies.49–64,66–68 There is a paucity of out testing and those who started testing at 42 weeks. All
data from randomized trials on the type and frequency of patients were at low risk. The study population consisted of
fetal surveillance in post-term pregnancy. There has been 1260 women. Of these, 908 started testing at 41 weeks, and
only one randomized trial on forms of antenatal testing in 352 started at 42 weeks. The control group consisted of
the post-term pregnancy.73 Alfirevic et al. randomized 145 1807 women who delivered between 41 and 42 weeks with-
women with singleton, uncomplicated pregnancies after 42 out any antenatal testing. Antepartum testing consisted of
weeks to a modified biophysical profile defined as comput- twice weekly amniotic fluid assessment, NST, and contrac-
erized cardiotocography, amniotic fluid index, and assess- tion stress test when necessary. The total number of adverse
ment of fetal breathing, tone, and gross body movements or outcomes in the untested group resulted in a significantly
to standard cardiotocography and maximum pool depth. increased incidence of neonatal morbidity (seizures, apnea,
Women were monitored at randomization and then twice pneumonia, severe meconium aspiration, or infection),
weekly until 43 weeks. Outcome measures were cord pH at compared with the tested group. Those who delivered after
delivery, number of abnormal monitoring tests, 42 weeks and whose testing started at 41 weeks had signifi-
intrapartum management, mode of delivery, and neonatal cantly fewer abnormal antepartum testing results leading to
outcome. There were significantly more abnormal monitor- labour induction and Caesarean sections due to fetal dis-
ing results in the modified biophysical group (47.2% vs. tress than whose testing started at 42 weeks. The group
20.5%; OR 3.5; 99% CI 1.3–9.1). Amniotic fluid volume whose testing started at 42 weeks had a significantly greater
was more likely to be labelled abnormal with amniotic fluid incidence of fetal distress.
index than with maximum pool depth (44.4% vs. 15.1%;
Despite the lack of evidence from RCTs that antenatal test-
OR 4.5; 99% CI 1.6–12.8). There were no differences in
ing improves perinatal outcome in uncomplicated pregnan-
cord blood gases, neonatal outcome, or outcomes related to
cies at 41 to 42 weeks’ gestation, most practitioners utilize
labour and delivery between the two groups. These results
some form of monitoring in this clinical situation. The ran-
suggest that monitoring pregnancies with their definition of
domized trials comparing labour induction with expectant
a modified biophysical profile after 42 weeks does not
management at 41 weeks and beyond have included fetal
improve pregnancy outcome as measured by cord pH; how-
assessment.49–64,66–68 For most trials, those women who
ever, the number of patients included in this trial is were randomized to induction did not undergo antenatal
insufficient to reach any definitive conclusions about the surveillance. In eight trials, however, fetal assessment was
impact of fetal testing on outcomes in post-term carried out before patients were eligible for study enrol-
pregnancies. ment, and they therefore had some type of fetal surveillance
There are no randomized trials regarding antepartum fetal between 41 and 42 weeks.51,53,55,56,61,62,67,68 Therefore, for
testing between 41 and 42 weeks. The commencement of some pregnancies, fetal surveillance started at 41 weeks and
antenatal testing at 41 weeks’ gestation is supported by for others at 42 weeks. For some women, fetal monitoring
case-control studies. Guidetti et al.74 reported on 293 was started at 41 weeks but only if they were randomized to
expectant management. Those randomized to expectant 10. Hilder L, Costeloe K, Thilaganathan B. Prolonged pregnancy: evaluating
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Twelve studies included assessment of amniotic fluid vol- Journal 1999;319:287–88.
ume and an NST for women randomized to expectant man- 12. Usher RH, Boyd ME, McLean FH, Kramer MA. Assessment of fetal risk in
agement.50,52,55,56,60–64,66–68 The Canadian trial, which is the postdate pregnancies. Am J Obstet Gynecol 1988;158:259–64.
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71. Gulmezoglu AM, Crowther CA, Middleton P. Induction of labour for
improving birth outcomes for women at or beyond term. Cochrane
76. American College of Obstetricians and Gynecologists. Practice Bulletin.
Database Syst Rev 2006 Oct 18;(4):CD004945.
Management of postterm pregnancy. No. 55, 2004.
72. Menticoglou SM, Hall PH. Routine induction of labour at 41 weeks
gestation: nonsensus consensus. Br J Obstet Gynaecol 2002;109:485–91. 77. Royal College of Obstetricians and Gynecologists. Induction of labour.
