2002-Immunoglobulin Infusion For Isoimmune Haemolytic Jaundice in Neonates.

Immunoglobulin infusion for isoimmune haemolytic jaundice
in neonates (Review)
Alcock GS, Liley H
This is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library
2009, Issue 1
http://www.thecochranelibrary.com
Immunoglobulin infusion for isoimmune haemolytic jaundice in neonates (Review)

Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
TABLE OF CONTENTS
HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
AUTHORS’ CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
Analysis 1.1. Comparison 1 IVIg plus phototherapy vs phototherapy, Outcome 1 Use of exchange transfusion (one or
more). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
Analysis 1.2. Comparison 1 IVIg plus phototherapy vs phototherapy, Outcome 2 Exchange transfusions per infant. . 16
Analysis 1.3. Comparison 1 IVIg plus phototherapy vs phototherapy, Outcome 3 Use of simple transfusion in 1st week. 16
Analysis 1.4. Comparison 1 IVIg plus phototherapy vs phototherapy, Outcome 4 Use of simple transfusion after 1st
week. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17
Analysis 1.5. Comparison 1 IVIg plus phototherapy vs phototherapy, Outcome 5 Maximum serum bilirubin
(micromol/L). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17
Analysis 1.6. Comparison 1 IVIg plus phototherapy vs phototherapy, Outcome 6 Duration of phototherapy (hours). 18
Analysis 1.7. Comparison 1 IVIg plus phototherapy vs phototherapy, Outcome 7 Duration of hospitalisation (hours). 18
Analysis 1.8. Comparison 1 IVIg plus phototherapy vs phototherapy, Outcome 8 Incidence of adverse reaction. . . 19
Analysis 2.1. Comparison 2 IVIg plus phototherapy vs phototherapy. Rh incompatibility, Outcome 1 Use of exchange
transfusion (one or more). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19
Analysis 2.2. Comparison 2 IVIg plus phototherapy vs phototherapy. Rh incompatibility, Outcome 2 Exchange transfusions
per infant. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20
Analysis 2.3. Comparison 2 IVIg plus phototherapy vs phototherapy. Rh incompatibility, Outcome 3 Use simple transfusion
in 1st week. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20
Analysis 2.4. Comparison 2 IVIg plus phototherapy vs phototherapy. Rh incompatibility, Outcome 4 Use of simple
transfusion after 1st week. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21
Analysis 2.5. Comparison 2 IVIg plus phototherapy vs phototherapy. Rh incompatibility, Outcome 5 Maximum serum
bilirubin (micromol/L). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21
Analysis 2.6. Comparison 2 IVIg plus phototherapy vs phototherapy. Rh incompatibility, Outcome 6 Duration of
phototherapy (hours). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22
Analysis 2.7. Comparison 2 IVIg plus phototherapy vs phototherapy. Rh incompatibility, Outcome 7 Duration of
hospitalisation (hours). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22
Analysis 3.1. Comparison 3 IVIg plus phototherapy vs phototherapy. ABO incompatibility only, Outcome 1 Use of
exchange transfusion (one or more). . . . . . . . . . . . . . . . . . . . . . . . . . . 23
Analysis 3.2. Comparison 3 IVIg plus phototherapy vs phototherapy. ABO incompatibility only, Outcome 2 Exchange
transfusions per infant. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23
Analysis 3.3. Comparison 3 IVIg plus phototherapy vs phototherapy. ABO incompatibility only, Outcome 3 Use of simple
transfusion in 1st week. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24
Analysis 3.4. Comparison 3 IVIg plus phototherapy vs phototherapy. ABO incompatibility only, Outcome 4 Use of simple
Analysis 3.5. Comparison 3 IVIg plus phototherapy vs phototherapy. ABO incompatibility only, Outcome 5 Maximum
serum bilirubin (micromol/L). . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25
Analysis 3.6. Comparison 3 IVIg plus phototherapy vs phototherapy. ABO incompatibility only, Outcome 6 Duration of
Immunoglobulin infusion for isoimmune haemolytic jaundice in neonates (Review) i
Analysis 3.7. Comparison 3 IVIg plus phototherapy vs phototherapy. ABO incompatibility only, Outcome 7 Duration of
Analysis 4.1. Comparison 4 IVIg plus phototherapy vs phototherapy. Prophylaxis, Outcome 1 Use of exchange transfusion
(one or more). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26
Analysis 4.2. Comparison 4 IVIg plus phototherapy vs phototherapy. Prophylaxis, Outcome 2 Exchange transfusions per
infant. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27
Analysis 4.5. Comparison 4 IVIg plus phototherapy vs phototherapy. Prophylaxis, Outcome 5 Maximum serum bilirubin
(micromol/L). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27
Analysis 5.1. Comparison 5 IVIg plus phototherapy vs phototherapy. Established jaundice, Outcome 1 Use of exchange
transfusion (one or more). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28
Analysis 5.2. Comparison 5 IVIg plus phototherapy vs phototherapy. Established jaundice, Outcome 2 Exchange
transfusions per infant. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28
Analysis 5.3. Comparison 5 IVIg plus phototherapy vs phototherapy. Established jaundice, Outcome 3 Use of simple
transfusion in 1st week. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29
Analysis 5.4. Comparison 5 IVIg plus phototherapy vs phototherapy. Established jaundice, Outcome 4 Use of simple
Analysis 5.5. Comparison 5 IVIg plus phototherapy vs phototherapy. Established jaundice, Outcome 5 Maximum serum
bilirubin (micromol/L). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30
Analysis 5.6. Comparison 5 IVIg plus phototherapy vs phototherapy. Established jaundice, Outcome 6 Duration of
Analysis 5.7. Comparison 5 IVIg plus phototherapy vs phototherapy. Established jaundice, Outcome 7 Duration of
WHAT’S NEW . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31
HISTORY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31
CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31
DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31
SOURCES OF SUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32
INDEX TERMS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32
Immunoglobulin infusion for isoimmune haemolytic jaundice in neonates (Review) ii

[Intervention Review]
Immunoglobulin infusion for isoimmune haemolytic jaundice

in neonates
Gary S Alcock1 , Helen Liley2
1 Department of Neonatology, The Canberra Hospital, Woden, Australia. 2 Mater Mothers’ Hospital, South Brisbane, Australia
Contact address: Gary S Alcock, Department of Neonatology, The Canberra Hospital, P.O. Box 11, Woden, ACT, 2606, Australia.
gary_alcock@health.qld.gov.au.
Editorial group: Cochrane Neonatal Group.

