Techniques of Intrauterine Fetal Transfusion For Women With Red-Cell Isoimmunisation For Improving Health Outcomes (Review)

Techniques of intrauterine fetal transfusion for women with
red-cell isoimmunisation for improving health outcomes

(Review)
Dodd JM, Windrim RC, van Kamp IL
This is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library
2012, Issue 9
http://www.thecochranelibrary.com
Techniques of intrauterine fetal transfusion for women with red-cell isoimmunisation for improving health outcomes (Review)
Copyright 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
TABLE OF CONTENTS
HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
AUTHORS CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
Analysis 1.1. Comparison 1 Intrauterine transfusion + IVIG versus intrauterine transfusion alone, Outcome 1 Perinatal
mortality. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
Analysis 1.2. Comparison 1 Intrauterine transfusion + IVIG versus intrauterine transfusion alone, Outcome 2
Neurodevelopmental handicap childhood follow up. . . . . . . . . . . . . . . . . . . . . 14
Analysis 1.3. Comparison 1 Intrauterine transfusion + IVIG versus intrauterine transfusion alone, Outcome 3 Preterm
birth less than 32 weeks. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
Analysis 1.4. Comparison 1 Intrauterine transfusion + IVIG versus intrauterine transfusion alone, Outcome 4 Need for
exchange transfusion. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
Analysis 1.5. Comparison 1 Intrauterine transfusion + IVIG versus intrauterine transfusion alone, Outcome 5 Need for
top-up transfusion. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
Analysis 1.6. Comparison 1 Intrauterine transfusion + IVIG versus intrauterine transfusion alone, Outcome 6 Fetal
death. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
WHATS NEW . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
HISTORY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17
SOURCES OF SUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17
DIFFERENCES BETWEEN PROTOCOL AND REVIEW . . . . . . . . . . . . . . . . . . . . . 17
INDEX TERMS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17
Techniques of intrauterine fetal transfusion for women with red-cell isoimmunisation for improving health outcomes (Review) i
[Intervention Review]
Techniques of intrauterine fetal transfusion for women with

red-cell isoimmunisation for improving health outcomes
Jodie M Dodd1 , Rory C Windrim2 , Inge L van Kamp3
1 School of Paediatrics and Reproductive Health, Discipline of Obstetrics and Gynaecology, The University of Adelaide, Adelaide,
Australia. 2 Department of Obstetrics and Gynaecology, University of Toronto, Toronto, Canada. 3 Department of Obstetrics, Fetal
Medicine Unit (K06-35), Leiden University Medical Center, Leiden, Netherlands
Contact address: Jodie M Dodd, School of Paediatrics and Reproductive Health, Discipline of Obstetrics and Gynaecology, The
University of Adelaide, Womens and Childrens Hospital, 72 King William Road, Adelaide, South Australia, 5006, Australia.
jodie.dodd@adelaide.edu.au.
Editorial group: Cochrane Pregnancy and Childbirth Group.

