Hypertensive Disorder of Pregnancy

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Hypertensive disorders of pregnancy
Updated 2014 Mar 17 06:49:00 AM: oral nif edipine associated with
shorter time to target blood pressure compared with IV labetalol in
pregnant women with hypertensive emergency (Obstet Gynecol 2013 Nov)
view updateShow more updates

General Inf ormation
Descript ion:
hypertension during pregnancy
(1, 2, 3, 4)
systolic blood pressure 140 mm Hg or diastolic blood pressure 90 mm Hg during pregnancy
may be pre-existing hypertension in woman with chronic hypertension
may be gestational hypertension (new onset af ter 20 weeks gestation)
preeclampsia
(1, 2, 3, 4)
typically def ined as hypertension with proteinuria (protein > 300 mg in 24-hour urine specimen)
af ter 20 weeks gestation
severe preeclampsia if any of
blood pressure 160/110 mm Hg on 2 occasions at least 6 hours apart during bed rest
proteinuria 5 g/24 hours or 3+ on 2 random urine specimens at least 4 hours apart
cerebral or visual disturbances, including headache
epigastric or right upper quadrant pain
f etal growth restriction
impaired liver f unction
oliguria < 500 mL/24 hours
pulmonary edema
thrombocytopenia
cyanosis
Also called:
preeclampsia
gestational hypertension
pregnancy-induced hypertension
PIH
toxemia of pregnancy
gestosis
preeclamptic toxemia
gestational hypertension has replaced term pregnancy-induced hypertension
(1)
Types:
definitions used in American guidelines
chronic hypertension def ined as systolic blood pressure 140 mm Hg or diastolic blood
pressure 90 mm Hg on > 2 occasions bef ore 20 weeks gestation or beyond 12 weeks
postpartum
(2, 4, 5, 6)
mild - 140-150 mm Hg systolic or 90-109 mm Hg diastolic
severe - 160 mm Hg systolic or 110 mm Hg diastolic
(1, 4)
replaces term of pregnancy-induced hypertension
hypertension without proteinuria developing af ter 20 weeks gestation
temporary diagnosis - either progresses to preeclampsia or chronic hypertension, or
resolves and becomes transient hypertension
transient hypertension - gestational hypertension with normal blood pressure by 12 weeks
postpartum
(4)
preeclampsia
hypertension (blood pressure 140/90 mm Hg) and proteinuria (> 300 mg/24 hours)
(1, 4, 5)
severe preeclampsia is preeclampsia with any of
(1, 5)
blood pressure 160/110 mm Hg on 2 occasions at least 6 hours apart during
bed rest
proteinuria 5 g/24 hours or 3+ on 2 random urine specimens at least 4 hours
apart
cerebral or visual disturbances
pulmonary edema or cyanosis
thrombocytopenia
preeclampsia superimposed on chronic hypertension
(4)
in woman with hypertension bef ore 20 weeks gestation - new onset proteinuria
in woman with hypertension and proteinuria bef ore 20 weeks gestation - any of
sudden 2- to 3-f old increase in proteinuria
sudden increase in blood pressure
thrombocytopenia
elevated aspartate aminotransf erase (AST) or alanine aminotransf erase (ALT)
Society of Obstetricians and Gynaecologists of Canada (SOGC) recommendations for
classification of hypertensive disorders of pregnancy
(3)
hypertension in pregnancy def ined as diastolic blood pressure 90 mm Hg, based on average
of at least 2 measurements using same arm (SOGC Grade B, Level II-2)
severe hypertension def ined as systolic blood pressure 160 mm Hg or diastolic blood
pressure 110 mm Hg (SOGC Grade B, Level II-2)
f or diagnosis of clinically signif icant proteinuria
strongly suspect proteinuria when urinary dipstick proteinuria 2+ (SOGC Grade A,
Level II-2)
proteinuria def ined as 0.3 g/day in 24-hour urine collection or 30 mg/mmol urinary
creatinine in spot (random) urine sample (SOGC Grade B, Level II-2)
insuf f icient evidence f or recommendations on accuracy of urinary albumin:creatinine
ratio (SOGC Grade I, Level II-2)
def initions of preeclampsia
in women with pre-existing hypertension - resistant hypertension, new or worsening
proteinuria, or 1 of other adverse conditions (SOGC Grade B, Level II-2)
in women with gestational hypertension - new-onset proteinuria or 1 of other adverse
conditions (SOGC Grade B, Level II-2)
severe preeclampsia def ined as preeclampsia with onset bef ore 34 weeks gestation, with
heavy proteinuria or with 1 adverse conditions (SOGC Grade B, Level II-2)
adverse conditions include
maternal symptoms of hypertension such as headache, visual changes, abdominal pain
maternal signs of end-organ dysf unction
abnormal maternal laboratory testing
elevated aspartate aminotransf erase (AST), alanine aminotransf erase (ALT), lactate
dehydrogenase (LDH) with symptoms
platelet count < 100 10
9
/L
albumin < 20 g/L
f etal morbidity
Who is most af f ect ed:
f or preeclampsia
(2, 4)
women with pre-existing chronic hypertension (especially if 4 years)
nulliparas
multiple gestations
women at > 20 weeks gestation
more f requent in women near term
Incidence/Prevalence:
hypertensive disorders
(1, 2, 3, 5)
most common medical complication of pregnancy
complicate about 5%-8% of pregnancies in United States
about 1% of pregnancies complicated by pre-existing hypertension
increasing number of hypertension-associated delivery hospitalizations in United
States
based on retrospective cohort of 36,537,061 delivery discharges f rom 1998-2006
Nationwide Inpatient Sample of the Healthcare Cost and Utilization Project
prevalence of hypertensive disorders among delivery hospitalizations
67.2 per 1,000 deliveries in 1998
81.4 per 1,000 deliveries in 2006
Ref erence - Obstet Gynecol 2009 Jun;113(6):1299
9.8% women have hypertensive disorder in pregnancy in Australia
based on study of 250,173 women and 255,931 inf ants discharged f rom hospital
f ollowing birth in New South Wales between 2000 and 2002
24,517 women (9.8%) had hypertensive disorder including gestational hypertension
(4.3%), preeclampsia (4.2%), chronic hypertension (0.6%) and chronic hypertension with
superimposed preeclampsia (0.3%)
Ref erence - Med J Aust 2005 Apr 4;182(7):332 f ull-text
7% rate of gestational hypertension in 39,615 pregnancies in World Health Organization
(WHO) Antenatal Care Trial (Am J Obstet Gynecol 2006 Apr;194(4):921)
preeclampsia
prevalence of preeclampsia 3.8% in United States in 2010
based on retrospective cohort study
120,000,000 women hospitalized f or delivery f rom 1980 to 2010 in United States were
analyzed
in 2010, prevalence of
any preeclampsia 3.8%
severe preeclampsia 1.4%
mild preeclampsia 2.5%
Ref erence - BMJ 2013 Nov 7;347:f 6564
median incidence of preeclampsia 3.9%
based on systematic review of 36 studies with 1,699,073 pregnant women
Ref erence - BJOG 2007 Dec;114(12):1477
2.2% rate of preeclampsia in 39,615 pregnancies in WHO Antenatal Care Trial (Am J Obstet
Gynecol 2006 Apr;194(4):921)
4.2% rate of preeclampsia among 804,448 pregnancies with f irst child, singleton birth af ter 24
weeks gestation in Norway between 1967 and 2003 (JAMA 2006 Sep 20;296(11):1357 f ull-text),
correction can be f ound in JAMA 2006 Dec 27;296(24):2926
3.8% rate of preeclampsia among 3,494 women giving birth in Norwegian population-based
study (BMJ 2007 Nov 10;335(7627):978 f ull-text), editorial can be f ound in BMJ 2007 Nov
10;335(7627):945, commentary can be f ound in BMJ 2007 Nov 24;335(7629):1059
higher prevalence among women with hypertension
(3, 4)
occurs in about 25% of women with chronic hypertension
develops in about 35% of women with gestational hypertension with onset < 34 weeks
gestation
severe preeclampsia (including hemolysis, elevated liver enzymes, low platelets (HELLP) syndrome
and eclampsia) expected to occur in 0.39% deliveries
based on case-control study f rom population of 48,865 women delivering in United Kingdom
compared with 4 randomly selected controls f or each case, risk f actors f or severe
preeclampsia were age > 34 years, nonwhite ethnic group, past or current hypertension,
previous preeclampsia, diabetes, antenatal admission to hospital, multiple pregnancy, and
social exclusion
Ref erence - BMJ 2001 May 5;322(7294):1089 f ull-text
Causes and Risk Factors
Causes:
cause unknown in most cases of hypertension during pregnancy, especially f or preeclampsia
(1)
Pat hogenesis:
reduced organ perf usion due to vasospasm and activation of coagulation cascade (Am J Obstet
Gynecol 2000 Jul;183(1):S1), commentary can be f ound in Am J Obstet Gynecol 2001 Aug;185(2):522
preeclampsia
abnormal and shallow placentation (due to f ailure of normal trophoblastic invasion of spiral
arteries) is hallmark of preeclampsia
(2)
hypotheses on pathogenesis
abnormal placental implantation
(1)
def ects in trophoblasts
def ects in spiral arterioles
angiogenic f actors
(1)
cardiovascular maladaptation and vasoconstriction
(1)
genetic predisposition (f or example, maternal or paternal thrombophilias)
(1)
immunologic intolerance between f etoplacental and maternal tissue
(1)
platelet activation
(1)
vascular endothelial damage or dysf unction
(1, 2, 3)
possible 2-stage process causing mismatch between uteroplacental supply and
f etal demands, leading to maternal endothelial cell dysf unction and maternal and
f etal manif estations
in f irst stage, placenta produces specif ic proteins or trophoblastic debris
that enter maternal circulation
in second stage, clinical disease dependent on circulating f actors and
health of mother
endothelial dysf unction implicated in case-control study (JAMA 2001 Mar
28;285(12):1607)
mRNA expression of pregnancy-specif ic beta1 glycoprotein and trophoblast
glycoprotein increased in study of 5 women with preeclampsia and 5 controls (Obstet
Gynecol 2007 Nov;110(5):1130)
prostacyclin (PGI2) def iciency implicated (JAMA 1999 Jul 28;282(4):356), commentary can
be f ound in JAMA 2000 Mar 22-29;283(12):1568
increased sympathetic vasoconstrictor activity (N Engl J Med 1996 Nov
14;335(20):1480 f ull-text), commentary can be f ound in N Engl J Med 1997 May
1;336(18):1326
signif icant structural capillary raref action (Obstet Gynecol 2012 May;119(5):967)
review of pathogenesis and genetics of preeclampsia can be f ound in Lancet 2001 Jan
6;357(9249):53
review of uric acid as pathogenic f actor in preeclampsia can be f ound in Placenta 2008 Mar;29
Suppl A:S67
Likely risk f act ors:
more important risk f actors f or preeclampsia (consider specialty ref erral if 1 f actor present)
(1, 3)
maternal age 40 years
medical, f amily and social history
previous preeclampsia, especially if severe or bef ore 32 weeks gestation
f amily history of preeclampsia (mother or sister)
antiphospholipid antibody syndrome
pre-existing hypertension or diastolic blood pressure 90 mm Hg at f irst antenatal visit
pre-existing renal disease or proteinuria at f irst antenatal visit
pre-existing diabetes mellitus
obesity (body mass index 35 kg/m
2
)
risk f actors in current pregnancy
multiple pregnancy
f irst ongoing pregnancy
interpregnancy interval 10 years
blood pressure 130 mm Hg systolic or 80 mm Hg diastolic at f irst antenatal visit
less important risk f actors f or preeclampsia (consider special ref erral risk if 2 risk f actors
present)
(1, 3)
demographic risk f actors
lower socioeconomic status
Nordic, Black, South Asian, or Pacif ic Island ethnicity
medical, f amily and social history
heritable thrombophilias
nonsmoking (based on observational studies)
increased prepregnancy triglyceride levels
f amily history of early-onset cardiovascular disease
cocaine and methamphetamine use
risk f actors in current pregnancy
interpregnancy interval < 2 years
use of reproductive technologies
new partner
gestational trophoblastic disease
excessive weight gain in pregnancy
inf ection during pregnancy (f or example, urinary tract inf ection, periodontal disease)
possible risk f actors occurring in second or third trimester of current pregnancy
elevated blood pressure
abnormal maternal serum screening
abnormal uterine artery Doppler velocimetry
cardiac output > 7.4 L/minute
elevated uric acid
evidence regarding specif ic risk f actors
increasing maternal age associated with increased risk of hypertensive disorders of
pregnancy
203,517 women (15% 35 years old) with singleton gestation stratif ied by maternal age
compared with women aged 25-29.9 years, increased risk of hypertensive disorders of
pregnancy in women aged
35-39.9 years (adjusted odds ratio [OR] 1.22, 95% CI 1.12-1.33)
40-44.9 years (adjusted OR 1.63, 95% CI 1.42-1.88)
45 years (adjusted OR 1.89, 95% CI 1.21-2.96)
Ref erence - Obstet Gynecol 2013 Dec;122(6):1184
estimated relative risks for multiple risk factors for preeclampsia
based on systematic review of 48 controlled cohort studies
previous history of preeclampsia (relative risk [RR] 7.19, 95% CI 5.85-8.83)
antiphospholipid antibodies (RR 9.72, 95% CI 4.34-21.75)
pre-existing diabetes (RR 3.56, 95% CI 2.54-4.99)
multiple gestations (RR 2.93, 95% CI 2.04-4.21)
nulliparity (RR 2.91, 95% CI 1.28-6.61)
f amily history (RR 2.9, 95% CI 1.7-4.93)
diastolic blood pressure 80 mm Hg (RR 1.38, 95% CI 1.01-1.87)
increased body mass index bef ore pregnancy (RR 2.47, 95% CI 1.66-3.67) or at
presentation (RR 1.55, 95% CI 1.28-1.88)
maternal age > 40 years (RR 1.96, 95% CI 1.34-2.87) f or multiparous women
additional possible risk f actors based on individual studies
interval 10 years since previous pregnancy
autoimmune disease
renal disease
chronic hypertension
Ref erence - BMJ 2005 Mar 12;330(7491):565 f ull-text, editorial can be f ound in BMJ
2005 Mar 12;330(7491):549
adjusted odds ratios for multiple risk factors for preeclampsia
based on prospective cohort study of 3,572 healthy, nulliparous women with singleton
pregnancy
preeclampsia in 5.3%
clinical risk f actors at 15 weeks gestation f or preeclampsia
f amily history of preeclampsia (adjusted odds ratio [OR] 2, 95% CI 1.3-3)
vaginal bleeding 5 days (adjusted OR 2, 95% CI 1.1-3.8)
f amily history of coronary artery disease (adjusted OR 1.9, 95% CI 1.2-2.8)
increase of 5 mm Hg in mean arterial pressure (calculated at 14-16 weeks
gestation) (adjusted OR 1.4, 95% CI 1.3-1.5)
Ref erence - BMJ 2011 Apr 7;342:d1875 f ull-text
circulatory risk profile appears common in women with history of preeclampsia
1,234 f ormerly preeclamptic nonpregnant women screened f or 4 possible risk prof iles
(circulatory [hypertension or latent hypertension], metabolic syndrome, thrombophilia
[f actor V Leiden, prothrombin mutation, or protein C or S def iciency], and
hyperhomocysteinemia) 6-12 months postpartum
77.6% had 1 risk prof ile
risk prof ile prevalence
circulatory 66.1%
metabolic syndrome 15.4%
thrombophilia 10.8%
hyperhomocysteinemia 18.7%
prevalence of circulatory, metabolic syndrome, and hyperhomocysteinemia risk prof iles
decreased signif icantly with gestational age at delivery
minimal overlap occurred between metabolic syndrome, thrombophilic, and
hyperhomocysteinemia risk prof iles
Ref erence - Obstet Gynecol 2013 Jan;121(1):97
risk factors for new-onset late postpartum preeclampsia
based on case-control study
34 women with new-onset late postpartum preeclampsia (LPP) af ter normal delivery and
68 women without new-onset LPP matched by delivery date were evaluated
increased risk of new-onset LPP associated with
aged 40 years (adjusted odds ratio [OR] 24.83, p = 0.03)
Black race (adjusted OR 78.35, p < 0.001)
Latino ethnicity (adjusted OR 19.08, p = 0.01)
gestational diabetes (adjusted OR 72.91, p < 0.001)
Ref erence - Am J Obstet Gynecol 2013 Nov 7 early online
additional risk f actors and subsequent studies include
obesity as risk factor supported by multiple subsequent studies
multiple gestation associated with increased risk of pregnancy-related
hypertensive disease
based on cohort of 34,374 pregnancies with 1-4 f etuses with no hypertension at
prenatal booking and delivery af ter 28 weeks gestation
incidence of pregnancy-related hypertensive conditions 6.5% f or singleton
pregnancies vs. 12.7%-19.6% f or multif etal pregnancies (p < 0.001)
incidence of severe pregnancy-related hypertensive conditions (hemolysis,
elevated liver enzymes, low platelets [HELLP] syndrome, disseminated
intravascular coagulation, eclampsia, low platelets, renal f ailure, abruption) was
0.5% f or singleton pregnancies vs. 1.6% f or twin and 3.1% f or triplet pregnancies
(p < 0.001)
independent risk f actors f or pregnancy-related hypertensive conditions were
increasing f etal number, nulliparity, and advanced maternal age
Ref erence - Obstet Gynecol 2005 Nov;106(5):927
preterm delivery in setting of preeclampsia and low fetal growth associated with
increased risk of preeclampsia in subsequent pregnancy
based on retrospective cohort of 536,419 women with f irst and second singleton
deliveries in Denmark f rom 1978 to 2007
rheumatologic disease associated with higher risk of preeclampsia
based on cohort of 114 mothers with rheumatologic disease (systemic lupus
erythematosus, rheumatoid arthritis, antiphospholipid antibody syndrome, or
other rheumatologic disease) vs. 18,534 mothers without rheumatologic disease
migraine headaches associated with increased risk of hypertensive disorders in
pregnancy
based on prospective cohort of 702 normotensive women with singleton
pregnancy at 11-16 weeks gestation
migraine diagnosis in 38.5%
hypertensive disorder developed in 9.1% women with migraines vs. 3.1% without
migraines (adjusted odds ratio 2.85, p < 0.05)
Ref erence - Cephalalgia 2009 Mar;29(3):286
prepregnancy lipid and blood pressure levels associated with risk for
preeclampsia
higher maternal triglyceride levels may be associated with higher risk for
preeclampsia
based on systematic review of 5 cohort studies and 24 case-control studies
Ref erence - BJOG 2013 Oct;120(11):1321
microalbuminuria or nephropathy associated with increased risk of preterm labor
and preeclampsia in women with diabetes mellitus type 1
based on cohort of 240 pregnant women with diabetes mellitus type 1
Ref erence - Diabetes Care 2001 Oct;24(10):1739
women born small for gestational age are at higher risk for preeclampsia
based on population-based cohort study of 118,634 women registered as
newborns and as mothers in Sweden
Ref erence - BJOG 2007 Mar;114(3):319
some antidepressants used during pregnancy associated with increased risk of
preeclampsia but not selective serotonin reuptake inhibitors(level 2 [mid-level] evidence)
69,448 pregnant women with depression had no treatment or monotherapy with selective
serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitor (SNRIs), or
tricyclic antidepressants (TCAs)
risk of preeclampsia increased with use of SNRIs and TCAs
use during gestational weeks 10-20 (vs. no antidepressant use)
SNRIs (adjusted relative risk [RR] 1.95, 95% CI 1.25-3.03)
TCAs (adjusted RR 3.23, 95% CI 1.87-5.59)
use during gestational weeks 10-24 among women with pre-pregnancy antidepressant
use (vs. discontinued use during gestational weeks 10-24)
SNRIs (adjusted RR 3.43, 95% CI 1.77-6.65)
TCAs (adjusted RR 3.26, 95% CI 1.04-10.24)
no signif icant dif f erences with use of SSRIs
Ref erence - Am J Epidemiol 2012 May 15;175(10):988
genetic predisposition
mother, aunt or paternal grandmother with preeclampsia associated with increased
risk of preeclampsia
based on population-based study of linked generational data f rom Norway with 438,597
mother-of f spring pairs and 286,945 f ather-of f spring pairs
Ref erence - BMJ 2005 Oct 15;331(7521):877 f ull-text
genetic predisposition comes f rom both mother and f ather (f etus f rom f ather who f athered a
preeclamptic pregnancy increases risk) (BMJ 1998 May 2;316(7141):1343 f ull-text)
interpregnancy interval
interpregnancy interval > 59 months associated with increased risk for preeclampsia
and eclampsia
based on 456,889 women delivering singleton inf ants between 1985 and 1997
pregnancy interval > 59 months in 19.5%
Ref erence - BMJ 2000 Nov 18;321(7271):1255
increasing interpregnancy interval associated with increasing risk for preeclampsia
based on study of 551,478 women with 2 singleton deliveries and 209,423 women with 3
singleton deliveries
preeclampsia in 3.9% with f irst pregnancy, 1.7% with second pregnancy and 1.8% with
third pregnancy
if > 10 years, odds ratio f or preeclampsia 1.12 f or each 1-year increase in interbirth
interval
Ref erence - N Engl J Med 2002 Jan 3;346(1):33, commentary can be f ound in N Engl J
Med 2002 Jun 6;346(23):1831
periodontal disease may be associated with increased risk of preeclampsia, but evidence
inconsistent
periodontitis during pregnancy not associated with preeclampsia in 1 cohort study
786 pregnant women with periodontal exam < 20 weeks gestation evaluated
retrospectively f ollowing delivery
311 women with periodontal disease
475 women without periodontal disease
preeclampsia def ined as hypertension (blood pressure 140/90 mm Hg) with proteinuria
periodontal disease not associated with preeclampsia (adjusted odds ratio 0.71, 95% CI
0.37-1.36, p = 0.3)
preeclampsia associated with chronic hypertension (adjusted odds ratio 3.54, 95% CI
1.48-8.48, p < 0.005)
Ref erence - Am J Obstet Gynecol 2009 May;200(5):497e1
active periodontal disease during pregnancy associated with increased risk of
preeclampsia in 1 cohort study
1,115 healthy pregnant women enrolled bef ore 26 weeks gestation, periodontal exams
done at enrollment and within 48 hours of delivery
preeclampsia def ined as blood pressure > 140/90 mm Hg on 2 occasions and
proteinuria on catheterized urine at least once
analysis based on 763 women who delivered live inf ants and had data available
39 (5.1%) had preeclampsia
severe periodontal disease associated with 2.1-2.4 times risk of preeclampsia
based on exam bef ore 26 weeks gestation, risk of preeclampsia at time of delivery was
2% if healthy gums
5% if mild periodontal disease
6% if severe periodontal disease
based on exam at time of delivery, risk of preeclampsia was
3% if healthy gums
5% if mild periodontal disease
10% if severe periodontal disease
Ref erence - Obstet Gynecol 2003 Feb;101(2):227
periodontal disease and urinary tract infection during pregnancy may be associated
with increased risk of preeclampsia
based on systematic review with heterogeneity
systematic review of 49 cohort, cross-sectional and case-control studies
periodontal disease associated with preeclampsia (odds ratio 1.76, 95% CI 1.43-2.18) in
6 studies with high degree of heterogeneity (I
2
= 79%)
urinary tract inf ection associated with preeclampsia (odds ratio 1.57, 95% CI 1.45-1.70)
in 17 studies with high degree of heterogeneity (I
2
= 80%)
no association f ound with HIV inf ection, malaria, or presence of antibodies to
Chlamydia pneumoniae, Helicobacter pylori, and cytomegalovirus
Ref erence - Am J Obstet Gynecol 2008 Jan;198(1):7, commentary can be f ound in Evid
Based Dent 2008;9(2):46
Possible risk f act ors:
anticardiolipin antibodies, MTHFR homozygosity, and hyperhomocysteinemia may increase risk f or
preeclampsia but evidence conf licting f or women with mutations in f actor V Leiden or prothrombin
G20210A
moderate-to-high levels of anticardiolipin antibodies may be associated with
preeclampsia
based on systematic review of observational studies limited by heterogeneity
systematic review of 12 studies (cohorts, case-controls, or cross-sectional studies)
evaluating association of anticardiolipin antibodies and preeclampsia
moderate-to-high levels of anticardiolipin antibodies associated with
preeclampsia (odds ratio [OR] 2.86, 95% CI 1.37-5.98) in analysis of 12 studies
(results limited by heterogeneity)
severe preeclampsia (OR 11.15, 95% CI 2.66-46.75) in analysis of 5 studies
(results limited by heterogeneity)
factor V Leiden heterozygosity, prothrombin heterozygosity, MTHFR homozygosity,
anticardiolipin antibodies, and hyperhomocysteinemia each associated with
preeclampsia
based on systematic review of trials with signif icant heterogeneity and observational
studies
systematic review of 79 randomized trials or observational studies (prospective or
retrospective) evaluating pregnant women or women up to 6 weeks postpartum with
thrombophilia
compared to women without thrombophilia, risk f or preeclampsia increased with
f actor V Leiden heterozygosity (odds ratio [OR] 2.19, 95% CI 1.46-3.27) in
analysis of 14 studies with 3,922 patients (results limited by signif icant
heterogeneity)
prothrombin heterozygosity (OR 2.54, 95% CI 1.52-4.23) in analysis of 8 studies
with 2,099 patients
methylenetetrahydrof olate reductase enzyme (MTHFR) homozygosity (OR 1.37,
95% CI 1.07-1.76) in analysis of 12 studies with 3,686 patients
anticardiolipin antibodies (OR 2.73, 95% CI 1.65-4.51) in analysis of 8 studies with
2,645 patients
hyperhomocysteinemia (OR 3.49, 95% CI 1.21-10.11) in analysis of 2 studies with
405 patients
Ref erence - Br J Haematol 2006 Jan;132(2):171
mutations in factor V Leiden and prothrombin G20210A may not be associated with
preeclampsia
based on systematic review of observational studies
systematic review of 10 prospective cohort studies comparing pregnancy complications
in pregnant women with prothrombin gene mutation or f actor V Leiden with women
without these conditions
review limited by heterogeneity due to baseline dif f erences in study populations