73. Alfirevic Z, Walkinshaw SA. A randomised controlled trial of simple Evidence based clinical Guideline No. 9, June 2001. London: RCOG Press.
compared with complex antenatal fetal monitoring after 42 weeks of Available at: http://www.rcog.org.uk/resources/public/pdf/
gestation. Br J Obstet Gynaecol 1995;102:638–43. rcog_induction_of_labour.pdf. Accessed July 9, 2008.
Ann Kathleen Wilson, BHSc, RM, Ilderton ON 6. Continuous electronic fetal monitoring of women attempting a TOL
after Caesarean section is recommended (II-2A).
SPECIAL CONTRIBUTOR
7. Suspected uterine rupture requires urgent attention and expedited
Gregory A. Davies, MD, FRCSC, Kingston ON laparotomy to attempt to decrease maternal and perinatal morbidity
and mortality (II-2A).
8. Oxytocin augmentation is not contraindicated in women undergoing
a TOL after Caesarean section (II-2A).
Abstract
9. Medical induction of labour with oxytocin may be associated with an
Objective: To provide evidence-based guidelines for the provision of increased risk of uterine rupture and should be used carefully after
a trial of labour (TOL) after Caesarean section. appropriate counselling (II-2B).
Outcome: Fetal and maternal morbidity and mortality associated with 10. Medical induction of labour with prostaglandin E2 (dinoprostone)
vaginal birth after Caesarean (VBAC) and repeat Caesarean is associated with an increased risk of uterine rupture and should
section. not be used except in rare circumstances and after appropriate
Evidence: MEDLINE database was searched for articles published counselling (II-2B).
from January 1, 1995, to February 28, 2004, using the key words 11. Prostaglandin E1 (misoprostol) is associated with a high risk of
“vaginal birth after Caesarean (Cesarean) section.” The quality of uterine rupture and should not be used as part of a TOL after
evidence is described using the Evaluation of Evidence criteria Caesarean section (II-2A).
outlined in the Report of the Canadian Task Force on the Periodic
Health Exam. 12. A foley catheter may be safely used to ripen the cervix in a woman
planning a TOL after Caesarean section (II-2A).
13. The available data suggest that a trial of labour in women with
more than 1 previous Caesarean section is likely to be successful
but is associated with a higher risk of uterine rupture (II-2B).
Key Words: Vaginal birth after Caesarean, trial of labour, uterine
rupture, induced labour, oxytocin, prostaglandins, misoprostol 14. Multiple gestation is not a contraindication to TOL after Caesarean
section (II-2B).
These guidelines reflect emerging clinical and scientific advances as of the date issued and are subject to change. The information
should not be construed as dictating an exclusive course of treatment or procedure to be followed. Local institutions can dictate
amendments to these opinions. They should be well documented if modified at the local level. None of these contents may be
reproduced in any form without prior written permission of the SOGC.
15. Diabetes mellitus is not a contraindication to TOL after Caesarean significant difference in maternal and perinatal outcomes;
section (II-2B).
and finally, a woman’s choice to attempt TOL after Caesar-
16. Suspected fetal macrosomia is not a contraindication to TOL after
Caesarean section (II-2B).
ean is heavily influenced by her health care provider and
17. Women delivering within 18 to 24 months of a Caesarean section
local resources, often leading to selection bias in published
should be counselled about an increased risk of uterine rupture in reports.12,16
labour (II-2B).
The level of evidence and quality of the recommendations
18. Postdatism is not a contraindication to a TOL after Caesarean
section (II-2B). in this guideline have been determined using the criteria
19. Every effort should be made to obtain the previous Caesarean described by the Canadian Task Force on the Periodic
section operative report to determine the type of uterine incision Health Examination (Table).17
used. In situations where the scar is unknown, information
concerning the circumstances of the previous delivery is helpful in
determining the likelihood of a low transverse incision. If the
TRIAL OF LABOUR VERSUS ELECTIVE
likelihood of a lower transverse incision is high, a TOL after REPEAT CAESAREAN SECTION
Caesarean section can be offered (II-2B).