Publication status and date: New search for studies and content updated (no change to conclusions), published in Issue 9, 2012.
Review content assessed as up-to-date: 9 July 2012.
Citation: Dodd JM, Windrim RC, van Kamp IL. Techniques of intrauterine fetal transfusion for women with red-cell isoim-
munisation for improving health outcomes. Cochrane Database of Systematic Reviews 2012, Issue 9. Art. No.: CD007096. DOI:
10.1002/14651858.CD007096.pub3.
ABSTRACT
Background
Red-cell alloimmunisation can occur when there are incompatibilities between a womans blood type and that of her unborn baby.
This can cause the baby to become anaemic (low red blood cell count), which may require treatment during the pregnancy by blood
transfusion while the baby remains within the uterus (called an intrauterine blood transfusion).
Objectives
To compare, using the best available evidence, the benefits and harms of different techniques of intrauterine fetal blood transfusion for
women with red-cell alloimmunisation.
Search methods
We searched the Cochrane Pregnancy and Childbirth Groups Trials Register (13 June 2012).
Selection criteria
We considered randomised controlled trials comparing different techniques of intrauterine fetal blood transfusion (either alone or in
combination with another technique) for inclusion.
Data collection and analysis
Two authors evaluated trials under consideration for appropriateness for inclusion and methodological quality, without consideration
of their results according to the prestated eligibility criteria. We planned to use a fixed-effect meta-analysis for combining study data if
we judged the trials to be sufficiently similar. We planned to investigate statistical heterogeneity using the I statistic; if this indicated a
high degree of statistical heterogeneity, we planned to use a random-effects model.
Techniques of intrauterine fetal transfusion for women with red-cell isoimmunisation for improving health outcomes (Review) 1
Main results
Our search strategy identified four reports of three studies for consideration, of which two met the inclusion criteria, involving 44
women. We identified a single trial comparing the use of intrauterine fetal blood transfusion and intravenous immunoglobulin versus
intrauterine fetal blood transfusion alone, and a single trial comparing the use of atracurium and pancuronium. There were no statistically
significant differences identified for any of the reported outcomes.
Authors conclusions
There is little available high quality information from randomised controlled trials to inform the optimal procedural technique when
performing fetal intrauterine fetal blood transfusions for women with an anaemic fetus due to red cell alloimmunisation. Further
research evaluating the benefits and harms associated with different techniques is required.
PLAIN LANGUAGE SUMMARY
Techniques of intrauterine fetal transfusion for women with red-cell isoimmunisation for improving health outcomes
Red-cell alloimmunisation can occur when there are incompatibilities between a womans blood type and that of her unborn baby (such
as Rhesus or Kell). During pregnancy, the babys blood can cross the placenta and enter the womans circulation, which may cause her
immune system to produce antibodies, that can then destroy the babys red blood cells (haemolysis). This can cause the baby to become
anaemic (have a low red blood cell count), and if severe, it may require a blood transfusion while the baby still remains within the uterus
(called an intrauterine blood transfusion). This review of two randomised controlled trials, involving 44 pregnant women, found that
there is currently insufficient information about the optimal technique for performing fetal intrauterine fetal blood transfusions. One
of the studies compared two different muscle relaxants to keep the baby still during the procedure, and the other gave intrauterine fetal
blood transfusions with and with intravenous immunoglobulin, without any clear differences.
BACKGROUND red blood cells, causing haemolysis (or breakdown of the babys
red blood cells). This can cause the baby to become anaemic (low
red blood cell count), which may require treatment during the
Description of the condition pregnancy by blood transfusion while the baby remains within the
uterus (called an intrauterine blood transfusion).
Red-cell alloimmunisation has been associated with considerable
Red-cell alloimmunisation and its consequences perinatal morbidity and mortality in obstetric practice over many
Red-cell alloimmunisation can occur when there are incompat- years, presenting as a major cause of stillbirth into the 1970s.
ibilities between a womans blood type and that of her unborn Recognition in the 1960s that sensitisation to Rhesus (D) posi-
baby. This may occur when the woman is negative for a particular tive blood could be prevented by the administration of anti Rh-D
red blood cell antigen (for example Rhesus or Kell), and where her immunoglobulin (Stern 1961), and the subsequent development
baby is positive (this arises due to differences in blood groups be- of Rhesus immunoglobulin prophylaxis programmes for Rhesus-
tween the mother and father). During pregnancy and birth, blood negative women both during and after pregnancy, has been asso-
from the baby can cross into the mothers circulation. The womans ciated with a dramatic reduction in the occurrence of Rhesus al-
body responds to this foreign blood by producing antibodies. A loimmunisation. Current estimates suggesting a reduction to less
woman may also produce antibodies to red blood cells following than 1% of Rhesus-negative women who carry a Rhesus-positive
a blood transfusion with incompatible blood. In any subsequent fetus (Urbaniak 2000), or between 0.1% and 0.6% of all live births
pregnancy, these antibodies (of the IgG type) can cross the pla- (Moise 2002). The Cochrane Systematic Review related to ante-
centa, and have the potential to damage the red blood cells of the natal and postpartum prophylaxis with anti-D immunoglobulin
baby (if the baby is positive for the antigen). This occurs when indicates a significant reduction in the risk of alloimmunisation
the red blood cell antibodies stick to the babys antigen-positive six months after birth (risk ratio (RR) 0.04; 95% confidence in-
tervals (CI) 0.02 to 0.06), and the risk of alloimmunisation in a sured by ultrasound. The use of Doppler ultrasound assessment
subsequent pregnancy (RR 0.12; 95% CI 0.07 to 0.23) (Crowther of fetal cerebral blood flow is considered to reliably identify the
1997). Concomitant with a reduction in the incidence of red-cell baby with anaemia, largely replacing the need for invasive testing
alloimmunisation, there has been a dramatic reduction in the risk (Oepkes 2006).
of neonatal mortality. Reports from Manitoba suggest a reduction
in perinatal deaths from approximately 100 per year in the early
1940s to one every three years in the mid-1990s (Bowman 1997). Description of the intervention
This has been attributed to antenatal and postnatal prophylaxis
programmes, as well as improved neonatal survival following in-
vasive intrauterine procedures (Moise 2002). Techniques of intrauterine blood transfusion
Red-cell alloimmunisation causes fetal haemolytic anaemia (where
When a fetus is identified as being at risk of anaemia, in-utero
red blood cells are broken down and destroyed) which, if un-
blood transfusion may be recommended to correct anaemia. Liley
treated, is progressive and can be associated with the development
1963 first described the use of intrauterine blood transfusion for
of fetal hydrops (collection of fluid within the babys body cavities)
an anaemic fetus, using an intraperitoneal approach (where blood
and perinatal death. In the past, treatment modalities for affected
is injected into the babys peritoneal cavity). Over time, the pro-
live-born infants suffering from anaemia and jaundice in the new-
cedure has been modified to involve an intravascular approach
born period, involved phototherapy, neonatal top-up transfusion
(where blood is injected directly into a fetal blood vessel) (Rodeck
and neonatal exchange transfusion, the latter being associated with
1981), the safety of which has increased with improvements in
a high risk of complications related to volume overload, infec-
ultrasound technology (Bang 1982; Daffos 1983). Currently, in-
tion, the development of neonatal jaundice and, if unsuccessfully
travascular transfusion is considered to be superior to intraperi-
treated, neonatal kernicterus and its subsequent risks of neurolog-
toneal transfusion (Bennebroek 1989; Harman 1990), with intra-
ical handicap and developmental delay (Pochedly 1970).
hepatic blood transfusion associated with improved fetal survival
when compared with injection of blood directly into the umbili-
cal cord (called cordocentesis) (Nicolini 1990). Recognised tech-
Identification of the fetus at risk of anaemia niques utilised for intrauterine blood transfusions include the in-
In-utero assessment of the fetus at risk of anaemia was revolu- jection of blood into the umbilical cord (usually into the umbil-
tionised by Liley during the 1960s, with evaluation of the biliru- ical vein either at the point where the cord inserts into the pla-
bin content in amniotic fluid taken by amniocentesis and assessed centa or into the babys liver, or into a free loop of cord), into the
by the optical density at 450 nanometres on spectrometry (Liley babys peritoneal cavity (called intraperitoneal transfusion), into
1961). The haemolytic process results in the breakdown of fetal a blood vessel in the babys liver (called intrahepatic transfusion),
red blood cells, and an increase in end-products, including biliru- and occasionally directly into the babys heart (called intracardiac
bin within the amniotic fluid. The use of serial amniocenteses to transfusion). Some practitioners advocate a combined intravascu-
plot changes in the bilirubin concentration (Green 1965; Liley lar (usually within the babys liver) and intraperitoneal technique
1961; Liley 1964; Liley 1965) has become a cornerstone in the (Moise 1989; Nicolini 1989), as a means of reducing large fluctu-
identification of the fetus developing anaemia and in need of in- ations in the babys haematocrit, and possibly increasing the time
trauterine blood transfusion. However, the need for serial amnio- interval between subsequent invasive interventions.
centesis places the pregnancy at risk of complications, including
rupture of the membranes, infection, preterm labour, as well as
exacerbation of the alloimmunisation process, increasing mater- Complications of intrauterine blood transfusion
nal antibody production further. Some consider the use of am- Each of the techniques mentioned above for transfusing blood
niotic fluid bilirubin levels to be unreliable in women who have to the fetus has potential complications. The vast majority of in-
had more than one sensitised pregnancy. Amniocentesis is also not formation related to the complications from each type of pro-
considered reliable in the detection of anaemia in pregnancies af- cedure has been obtained from case series, which can be associ-
fected by Kell antibodies (these antibodies damage the formation ated with potential bias. Recognised complications following in-
of red blood cells rather than causing haemolysis) (Weiner 1996). trauterine blood transfusion include preterm prelabour rupture of
More recently, the use of non-invasive ultrasound assessment of membranes (PPROM), infection (also called chorioamnionitis),
fetal cerebral blood flow (called middle cerebral artery peak systolic preterm labour, and fetal distress (non-reassuring fetal heart rate
Doppler flow) has been used to identify the fetus at risk of anaemia trace) All of these may require emergency delivery and result in
(Mari 1995). As anaemia develops, the baby responds by increas- preterm birth, with its associated complications for the infant, in-
ing the work of the heart (called cardiac output), and the blood cluding the risk of perinatal death. The underlying process causing
becomes less viscous (or less thick). This results in an increased the anaemia means that often a baby will require several repeated
speed in blood flow through the babys brain, which can be mea- in-utero transfusions during the course of a pregnancy. The need
for these repeated procedures can place the woman at risk of addi- To compare, using the best available evidence, the benefits and
tional antibody formation, increasing antibody sensitisation, and harms of different techniques of intrauterine fetal blood transfu-
further exacerbating the fetal haemolytic process. Furthermore, sion for women with red-cell alloimmunisation.
transfusing the baby while in utero will suppress the babys ability
to produce its own red blood cells (called fetal erythropoiesis). The
effect of this suppression is the need for repeat procedures during METHODS
the course of the pregnancy, and the need for top-up transfusions
after the babys birth.
Criteria for considering studies for this review
Risk of a fatal complication following cordocentesis
and intrauterine transfusion
The overall chance of survival for babies who require intrauter- Types of studies
ine blood transfusion for anaemia is of the order of 85% to 90% We considered all published, unpublished, and ongoing ran-
(Schumacher 1996; Somerset 2006; Van Kamp 2004). The risk of domised controlled trials (RCTs) comparing different techniques
a fatal complication following cordocentesis or intrauterine trans- of intrauterine fetal blood transfusion (either alone or in combi-
fusion varies across the literature, from 1.3% to 2.5% per pro- nation with another technique) for inclusion.
cedure (Ghidini 1993; Schumacher 1996; Tongsong 2001; Van We considered quasi-RCTs (e.g. those randomised by date of birth
Kamp 2004; Van Kamp 2005). Similarly, the procedure related or hospital number) for inclusion and performed subsequent sen-
risk of PPROM varies from 0.1% to 2% (Poissonnier 1989; Van sitivity analyses to assess the effect of trial quality. We have in-
Kamp 2005; Weiner 1996), as does the procedure related risk of cluded studies reported only in abstract form in the Studies await-
infection from 0.3% to 1.2% (Grannum 1988; Tongsong 2001; ing classification category; we will include these in analyses when
Van Kamp 2005; Weiner 1996). Fetal distress secondary to com- published as full reports.
plications of the procedure may be due to inadvertent injection of
blood into an artery (rather than vein) causing spasm of the vessel,
Types of participants
or due to excessive bleeding at the site of the injection (Bernaschek
1995; Goodrum 1997; Mouw 1999; Weiner 1996). This may re- Women with red-cell alloimmunisation undergoing intrauterine
sult from sudden fetal movements, causing the needle to dislodge fetal blood transfusion for treatment of fetal haemolytic anaemia.
from its intended site. For this reason, fetal paralysis is often rec-
ommended (Mouw 1999). Intrauterine blood transfusions, par-
Types of interventions
ticularly where the baby has features of hydrops (where fluid has
accumulated in the babys body, indicating severe anaemia), can We considered any technique for intrauterine fetal blood transfu-
be associated with an increase in the chance of perinatal death sion (alone or in combination) compared with any other technique
(Schumacher 1996; Van Kamp 2004; Van Kamp 2005). for intrauterine fetal blood transfusion (alone or in combination)
for inclusion.
How the intervention might work Types of outcome measures