Publication status and date: Edited (no change to conclusions), published in Issue 1, 2009.
Review content assessed as up-to-date: 26 March 2002.
Citation: Alcock GS, Liley H. Immunoglobulin infusion for isoimmune haemolytic jaundice in neonates. Cochrane Database of
Systematic Reviews 2002, Issue 3. Art. No.: CD003313. DOI: 10.1002/14651858.CD003313.
ABSTRACT
Background
Exchange transfusion and phototherapy have traditionally been used to treat jaundice and avoid the associated neurological compli-
cations. Exchange transfusion is not without risk and intravenous immunoglobulin has been suggested as an alternative therapy for
isoimmune haemolytic jaundice to reduce the need for exchange transfusion.
Objectives
To assess whether the use of intravenous immunoglobulin, in newborn infants with isoimmune haemolytic jaundice, is effective in
reducing the need for exchange transfusion.
Search strategy
The search strategy of the Cochrane Neonatal Review group was used. Searches were made of MEDLINE 1966-2002, EMBASE Drugs
and Pharmacology 1990-2002, Cochrane Controlled Trials Register, The Cochrane Library, Issue 1, 2002, expert informants, review
articles, cross references, and hand searching of abstracts and conference proceedings of the annual meetings of The Society for Pediatric
Research 1990-2001 and The European Society for Paediatric Research 1990-2001.
Selection criteria
All randomised and quasi-randomised controlled trials of the use of intravenous immunoglobulin in the treatment of isoimmune
haemolytic disease were considered.
Data collection and analysis
The standard methods of the Cochrane Collaboration and its Neonatal Review Group were used. Studies were assessed for inclusion
and quality by two reviewers working independently, with the second reviewer blinded to trial author, institution and journal of
publication. Data were extracted independently by the two reviewers. Any differences of opinion were discussed and a consensus reached.
Investigators were contacted for additional or missing information. For categorical outcomes, the relative risk (RR), risk difference
(RD) and the number needed to treat (NNT) were calculated. For continuous variables, the weighted mean difference (WMD) was
calculated.
Immunoglobulin infusion for isoimmune haemolytic jaundice in neonates (Review) 1
Main results
Seven studies were identified. Three of these fulfilled the inclusion criteria and included a total of 189 infants. Term and preterm
infants and infants with rhesus and ABO incompatibility were included. The use of exchange transfusion decreased significantly in the
immunoglobulin treated group (typical RR 0.28, 95% CI 0.17, 0.47; typical RD -0.37, 95% CI -0.49, -0.26; NNT 2.7). The mean
number of exchange transfusions per infant was also significantly lower in the immunoglobulin treated group (WMD -0.52, 95% CI
-0.70, -0.35). None of the studies assessed long term outcomes.
Authors’ conclusions
Although the results show a significant reduction in the need for exchange transfusion in those treated with intravenous immunoglobulin,
the applicability of the results is limited. The number of studies and infants included is small and none of the three included studies
was of high quality. The protocols of two of the studies mandated the use of early exchange transfusion, limiting the generalizability of
the results. Further well designed studies are needed before routine use of intravenous immunoglobulin can be recommended for the
treatment of isoimmune haemolytic jaundice.
PLAIN LANGUAGE SUMMARY
Immunoglobulin infusion for isoimmune haemolytic jaundice in neonates
Plain language summary will be included with future review update.
BACKGROUND
change transfusion-associated mortality as that occurring within
The use of anti-D prophylaxis in rhesus negative women has led six hours of the procedure. This definition was used by Boggs et
to a marked decline in rhesus sensitisation and haemolytic disease al. but was an arbitrary time limit and does not include deaths
of the newborn. However, anti-D immunoglobulin is a valuable attributable to later complications such as sepsis. Using this defi-
resource and often in short supply world wide. Sensitisation can nition, published mortality rates vary from 0.53-3.3% per infant
occur despite anti-D immunoglobulin, particularly if it is given (Boggs 1960; Panagopoulos 1969; Keenan 1985; Guaran 1992).
too late or in insufficient dose after a large feto-maternal haemor- Death is more common in sick or premature infants and is rare
rhage. Fetal therapy has led to a reduction in the severity of disease when exchange transfusions are performed on healthy term infants
in rhesus sensitised fetuses. In developed countries a high propor- (Boggs 1960; Keenan 1985; Jackson 1997).
tion of significant haemolytic disease of the newborn is caused
by antibodies to antigens other than D and therefore is not pre- Complications of exchange transfusion include haemodynamic
ventable with anti-D immunoglobulin. Exchange transfusion and instability, apnoea, pulmonary haemorrhage, thrombocytopaenia,
phototherapy have traditionally been the primary modes of treat- coagulopathies, hypoglycaemia, hypocalcaemia, electrolyte imbal-
ment for affected newborn infants to reduce both mortality and ance, vasospasm, vascular thromboses, hypertension, arrhythmias,
the risk of kernicterus. The historical aspects of both the antenatal sepsis, necrotizing enterocolitis and bowel perforation. Published
and neonatal management of rhesus disease have been reviewed morbidity rates have been relatively low, varying from 2.8-5.2%
recently by others (Peterec 1995; Liley 1997; Bowman 1998). Re- per procedure. However, in the most recent study published in
cent attention has turned to therapies aimed at reducing the need 1997 (Jackson 1997), looking at exchange transfusions performed
for exchange transfusion. New therapies include haem oxygenase between 1980 and 1995, mortality was 4.7% per infant and 23.5%
inhibitors and intravenous immunoglobulin (IVIg). of infants suffered serious non-fatal complications. Twenty-eight
percent of these complications had prolonged or permanent se-
The safety of exchange transfusion has been reported for over 40 quelae. Although improved obstetric care has led to a reduction
years. Most studies of the safety of exchange transfusion report ex- in the frequency with which exchange transfusions are performed,
the complication rate is likely to increase as neonatal staff become pital stay, simple transfusion requirements, and long term out-
less experienced with the procedure. comes such as hearing loss, kernicterus and cerebral palsy.
IVIg is an alternative therapy which may be effective in treating Sub-group analyses were planned to determine if effects depend
isoimmune haemolytic jaundice. In isoimmune haemolysis red on:
blood cells are probably destroyed by an antibody-dependent cy-
totoxic mechanism mediated by Fc receptor bearing cells of the Population:
neonatal reticuloendothelial system (Urbaniak 1979). The puta-
1. Rhesus incompatibility
tive mechanism of IVIg action is non-specific blockade of Fc recep-
tors. Ergaz et al. (Ergaz 1995) demonstrated a decline in carboxy- 2. ABO incompatibility
haemoglobin levels in four out of five infants treated with IVIg for
isoimmune haemolytic jaundice. Carboxyhaemoglobin levels are 3. All other causes of isoimmune haemolytic jaundice
a sensitive index of haemolysis and hence the study indicated that
4. Gestation (less than 37 weeks or 37 weeks and above)
immunoglobulin could decrease haemolysis. Also Hammerman et
al (Hammerman 1996a) demonstrated a significant reduction in Intervention:
carboxyhaemoglobin levels in 19 of 26 Coombs positive infants
treated with IVIg. 1. Prophylactic
In 1987 the first report was published of the successful treatment 2. Treatment of established jaundice
of late anaemia due to rhesus E incompatibility with IVIg (Hara
3. Single versus multiple doses
1987). Since then case reports and case series have reported success
of IVIg treatment of jaundice due to both rhesus and ABO incom-
patibility (Kubo 1991; Sato 1991; Ergaz 1993). Hammerman et al.
investigated factors associated with successful treatment of jaun- METHODS
dice with IVIg in infants with ABO incompatibility (Hammerman
1996b). Those with early and severe haemolysis showed a reduced
or no response to the therapy.
Criteria for considering studies for this review
It is easy to recognise the potential benefits of IVIg over exchange
transfusion. Administration is less complicated and less labour in-
tensive. As well as being a less invasive therapy, IVIg may also al-
low treatment of some infants in level two centres or avoid de- Types of studies
laying treatment whilst transferring infants to tertiary centres for
All randomised and quasi-randomised controlled trials of in-
exchange transfusion. The use of immunoglobulin in neonates has
travenous immunoglobulin in the treatment of isoimmune
been studied extensively, particularly in the treatment of sepsis,
haemolytic disease.
and has been shown to be safe and well tolerated. It is established
therapy for alloimmune thrombocytopaenia due to PLA1 incom-
patibility. The risk of transmission of viral infection is extremely
low (Fischer 1988). Haemolysis has been reported as an uncom- Types of participants
mon complication (Copelan 1986) as has acute renal failure. One Neonates with isoimmune haemolytic disease.
study showed an increased incidence of sepsis in premature infants
receiving prophylactic IVIg (Magny 1991). However supplies of
IVIg are limited and so its use should be restricted to treatment of Types of interventions
conditions for which it is of proven benefit.
Intravenous immunoglobulin given either prophylactically or for
treatment of established isoimmune haemolytic jaundice, versus
control (placebo or nothing).
OBJECTIVES Prophylactic IVIg has been defined (for this review) as use in in-
fants with evidence of isoimmune haemolysis within the first few
The primary objective was to assess whether the use of intravenous
hours of life, before the bilirubin has been shown to rise. Estab-
immunoglobulin, in newborn infants with isoimmune haemolytic
lished jaundice has been defined as jaundice reaching a predefined
jaundice, is effective in reducing the need for exchange transfusion.
bilirubin level.
The review also assessed complications of therapy, short-term out- Studies should include predefined criteria for both IVIg and trans-
comes such as bilirubin levels, duration of phototherapy and hos- fusion therapy.