compared to women without thrombophilia, no signif icant dif f erence in risk f or
preeclampsia
f actor V Leiden (homozygous or heterozygous) in analysis of 9 studies with
21,833 women
prothrombin G20210A mutation (homozygous or heterozygous) in analysis of 6
studies with 14,254 women
Ref erence - PLoS Med 2010 Jun 15;7(6):e1000292 f ull-text
see Thrombophilia in pregnancy f or details
in utero diethylstilbestrol (DES) exposure associated with preeclampsia
based on 2 cohort studies
cohort study of 7,313 live births, including 4,759 with in utero DES exposure
incidence of preeclampsia was 4.4% in DES exposed and 2.9% DES unexposed
pregnancies
Ref erence - Obstet Gynecol 2007 Jul;110(1):113
retrospective cohort study of 4,653 women exposed to DES in utero and 1,927 women without
DES exposure
DES exposure associated with increased risk of preeclampsia compared to no exposure
(26.4% vs. 13.7%, p < 0.05)
Ref erence - N Engl J Med 2011 Oct 6;365(14):1304
vitamin D insufficiency during pregnancy associated with increased risk of preeclampsia
based on systematic review
systematic review of 31 observational studies evaluating association between maternal serum
25-hydroxyvitamin D level during pregnancy, and pregnancy and neonatal outcomes
insuf f icient maternal serum 25-hydroxyvitamin D level associated with increased risk of
preeclampsia (odds ratio 1.79, 95% CI 1.25-2.58) in analysis of 7 studies
Ref erence - BMJ 2013 Mar 26;346:f 1169 f ull-text, similar results f ound in systematic review of
15 observational studies evaluating association between serum 25-hydroxyvitamin D level
during pregnancy and risk of preeclampsia (J Clin Endocrinol Metab 2013 Aug;98(8):3165-73)
secondary hyperparathyroidism plus low vitamin D level associated with increased risk of
preeclampsia
1,141 pregnant women of low-income and minority status were analyzed
presence of secondary hyperparathyroidism plus 25-hydroxyvitamin D < 20 ng/mL associated
with increased risk of preeclampsia (adjusted odds ratio 2.86, 95% CI 1.28-6.41)
Ref erence - Am J Clin Nutr 2013 Sep;98(3):787
polycystic ovary syndrome associated with increased risk for gestational diabetes,
preeclampsia, and preterm delivery
based on systematic review of cohort studies and additional large cohort study
systematic review of 23 cohort studies (8 prospective, 15 retrospective) reporting association
between polycystic ovary syndrome and pregnancy outcomes in 2,544 women with polycystic
ovary syndrome and 89,848 women without polycystic ovary syndrome
polycystic ovary syndrome associated with increased risk of
gestational diabetes (odds ratio [OR] 2.8, 95% CI 1.9-4)
pregnancy-induced hypertension (OR 4, 95% CI 2.8-6)
preeclampsia (OR 4.2, 95% CI 2.8-6.5)
preterm delivery (OR 2.2, 95% CI 1.6-3)
inf ants born to mothers with polycystic ovary syndrome had increased risk of small-f or-
gestational-age (OR 2.62, 95% CI 1.35-5.1)
no signif icant association between polycystic ovary syndrome and cesarean delivery,
operative vaginal delivery, and birth of large-f or-gestational-age inf ants
Ref erence - Am J Obstet Gynecol 2011 Jun;204(6):558.e1
prospective cohort study comparing 3,787 births among women with polycystic ovary
syndrome and 1,191,336 births among women without polycystic ovary syndrome
polycystic ovary syndrome associated with increased risk of
preeclampsia (adjusted odds ratio [OR] 1.45, 95% CI 1.24-1.69)
very preterm birth (adjusted OR 2.21, 95% CI 1.69-2.9)
gestational diabetes (adjusted OR 2.32, 95% CI 1.88-2.88)
inf ants born to mothers with polycystic ovary syndrome had increased risk of
being large f or gestational age (adjusted OR 1.39, 95% CI 1.19-1.62)
meconium aspiration (adjusted OR 2.02, 95% CI 1.13-3.61)
low Apgar score (< 7) at 5 minutes (adjusted OR 1.41, 95% CI 1.09-1.83)
Ref erence - BMJ 2011 Oct 13;343:d6309 f ull-text, editorial can be f ound in BMJ 2011
Oct 13;343:d6407
increase of 3 BMI units between first and second pregnancies associated with increased
risk of pregnancy-induced hypertension in normal and underweight women
based on cohort study
7,897 women with f irst 2 consecutive deliveries between 2009 and 2011 evaluated f or
interpregnancy weight change (dif f erence between prepregnancy body mass indices [BMI] of
f irst and second pregnancies)
f or normal and underweight women only, increase in interpregnancy interval by 3 BMI units
associated with increased risk of pregnancy-induced hypertension (adjusted odds ratio 3.76,
95% CI 2.16-6.57)
subclinical hypothyroidism may increase risk of hypertensive disorders in pregnancy
based on prospective cohort study
24,883 women who delivered a singleton inf ant were assessed f or hypertension in pregnancy
2.1% had subclinical hypothyroidism
overall incidence of hypertensive disorders in pregnancy
10.9% in patients with subclinical hypothyroidism (p = 0.016 vs. other groups)
6.2% in patients with subclinical hyperthyroidism
8.5% in euthyroid patients
subclinical hypothyroidism associated with increased risk of severe preeclampsia (adjusted
odds ratio 1.6, 95% CI 1.1-2.4)
Ref erence - Obstet Gynecol 2012 Feb;119(2 Pt 1):315
higher HbA1c associated with increased risk of preeclampsia in women with type 1 diabetes
based on prospective cohort analysis of DAPIT trial
127 (17% of original trial) women with type 1 diabetes had preeclampsia and 83 (11%) had
preeclampsia associated with higher HbA1c bef ore and during pregnancy (p < 0.05 vs. no
preeclampsia development)
HbA1c 8% in early pregnancy increased risk of preeclampsia (odds ratio [OR] 3.68, 95% CI
1.17-11.6) (vs. HbA1c 6.1% as optimal control)
increased risk of preeclampsia at 26 weeks gestation with (vs. HbA1c < 6.1%)
HbA1c 6.1%-6.9% (OR 2.09, 95% CI 1.03-4.21)
HbA1c 7%-7.9% (OR 3.2, 95% CI 1.47-7)
HbA1c 8% (OR 3.81, 95% CI 1.3-11.1)
increased risk of preeclampsia at 34 weeks gestation (vs. HbA1c < 6.1%)
HbA1c 7%-7.9% (OR 3.27, 1.31-8.2)
HbA1c 8% (OR 8.01, 2.04-31.5)
no signif icant association of glycemic control with gestational hypertension risk
Ref erence - Diabetes Care 2011 Aug;34(8):1683
angiogenesis-related biomarkers associated with risk of preeclampsia
elevated levels of soluble fms-like tyrosine kinase 1 (sFlt-1) and reduced levels of
placental growth factor (PlGF)
other maternal serum angiogenesis-related biomarkers associated with preeclampsia in case-
control study comparing 40 women with preeclampsia and 100 controls
increased soluble endoglin (sEng)
increased ratio sFlt-1/placental growth f actor (PlGF)
increased ratio soluble endoglin/transf orming growth f actor-beta1 (TGF-beta1)
increased combined ratio of (sFlt-1 + soluble endoglin)/(PlGF + TGF-beta1)
decreased TGF-beta1
Ref erence - Obstet Gynecol 2008 Jun;111(6):1403, correction can be f ound in Obstet
Gynecol 2008 Sep;112(3):710
elevated plasma kynurenic acid may be associated with increased risk of preeclampsia
2,936 women with singleton pregnancies evaluated f or six kynurenine pathway metabolites at
approximately 18 weeks gestation
4% subsequently developed preeclampsia
kynurenic acid concentration > 95th percentile associated with increased risk of preeclampsia
compared to kynurenic acid concentration in 25th-75th percentile (adjusted odds ratio 3.6,
95% CI 1.9-6.8)Ref erence - Obstet Gynecol 2012 Jun;119(6):1243
HLA-DR genotypes (particularly DR4) may be associated with preeclampsia risk
based on systematic review of 22 studies of HLA allele f requencies in association with
preeclampsia or intrauterine growth retardation
9 of 10 studies suggested DR allelic dif f erences associated with preeclampsia
2 of 3 studies suggested no association between HLA alleles and intrauterine growth
retardation
6 studies of HLA homozygosity as risk f actor f or preeclampsia had mixed results
cytokine genotype associated with preeclampsia in case-control study of 150 primiparous
preeclamptic women and 661 primiparous normotensive women (Am J Obstet Gynecol 2005
Jul;193(1):209)
plasma adiponectin levels < 6.4 mcg/mL associated with hypertensive disorders in
pregnancy, especially preeclampsia, in case-control study (Obstet Gynecol 2005 Aug;106(2):340)
history of fertility treatment and recurrent miscarriage may be associated with increased
risk of preeclampsia in pregnant nulliparous women
based on cohort study in Norway
20,846 nulliparous women with singleton pregnancies completed questionnaires on
miscarriage and inf ertility
preeclampsia diagnosis retrieved f rom national registry
preeclampsia associated with
recurrent miscarriage and f ertility treatment (p < 0.05)
f ertility treatment (p < 0.05)
recurrent miscarriage (not signif icant)
Ref erence - BJOG 2009 Jan;116(1):108
in vitro fertilization with donor egg associated with increased risk of gestational
hypertension and preeclampsia compared with autologous in vitro fertilization
158 pregnancies resulting f rom donor egg or autologous in vitro f ertilization (IVF) were
evaluated
comparing donor ovum vs. autologous IVF
gestational hypertension in 24.7% vs. 7.4% (p < 0.01)
preeclampsia in 16.9% vs. 4.9% (p = 0.02)
premature delivery in 34.2% vs. 19% (p = 0.03)
Fact ors not associat ed wit h increased risk:
smoking
smoking in pregnancy associated with decreased risk of preeclampsia in younger
women without pregestational hypertension
based on cohort study of 674,250 singleton pregnancies in New York City f rom 1995-
2003
smoking associated with overall reduced risk of preeclampsia (adjusted odds ratio 0.88,
p < 0.05) with greatest ef f ect observed in women 30 years
smoking not associated with reduced risk of preeclampsia in women with chronic
hypertension (adjusted odds ratio 1.04, p > 0.05)
Ref erence - Am J Epidemiol 2009 Jan 1;169(1):33
moderate smoking during pregnancy (1-9 cigarettes/day) associated with DECREASED
risk of preeclampsia in retrospective analysis of 127,721 singleton pregnancies, reasons
unknown (Acta Obstet Gynecol Scand 1999 Sep;78(8):693)
smoking during pregnancy in overweight and obese women may not protect against
preeclampsia
based on retrospective cohort of 7,757 healthy primigravid women with singleton
pregnancies between 1959 and 1965
smoking decreased risk of preeclampsia in underweight and normal weight women
Ref erence - Am J Epidemiol 2008 Aug 15;168(4):427 f ull-text
history of abortion or preterm birth does not increase risk of preeclampsia compared to
nulliparous women
based on retrospective study of 140,773 pregnancies
history of term pregnancy decreases risk
Ref erence - Am J Obstet Gynecol 2002 Oct;187(4):1013 in JAMA 2003 Jan 15;289(3):280
psychosocial stress before 24 weeks gestation does not appear associated with increased
incidence of preeclampsia or gestational hypertension during first pregnancy
based on cohort study with low completion rates
3,679 nulliparous women pregnant with singleton pregnancy completed questionnaires on
sociodemographic and psychosocial f actors bef ore 24 weeks gestation
preeclampsia in 3.5%
gestational hypertension in 4.4%
no association observed between preeclampsia or gestational hypertension and work stress,
anxiety, pregnancy-related anxiety or depression
Ref erence - BJOG 2008 Apr;115(5):607
inhaled corticosteroids not associated with increased risk of pregnancy-induced
hypertension
based on case control study
302 cases of pregnancy-induced hypertension (including 165 cases of preeclampsia)
compared with 3,013 matched controls (including 1,643 matched controls f or preeclampsia
comparison)
no signif icant dif f erences in either outcome with adjusted odds ratios about 1
oral corticosteroids were associated with
increased risk f or pregnancy-induced hypertension (adjusted odds ratio 1.57, 95% CI
1.02-2.41)
trend f or preeclampsia (adjusted odds ratio 1.72, 95% CI 0.98-3.02)
Ref erence - BMJ 2005 Jan 29;330(7485):230 f ull-text
serum folate levels in early pregnancy appear high and similar in normotensive and
hypertensive pregnant women exposed to folic acid supplementation
based on nested case-control study
214 pregnant women who developed a hypertensive disorder of pregnancy compared with 428
similar normotensive pregnant women
> 98% took f olic acid supplement 0.4-2 mg daily bef ore the end of the f irst trimester
no patients considered f olate def icient (< 10 nmol/L)
mean serum f olate level 60.1 nmol/L in women with hypertensive disorder vs. 57.9 nmol/L in
controls (not signif icant)
Ref erence - Obstet Gynecol 2013 Aug;122(2 Pt 1):345
angiotensin-1 converting enzyme gene (ACD-I/D) variant not likely to affect risk of
preeclampsia
no signif icant association in large case-control study with 665 cases and 1,046 healthy
pregnant controls
signif icant association in meta-analysis of 22 studies with 2,596 cases and 3,828 controls, but
signif icant dif f erences mostly attributed to smaller studies
Ref erence - PLoS Med 2006 Dec;3(12):e520 f ull-text
Complications and Associated Conditions
Complicat ions:
Eclampsia:
eclampsia (generalized seizures) - convulsive stage of preeclampsia
(1, 2, 3)
may be lif e-threatening
eclamptic seizures may f ollow increasingly severe preeclampsia or occur unexpectedly in
patients with no apparent or minimally elevated blood pressure and no proteinuria
of ten preceded by premonitory signs, such as headache, visual disturbances, epigastric pain,
constricting sensation in thorax, apprehension, excitability and hyperref lexia
most convulsions occur prepartum, intrapartum or 48 hours postpartum
seizures usually isolated
neuroimaging may show ischemia with edema
rate of eclampsia 0.38 per 1,000 deliveries in Canada f rom 1991 to 2001 based on 973 cases, 4
deaths (0.4% case f atality rate) (CMAJ 2005 Sep 27;173(7):759 f ull-text)
incidence of eclampsia 6.2 per 10,000 deliveries with case f atality 1 in 74 in the Netherlands f rom
2004 to 2006 based on cohort study of 371,021 pregnancies (Obstet Gynecol 2008 Oct;112(4):820)
postpartum eclampsia complicated by brain edema and ischemic and hemorrhagic strokes in case
presentation (N Engl J Med 2009 Mar 12;360(11):1126)
late postpartum eclampsia can occur f rom 48 hours to several weeks af ter delivery
90% of postpartum eclampsia cases occur within 7 days of delivery discharge
based on retrospective cohort study of 152 women meeting criteria f or diagnosis of
delayed postpartum preeclampsia at > 2 days to 6 weeks f ollowing delivery
no preceding diagnosis of hypertensive disorder in 63.2%
headache was most common presenting symptom (69.1%)
postpartum eclampsia
developed in 22 patients (14.5%)
90% of cases presented within 7 days of discharge af ter delivery
mean age 23 years in patients who developed eclampsia vs. 28 years in patients without
eclampsia (p = 0.03)
Mat ernal complicat ions:
possible maternal complications include
(1, 2, 3)
hypertensive-associated delivery hospitalizations associated with increased risk for severe
obstetric complications
based on retrospective cohort of 36,537,061 delivery discharges f rom 1998 to 2006
Nationwide Inpatient Sample of the Healthcare Cost and Utilization Project
compared with delivery hospitalizations without hypertensive disorders, risk of severe
obstetric complications f or delivery hospitalizations with any hypertensive disorder
(pregnancy-induced hypertension, preeclampsia, eclampsia) (p < 0.05 f or all)
acute renal f ailure (adjusted odds ratio [OR] 10.7)
pulmonary edema (adjusted OR 4.7)
adult respiratory distress syndrome (adjusted OR 4.1)
puerperal cerebrovascular disorder (adjusted OR 5.1)
disseminated intravascular coagulation syndrome (adjusted OR 4.5)
ventilation (adjusted OR 4)
mortality (adjusted OR 2.7)
hypertensive disorders in pregnancy (HDP) may increase risk of subsequent stroke with
greatest risk in women < 18 years, > 35 years or with preterm delivery
1,092 women aged 15-40 years in Taiwan with newly diagnosed hypertensive disorder of
pregnancy in 2000-2004 compared to 4,715 control women without HDP who were f ollowed
through 2008
incidence of stroke 30.1/10,000 person-years with HDP vs. 12.8/10,000 person-years without
HDP (hazard ratio [HR] 2.04, 95% CI 1.18-3.51)
increased risk of stroke with HDP and
preterm delivery (HR 3.22, 95% CI 1.48-6.99)
age 15-18 years (HR 13.4, 95% CI 1.54-116.7)
age 35 years (HR 5.56, 95% CI 1.47-21)
Ref erence - Stroke 2011 Mar;42(3):716
case report of f atal necrotizing pancreatitis in patient with severe preeclampsia can be f ound in
Obstet Gynecol 2012 Aug;120(2 Pt 2):453
Fet al/childhood complicat ions:
possible f etal complications
(1, 2, 3)
intrauterine growth restriction (IUGR) may complicate up to 30% of preeclampsia pregnancies
oligohydramnios
preterm birth
f etal death
hypertension in pregnancy associated with increased risk of preterm birth and small for
gestational age birth
based on study of all 250,173 women and 255,931 inf ants discharged f rom hospital f ollowing
birth in New South Wales f rom 2000 to 2002
exposure to pregnancy-induced hypertension in children born after 37 weeks gestation may
be associated with increased risk of epilepsy in childhood
based on population-based cohort study
1,537,860 children born in Denmark were assessed f or epilepsy and maternal
preeclampsia/eclampsia
45,288 (2.9%) exposed to preeclampsia and 654 (0.04%) to eclampsia
20,260 (1.3%) had epilepsy during f ollow-up period of up to 27 years
incidence rate ratios (IRR) of epilepsy f or children born at term (37-41 weeks gestational age)
1.16 IRR f or mild preeclampsia (p < 0.05)
1.41 IRR f or severe preeclampsia (p < 0.05)
1.29 IRR f or eclampsia (p < 0.05)
incidence rate ratios of epilepsy f or children born postterm ( 42 weeks gestational age)
1.68 IRR f or mild preeclampsia (p < 0.05)
2.57 IRR f or severe preeclampsia (p < 0.05)
5.03 IRR f or eclampsia (p < 0.05)
no signif icant association with preeclampsia or eclampsia f or children born preterm (< 37
weeks gestational age)
Ref erence - Pediatrics 2008 Nov;122(5):1072
Associat ed condit ions:
hemolysis, elevated liver enzymes, low platelets (HELLP) syndrome may occur in up to 20% of
pregnancies complicated by severe preeclampsia
(1)
cardiovascular disease and diabetes
women with preeclampsia and preterm delivery have increased long-term risk for
cardiovascular mortality
based on study of 626,272 f irst deliveries with up to 25 years of f ollow-up
Ref erence - BMJ 2001 Nov 24;323(7323):1213 f ull-text
low-dose aspirin initiated at 16 weeks gestation associated with reduced risk of
perinatal mortality and other adverse perinatal outcomes in pregnant women with risk
factors for preeclampsia (level 2 [mid-level] evidence)
based on systematic review with inadequate assessment of trial quality
systematic review of 42 randomized trials comparing prophylactic low-dose aspirin (50-
150 mg/day) with or without dipyridamole ( 300 mg/day) initiated at 16 weeks or > 16
weeks gestation vs. placebo or no treatment (control) in 27,222 pregnant women with
risk f actors f or preeclampsia
risk f actors f or preeclampsia included nulliparity, multiple pregnancy, chronic
hypertension, cardiovascular or endocrine disease, prior gestational hypertension, f etal
growth restriction, and/or abnormal uterine artery Doppler
trial-specif ic quality measures not reported
perinatal mortality def ined as f etal death at > 16 weeks gestation or neonatal death at <
28 days old
comparing low-dose aspirin initiated at 16 weeks gestation vs. control, aspirin
initiation at 16 weeks gestation associated with reduced
perinatal mortality (risk ratio [RR] 0.41, 95% CI 0.19-0.92) in analysis of 12 trials
with 1,308 women
preterm birth (RR 0.35, 95% CI 0.22-0.57) in analysis of 6 trials with 904 women
preeclampsia (RR 0.47, 95% CI 0.36-0.62) in analysis of 13 trials with 1,479
women
severe preeclampsia (RR 0.18, 95% CI 0.08-0.41) in analysis of 6 trials with 649
women
f etal growth restriction (RR 0.46, 95% CI 0.33-0.64) in analysis of 10 trials with
1,064 women
comparing low-dose aspirin initiated at > 16 weeks gestation vs. control
aspirin initiation at >16 weeks gestation associated with reduced
preeclampsia (RR 0.78, 95% CI 0.61-0.99) in analysis of 20 trials with
10,673 women
preterm birth (RR 0.9, 95% CI 0.83-0.97) in analysis of 16 trials with 10,398
women
no signif icant dif f erences in
perinatal mortality in analysis of 20 trials with 9,557 women
severe preeclampsia in analysis of 5 trials with 1,494 women
f etal growth restriction in analysis of 17 trials with 7,196 women
in indirect comparisons of aspirin initiation at 16 weeks vs. > 16 weeks gestation,
earlier initiation associated with reduced risk of perinatal mortality (p = 0.02),
preeclampsia and severe pre-eclampsia (p < 0.01 f or each), intrauterine growth
restriction (p < 0.001), and preterm birth (p < 0.001)
Ref erence - Ultrasound Obstet Gynecol 2013 May;41(5):491 f ull-text, editorial can be
f ound in Ultrasound Obstet Gynecol 2013 May;41(5):479
preeclampsia associated with increased risk of future development of hypertension
and diabetes
based on cohort of 15,065 women with f irst singleton birth between 1967 and 1995
9.5% had hypertensive disorder in 1 pregnancy
preeclampsia associated with increased risk of
diabetes (adjusted odds ratio 3.8, 95% CI 2.16.6)
f uture use of antihypertensive medication (adjusted odds ratio 3.1, 95% CI 2.2 to
4.3)
Ref erence - Obstet Gynecol 2009 Nov;114(5):961, editorial can be f ound in Obstet
Gynecol 2009 Nov;114(5):958
hypertensive disorder of pregnancy associated with increased risk of postpartum
diabetes
based on retrospective cohort study of 1,139 women aged 19-40 years with f irst
hypertensive disorder of pregnancy and 4,527 women with normal pregnancy
none had prior gestational diabetes, diabetes, or hypertension
compared to normal pregnancy, hypertensive disorder of pregnancy associated with
increased risk of postpartum diabetes
overall (hazard ratio [HR] 3.42, 95% CI 2.07-5.64)
in women also with hyperlipidemia and obesity (HR 39.5, 95% CI 13-120.6)
Ref erence - Am J Med 2012 Mar;125(3):251 f ull-text
maternal placental syndrome associated with increased incidence of cardiovascular
disease in women
retrospective cohort study of 1,026,265 pregnant women in Ontario, Canada f ree f rom
cardiovascular disease bef ore f irst documented delivery at ages 14-50 years, median
f ollow-up 8.7 years
75,380 (7%) had maternal placental syndromes def ined as preeclampsia, gestational
hypertension, placental abruption and placental inf arction
composite outcome of cardiovascular disease included coronary artery disease
(occurring in 75% of those reaching composite outcome), cerebrovascular disease
(occurring in 21%) and peripheral arterial disease (occurring in 5.5%)
incidence of cardiovascular disease per 100,000 person-years
20 f or women without maternal placental syndrome
50 f or women with maternal placental syndrome (adjusted hazard ratio 2, 95% CI
1.7-2.2)
adjusted hazard ratios f or cardiovascular disease were
2.1 (95% CI 1.8-2.4) f or 36,982 women with preeclampsia
1.8 (95% CI 1.4-2.2) f or 20,942 women with gestational hypertension
1.7 (95% CI 1.3-2.2) f or placental abruption (11,156 women) or inf arction (9,303
women)
3.1 (95% CI 2.2-4.5) f or 4,390 women with maternal placental syndrome and poor
f etal growth
4.4 (95% CI 2.4-7.9) f or 1,171 women with maternal placental syndrome and
intrauterine f etal death
Ref erence - Lancet 2005 Nov 19;366(9499):1797
history of maternal placental syndrome associated with increased risk of
hospitalization for heart failure and atrial dysrhythmia
1,130,764 pregnant women in Ontario, Canada f ree f rom cardiovascular or thyroid
disease bef ore f irst documented delivery at ages 14-50 years were f ollowed f or median
7.8 years
6.7% had maternal placental syndrome (MPS) def ined as gestational hypertension,
preeclampsia, or placental abruption and/or inf arction at baseline
rate of hospitalization f or heart f ailure or atrial or ventricular dysrhythmia starting 1
year af ter delivery
2.54 per 10,000 person-years in women with MPS
1.28 per 10,000 person-years in women without MPS
history of MPS associated with
increased risk of hospitalization f or heart f ailure or atrial or ventricular
dysrhythmia (adjusted hazard ratio [HR] 1.61, 95% CI 1.35-1.91)
increased risk of hospitalization f or heart f ailure (adjusted HR 1.8, 95% CI 1.42-
2.29)
increased risk of hospitalization f or atrial dysrhythmia (adjusted HR 1.48, 95% CI
1.1-1.98)
nonsignif icant increase in increased risk of hospitalization f or ventricular
dysrhythmia (adjusted HR 1.41, 95% CI 0.96-2.07)
Ref erence - Heart 2012 Aug;98(15):1136, editorial can be f ound in Heart 2012
Aug;98(15):1109
preeclampsia associated with increased risk of microalbuminuria
based on systematic review of 7 observational studies evaluating kidney outcomes in 273
women with history of preeclampsia compared with 333 women with uncomplicated
pregnancies
weighted mean f ollow-up 7.1 years postpartum
history of preeclampsia associated with increased risk of microalbuminuria (31% vs. 7%,
relative risk [RR] 4.31, 95% CI 2.7-6.89)