When a fetus is identified as being at risk of anaemia, in-utero
blood transfusion may be recommended to correct the anaemia.
Primary outcomes
1. Perinatal mortality
Why it is important to do this review 2. Preterm birth (less than 34 weeks gestation)
3. Major neurodevelopmental handicap at childhood follow
There are many different techniques that practitioners utilise to
up
perform an intra-uterine fetal blood transfusion. The aim of this
review is to use the best available evidence to assess the benefits
and harms of different techniques of intrauterine fetal blood trans- Secondary outcomes
fusion for women with red-cell alloimmunisation.
Maternal
1. Preterm prelabour ruptured membranes
OBJECTIVES 2. Preterm labour (actual or threatened)
3. Chorioamnionitis within the editorial information about the Cochrane Pregnancy
4. Use of antenatal corticosteroids for fetal lung maturation and Childbirth Group.
5. Mode of birth Trials identified through the searching activities described above
6. Antibiotic use after birth are each assigned to a review topic (or topics). The Trials Search
7. Maternal antibody sensitisation Co-ordinator searches the register for each review using the topic
list rather than keywords.
We did not apply any language restrictions.
Infant
1. Birth before 37, 32, and 28 completed weeks
2. Birthweight less than the 10th centile for gestational age
3. Birthweight less than 2500 grams Data collection and analysis
4. Apgar score of less than seven at five minutes
5. Need for exchange transfusion
6. Need for top-up transfusion
Selection of studies
7. Respiratory distress syndrome
8. Use of mechanical ventilation Two review authors independently assessed for inclusion all the
9. Duration of mechanical ventilation potential studies identified as a result of the search strategy. We
10. Intraventricular haemorrhage - Grades III or IV resolved any disagreement through discussion or, if required, we
11. Periventricular leucomalacia consulted a third person.
12. Retinopathy of prematurity
13. Retinopathy of prematurity - Grades III or IV
14. Chronic lung disease Data extraction and management
15. Necrotising enterocolitis
We designed a form to extract data. For eligible studies, two review
16. Neonatal sepsis
authors extracted the data using the agreed form. We resolved
17. Fetal death
discrepancies through discussion or, if required, we consulted a
18. Neonatal death
third person. We entered data into Review Manager software (
19. Admission to neonatal intensive care unit
RevMan 2008) and checked for accuracy.
20. Neonatal length of hospital stay
When information regarding any of the above was unclear, we
attempted to contact authors of the original reports to provide
further details.
Search methods for identification of studies
Assessment of risk of bias in included studies