Types of outcome measures reached. Investigators were contacted for additional or missing in-
Efficacy: formation if necessary.
Use of exchange transfusion (proportion of infants receiving one For categorical outcomes, such as the incidence of exchange trans-
or more exchange transfusions) fusion, the relative risk and risk difference were calculated. For con-
Exchange transfusions performed per infant tinuous variables, such as the maximum bilirubin level, weighted
Maximum serum bilirubin (micromol/litre) mean differences were calculated. The number needed to treat
Absolute rise of bilirubin in first 24 hours to avoid exchange transfusion was calculated. Ninety-five percent
Absolute rise of bilirubin in first 48 hours confidence intervals were used and a fixed effects model was as-
Percentage change in bilirubin in first 24 hours (%) sumed for the meta-analysis.
Percentage change in bilirubin in first 48 hours (%)
Duration of phototherapy (days)
Duration of hospital stay (days)
Use of simple transfusion in first week of life (%) RESULTS
Use of simple transfusion after 1 week of age (%)
Number of simple transfusions performed after 1 week of age per
infant
Incidence of sensorineural hearing loss (any severity) Description of studies
Incidence of kernicterus See: Characteristics of included studies; Characteristics of excluded
Incidence of cerebral palsy studies; Characteristics of studies awaiting classification.
Safety: The search strategy uncovered seven studies. Three studies have
Neonatal mortality been included in the review (Rubo 1992; Dagoglu 1995; Alpay
Incidence of adverse reactions requiring cessation of therapy or 1999). Details of the studies are given in the table of included
treatment studies. Three studies have been excluded until further informa-
tion is available from the authors (Voto 1995; Silvia 2001; Tanyer
2001). One study contained serious methodological flaws (Rubo
Search methods for identification of studies 1996). Correspondence with an author indicated that no further
The search strategy of the Cochrane Neonatal Review group was information will be available and the study has been excluded.
used. INCLUDED STUDIES
Searches were made of MEDLINE 1966-2002, EMBASE Drugs Population
and Pharmacology 1990-2002, Cochrane Controlled Trials Reg- The three studies which met inclusion criteria included 189 in-
ister, The Cochrane Library, Issue 1, 2002, expert informants, re- fants. Two studies included only infants with Rh incompatibility
view articles, cross references, and hand searching of abstracts and (Rubo 1992; Dagoglu 1995). Alpay et al. predominantly enrolled
conference proceedings of the annual meetings of The Society for infants with ABO incompatibility (n = 93) but also included in-
Pediatric Research (1990-2001) and The European Society for fants with Rh incompatibility (n = 16) and both Rh and ABO
Paediatric Research (1990-2001). Search terms were immunoglob- incompatibility (n = 7), however results were not given for each
ulin or gammaglobulin (textwords) and jaundice, hyperbilirubine- group separately. One study (Alpay 1999) enrolled only term in-
mia, hemolysis (MeSH terms), haemolytic, hemolytic, haemoly- fants > 37 weeks gestation. One study (Dagoglu 1995) included
sis, hyperbilirubinaemia, rhesus or isoimmune (textwords). 29 preterm and 12 term infants but did not define the gestational
No language restrictions applied. cut-off for prematurity. Rubo et al. did not give details of the ges-
tation of enrolled infants.
Intervention
The three studies which met inclusion criteria examined the effect
Data collection and analysis of a single dose of IVIg in combination with phototherapy. The
The standard method of the Cochrane Collaboration and its control groups received phototherapy alone. None of the studies
Neonatal Review Group was used. Studies were assessed for in- described the intensity or topography of phototherapy in detail.
clusion and quality by two reviewers working independently, with Two studies used IVIg in a prophylactic approach (Rubo 1992;
the second reviewer blinded to trial author, institution and jour- Dagoglu 1995) and in one study established jaundice (bilirubin >
nal of publication. Criteria used to assess methodological quality 204 micromol/L) was a necessary criterion for entry (Alpay 1999).
were: blinding of randomisation, blinding of intervention, com- Outcomes
plete follow up and blinding of outcome measurement. Data were All three included studies reported exchange transfusion as the
extracted from included studies independently by the two review- primary outcome and for two studies (Rubo 1992; Dagoglu 1995)
ers. Any differences of opinion were discussed and a consensus we were able to calculate the number of exchange transfusions per

infant and its standard deviation. The maximum bilirubin was both further methodological information and results. We have
reported in two studies (Rubo 1992; Dagoglu 1995). Unpublished to date successfully contacted the authors of three papers (Rubo
data were provided by the authors of the other study (Alpay 1999) 1992; Rubo 1996; Alpay 1999).
on these two outcomes. Although all three studies commented on
the duration of phototherapy in their results, the numerical data
were given in only one study (Alpay 1999). This study also used Risk of bias in included studies
predetermined criteria for commencing and ceasing phototherapy.
The study by Alpay et al was also the only one to report duration See: Table of included studies
of hospitalisation. All three studies included simple transfusion None of the studies were of high quality. All three included studies
as an outcome but as predefined criteria for simple transfusion were RCTs but allocation concealment was adequately described
were provided by only one study (Alpay 1999) the results from in only one study (Dagoglu 1995). The other two studies (Rubo
the other two studies were not included in the analysis. All studies 1992; Alpay 1999) did not describe the method of allocation con-
also reported short-term adverse events. No data were reported for cealment. None of the studies used a placebo in the control group
changes in bilirubin or on neurodevelopmental outcomes. or described any method of blinding of intervention after alloca-
STUDIES AWAITING ASSESSMENT tion. Dagoglu et al. used post randomisation consent. Although
Tanyer 2001 follow-up was complete for all infants in whom consent was ob-
This was not a randomised trial. The methodology did not clearly tained, two infants randomised to each arm of the study were ex-
indicate a quasi-random method, stating only that infants were cluded because consent was withheld. Two infants were also ex-
divided into three groups by “order of admission”. No further cluded post-randomisation in one other study (Rubo 1992) be-
details were given of the allocation method or whether there were cause of “protocol violations” but no details were given. Blinding
infants eligible for the study who were not enrolled. The study of outcome assessment was not mentioned in any study.
compared groups receiving one dose and three doses of IVIg with
control. Further information has been requested from the authors.
Silvia 2001 Effects of interventions
The study has as yet been published in abstract form only.
EXCHANGE TRANSFUSION (Outcomes 1&2)
Voto 1995
The results of all three included studies (Rubo 1992; Dagoglu
This was an RCT comparing a single dose of IVIg with control.
1995; Alpay 1999) could be entered into the meta-analysis. Two
The methods for randomisation and allocation concealment were
studies used a prophylactic approach (Rubo 1992; Dagoglu 1995)
unclear. Forty infants were enrolled but results are given for only
and the other used IVIg to treat established jaundice. Each of the
thirty-seven, with no mention of the other three infants. Results
three trials found a statistically significant reduction in the use
were given for total transfusion therapy and not divided into sim-
of exchange transfusion. The meta-analysis supports a statistically
ple and exchange transfusion. Results for bilirubin levels were pre-
significant reduction in the incidence of exchange transfusion in
sented as graphs rather than tables. The only outcomes that could
the IVIG treated group (typical RR 0.28, 95%CI 0.17, 0.47; typ-
potentially be assessed in the meta-analysis were duration of hos-
ical RD -0.37, 95%CI -0.49, -0.26; NNT 2.7).
pitalisation and phototherapy. Further information has been re-
All three studies included infants with Rh incompatibility and in
quested.
two (Rubo 1992; Dagoglu 1995) there was a statistically significant
EXCLUDED STUDIES
reduction in the use of exchange transfusion. The overall reduction
Rubo 1996
was also significant (typical RR 0.23, 95%CI 0.12, 0.44; typical
This was a multicentre RCT comparing both one dose (group 1)
RD -0.53, 95%CI -0.70, -0.73: NNT 1.9).
and two doses (group 2) of IVIg used in a prophylactic approach,
The study by Alpay et al included infants with only ABO incom-
with control (group 3). The randomisation and allocation con-
patibility and for these infants the reduction in the use of exchange
cealment method was unclear. Seventy-six infants were enrolled.
transfusion was also significant (RR 0.38, 95%CI 0.16, 0.87; RD
Two infants were excluded because of unspecified protocol viola-
-0.22, 95%CI -0.39, -0.05, NNT 4.5).
tions and results were available for 74 infants. However four in-
Statistically significant reductions in the use of exchange transfu-
fants randomised to the control group were given a single dose
sion were also found in the two studies in which a prophylactic
of IVIg because they were perceived to have severe disease. The
approach was used (Rubo 1992; Dagoglu 1995) (typical RR 0.21,
data for these four infants were analysed with those for group 1
95%CI 0.10, 0.45; typical RD -0.59, 95%CI -0.77, -0.40; NNT
rather than on an intention to treat basis. Further information is
1.7) and in the only study which had established jaundice as a
not available. This was the only study to suggest that IVIg was of
necessary criterion of entry (Alpay 1999) (RR 0.36, 95%CI 0.18,
no clinical benefit in reducing the need for exchange transfusion.
0.75; RD -0.24, 95%CI -0.39, -0.09; NNT 4.2).
ADDITIONAL DATA.
Overall, immunoglobulin treatment also led to a reduction in
We have attempted to contact the authors of all studies to request
the mean number of exchange transfusions per infant (WMD -