history of severe preeclampsia associated with increased risk of microalbuminuria compared
with
uncomplicated pregnancies (RR 8.17, 95% CI 1.19-44.93]
pregnancy-induced hypertension without proteinuria (RR 2.2, 95% CI 1.17-4.13)
mild preeclampsia (RR 4.64, 95% CI 2.47-8.7)
Ref erence - Am J Kidney Dis 2010 Jun;55(6):1026
small increased risk of end-stage renal disease in women with preeclampsia
based on medical chart review of 570,433 women having a singleton birth in Norway f rom 1967
to 1991
end-stage renal disease developed in 477 (0.08%) women af ter mean 17 years f rom f irst
pregnancy (overall rate 3.7 per 100,000 women/year)
risk of end-stage renal disease
signif icantly increased if preeclampsia during f irst pregnancy
increased with preeclampsia in each additional pregnancy
associated with having low-birth-weight or preterm inf ant
Ref erence - N Engl J Med 2008 Aug 21;359(8):800, editorial can be f ound in N Engl J Med 2008
Aug 21;359(8):858
increased serum concentration of soluble fms-like tyrosine kinase 1 during preeclampsia
associated with subclinical hypothyroidism during pregnancy
History and Physical
Hist ory:
Chief concern (CC):
may be asymptomatic
hypertensive disorders in pregnancy may present with
(1, 2, 3)
rapid weight gain
generalized edema (af f ecting f ace and hands)
visual disturbances (f or example, blurred vision, scotomata, and cortical blindness [rarely])
severe headache
nausea and/or vomiting
oliguria
hyperref lexia
chest pain
dyspnea
Hist ory of present illness (HPI):
preeclampsia
(2)
blood pressure highest at night (reversal of normal circadian rhythm)
may rapidly progress
f ulminant preeclampsia may progress f rom mild to severe, or to eclampsia, in hours
eclampsia
(1, 2)
eclamptic seizures may f ollow increasingly severe preeclampsia or occur unexpectedly in
patients with mildly elevated blood pressure and no proteinuria
seizure lasts 60-90 seconds
postictal phase may f ollow
most eclamptic convulsions occur antepartum (about 53%), intrapartum (about 19%) or within
48 hours postpartum (about 28%)
late postpartum eclampsia may occur f rom 48 hours to several weeks af ter delivery
eclampsia may be preceded by premonitory symptoms, such as
(2)
headache
visual disturbances
epigastric pain
constricting sensation in thorax
apprehension
excitability
symptoms preceding eclamptic seizure
based on series of 46 women with eclamptic seizure
prodromal headache reported in 80%
prodromal visual disturbance reported in 45%
prodromal epigastric pain reported in 20%
absence of any prodromal symptoms preceding eclamptic seizure in 17%
Ref erence - Obstet Gynecol 2011 Nov;118(5):995, editorial can be f ound in Obstet Gynecol
2011 Nov;118(5):976
Past medical hist ory (PMH):
ask about
(1, 3)
previous preeclampsia, especially if severe or bef ore 32 weeks gestation
antiphospholipid antibody syndrome
pre-existing hypertension
pre-existing renal disease
pre-existing diabetes mellitus
obesity (body mass index 35 kg/m
2
)
heritable thrombophilias
increased prepregnancy triglyceride levels
interpregnancy interval (increased risk if 10 years or < 2 years)
Family hist ory (FH):
ask about f amily history of
(3)
preeclampsia
early-onset cardiovascular disease
mother, aunt or paternal grandmother with preeclampsia associated with increased risk of
preeclampsia in population-based study of linked generational data f rom Norway with 438,597
mother-of f spring pairs and 286,945 f ather-of f spring pairs (BMJ 2005 Oct 15;331(7521):877 f ull-text)
Social hist ory (SH):
Physical:
General physical:
blood pressure highest at night (reversal of normal circadian rhythm)
(2)
generalized edema (including f ace and hands) of ten present with preeclampsia
(1)
HEENT:
choroidal ischemia seen on ophthalmoscopy in patient with pregnancy-induced hypertension (picture
in N Engl J Med 2001 Mar 8;344(10):739)
Neuro:
hyperref lexia may be present
(1)
occurrence of neurologic exam f indings (in descending order) among 40 women with eclampsia in
prospective cohort study
memory def icits
increased deep tendon ref lexes (some asymmetric)
visual perception def icits
visual inf ormation processing def icits
altered mental status
cranial nerve def icits
Ref erence - J Neurol Sci 2008 Aug 15;271(1-2):158
Diagnosis
Making t he diagnosis:
classification of hypertensive disorders of pregnancy
(3)
hypertension in pregnancy def ined as diastolic blood pressure 90 mm Hg, based on average
of at least 2 measurements using same arm (SOGC Grade B, Level II-2)
severe hypertension def ined as systolic blood pressure 160 mm Hg or diastolic blood
pressure 110 mm Hg (SOGC Grade B, Level II-2)
Level II-2)
def initions of preeclampsia
in women with pre-existing hypertension - resistant hypertension, new or worsening
proteinuria, or 1 of other adverse conditions (SOGC Grade B, Level II-2)
in women with gestational hypertension - new-onset proteinuria or 1 of other adverse
conditions (SOGC Grade B, Level II-2)
severe preeclampsia def ined as preeclampsia with onset bef ore 34 weeks gestation, with
heavy proteinuria or with 1 adverse conditions (SOGC Grade B, Level II-2)
adverse conditions include
maternal symptoms of hypertension such as headache, visual changes, abdominal pain
maternal signs of end-organ dysf unction
abnormal maternal laboratory testing
elevated aspartate aminotransf erase (AST), alanine aminotransf erase (ALT), lactate
dehydrogenase (LDH) with symptoms
platelet count < 100 10
9
/L
albumin < 20 g/L
f etal morbidity
definitions used in American guidelines
chronic hypertension def ined as systolic blood pressure 140 mm Hg or diastolic blood
pressure 90 mm Hg on > 2 occasions bef ore 20 weeks gestation or beyond 12 weeks
postpartum
(2, 4, 5, 6)
mild - 140-150 mm Hg systolic or 90-109 mm Hg diastolic
severe - 160 mm Hg systolic or 110 mm Hg diastolic
(1, 4)
replaces term of pregnancy-induced hypertension
hypertension without proteinuria developing af ter 20 weeks gestation
temporary diagnosis - either progresses to preeclampsia or chronic hypertension, or
resolves and becomes transient hypertension
transient hypertension - gestational hypertension with normal blood pressure by 12 weeks
postpartum
(4)
preeclampsia
hypertension (blood pressure 140/90 mm Hg) and proteinuria (> 300 mg/24 hours)
(1, 4, 5)
severe preeclampsia is preeclampsia with any of
(1, 5)
blood pressure 160/110 mm Hg on 2 occasions at least 6 hours apart during
bed rest
proteinuria 5 g/24 hours or 3+ on 2 random urine specimens at least 4 hours
apart
cerebral or visual disturbances
pulmonary edema or cyanosis
thrombocytopenia
preeclampsia superimposed on chronic hypertension
(4)
in woman with hypertension bef ore 20 weeks gestation - new onset proteinuria
in woman with hypertension and proteinuria bef ore 20 weeks gestation - any of
sudden 2- to 3-f old increase in proteinuria
sudden increase in blood pressure
thrombocytopenia
elevated aspartate aminotransf erase (AST) or alanine aminotransf erase (ALT)
Test ing overview:
Mat ernal t est ing:
measure blood pressure
American College of Obstetricians and Gynecologists (ACOG) recommendations
in women with chronic hypertension
(6)
pre-conception or early pregnancy evaluation of possible end-organ involvement
(ACOG Level C)
specif ic testing may include renal f unction evaluation, electrocardiography,
echocardiography, and ophthalmologic evaluation
choice of tests depends on severity of chronic hypertension
evaluation f or secondary cause in young women with chronic hypertension diagnosis
early in pregnancy, especially if hypertension severe, including
initial testing in preeclampsia (perf orm weekly in mild preeclampsia, more of ten if disease
progression suspected)
(5)
renal f unction
liver enzymes
platelet count
12-24 hour urine collection f or protein
consider invasive hemodynamic monitoring in preeclamptic women with severe cardiac disease,
renal disease, ref ractory hypertension, pulmonary edema or unexplained oliguria (ACOG Level
B)
(5)
Society of Obstetricians and Gynaecologists of Canada (SOGC) recommendations
(3)
f or blood pressure monitoring
f or measurement of proteinuria
urinary dipstick testing may be used f or screening if low suspicion of preeclampsia
(SOGC Grade B, Level II-2)
use more def initive proteinuria testing if suspicion of preeclampsia (SOGC Grade A,
Level II-2)
urinary protein:creatinine ratio
24-hour urine collection
f or women with pre-existing hypertension
measure serum creatinine, serum potassium, and urinalysis in early pregnancy if not
previously documented (SOGC Grade B, Level II-2)
consider additional baseline laboratory testing based on other considerations deemed
important by healthcare providers (SOGC Grade C, Level III)
f or women with suspected preeclampsia (SOGC Grade B, Level II-2)
hemoglobin (higher in women with preeclampsia unless microangiopathic hemolytic
anemia)
white blood cell (WBC) count and dif f erential (higher in preeclampsia)
platelet count (lower in preeclampsia)
blood f ilm (shows microangiopathy with red blood cell f ragments in preeclampsia)
serum creatinine (higher in preeclampsia)
serum uric acid (higher in preeclampsia)
glucose
aspartate aminotransf erase (AST) and alanine aminotransf erase (ALT) (higher in
preeclampsia)
lactate dehydrogenase (LDH) (higher in preeclampsia)
albumin (lower in preeclampsia)
bilirubin (higher in preeclampsia)
urinalysis (routine and microscopy)
proteinuria (assessed by urinary dipstick, spot or 24-hour) (higher in preeclampsia)
coagulation tests if presence of thrombocytopenia or placental abruption
INR and activated partial thromboplastin time (aPTT)
f ibrinogen (lower in preeclampsia)
repeat initial testing if ongoing concern about preeclampsia (f or example, change in maternal
or f etal condition) (SOGC Grade C, Level III)
in hypertensive pregnant women, uterine artery Doppler velocimetry may support placental
origin f or hypertension, proteinuria or adverse conditions (SOGC Grade B, Level II-2)
Fet al monit oring:
American College of Obstetricians and Gynecologists (ACOG) recommendations for fetal
testing in women with chronic hypertension
(6)
ultrasound to evaluate f etal growth (ACOG Level C)
if suspected growth restriction, monitor f etal status by
nonstress testing or biophysical prof ile testing twice weekly
umbilical vessel Doppler velocimetry
Society of Obstetricians and Gynaecologists of Canada (SOGC) recommendations for fetal
testing in women with suspected preeclampsia (SOGC Grade B, Level II-1)
(3)
f etal movement count (lower in preeclampsia)
nonstress test (nonreassuring f etal heart rate in preeclampsia)
biophysical prof ile (lower score in preeclampsia)
deepest amniotic f luid pocket (lower in preeclampsia)
ultrasound f or f etal growth (usually asymmetrical intrauterine growth in preeclampsia)
umbilical artery Doppler (increased resistance, absent or reversed end-diastolic f low in
preeclampsia)
umbilical artery Doppler velocimetry may support placental origin f or intrauterine f etal growth
restriction (SOGC Grade B, Level II-2)
fetal monitoring during expectant management of mild preeclampsia
(1)
nonstress test twice weekly
amniotic f luid index once or twice weekly
biophysical prof ile may be done weekly as substitute f or 1 twice weekly nonstress test and
amniotic f luid index
ultrasound f or f etal growth every 3-4 weeks
fetal monitoring in severe preeclampsia
(1)
continuous f etal heart rate monitoring
nonstress test on admission
ultrasound f or estimated f etal weight
amniotic f luid volume
umbilical artery Doppler measurements
Blood t est s:
decreased placental growth factor levels may help diagnose preeclampsia in pregnant
women < 35 weeks gestational age (level 2 [mid-level] evidence)
based on diagnostic cohort study without validation
625 pregnant women with suspected preeclampsia had measurement of placental growth
f actor (PIGF) in plasma
287 pregnant women gestational age 20 to < 35 weeks
137 pregnant women gestational age 35 weeks to < 37 weeks
201 pregnant women gestational age 37 weeks
outcome was delivery within 14 days f or conf irmed preeclampsia (as determined by consensus
diagnosis of 2-3 senior physicians)
diagnostic thresholds f or preeclampsia were PlGF levels < 5th percentile f or gestational age
(Pregnancy Hypertension 2013; 3(2):124)
< 76.4 pg/mL at 20-24 weeks
< 141.1 pg/mL at 24-29 weeks
< 139.3 pg/mL at 29-32 weeks
< 31.7 pg/mL at 35 -37 weeks
f or detection of preeclampsia at gestational age 20 to < 35 weeks, PlGF < 5th percentile had
sensitivity 96%
specif icity 55%
positive predictive value 43%
negative predictive value 98%
PlGF < 5th percentile had sensitivity 70% and specif icity 64% at 35 weeks to < 37 weeks and
sensitivity 57% and specif icity 77% at 37 weeks
Ref erence - Circulation 2013 Nov 5;128(19):2121
ratio of serum soluble fms-like tyrosine kinase to placental growth factor (sFlt-1/PlGF)
appears specific for preeclampsia (level 2 [mid-level] evidence)
based on case-control study
71 patients with preeclampsia and 280 gestational age-matched controls had 595 serum
samples measured f or soluble f ms-like tyrosine kinase (sFlt-1) and placental growth f actor
(PlGF) using automated immunoassay platf orm
preeclampsia detection f or sFlt-1/PIGF cutof f 85
sensitivity 82%
specif icity 95%
Ref erence - Am J Obstet Gynecol 2010 Feb;202(2):161e1
Urine st udies:
spot urine protein/creatinine ratio
spot protein:creatinine ratio appears to have moderate accuracy for detecting
proteinuria in women with suspected preeclampsia (level 2 [mid-level] evidence)
based on systematic review limited by clinical heterogeneity
systematic review of 20 diagnostic studies (15 cohort, 4 cross-sectional, 1 case-
control) evaluating urinary spot protein:creatinine ratio or albumin:creatinine ratio f or
detection of signif icant proteinuria or adverse pregnancy outcome in 2,978 pregnant
women with suspected preeclampsia
signif icant proteinuria def ined as 0.3 g/24 hours
ref erence standards were 24-hour total urine collection f or protein or adverse
pregnancy outcome
clinical heterogeneity due to variations across studies in patient populations, ref erence
test, and cut-of f values f or spot protein:creatinine ratio
in 13 studies evaluating spot protein:creatinine ratio
diagnostic cut-of f values ranged f rom 0.13-0.5 mg/mg
no diagnostic cut-of f gave > 80% estimate f or both sensitivity and specif icity
pooled predictive perf ormance of spot protein:creatinine ratio using cut-of f of 0.3
mg/mg f or detecting signif icant proteinuria in analysis of 5 studies
sensitivity 81% (95% CI 77%-85%)
specif icity 76% (95% CI 71%-80%)
positive likelihood ratio 3.33 (95% CI 2.68-4.12)
negative likelihood ratio 0.25 (0.19-0.33)
insuf f icient evidence to support specif ic cut-of f f or detection of signif icant proteinuria
in 5 studies evaluating albumin:creatinine ratio
Ref erence - BMJ 2012 Jul 9;345:e4342 f ull-text
spot protein:creatinine ratio may help rule out proteinuria in hypertensive pregnant
women but optimal cut-off point unclear
based on systematic review of diagnostic studies
systematic review of 15 diagnostic studies comparing spot urinalysis (13 evaluated
urine protein:creatinine ratio and 2 evaluated albumin:creatinine ratio) vs. 24 hour
urinalysis in women with suspected or conf irmed hypertensive pregnancy
laboratory assays not well described
prevalence of signif icant proteinuria ( 0.3 g/day) ranged f rom 21% to 83% in 11 studies
in analysis of spot protein:creatinine ratio
8 dif f erent cut-of f points reported in 9 studies with ranging f rom 0.15 mg/mg (17
mg/mmol) to 0.5 mg/mg (57 mg/mmol)
pooled values of spot protein:creatinine ratio 30 mg/mmol in 9 studies with 1,003
women
sensitivity 83.6% (95% CI 77.5%-89.7%)
specif icity 76.3% (95% CI 72.6%-80%)
positive likelihood ratio 3.53 (95% CI 2.83-4.49)
negative likelihood ratio 0.21 (95% CI 0.13-0.31)
insuf f icient data f or pooled analysis in 2 studies evaluating albumin:creatinine ratio in
225 women
optimal cut-of f point f or proteinuria of 0.3 g/day was 2 mg/mmol
optimal cut-of f point f or albuminuria was 27 mg/mmol
Ref erence - BMJ 2008 May 3;336(7651):1003 f ull-text, editorial can be f ound in BMJ
2008 May 3;336(7651):968 f ull-text, commentary can be f ound in ACP J Club 2008
Oct;149(4):14
random urine protein:creatinine ratio < 130-150 mg/g or > 600 mg/g in pregnant
patients with suspected preeclampsia may eliminate need for 24-hour urine collection
based on systematic review with heterogeneity
systematic review of 7 studies evaluating dif f erent cut-of f points of urine
protein:creatinine ratio (f rom 130 mg/g to 700 mg/g) f or predicting protein 300 mg in
24-hour urine collection in 1,717 women (primarily inpatients) with suspected
preeclampsia
mean gestational age 32-36 weeks
mean prevalence of preeclampsia by 24-hour urine 38%
f or protein:creatinine ratio < 130-150 mg/g (meta-analysis not possible due to
heterogeneity)
sensitivity 90%-99%
specif icity 32.7%-65%
positive predictive value 40.7%-81.7%
negative predictive value 58.8%-98.1%
f or protein:creatinine ratio 600-700 mg/g in 1 study with 105 patients
sensitivity 85%-87%
specif icity 96%-97%
positive predictive value 95%-96.1%
negative predictive value 88.1%-89.4%
urinary protein:creatinine ratio significantly correlated with 24-hour proteinuria in
hospitalized pregnant women with hypertensive disorders of pregnancy
based on study with inception and validation cohorts
927 hospitalized pregnant women at 20 weeks gestational age with hypertensive
disorders had protein:creatinine ratios in random urine samples and protein contents of
24-hour urine samples measured
protein excretion 300 mg/24 hours in 282 (30.4%) patients
urine protein:creatinine ratio and 24-hour protein excretion signif icantly correlated (p <
0.001)
protein:creatinine ratio 0.3 was indicator of protein excretion 300 mg/24 hours
sensitivity 98.2%
specif icity 98.8%
similar results in validation cohort of 161 pregnant women
Ref erence - Clin Chem 2007 Sep;53(9):1623 PDF, commentary can be f ound in Evid
Based Med 2008 Jun;13(3):84
in women with suspected preeclampsia, 12-hour urine protein > 165 mg appears to
predict 24-hour proteinuria and spot urine protein to creatinine ratio may help rule out
proteinuria (level 2 [mid-level] evidence)
based on diagnostic cohort study without validation
90 pregnant women at > 20 weeks gestational age (median age 30 years) with
suspected preeclampsia were assessed f or 12-hour and 24-hour urine protein and f or
spot urine protein to creatinine ratio
28 women had proteinuria def ined as 24-hour urine protein 300 mg (ref erence
standard)
f or detection of signif icant proteinuria
12-hour urine protein with cut-of f > 165 mg had
sensitivity 96%
specif icity 100%
spot urine protein to creatinine ratio with cut-of f > 0.15 had
sensitivity 89%
specif icity 49%
Ref erence - Am J Obstet Gynecol 2012 Sep;207(3):233.e1
review of clinical signif icance of proteinuria in pregnancy can be f ound in Obstet Gynecol Surv
2007 Feb;62(2):117
degree of proteinuria not associated with accurate prediction of maternal or fetal
complications in preeclampsia
hypocalciuria may occur in preeclampsia
hypocalciuria (mean 1.5 mmol/24 hours) signif icantly associated with preeclampsia in case-
control study of 47 women with preeclampsia and 50 controls (Eur J Obstet Gynecol Reprod
Biol 2006 Apr 1;125(2):193)
total (and f ractional) urinary calcium excretion signif icantly lower in women with preeclampsia
(mean 82 mg/24 hours) compared to controls (mean 171 mg/24 hours) in cross-sectional
study of 26 women with preeclampsia and 26 normotensive controls (J Steroid Biochem Mol
Biol 2007 Mar;103(3-5):803)
Ot her diagnost ic t est ing:
Blood pressure measurement :
(3)
if blood pressure consistently higher in 1 arm, use that arm f or all blood pressure
measurements (SOGC Grade B, Level III)
ambulatory blood pressure monitoring may detect isolated (white coat) hypertension (SOGC
Grade B, Level II-2)
recommendations f or diagnosis of hypertension
make diagnosis based on of f ice or in-hospital blood pressure measurements (SOGC
hypertension in pregnancy def ined as diastolic blood pressure 90 mm Hg, based on
mean of 2 measurements taken on same arm (SOGC Grade B, Level II-2)
f or severe hypertension, take repeat measurement f or conf irmation in 15 minutes
(SOGC Grade B, Level III)
isolated (white coat) hypertension def ined as of f ice diastolic blood pressure of 90
mm Hg, but home blood pressure < 135/85 mm Hg (SOGC Grade B, Level III)
mean arterial pressure may be better predictor of preeclampsia than systolic and diastolic
blood pressures
systematic review and meta-analysis of 34 trials with variable methodology of blood pressure
measurement during f irst and second trimester of pregnancy used to predict preeclampsia in
60,599 women
3,341 (5.5%) cases of preeclampsia occurred
second trimester mean arterial pressure 90 mm Hg had positive likelihood ratio 3.5 (95% CI
2-5) and negative likelihood ratio 0.46 (95% CI 0.16-0.75)
diastolic blood pressure 75 mm Hg at 13-20 weeks gestation best predicted preeclampsia in
women at high-risk with positive likelihood ratio 2.8 (95% CI 1.8-3.6) and negative likelihood
ratio 0.39 (95% CI 0.18-0.71)
Ref erence - BMJ 2008 May 17;336(7653):1117 f ull-text
no randomized trials identified to evaluate use of ambulatory blood pressure monitoring in
pregnancy
based on Cochrane review
Ref erence - Cochrane Database Syst Rev 2002;(2):CD001231 (review updated 2012 Mar 9)
no randomized trials found evaluating pulmonary artery flow catheters for monitoring fluid
status in women with severe preeclampsia
Ref erence - Cochrane Database Syst Rev 2012 Jun 13;(6):CD008882
24-hour blood pressure monitoring may be better than office monitoring for predicting
preeclampsia
based on 2 cohort studies
cohort of 254 women in third trimester having 24-hour noninvasive blood pressure monitoring
preeclampsia in
5.8% with normal blood pressure
7.1% with white-coat hypertension
61.7% with hypertension
Ref erence - JAMA 1999 Oct 20;282(15):1447
cohort of 241 women with early pregnancy diagnosis of essential hypertension who had 24-
hour ambulatory blood pressure monitoring
prepregnancy diagnosis in 35.6%
white coat hypertension diagnosed in 32% (40% developed benign gestational
hypertension)
proteinuric preeclampsia developed in
8% with white coat hypertension
22% with essential hypertension
Ref erence - BJOG 2005 May;112(5):601
Treatment
Treat ment overview:
hospitalize if severe hypertension or severe preeclampsia (SOGC Grade B, Level II-2), preeclampsia
remote f rom term, signs of disease progression or compliance dif f iculties (including logistic barriers)
delivery
f or women with eclampsia, magnesium sulf ate considered f irst-line treatment (SOGC Grade A, Level
I, ACOG Level A)
most studied dose is loading dose 14 g (4 g IV plus 5 g intramuscularly in each buttock) then
either 1 g/hour IV inf usion or 4 g intramuscularly every 4 hours f or 24 hours
magnesium sulf ate reduces recurrence of seizures compared to diazepam or phenytoin in
women with eclampsia (level 1 [likely reliable] evidence)
f or women with preeclampsia
if mild preeclampsiaexpectant management includes monitoring of mother and f etus, such as
blood pressure twice weekly
weekly blood tests - complete blood count (CBC), platelet count, liver enzymes, lactate
dehydrogenase (LDH), uric acid, creatinine
f etal monitoring - nonstress test twice weekly, amniotic f luid index once or twice weekly
f or women with severe preeclampsia at 24-34 weeks, ef f ect of choosing prompt delivery or
expectant management on neonatal morbidity or mortality is uncertain
f or women with hypertension during pregnancy, insuf f icient evidence to evaluate bed rest or
restriction of activity
some bed rest in hospital (vs. unrestricted activity at home) may be usef ul f or women with
gestational hypertension without preeclampsia (SOGC Grade B, Level I)
strict bed rest NOT recommended f or hospitalized women with preeclampsia (SOGC Grade D,
Level I)
antihypertensive medications
American College of Obstetricians and Gynecologists (ACOG) recommends antihypertensive
therapy f or diastolic blood pressure 105-110 mm Hg (ACOG Level C)
Canadian guidelines recommend target blood pressure 130-155/80-105 mm Hg, or 130-
139/80-89 mm Hg if comorbid conditions (SOGC Grade C, Level III)
overall risks and benef its of antihypertensive drugs is uncertain f or women with mild to
moderate hypertension during pregnancy
medications f or chronic or mild to moderate hypertension
methyldopa 0.5-3 g/day in 2 divided doses
labetalol 200-1,200 mg/day in 2-3 divided doses
other beta blockers (except atenolol)
nif edipine 30-120 mg/day of slow-release preparation
hydralazine 50-300 mg/day in 2-4 divided doses
hydrochlorothiazide 25 mg/day
medications f or acute severe hypertension (doses in dif f erent guidelines vary)
hydralazine 5-10 mg IV every 20 minutes as needed
labetalol 20 mg IV bolus, then 40 mg in 10 minutes if needed, then 80 mg every 10
minutes (maximum 220 mg)