Validation: These guidelines were approved by the Clinical Practice
The success rate of a TOL after Caesarean ranges between
Obstetrics and Executive Committees of the Society of 50% and 85%.3,4,14,18–21 In a study examining 1776 women
Obstetricians and Gynaecologists of Canada. undergoing TOL after Caesarean, the overall success rate
J Obstet Gynaecol Can 2005;27(2):164–174 was 74%.14 A Canadian study reported similar results, quot-
ing a success rate of 76.6%.2 Predictors of successful VBAC
BACKGROUND include nonrecurring indication for Caesarean birth, such as
his document reviews the contraindications to and malpresentation (odds ratio [OR], 1.9; 95% confidence
T maternal and fetal risks of a trial of labour (TOL) after
Caesarean birth and makes recommendations for
interval [CI], 1.0–3.7)22 or gestational hypertension (OR,
2.3; 95% CI, 1.0–5.8),22 and a previous vaginal delivery (OR,
achieving vaginal birth after Caesarean (VBAC) safely. 1.8; 95% CI, 1.1–3.1),22 where success rates are as high as
Delivery by Caesarean section occurs in 15% to 25% of 82%.1,22,23 When the previous Caesarean birth was for
births.1–5 In 2000 and 2001, the Caesarean section rate in dystocia, failure to progress, or cephalopelvic dispropor-
Canada was 21.2%.6 The most frequent indications for Cae- tion, some studies found the rates of successful VBAC
sarean delivery are previous Caesarean delivery, dystocia, comparable,24,25 while others reported lower-than-expected
malpresentation, and nonreassuring fetal status.7,8 In any rates.14,18,22,26
given region, the rate of birth by Caesarean section and the In 1996 McMahon et al. published a report of maternal mor-
rate of VBAC tend to be inversely related.4 Schell first bidity in TOL compared with ERCS in Nova Scotia from
reported VBAC in 1923, describing the successful vaginal 1986 to 1992.1 In an examination of 3249 women undergo-
delivery of 34 infants in 23 mothers with previous Caesar- ing a TOL and 2889 women who delivered by ERCS, the
ean deliveries.9 risk of major complications (for example, hysterectomy,
A trial of labour after Caesarean should be considered in uterine rupture, and operative injury) was almost doubled
women who present for prenatal care with a history of pre- (1.6% vs. 0.8%) in the TOL group (OR, 1.8; 95% CI,
vious Caesarean birth.10–12 In certain situations, a TOL after 1.1–3.0).1 Complications like puerperal fever, transfusion,
Caesarean will be contraindicated3 and a repeat Caesarean and abdominal wound infection were comparable. When
section will be advised, but in most cases, successful vaginal comparing women who had a successful TOL with those
birth can be safely achieved for both mother and infant.13–15 who required a repeat Caesarean section after failed TOL,
Women and their health care providers will need to discuss the risks were greater of operative injury (3.0% vs. 0.1%;
the risks and benefits of VBAC when planning the birth. OR, 5.1; 95% CI, 2.5–10.7) and fever (8.0% vs. 3.5%; OR,
1.5; 95% CI, 1.3–1.8) in the failed TOL group.1 Hibbard et
A Canadian consensus statement on VBAC was published
al. also reported a greater rate of complication in women
in 1985, and Clinical Practice Guidelines were published by
who attempted a TOL and failed.27
the Society of Obstetricians and Gynaecologists of Canada
(SOGC) in 1997.3 This document updates the 1997 SOGC In 1999 Rageth et al. reviewed 17 613 TOL and 11 433
Guidelines with articles published from January 1, 1995, to ERCS deliveries.20 The rates of hysterectomy (relative risk
February 28, 2004. Articles were obtained by searching the [RR], 0.36; 95% CI, 0.23–0.56), febrile morbidity (RR, 0.65;
MEDLINE database, using the key words “vaginal birth 95% CI, 0.55–0.77), and thromboembolic complications
after Caesarean (Cesarean) section.” The data are limited by (RR, 0.52; 95% CI, 0.34–0.78) were less in the TOL group
3 important factors: first, there are no randomized trials of than in the ERCS group.20 There is less blood loss with a
TOL versus elective repeat Cesarean section (ERCS); sec- successful VBAC (OR, 0.50; 95% CI, 0.3–0.9)27 and a
ond, adverse maternal or perinatal outcomes are rare, and shorter hospital stay with a more rapid recovery and return
large study populations are necessary to observe a to full activity.