0.52, 95%CI -0.70, -0.35). The difference was significant in each 23.5 hours, 95%CI -37.7, -9.3) for all infants in the study and for
individual study and for all subgroups except for those infants with the subgroup with ABO incompatibility only (Mean Difference -
ABO incompatibility only (Mean Difference -0.17, 95%CI -0.37, 31.5 hours, 95%CI -49.3, -13.7).
0.03) INCIDENCE OF ADVERSE REACTIONS (Outcome 8)
There were no reported adverse reactions as a consequence of IVIg
SIMPLE TRANSFUSION DURING AND AFTER THE or exchange transfusion in the treatment groups. Three control
FIRST WEEK (Outcomes 3&4) infants receiving exchange transfusion had adverse reactions. One
Alpay et al. provided unpublished data for this outcome. Although infant each developed hypoglycaemia, hypocalcaemia and sepsis.
fewer infants treated with IVIg required simple transfusions during There was no mortality in any study.
the first week (RR 0.71, 95%CI 0.24, 2.21), more required simple OTHER COMPARISONS AND OUTCOMES
transfusions after the first week (RR 11.00, 95%CI 0.62, 194.50). Data were not available to evaluate treatment by gestation or with
However these differences were not statistically significant. The multiple doses of IVIg. We were also unable to examine the effects
number of infants with Rh incompatibility was too small to allow of IVIg on the rate of change of bilirubin or on long term outcomes
any meaningful conclusion. Results were similarly not significant such as the incidence of hearing loss, kernicterus and cerebral palsy.
for those infants with ABO incompatibility only (RR 0.80, 95%CI HETEROGENEITY
0.19, 3.38 and RR 7.46, 95%CI 0.40, 140.45). Statistically significant heterogeneity of treatment effect was de-
MAXIMUM SERUM BILIRUBIN (Outcome 5) tected for two outcomes (02 Exchange transfusions per infant and
Results were available for all three studies (Rubo 1992; Dagoglu 05 Maximum serum bilirubin), when the results of all three in-
1995; Alpay 1999). Although only one individual study showed cluded studies were combined (Comparison 01). The heterogene-
a significant lower maximum serum bilirubin in those receiving ity appears to arise from the results of the study by Alpay et al.
IVIg (Alpay 1999), overall there was a significant difference in
maximum bilirubin levels (WMD -46.6 micromol/L, 95%CI -
68.4, -24.7).
All three studies included infants with Rh incompatibility. Only DISCUSSION

one (Alpay 1999) found a significant reduction in maximum Seven trials were identified which studied the effects of IVIg in
serum bilirubin for this subgroup and the overall reduction was neonatal isoimmune haemolysis. Only three trials, encompassing
not significant (WMD -26.0 micromol/L, 95%CI -58.7, 6.7). a total of 189 infants, fulfilled inclusion criteria for the review.
For the subgroup of infants with ABO incompatibility only (Alpay Analysis of the data available provides some evidence to support
1999), maximum serum bilirubin was lower in those treated with the use of IVIg in isoimmune haemolysis. The trials showed a sta-
IVIg (Mean Difference -60.6 micromol/L, 95%CI -83.2, -38.0). tistically significant reduction in both the incidence of exchange
In the two studies using a prophylactic approach (Rubo 1992; transfusion and the mean number of exchange transfusions re-
Dagoglu 1995) both the individual studies and the combined anal- quired per infant in those treated with a combination of IVIg
ysis failed to detect a difference (WMD -3.8 micromol/L, 95%CI and phototherapy, compared to infants treated with phototherapy
-46.0, 38.4). alone. All the trials used predefined criteria for exchange transfu-
One study examined the effects of IVIg in infants with established sion. Overall, immunoglobulin treatment was associated with a
jaundice (Alpay 1999). Maximum bilirubin levels were signifi- significantly lower maximum bilirubin level although this finding
cantly lower in those infants receiving IVIg (Mean Difference - was not consistent across all subgroups.
62.2 micromol/L, 95%CI -87.7, -36.7)
DURATION OF PHOTOTHERAPY (Outcome 6) The data on other markers of effect such the durations of pho-
Although criteria for commencing phototherapy were given in all totherapy and hospitalisation were reported in only some of the
three studies, only two (Rubo 1992; Alpay 1999) used predeter- three studies. When reported, there was either no difference or an
mined criteria for ceasing phototherapy. Rubo et al. stated that no improvement suggesting that IVIg is, at the least, no worse than
significant difference existed in the duration of phototherapy but conventional treatment.
data were not given. In the other study duration of phototherapy
Despite these positive findings, the conclusions that can be drawn
was significantly lower in the IVIg treated infants (Mean Differ-
from the review are limited. None of the trials fulfilled criteria for a
ence -22.4 hours, 95%CI -34.8, -9.9) with an almost identical re-
high quality study and the review included only three trials and 189
sult for those infants with ABO incompatibility only (Mean Dif-
infants. An adequate randomisation and allocation concealment
ference -22.8 hours, 95%CI -38.0, -7.7).
method was described for only one study. None of the studies
DURATION OF HOSPITALISATION (Outcome 7)
used blinding of the intervention, nor described blinding of the
Alpay et al, who were the only investigators to measure duration
outcome assessors. In two trials eligible infants were excluded after
of hospital stay, found a significant decrease (Mean Difference -
randomisation.

The incidence of late transfusion is an important outcome, es- Implications for practice
pecially in areas with a limited supply of safe blood for transfu-
Although the review supports an effect of IVIg in the treatment
sion. However, as thresholds for simple transfusion in neonates
of isoimmune haemolytic jaundice, the evidence is limited by the
vary widely, this outcome is susceptible to bias, particularly in an
small size and weak design of the studies. The role of IVIg remains
unblinded study. Although all the studies reported the incidence
uncertain, particularly in hospitals that do not use early rate of
of simple transfusion only one provided (unpublished) predefined
rise of bilirubin as an indicator for exchange transfusion. Since
criteria, thus limiting the conclusions that could be drawn for this
it appears safe, it may have a role in special circumstances such
outcome.
as parental refusal for exchange transfusion, or where appropri-
Although phototherapy and exchange transfusion are widely used ate blood components for exchange transfusion are unavailable.
in the management of isoimmune haemolytic jaundice, there is no However, routine use of IVIg for the treatment of isoimmune
standard or evidence basis for the thresholds for each intervention. haemolytic jaundice cannot yet be recommended.
The safe upper limit of bilirubin level is unclear, as is whether
bilirubin level alone is a sufficient predictor of the need for ex- Implications for research
change transfusion or of neurodevelopmental outcome (Ahlfors
1994). Many practitioners now use intensive phototherapy and de- Future research into the role of IVIg in the treatment of isoim-
fer exchange transfusion until the serum bilirubin has risen above mune haemolytic jaundice is warranted. Such a trial should exam-
high thresholds, others appear to still use early rate of rise of biliru- ine the safety and efficacy of IVIg by recording both short term
bin as an indicator for exchange transfusion. The approach used outcomes such as the need for transfusion therapy and the inci-
could affect the apparent effectiveness of IVIg, particularly if IVIg dence of adverse events and also long term neurodevelopmental
were better at slowing the rate of rise of bilirubin than reducing outcomes. Consideration should also be given to including addi-
the ultimate peak. The three studies in this review all used dif- tional measures to assess the severity of haemolysis such as car-
ferent criteria for performing an exchange transfusion and none boxyhaemoglobin or end tidal carbon monoxide. In view of the
described their method of phototherapy in detail. The criteria for declining incidence and severity of isoimmune haemolytic disease,
exchange transfusion in two of the studies (Rubo 1992Rubo 1992, and the reduction in the use of exchange transfusion, the use of
Dagoglu 1995) mandated the use of early transfusion, with 69% IVIg to treat established jaundice will probably require a multi-
and 79% of control infants respectively receiving exchange trans- centre randomised controlled trial, incorporating either a placebo
fusion. These clinical differences are also reflected in the statisti- or blinding of outcome assessment. Future trials should be well
cally significant heterogeneity of treatment effect found for two planned and give priority to establishing guidelines for the “con-
outcomes (02 Exchange transfusions per infant and 05 Maximum ventional” management of isoimmune haemolytic jaundice, fo-
serum bilirubin), when the results of all three included studies cussing on the criteria for performing both simple and exchange
were combined. transfusions and on the role of intensive phototherapy.
Although data on the short-term efficacy and safety of IVIg were