nif edipine 10-30 mg orally, repeat in 45 minutes if needed
last resort - sodium nitroprusside 0.5-10 mcg/kg/minute (risk of f etal cyanide toxicity if
used > 4 hours)
f ollow-up af ter delivery to evaluate f or and treat hypertension and related conditions
insuf f icient evidence to recommend
dietary salt restriction
plasma volume expansion (minimizing f luid intake recommended)
low-dose aspirin
Treat ment set t ing:
indications f or hospitalization
(2, 5)
suspicion of preeclampsia
severe preeclampsia
preeclampsia remote f rom term
signs of disease progression
compliance dif f iculties (including logistic barriers)
Society of Obstetricians and Gynaecologists of Canada (SOGC) recommendations for place
of care
(3)
antenatal day care as alternative to hospitalization
antenatal day care may reduce risk of inpatient hospital admission but increase
number of outpatient visits (level 2 [mid-level] evidence)
based on Cochrane review with limited evidence
systematic review of 3 randomized trials comparing ref erral to day care vs. inpatient or
routine care in 504 women with complicated pregnancy
largest trial described below
day care associated with
lower risk of hospital admission (risk ratio 0.46, 95% CI 0.34-0.62) in analysis of 2
trials with 109 women
reduced length of stay f or those admitted in 2 trials
lower risk of labor induction (risk ratio 0.43, 95% CI 0.22-0.83) in 1 trial with 54
women
more outpatient hospital visits (mean dif f erence 1.5 visits, 95% CI 0.54-2.46
visits) in 1 trial with 54 women
most women satisf ied with care received, but pref erred day care
no signif icant dif f erences between groups in other outcomes
Ref erence - Cochrane Database Syst Rev 2009 Oct 7;(4):CD001803
hospitalization and antenatal day care associated with similar cost and perinatal
outcomes (level 2 [mid-level] evidence)
based on randomized trial with inadequate power to detect clinically relevant dif f erences
395 women with nonproteinuric hypertension, proteinuric hypertension, and preterm
premature rupture of membranes were randomized to hospitalization vs. antenatal day
care
no signif icant dif f erences in cost, maternal or perinatal outcomes
greater patient satisf action reported in day care group
Ref erence - Lancet 2004 Apr 3;363(9415):1104, editorial can be f ound in Lancet 2004
Apr 3;363(9415):1089
Delivery:
(3)
for timing of delivery in women with preeclampsia
consider immediate delivery f or women at 37 weeks gestation with preeclampsia
(severe or nonsevere) (SOGC Grade B, Level III)
f or women at 34-36 weeks gestation with nonsevere preeclampsia, insuf f icient evidence
to recommend f or or against expectant management (SOGC Grade I, Level III)
f or women at < 34 weeks gestation, expectant management of preeclampsia (severe or
nonsevere) may be considered in perinatal centers able to care f or very preterm inf ants
(SOGC Grade C, Level I)
for mode of delivery in women with hypertensive disorders of pregnancy
for anesthesia administration during delivery
inf orm anesthesiologist when woman with preeclampsia admitted to delivery suite
perf orm platelet count in all women with hypertensive disorder of pregnancy admitted to
delivery suite (but tests of platelet f unction NOT recommended) (SOGC Grade C, Level
III)
regional analgesia and/or anesthesia appropriate f or women with platelet count > 75
10
9
/L unless (SOGC Grade B, Level III)
coagulopathy
f alling platelet concentration
co-administration of antiplatelet agent or anticoagulant
regional anesthesia appropriate f or
women taking low-dose aspirin in absence of coagulopathy and in presence of
adequate platelet count (SOGC Grade A, Level I)
women on low-molecular-weight heparin 12 hours af ter prophylactic dose or 24
hours af ter therapeutic dose (SOGC Grade B, Level III)
early insertion of epidural catheter recommended f or pain control (if no
contraindications) (SOGC Grade A, Level I)
f ixed IV f luid bolus should NOT be given prior to regional analgesia and/or anesthesia
(SOGC Grade D, Level I)
small doses of phenylephrine or ephedrine may be used to prevent or treat hypotension
during regional anesthesia (SOGC Grade A, Level I)
in absence of contraindications, acceptable methods of anesthesia f or women having
cesarean include (SOGC Grade A, Level I)
epidural
spinal
combined spinal-epidural
general
indications f or delivery
(1)
gestational age 40 weeks
gestational age 37 weeks with
labor
f avorable cervix (Bishop score 6)
worsening maternal or f etal condition
gestational age 34 weeks with
labor or rupture of membranes
severe preeclampsia and nonreassuring f etal status
maternal distress in severe preeclampsia
treatment-resistant severe hypertension
thrombocytopenia
imminent eclampsia
pulmonary edema
hemolysis, elevated liver enzymes, low platelets (HELLP) syndrome
gestational age 24-34 weeks with severe preeclampsia and
persistent severe symptoms
multiorgan dysf unction
severe intrauterine growth restriction (IUGR) (estimated f etal weight < f if th percentile)
suspected placental abruption
nonreassuring f etal testing
indications f or cesarean delivery
emergent - immediate threat to lif e of woman or f etus
other indications
maternal or f etal compromise that is not immediately lif e-threatening
f ailure to progress in labor
placenta previa
morbidly adherent placenta
in women with previous cesarean delivery, Doppler ultrasound may be used f or
initial diagnosis, magnetic resonance imaging may help conf irm diagnosis
intervention options f or women with morbidly adherent placenta include cross-
matching blood and planned cesarean delivery with consultant obstetrician,
anesthesiologist, and pediatrician present, and senior hematologist on call
breech presentation
multiple pregnancy
cephalopelvic disproportion in labor
mother to child transmission of maternal inf ections
HIV if mother not receiving antiretroviral therapy or has viral load 400 copies per
mL with any antiretroviral therapy
hepatitis C if mother has co-inf ection with HIV
primary genital herpes simplex in third trimester
maternal request af ter discussion about risks and benef its and of f er of support
(including perinatal mental health support f or women with anxiety about vaginal delivery)
Ref erence - National Institute f or Health and Care Excellence (NICE) guideline on cesarean
section (NICE 2011 Nov:CG132), summary can be f ound in BMJ 2011 Nov 23;343:d7108
labor induction may reduce severe hypertension in women with gestational hypertension or
mild preeclampsia, and might reduce intensive maternal hospital care (level 2 [mid-level]
evidence)
based on quasi-randomized trial without blinding
756 patients with singleton pregnancy at 36-41 weeks gestation with gestational hypertension
or mild preeclampsia were randomized to induction of labor vs. expectant monitoring
397 patients ref used randomization but allowed use of medical records
comparing induction of labor vs. expectant monitoring in randomized women
severe hypertension (systolic blood pressure) in 15% vs. 23% (p = 0.003, NNT 13)
severe hypertension (diastolic blood pressure) in 16% vs. 27% (p < 0.0001, NNT 10)
HELLP syndrome in 1% vs. 3% (p = 0.07)
intensive maternal hospital care in 2% vs. 4% (p = 0.059)
no signif icant dif f erence or insuf f icient cases to make comparison in
maternal death (0 vs. 0 cases)
severe proteinuria
eclampsia (0 vs. 0 cases)
lung edema
postpartum hemorrhage
thromboembolic disease
placental abruption (0 vs. 0 cases)
neonatal death (0 vs. 0 cases)
composite neonatal morbidity
Ref erence - HYPITAT trial (Lancet 2009 Sep 19;374(9694):979), editorial can be f ound in
Lancet 2009 Sep 19;374(9694):951, commentary can be f ound in Lancet 2010 Jan
9;375(9709):119
labor induction associated with decrease in high-risk maternal complications
compared to expectant monitoring in women with longer cervix
based on post hoc analysis of HYPITAT trial with all women evaluated f or cervix length
(median length 30 mm, range 0-64 mm)
compared to expectant monitoring, labor induction associated with decrease in high-risk
maternal complications with increasing cervix length (p = 0.03)
f or expectant monitoring, 1 cm increase in cervical length associated with 32% increase
in high-risk maternal complications
f or labor induction, 1 cm increase in cervical length associated with 3% decrease in
high-risk maternal complications
no signif icant dif f erences in cesarean delivery or neonatal outcomes with increasing
cervix length
Ref erence - BJOG 2012 Aug;119(9):1123 f ull-text
planned cesarean delivery may not reduce maternal and perinatal mortality and
complications compared to planned vaginal delivery in women with eclampsia (level 2 [mid-
level] evidence)
based on randomized trial with inadequate statistical power
200 women with singleton pregnancy gestational age 34 weeks and antepartum or
intrapartum eclampsia randomized to cesarean delivery vs. vaginal delivery
27% of vaginal delivery group required cesarean delivery
maternal complications included respiratory depression, ventilation, pulmonary edema,
pneumonia, renal f ailure, hepatic f ailure, coagulopathy, admission to intensive care unit
power calculation estimated sample size at least 294 women per arm necessary to show 10%
dif f erence in composite of complications and death
comparing cesarean delivery vs. vaginal delivery
maternal death in 2% vs. 2% (not signif icant)
maternal complications or death in 10.9% vs. 7.1% (not signif icant)
stillbirth or death in f irst week in 4% vs. 5% (not signif icant)
Apgar score < 7 at 5 minutes in 10.9% vs. 17.2% (not signif icant)
delivery room intubation in 6.9% vs. 13.1% (not signif icant)
admission to special baby care unit in 4.9% vs. 8.1% (not signif icant)
Ref erence - Am J Obstet Gynecol 2012 Jun;206(6):484.e1 f ull-text
Medicat ions during delivery:
continue antihypertensive treatment throughout labor and delivery to maintain systolic blood
pressure < 160 mm Hg and diastolic blood pressure < 110 mm Hg (SOGC Grade B, Level II-2)
(3)
use oxytocin 5 units IV or 10 units intramuscularly f or active management of third stage of labor,
especially if thrombocytopenia or coagulopathy (SOGC Grade A, Level I)
(3)
ergometrine should not be given in any f orm (SOGC Grade D, Level II-3)
(3)
perioperative prophylactic platelet transf usion f or cesarean delivery
(3)
not necessary if platelets > 50 10
9
/L
consider if platelets < 10-20 10
9
/L
Fluid and elect rolyt es:
Plasma volume expansion:
plasma volume expansion NOT recommended f or women with preeclampsia (SOGC Grade E, Level
I)
(3)
insufficient evidence for any reliable estimates of effects of plasma volume expansion
systematic review of 3 randomized trials evaluating plasma volume expansion in 61 women
with hypertension during pregnancy (with or without proteinuria)
all trials compared colloid solution vs. no plasma volume expansion but wide conf idence
intervals result in no signif icant dif f erences
14 citations awaiting classif ication may alter conclusions of Cochrane review once assessed
Ref erence - Cochrane Database Syst Rev 2000;(2):CD001805 (review updated 2009 Oct 1)
Addit ional considerat ions:
(3)
Diet :
Society of Obstetricians and Gynaecologists of Canada (SOGC) recommendations for diet
changes in hypertensive disorders of pregnancy
(3)
new dietary salt restriction NOT recommended (SOGC Grade D, Level II-2)
insuf f icient evidence f or recommendations on usef ulness of
ongoing salt restriction in women with pre-existing hypertension (SOGC Grade I, Level
III)
heart-healthy diet (SOGC Grade I, Level III)
calorie restriction f or obese women (SOGC Grade I, Level III)
insufficient evidence to recommend increasing or decreasing salt intake during pregnancy
systematic review of 2 randomized trials of reduced dietary salt intake during pregnancy with
603 women, no signif icant dif f erences but conf idence intervals were wide
no trials of increased dietary salt intake f ound
Ref erence - Cochrane Database Syst Rev 2005 Oct 19;(4):CD005548 (review updated 2012
Jan 18)
Act ivit y:
lifestyle changes in hypertensive disorders of pregnancy
(3)
insuf f icient evidence f or recommendations about exercise, workload reduction or stress
reduction (SOGC Grade I, Level III)
bed rest
some bed rest in hospital (vs. unrestricted activity at home) may be usef ul f or women
with gestational hypertension without preeclampsia (SOGC Grade B, Level I)
strict bed rest NOT recommended f or hospitalized women with preeclampsia (SOGC
Grade D, Level I)
insuf f icient evidence f or bed rest f or all other women with hypertensive disorders of
pregnancy (SOGC Grade C, Level III)
consider thromboprophylaxis f or women prescribed bed rest (SOGC Grade C, Level II-2)
insufficient evidence to evaluate bed rest or restriction of activity for women with
hypertension during pregnancy
systematic review of 4 randomized trials evaluating bed rest f or 449 women with hypertension
in pregnancy
2 trials (145 women) compared strict bed rest with some rest in hospital f or women with
proteinuric hypertension; insuf f icient evidence to demonstrate any dif f erences between
groups f or reported outcomes
2 trials (304 women) compared some bed rest in hospital with routine activity at home f or
nonproteinuric hypertension
1 trial with 218 women reported reduced risk of severe hypertension (relative risk [RR]
0.58, 95% CI 0.38-0.89) and borderline reduction in risk of preterm birth (RR 0.53, CI
0.29-0.99) with some rest
1 trial with 86 women reported more women in bed rest group opted not to have similar
management in f uture pregnancies if choice were given (RR 3, 95% CI 1.43-6.31)
no signif icant dif f erences f or any other outcomes
Ref erence - Cochrane Database Syst Rev 2010 Feb 17;(2):CD003514
Medicat ions:
Ant ihypert ensive t herapy:
Target blood pressure:
American College of Obstetricians and Gynecologists (ACOG) recommends antihypertensive therapy
f or diastolic blood pressure 105-110 mm Hg (ACOG Level C)
(5)
(3)
if nonsevere hypertension (blood pressure 140-159/90-109 mm Hg)
f or women without comorbid conditions - antihypertensive drugs recommended to
maintain blood pressure 130-155 mm Hg systolic and 80-105 mm Hg diastolic (SOGC
Grade C, Level III)
f or women with comorbid conditions - antihypertensive drugs recommended to maintain
blood pressure 130-139 mm Hg systolic and 80-89 mm Hg diastolic (SOGC Grade C,
Level III)
if severe hypertension (blood pressure > 160 mm Hg systolic or 110 mm Hg diastolic) - blood
pressure should be lowered to < 160 mm Hg systolic and < 110 mm Hg diastolic (SOGC Grade
B, Level II-2)
insufficient evidence to determine target blood pressure in pregnant women with mild-to-
moderate hypertension
systematic review of randomized trials comparing tight to very tight control of mild-to-
moderate pre-existing or nonproteinuric gestational hypertension
2 pilot trials with 256 pregnant women met inclusion criteria
mild-to-moderate hypertension def ined as systolic blood pressure 140-169 mm Hg or
diastolic pressure 90-109 mm Hg
tight control def ined as blood pressure < 140/90 mm Hg and very tight control def ined
as blood pressure < 130/80 mm Hg
only 3 perinatal deaths occurred and no cases of eclampsia, stroke, or maternal deaths
reported
comparing tight vs. very tight control
incidence of severe preeclampsia in analysis of both trials
cesarean delivery in analysis of both trials
labor induction in 1 trial with 125 patients
intrauterine growth retardation in analysis of both trials
admission to neonatal intensive care unit in analysis of both trials
wide conf idence intervals cannot rule out possibility of clinically relevant dif f erences
between groups
hospitalization during pregnancy in 29% of tight group vs. 11% of very tight group (p <
0.05, NNT 6 f avoring very tight control) in 1 trial with 125 patients
Ref erence - Cochrane Database Syst Rev 2011 Jul 6;(7):CD006907
Ant ihypert ensive drug select ion:
American College of Obstetricians and Gynecologist (ACOG) recommendations
f or treatment of chronic hypertension in pregnancy
(6)
women with severe hypertension require antihypertensive medications f or acute blood
pressure elevation (ACOG Level B)
labetalol is good f irst-line option (ACOG Level B)
oral dose 200-2,400 mg/day in 2-3 divided doses
IV dose f or urgent control of severe acute hypertension with either of
20 mg IV bolus, then 20-80 mg every 5-15 minutes up to maximum 300 mg
constant inf usion 1-2 mg/minute
thiazide diuretics do not need to be discontinued if started bef ore pregnancy (ACOG
Level B)
angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers
contraindicated in pregnancy (ACOG Level A)
atenolol not recommended f or treatment of chronic hypertension in pregnancy due to
association with growth restriction (ACOG Level B)
f or treatment of preeclampsia and eclampsia (ACOG Level C)
(5)
hydralazine or labetalol f or diastolic blood pressure 105-110 mm Hg
hydralazine 5-10 mg IV every 15-20 minutes until desired response
labetalol 20 mg IV bolus, f ollowed by
40 mg if not ef f ective within 10 minutes, then 80 mg every 10 minutes
maximum total dose 220 mg
(3)
f or nonsevere hypertension (blood pressure 140-159/90-109 mm Hg)
f or severe hypertension (blood pressure > 160 mm Hg systolic or 110 mm Hg diastolic)
American Society of Hypertension (ASH) recommendations
(2)
f or chronic hypertension in pregnancy
methyldopa 0.5-3 g/day in 2 divided doses (Pregnancy Category B)
labetalol 200-1,200 mg/day in 2-3 divided doses (Pregnancy Category C)
nif edipine 30-120 mg/day of slow-release preparation (Pregnancy Category C)
hydralazine 50-300 mg/day in 2-4 divided doses (Pregnancy Category C)
hydrochlorothiazide 25 mg/day (Pregnancy Category C)
beta blockers - dose depends on specif ic agent (Pregnancy Category C)
contraindicated medications include ACE inhibitors and angiotensin receptor
antagonists (ARBs) (Pregnancy Category D)
f or urgent control of severe hypertension in pregnancy
hydralazine (1 of 2 options)
initial dose 5 mg IV or intramuscularly, f ollowed by 5-10 mg every 20-40 minutes
continuous inf usion 0.5-10 mg/hour
labetalol (1 of 2 options)
initial dose 20 mg IV, f ollowed by 20-80 mg every 20-30 minutes (maximum 300
mg)
continuous inf usion 1-2 mg/minute
nif edipine
10-30 mg orally, repeat in 45 minutes if needed
tablets recommended only
might interf ere with labor
relatively contraindicated - sodium nitroprusside
agent of last resort
continuous inf usion 0.5-10 mcg/kg/minute
associated with risk of cyanide toxicity
Seventh Joint National Committee on Prevention, Detection, Evaluation and Treatment of
High Blood Pressure (JNC 7) recommendations
(4)
f or chronic hypertension in pregnancy
methyldopa pref erred based on long-term studies supporting saf ety
labetalol increasingly pref erred to methyldopa due to reduced side ef f ects
beta blockers generally saf e, but reports of intrauterine growth retardation with atenolol
diuretics probably saf e, but not f irst-line agents
clonidine has limited data
calcium channel blockers have limited data, but no increase in major teratogenicity
contraindicated medications include ACE inhibitors and ARBs
f or treatment of acute severe hypertension in preeclampsia
hydralazine 5 mg IV bolus, then 10 mg every 20-30 minutes to maximum 25 mg, repeat in
several hours as needed
labetalol (second-line) 20 mg IV bolus, then 40 mg 10 minutes later, then 80 mg every 10
minutes f or 2 additional doses to maximum 220 mg
nif edipine (controversial)
10 mg orally, repeat every 20 minutes to maximum 30 mg
caution if used with magnesium sulf ate due to risk f or precipitous blood pressure
decreases
short-acting nif edipine not FDA approved f or hypertension
f or rare use when other treatments f ail - sodium nitroprusside
0.25-5 mcg/kg/minute
f etal cyanide toxicity may occur if used > 4 hours
Ef f icacy of ant ihypert ensive t herapy in mild t o moderat e hypert ension:
overall risks and benefits of antihypertensive drugs is uncertain for women with mild-to-
moderate hypertension during pregnancy; antihypertensive drugs may
based on Cochrane review of trials with methodologic limitations
systematic review of 49 randomized trials evaluating antihypertensive drugs in 4,723 pregnant
women with mild-to-moderate hypertension
mild-to-moderate hypertension def ined as systolic blood pressure 140-169 mm Hg and/or
diastolic blood pressure 90-109 mm Hg
46 trials had 1 limitation including
unclear allocation concealment
lack of blinding
of 3 trials without such limitations, data f or clinical outcomes limited by wide conf idence
intervals or inconsistency
29 trials compared any antihypertensive drug to placebo or no antihypertensive drug (control)
antihypertensive drugs associated with
reduced risk of severe hypertension in analysis of 20 trials with 2,558 women
risk ratio (RR) 0.49 (95% CI 0.4-0.6)
NNT 9-13 with severe hypertension in 20% of control group
statistically signif icant reductions reported in subgroup analyses with beta
blockers alone, with combination therapies including beta blockers, and with
methyldopa
decreased miscarriage in analysis of 7 trials with 1,058 women
RR 0.39 (95% CI 0.17-0.93)
NNT 35-409 with miscarriage in 3.5% of control group
no high-quality trials contributed to analysis
decreased respiratory distress syndrome in analysis of 5 trials with 825 neonates
RR 0.28 (95% CI 0.12-0.63)
NNT 19-45 with respiratory distress syndrome in 6% of control group
analysis includes 2 high-quality trials with nonsignif icant results f avoring
antihypertensive drug group
increased maternal side ef f ects in analysis of 11 trials with 934 women
RR 1.53 (95% CI 1.1-2.12)
NNH 11-125 with maternal side ef f ects in 8% of control group
signif icant increase with beta blockers, but no signif icant dif f erence with other
antihypertensive drugs
no signif icant dif f erences in rates of
proteinuria/preeclampsia in analysis of 23 trials with 2,851 women, results limited by
signif icant heterogeneity (signif icantly reduced risk with beta blockers but signif icantly
increased risk with calcium channel blockers)
cesarean section in analysis of 20 trials with 2,624 women
preterm birth in analysis of 15 trials with 2,141 neonates
stillbirth in analysis of 18 trials with 2,480 neonates
perinatal death in analysis of 20 trials with 2,382 neonates
maternal mortality in analysis of 5 trials with 525 women
eclampsia in analysis of 5 trials with 578 women
placental abruption in analysis of 11 trials with 1,433 women
preterm birth in analysis of 15 trials with 2,141 women
small-f or-gestational-age in analysis of 20 trials with 2,586 women
oral beta blockers effective at reducing blood pressure for women with mild to moderate
hypertension (blood pressure < 170/110 mm Hg) during pregnancy but no clear evidence of
effect on clinical outcomes
systematic review of 29 controlled trials evaluating beta blockers in about 2,500 women with
mild to moderate hypertension during pregnancy
13 trials with 1,480 women comparing beta blockers to placebo or no treatment f ound reduced
risk of severe hypertension and need f or additional antihypertensive agents, but insuf f icient
data regarding perinatal mortality or preterm delivery, possible decreases in maternal hospital
admission and respiratory distress syndrome, and possible increase in small f or gestational
age babies and neonatal bradycardia
13 trials with 854 women comparing beta blockers to methyldopa f ound no signif icant
dif f erences in outcomes
authors note that there is insuf f icient evidence regarding the ef f ect of antihypertensive
therapy in general on clinical outcomes in this patient population
Ref erence - Cochrane Database Syst Rev 2003;(3):CD002863 (review updated 2012 Jul 4)
Ef f icacy of ant ihypert ensive t herapy in severe hypert ension:
limited evidence to guide antihypertensive treatment for severe hypertension during
pregnancy
systematic review of 35 randomized trials comparing dif f erent antihypertensive drugs (15
comparisons) in 3,573 pregnant women with very high blood pressure (diastolic blood
pressure 105 mm Hg, systolic blood pressure 160 mm Hg)
calcium channel blockers (nif edipine, isradipine) associated with decreased persistent high
blood pressure compared to hydralazine in analysis of 6 trials with 313 women
risk ratio (RR) 0.37 (95% CI 0.21-0.66)
NNT 6-14 with persistent high blood pressure in 22% of hydralazine group
comparing ketanserin to hydralazine
ketanserin associated with
increased persistent high blood pressure (RR 4.79, 95% CI 1.95-11.73) in analysis
of 3 trials with 180 women
decreased side ef f ects (RR 0.32, 95% CI 0.19-0.53) in analysis of 3 trials with 120
women
decreased risk of hemolysis, elevated liver enzymes, and lowered platelets
(HELLP) syndrome (9.1% with ketanserin vs. 45.5% with hydralazine, p = 0.024,
NNT 3) in 1 trial with 44 women
labetalol did not signif icantly decrease persistent hypertension but signif icantly decreased
hypotension requiring treatment and nonsignif icantly decreased cesarean section vs.