Electronic searches
Two review authors (JD and RW) independently assessed risk of
We searched the Cochrane Pregnancy and Childbirth Groups Tri-
bias for each study using the criteria outlined in the Cochrane
als Register by contacting the Trials Search Co-ordinator (13 June Handbook for Systematic Reviews of Interventions (Higgins 2008).
2012). We resolved any disagreement by discussion or by involving a third
The Cochrane Pregnancy and Childbirth Groups Trials Register assessor (IK).
is maintained by the Trials Search Co-ordinator and contains trials
identified from:
1. monthly searches of the Cochrane Central Register of
(1) Sequence generation (checking for possible selection
Controlled Trials (CENTRAL);
bias)
2. weekly searches of MEDLINE;
3. weekly searches of EMBASE; We described for each included study the method used to generate
4. handsearches of 30 journals and the proceedings of major the allocation sequence in sufficient detail to allow an assessment
conferences; of whether it should have produced comparable groups.
5. weekly current awareness alerts for a further 44 journals We assessed the method as:
plus monthly BioMed Central email alerts. adequate (any truly random process, e.g. random number
Details of the search strategies for CENTRAL, MEDLINE and table; computer random number generator);
EMBASE, the list of handsearched journals and conference pro- inadequate (any non-random process, e.g. odd or even date
ceedings, and the list of journals reviewed via the current aware- of birth; hospital or clinic record number);
ness service can be found in the Specialized Register section unclear.
(2) Allocation concealment (checking for possible selection inadequate (where not all the studys prespecified outcomes
bias) have been reported; one or more reported primary outcomes were
We described for each included study the method used to conceal not prespecified; outcomes of interest are reported incompletely
the allocation sequence in sufficient detail and determine whether and so cannot be used; study fails to include results of a key
intervention allocation could have been foreseen in advance of, or outcome that would have been expected to have been reported);
during recruitment, or changed after assignment. unclear.
We assessed the methods as:
adequate (e.g. telephone or central randomisation;
(6) Other sources of bias
consecutively numbered sealed opaque envelopes);
inadequate (open random allocation; unsealed or non- We described for each included study any important concerns we
opaque envelopes, alternation; date of birth); had about other possible sources of bias.
unclear. We assessed whether each study was free of other problems that
could put it at risk of bias:
yes;
(3) Blinding (checking for possible performance bias) no;
unclear.
We described for each included study the methods used, if any, to
blind study participants and personnel from knowledge of which
intervention a participant received. We judged studies at low risk (7) Overall risk of bias
of bias if they were blinded, or if we judged that the lack of blinding
We made explicit judgements about whether studies are at high risk
could not have affected the results. We assessed blinding separately
of bias, according to the criteria given in the Handbook (Higgins
for different outcomes or classes of outcomes.
2008). With reference to (1) to (6) above, we assessed the likely
magnitude and direction of the bias and whether we considered
adequate, inadequate or unclear for participants;
it is likely to impact on the findings. We explored the impact
adequate, inadequate or unclear for personnel;
of the level of bias through undertaking sensitivity analyses - see
adequate, inadequate or unclear for outcome assessors
Sensitivity analysis.
(4) Incomplete outcome data (checking for possible attrition

Measures of treatment effect
bias through withdrawals, dropouts, protocol deviations)
We described for each included study, and for each outcome or
class of outcomes, the completeness of data including attrition Dichotomous data
and exclusions from the analysis. We stated whether attrition and For dichotomous data, we present results as summary risk ratio
exclusions were reported, the numbers included in the analysis at with 95% confidence intervals.
each stage (compared with the total randomised participants), rea-
sons for attrition or exclusion where reported, and whether miss-
ing data were balanced across groups or were related to outcomes. Continuous data
Where sufficient information was reported, or could be supplied For continuous data, we have used the mean difference if outcomes
by the trial authors, we re-included missing data in the analyses were measured in the same way between trials. We have used the
which we undertook. We considered greater than 20% missing standardised mean difference to combine trials that measure the
data to be inadequate. We assessed methods as: same outcome, but used different methods.
adequate;
inadequate:
unclear. Unit of analysis issues
(5) Selective reporting bias Cluster-randomised trials

We described for each included study how we investigated the We did not identify any eligible cluster-randomised trials.
possibility of selective outcome reporting bias and what we found.
adequate (where it is clear that all of the studys prespecified Crossover trials
outcomes and all expected outcomes of interest to the review This is not considered a valid study design for the evaluation of
have been reported); this intervention.
Dealing with missing data For fixed-effect meta-analyses we conducted planned subgroup
For included studies, we noted levels of attrition. We explored the analyses classifying whole trials by interaction tests as described by
impact of including studies with high levels of missing data in the Deeks 2001. For random-effects meta-analyses we assessed differ-
overall assessment of treatment effect by using sensitivity analysis. ences between subgroups by inspection of the subgroups confi-
For all outcomes we have carried out analyses, as far as possible, on dence intervals; non-overlapping confidence intervals indicated a
an intention-to-treat basis, i.e. we attempted to include all partici- statistically significant difference in treatment effect between the
pants randomised to each group in the analyses. The denominator subgroups.
for each outcome in each trial was the number randomised minus
any participants whose outcomes were known to be missing.
Sensitivity analysis
We planned sensitivity analyses to account for methodological
Assessment of heterogeneity
quality of the studies involved.
We used the I statistic to measure heterogeneity among the trials
in each analysis. If we identified substantial heterogeneity we ex-
plored it by prespecified subgroup analysis.
RESULTS
Assessment of reporting biases
Where we suspected reporting bias (see Selective reporting bias
above), we attempted to contact study authors asking them to pro-
vide missing outcome data. Where this was not possible, and the Description of studies
missing data were thought to introduce serious bias, we explored See: Characteristics of included studies; Characteristics of excluded
the impact of including such studies in the overall assessment of studies.
results by a Sensitivity analysis.
Results of the search