reported in all the studies, none examined long term safety issues
such as audiological or neurodevelopmental outcome.
ACKNOWLEDGEMENTS
AUTHORS’ CONCLUSIONS The Centre for Clinical Studies, Mater Mothers’ Hospital.
REFERENCES
References to studies included in this review Rubo 1992 {published data only}
Rubo J, Albrecht K, Lasch P, Lauftkotter E, Leititis J, Marsan D, et
al.High-dose intravenous immune globulin therapy for
Alpay 1999 {published and unpublished data}
hyperbilirubinaemia caused by Rh hemolytic disease. Journal of
Alpay F, Sarici SU, Okutan V, Erdem G, Ozcan O, Gokcay E.
Pediatrics 1992;121:93–7.
High-dose intravenous immunoglobulin therapy in neonatal
immune haemolytic jaundice. Acta Paediatrica 1999:216–9. References to studies excluded from this review
Dagoglu 1995 {published data only} Rubo 1996 {published data only}
Dagoglu T, Ovali F, Samanci N, Bengisu E. High-dose intravenous Rubo J, Wahn V, Studiengruppe Rhesusinkompatabilitat. Influence
immunoglobulin therapy for rhesus haemolytic disease. Journal of of high dose immuno-globulin therapy on hyperbilirubinemia in
International Medical Research 1995;23:264–71. rhesus-hemolytic disease. A cooperative study. [Kooperative studie
zum einfluss einer hochdosierten immunglobulintherapie auf die Hammerman 1996a
hyperbilirubinamie bei rhesusinkompatibilitat]. Monatsschr Hammerman C, Vreman HJ, Kaplan M, Stevenson DK.
Kinderheilkd 1996;144:516–9. Intravenous immune globulin in neonatal immune hemolytic
disease: Does it reduce hemolysis?. Acta Paediatr 1996;85:1351–3.
References to studies awaiting assessment
Hammerman 1996b
Hammerman C, Kaplan M, Vreman HJ, Stevenson DK.
Silvia 2001 {published data only} Intravenous immune globulin in neonatal isoimmunization: factors
Silvia L, Spinelli I, Lydia E, Otheguy I, Miguel A, Larguia I. associated with clinical efficacy. Biol Neonate 1996;70:69–74.
Postnatal use of high-dose intravenous immunoglobulin therapy in
Hara 1987
rhesus hemolytic disease treatment. Journal of Perinatal Medicine
Hara T, Mizuno Y, Kawano M, Ueki Y, Ueda K. Treatment of
2001;29 Suppl 1:683.
immune hemolytic anaemia with gammaglobulin. J Pediatr 1987;
Tanyer 2001 {published data only} 110:817–8.
Tanyer G, Siklar Z, Dallar Y, Yildirmak Y, Tiras U. Multiple dose Jackson 1997
IVIG treatment in neonatal immune hemolytic jaundice. Journal of Jackson JC. Adverse events associated with exchange transfusion in
Tropical Pediatrics 2001;47:50–3. healthy and ill newborns. Pediatrics 1997;99:E7.
Voto 1995 {published data only} Keenan 1985
Voto L, Sexer H, Ferreiro G, Tavosnanska J, Orti J, Mathet E, et Keenan WJ, Novak KK, Sutherland JM, Bryla DA, Fetterly KL.
al.Neonatal administration of high dose intravenous Morbidity and mortality associated with exchange transfusion.
immunoglobulin in rhesus hemolytic disease.. Journal of Perinatal Pediatrics 1985;75(suppl):422–6.
Medicine 1995;23:443–51.
Kubo 1991
Additional references Kubo S, Ariga T, Tsuneta H, Ishii T. Can high-dose
immunoglobulin therapy be indicated in neonatal rhesus
Boggs 1960 haemolysis?A successful case of haemolytic disease due to rhesus
Boggs TR, Westphal MC Jr. Mortality of exchange transfusion. (c+E) incompatibility. Eur J Pediatr 1991;150:507–8.
Pediatrics 1960;26:745–55. Liley 1997
Bowman 1998 Liley HG. Rescue in inner space: management of Rh hemolytic
Bowman JM. RhD hemolytic disease of the newborn. New England disease. J Pediatr 1997;131:340–342.
Journal of Medicine 1998;339:1775–7. Magny 1991
Magny JF, Bremard-Oury C, Brault D, Menguy C, Voyer M,
Copelan 1986
Landais P, et al.Intravenous immunoglobulin therapy for
Copelan EA, Strohm PL, Kennedy MS, Tutschka PJ. Hemolysis
prevention of infection in high-risk premature infants: report of a
following intravenous immune globulin therapy. Transfusion 1986;
multicenter, double blind study. Pediatrics 1991;88:437–443.
26:410–12.
Panagopoulos 1969
Ergaz 1993
Panagopoulos G, Valaes T, Doxiadis SA. Morbidity and mortality
Ergaz Z, Arad I. Intravenous immunoglobulin therapy in neonatal
related to exchange transfusion. J Pediatr 1969;74:247–54.
immune hemolytic jaundice. Journal of Perinatal Medicine 1993;
21:183–7. Peterec 1995
Peterec SM. Management of neonatal Rh disease. Clin Perinatol
Ergaz 1995
1995;22:561–593.
Ergaz Z, Gross D, Bar-Oz B, Peleg O, Arad I. Carboxyhemoglobin
levels in neonatal immune hemolytic jaundice treated with Sato 1991
intravenous gammaglobulin. Vox Sang 1995;69:95–9. Sato K, Hara T, Kondo T, Iwoa H, Honda S, Ueda K. High-dose
intravenous gammaglobulin therapy for neonatal immune
Fischer 1988 haemolytic jaundice due to blood group incompatability. Acta
Fischer GW. Therapeutic uses of intravenous gammaglobulin for Paediatr Scand 1991;80:163–6.
pediatric infections. Pediatr Clin North Am 1988;35:517–33.
Urbaniak 1979
Guaran 1992 Urbaniak SJ. ADCC (K-cell) lysis of human erythrocytes sensitized
Guaran RL, Drew JH, Watkins AM. Jaundice: Clinical practice in with rhesus alloantibodies. II. Investigation into the mechanism of
88,000 liveborn infants. Aust NZ J Obstet Gynaecol 1992;32: lysis. Br J Haematol 1979;42:315–25.
186–92. ∗
Indicates the major publication for the study

CHARACTERISTICS OF STUDIES
Characteristics of included studies [ordered by study ID]
Alpay 1999
Methods RCT
Blinding of randomisation: Unclear
Blinding of intervention: No
Complete follow-up: Yes
Blinding of outcome: Unclear
Participants 116 newborn term infants. ABO and/or Rh incompatability. SBR > 204 micromol/l, positive direct
Coombs test and reticulocyte count > 10%.
Interventions Treatment of established jaundice (qualifying SBR>204 micromol/L)

Treatment group: Single doses IVIg 1g/kg (ISIVEN) plus phototherapy. (n = 58)
Contol group:
Phototherapy only. (n = 58)
Outcomes Exchange transfusion, duration of phototherapy, duration of hospitalisation, simple transfusions, maxi-
mum SBR and adverse events. Criteria for exchange transfusion:
SBR > 290 micromol/L and increased by > 17 micromol/L/ hour.
Criteria for
phototherapy : Tables from Avery GB, Neonatology: 1994.
Notes Unpublished data and information supplied.
Risk of bias
Item Authors’ judgement Description
Allocation concealment? Unclear B - Unclear
Dagoglu 1995
Methods RCT
Blinding of randomisation: Yes
Complete follow-up: Yes
Participants 45 term and preterm infants with Rh incompatability.

Rh +ve infant, Rh -ve mother and +ve direct Coombs test.
Interventions Prophylactic approach.