diazoxide in 1 trial with 90 women
nimodipine signif icantly decreased persistent high blood pressure, maternal respiratory
dif f iculties, side ef f ects, and postpartum hemorrhage vs. magnesium sulf ate in 1 trial with
1,650 women (below), but high incidence of persistent elevated blood pressure in both groups
oral nifedipine associated with shorter time to target blood pressure compared with IV
labetalol in pregnant women with hypertensive emergency (level 3 [lacking direct] evidence)
based on randomized trial without primary clinical outcome
60 pregnant women at 24 weeks gestation with hypertensive emergency (sustained increase
in systolic blood pressure 160 mm Hg or diastolic blood pressure 110 mm Hg) randomized
to nif edipine 10 mg orally up to 5 doses plus IV placebo saline injections every 20 minutes vs.
labetalol in escalating doses of 20, 40, 80, 80, and 80 mg IV plus placebo tablet every 20
minutes until target blood pressure ( 150 mm Hg systolic and 100 mm Hg diastolic) reached
crossover treatment administered if initial treatment f ailed
comparing nif edipine vs. labetalol
median time to target blood pressure 40 minutes vs. 60 minutes (p = 0.008)
median doses to achieve target blood pressure 2 vs. 3 (p = 0.008)
f ailure to reach treatment target with initial therapy in 1 patient vs. 5 patients (not
signif icant)
af ter crossover, target blood pressure achieved with maximum of 2 doses nif edipine in all 5
patients f ailing initial treatment with labetalol
no signif icant dif f erences in maternal or neonatal outcomes
oral nifedipine and labetalol IV associated with similar efficacy for control of severe
gestational hypertension and similar maternal and neonatal outcomes (level 2 [mid-level]
evidence)
based on small randomized trial
50 pregnant women at gestational age 24 weeks with requiring immediate treatment f or
severe gestational hypertension ( 160/110 mm Hg) randomized to up to 5 doses of nif edipine
10 mg orally vs. labetalol 20-80 mg escalating dose IV every 15 minutes
treatment continued until target blood pressure ( 150/100 mm Hg) reached
20% crossover rate in both groups
comparing nif edipine vs. labetalol
mean time to achieve target blood pressure 30 minutes vs. 45 minutes (not signif icant)
mean number of doses of medication to achieve target blood pressure 2 vs. 3 (not
signif icant)
cesarean section in 64% vs. 52% (not signif icant)
no signif icant dif f erence in maternal dizziness, headache, or shortness of breath, or neonatal
birthweight, or intensive care admission
Magnesium sulf at e:
Recommendat ions:
(3)
magnesium sulf ate recommended f or f irst-line treatment of eclampsia (SOGC Grade A, Level I)
magnesium sulf ate recommended f or preventing eclampsia in women with severe preeclampsia
(SOGC Grade A, Level I)
magnesium sulf ate may be considered f or women with nonsevere preeclampsia (SOGC Grade
C, Level I)
dosing
magnesium sulf ate 4 g IV bolus, f ollowed by 1 g/hour inf usion
treat recurrent seizure with additional 2-4 g IV bolus
phenytoin and benzodiazepines should NOT be used f or eclampsia prophylaxis or treatment
unless magnesium sulf ate contraindicated or inef f ective (SOGC Grade E, Level I)
American College of Obstetricians and Gynecologists (ACOG) recommendations
(5)
use magnesium sulf ate f or prevention and treatment of seizures in women with severe
preeclampsia or eclampsia (ACOG Level A)
sample protocol is 4-6 g loading dose in 100 mL f luid IV given over 15-20 minutes, then 2
g/hour continuous inf usion
Dosing:
magnesium sulf ate loading dose 14 g given as
4 g IV
10 g intramuscularly (5 g in each buttock)
f ollowed by 24 hours of either
1 g/hour IV inf usion
4 g intramuscularly every 4 hours
DynaMed commentary -- avoid use of MgSO
4
abbreviation which may be conf used with morphine
sulf ate (MSO
4
)
dosing variations
insufficient evidence to evaluate different magnesium sulfate treatment regimens for
prevention and treatment of eclampsia
systematic review of 6 randomized trials comparing dif f erent regimens f or
administration of magnesium sulf ate in 866 women with preeclampsia or eclampsia
most trials too small to draw reliable conclusions
1 treatment trial comparing loading dose alone vs. loading dose plus maintenance
therapy f or 24 hours in 401 women with preeclampsia reported no signif icant dif f erence
in risk of recurrence of convulsions or stillbirth, but conf idence intervals were wide
Ref erence - Cochrane Database Syst Rev 2010 Aug 4;(8):CD007388
limiting magnesium sulfate to 12 hours postpartum may be safe in women with mild
preeclampsia (level 2 [mid-level] evidence)
based on randomized trial with inadequate power to detect small dif f erences
200 women with mild preeclampsia randomized to magnesium sulf ate f or 12 vs. 24
hours of postpartum therapy
extension of magnesium sulf ate f or severe preeclampsia occurred in 6.9% 12 hour vs.
1.1% 24 hour group (p = 0.07)
no cases of seizures, magnesium sulf ate toxicity or intolerance
Ref erence - Obstet Gynecol 2006 Oct;108(4):833, editorial can be f ound in Obstet
Gynecol 2006 Oct;108(4):824
magnesium sulfate 14 g reported to prevent recurrent seizure in patients with
eclampsia (level 3 [lacking direct] evidence)
based on uncontrolled cohort study
121 patients aged 14-38 years with eclampsia in Nigeria were treated with magnesium
sulf ate 14 g given as
4 g IV over 14 minutes
10 g intramuscularly (5 g in each buttock)
recurrent seizure in 7.4% within 4 hours of loading dose
maternal mortality 9.9%
stillbirths in 55.4% (most f etal deaths occurred prior to hospital admission)
Ref erence - BMC Res Notes 2009 Aug 19;2:165 f ull-text
Ef f icacy:
magnesium sulfate in women with preeclampsia reduces risk of eclampsia (level 1 [likely
reliable] evidence) and appears more effective than phenytoin or nimodipine (level 2 [mid-
level] evidence)
magnesium sulfate in women with preeclampsia reduces risk of eclampsia (level 1
[likely reliable] evidence)
systematic review of 15 randomized trials evaluating anticonvulsants f or preeclampsia
6 trials with 11,444 women with preeclampsia compared magnesium sulf ate vs. placebo
or no anticonvulsant
magnesium sulf ate associated with
reduced risk of eclampsia (relative risk [RR] 0.41, 95% CI 0.29-0.58; NNT
100, 95% CI 50-100)
reduced risk of placental abruption (RR 0.64, 95% CI 0.5 - 0.83; NNT 100,
95% CI 50-1,000)
increased risk of cesarean section (RR 1.05 95% CI 1-10)
nonsignif icant reduction in mortality (RR 0.54, 95% CI 0.26-1.1)
no signif icant dif f erence in stillbirth or neonatal death (RR 1.04, 95% CI 0.93-1.15)
magnesium sulf ate reduced risk of eclampsia (RR 0.08, 95% CI 0.01-0.6) compared to
phenytoin in analysis of 3 trials with 2,291 women; largest trial summarized below
magnesium sulf ate reduced risk of eclampsia compared to nimodipine in 1 trial with
1,650 women (RR 0.33, 95% CI 0.14-0.77) summarized below
Ref erence - Cochrane Database Syst Rev 2010 Nov 10;(11):CD000025
magnesium sulfate reduces risk of eclampsia (level 1 [likely reliable] evidence)
based on randomized trial (largest trial in Cochrane review)
10,141 women (in 33 countries) who were pregnant or within 24 hours postpartum and had
blood pressure at least 140/90 mm Hg and proteinuria 1+ (30 mg/dL) or more were randomized
to magnesium sulf ate vs. placebo (normal saline under double-blind conditions with allocation
concealment)
magnesium sulf ate was given as 4 g IV loading dose over 10-15 minutes then maintenance of
either 1 g/hour IV or 5 g intramuscularly into each buttock (10 g total) every 4 hours f or 24
hours
women who received magnesium sulf ate loading bef ore trial entry or needed to continue
treatment af ter 24 hours were included, and this may introduce bias against ef f icacy of
magnesium sulf ate by introducing magnesium sulf ate to placebo group
f ollow-up data available f or 10,110 (99.7%) women and 9,024 (98.6%) babies (babies of
women with treatment initiated postpartum were not evaluated)
comparing magnesium sulf ate vs. placebo
eclamptic convulsions in 0.8% vs. 1.9% (NNT 91, 95% CI 62.5-143)
NNT 63 f or women with severe preeclampsia (95% CI 38-181)
NNT 109 f or women without severe preeclampsia (95% CI 72-225)
eclampsia in 2% vs. 6% with multiple pregnancy (NNT 25)
maternal death in 0.2% vs. 0.4% (study underpowered to detect statistical signif icance)
placental abruption in 2% vs. 3.2% (NNT 84)
potential harms comparing magnesium sulf ate vs. placebo
no clear dif f erences in maternal morbidity
no clear dif f erences in neonatal mortality (12.7% vs. 12.4%) or morbidity
16% vs. 12% stopped treatment early (NNH 25)
side ef f ects in 24% vs. 5% (NNH 5), most f requently f lushing which was more common
with IV regimen (24% vs. 2%, NNH 4.5) than intramuscular regimen (16% vs. 2%, NNH 7)
Ref erence - Magpie trial (Lancet 2002 Jun 1;359(9321):1877), editorial can be f ound in Lancet
2002 Jun 1;359(9321):1872, commentary can be f ound in BMJ 2002 Sep 21;325(7365):609,
Lancet 2002 Oct 26;360(9342):1329, BMJ 2003 Jan 4;326(7379):50 f ull-text, Evidence-Based
Medicine 2003 Jan-Feb;8(1):9
magnesium more cost-effective in lower-income countries
based on subgroup analyses of 9,996 women in Magpie trial
NNT 324 to prevent 1 case of eclampsia in countries with high gross national income,
incremental cost $21,202
NNT 184 in middle-income countries, incremental cost $2,473
NNT 43 in low-income countries, incremental cost $456
Ref erence - BJOG 2006 Feb;113(2):144
magnesium sulfate associated with less eclampsia compared to phenytoin in women with
hypertension (level 2 [mid-level] evidence)
based on randomized trial with inadequate allocation concealment
2,138 women with hypertension admitted f or labor and delivery randomized to magnesium
sulf ate vs. phenytoin continued f or 24 hours postpartum
magnesium given as 10 g intramuscular loading dose, then 5 g maintenance dose
intramuscularly every f our hours; additional 4 g loading dose IV f or women with severe
preeclampsia
phenytoin given as 1,000 mg loading dose inf used over 1 hour plus 500 mg orally 10
hours later
eclampsia occurred in 0 with magnesium and 0.92% with phenytoin (p = 0.004)
cesarean section in 27% vs. 22% (p = 0.047, NNH 20)
no signif icant dif f erences in other maternal or neonatal outcomes
Ref erence - N Engl J Med 1995 Jul 27;333(4):201 f ull-text
magnesium sulfate appears more effective than nimodipine for preventing seizures in
severe preeclampsia (level 2 [mid-level] evidence)
based on randomized trial with unclear allocation concealment
1,650 women with severe preeclampsia were randomized to magnesium sulf ate IV based on
institutional protocol vs. nimodipine 60 mg orally every 4 hours until 24 hours postpartum
hydralazine IV used as needed to control blood pressure
0.8% magnesium sulf ate patients vs. 2.6% nimodipine patients had witnessed tonic-clonic
seizure (p = 0.01, NNT 56) with dif f erence primarily related to increased postpartum seizure
rate with nimodipine (0 vs. 1.1%)
more magnesium sulf ate patients required hydralazine f or blood pressure control (54% vs.
46%)
no signif icant dif f erences in neonatal outcomes
Ref erence - N Engl J Med 2003 Jan 23;348(4):304, editorial can be f ound in N Engl J Med 2003
Jan 23;348(4):275, correction can be f ound in N Engl J Med 2003 Apr 24;348(17):1730,
commentary can be f ound in N Engl J Med 2003 May 22;348(21):2154
magnesium sulfate reduces recurrence of seizures compared to diazepam or phenytoin in
women with eclampsia (level 1 [likely reliable] evidence)
based on Cochrane reviews and large randomized trial
magnesium sulfate reduces maternal mortality and recurrent seizures more than
diazepam for treatment of eclampsia (level 1 [likely reliable] evidence)
systematic review of 7 randomized trials comparing magnesium sulf ate (IV or
intramuscular) vs. diazepam in 1,396 women with clinically diagnosed eclampsia
magnesium sulf ate associated with reduced risk of
maternal death (risk ratio [RR] 0.59, 95% CI 0.38-0.92) in analysis of 7 trials with
1,396 women
recurrent seizures (RR 0.43, 95% CI 0.33-0.55, NNT 7, 95% CI f or NNT 5-9) in
analysis of 7 trials with 1,390 women
Apgar scores < 7 at 5 minutes (RR 0.7, 95% CI 0.54-0.9) in analysis of 3 trials with
643 neonates
special care unit stay > 7 days (RR 0.66, 95% CI 0.46-0.96) in analysis of 3 trials
with 631 neonates
maternal risk of stroke or other serious morbidity including renal f ailure, cardiac
arrest, liver f ailure, respiratory depression, or pneumonia
perinatal mortality, neonatal mortality, or admission to special care unit
Ref erence - Cochrane Database Syst Rev 2010 Dec 8;(12):CD000127
magnesium sulfate reduces recurrent seizures, pneumonia and intensive care more
than phenytoin for treatment of eclampsia (level 1 [likely reliable] evidence)
systematic review of 7 randomized trials comparing magnesium sulf ate (IV or
intramuscular) vs. phenytoin in 974 women with clinically diagnosed eclampsia
magnesium sulf ate associated with
reduced recurrence of seizures in analysis of 6 trials with 972 women
risk ratio (RR) 0.34 (95% CI 0.24-0. 49)
NNT 7-10 assuming recurrent seizures in 20% of phenytoin group
trend toward reduced maternal mortality (RR 0.5, 95% CI 0.24-1.05) in analysis of
3 trials with 847 women
reduced pneumonia and admission to intensive care unit in individual trials
trend toward increased renal f ailure (RR 1.52, 95% CI 0.98-2.36) in analysis of 3
f ewer admissions to a special care baby unit in 1 trial with 518 babies
magnesium sulfate reduces recurrence of seizures compared to diazepam or
phenytoin in women with eclampsia (level 1 [likely reliable] evidence)
based on randomized trial (largest trial in Cochrane reviews above)
910 women with eclampsia (at 23 centers in 8 countries) randomized to magnesium
sulf ate vs. diazepam
777 women with eclampsia (at 4 centers in South Af rica and India) randomized to
magnesium sulf ate vs. phenytoin
magnesium sulf ate dosing
intramuscular regimen - 4 g IV loading dose over 5 minutes plus 5 g
intramuscularly into each buttock, then 5 g intramuscularly every 4 hours (if
respiratory rate > 16 breaths/minute, urine output > 25 mL/hour and knee jerks
present) f or 24 hours
IV regimen - 4-5 g IV loading dose, then 1 g/hour inf usion f or 24 hours
recurrent seizures occurred in
13.2% with magnesium sulf ate vs. 27.9% with diazepam (p < 0.0001)
5.7% with magnesium sulf ate vs. 17.1% with phenytoin (p < 0.0001)
maternal mortality nonsignif icantly lower in magnesium sulf ate groups
Ref erence - Collaborative Eclampsia Trial (Lancet 1995 Jun 10;345(8963):1455)
magnesium sulfate may reduce maternal death, serious morbidity and recurrence of
seizures compared to lytic cocktail in women with eclampsia (level 2 [mid-level] evidence)
based on Cochrane review of low-to-moderate quality trials
systematic review of 3 randomized trials comparing magnesium sulf ate (IV or intramuscularly)
vs. lytic cocktail in 397 women with clinical diagnosis of eclampsia
lytic cocktail (usually chlorpromazine, promethazine and pethidine [meperidine]) was once
standard treatment in India but no longer widely used
magnesium sulf ate associated with reduced
maternal mortality in analysis of all trials
risk ratio (RR) 0.14 (95% CI 0.03-0.59)
NNT 15-35 assuming 7% mortality in lytic cocktail group
seizure recurrence in analysis of all trials
RR 0.06 (95% CI 0.03-0.12)
NNT 1-2 assuming 55% seizure recurrence in lytic cocktail group
respiratory depression (2 trials), coma (1 trial), pneumonia (2 trials)
no signif icant dif f erences between groups in perinatal mortality in analysis of 2 trials with 177
inf ants
Ref erence - Cochrane Database Syst Rev 2010 Sep 8;(9):CD002960
Adverse ef f ect s on f et us:
magnesium sulfate associated with minimal decrease in baseline fetal heart rate and
increased rate of absent or minimal variability but fewer prolonged decelerations (level 3
[lacking direct] evidence)
based on retrospective cohort study without clinical outcomes
5,387 with term delivery reaching second stage of labor evaluated f or exposure to magnesium
sulf ate f or severe preeclampsia (228 women) vs. no exposure to magnesium sulf ate (5,139
women)
mean f etal heart rate baseline 136.9 beats per minute (within normal range) vs. 139 beats per
minute (p = 0.02)
magnesium sulf ate exposure associated with
increased risk of f etal heart rate baseline < 120 beats per minutes (adjusted odds ratio
[OR] 1.76, 95% CI 1.21-2.56)
increased risk of absent or minimal variability (adjusted OR 2.41, 95% CI 1.78-3.27)
f ewer prolonged decelerations (adjusted OR 0.64, 95% CI 0.49-0.84)
no signif icant dif f erence in presence or number of accelerations or decelerations
reviews
Cort icost eroids:
give antenatal corticosteroid therapy f or all women with preeclampsia bef ore 34 weeks gestation
(3)
antenatal corticosteroid therapy may be considered bef ore 34 weeks gestation f or women with
gestational hypertension (despite absence of proteinuria or adverse conditions) if delivery planned
within 7 days (SOGC Grade I, Level III)
(3)
Medicat ions wit h limit ed role or insuf f icient evidence:
low-dose aspirin NOT recommended f or preeclampsia (SOGC Grade E, Level I)
(3)
phenytoin and benzodiazepines should NOT be used f or eclampsia prophylaxis or treatment unless
magnesium sulf ate contraindicated or inef f ective (SOGC Grade E, Level I)
(3)
insufficient evidence to evaluate low-dose dopamine in women with severe preeclampsia
and oliguria
systematic review of randomized trials comparing low-dose dopamine (5 mcg/kg/minute or
lower) to placebo or no dopamine in women with severe preeclampsia and acute renal f ailure
only 1 trial f ound, comparing low-dose dopamine vs. placebo in 40 postpartum women with
oliguria
dopamine increased urinary output over 6 hours but clinical benef it not established
insuf f icient evidence f or recommendations on usef ulness of treatment with
no randomized trials identified to evaluate Chinese herbal medicines for women with
preeclampsia
Ref erence - Cochrane Database Syst Rev 2010 Jan 20;(1):CD005126
Consult at ion and ref erral:
(3)
at scheduling of antenatal care, of f er obstetric consultation to women with markers of
increased risk f or preeclampsia (SOGC Grade B, Level II-2)
consider risk stratif ication involving multivariable clinical and laboratory approach f or women at
increased risk of preeclampsia (SOGC Grade B, Level II-2)
obstetric consultation mandatory f or women with severe preeclampsia (SOGC Grade B, Level
III)
Ot her management :
Expect ant management :
American College of Obstetricians and Gynecologists (ACOG) recommends considering
expectant management f or women remote f rom term with mild preeclampsia (ACOG Level C)
(5)
maternal and fetal wellbeing surveillance in preeclampsia
(3)
antenatal and postpartum serial surveillance of maternal wellbeing recommended (SOGC
f requency of maternal surveillance should be at least once weekly antenatally and at least
once in f irst 3 days postpartum (SOGC Grade C, Level III)
serial surveillance of f etal wellbeing recommended (SOGC Grade B, Level II-2)
antenatal f etal surveillance should include umbilical artery Doppler velocimetry (SOGC Grade A,
Level I)
women who develop gestational hypertension without proteinuria or adverse conditions prior
to 34 weeks gestation should be f ollowed closely f or maternal and perinatal complications
expectant management of mild preeclampsia
(1)
measure blood pressure twice weekly
obtain lab tests weekly
complete blood count (CBC)
platelet count
alanine transaminase (ALT)
aspartate transaminase (AST)
lactate dehydrogenase (LDH)
uric acid
creatinine
assess f or proteinuria
screen with dipstick or spot protein:creatinine ratio
obtain periodic 24-hour urine collections
f etal monitoring
obtain nonstress test twice weekly
measure amniotic f luid index once or twice weekly
biophysical prof ile may be done weekly to replace 1 of the twice-weekly nonstress tests
and amniotic f luid index
perf orm ultrasound f or f etal growth every 3-4 weeks
for women with severe preeclampsia at 24-34 weeks, effect of choosing prompt delivery or
expectant management on neonatal morbidity or mortality is uncertain (level 2 [mid-level]
evidence)
based on Cochrane review and subsequent randomized trial with inconsistent results on
possible harms
Cochrane review of trials with methodologic limitations (24-34 weeks gestation)
systematic review of 4 randomized trials comparing interventionist vs. expectant care in
425 women with severe preeclampsia at 34 weeks gestation
interventionist care def ined as policy of early elective delivery by induction of labor or
cesarean section
all trials had 1 limitation including
lack of or unclear blinding
subgroup analysis
interventionist care associated with
increased cesarean section in analysis of all trials
risk ratio (RR) 1.09 (95% CI 1.01-1.18)
NNH 6-122 with cesarean section in 82% of expectant care group
increased hyaline membrane disease in analysis of 2 trials with 133 neonates
RR 2.3 (95% CI 1.39-3.81)
NNH 1-11 with hyaline membrane disease in 22% of expectant care group
increased need f or neonatal ventilation in analysis of 2 trials with 300 neonates
RR 1.5 (95% CI 1.11-2.02)
NNH 3-30 with neonatal ventilation in 30% of expectant care group
increased intraventricular hemorrhage (24% in interventionist group vs. 13% in
expectant care group, p = 0.03, NNH 9) in 1 trial with 262 neonates
nonsignif icant increase in necrotizing enterocolitis (RR 2.1, 95% CI 0.93-4.79) in
analysis of 3 trials with 395 neonates
no signif icant dif f erence in neonatal mortality in analysis of all trials
randomized trial in Latin America with wide conf idence intervals (28-33 weeks gestation)
267 women at 28-33 weeks gestation with severe hypertensive disorder and living in
Latin America were randomized to 1 of 2 groups
steroids plus expectant management (delivery only f or specif ic maternal/f etal
indications or reaching 34 weeks gestation)
steroids f ollowed by prompt delivery within 24-72 hours
exclusion criteria included small-f or-gestational-age at time of admission
antihypertensive medications used to maintain systolic blood pressure < 160 mm Hg and
diastolic blood pressure < 110 mm Hg were dif f erent between groups
in prompt delivery group bolus doses of hydralazine, labetalol, or oral nif edipine
were used; f requency of use not reported
in expectant management group oral antihypertensive medications used only in
some hospitals, use reported in 46.5% of women in expectant management group
neonatal morbidity was composite outcome including respiratory distress syndrome,
necrotizing enterocolitis, intraventricular hemorrhage, and neonatal sepsis
maternal morbidity was composite outcome including placental abruption, eclampsia,
pulmonary edema, renal insuf f iciency, oliguria, disseminated intravascular coagulation,
and hemolysis, elevated liver enzymes, low platelet count (HELLP) syndrome
comparing expectant management vs. prompt delivery
mean pregnancy prolongation was 10.3 days vs. 2.2 days (p = 0.0001)
perinatal mortality 8.7% vs. 9.4% (not signif icant, relative risk 0.91, 95% CI 0.34-
1.93)
neonatal morbidity in 55.6% vs. 56.4% (not signif icant)
maternal morbidity in 25.2% vs. 20.3% (not signif icant)
small gestational age in 21.7% vs. 9.4% (p = 0.005, NNH 8)
placental abruption in 7.6% vs. 1.5% (p = 0.01, NNH 16)
Ref erence - MEXPRE Latin trial (Am J Obstet Gynecol 2013 Nov;209(5):425.e1),
commentary can be f ound in Am J Obstet Gynecol 2013 Nov;209(5):e1
Abdominal decompression:
abdominal decompression may improve perinatal outcomes in women with preeclampsia or
impaired fetal growth (level 2 [mid-level] evidence)
based on Cochrane review of trials with inadequate allocation concealment
systematic review of 3 randomized or quasi-randomized trials comparing abdominal
decompression (negative pressure to space around abdomen) to no decompression in 356
women with preeclampsia or impaired f etal growth
1 trial included women with preeclampsia, essential hypertension, or chronic nephritis; 2 trials
included women with small-f or-gestational-age f etus
comparing abdominal decompression to no decompression
abdominal decompression associated with decreased risk of
perinatal mortality in analysis of 3 trials with 367 inf ants
risk ratio (RR) 0.39 (95% CI 0.22-0.71)
NNT 7-19 with perinatal mortality in 19% in no decompression group
low birth weight in analysis of 2 trials with 304 inf ants, results limited by
signif icant heterogeneity
RR 0.5 (95% CI 0.4-0.63)
NNT 3-4 with low birth weight in 75% of no decompression group
f etal distress in labor in 14.3% vs. 38.6% (p = 0.0026, NNT 5) in 1 trial with 140 inf ants
Apgar score < 6 at 1 minute in 10% vs. 38.6% (p = 0.00052, NNT 4) in 1 trial with 140
inf ants
unchanged or worsening preeclampsia in 19% vs. 52.6% (p = 0.004, NNT 3) in 1 trial with
80 women
Post delivery care:
(3)
for care during first 6 weeks postpartum
measure blood pressure during time of peak postpartum blood pressure at 3-6 days
af ter delivery (SOGC Grade B, Level III)
antihypertensive therapy
antihypertensive medication can be restarted postpartum, especially in women
with severe preeclampsia and women who delivered preterm (SOGC Grade I, Level
II-2)
treat severe postpartum hypertension with antihypertensive medication to keep
systolic blood pressure < 160 mm Hg and diastolic blood pressure < 110 mm Hg
antihypertensive medication can be used to treat nonsevere postpartum
hypertension, especially in women with comorbidities (SOGC Grade I, Level III)
antihypertensive medications acceptable f or use in breastf eeding include (SOGC
Grade B, Level III)
conf irm resolution of end-organ dysf unction (SOGC Grade I, Level III)
nonsteroidal anti-inf lammatory drugs (NSAIDs) should NOT be given postpartum if any
of f ollowing criteria present (SOGC Grade I, Level III)
hypertension dif f icult to control
oliguria
elevated creatinine
platelets < 50 10
9
/L
consider postpartum thromboprophylaxis in women with preeclampsia, especially af ter
antenatal bed rest f or > 4 days or af ter cesarean section (SOGC Grade I, Level III)
low-molecular-weight heparin should NOT be given postpartum until 2 hours af ter
epidural catheter removal (SOGC Grade B, Level III)
for care beyond 6 weeks postpartum
f or women with history of severe preeclampsia, especially those who presented or
delivered bef ore 34 weeks gestation, screen f or
advise women that intervals between pregnancies < 2 or 10 years associated with
recurrent preeclampsia (SOGC Grade D, Level II-2)
encourage overweight women to attain healthy body mass index (BMI) f or decreasing
risk in f uture pregnancies (SOGC Grade A, Level II-2) and f or long-term health (SOGC
Grade A, Level I)
women with pre-existing hypertension should have (if not done previously) (SOGC
Grade I, Level III)
urinalysis
serum sodium, potassium and creatinine
f asting glucose
f asting total cholesterol, high-density lipoprotein cholesterol, low-density
lipoprotein cholesterol and triglycerides
standard 12-lead electrocardiography
consider assessing traditional cardiovascular risk markers in normotensive women with
hypertensive disorders of pregnancy (SOGC Grade B, Level II-2)
advise all women with history of hypertensive disorder of pregnancy to pursue healthy
diet and lif estyle (SOGC Grade B, Level I)
empiric postnatal furosemide may decrease need for postnatal antihypertensive therapy in
women with preeclampsia; no significant differences between various antihypertensives for
treating postnatal hypertension (level 3 [lacking direct] evidence)
based on nonclinical outcome in Cochrane review
systematic review of 9 randomized trials evaluating interventions f or postpartum hypertension
in 667 women with antenatal hypertensive disorder of pregnancy or de novo postpartum
hypertension
postpartum hypertension def ined as elevated blood pressure ( 140/90 mm Hg) measured
twice 4 hours apart between delivery and 6 weeks post partum
3 trials compared empiric interventions to placebo
comparing f urosemide 20-40 mg orally once daily f or 5-7 days to placebo or no therapy
f urosemide plus potassium signif icantly decreased use of additional
antihypertensive therapy in hospital (34.8% with f urosemide vs. 47% with placebo,
p = 0.048, NNT 9) in 1 trial with 264 women (summarized below)
no signif icant dif f erence in postnatal antihypertensive medication use at hospital
discharge in analysis of 2 trials with 282 women
no signif icant dif f erence in severe hypertension comparing
nif edipine 10 mg orally every 4 hours f or 48 hours vs. placebo in 1 trial with 31
women
L-arginine given bef ore delivery and f or 3 days post partum vs. placebo in 1 trial
with 45 women
no maternal deaths reported
5 trials evaluated comparative ef f icacy of antihypertensive interventions f or treating
postpartum hypertension
no trials compared antihypertensive therapy vs. placebo
no signif icant dif f erences in use of additional antihypertensive therapy comparing
no maternal deaths or severe hypotension reported
Ref erence - Cochrane Database Syst Rev 2013 Apr 30;(4):CD004351
DynaMed commentary -- f urosemide Pregnancy Category C and may inhibit lactation (FDA
MedWatch March 2012)
empiric postnatal furosemide may decrease need for postnatal antihypertensive
therapy in hospital compared to placebo in women with severe preeclampsia (level 3
based on randomized trial without clinical outcomes
264 women with preeclampsia or chronic hypertension randomized af ter delivery to
empiric f urosemide (20 mg/day) and potassium (K-Dur, 20 mEq/day) f or 5 days or no
treatment
patients excluded if already taking diuretics or potassium, < 20 weeks gestation, or had
peripartum hemodynamic instability
treatment started af ter IV magnesium discontinued and spontaneous diuresis initiated
comparing empiric f urosemide to placebo, f urosemide associated with
f or all patients
reduction in patients requiring additional hypertensive medication in
hospital (34.8% vs. 47%, no p value reported)
reduction in patients requiring additional hypertensive medication at
discharge (28.8% vs. 37.1%, no p value reported)
in severe preeclamptics (70 patients)
signif icant reduction in number of patients with severe preeclampsia
requiring additional hypertensive medication at discharge (26% vs. 6%, p <
0.045)
51% hypertensive immediately post partum and 43% upon transf er to
postpartum ward
lower systolic blood pressure on second postpartum day (142 mm Hg vs.