Data synthesis
The search of the Pregnancy and Childbirth Groups Trials Reg-
We carried out statistical analysis using the Review Manager soft-
ister found four reports of three randomised trials (Dooren 1994;
ware (RevMan 2008). We used fixed-effect inverse variance meta-
Fairweather 1967; Mouw 1999; Mouw 1997). We included two
analysis for combining data where trials were examining the same
trials (three reports) and excluded one.
intervention, and the trials populations and methods were judged
sufficiently similar. Where we suspected clinical or methodological
heterogeneity between studies sufficient to suggest that treatment
effects may differ between trials, we used random-effects meta- Included studies
analysis. Two randomised trials (from three reports) involving 44 women
If we identified substantial heterogeneity in a fixed-effect meta- met the inclusion criteria (Dooren 1994; Mouw 1999). Refer to
analysis, we noted this and repeated the analysis using a random- the table Characteristics of included studies for further details.
effects method.
Interventions
Subgroup analysis and investigation of heterogeneity
The interventions compared were:
We planned to carry out the following subgroup analyses to assess
fetal intrauterine blood transfusion and fetal intravenous
the effect of:
immunoglobulin (IVIG) compared with fetal intrauterine blood
1. gestational age at the time of randomisation (before 20
transfusion alone (Dooren 1994); and
weeks gestation versus 20 to 28 weeks gestation versus after 28
fetal atracurium compared with fetal pancuronium (Mouw
weeks gestation);
1999).
2. antibody type (e.g. Rhesus, Kell);
3. maternal sedation (maternal sedation versus no maternal
sedation); and
Participant population
4. fetal paralysis (paralysis of the fetus versus no paralysis of
the fetus). The trials recruited women with severe RhD alloimmunisation
We used only the listed primary outcomes in subgroup analysis. only.
Reported outcomes Fetal atracurium compared with fetal pancuronium
The trial by Dooren (Dooren 1994) reported perinatal mortality, We included a single study involving 24 women (Mouw 1999).
childhood neurodevelopmental disability, preterm birth less than The study did not report any of the prespecified review outcomes.
32 weeks gestation, and need for exchange and top-up transfu-
sions. Mouw 1999 did not report any of the prespecified out-
comes; reported outcomes included fetal heart rate patterns, fetal
movements, time to complete the procedure and volume of blood DISCUSSION
transfused.
Fetal anaemia secondary to red cell alloimmunisation remains a
significant cause of perinatal morbidity and mortality. The first
description of intrauterine fetal blood transfusion was in 1963
Excluded studies by Liley (Liley 1963), utilising an intraperitoneal approach. Over
We excluded one trial (Fairweather 1967) as women were identi- time, the procedure has been modified to involve an intravascu-
fied by virtue of increased liquor bilirubin concentration but were lar approach (where blood is injected directly into a fetal blood
then randomised to either intrauterine blood transfusion or to no vessel) (Rodeck 1981), the safety of which has increased with im-
intrauterine blood transfusion. provements in ultrasound technology (Bang 1982; Daffos 1983).
Refer to the Characteristics of excluded studies table for more Currently, based on observational studies, intravascular transfu-
details. sion is considered to be superior to intraperitoneal transfusion
(Bennebroek 1989; Harman 1990), with intrahepatic blood trans-
fusion associated with improved fetal survival when compared with
injection of blood directly into the umbilical cord (called cordo-
Risk of bias in included studies centesis) (Nicolini 1990).
The overall quality of the included trials was fair to good. Both Despite these modifications over time, to date there has been in-
trials were stated to be randomised, although the precise method sufficient evaluation of various components of the procedure by
of sequence generation was unclear in both (Dooren 1994; Mouw RCTs to allow reliable assessment of the benefits and harms of
1999). The method of allocation concealment was adequate in each. Further research evaluating the techniques utilised during
both (identical appearing medication syringes (Dooren 1994) and intrauterine fetal blood transfusions is required.
sealed opaque envelopes (Mouw 1999). Blinding was achieved in
the Mouw trial (Mouw 1999).
Refer to the table Characteristics of included studies for further
AUTHORS CONCLUSIONS
details.
Implications for practice
There is little available high-quality information from RCTs to
Effects of interventions inform the optimal procedural technique when performing fetal
intrauterine fetal blood transfusions for women with an anaemic
fetus due to red cell alloimmunisation.
Fetal intrauterine blood transfusion and fetal Implications for research