Rosen et al. also reported that the risk of febrile morbidity is CONTRAINDICATIONS TO VAGINAL BIRTH
lower in women who attempt a TOL after Caesarean (OR, AFTER CAESAREAN SECTION
0.5; 95% CI, 0.5–0.6) and is lowest in those who succeed The following situations are contraindications to a TOL
(OR, 0.2; 95% CI, 0.2–0.2), compared with ERCS, but is after Caesarean:
increased in those who attempt a TOL and ultimately
deliver by Caesarean (OR, 2.0; 95% CI, 1.7–2.5).28 1. previous classical or inverted “T” uterine scar3,13;
2. previous hysterotomy or myomectomy entering the uter-
ine cavity3,19;
An examination of 16 938 Finnish women who had under-
gone a Caesarean delivery found that previous Caesarean 3. previous uterine rupture3,19;
section is associated with an increased risk of ectopic preg- 4. presence of a contraindication to labour, such as placenta
nancy (RR, 1.28), placenta previa (RR, 3.89), and abruptio previa or malpresentation3;
placenta (RR, 2.41).29 A repeat Caesarean has been associ-
ated with an increase in the risk of placenta previa (OR, 5. the woman declines a TOL after Caesarean and requests
ERCS.3,19
1.59; 95% CI, 1.21–2.08)30 and placenta accreta in subse-
quent pregnancies.31 Recommendation
1. Provided there are no contraindications, a woman with 1
previous transverse low-segment Caesarean section should
A meta-analysis published in 2000 demonstrated that the
be offered a trial of labour after Caesarean with appropriate
overall risk of perinatal death is increased in women discussion of maternal and perinatal risks and benefits. The
attempting a TOL (OR, 1.71; 95% CI, 1.28–2.28).32 The process of informed consent with appropriate documenta-
risks of perinatal mortality and severe morbidity are directly tion should be an important part of the birth plan in women
related to uterine rupture as a sentinel event. If uterine rup- with a previous Caesarean section (II-2B).
ture occurs, the risks of perinatal mortality and severe mor-
bidity are increased. The risk of suspected neonatal sepsis is PLANNING A TRIAL OF LABOUR AFTER
greater in women attempting TOL but appears to be con- CAESAREAN SECTION
fined to those who fail TOL and require a repeat Caesarean A woman and her health care provider must decide together
section (OR, 4.8; 95% CI, 2.6–9.0).33 In women who whether an appropriate situation exists for considering
choose ERCS, the risk of respiratory problems in the new- TOL after Caesarean. The evaluation and discussion should
born is increased (6% vs. 3%), compared with women who address the issues outlined below and should be well docu-
have a successful VBAC (OR, 2.3; 95% CI, 1.4–3.8).33 mented in the prenatal record or chart.
Documentation of Previous Uterine Incision Labour and delivery in women who have had a previous
Caesarean section should be conducted in a hospital setting
Documentation of the location and type of uterine incision
with facilities for a laparotomy.
used during the previous Caesarean section is ideal.3 In
most cases, this information can be obtained by reviewing Recommendation
the operative record from the previous surgery. Other 3. For a safe labour after Caesarean section, the woman
information in this record, such as the indication for the should deliver in a hospital where a timely Caesarean sec-
Caesarean section and the opinion of the previous surgeon, tion is available. The woman and her health care provider
may be helpful in counselling as well. The fact that the must be aware of the hospital resources and the availability
record has been reviewed and that no contraindications to a of obstetric, anesthetic, pediatric, and operating-room staff
TOL after Caesarean are present should be documented (II-2A).
clearly on the prenatal record.34 If the operative record is 4. Each hospital should have a written policy in place
not available, the scar is considered “unknown.” Review of regarding the notification and (or) consultation for the phy-
the operative report from previous hysterotomy or sicians responsible for a possible timely Caesarean (III-B).
myomectomy should be documented in detail.
5. In the case of a TOL after Caesarean, an approximate
Recommendation time frame of 30 minutes should be considered adequate in
the set-up of an urgent laparotomy (III-C).
2. The intention of a woman undergoing a TOL after Cae-
sarean should be clearly stated, and documentation of the Maternal Monitoring
previous uterine scar should be clearly marked on the pre- Women planning a TOL after Caesarean should have
natal record (II-2B). appropriate monitoring in labour. The presence of a
devoted birth attendant is ideal. Progress of labour should
be assessed frequently, as there is some evidence that pro-
Facilities and Resources
longed or desultory labour is associated with an increased
A trial of labour after Caesarean is always associated with a risk of failure and uterine rupture.19,36,37 Epidural analgesia
risk of uterine rupture, however small, and a good outcome is not contraindicated.7,19,34,38
is not guaranteed under any circumstances. Further, little
evidence exists about the exact timing of a Caesarean sec- Fetal Monitoring
tion following a suspected uterine rupture, which would Continuous electronic fetal monitoring in labour is recom-
prevent a poor neonatal outcome. A TOL after Caesarean mended for all women attempting TOL after Caesar-
can be offered to women within any hospital setting where ean.19,34,39 The most reliable first sign of uterine rupture is a
there is an ability to perform a Caesarean section.13,34,35 This nonreassuring fetal heart tracing.34 This may be sudden in
document does not intend to set a standard regarding onset and may not be related to contractions.40
whether staff must be “in house” or “on site” to provide Recommendation
safe intrapartum care and therefore makes no statements on 6. Continuous electronic fetal monitoring of women
such attendance. Facilities providing TOL after Caesarean attempting TOL after Caesarean is recommended (II-2A).