153 mm Hg, p < 0.004)
no signif icant dif f erence in diastolic blood pressure
no signif icant dif f erences in mild preeclampsia and chronic hypertension groups
Ref erence - Obstet Gynecol 2005 Jan;105(1):29
Follow-up:
Neonat al f ollow-up:
Prognosis
preeclampsia rarely remits spontaneously and usually worsens with time but resolves af ter delivery
(4)
stroke and pulmonary edema most common causes of maternal death in preeclampsia
(3)
severity and duration of preeclampsia associated with increasing time to resolution of
hypertension
205 women hospitalized with preeclampsia f rom 1990 to 1992 in the Netherlands f ollowed f or
2 years af ter delivery
persistent hypertension (def ined as blood pressure 140/90 mm Hg or use of
antihypertensive drugs) in
39% at 3 months postpartum
18% at 2 years postpartum
persistent proteinuria (def ined as 0.3 g/day) in
14% at 3 months postpartum
2% at 2 years postpartum
time to resolution of hypertension increased by
60% f or every 10 mm Hg increase in maximal systolic blood pressure (p < 0.001)
40% f or every 10 mm Hg increase in maximal diastolic blood pressure (p = 0.044)
3.6% f or every 1 day increase in time f rom preeclampsia diagnosis to delivery (p =
0.001)
time to resolution of proteinuria increased by 16% f or every 1 g/day increase in maximal
proteinuria (p = 0.001)
Mat ernal out comes:
physiologic changes of pregnancy may reveal risk of chronic diseases, preeclampsia and gestational
diabetes may predict cardiovascular and metabolic diseases (JAMA 2005 Dec 7;294(21):2751)
untreated chronic hypertension associated with increased risk of preeclampsia (level 2 [mid-
level] evidence)
100,029 deliveries f rom 1998 to 2008 were examined
1,074 mothers with chronic hypertension untreated during pregnancy and 97,820 mothers
without hypertension were analyzed
compared to no hypertension, chronic hypertension not treated during pregnancy associated
with increased risk of preeclampsia (adjusted odds ratio 7.02, 95% CI 5.54-8.89)
Ref erence - Am J Obstet Gynecol 2013 Apr;208(4):301.e1
preeclampsia may be associated with future maternal risk of cardiovascular disease
preeclampsia associated with increased risk of vascular disease and overall mortality
but not cancer
based on systematic review of cohort studies
systematic review of 25 cohort studies with 3,488,160 women
198,252 women (5.7%) developed preeclampsia
29,495 (0.85%) had episodes of cardiovascular disease and cancer
preeclampsia associated with increased subsequent overall mortality (7,537 of 49,049
women [15.3%] with preeclampsia), relative risk 1.49 in 4 studies with 794,462 women
f ollowed f or mean 14.5 years
preeclampsia signif icantly associated with subsequent increased risk f or
chronic hypertension developed in 1,885 of 3,658 women (51.5%) with
preeclampsia, relative risk (RR) 3.7 in 13 studies with 21,030 women f ollowed f or
mean 14.1 years
ischemic heart disease developed in 5,097 of 121,487 women (4.2%) with
preeclampsia, RR 2.16 in 8 studies with 2,346,997 women f ollowed f or mean 11.7
years
stroke developed in 907 of 64,551 women (1.4%) with preeclampsia, RR 1.81 in 4
studies with 1,671,578 women f ollowed f or mean 10.4 years
venous thromboembolism developed in 470 of 35,772 women (1.3%) with
preeclampsia, RR 1.79 in 3 studies with 427,693 women f ollowed f or mean 4.7
years
cancer was not signif icantly associated with preeclampsia in meta-analysis of 3 studies
with 729,025 women f ollowed f or mean 13.9 years
Ref erence - BMJ 2007 Nov 10;335(7627):974 f ull-text, editorial can be f ound in BMJ
2007 Nov 10;335(7627):945, commentary can be f ound in BMJ 2007 Nov
24;335(7629):1059
preeclampsia/eclampsia associated with future cardiovascular disease and severity of
preeclampsia may be associated with increased risk
based on systematic review of cohort and case-control studies
meta-analysis of 5 case-control and 10 cohort studies with 116,175 women evaluated
f or cardiovascular disease > 6 weeks postpartum
compared to women without preeclampsia/eclampsia, women with
preeclampsia/eclampsia had increased risk f or
subsequent cardiac disease (relative risk [RR] 2.33, 95% CI 1.95-2.78)
cerebrovascular disease (RR 2.03, 95% CI 1.54-2.67)
cardiovascular mortality (RR 2.29, 95% CI 1.73-3.04)
relative risk of subsequent cardiac disease by severity of preeclampsia/eclampsia
mild RR 2 (95% CI 1.83-2.19)
moderate RR 2.99 (95% CI 2.51-3.58)
severe RR 5.36 (95% CI 3.96-7.27)
Ref erence - Am Heart J 2008 Nov;156(5):918
preterm or term preeclampsia during first pregnancy associated with greatest risk of
cardiovascular death in women with only 1 lifetime pregnancy
836,147 women with f irst singleton birth between 1967 and 2002 were f ollowed f or
median 25 years
4.2% had preeclampsia during f irst pregnancy and 84% had 2 children
2.8% overall mortality during f ollow-up including 3,891 cardiovascular-related deaths
compared to no preeclampsia during f irst pregnancy, preeclampsia during f irst
pregnancy associated with increased risk of cardiovascular death in overall analysis
(adjusted hazard ratio [HR] 1.9, 95% CI 1.6-2.2)
compared to no preeclampsia during f irst pregnancy and term birth, risk of
cardiovascular death increased with
term preeclampsia during f irst pregnancy (adjusted HR 1.6, 95% CI 1.4-2)
preterm preeclampsia during f irst pregnancy (adjusted HR 3.7, 95% CI 2.7-4.8)
compared to no preeclampsia during f irst pregnancy and term birth and 2 lif etime
pregnancies, risk of cardiovascular death increased with
term preeclampsia during f irst and only lif etime pregnancy (adjusted HR 3.4, 95%
CI 2.6-4.6)
preterm preeclampsia during f irst and only lif etime pregnancy (adjusted HR 9.4,
95% CI 6.5-13.7)
term preeclampsia during f irst pregnancy in multiparous women (adjusted HR 1.5,
95% CI 1.2-2)
preterm preeclampsia during f irst pregnancy in multiparous women (adjusted HR
2.4, 95% CI 1.5-3.9)
Ref erence - BMJ 2012 Nov 27;345:e7677 f ull-text
increasing severity of hypertensive disease in pregnancy associated with increasing
risk of ischemic heart disease
based on 15-year f ollow-up of 403,550 women giving birth to f irst child
Ref erence - BJOG 2005 Nov;112(11):1486
hypertension in pregnancy associated with increased risk of maternal death and major
morbidity
based on study of all 250,173 women and 255,931 inf ants discharged f rom hospital
f ollowing birth in New South Wales f rom 2000 to 2002
preeclampsia/eclampsia associated with increased risk of stroke during first year
postpartum
based on retrospective cohort study of 1,132,019 parturients in Taiwan f rom 1999 to
2003
women f ollowed f or 1 year postpartum
stroke incidence 21.47 cases per 100,000 deliveries
Ref erence - Stroke 2009 Apr;40(4):1162
preeclampsia associated with 3.6 times risk of fatal stroke in later life
presence of 2 components of metabolic syndrome associated with future
hypertension in women with preeclampsia who are normotensive at initial postpartum
screen
based on cohort study
683 primiparous women with history of preeclampsia evaluated f or obesity,
hypertension, insulin resistance, dyslipidemia, and microalbuminuria at postpartum
screening
among women initially normotensive at postpartum screening, 4% developed
hypertension during median 6-year f ollow-up
compared with presence of < 2 components of metabolic syndrome, increased risk of
hypertension f ollowing normal postpartum screening if
2 components of metabolic syndrome (adjusted hazard ratio [HR] 2.9, 95% CI 1.2-
7.5)
3 components of metabolic syndrome (adjusted HR 8.1, 95% CI 2.8-22.9)
Ref erence - Obstet Gynecol 2012 Aug;120(2 Pt 1):311
preeclampsia associated with > 2 times risk of venous thromboembolism
based on study of 12,849 women with preeclampsia and 284,188 control women f ollowed f or
mean 3 years af ter delivery
rates of venous thromboembolism were 0.12% (41.7 per 100,000 person-years) in
preeclampsia group and 0.01%-0.08% (3-33.8 per 100,000 person-years) among 10 dif f erent
control groups
Ref erence - BMJ 2003 Apr 12;326(7393):791 f ull-text, correction can be f ound in BMJ 2003 Jun
21;326(7403):1362
fullPIERS model may predict risk of life-threatening complications within 48 hours of
hospital admission in women with preeclampsia (level 2 [mid-level] evidence)
based on prospective cohort study without external validation
2,023 women with preeclampsia were analyzed
5% had lif e-threatening complications within 48 hours of hospital admission
risk model based on
gestational age
chest pain or dyspnea
oxygen saturation
platelet count
creatinine concentration
aspartate transaminase concentration
predictive perf ormance of f ullPIERS f or complications within 48 hours of hospital admission in
internal validation
sensitivity 75.5%
specif icity 86.9%
positive predictive value 23.6%
negative predictive value 98.5%
Ref erence - Lancet 2011 Jan 15;377(9761):219, editorial can be f ound in Lancet 2011 Jan
15;377(9761):185
chronic hypertension, preeclampsia, and eclampsia associated with increased risk of
maternal mortality at delivery hospitalization
based on cohort study of 1,084,862 women with singleton pregnancies
1.8% had chronic hypertension, and 4.1% had preeclampsia or eclampsia
132 maternal deaths occurred (including 24 women with chronic hypertension and 42 women
with preeclampsia or eclampsia)
increased risk of maternal mortality during delivery hospitalization f or
preeclampsia or eclampsia (adjusted odds ratio [OR] 8.1, 95% CI 5.5-12.1)
chronic hypertension (adjusted OR 7.7, 95% CI 4.7-12.5)
Ref erence - Obstet Gynecol 2013 Sep;122(3):627
eclampsia associated with increased risk of maternal mortality
based on cohort study of 1,910,729 women and their newborns delivered in Canada f rom
2003-2009
incidence of eclampsia f ell f rom 12.4 per 10,000 deliveries in 2003 to 5.9 per 10,000 deliveries
in 2009
eclampsia associated with increased risk of
maternal mortality (adjusted odds ratio [OR] 26.8, 95% CI 9.7-73.8)
assisted ventilation (adjusted OR 102.3, 95% CI 78.2-133.8)
respiratory distress syndrome (adjusted OR 36.2, 95% CI 15.3-85.3)
acute renal f ailure (adjusted OR 20.9, 95% CI 11.4-38.3)
obstetric embolism (adjusted OR 9.1, 95% CI 4.1-19.9)
2011 Nov;118(5):976
eclampsia and eclampsia-associated white-matter lesions may increase risk of long-term
visual function deficits (level 2 [mid-level] evidence)
47 f ormerly eclamptic women and 47 matched parous controls with normotensive pregnancies
evaluated f or long-term visual f unction 10-11.5 years f ollowing index pregnancy
vision-specif ic health-related quality of lif e questionnaire consisted of base set of 25
questions and 14 additional questions generating vision-targeted subscales with each
subscale question scored 0-100 (100 being best possible score)
white matter lesions f ound on magnetic resonance imaging in 35.7% f ormerly eclamptic women
subscale composite scores comparing f ormerly eclamptic women vs. controls
general vision score 80.5 vs. 83.3 (not signif icant)
vision-related driving dif f iculties score 75.6 vs. 85.9 (p = 0.001)
peripheral vision score 90.8 vs. 98.4 (p = 0.002)
subscale composite scores comparing f ormerly eclamptic women with vs. without white matter
lesions
general vision score 75 vs. 85 (p = 0.01)
vision-related role f unction score 90.6 vs. 100 (p = 0.028)
peripheral vision score 87.5 vs. 100 (p = 0.045)
Ref erence - Obstet Gynecol 2012 May;119(5):959
Child out comes:
perinatal mortality
perinatal mortality with preeclampsia has declined
based on study of 33,835 pregnancies with f irst child, singleton birth af ter 24 weeks
gestation and preeclampsia in Norway
rate of perinatal death was 5.64% in 1967 to 1978, 1.76% in 1979 to 1990, and 0.86% in
1991 to 2003
rate of stillbirth was 4.41% in 1967 to 1978, 1.19% in 1979 to 1990, and 0.58% in 1991
to 2003
Ref erence - JAMA 2006 Sep 20;296(11):1357, correction can be f ound in JAMA 2006 Dec
27;296(24):2926
highest antepartum diastolic blood pressure 70-90 mm Hg associated with highest
birth weight and lowest risk of perinatal mortality
based on prospective study of 210,814 f irst singleton births among women without
hypertension prior to 20 weeks gestation
Ref erence - BMJ 2004 Dec 4;329(7478):1312 f ull-text
DynaMed commentary -- study does not establish that interventions to modif y blood
pressure would alter birth weight or perinatal mortality
severe preeclampsia before 24 weeks gestation associated with very low perinatal survival
(level 2 [mid-level] evidence)
46 women (with 51 f etuses) with severe preeclampsia at < 27 weeks gestation evaluated
corticosteroids given beyond 23 weeks
median 6 days of pregnancy prolongation (range 2-46 days)
overall perinatal survivor 57% (29 of 51)
perinatal survival by gestational age
0 of 7 with gestational age < 23 weeks
20% (2 of 10) f or 23 weeks to 23 6/7 weeks
46% overall rate of composite maternal morbidity (hemolysis, elevated liver enzymes, low
platelets [HELLP] syndrome, pulmonary edema, eclampsia, renal insuf f iciency)
Ref erence - Am J Obstet Gynecol 2008 Sep;199(3):247 e1, editorial can be f ound in Am J
Obstet Gynecol 2008 Sep;199(3):209
severe early-onset maternal hypertensive disorder may be associated with moderate delays
in mental and psychomotor development at age 1 year
172 children (median gestational age 31.6 weeks) born to mothers with severe early-onset
maternal hypertensive disorder
inf ant outcomes at 1 year
moderately delayed mental development in 37%
moderately delayed psychomotor development in 51%
severe delays in mental and/or psychomotor development in 18%
eclampsia associated with increased risk of neonatal mortality, respiratory distress
syndrome (RDS) and small-for-gestational age (SGA) birth
based on cohort study of 1,910,729 women and their newborns delivered in Canada f rom
2003-2009
incidence of eclampsia f ell f rom 12.4 per 10,000 deliveries in 2003 to 5.9 per 10,000 deliveries
in 2009
eclampsia associated with increased risk of
neonatal mortality (adjusted [OR] odds ratio 2.9, 95% CI 1.6-5.5)
RDS (adjusted OR 5.1, 95% CI 4.1-6.3)
SGA birth (adjusted OR 2.6, 95% CI 2.3-3)
2011 Nov;118(5):976
untreated chronic hypertension associated with increased risk of preterm delivery,
intrauterine growth restriction, and small-for-gestational age infants (level 2 [mid-level]
evidence)
based on retrospective cohort study of 100,029 deliveries f rom 1998 to 2008
1,074 mothers with chronic hypertension untreated during pregnancy and 97,820 mothers
without hypertension were analyzed
compared to no hypertension, chronic hypertension untreated during pregnancy associated
with increased risk of
preterm delivery (adjusted odds ratio [OR] 1.89, 95% CI 1.59-2.25)
intrauterine growth restriction (adjusted OR 2.09, 95% CI 1.51-2.89)
small-f or-gestational age (adjusted OR 2.06, 95% CI 1.44-2.95)
Ref erence - Am J Obstet Gynecol 2013 Apr;208(4):301.e1
Recurrence of preeclampsia:
preeclampsia associated with increased risk for recurrence of preeclampsia
based on prospective cohort study of 763,795 mothers having f irst births in Sweden f rom
1987 to 2004
risk of preeclampsia
4.1% in f irst pregnancy overall
1.7% in later pregnancies overall
1% in multiparous women without history of preeclampsia
14.7% in second pregnancy of women with preeclampsia in f irst pregnancy
31.9% in women with preeclampsia in previous 2 pregnancies
incidence of preeclampsia associated with delivery < 34 weeks gestation
0.42% in primiparous women without history of preeclampsia
0.11% in multiparous women without history of preeclampsia
6.8% in women with preeclampsia in 1 previous pregnancy
12.5% in women with preeclampsia in 2 previous pregnancies
Ref erence - BMJ 2009 Jun 18;338:b2255 f ull-text
Prevention and Screening
Prevent ion:
Recommendat ions f or prevent ion of preeclampsia:
preventing preeclampsia and complications
(3)
preconceptual counseling recommended f or women with pre-existing hypertension (SOGC
Grade I, Level III)
at f irst antenatal care visit women with increase risk f or preeclampsia should be of f ered
obstetric consultation (SOGC Grade B, Level II-2)
f or women at increased risk
low-dose aspirin (SOGC Grade A, Level I)
calcium supplementation 1 g/day f or women with low calcium intake (< 600 mg/day)
strategies recommended f or other benef icial ef f ects in pregnancy
strategies that may be usef ul include
interventions NOT recommended f or preeclampsia prevention
insuf f icient evidence f or recommendations about usef ulness of
dietary salt restriction during pregnancy (SOGC Grade I, Level III)
heart healthy diet (SOGC Grade I, Level III)
exercise (SOGC Grade I, Level I)
heparin (even among women with thrombophilia and/or prior preeclampsia) (SOGC
Grade I, Level II-2)
selenium (SOGC Grade I, Level I)
garlic (SOGC Grade I, Level I)
zinc (SOGC Grade I, Level III)
pyridoxine supplementation (SOGC Grade I, Level III)
iron supplementation with or without f olate (SOGC Grade I, Level III)
multivitamins (with or without micronutrients) (SOGC Grade i, Level III)
f or women at low risk
calcium supplementation 1 g/day orally recommended f or women with low dietary
calcium intake (< 600 mg/day) (SOGC Grade A, Level I)
strategies recommended f or other benef icial ef f ects in pregnancy
interventions NOT recommended f or preeclampsia prevention
prostaglandin precursors (SOGC Grade C, Level I), but may be usef ul f or
preventing other pregnancy complications
magnesium supplementation (SOGC Grade C, Level I), but may be usef ul f or
preventing other pregnancy complications
zinc supplementation (SOGC Grade C, Level I), but may be usef ul f or preventing
other pregnancy complications
dietary salt restriction during pregnancy (SOGC Grade D, Level I)
calorie restriction in overweight women during pregnancy (SOGC Grade D, Level I)
low-dose aspirin (SOGC Grade E, Level I)
vitamin C and vitamin E (SOGC Grade E, Level I)
thiazide diuretics (SOGC Grade E, Level I)
insuf f icient evidence f or recommendations about usef ulness of
Seventh Joint National Committee on Prevention, Detection, Evaluation and Treatment of
High Blood Pressure (JNC 7) recommendations for prevention of preeclampsia
(4)
identif y high-risk women
perf orm close clinical and laboratory monitoring f or early recognition
institute intensive monitoring or delivery when indicated
American College of Obstetricians and Gynecologists (ACOG)
(5)
does NOT recommend low-dose aspirin to prevent preeclampsia in women at low risk (ACOG
Level A)
does NOT recommend daily calcium supplementation to prevent preeclampsia (ACOG Level A)
f or women considered at risk f or preeclampsia, low-dose aspirin throughout pregnancy, starting
f rom second trimester, recommended over no treatment (ACCP Grade 1B)
systematic review of methods of prediction and prevention of preeclampsia can be f ound in Health
Technol Assess 2008 Mar;12(6):iii f ull-text
Rest and exercise:
daily rest may reduce risk of preeclampsia for women with normal blood pressure (level 3
based on Cochrane review without clinical outcomes
systematic review of 2 randomized trials evaluating rest or advice to reduce physical activity
f or preventing preeclampsia and its complications in 106 women with normal blood pressure
trials did not report allocation concealment or blinding of outcome assessor
both trials included nulliparous women with singleton pregnancy at moderate risk of
preeclampsia f rom 28-32 weeks gestation
1 trial with 32 women f ound rest f or 4-6 hours/day associated with statistically signif icant
reduction in risk of preeclampsia, but reduced risk of gestational hypertension was not
statistically signif icant
1 trial with 74 women f ound rest f or 30 minutes/day plus nutritional supplementation
associated with reduction in risk of preeclampsia and gestational hypertension
physical activity or exercise may prevent preeclampsia (level 2 [mid-level] evidence)
based on systematic review without assessment of trial quality
systematic review of 17 trials (10 prospective cohort, 6 case-control, 1 randomized) evaluating
exercise or physical activity to prevent preeclampsia
no signif icant benef it of physical activity in analysis of 10 prospective cohort studies
physical activity associated with reduced preeclampsia (odds ratio 0.77, 95% CI 0.64-0.91) in
analysis of 6 case-control studies
low-intensity stretching (vs. moderate-intensity walking) beginning at 18 weeks gestation
associated with protective ef f ect on development of preeclampsia (odds ratio 6.34, 95% CI
0.72-55.37) in analysis of 1 randomized trial
Ref erence - Acta Obstet Gynecol Scand 2012 Oct;91(10):1147
insufficient evidence to determine if exercise is helpful in prevention of preeclampsia
based on Cochrane review of 2 small, good quality randomized trials in 45 women both
comparing moderate intensity regular aerobic exercise with maintenance of normal physical
activity during pregnancy
Ref erence - Cochrane Database Syst Rev 2006 Apr 19;(2):CD005942
Calcium:
calcium supplementation during pregnancy may reduce risk of preeclampsia (level 3 [lacking
direct] evidence)and composite outcome of maternal death or serious morbidity (level 1
[likely reliable] evidence)
systematic review of 13 randomized placebo-controlled trials evaluating calcium
supplementation with at least 1 g/day in 15,730 pregnant women
calcium supplementation associated with reduced
preeclampsia in analysis of 13 trials with 15,730 women
risk ratio (RR) 0.45 (95% CI 0.31-0.65)
NNT 25-48 assuming preeclampsia in 6% of placebo group
results limited by heterogeneity
composite outcome of maternal death or serious morbidity in analysis of 4 trials with
9,732 women
RR 0.8 (95% CI 0.65-0.97)
NNT 72-834 assuming outcome in 4% of placebo group
almost all women were low-risk and had a low-calcium diet
results almost entirely based on WHO trial
systolic blood pressure > 95th percentile in childhood in 1 trial with 514 children
high blood pressure (RR 0.65, 95% CI 0.53-0.81) in analysis of 12 trials with 15,470
women, results limited by heterogeneity
f or outcomes of preeclampsia and preterm birth, greater risk reductions observed in high-risk
women, those with low baseline calcium intake and in trials with < 400 women (smaller trials
tended to enroll high-risk women)
calcium supplementation increased risk of hemolysis, elevated liver enzymes, low platelets
(HELLP) syndrome (RR 2.67, 95% CI 1.05-6.82) in analysis of 2 trials with 12,901 women
no signif icant dif f erences in risk of stillbirth or death bef ore hospital discharge in analysis of
11 trials with 15,665 inf ants
Ref erence - Cochrane Database Syst Rev 2010 Aug 4;(8):CD001059
inconsistent evidence for calcium supplementation on risk of preterm birth (level 2 [mid-
level] evidence)
based on 2 Cochrane reviews with dif f erences potentially attributed to dif f erences in inclusion
criteria
systematic review of 13 randomized placebo-controlled trials evaluating calcium