Treatment group: Single doses IVIg 500mg/kg (Sandoglobulin)as soon as possible after birth (most within
2 hours) plus phototherapy.
(n = 22)

Dagoglu 1995 (Continued)
Control group: Phototherapy alone. (n = 19)
Outcomes Exchange transfusion, maximun SBR, duration of phototherapy, simple transfusion and adverse events.
Criteria for exchange transfusion: SBR increase by > 17 micromol/L/hour or SBR > 340 micromol/L in
term infants (or if SBR > 306 micromol/L if weight > 2000g).
Criteria for commencing phototherapy: (Incorrect reference given)
Notes 45 infants eligible. Post-randomisation consent with consent withheld for 2 infants in each group. Further
information requested.
Risk of bias
Allocation concealment? Yes A - Adequate
Rubo 1992
Methods RCT
Blinding of randomisation: Unclear
Complete follow-up: No
Participants 34 newborn infants. Rhesus incompatability. Rh -ve infant, Rh +ve mother and +ve direct Coombs test.
Interventions Prophylactic approach.

Treatment group: Single doses IVIg 500mg/kg (Polyglobulin N) as soon as Rh status confirmed, plus
phototherapy. (n = 17)
Control group:
Phototherapy alone. (n = 17)
Outcomes Exchange transfusion, maximum SBR, duration of phototherapy, simple transfusions and adverse events.
Criteria for exchange transfusion: SBR 34 micromol/L > modified curve of Polacek.
Criteria for phototherapy: SBR 68 micromol/ L < modified curve of Polacek.
Notes Two infants were excluded post randomisation because of unspecified “protocol violatios”. Authors con-
tacted. No further information available.
Risk of bias
Allocation concealment? Unclear B - Unclear

Characteristics of excluded studies [ordered by study ID]
Rubo 1996 The randomisation and allocation concealment method was unclear. Seventy-six infants were enrolled. Two infants
were excluded because of unspecified protocol violations and results were available for seventy-four infants. However
four infants randomised to the control group were given a single dose of IVIg because they were perceived to have
severe disease. The data for these four infants were analysed with those for group 1 rather than on an intention to treat
basis. Further information is not available.
Characteristics of studies awaiting assessment [ordered by study ID]
Silvia 2001
Methods Not known
Participants Not known
Interventions Not known
Outcomes Not known
Notes
Tanyer 2001
Methods Not known
Outcomes Not known
Notes
Voto 1995
Methods Not known
Outcomes Not known

Voto 1995 (Continued)
Notes

DATA AND ANALYSES
Comparison 1. IVIg plus phototherapy vs phototherapy
No. of No. of
Outcome or subgroup title studies participants Statistical method Effect size
1 Use of exchange transfusion (one 3 189 Risk Ratio (M-H, Fixed, 95% CI) 0.28 [0.17, 0.47]
or more)
2 Exchange transfusions per infant 3 189 Mean Difference (IV, Fixed, 95% CI) -0.52 [-0.70, -0.35]
3 Use of simple transfusion in 1st 1 116 Risk Ratio (M-H, Fixed, 95% CI) 0.71 [0.24, 2.12]
week
4 Use of simple transfusion after 1 116 Risk Ratio (M-H, Fixed, 95% CI) 11.0 [0.62, 194.49]
1st week
5 Maximum serum bilirubin 3 189 Mean Difference (IV, Fixed, 95% CI) -46.55 [-68.39, -
(micromol/L) 24.71]
6 Duration of phototherapy 1 116 Mean Difference (IV, Fixed, 95% CI) -22.37 [-34.83, -
(hours) 9.91]
7 Duration of hospitalisation 1 116 Mean Difference (IV, Fixed, 95% CI) -23.48 [-37.71, -
(hours) 9.25]
8 Incidence of adverse reaction 3 189 Risk Ratio (M-H, Fixed, 95% CI) 0.25 [0.03, 2.17]
Comparison 2. IVIg plus phototherapy vs phototherapy. Rh incompatibility
No. of No. of
or more)
3 Use simple transfusion in 1st 1 23 Risk Ratio (M-H, Fixed, 95% CI) 0.51 [0.10, 2.51]
week
1st week
5 Maximum serum bilirubin 3 96 Mean Difference (IV, Fixed, 95% CI) -25.98 [-58.69,
(micromol/L) 6.73]
6 Duration of phototherapy 1 23 Mean Difference (IV, Fixed, 95% CI) -10.32 [-37.78,
(hours) 17.14]
7 Duration of hospitalisation 1 23 Mean Difference (IV, Fixed, 95% CI) -20.22 [-48.17,
(hours) 7.73]

Comparison 3. IVIg plus phototherapy vs phototherapy. ABO incompatibility only
No. of No. of
or more)
2 Exchange transfusions per infant 1 93 Mean Difference (IV, Fixed, 95% CI) -0.17 [-0.37, 0.03]
week
1st week
(micromol/L) 37.95]
(hours) 7.69]
(hours) 13.72]
Comparison 4. IVIg plus phototherapy vs phototherapy. Prophylaxis
No. of No. of
or more)
5 Maximum serum bilirubin 2 73 Mean Difference (IV, Fixed, 95% CI) -3.83 [-46.01,
(micromol/L) 38.35]
Comparison 5. IVIg plus phototherapy vs phototherapy. Established jaundice
No. of No. of
or more)
week
1st week
(micromol/L) 36.67]
(hours) 9.91]
(hours) 9.25]
Analysis 1.1. Comparison 1 IVIg plus phototherapy vs phototherapy, Outcome 1 Use of exchange
transfusion (one or more).
Review: Immunoglobulin infusion for isoimmune haemolytic jaundice in neonates
Comparison: 1 IVIg plus phototherapy vs phototherapy
Outcome: 1 Use of exchange transfusion (one or more)
Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI
Alpay 1999 8/58 22/58 44.8 % 0.36 [ 0.18, 0.75 ]
Dagoglu 1995 4/22 15/19 32.8 % 0.23 [ 0.09, 0.58 ]
Rubo 1992 2/16 11/16 22.4 % 0.18 [ 0.05, 0.69 ]
Total (95% CI) 96 93 100.0 % 0.28 [ 0.17, 0.47 ]

Total events: 14 (Treatment), 48 (Control)
Heterogeneity: Chi2 = 1.08, df = 2 (P = 0.58); I2 =0.0%
Test for overall effect: Z = 4.82 (P < 0.00001)
0.05 0.2 1 5 20
Favours treatment Favours control

Analysis 1.2. Comparison 1 IVIg plus phototherapy vs phototherapy, Outcome 2 Exchange transfusions per
infant.
Outcome: 2 Exchange transfusions per infant
Study or subgroup Treatment Control Mean Difference Weight Mean Difference

N Mean(SD) N Mean(SD) IV,Fixed,95% CI IV,Fixed,95% CI
Alpay 1999 58 0.19 (0.51) 58 0.5 (0.68) 63.5 % -0.31 [ -0.53, -0.09 ]
Dagoglu 1995 22 0.18 (0.39) 19 1.05 (0.71) 23.6 % -0.87 [ -1.23, -0.51 ]
Rubo 1992 16 0.13 (0.34) 16 1.06 (0.93) 12.9 % -0.93 [ -1.42, -0.44 ]
Total (95% CI) 96 93 100.0 % -0.52 [ -0.70, -0.35 ]

Heterogeneity: Chi2 = 9.95, df = 2 (P = 0.01); I2 =80%
-1 -0.5 0 0.5 1
Analysis 1.3. Comparison 1 IVIg plus phototherapy vs phototherapy, Outcome 3 Use of simple transfusion
in 1st week.
Outcome: 3 Use of simple transfusion in 1st week

Alpay 1999 5/58 7/58 100.0 % 0.71 [ 0.24, 2.12 ]
Total (95% CI) 58 58 100.0 % 0.71 [ 0.24, 2.12 ]

Heterogeneity: not applicable
Test for overall effect: Z = 0.61 (P = 0.54)
0.2 0.5 1 2 5

Analysis 1.4. Comparison 1 IVIg plus phototherapy vs phototherapy, Outcome 4 Use of simple transfusion
after 1st week.
Outcome: 4 Use of simple transfusion after 1st week

Alpay 1999 5/58 0/58 100.0 % 11.00 [ 0.62, 194.49 ]
Total (95% CI) 58 58 100.0 % 11.00 [ 0.62, 194.49 ]

0.001 0.01 0.1 1 10 100 1000

Analysis 1.5. Comparison 1 IVIg plus phototherapy vs phototherapy, Outcome 5 Maximum serum bilirubin
(micromol/L).
Outcome: 5 Maximum serum bilirubin (micromol/L)