should have a policy in place to manage such parturients, so
that all resources are mobilized promptly if an intrapartum POSTPARTUM EVALUATION
emergency occurs.23 The SOGC recognizes that in such
cases of maternal fetal compromise, necessitating timely Routine digital exploration of the Caesarean scar
Caesarean section, an approximate time frame of 30 min- postpartum is not necessary, except when signs or symp-
utes may be required to assemble the team and commence toms suggest uterine rupture.41
laparotomy. This availability and time required for obstet-
UTERINE RUPTURE
ric, anesthetic, and pediatric services to attend such an
emergency should be fully discussed with the woman. Uterine rupture, the most serious complication of a TOL
Women who live in areas where local hospitals cannot pro- after Caesarean, is defined as complete separation of the
vide a timely Caesarean section should be offered the myometrium with or without extrusion of the fetal parts
opportunity for transfer to a facility where this service is into the maternal peritoneal cavity and requires emergency
available, in order to permit a TOL after Caesarean.13 The Caesarean section or postpartum laparotomy.19,42 It is an
members of the team who could be called urgently in the uncommon complication of VBAC but is associated with
case of an intrapartum complication (anesthetic, pediatric, significant maternal and perinatal morbidity and mortal-
and obstetric services) should be notified that the woman is ity.1,7 The most common sign or symptom of uterine rup-
in hospital and in labour, and their availability should be ture is nonreassuring fetal heart rate monitoring.18,20,43
confirmed. Other clinical signs include the cessation of contractions,
loss of the presenting part on vaginal examination, abdomi- encephalopathy, and 1 (0.04%) died.52 The presence of pla-
nal pain, vaginal bleeding, hematuria, or maternal cardio- cental or fetal part extrusion at laparotomy was associated
vascular instability.16,44 with severe metabolic acidosis (P < 0.001).52 Other vari-
The type and location of the previous uterine incision helps ables (e.g., induction, birth weight, or use of epidural) did
to determine the risk of uterine rupture. The incidence of not demonstrate an association with uterine rupture. Even
uterine rupture is 0.2% to 1.5% in women who attempt in situations where very rapid decision to delivery times
labour after a transverse lower uterine segment inci- were recorded, some cases of perinatal acidosis could not
sion14,16,18,27,45 and 1% to 1.6% in women who have had a be avoided.52
vertical incision in the lower uterine segment.46–49 The risk Smith et al. published a large series of 15 515 women under-
is 4% to 9% with a classical or “T” incision; thus TOL after going a TOL after Caesarean compared with 9014 women
Caesarean is contraindicated in these situations.16,19,30 who underwent ERCS between 1992 and 1997.53 The rate
Shimonovitz et al. found the risk of uterine rupture after 0, of perinatal death in the TOL group was 0.129%, 11.6 times
1, 2, and 3 VBAC deliveries to be 1.6%, 0.3%, 0.2%, and higher than that of the ERCS group (OR, 11.6; 95% CI,
0.35%, respectively, indicating that the risk of uterine rup- 1.6–86.7).53 Smith compared this to the risk of perinatal
ture decreases after the first successful VBAC.50 death in other common obstetrical situations: TOL com-
Since uterine rupture is a rare event, a realistic appraisal of pared with multiparous women in labour (OR, 2.2; 95% CI,
potential maternal and perinatal risks is difficult to accom- 1.3–3.5) and TOL compared with nulliparous women in
plish outside of large series, literature reviews, or meta- labour (OR, 1.3; 95% CI, 0.8–21).53
analyses. The most important published reports in this area In 2003 Chauhan et al. published a review of data on the
are discussed below, as well as those applicable to the Cana- maternal and perinatal complications of uterine rupture in
dian population. those attempting a TOL after Caesarean.54 Examining 142
In 1991 Rosen et al. performed a meta-analysis of 10 studies 075 trials of labour revealed an overall rate of uterine rup-
that examined a total of 4617 women who had a TOL after ture of 0.62%.54 The rate of maternal death was 0.002%;
Caesarean compared with 3831 women who had ERCS hysterectomy, 0.09%; transfusion, 0.18%; and genitouri-
births.28 The rate of uterine rupture was similar in the 2 nary tract injury, 0.08%.54 In this study, the rate of neonatal
groups: TOL 0.18% and ERCS 0.19% (P = 0.5). There was acidosis was 0.15%, and the rate of perinatal death was
no difference in the rate of maternal death (0.028% vs. 0.04%.54 Oxytocin was involved in 43% of the uterine rup-
0.024%) or perinatal death (0.3% vs. 0.4%) in the TOL tures in this series.54
group, compared with the ERCS group.28 The data indicate that the relative risk of uterine rupture,
In 2000 Mozurkewich and Hutton published a meta- maternal morbidity, and perinatal mortality or severe mor-
analysis of 15 studies that examined a total of 28 813 bidity is increased in women undergoing a TOL after Cae-
women undergoing a TOL compared with ERCS between sarean, compared with ERCS, but that the absolute risk
1989 and 1999.32 There was an increased rate of uterine rup- remains very low.