supplementation with at least 1 g/day in 15,730 pregnant women
calcium supplementation associated with reduced preterm birth < 37 weeks gestation in
analysis of 11 trials with 15,275 women
RR 0.76 (95% CI 0.6-0.97)
NNT 25-334 assuming preterm birth in 10% of placebo group
results limited by heterogeneity
f or outcomes of preeclampsia and preterm birth, greater risk reductions observed in
high-risk women, those with low baseline calcium intake, and in trials with < 400 women
(smaller trials tended to enroll high-risk women)
no signif icant dif f erences in risk of stillbirth or death bef ore hospital discharge in
analysis of 11 trials with 15,665 inf ants
Ref erence - Cochrane Database Syst Rev 2010 Aug 4;(8):CD001059 f ull-text
systematic review of 21 randomized trials comparing any dose of calcium supplementation to
placebo or no treatment in 16,602 pregnant women
use of calcium f or treatment or prevention of hypertension not evaluated
no signif icant dif f erence between groups in
preterm birth < 37 weeks gestation in analysis of 12 trials with 15,615 women
low birth weight (< 2,500 g) in analysis of 5 trials with 13,638 inf ants
admission to neonatal intensive care unit (ICU) in analysis of 4 trials with 14,062
inf ants
stillbirth or f etal death in analysis of 4 trials with 14,083 inf ants
borderline reduction in maternal death with calcium supplementation in WHO trial with
8,325 women (p = 0.098)
Ref erence - Cochrane Database Syst Rev 2011 Oct 5;(10):CD007079 f ull-text
calcium supplementation reduces risk of eclampsia and neonatal death in pregnant women
in communities with low dietary calcium intake (level 1 [likely reliable] evidence)
based on randomized trial (WHO trial was largest trial in both Cochrane reviews)
8,325 healthy nulliparous women in communities with low dietary calcium intake (< 600 mg/day)
were randomized to calcium carbonate (500 mg of calcium) vs. placebo chewable tablets 3
times daily (at meal time but > 3 hours f rom iron supplements) until delivery
exclusion criteria at enrollment were gestational week > 20, systolic blood pressure > 140 mm
Hg, diastolic blood pressure > 90 mm Hg, history of chronic hypertension or renal disease,
history or symptoms of nephrolithiasis, parathyroid disorder or need f or digoxin, phenytoin or
tetracycline
assigned treatment discontinued if nephrolithiasis occurred or magnesium sulf ate used to
treat preeclampsia
9 women determined not to be pregnant and 4 women lost to f ollow-up bef ore starting
treatment were excluded, so 8,312 women analyzed
calcium status of patients not reported
comparing calcium vs. placebo
85% vs. 86% tablets ingested
11.2% vs. 10.2% dropout rate (not statistically signif icant)
2 vs. 3 cases of nephrolithiasis
preeclampsia outcomes comparing calcium vs. placebo
4.1% vs. 4.5% had preeclampsia def ined as new hypertension (blood pressure 140/90
mm Hg or higher twice at least 4 hours apart) and new proteinuria (at least +2 on
dipstick or at least 300 mg/24 hours) (not statistically signif icant)
0.8% vs. 1.1% had severe preeclampsia def ined as systolic blood pressure at least 160
mm Hg or diastolic blood pressure at least 110 mm Hg twice at least 4 hours apart or
eclampsia (not statistically signif icant)
0.5% vs. 0.5% had preeclampsia bef ore 32 weeks gestation (not statistically signif icant)
1% vs. 1.4% had severe gestational hypertension (blood pressure at least 160/110 mm
Hg) without proteinuria (NNT 250)
preeclampsia complications comparing calcium vs. placebo
0.4% vs. 0.6% had eclampsia (NNT 500)
2.7% vs. 3.5% had severe preeclamptic complication def ined as severe preeclampsia,
preeclampsia bef ore 32 weeks gestation, eclampsia, placental abruption, hemolysis,
elevated liver enzymes, low platelets (HELLP) syndrome or severe gestational
hypertension (NNT 125)
other complications comparing calcium vs. placebo
9.9% vs. 10.8% had preterm delivery bef ore 37 weeks gestation (not signif icant)
2.6% vs. 3.2% had preterm delivery bef ore 32 weeks gestation (NNT 167) with
signif icant ef f ect limited to subgroup with age 20 years or younger (2.4% vs. 3.8%, NNT
71)
2.8% vs. 3.3% had any maternal admission to intensive or special care unit (NNT 200)
mortality comparing calcium vs. placebo
0.024% vs. 0.144% had maternal death (NNT 833)
0.94% vs. 1.34% had neonatal death (NNT 250)
Ref erence - Am J Obstet Gynecol 2006 Mar;194(3):639
calcium and linoleic acid during third trimester may reduce incidence of preeclampsia in
high-risk patients (level 3 [lacking direct] evidence)
based on randomized trial without clinical outcomes
1,676 healthy primigravid patients at 28-32 weeks gestation screened f or high-risk of
preeclampsia (def ined as biopsychosocial prof ile score of 3 or more, positive roll-over test
and mean arterial pressure at least 85 mm Hg)
89 women (5.3%) met high-risk criteria and were randomized to linoleic acid 450 mg plus
calcium 600 mg vs. placebo orally once daily
9.3% treatment vs. 37.2% placebo had preeclampsia (def ined as blood pressure > 140/90
repeatedly and proteinuria > 0.3 g/L) (NNT 4)
4.7% vs. 14% severe preeclamptic toxemia (not statistically signif icant)
no side ef f ects reported
Ref erence - Obstet Gynecol 1998 Apr;91(4):585 in Am Fam Physician 1998 Jul;58(1);252
DynaMed commentary
use of < 6% screened patients and atypical inclusion criteria limits generalizability of
results
this trial excluded f rom Cochrane review because of co-treatment with linoleic acid
see also Calcium intake and supplementation
Ant iplat elet agent s:
antiplatelet agents, mostly low-dose aspirin, may reduce incidence of preeclampsia, preterm
birth, and fetal or neonatal death (level 2 [mid-level] evidence)
based on Cochrane review with signif icant dif f erences dependent on lower-quality trials
systematic review of 59 randomized trials with 37,560 women at risk of developing
preeclampsia
18 trials had adequate allocation concealment, of which 14 were placebo-controlled; higher-
quality trials tended toward f ewer signif icant dif f erences
comparing antiplatelet agents vs. placebo or no treatment overall
6.6% vs. 8% rate of preeclampsia (p < 0.0001, NNT 72), based on 46 trials with 32,590
women, results limited by heterogeneity (p = 0.0006)
16.7% vs. 18% rate of preterm birth < 37 weeks (p = 0.001, NNT 77), based on 29 trials
with 31,151 women
2.5% vs. 2.9% rate of f etal or neonatal deaths (p = 0.02, NNT 250), based on 40 trials
with 33,098 women
8.3% vs. 9.1% rate of small f or gestational age inf ants (p = 0.02, NNT 125), based on
36 trials with 23,638 women
0.3% vs. 0.3% rate of eclampsia in 9 trials with 22,584 women
0.047% vs. 0.016% maternal mortality (not signif icant) in 3 trials with 12,709 women
comparing antiplatelet agents vs. placebo or no treatment in high-risk women
15.6% vs. 20.7% rate of preeclampsia (p = 0.0001, NNT 20), based on 18 trials with
4,121 women, results limited by heterogeneity (p = 0.03)
33.7% vs. 38.1% rate of preterm birth < 37 weeks (p = 0.01, NNT 23), based on 10 trials
with 3,252 women
4% vs. 5.8% rate of f etal or neonatal deaths (p = 0.006, NNT 56), based on 17 trials
with 4,443 women
8.7% vs. 9.7% rate of small f or gestational age inf ants (not signif icant), based on 13
trials with 4,239 women
f urther inf ormation needed to guide patient selection, timing and dose
Ref erence - Cochrane Database Syst Rev 2007 Apr 18;(2):CD004659 (review updated 2008
Sep 1)
low-dose aspirin initiated prior to 16 weeks gestation associated with decrease in
preeclampsia and intrauterine growth restriction (level 2 [mid-level] evidence)
based on systematic review of mostly moderate-quality trials
systematic review of 34 trials evaluating incidence of preeclampsia and intrauterine growth
restriction (IUGR) with use of low-dose aspirin (50-150 mg acetylsalicylic acid daily alone or
with < 300 mg dipyridamole) vs. placebo (or no treatment) in 11,348 pregnant women at risk f or
preeclampsia
risk of preeclampsia included nulliparity, history of preeclampsia or other hypertensive
disorders, abnormal uterine artery Doppler ultrasound
low-dose aspirin initiated prior to 16 weeks gestation associated with decreased incidence of
preeclampsia in analysis of 9 trials with 764 women
relative risk (RR) 0.47 (95% CI 0.34-0.65)
NNT 9 (95% CI 6-25)
IUGR in analysis of 9 trials with 853 women
RR 0.44 (95% CI 0.3-0.65)
NNT 11 (95% CI 8-20)
no signif icant dif f erence between low-dose aspirin initiated af ter 16 weeks gestation vs.
placebo (or no treatment) in incidence of
preeclampsia in analysis of 18 trials
IUGR in analysis of 15 trials
Ref erence - Obstet Gynecol 2010 Aug;116(2 Part 1):402
antiplatelet agents during pregnancy associated with reduced risk of preeclampsia, birth <
34 weeks gestation, and pregnancy with serious adverse outcomes
low-dose aspirin (50-150 mg/day) may reduce risk of perinatal death and preeclampsia in
high-risk women
low-dose aspirin initiated at or prior to 16 weeks gestation associated with reduced
preeclampsia in high-risk women with abnormal uterine artery Doppler flow (level 2 [mid-
level] evidence)
based on systematic review without trial quality assessment
in single randomized trial (PREDO trial)
152 women at 12-14 weeks gestation at risk f or preeclampsia and with abnormal uterine
artery Doppler velocimetry were randomized to aspirin 100 mg/day vs. placebo until 35
weeks gestation or delivery
121 women were analyzed, unclear if 31 women were excluded bef ore or af ter
randomization
comparing aspirin vs. placebo
preeclampsia (systolic blood pressure 140 mm Hg and/or diastolic blood
pressure 90 mm Hg in 2 consecutive measurements and proteinuria 0.3 g/24
hours) in 13.1% vs. 18.3% (not signif icant)
gestational hypertension in 16.4% vs. 10% (not signif icant)
severe preeclampsia (systolic blood pressure 160 mm Hg and/or diastolic blood
pressure 110 mm Hg, and/or proteinuria 5 g/24 hours) in 4.9% vs. 13.3% (not
signif icant)
systematic review identif ied 2 additional randomized trials comparing low-dose aspirin (50-150
mg/day) vs. placebo or no treatment started at or bef ore 16 weeks gestation f or preventing
preeclampsia in women with abnormal uterine artery Doppler f low
total number of women in these 3 trials was 346
aspirin associated with reduced risk of preeclampsia in analysis of 3 trials
risk ratio 0.55 (95% CI 0.37-0.83)
NNT 5-17 with preeclampsia in 36.3% of controls
aspirin associated with reduced risk of severe preeclampsia in analysis of 3 trials
risk ratio 0.27 (95% CI 0.11-0.69)
NNT 10-29 with preeclampsia in 11.3% of controls
review of low-dose aspirin and preeclampsia reduction can be f ound in J Fam Pract 2008
Jan;57(1):54
Ant icoagulant s:
prophylactic enoxaparin may reduce preeclampsia in women with previous placental
abruption (level 2 [mid-level] evidence)
based on randomized trial without blinding
160 women with previous placental abruption without f etal loss during f irst pregnancy and
negative f or antiphospholipid antibodies randomized to enoxaparin 4,000 units once daily
subcutaneously started at positive pregnancy test vs. no enoxaparin
comparing enoxaparin vs. no enoxaparin
composite placental complications in 12.5% vs. 31.3% (p = 0.04, NNT 6)
abruptio placenta in 1.3% vs. 3.8% (not signif icant)
preeclampsia in 7.5% vs. 22.5% (p = 0.009, NNT 2)
birth weight < 5th percentile in 2.5% vs. 7.5% (not signif icant)
f etal loss af ter 20 weeks in 2.5% vs. 6.3% (not signif icant)
Ref erence - NOH-AP trial (Thromb Haemost 2010 Oct;104(4):771)
addition of enoxaparin to aspirin may decrease risk of preeclampsia and placental
complications in second pregnancy in women with history of severe preeclampsia (level 2
[mid-level] evidence)
224 women with previous severe preeclampsia without f etal loss during f irst pregnancy were
randomized to enoxaparin 4,000 units subcutaneously once daily starting immediately af ter
positive test f or second pregnancy vs. no enoxaparin
all women were negative f or antiphospholipid antibodies at baseline and received aspirin 100
mg daily
comparing enoxaparin vs. no enoxaparin
composite placental complications in 8.9% vs. 25% (p = 0.004, NNT 7)
preeclampsia in 5.8% vs. 16.7% (p < 0.05, NNT 10)
placental abruption in 0.9% vs. 1.9% (not signif icant)
birthweight < 5th percentile in 2.9% vs. 8.6% (not signif icant)
f etal loss af ter 20 weeks in 2.9% vs. 5.9% (not signif icant)
Ref erence - NOH-PE trial (Thromb Haemost 2011 Dec;106(6):1053)
antenatal heparin may decrease perinatal mortality, intrauterine growth restriction, and birth
at < 34 weeks and at < 37 weeks gestation in women at risk of placental dysfunction (level 2
based on Cochrane review of trials with methodologic limitations
systematic review of 10 randomized trials evaluating antenatal antithrombotic therapy in 1,139
women at risk of placental dysf unction
all trials had 1 limitation including
lack of or unclear blinding
risk of placental dysf unction based on prior history of preeclampsia, eclampsia, renal disease,
f etal growth restriction, or f etal death
comparing heparin (alone or in combination with dipyridamole or low-dose aspirin) to no
treatment, heparin associated with
decreased perinatal mortality in analysis of 6 trials with 653 neonates
risk ratio (RR) 0.4 (95% CI 0.2-0.78)
NNT 14-51 with 9% perinatal mortality in no treatment group
decreased birth weight < 10th percentile f or gestational age in analysis of 7 trials with
710 neonates
RR 0.41 (95% CI 0.27-0.61)
NNT 8-14 with birth weight < 10th percentile f or gestational age in 19% of no
treatment group
decreased preterm birth at < 34 weeks gestation in analysis of 3 trials with 494 women
RR 0.46 (95% CI 0.29-0.73)
NNT 8-20 with preterm birth at < 34 weeks gestation in 19% of no treatment
group
decreased preterm birth at < 37 weeks gestation in analysis of 5 trials with 621 women
RR 0.72 (95% CI 0.58-0.90)
NNT 6-26 with preterm birth at < 37 weeks gestation in 40% of no treatment
group
nonsignif icant decrease in preeclampsia (RR 0.47, 95% CI 0.22-1.03) in analysis of 7
no signif icant dif f erence in preeclampsia comparing trapidil vs. placebo in 1 trial with 160
women
low-molecular weight heparin does not appear to decrease risk of recurrence of placenta-
mediated complications during late pregnancy (level 2 [mid-level] evidence)
135 women at 12 gestational weeks randomized to low-molecular weight heparin (nadroparin)
3,800 units daily subcutaneously vs. no heparin
all women had prior history of low platelet count syndrome, intrauterine f etal death, f etal
growth restriction, or placental abruption
all women received medical surveillance monthly including weight, blood pressure, aspirin
intake, abdominal growth, and ultrasound evaluation of f etal biometry
late pregnancy complications included preeclampsia, eclampsia, low platelet count syndrome,
intrauterine f etal death, f etal growth restriction, and placental abruption
comparing heparin vs. no heparin
late pregnancy complications in 20.6% vs. 18.5% (not signif icant)
mean gestational age at delivery 38 weeks vs. 37 weeks (not signif icant)
cesarean section in 50% vs. 38% (not signif icant)
no signif icant dif f erence in adverse events
Ref erence - Blood 2012 Apr 5;119(14):3269 f ull-text, editorial can be f ound in Blood 2012 Apr
5;119(14):3192 f ull-text
Ant ioxidant s:
Concomit ant vit amin C and E:
vitamin C and E supplementation does not reduce risk of preeclampsia and increases risk of
gestational hypertension and premature rupture of membranes (level 1 [likely reliable]
evidence)
systematic review of 9 randomized trials evaluating vitamin C 1,000 mg and vitamin E 400 units
supplement daily f or prevention of preeclampsia in 19,810 women at 22 weeks gestation
no signif icant dif f erence in risk of preeclampsia comparing vitamin C and E vs. placebo in
all women in analysis of 9 trials with 19,810 women
women with low/moderate risk in analysis of 3 trials with 13,525 women
women with high risk in analysis of 7 trials with 6,285 women
vitamin C and E supplement associated with
increased risk of gestational hypertension in analysis of 7 trials with 19,003 women
relative risk (RR) 1.11 (95% CI 1.05-1.17)
NNH 47 assuming gestational hypertension in 19% of placebo group
decreased risk of abruptio placentae in analysis of 5 trials with 13,075 women
RR 0.63 (95% CI 0.43-0.94)
NNT 280 assuming abruptio placentae in 1% of placebo group
increased risk of premature rupture of membranes in analysis of 2 trials with 3,070
women
RR 1.73 (95% CI 1.34-2.23)
NNH 25 assuming premature rupture of membranes in 6% of placebo group
no signif icant dif f erences in adverse f etal or perinatal outcomes
Ref erence - Am J Obstet Gynecol 2011 Jun;204(6):503.e1 f ull-text
concomitant vitamin C and vitamin E supplementation does not reduce risk of preeclampsia
or its complications (level 1 [likely reliable] evidence)
based on randomized trial
10,154 nulliparous women at low risk f or preeclampsia randomized to begin vitamin C 1,000 mg
plus vitamin E 400 units vs. placebo daily supplementation between weeks 9-16 of pregnancy
and continue through delivery
randomized women had completed 2-week placebo run-in with > 50% adherence
77% taking prenatal vitamin or multivitamin at baseline
9,969 (98%) women who completed trial included in analysis
comparing vitamin supplementation vs. placebo
preeclampsia in 7.2% and 6.7% (not signif icant)
pregnancy-associated hypertension in 29.2% vs. 26.6% (p = 0.004, NNH 38)
medically indicated delivery due to hypertension in 10.3% vs. 9.6% (not signif icant)
antepartum bleeding in 1.1% vs. 0.9% (not signif icant)
premature rupture of membranes in 2.5% vs. 2.6% (not signif icant)
postpartum pulmonary edema in 0.1% vs. 0.2% (not signif icant)
median hospital stay was 2 days vs. 2 days (not signif icant)
preterm birth in 10.3% vs. 10.6% (not signif icant)
no signif icant dif f erences f or women with mild or severe hypertension in
elevated liver enzyme levels
thrombocytopenia
elevated creatinine levels
eclamptic seizure in
medically indicated preterm birth
perinatal death
Ref erence - N Engl J Med 2010 Apr 8;362(14):1282 f ull-text
concomitant vitamin C and vitamin E supplementation does not appear to reduce risk of
preeclampsia or complications in women with type 1 diabetes (level 2 [mid-level] evidence)
based on randomized trial with wide conf idence intervals
762 women 16 years old with type 1 diabetes presenting with singleton pregnancy at 8-22
weeks gestation were randomized to vitamin C 1,000 mg plus vitamin E 400 units daily vs.
placebo until delivery
modif ied intention-to-treat analysis included 749 (98%) pregnancies > 20 weeks gestation
preeclampsia def ined as gestational hypertension with proteinuria
no signif icant dif f erences comparing antioxidant vitamins vs. placebo in
preeclampsia in 15% vs. 19% (risk ratio 0.81, 95% CI 0.59-1.12)
gestational hypertension in 11% vs. 11%
birth weight < 10th percentile f or gestational age in 6% vs. 10% (p = 0.08, risk ratio 0.64,
95% CI 0.39-1.05)
birth at < 34 weeks gestation in 3% vs. 3%
birth at < 37 weeks gestation in 11% vs. 13% (risk ratio 0.89, 95% CI 0.61-1.31)
admission to neonatal intensive care unit in 54% vs. 56%
no signif icant dif f erences in any clinical neonatal outcome (including f etal malf ormation, f etal
loss, inf ant death, or miscarriage, or various complications); most of these outcomes
occurred in 1% patients so wide conf idence intervals
Ref erence - DAPIT trial (Lancet 2010 Jul 24;376(9737):259 f ull-text), commentary can be f ound
in Lancet 2010 Jul 24;376(9737):214
Ot her ant ioxidant s:
antioxidant supplementation may not affect risk of preeclampsia or clinical outcomes (level
2 [mid-level] evidence)
based on Cochrane review with heterogeneity and wide conf idence intervals
systematic review and meta-analysis of 10 randomized trials of antioxidants f or prevention of
preeclampsia in 6,533 women
5 trials met all quality criteria (allocation concealment, f ull blinding, < 3% excluded)
comparing antioxidants vs. placebo or no antioxidants
10.1% vs. 11.4% preeclampsia (not signif icant, p = 0.1) in meta-analysis of 9 trials with
5,446 patients, analysis limited by heterogeneity (p = 0.02)
5.7% vs. 4.6% severe preeclampsia (not signif icant) in meta-analysis of 2 trials with
2,495 patients
3% vs. 2.7% any baby death (not signif icant) in meta-analysis of 4 trials with 5,144
patients
0.05% vs. 0.05% maternal death (not signif icant) in meta-analysis of 2 trials with 4,272
patients
36.3% vs. 32.7% labor induction or elective cesarean delivery (not signif icant, p = 0.08)
in meta-analysis of 2 trials with 2,077 patients
Ref erence - Cochrane Database Syst Rev 2008 Jan 23;(1):CD004227 (review updated 2008
Feb 4)
low dietary intake of vitamin C may be associated with increased incidence of severe
preeclampsia, eclampsia, or HELLP (hemolysis, elevated liver enzymes, low platelets)
syndrome (level 2 [mid-level] evidence)
57,346 women f rom Danish National Birth Cohort completed f ood f requency questionnaire f or
previous 4 weeks at 25 weeks gestation
diagnosis of preeclampsia, eclampsia and HELLP diagnosis obtained through Danish National
Patient Registry
decreasing trend in severe preeclampsia, eclampsia and HELLP syndrome with increasing
intake of vitamin C (ref erence 130-170 mg/day) (p = 0.04 in test f or overall signif icance)
Ref erence - BJOG 2009 Jun;116(7):964 f ull-text
phytonutrient supplement not associated with reduced risk of preeclampsia (level 2 [mid-
level] evidence)
based on randomized trial with high loss to f ollow-up
684 women (mean age 27 years) randomized to phytonutrient supplement (primarily blended
f ruit and vegetable juice powder concentrate including vitamins C and E) vs. placebo daily
starting at week 12 gestation through delivery
39% completed trial and included in analyses (most dropouts due to withdrawal f rom trial)
comparing supplement vs. placebo
preeclampsia in 15.9% vs. 16.3% (not signif icant)
placenta-related obstetrical complications in 8.3% vs. 15.5% (not signif icant)
respiratory distress syndrome in 5.3% vs. 15.4% in high-risk stratif ied group (not
signif icant)
Ref erence - J Perinatol 2013 Aug;33(8):593
insufficient evidence to support vitamin E supplementation in pregnancy
based on systematic review of 4 randomized or quasi-randomized trials of vitamin E in 566
pregnant women with or at high risk f or preeclampsia
no signif icant dif f erences in stillbirth, neonatal death, perinatal death, preterm birth,
intrauterine growth restriction, or birth weight
May 7)
L-arginine:
L-arginine plus antioxidant supplementation during pregnancy reduces risk of preeclampsia
and preterm delivery in high-risk women (level 1 [likely reliable] evidence)
based on randomized trial
672 pregnant women at high risk of preeclampsia randomized to supplementation with medical
f ood bar containing L-arginine plus antioxidant vitamins vs. antioxidant vitamins alone vs.