intravenous immunoglobulin (IVIG) compared with
Further research evaluating the benefits and harms associated with
fetal intrauterine blood transfusion alone
techniques utilised during intrauterine fetal blood transfusions is
We included a single study involving 20 women (Dooren 1994). required.
For the primary outcomes perinatal death (risk ratio (RR) 3.00;
95% confidence interval (CI) 0.37 to 24.17 (one study, 20
women)) and neurodevelopmental delay at childhood follow up
(RR 1.29; 95% CI 0.10 to 17.41 (one study 16 children)), there
ACKNOWLEDGEMENTS
were no statistically significant differences identified between the
two intervention groups. There were no statistically significant As part of the pre-publication editorial process, this review has
differences identified between the two intervention groups for the been commented on by four peers (an editor and three referees
secondary outcomes: preterm birth less than 32 weeks; need for who are external to the editorial team) and the Groups Statistical
exchange transfusion; need for top-up transfusion; or fetal death. Adviser.
REFERENCES
References to studies included in this review of fifty-three cases. American Journal of Obstetrics and
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Dooren 1994 {published data only}
Dooren MC, van Kamp IL, Scherpenisse JW, Brand R, Deeks 2001
Ouwehand WH, Kanhai HHH, et al.No beneficial effect of Deeks JJ, Altman DG, Bradburn MJ. Statistical methods
low-dose fetal intravenous gammaglobulin administration for examining heterogeneity and combining results from
in combination with intravascular transfusions in severe Rh several studies in meta-analysis. In: Egger M, Davey Smith
D haemolytic disease. Vox Sanguinis 1994; Vol. 66:2537. G, Altman DG editor(s). Systematic reviews in health care:
meta-analysis in context. London: BMJ Books, 2001.
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Mouw RJC, Hermans J, Brandenburg HCR, Kanhai HHH. Ghidini 1993
Effects of pancuronium or atracurium on the anemic fetus Ghidini A, Sepulveda W, Lockwood CJ, Romero R.
during and directly after intrauterine transfusion (IUT): Complications of fetal blood sampling. American Journal of
a double blind randomized study. American Journal of Obstetrics and Gynecology 1993;168:133944.
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Kanhai HHH. Effect of atracurium or pancuronium on Carpenter RJ. Effects of intravascular transfusion for red
the anemic fetus during and directly after intravascular cell alloimmunization on fetal arterial blood pressure. Fetal
intrauterine transfusion. Acta Obstetricia et Gynecologica Diagnosis and Therapy 1997;12:14952.
Scandinavica 1999;78:7637.
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Fairweather 1967 {published data only}
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Fairweather DVI, Tacchi D, Coxon A, Hughes MI,
Murray S, Walker W. Intrauterine transfusion in Rh- Green 1965
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transfusion in haemolytic disease. A report of 22
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Bang 1982 Journal of Obstetrics and Gynaecology 1965;90:539.
Bang J, Bock JE, Trolle D. Ultrasound-guided fetal Harman 1990
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BMJ 1982;284:3734. Intrauterine transfusion - intraperitoneal versus intravascular
Bennebroek 1989 approach: a case-control comparison. American Journal of
Bennebroek Gravenhorst J, Kanhai HH, Meerman RH, Obstetrics and Gynecology 1990;162:10539.
Ruys JH, Eernisse JG, Stroes TJ, et al.Twenty-two years of Higgins 2008
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Duetinger J. Complications of cordocentesis in high-
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Daffos F, Caplla-Pavlovski M, Forestier F. A new procedure Liley AW. The use of amniocentesis and fetal transfusion in
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Mari G, Adrignolo A, Abuhamad AZ, Pirhonen J, Jones Rodeck CH, Kemp JR, Holman CA, Whitmore DN,
DC, Ludomirsky A, et al.Diagnosis of fetal anemia with Karnicki J, Austin MA. Direct intravascular fetal blood
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Moise 1989
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JD, Cano LE. Comparison of four types of intrauterine
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An audit of outcome in intravascular transfusions using the
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pregnancy. Obstetrics & Gynecology 2002;100:60011. 2726.
Mouw 1997 Stern 1961
Mouw RJC, Hermans J, Brandenburg HCR, Kanhai HHH. Stern K, Goodman HS, Berger M. Experimental
Effects of pancuronium or atracurium on the anemic fetus isoimmunisation to hemoantigens in man. Journal of
during and directly after intrauterine transfusion (IUT): Immunology 1961;81:189.
a double blind randomized study. American Journal of Tongsong 2001
Obstetrics and Gynecology 1997;176(1 Pt 2):S18. Tongsong T, Wanapirak C, Kunavikatiku C, Sirirchotiyakul
S, Piyamongkol W, Chanprapaph P. Fetal loss rate associated
Nicolini 1989
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Nicolini U, Kochenour NK, Greco P, Letsky E, Rodeck
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CH. When to perform the next intra-uterine transfusion
in patients with Rh allo-immunization: combined Urbaniak 2000
intravascular and intraperitoneal transfusion allows longer Urbaniak SJ, Greiss MA. RhD haemolytic disease of the
intervals. Fetal Therapy 1989;4(1):1420. fetus and the newborn. Blood Reviews 2000;14:4461.
Van Kamp 2004
Nicolini 1990
Van Kamp IL, Klumper FJ, Meerman RH, Oepkes D,
Nicolini U, Nicolaidis P, Fisk NM, Tannirandorn Y,
Scherjon SA, Kanhai HH. Treatment of fetal anemia due
Rodeck CH. Fetal blood sampling from the intrahepatic
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Kingdom J, Beyene J, et al.Doppler ultrasonography versus Scherjon SA, Vandenbussche FP, et al.Complications of
amniocentesis to predict fetal anemia. New England Journal intrauterine intravascular transfusion for fetal anemia due
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Pochedly 1970
Pochedly C. History of exchange transfusion: its use in Weiner 1996
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11:16975.
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Poissonnier MH, Brossard Y, Demedeiros N, Vassileva J, References to other published versions of this review
Parnet F, Larsen M. Two hundred intrauterine exchange
Dodd 2010
transfusions in severe blood incompatabilities. American
Dodd JM, Windrim RC, van Kamp IL. Techniques of
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intrauterine fetal transfusion for women with red-cell
RevMan 2008 isoimmunisation for improving health outcomes. Cochrane
The Nordic Cochrane Centre, The Cochrane Collaboration. Database of Systematic Reviews 2010, Issue 6. [DOI:
Review Manager (RevMan). 5.0. Copenhagen: The Nordic 10.1002/14651858.CD007096.pub2]
Cochrane Centre, The Cochrane Collaboration, 2008.
Indicates the major publication for the study
CHARACTERISTICS OF STUDIES
Characteristics of included studies [ordered by study ID]
Dooren 1994
Methods Trial conducted in the Netherlands between January 1989 and March 1991
Participants 20 women with a history of previous severe RhD alloimmunisation, and in the current
pregnancy carrying a known Rh positive fetus, at less than or equal to 32 weeks gestation,
with maternal antibody titre > 1:256, and biological activity of anti D (by antibody
dependent cell mediated cytotoxicity test) > 80%
Interventions Women randomised to 1) intrauterine fetal blood transfusion followed by intravenous

gammaglobulin infusion or 2) intrauterine fetal blood transfusion alone
Outcomes Perinatal mortality; major neurodevelopmental handicap at childhood follow up; preterm
birth before 32 weeks gestation; need for exchange transfusion; need for top-up trans-
fusion
Notes Method of randomisation: not stated.