ture (0.39% vs. 0.16%; OR, 2.1; 95% CI, 1.45–3.05) and The treatment of suspected uterine rupture is timely
perinatal mortality (0.58% vs. 0.28%; OR, 1.71; 95% CI, laparotomy after maternal stabilization and anaesthesia.
1.28–2.28) in the TOL group. The rates of maternal mortal- Urgent intervention is mandatory to obtain the best possi-
ity and low 5-minute Apgar scores were not different.32 ble outcome for both mother and fetus. Once the fetus is
In 2002 Keiser et al. reviewed the incidence and conse- delivered, maternal hemorrhage must be arrested, and if the
quences of uterine rupture in Nova Scotia from 1988 to uterus cannot be salvaged, hysterectomy may be required.
1997.51 Among 4516 women undergoing a TOL, 18 Although the risk of uterine rupture has been found to be
(0.39%) uterine ruptures were documented over 10 years. increased in situations of prolonged labour with augmenta-
All women underwent laparotomy, and there were no tion,55 when Phelan et al. retrospectively examined the pat-
maternal deaths. Of those who had a uterine rupture, 3 terns of uterine activity before uterine rupture, no associa-
women underwent hysterectomy, 10 required transfusion, tion with frequency or intensity of contractions could be
and 5 suffered a cystotomy. After excluding lethal anoma- discerned.40
lies, there was 1 perinatal death (0.02%) and 6 neonates with In 1996 Rozenberg et al. examined ultrasonographic mea-
severe asphyxia (0.13%).51 surement of the lower uterine segment’s myometrial thick-
In 2002 Bujold et al. examined the risk factors for serious ness at 36 to 38 weeks’ gestation as a predictor of uterine
neonatal morbidity associated with 23 cases of uterine rup- rupture and found that if the lower segment thickness was
ture among 2233 women attempting a TOL (rate 1.03%).52 less than 3.5 mm, the risk of uterine rupture or dehiscence
Nine neonates (0.4%) had a pH < 7.0 (severe metabolic aci- was 11.8%; if the measurement was greater than 3.5 mm,
dosis), 3 (0.13%) were diagnosed with hypoxic ischemic the risk of uterine rupture was minimal.56 However, the
incidence of uterine rupture in this population was 2.3%, E2 for cervical ripening in women with a previous Caesar-
significantly greater than the usually quoted 1%. Therefore, ean section and found it to be effective and not associated
the positive predictive value of this test in clinical practice with an increased risk of uterine rupture (OR, 1.46; 95% CI,
will be much lower.56 In a follow-up open study, Rozenberg 0.96–2.22), compared with spontaneous labour.62
et al. found that the use of the lower-uterine-segment mea- In 2003 Delaney and Young reported the examination of
surement helped clinicians select women for a TOL after 3746 women with a prior Caesarean delivery who under-
Caesarean.57 The rate of successful VBAC for those with 1 went either induced or spontaneous labour.63 They found
previous Caesarean section did not change but was that induced labour was associated with a greater risk of
increased in those with 2 previous Caesarean deliveries.57 early postpartum hemorrhage (7.3% vs. 5.0%: OR, 1.66;
These findings will need to be confirmed in further ran- 95% CI, 1.18–2.32), Caesarean delivery (37.5% vs. 24.2%:
domized studies before ultrasonography can be used to OR, 1.84; 95% CI, 1.51–2.25), and admission to a neonatal
make a decision about the safety of TOL after Caesarean. intensive care unit (13.3% vs. 9.4%: OR, 1.69; 95% CI,
Recommendation 1.25–2.29).63 There was a trend toward a higher rate of uter-
7. Suspected uterine rupture requires urgent attention and ine rupture, but this was not statistically significant (0.7%
expedited laparotomy to attempt to decrease maternal and vs. 0.3%, P = 0.128).63
perinatal morbidity and mortality (II-2A). In another retrospective study of 560 women, the rate of