placebo during pregnancy starting at 14-32 weeks gestation and f ollowed until delivery
125 patients (18.6%) discontinued assigned treatment but were f ollowed and analyzed by
intention-to-treat
Results:
Outcome Placebo
Antioxidants
Alone L-arginine Plus Antioxidants
Preeclampsia or
eclampsia
30% 23% (p = 0.052
vs. placebo)
13% (p < 0.001 vs. placebo, NNT 6; p =
0.004 vs. antioxidants alone, NNT 10)
Preterm delivery 20% 23% 11% (p = 0.003 vs. placebo, NNT 11; p <
0.001 vs. antioxidants alone, NNT 9)
Spontaneous
preterm delivery
6% 7% 5%
Cesarean delivery 68.4% 66.6% 67.9%
adverse ef f ects more common with medical f ood bar with L-arginine compared to placebo
included
nausea (p = 0.019, NNH 20)
dyspepsia (p = 0.04, NNH 33)
dizziness (p = 0.039, NNH 33)
palpitations (p = 0.019, NNH 25)
headache (p = 0.01, NNH 16)
Ref erence - BMJ 2011 May 19;342:d2901 f ull-text, editorial can be f ound in BMJ 2011 May
19;342:d2777
Ot her diet ary and supplement considerat ions:
higher total dietary fiber intake in early pregnancy may reduce risk for preeclampsia (level 3
based on prospective cohort study without clinical outcomes
1,538 pregnant women completed f ood f requency questionnaire to assess f iber intake during
3 months prior to pregnancy and during early pregnancy
total dietary f iber intake 21.2 g/day associated with reduced risk f or preeclampsia compared
to total dietary intake < 11.9 g/day (adjusted relative risk 0.28, 95% CI 0.11-0.75)
Ref erence - Am J Hypertens 2008 Aug;21(8):903
daily coenzyme Q10 supplementation may reduce risk of preeclampsia (level 3 [lacking
direct] evidence)
based on randomized trial without intention to treat analysis and without clinical outcomes
235 pregnant women (mean age 17.5 years) randomized at gestational week 20 to coenzyme
Q10 200 mg daily vs. placebo until delivery
83.8% completed f ollow-up (attended 2 visits)
65.5% analyzed (patients taking < 80% coenzyme Q10 sof tgels excluded)
overall rate of preeclampsia 20%
preeclampsia developed in 14.4% with coenzyme Q10 vs. 25.6% with placebo (p = 0.035, NNT
9)
Ref erence - Int J Gynaecol Obstet 2009 Apr;105(1):43
insufficient evidence to recommend garlic for preventing preeclampsia
systematic review of randomized trials of garlic f or prevention of preeclampsia and its
complications
only 1 placebo-controlled trial of uncertain quality with 100 women met inclusion criteria; 1
other trial excluded due to 29% loss to f ollow-up
comparing garlic vs. placebo
preeclampsia in 14% vs. 18% (not signif icant)
gestational hypertension in 18% vs. 36% (p = 0.051)
no signif icant dif f erences in adverse ef f ects except f or more f requent occurrence of
odor in garlic group (p = 0.003)
Ot her medicat ions:
insufficient evidence to recommend use of diuretics for preventing preeclampsia
based on Cochrane review of trials with poor reporting
systematic review of 5 randomized trials comparing thiazide diuretics with placebo or no
intervention f or preventing preeclampsia in 1,836 women
allocation concealment not reported in 4 trials; 1 trial with allocation concealment had
dif f erential loss to f ollow up
perinatal death in analysis of 5 trials with 1,836 women
preterm birth in analysis of 2 trials with 465 women
wide conf idence intervals cannot exclude possible clinical benef it
diuretics associated with
trend toward lower risk of preeclampsia in analysis of 4 trials with 1,391 women (risk
ratio [RR] 0.68, 95% CI 0.45-1.03)
increased risk of nausea and vomiting in analysis of 2 trials with 1,217 women (RR 5.81,
95% CI 1.04-32.46)
atenolol may prevent preeclampsia based on preliminary trial
pregnant nulliparous women with no signif icant medical complications or pregnant women with
insulin-requiring diabetes and proteinuria < 1 g/24 hours f rom university-based maternal inf ant
care clinic underwent Doppler cardiac output screening at 22-25 weeks gestation
patients with cardiac output > 7.4 L/minute (increased risk f or preeclampsia) were randomized
to atenolol 100 mg/day vs. placebo f or remainder of pregnancy
comparing atenolol vs. placebo
3.8% vs. 18% preeclampsia (NNT 7)
29% vs. 71% hypertension (NNT 3)
mean birth weight in nulliparous patients 440 g less with atenolol
no signif icant dif f erence in mean birth weight in diabetic group
Ref erence - Obstet Gynecol 1999 May;93(5 Part 1):725 in J Fam Pract 1999 Aug;48(8):580
progesterone does not prevent preeclampsia or perinatal mortality (level 1 [likely reliable]
evidence)
systematic review of 4 randomized trials evaluating progesterone in 1,445 women f or
prevention of preeclampsia
preeclampsia in analysis of 3 trials with 1,277 women (nonsignif icant increase with risk
ratio 1.25, 95% CI 0.95-1.63)
pregnancy-induced hypertension in 1 trial with 168 women
cesarean section in analysis of 2 trials with 1,146 women
stillbirths or neonatal deaths in analysis of 4 trials with 2,594 inf ants (higher numbers
because 2 trials were in twin pregnancies, risk ratio 1.34, 95% CI 0.78-2.31)
small f or gestational age in 1 trial with 168 inf ants
preterm birth in 3 trials with 1,313 women
insufficient evidence for use of nitric oxide donors for preventing preeclampsia and its
complications
systematic review of 6 randomized trials of nitric oxide donor or precursors in 310 women at
risk f or preeclampsia
4 of 6 trials had good quality
4 trials compared nitric oxide donors (glyceryl trinitrate) or precursors (L-arginine) to placebo
or no intervention in 170 women
1 trial (36 women) compared nitric oxide donor to nif edipine
1 trial (76 women) comparing nitric oxide donor to antiplatelet agents
no signif icant dif f erences in any ef f icacy analysis but wide conf idence intervals make
conclusions unreliable
Jan 18)
treatment of mild gestational diabetes, including the use of insulin to achieve blood glucose
goals, during pregnancy may reduce risk for preeclampsia and serious perinatal
complications (level 2 [mid-level] evidence)
based on randomized trial with baseline dif f erences between groups
1,000 women with singleton or twin pregnancy (1,030 live births) in Australia and United
Kingdom with glucose intolerance at 24-34 weeks gestation were randomized to be inf ormed
they had glucose intolerance of pregnancy (intervention group) vs. inf ormed they did not have
gestational diabetes mellitus (GDM) (control group)
glucose intolerance def ined as venous plasma glucose level < 140 mg/dL (7.8 mmol/L)
af ter overnight f ast and 140-198 mg/dL (7.8-11 mmol/L) 2 hours af ter 75-g oral glucose
load (World Health Organization criteria)
women with 2-hour glucose level > 198 mg/dL (11 mmol/L) were diagnosed with GDM and
were not randomized
women with glucose intolerance of pregnancy and their providers were blinded to true
results until af ter birth
interventions provided to those inf ormed of glucose intolerance of pregnancy were
individualized dietary advice f rom a dietitian
instructions on self -monitoring glucose levels 4 times daily until recommended
range (f asting 63-99 mg/dL [3.5-5.5 mmol/L], preprandial < 99 mg/dL [5.5 mmol/L],
and 2-hour postprandial < 126 mg/dL [7 mmol/L]) f or 2 weeks then daily at rotating
times
insulin therapy, with dose adjusted based on glucose levels
control group could have testing f or GDM at discretion of attending clinician if
indications arose
20% of control group included women with normal glucose tolerance tests
primary outcome of serious perinatal complications was composite of death, shoulder
dystocia, bone f racture, and nerve palsy
intervention group was slightly older (mean 30.9 years vs. 30.1 years), less likely to be
primiparous (43% vs. 49%), less likely to be white (73% vs. 78%), and more likely to be Asian
(19% vs. 14%); analyses adjusted f or these f actors
comparing intervention group vs. control
preeclampsia in 11.8% vs. 18.2% (p = 0.0053, NNT 16)
serious perinatal complications in 1% vs. 4% (p = 0.01, NNT 34, 95% CI 20-103)
perinatal deaths 0 vs. 5 (not signif icant)
shoulder dystocia in 7 cases (1%) vs. 16 cases (3%) (not signif icant)
bone f racture in 0 vs. 1 (not signif icant)
nerve palsies in 0 vs. 3 (not signif icant)
admission to neonatal nursery in 71% vs. 61% (p = 0.01, NNH 10)
induction of labor in 39% vs. 29% (p < 0.001, NNH 10)
macrosomia in 10% vs. 21% (p < 0.001, NNT 9)
no signif icant dif f erence in rates of jaundice requiring phototherapy (9% vs. 9%) or
cesarean delivery (31% vs. 32%)
Ref erence - N Engl J Med 2005 Jun 16;352(24):2477, editorial can be f ound in N Engl J Med
2005 Jun 16;352(24):2544, commentary can be f ound in CMAJ 2005 Aug 2;173(3):250 f ull-text,
BMJ 2005 Aug 13;331(7513):361 f ull-text, N Engl J Med 2005 Oct 13;353(15):1629, or in ACP J
Club 2005 Nov-Dec;143(3):65
Screening:
(3)
f or blood pressure monitoring
f or measurement of proteinuria
Level II-2)
no clinically useful screening test during pregnancy to predict development of preeclampsia
based on systematic review of 87 studies with 211,369 women
Ref erence - Obstet Gynecol 2004 Dec;104(6):1367, correction can be f ound in Obstet Gynecol
2005 Oct;106(4):869, editorial can be f ound in Lancet 2005 Apr 16-22;365(9468):1367
insufficient evidence to support hyperuricemia as predictive of preeclampsia
systematic review of 5 studies evaluating serum uric acid measurement bef ore 25 weeks
gestation and risk of preeclampsia in 572 women
44 women developed preeclampsia
pooling of data not appropriate due to heterogeneity and poor reporting of methodology
between studies
incidence of preeclampsia ranged f rom 3.4% to 40.1%
sensitivity of serum uric acid ranged f rom 0% to 55.6%, specif icity ranged f rom 76.9%-94.9%
Ref erence - Acta Obstet Gynecol Scand 2006;85(5):519
algorithm may detect women in first trimester at risk for pregnancy-associated
hypertension
population-based cohort of 7,797 women with singleton pregnancies
34 developed early preeclampsia (preeclampsia requiring delivery bef ore 34 weeks)
123 developed late preeclampsia (with delivery 34 weeks)
algorithm based on maternal variables including mean arterial pressure, uterine artery
pulsatility index, pregnancy-associated plasma protein-A, and placental growth f actor
early and late preeclampsia associated with
increased mean arterial pressure
increased uterine artery pulsatility index
decreased pregnancy-associated plasma protein-A
decreased placental growth f actor
Ref erence - Hypertension 2009 May;53(5):812, editorial can be f ound in Hypertension 2009
May;53(5):747
urinalysis
National Academy of Clinical Biochemistry laboratory medicine practice guideline
recommends against routinely screening for antenatal evaluation of hypertension or
preeclampsia with urine dipstick testing at point of care (grade B recommendation
[inconsistent or limited evidence])
f air evidence that protein dipstick testing in this environment largely inef f ective (level 2
Ref erence - National Academy of Clinical Biochemistry laboratory medicine practice
guideline on renal f unction testing (National Guideline Clearinghouse 2007 Oct
22:10822)
repeated routine urinalysis throughout pregnancy (in absence of hypertension) is
NOT useful for predicting preeclampsia
based on prospective study of 913 pregnant women
35 had dipstick proteinuria at f irst antenatal visit, of whom 2 (6%) were diagnosed with
preeclampsia at some time during pregnancy
among 867 women without dipstick proteinuria at f irst antenatal visit, 338 (39%)
developed dipstick proteinuria but only 6 of these women (1.8%) developed proteinuria
bef ore onset of hypertension
Ref erence - Med J Aust 2002 Nov 4;177(9):477 f ull-text
uterine artery Doppler ultrasound
Guidelines and Resources
Guidelines:
Int ernat ional guidelines:
Unit ed St at es guidelines:
Unit ed Kingdom guidelines:
Royal College of Obstetricians and Gynaecologists (RCOG) guideline on maternal collapse in
pregnancy and puerperium can be f ound at RCOG 2011 Jan PDF
Action on Pre-eclampsia (APEC) preeclampsia community guidelines (PRECOG)
Canadian guidelines:
Society of Obstetricians and Gynaecologists of Canada (SOGC) guidelines on
European guidelines:
French Society of Anesthesia and Intensive Care/French National College of Gynecology and
Obstetrics/French Society of Perinatal Medicine/French Society of Neonatology
(SFAR/CNGOF/SFMP/SFNN) guidelines on
Mexican guidelines:
Colegio Mexicano de Especialistas en Ginecologa y Obstetricia (COMEGO) clinical practice guideline
on diagnosis and treatment of preeclampsia-eclampsia can be f ound in Ginecol Obstet Mex 2010
Jun;78(6):S461 [Spanish]
Grupos de Desarrollo de las Instituciones Pblicas del Sistema Nacional de Salud de Mxico
(Secretara de Salud, IMSS, ISSSTE, SEDENA, SEMAR, DIF, PEMEX) guas de prctica clnica en
deteccin y diagnstico de enf ermedades hipertensivas del embarazo se pueden encontrar en
Secretara de Salud-Mxico 2010 PDF [Spanish]
Mexican expert clinical guideline on detection and diagnosis of hypertensive pregnancy disease can
be f ound in Rev Med Inst Mex Seguro Soc 2011 Mar-Apr;49(2):213 [Spanish]
Aust ralian and New Zealand guidelines:
Review art icles:
review of postpartum management of hypertension can be f ound in BMJ 2013 Feb 25;346:f 894
MEDLINE search:
to search MEDLINE f or (Hypertensive disorders of pregnancy) with targeted search (Clinical
Queries), click therapy, diagnosis, or prognosis
Patient Inf ormation
ICD-9/ICD-10 Codes
ICD-9 codes:
f or the many related ICD-9 codes
642.0 benign essential hypertension complicating pregnancy, childbirth, and the puerperium
642.00 benign essential hypertension complicating pregnancy, childbirth, and the
puerperium, unspecif ied as to episode of care
642.01 benign essential hypertension with delivery
642.02 benign essential hypertension, with delivery, with mention of postpartum
complication
642.03 antepartum benign essential hypertension
642.04 postpartum benign essential hypertension
642.1 hypertension secondary to renal disease, complicating pregnancy, childbirth, and the
puerperium
642.10 hypertension secondary to renal disease, complicating pregnancy, childbirth, and
the puerperium, unspecif ied as to episode of care
642.11 hypertension secondary to renal disease, with delivery
642.12 hypertension secondary to renal disease, with delivery, with mention of
postpartum complication
642.13 hypertension secondary to renal disease, antepartum
642.14 hypertension secondary to renal disease, postpartum
642.2 other pre-existing hypertension complicating pregnancy, childbirth, and the puerperium
642.20 other pre-existing hypertension complicating pregnancy, childbirth, and the
puerperium, unspecif ied as to episode of care
642.21 other pre-existing hypertension, with delivery
642.22 other pre-existing hypertension, with delivery, with mention of postpartum
complication
642.23 other pre-existing hypertension, antepartum
642.24 other pre-existing hypertension, postpartum
642.3 transient hypertension of pregnancy
642.30 transient hypertension of pregnancy, unspecif ied as to episode of care
642.31 transient hypertension of pregnancy, with delivery
642.32 transient hypertension of pregnancy, with delivery, with mention of postpartum
complication
642.33 antepartum transient hypertension
642.34 postpartum transient hypertension
642.4 mild or unspecif ied preeclampsia
642.40 mild or unspecif ied preeclampsia, unspecif ied as to episode of care
642.41 mild or unspecif ied preeclampsia, with delivery
642.42 mild or unspecif ied preeclampsia, with delivery, with mention of postpartum
complication
642.43 mild or unspecif ied preeclampsia, antepartum
642.44 mild or unspecif ied preeclampsia, postpartum
642.5 severe preeclampsia
642.50 severe preeclampsia, unspecif ied as to episode of care
642.51 severe preeclampsia, with delivery
642.52 severe preeclampsia, with delivery, with mention of postpartum complication
642.53 severe preeclampsia, antepartum
642.54 severe preeclampsia, postpartum
642.6 eclampsia complicating pregnancy, childbirth or the puerperium
642.60 eclampsia complicating pregnancy, childbirth or the puerperium, unspecif ied as to
episode of care
642.61 eclampsia, with delivery
642.62 eclampsia, with delivery, with mention of postpartum complication
642.63 eclampsia, antepartum
642.64 eclampsia, postpartum
642.7 preeclampsia or eclampsia superimposed on pre-existing hypertension
642.70 preeclampsia or eclampsia superimposed on pre-existing hypertension,
complicating pregnancy, childbirth, or the puerperium, unspecif ied as to episode of care
642.71 preeclampsia or eclampsia superimposed on pre-existing hypertension, with
delivery
642.72 preeclampsia or eclampsia superimposed on pre-existing hypertension, with
delivery, with mention of postpartum complication
antepartum
postpartum
642.9 unspecif ied hypertension complicating pregnancy, childbirth, or the puerperium
642.90 unspecif ied hypertension complicating pregnancy, childbirth, or the puerperium,
unspecif ied as to episode of care
642.91 unspecif ied hypertension, with delivery
642.92 unspecif ied hypertension, with delivery, with mention of postpartum complication
642.93 unspecif ied antepartum hypertension
642.94 unspecif ied postpartum hypertension
760.0 maternal hypertensive disorders af f ecting f etus or newborn
ICD-10 codes:
O10 pre-existing hypertension complicating pregnancy, childbirth and the puerperium
O10.0 pre-existing essential hypertension complicating pregnancy, childbirth and the
puerperium
O10.1 pre-existing hypertensive heart disease complicating pregnancy, childbirth and the
puerperium
O10.2 pre-existing hypertensive renal disease complicating pregnancy, childbirth and the
puerperium
O10.3 pre-existing hypertensive heart and renal disease complicating pregnancy, childbirth and
the puerperium
O10.4 pre-existing secondary hypertension complicating pregnancy, childbirth and the
puerperium
O10.9 unspecif ied pre-existing hypertension complicating pregnancy, childbirth and the
puerperium
O11 pre-existing hypertensive disorder with superimposed proteinuria
O12 gestational [pregnancy-induced] oedema and proteinuria without hypertension
O12.0 gestational oedema
O12.1 gestational proteinuria
O12.2 gestational oedema with proteinuria
O13 gestational [pregnancy-induced] hypertension without signif icant proteinuria
O14 gestational [pregnancy-induced] hypertension with signif icant proteinuria
O14.0 moderate preeclampsia
O14.1 severe preeclampsia
O14.9 preeclampsia, unspecif ied
ICD-10-CA modif ication in Canada: O14 code range revised as f ollows
O14.001 delivered, with or without mention of antepartum condition
O14.002 delivered, with mention of postpartum complication
O14.003 antepartum condition or complication
O14.004 postpartum condition or complication
O14.009 unspecif ied as to episode of care, or not applicable
O15 eclampsia
O15.0 eclampsia in pregnancy
O15.1 eclampsia in labour
O15.2 eclampsia in the puerperium
O15.9 eclampsia, unspecif ied as to time period
O16 unspecif ied maternal hypertension
P00.0 f etus and newborn af f ected by maternal hypertensive disorders
Ref erences
General ref erences used:
1. Leeman L, Fontaine P. Hypertensive disorders of pregnancy. Am Fam Physician. 2008 Jul 1;78(1):93-
100 f ull-text
2. Lindheimer MD, Taler SJ, Cunningham FG. ASH position paper: hypertension in pregnancy. J Clin
Hypertens (Greenwich). 2009 Apr;11(4):214-25
3. Magee LA, Helewa M, Moutquin JM, von Dadelszen P, Hypertension Guideline Committee, Society
of Obstetricians and Gynaecologists of Canada. Diagnosis, evaluation, and management of the
hypertensive disorders of pregnancy. J Obstet Gynaecol Can 2008 Mar;30(3 Suppl 1):S1-48 PDF
4. Chobanian AV, Bakris GL, Black HR, et al; Joint National Committee on Prevention, Detection,
Evaluation, and Treatment of High Blood Pressure. National Heart, Lung, and Blood Institute,
National High Blood Pressure Education Program Coordinating Committee. Seventh report of the
Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood
Pressure. Hypertension. 2003 Dec;42(6):1206-52 f ull-text, commentary can be f ound in Hypertension
2004 Jan;43(1):1 f ull-text, Hypertension 2004 Apr;43(4):e27 f ull-text, Hypertension 2004
May;43(5):e31. f ull-text
5. American College of Obstetricians and Gynecologists (ACOG) Committee on Practice Bulletins--
Obstetrics. ACOG practice bulletin. Diagnosis and management of preeclampsia and eclampsia.
Number 33, January 2002. Obstet Gynecol. 2002 Jan;99(1):159-67
6. ACOG Practice Bulletin No. 125: Chronic hypertension in pregnancy. Obstet Gynecol. 2012
Feb;119(2 Pt 1):396-407
Recommendat ion grading syst ems used:
American College of Obstetricians and Gynecologists (ACOG) levels of evidence
Level A - based on good and consistent scientif ic evidence
Level B - based on limited or inconsistent scientif ic evidence
Level C - based primarily on consensus and expert opinion
Ref erences
ACOG practice bulletin on diagnosis and management of preeclampsia and eclampsia
(Obstet Gynecol 2002 Jan;99(1):159)
ACOG Practice Bulletin 125 on chronic hypertension in pregnancy (Obstet Gynecol 2012
Feb;119(2 Pt 1):396)
Society of Obstetricians and Gynaecologists of Canada (SOGC) grades of recommendation
classif ications of recommendations
Grade A - good evidence to recommend clinical preventive action
Grade B - f air evidence to recommend clinical preventive action
Grade C - existing evidence is conf licting and does not allow to make recommendation
f or or against use of clinical preventive action; however, other f actors may inf luence
decision-making
Grade D - f air evidence to recommend against clinical preventive action
Grade E - good evidence to recommend against clinical preventive action
Grade I - insuf f icient evidence (in quantity or quality) to make recommendation; however,
other f actors may inf luence decision-making
levels of evidence
Level I - evidence obtained f rom 1 properly randomized controlled trial
Level II-1 - evidence f rom well-designed controlled trials without randomization
Level II-2 - evidence f rom well-designed cohort (prospective or retrospective) or case-
control studies, pref erably f rom more than 1 center or research group
Level II-3 - evidence obtained f rom comparisons between times or places with or without
the intervention; dramatic results in uncontrolled experiments (such as the results of
treatment with penicillin in the 1940s) could also be included in this category
Level III - opinions of respected authorities, based on clinical experience, descriptive
studies, or reports of expert committees
Ref erence - SOGC guideline on diagnosis, evaluation, and management of the hypertensive
disorders of pregnancy (J Obstet Gynaecol Can 2008 Mar;30(3 Suppl 1):S1 PDF)
American College of Chest Physicians (ACCP) grades
Grade 1 - strong recommendation based on clear risk/benef it balance
Grade 2 - weak recommendation based on unclear or close risk/benef it balance
Grade A - high-quality evidence based on consistent evidence f rom randomized trials without
important limitations or exceptionally strong evidence f rom observational studies
Grade B - moderate-quality evidence based on randomized trials with important limitations
(inconsistent results, methodologic f laws, indirect or imprecise results) or very strong
evidence f rom observational studies
Grade C - low- or very low-quality evidence based on observational studies, case series, or
randomized trials with serious f laws or indirect evidence
Ref erence - ACCP Evidence-Based Clinical Practice Guidelines (Ninth Edition) Methodology f or
the Development of Antithrombotic Therapy and Prevention of Thrombosis Guidelines (Chest
2012 Feb;141(2 Suppl):53S f ull-text)
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Updates. Over 1,000 practicing physicians f rom 61 disciplines in 77 countries rate these articles to
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Special acknowledgement s:
Antigoni Woodland, MD (North Shore Obstetrician and Gynecologist Associates; Massachusetts,
United States) provides peer review.
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