Allocation concealment: sealed opaque envelopes.
Blinding of participants, caregivers, and outcome assessors: not stated
Risk of bias
Bias Authors judgement Support for judgement
Random sequence generation (selection Unclear risk Method of randomisation not stated.
bias)
Allocation concealment (selection bias) Low risk Sealed opaque envelopes.
Blinding (performance bias and detection Unclear risk Not stated.

bias)
All outcomes
Incomplete outcome data (attrition bias) Low risk

All outcomes
Selective reporting (reporting bias) Low risk
Other bias Low risk
Mouw 1999
Methods Trial conducted in the Netherlands.
Participants 24 women with RhD alloimmunisation requiring fetal transfusion at 24 to 36 weeks

gestation
Interventions Women were randomised to 1) fetal atracurium (0.4 mg/kg) or 2) fetal pancuronium
(0.1 mg/kg)
Outcomes No prespecified outcomes of the review were reported; authors reported fetal heart rate
patterns, fetal movements, time to complete the procedure and volume of blood trans-
fused
Notes Method of randomisation: stated to be block randomisation.

Allocation concealment: identical appearing medication syringes.
Blinding of participants, caregivers and outcome assessors: yes
Risk of bias
Bias Authors judgement Support for judgement
Random sequence generation (selection Unclear risk Stated to be block randomisation.

bias)
Allocation concealment (selection bias) Low risk Identical appearing medication syringes.
Blinding (performance bias and detection Low risk Blinding of participants, caregivers, and outcome
bias) assessors.
All outcomes
Incomplete outcome data (attrition bias) Low risk

All outcomes
Selective reporting (reporting bias) Low risk
Other bias Low risk
Characteristics of excluded studies [ordered by study ID]
Study Reason for exclusion
Fairweather 1967 Patients identified as eligible for intrauterine transfusion by means of liquor bilirubin concentration (critical liquor
ratio) > 1.1; women were then randomised to receive intrauterine fetal blood transfusion or to no intrauterine
fetal blood transfusion
DATA AND ANALYSES
Comparison 1. Intrauterine transfusion + IVIG versus intrauterine transfusion alone
No. of No. of
Outcome or subgroup title studies participants Statistical method Effect size
1 Perinatal mortality 1 20 Risk Ratio (IV, Fixed, 95% CI) 3.0 [0.37, 24.17]
2 Neurodevelopmental handicap 1 16 Risk Ratio (IV, Fixed, 95% CI) 1.29 [0.10, 17.14]
childhood follow up
3 Preterm birth less than 32 weeks 1 16 Risk Ratio (IV, Fixed, 95% CI) 6.25 [0.35, 112.52]
4 Need for exchange transfusion 1 16 Risk Ratio (IV, Fixed, 95% CI) 0.86 [0.60, 1.23]
5 Need for top-up transfusion 1 16 Risk Ratio (IV, Fixed, 95% CI) 0.92 [0.51, 1.65]
6 Fetal death 1 20 Risk Ratio (IV, Fixed, 95% CI) 3.0 [0.37, 24.17]
Analysis 1.1. Comparison 1 Intrauterine transfusion + IVIG versus intrauterine transfusion alone, Outcome
1 Perinatal mortality.
Review: Techniques of intrauterine fetal transfusion for women with red-cell isoimmunisation for improving health outcomes
Comparison: 1 Intrauterine transfusion + IVIG versus intrauterine transfusion alone
Outcome: 1 Perinatal mortality
Study or subgroup IUT + IVIG IUT alone Risk Ratio Weight Risk Ratio
n/N n/N IV,Fixed,95% CI IV,Fixed,95% CI
Dooren 1994 3/10 1/10 100.0 % 3.00 [ 0.37, 24.17 ]
Total (95% CI) 10 10 100.0 % 3.00 [ 0.37, 24.17 ]

Total events: 3 (IUT + IVIG), 1 (IUT alone)
Heterogeneity: not applicable
Test for overall effect: Z = 1.03 (P = 0.30)
Test for subgroup differences: Not applicable
0.01 0.1 1 10 100

Favours experimental Favours control
2 Neurodevelopmental handicap childhood follow up.
Outcome: 2 Neurodevelopmental handicap childhood follow up
Dooren 1994 1/7 1/9 100.0 % 1.29 [ 0.10, 17.14 ]
Total (95% CI) 7 9 100.0 % 1.29 [ 0.10, 17.14 ]

0.01 0.1 1 10 100

3 Preterm birth less than 32 weeks.
Outcome: 3 Preterm birth less than 32 weeks
Dooren 1994 2/7 0/9 100.0 % 6.25 [ 0.35, 112.52 ]
Total (95% CI) 7 9 100.0 % 6.25 [ 0.35, 112.52 ]

0.01 0.1 1 10 100

4 Need for exchange transfusion.
Outcome: 4 Need for exchange transfusion
Dooren 1994 6/7 9/9 100.0 % 0.86 [ 0.60, 1.23 ]
Total (95% CI) 7 9 100.0 % 0.86 [ 0.60, 1.23 ]

0.01 0.1 1 10 100

5 Need for top-up transfusion.
Outcome: 5 Need for top-up transfusion
Dooren 1994 5/7 7/9 100.0 % 0.92 [ 0.51, 1.65 ]
Total (95% CI) 7 9 100.0 % 0.92 [ 0.51, 1.65 ]