Alpay 1999 58 350.5 (63.4) 58 412.7 (76.3) 73.2 % -62.20 [ -87.73, -36.67 ]
Dagoglu 1995 22 198.4 (106) 19 224 (99.2) 12.1 % -25.60 [ -88.46, 37.26 ]
Rubo 1992 16 254 (86) 16 240 (78) 14.7 % 14.00 [ -42.89, 70.89 ]
Total (95% CI) 96 93 100.0 % -46.55 [ -68.39, -24.71 ]

-100 -50 0 50 100


Analysis 1.6. Comparison 1 IVIg plus phototherapy vs phototherapy, Outcome 6 Duration of phototherapy
(hours).
Outcome: 6 Duration of phototherapy (hours)

Alpay 1999 58 84.53 (28.93) 58 106.9 (38.84) 100.0 % -22.37 [ -34.83, -9.91 ]
Total (95% CI) 58 58 100.0 % -22.37 [ -34.83, -9.91 ]

-20 -10 0 10 20
Analysis 1.7. Comparison 1 IVIg plus phototherapy vs phototherapy, Outcome 7 Duration of hospitalisation
(hours).
Outcome: 7 Duration of hospitalisation (hours)

Alpay 1999 58 108.55 (34.27) 58 132.03 (43.41) 100.0 % -23.48 [ -37.71, -9.25 ]
Total (95% CI) 58 58 100.0 % -23.48 [ -37.71, -9.25 ]

-20 -10 0 10 20

Analysis 1.8. Comparison 1 IVIg plus phototherapy vs phototherapy, Outcome 8 Incidence of adverse
reaction.
Outcome: 8 Incidence of adverse reaction
Study or subgroup Treatment Control Risk Ratio Risk Ratio

Alpay 1999 0/58 2/58 0.20 [ 0.01, 4.08 ]
Dagoglu 1995 0/22 0/19 0.0 [ 0.0, 0.0 ]
Rubo 1992 0/16 1/16 0.33 [ 0.01, 7.62 ]
Total (95% CI) 96 93 0.25 [ 0.03, 2.17 ]

0.01 0.1 1 10 100

Analysis 2.1. Comparison 2 IVIg plus phototherapy vs phototherapy. Rh incompatibility, Outcome 1 Use of
exchange transfusion (one or more).
Comparison: 2 IVIg plus phototherapy vs phototherapy. Rh incompatibility

Alpay 1999 2/13 5/10 17.3 % 0.31 [ 0.07, 1.27 ]
Dagoglu 1995 4/22 15/19 49.2 % 0.23 [ 0.09, 0.58 ]
Rubo 1992 2/16 11/16 33.6 % 0.18 [ 0.05, 0.69 ]
Total (95% CI) 51 45 100.0 % 0.23 [ 0.12, 0.44 ]

0.01 0.1 1 10 100


Analysis 2.2. Comparison 2 IVIg plus phototherapy vs phototherapy. Rh incompatibility, Outcome 2
Exchange transfusions per infant.

Alpay 1999 13 0.23 (0.59) 10 1.2 (1.03) 14.0 % -0.97 [ -1.68, -0.26 ]
Dagoglu 1995 22 0.18 (0.39) 19 1.05 (0.71) 55.6 % -0.87 [ -1.23, -0.51 ]
Rubo 1992 16 0.13 (0.34) 16 1.06 (0.93) 30.4 % -0.93 [ -1.42, -0.44 ]
Total (95% CI) 51 45 100.0 % -0.90 [ -1.17, -0.63 ]

-4 -2 0 2 4
Analysis 2.3. Comparison 2 IVIg plus phototherapy vs phototherapy. Rh incompatibility, Outcome 3 Use
simple transfusion in 1st week.
Outcome: 3 Use simple transfusion in 1st week

Alpay 1999 2/13 3/10 100.0 % 0.51 [ 0.10, 2.51 ]
Total (95% CI) 13 10 100.0 % 0.51 [ 0.10, 2.51 ]

0.01 0.1 1 10 100


Analysis 2.4. Comparison 2 IVIg plus phototherapy vs phototherapy. Rh incompatibility, Outcome 4 Use of
simple transfusion after 1st week.

Alpay 1999 2/13 0/10 100.0 % 3.93 [ 0.21, 73.71 ]
Total (95% CI) 13 10 100.0 % 3.93 [ 0.21, 73.71 ]

0.001 0.01 0.1 1 10 100 1000


Maximum serum bilirubin (micromol/L).

Alpay 1999 13 348.1 (68.3) 10 407.5 (58.3) 39.9 % -59.40 [ -111.21, -7.59 ]
Dagoglu 1995 22 198.4 (106) 19 224 (99.2) 27.1 % -25.60 [ -88.46, 37.26 ]
Rubo 1992 16 254 (86) 16 240 (78) 33.1 % 14.00 [ -42.89, 70.89 ]
Total (95% CI) 51 45 100.0 % -25.98 [ -58.69, 6.73 ]

-100 -50 0 50 100


Duration of phototherapy (hours).

Alpay 1999 13 78.83 (30.26) 10 89.15 (35.47) 100.0 % -10.32 [ -37.78, 17.14 ]
Total (95% CI) 13 10 100.0 % -10.32 [ -37.78, 17.14 ]

-100 -50 0 50 100


Duration of hospitalisation (hours).

Alpay 1999 13 100.23 (29.07) 10 120.45 (37.19) 100.0 % -20.22 [ -48.17, 7.73 ]
Total (95% CI) 13 10 100.0 % -20.22 [ -48.17, 7.73 ]

-100 -50 0 50 100


Analysis 3.1. Comparison 3 IVIg plus phototherapy vs phototherapy. ABO incompatibility only, Outcome 1
Use of exchange transfusion (one or more).
Comparison: 3 IVIg plus phototherapy vs phototherapy. ABO incompatibility only

Alpay 1999 6/45 17/48 100.0 % 0.38 [ 0.16, 0.87 ]
Total (95% CI) 45 48 100.0 % 0.38 [ 0.16, 0.87 ]

0.01 0.1 1 10 100


Alpay 1999 45 0.18 (0.49) 48 0.35 (0.48) 100.0 % -0.17 [ -0.37, 0.03 ]
Total (95% CI) 45 48 100.0 % -0.17 [ -0.37, 0.03 ]

-1 -0.5 0 0.5 1

Use of simple transfusion in 1st week.

Alpay 1999 3/45 4/48 100.0 % 0.80 [ 0.19, 3.38 ]
Total (95% CI) 45 48 100.0 % 0.80 [ 0.19, 3.38 ]

0.01 0.1 1 10 100

Use of simple transfusion after 1st week.

Alpay 1999 3/45 0/48 100.0 % 7.46 [ 0.40, 140.45 ]
Total (95% CI) 45 48 100.0 % 7.46 [ 0.40, 140.45 ]

0.001 0.01 0.1 1 10 100 1000



Alpay 1999 45 354.72 (55.92) 48 415.3 (55.37) 100.0 % -60.58 [ -83.21, -37.95 ]
Total (95% CI) 45 48 100.0 % -60.58 [ -83.21, -37.95 ]

-100 -50 0 50 100


Alpay 1999 45 89.76 (26.2) 48 112.6 (46.2) 100.0 % -22.84 [ -37.99, -7.69 ]
Total (95% CI) 45 48 100.0 % -22.84 [ -37.99, -7.69 ]

-100 -50 0 50 100



Alpay 1999 45 112.37 (38.14) 48 143.88 (49.03) 100.0 % -31.51 [ -49.30, -13.72 ]
Total (95% CI) 45 48 100.0 % -31.51 [ -49.30, -13.72 ]

-100 -50 0 50 100

Analysis 4.1. Comparison 4 IVIg plus phototherapy vs phototherapy. Prophylaxis, Outcome 1 Use of
exchange transfusion (one or more).
Comparison: 4 IVIg plus phototherapy vs phototherapy. Prophylaxis

Dagoglu 1995 4/22 15/19 59.4 % 0.23 [ 0.09, 0.58 ]
Rubo 1992 2/16 11/16 40.6 % 0.18 [ 0.05, 0.69 ]
Total (95% CI) 38 35 100.0 % 0.21 [ 0.10, 0.45 ]

0.01 0.1 1 10 100


Analysis 4.2. Comparison 4 IVIg plus phototherapy vs phototherapy. Prophylaxis, Outcome 2 Exchange
transfusions per infant.