uterine rupture in women whose labour was induced with
OXYTOCICS AND TOL AFTER oxytocin was 2%, with prostaglandin was 2.9%, and with
CAESAREAN SECTION both was 4.5%.59
Augmentation Up to 2001, there were conflicting data on the risk of labour
In 1987 Flamm et al. performed a multicentre examination induction with prostaglandin E2. Several other smaller stud-
of 485 women who received oxytocin to augment their ies reported that it appeared to be safe, effective, and not
spontaneous labour in a planned TOL after Caesarean.58 associated with an increased risk of uterine rupture.45,64–66
No increase in the risk of uterine rupture, maternal morbid- In the largest study published to date, conducted by
ity, or perinatal morbidity or mortality was detected.58 Lydon-Rochelle et al., the incidence of uterine rupture was
Zelop et al. supported the same conclusion about the risk of reviewed retrospectively in 20 095 women with a previous
uterine rupture with augmentation in a 1999 study (OR, 2.3; Caesarean section and was reported as follows: ERCS (no
95% CI, 0.8–7.0).59 Goetzl et al. examined the relation labour) 0.16%; spontaneous labour 0.52% (RR, 3.3; 95%
between the dose of oxytocin used and the risk of uterine CI, 1.8–6.0); labour induced without prostaglandin 0.77%
rupture in women undergoing a TOL after Caesarean.60 No (RR, 4.9; 95% CI, 2.4–9.7); and labour induced with prosta-
significant association was detected between exposure to glandin 2.45% (RR, 15.6; 95% CI, 8.1–30.0).67
oxytocin and the risk of uterine rupture.60 Careful surveil-
As for all inductions, the indication for induction in women
lance for progress of labour is required, especially when the
undergoing a planned TOL after Caesarean should be com-
diagnosis of dystocia is being considered.19,34 There are
pelling and documented. The possibility that the use of
insufficient studies examining the use of other agents to
oxytocin and (or) prostaglandin for labour induction in
augment labour, such as prostaglandins, and their safety in a
women considering TOL after Caesarean may be associated
TOL after Caesarean.
with an increased risk of uterine rupture and its sequelae
must be discussed with the parturient. The absolute risks of
Induction
uterine rupture are low, but the relative risks (especially with
In 2000 Ravasia et al. reviewed the risk of uterine rupture in the use of prostaglandin E2, compared with spontaneous
women undergoing an induction TOL after Caesarean.61 In labour) are greater.
575 women with a previous Caesarean section, labour was
induced with prostaglandin E2 gel (n = 172), intracervical Misoprostol
foley catheter (n = 129), or amniotomy and (or) oxytocin Misoprostol has been proposed as an effective and eco-
(n = 274).61 Outcomes were compared with women under- nomical agent for cervical ripening and induction.68 In 1998
going a TOL with spontaneous labour. The risk of uterine Sciscione et al. reported a case of uterine rupture in a woman
rupture was not increased in women who underwent either with 2 previous Caesarean deliveries after misoprostol was
amniotomy/oxytocin or foley catheter induction but was administered as a cervical ripening agent.69 Several small
significantly increased in those who underwent a prosta- series reported a risk from 0% to 11.7% of uterine rupture
glandin E2 induction (P = 0.004).61 with misoprostol in women undergoing a TOL after Cae-
Also in 2000, Sanchez-Ramos et al. performed a meta- sarean 43,70–73 Blanchette et al. compared prostaglandin E2 to
analysis looking at the efficacy and safety of prostaglandin misoprostol in women undergoing induction TOL after
External cephalic version is not contraindicated in women control subjects (17.4% vs. 4.7%, P = 0.05).102 Shipp et al.