0.01 0.1 1 10 100

6 Fetal death.
Outcome: 6 Fetal death
Dooren 1994 3/10 1/10 100.0 % 3.00 [ 0.37, 24.17 ]
Total (95% CI) 10 10 100.0 % 3.00 [ 0.37, 24.17 ]

0.01 0.1 1 10 100

WHATS NEW
Last assessed as up-to-date: 9 July 2012.
Date Event Description
9 July 2012 New citation required but conclusions have not changed Review updated with a new search.
9 July 2012 New search has been performed Search updated. No new trials identified.
HISTORY
Protocol first published: Issue 2, 2008
Review first published: Issue 6, 2010
CONTRIBUTIONS OF AUTHORS
Jodie Dodd drafted the initial protocol and review. Jodie Dodd and Rory Windrim were involved in the evaluation of studies and data
extraction. Jodie Dodd, Rory Windrim and Inge van Kamp all contributed to the content and revision of subsequent drafts.
DECLARATIONS OF INTEREST
Inge van Kamp was co-author of one of the included studies (Dooren 1994). This trial was independently assessed and data extracted
by Jodie Dodd and Rory Windrim.
SOURCES OF SUPPORT
Internal sources
Discipline of Obstetrics and Gynaecology, The University of Adelaide, Australia.
External sources
Neil Hamilton Fairley Fellowship supported by the NHMRC (ID 399224), Australia.
DIFFERENCES BETWEEN PROTOCOL AND REVIEW

The secondary infant outcome Need for exchange transfusion was not prespecified in the protocol for the review. We have updated
the methods section to reflect the latest methods of the Pregnancy and Childbirth Group.
INDEX TERMS
Medical Subject Headings (MeSH)

Atracurium [therapeutic use]; Blood Transfusion, Intrauterine [adverse effects; methods]; Erythrocyte Transfusion [adverse effects;
methods]; Immunoglobulins, Intravenous [ therapeutic use]; Neuromuscular Depolarizing Agents [therapeutic use]; Pancuronium
[therapeutic use]; Randomized Controlled Trials as Topic; Rh Isoimmunization [ therapy]; Treatment Outcome
MeSH check words

Female; Humans; Pregnancy

Techniques of Intrauterine Fetal Transfusion For Women With Red-Cell Isoimmunisation For Improving Health Outcomes (Review)

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Techniques of Intrauterine Fetal Transfusion For Women With Red-Cell Isoimmunisation For Improving Health Outcomes (Review)

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Verfügbare Formate

Techniques of intrauterine fetal transfusion for women with

red-cell isoimmunisation for improving health outcomes

Dodd JM, Windrim RC, van Kamp IL

Techniques of intrauterine fetal transfusion for women with

Jodie M Dodd1 , Rory C Windrim2 , Inge L van Kamp3

Editorial group: Cochrane Pregnancy and Childbirth Group.

Data collection and analysis

PLAIN LANGUAGE SUMMARY

How the intervention might work Types of outcome measures

Assessment of risk of bias in included studies

(4) Incomplete outcome data (checking for possible attrition

(5) Selective reporting bias Cluster-randomised trials

Results of the search

Fetal intrauterine blood transfusion and fetal Implications for research

Characteristics of included studies [ordered by study ID]

Interventions Women randomised to 1) intrauterine fetal blood transfusion followed by intravenous

Notes Method of randomisation: not stated.

Bias Authors judgement Support for judgement

Allocation concealment (selection bias) Low risk Sealed opaque envelopes.

Blinding (performance bias and detection Unclear risk Not stated.

Incomplete outcome data (attrition bias) Low risk

Selective reporting (reporting bias) Low risk

Other bias Low risk

Methods Trial conducted in the Netherlands.

Participants 24 women with RhD alloimmunisation requiring fetal transfusion at 24 to 36 weeks

Notes Method of randomisation: stated to be block randomisation.

Bias Authors judgement Support for judgement

Random sequence generation (selection Unclear risk Stated to be block randomisation.

Incomplete outcome data (attrition bias) Low risk

Selective reporting (reporting bias) Low risk

Other bias Low risk

Characteristics of excluded studies [ordered by study ID]

Study Reason for exclusion

Comparison 1. Intrauterine transfusion + IVIG versus intrauterine transfusion alone

Comparison: 1 Intrauterine transfusion + IVIG versus intrauterine transfusion alone

Outcome: 1 Perinatal mortality

Total (95% CI) 10 10 100.0 % 3.00 [ 0.37, 24.17 ]

0.01 0.1 1 10 100

Comparison: 1 Intrauterine transfusion + IVIG versus intrauterine transfusion alone

Outcome: 2 Neurodevelopmental handicap childhood follow up

Total (95% CI) 7 9 100.0 % 1.29 [ 0.10, 17.14 ]

0.01 0.1 1 10 100

Comparison: 1 Intrauterine transfusion + IVIG versus intrauterine transfusion alone

Outcome: 3 Preterm birth less than 32 weeks

Total (95% CI) 7 9 100.0 % 6.25 [ 0.35, 112.52 ]

0.01 0.1 1 10 100

Comparison: 1 Intrauterine transfusion + IVIG versus intrauterine transfusion alone

Outcome: 4 Need for exchange transfusion

Total (95% CI) 7 9 100.0 % 0.86 [ 0.60, 1.23 ]

0.01 0.1 1 10 100

Comparison: 1 Intrauterine transfusion + IVIG versus intrauterine transfusion alone

Outcome: 5 Need for top-up transfusion

Total (95% CI) 7 9 100.0 % 0.92 [ 0.51, 1.65 ]

0.01 0.1 1 10 100

Comparison: 1 Intrauterine transfusion + IVIG versus intrauterine transfusion alone

Outcome: 6 Fetal death

Total (95% CI) 10 10 100.0 % 3.00 [ 0.37, 24.17 ]

0.01 0.1 1 10 100

Date Event Description

DIFFERENCES BETWEEN PROTOCOL AND REVIEW

Medical Subject Headings (MeSH)

MeSH check words

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