Dagoglu 1995 22 0.18 (0.39) 19 1.05 (0.71) 64.7 % -0.87 [ -1.23, -0.51 ]
Rubo 1992 16 0.13 (0.34) 16 1.06 (0.93) 35.3 % -0.93 [ -1.42, -0.44 ]
Total (95% CI) 38 35 100.0 % -0.89 [ -1.18, -0.60 ]

-4 -2 0 2 4
Analysis 4.5. Comparison 4 IVIg plus phototherapy vs phototherapy. Prophylaxis, Outcome 5 Maximum
serum bilirubin (micromol/L).

Dagoglu 1995 22 198.4 (106) 19 224 (99.2) 45.0 % -25.60 [ -88.46, 37.26 ]
Rubo 1992 16 254 (86) 16 240 (78) 55.0 % 14.00 [ -42.89, 70.89 ]
Total (95% CI) 38 35 100.0 % -3.83 [ -46.01, 38.35 ]

-100 -50 0 50 100


Analysis 5.1. Comparison 5 IVIg plus phototherapy vs phototherapy. Established jaundice, Outcome 1 Use
of exchange transfusion (one or more).
Comparison: 5 IVIg plus phototherapy vs phototherapy. Established jaundice

Alpay 1999 8/58 22/58 100.0 % 0.36 [ 0.18, 0.75 ]
Total (95% CI) 58 58 100.0 % 0.36 [ 0.18, 0.75 ]

0.01 0.1 1 10 100

Analysis 5.2. Comparison 5 IVIg plus phototherapy vs phototherapy. Established jaundice, Outcome 2

Alpay 1999 58 0.19 (0.51) 58 0.5 (0.68) 100.0 % -0.31 [ -0.53, -0.09 ]
Total (95% CI) 58 58 100.0 % -0.31 [ -0.53, -0.09 ]

-1 -0.5 0 0.5 1

of simple transfusion in 1st week.

Alpay 1999 5/58 7/58 100.0 % 0.71 [ 0.24, 2.12 ]
Total (95% CI) 58 58 100.0 % 0.71 [ 0.24, 2.12 ]

0.01 0.1 1 10 100

of simple transfusion after 1st week.

Alpay 1999 5/58 0/58 100.0 % 11.00 [ 0.62, 194.49 ]
Total (95% CI) 58 58 100.0 % 11.00 [ 0.62, 194.49 ]

0.001 0.01 0.1 1 10 100 1000



Alpay 1999 58 350.5 (63.4) 58 412.7 (76.3) 100.0 % -62.20 [ -87.73, -36.67 ]
Total (95% CI) 58 58 100.0 % -62.20 [ -87.73, -36.67 ]

-100 -50 0 50 100


Alpay 1999 58 84.53 (28.93) 58 106.9 (38.84) 100.0 % -22.37 [ -34.83, -9.91 ]
Total (95% CI) 58 58 100.0 % -22.37 [ -34.83, -9.91 ]

-100 -50 0 50 100



Alpay 1999 58 108.55 (34.27) 58 132.03 (43.41) 100.0 % -23.48 [ -37.71, -9.25 ]
Total (95% CI) 58 58 100.0 % -23.48 [ -37.71, -9.25 ]

-100 -50 0 50 100

WHAT’S NEW
Last assessed as up-to-date: 26 March 2002.
21 October 2008 Amended Converted to new review format.
HISTORY
Protocol first published: Issue 4, 2001
Review first published: Issue 3, 2002
27 March 2002 New citation required and conclusions have changed Substantive amendment
CONTRIBUTIONS OF AUTHORS
Gary Alcock is the primary reviewer and wrote the text of the protocol and review. He also performed the literature search, assessed study
methodology, extracted relevant data from included studies and contacted authors for any additional information required. Helen Liley
is the co-reviewer and assisted in writing the protocol and review. She also independently assessed study methodology and extracted
data from those studies included.

DECLARATIONS OF INTEREST
None
SOURCES OF SUPPORT
Internal sources
• Centre for Clinical Studies, Mater Mothers’ Hospital, Brisbane, Australia.

• JP Kelly Mater Research Foundation, Mater Public Hospitals, Brisbane, Australia.
External sources
• No sources of support supplied
INDEX TERMS
Medical Subject Headings (MeSH)

∗ Immunoglobulins, Intravenous; Anemia, Hemolytic [immunology; ∗ therapy]; Anemia, Neonatal [immunology; ∗ therapy]; Infant,
Newborn; Jaundice, Neonatal [immunology; ∗ therapy]; Randomized Controlled Trials as Topic
MeSH check words

Humans


2002-Immunoglobulin Infusion For Isoimmune Haemolytic Jaundice in Neonates.

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2002-Immunoglobulin Infusion For Isoimmune Haemolytic Jaundice in Neonates.

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Immunoglobulin infusion for isoimmune haemolytic jaundice

Alcock GS, Liley H

Immunoglobulin infusion for isoimmune haemolytic jaundice in neonates (Review)

Immunoglobulin infusion for isoimmune haemolytic jaundice in neonates (Review) ii

Immunoglobulin infusion for isoimmune haemolytic jaundice

Gary S Alcock1 , Helen Liley2

Editorial group: Cochrane Neonatal Group.

Data collection and analysis

PLAIN LANGUAGE SUMMARY

Immunoglobulin infusion for isoimmune haemolytic jaundice in neonates

Plain language summary will be included with future review update.

Immunoglobulin infusion for isoimmune haemolytic jaundice in neonates (Review) 3

Immunoglobulin infusion for isoimmune haemolytic jaundice in neonates (Review) 4

Immunoglobulin infusion for isoimmune haemolytic jaundice in neonates (Review) 5

All three studies included infants with Rh incompatibility. Only DISCUSSION

Immunoglobulin infusion for isoimmune haemolytic jaundice in neonates (Review) 6

Although data on the short-term efficacy and safety of IVIg were

Immunoglobulin infusion for isoimmune haemolytic jaundice in neonates (Review) 8

Characteristics of included studies [ordered by study ID]

Interventions Treatment of established jaundice (qualifying SBR>204 micromol/L)

Notes Unpublished data and information supplied.

Item Authors’ judgement Description

Allocation concealment? Unclear B - Unclear

Participants 45 term and preterm infants with Rh incompatability.

Interventions Prophylactic approach.

Immunoglobulin infusion for isoimmune haemolytic jaundice in neonates (Review) 9

Control group: Phototherapy alone. (n = 19)

Item Authors’ judgement Description

Allocation concealment? Yes A - Adequate

Interventions Prophylactic approach.

Item Authors’ judgement Description

Allocation concealment? Unclear B - Unclear

Immunoglobulin infusion for isoimmune haemolytic jaundice in neonates (Review) 10

Characteristics of studies awaiting assessment [ordered by study ID]

Methods Not known

Participants Not known

Interventions Not known

Outcomes Not known

Methods Not known

Participants Not known

Interventions Not known

Outcomes Not known

Methods Not known

Participants Not known

Interventions Not known

Outcomes Not known

Immunoglobulin infusion for isoimmune haemolytic jaundice in neonates (Review) 11

Immunoglobulin infusion for isoimmune haemolytic jaundice in neonates (Review) 12

Comparison 1. IVIg plus phototherapy vs phototherapy

Comparison 2. IVIg plus phototherapy vs phototherapy. Rh incompatibility

Immunoglobulin infusion for isoimmune haemolytic jaundice in neonates (Review) 13

Comparison 4. IVIg plus phototherapy vs phototherapy. Prophylaxis

Comparison 5. IVIg plus phototherapy vs phototherapy. Established jaundice

Review: Immunoglobulin infusion for isoimmune haemolytic jaundice in neonates

Comparison: 1 IVIg plus phototherapy vs phototherapy

Outcome: 1 Use of exchange transfusion (one or more)

Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio

Dagoglu 1995 4/22 15/19 32.8 % 0.23 [ 0.09, 0.58 ]

Rubo 1992 2/16 11/16 22.4 % 0.18 [ 0.05, 0.69 ]

Total (95% CI) 96 93 100.0 % 0.28 [ 0.17, 0.47 ]

Immunoglobulin infusion for isoimmune haemolytic jaundice in neonates (Review) 15

Comparison: 1 IVIg plus phototherapy vs phototherapy

Outcome: 2 Exchange transfusions per infant