with a previous Caesarean birth.94,95 reviewed 311 women who underwent a TOL after Caesar-
ean less than 18 months after their Caesarean section and
Diabetes Mellitus compared them with 2098 women who underwent a TOL
In a retrospective cohort study, Coleman et al. examined the after Caesarean after more than 18 months.103 The shorter
issue of TOL after Caesarean in women with gestational interval was associated with a threefold increase in the risk
diabetes mellitus (GDM).96 Coleman examined 156 women of uterine rupture (2.25% vs. 1.05%: OR, 3.0; 95% CI,
with GDM and planned TOL after Caesarean and com- 1.2–7.2).103 Huang et al. reviewed 1185 women undergoing a
pared them with women with no GDM and attempting TOL after Caesarean and noted no difference in the success
TOL after Caesarean. They reported that the success rate of vaginal delivery in women with a shorter interval of less
for VBAC of 64.1% in women with GDM was lower than than 19 months (79% vs. 85.5%, P = 0.12); however, they
the 77.2% of women without GDM (P < 0.001).96 Maternal did note a significant difference in successful VBAC in
and fetal morbidities were comparable.96 A retrospective women who underwent medical induction, compared with
study of TOL after Caesarean in women with pregestational spontaneous labour (14.3% vs. 86.1%, P < 0.01).104 Their
or gestational diabetes found similar results.97 Based on study noted no difference in the rate of uterine rupture.104
these studies, diabetes mellitus should not be considered a In 2002 Bujold et al. reported an observational study of 1527
contraindication to TOL after Caesarean. women undergoing a planned TOL after Caesarean at dif-
ferent intervals from the index Caesarean delivery.105 The
Recommendation
rates of uterine rupture were as follows: < 12 months, 4.8%;
15. Diabetes mellitus is not a contraindication to TOL after
13 to 24 months, 2.7%; 25 to 36 months, 0.9%; and > 36
Caesarean (II-2B).
months, 0.9%.105 After adjusting for such confounders as
number of layers in the uterine closure, induction, oxytocin,
Macrosomia
and epidural use, the odds ratio for uterine rupture in a
In a study examining the outcome of 365 women who
woman less than 24 months from her last delivery was 2.65
underwent a TOL after Caesarean and who were giving
(95% CI, 1.08–6.46).105
birth to neonates weighing more than 4000 g, Zelop et al.
demonstrated a success rate of 60%, with no increase in Recommendation
maternal or fetal morbidity and no increase in the risk of
uterine rupture.98 These data support previously reported 17. Women delivering within 18 to 24 months of a Caesar-
findings by Flamm (success rate 58%)99 and Phelan (success ean section should be counselled about an increased risk of
rate 67%).100 In 2003 Elkousy et al. reported an examination uterine rupture in labour (II-2B).
of 9960 women with a previous Caesarean section planning
a trial of labour. The study was further stratified by neonatal Postdatism
birth weights and birth history (primarily, whether they had Three studies have examined postdatism and TOL after
a previous vaginal delivery and whether it occurred before Caesarean.106–108 In 2 of these studies, the rate of successful
or after their Caesarean).101 Their results indicate that the VBAC and uterine rupture in women who delivered at less
likelihood of successful VBAC decreases with increasing than 40 weeks’ gestation was compared with those who
birth weight and is lowest in women who have never had a delivered at more than 40 weeks.106,107 Success rates for
successful vaginal birth.101 According to these results, sus- VBAC after 40 weeks were reported from 65.6%107 to
pected macrosomia is not a contraindication to TOL after 73.1%106 and were comparable to success rates for women
Caesarean, though it may be associated with a lower chance who delivered before 40 weeks’ gestation.106,107 Zelop et al.
of success. also compared the risk of uterine rupture in women who
Recommendation delivered before and after 40 weeks’ gestation in spontane-
16. Suspected fetal macrosomia is not a contraindication to ous labour and induced labour.108 They reported that the
a TOL after Caesarean (II-2B). risk of uterine rupture in a TOL after Caesarean after 40
weeks’ gestation was not significantly increased when com-
Interdelivery Interval pared with women who delivered before 40 weeks, whether
Four studies have examined the relation between the in spontaneous labour (1.0 % vs. 0.5%, P = 0.2, adjusted
interdelivery interval and the rate of successful VBAC and OR, 2.1; 95% CI, 0.7–5.7) or after induction (2.6% vs.
uterine rupture.102–105 Esposito et al. examined 23 cases of 2.1%, P = 0.7, adjusted OR, 1.1; 95% CI, 0.4–3.4).108
uterine rupture and compared them with 127 control sub-
jects.102 There was an increased risk of uterine rupture with Recommendation
a short interpregnancy interval (< 6 months between preg- 18. Postdatism is not a contraindication to a TOL after Cae-
nancies; < 15 months between deliveries), compared with sarean (II-2B).
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