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Immunoglobulin infusion for isoimmune haemolytic jaundice in neonates

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Authors

Alcock GS, Liley H

Background - Methods - Results - Characteristics of Included Studies - References - Data Tables & Graphs


Dates

Date edited: 27/05/2003
Date of last substantive update: 27/03/2002
Date of last minor update: 11/04/2003
Date next stage expected 28/08/2004
Protocol first published: Issue 4, 2001
Review first published: Issue 3, 2002

Contact reviewer

Dr Gary S Alcock

Consultant Neonatologist
Department of Neonatology
The Canberra Hospital
P.O. Box 11
Woden
ACT AUSTRALIA
2606
Facsimile: 07 3840 1949

E-mail: Gary.Alcock@act.gov.au

Contribution of reviewers

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.

Sources of Support

Internal sources of support

Centre for Clinical Studies, Mater Mothers' Hospital, Brisbane, AUSTRALIA
JP Kelly Mater Research Foundation, Mater Public Hospitals, Brisbane, AUSTRALIA

External sources of support

  • None noted.

What's new

Date / Event Description

History

Date / Event Description

Synopsis

  • Synopsis pending

Abstract

Background

Exchange transfusion and phototherapy have traditionally been used to treat jaundice and avoid the associated neurological complications. 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 & 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.

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.

Reviewers' 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.

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Background

The use of anti-D prophylaxis in rhesus negative women has led to a marked decline in rhesus sensitisation and haemolytic disease of the newborn. However, anti-D immunoglobulin is a valuable resource and often in short supply world wide. Sensitisation can occur despite anti-D immunoglobulin, particularly if it is given too late or in insufficient dose after a large feto-maternal haemorrhage. Fetal therapy has led to a reduction in the severity of disease in rhesus sensitised fetuses. In developed countries a high proportion of significant haemolytic disease of the newborn is caused by antibodies to antigens other than D and therefore is not preventable with anti-D immunoglobulin. Exchange transfusion and phototherapy have traditionally been the primary modes of treatment for affected newborn infants to reduce both mortality and the risk of kernicterus. The historical aspects of both the antenatal and neonatal management of rhesus disease have been reviewed recently by others (Peterec 1995; Liley 1997; Bowman 1998). Recent attention has turned to therapies aimed at reducing the need for exchange transfusion. New therapies include haem oxygenase inhibitors and intravenous immunoglobulin (IVIg).

The safety of exchange transfusion has been reported for over 40 years. Most studies of the safety of exchange transfusion report exchange transfusion-associated mortality as that occurring within six hours of the procedure. This definition was used by Boggs et al. but was an arbitrary time limit and does not include deaths attributable to later complications such as sepsis. Using this definition, published mortality rates vary from 0.53-3.3% per infant (Boggs 1960; Panagopoulos 1969; Keenan 1985; Guaran 1992). Death is more common in sick or premature infants and is rare when exchange transfusions are performed on healthy term infants (Boggs 1960Boggs 1960, Keenan 1985; Jackson 1997).

Complications of exchange transfusion include haemodynamic instability, apnoea, pulmonary haemorrhage, thrombocytopaenia, coagulopathies, hypoglycaemia, hypocalcaemia, electrolyte imbalance, vasospasm, vascular thromboses, hypertension, arrhythmias, sepsis, necrotizing enterocolitis and bowel perforation. Published morbidity rates have been relatively low, varying from 2.8-5.2% per procedure. However, in the most recent study published in 1997 (Jackson 1997), looking at exchange transfusions performed between 1980 and 1995, mortality was 4.7% per infant and 23.5% of infants suffered serious non-fatal complications. Twenty-eight percent of these complications had prolonged or permanent sequelae. Although improved obstetric care has led to a reduction in the frequency with which exchange transfusions are performed, the complication rate is likely to increase as neonatal staff become less experienced with the procedure.

IVIg is an alternative therapy which may be effective in treating isoimmune haemolytic jaundice. In isoimmune haemolysis red blood cells are probably destroyed by an antibody-dependent cytotoxic mechanism mediated by Fc receptor bearing cells of the neonatal reticuloendothelial system (Urbaniak 1979). The putative mechanism of IVIg action is non-specific blockade of Fc receptors. Ergaz et al. (Ergaz 1995) demonstrated a decline in carboxyhaemoglobin levels in four out of five infants treated with IVIg for isoimmune haemolytic jaundice. Carboxyhaemoglobin levels are a sensitive index of haemolysis and hence the study indicated that immunoglobulin could decrease haemolysis. Also Hammerman et al (Hammerman 1996a) demonstrated a significant reduction in carboxyhaemoglobin levels in 19 of 26 Coombs positive infants treated with IVIg.

In 1987 the first report was published of the successful treatment of late anaemia due to rhesus E incompatibility with IVIg (Hara 1987). Since then case reports and case series have reported success of IVIg treatment of jaundice due to both rhesus and ABO incompatibility (Kubo 1991; Sato 1991; Ergaz 1993). Hammerman et al. investigated factors associated with successful treatment of jaundice with IVIg in infants with ABO incompatibility (Hammerman 1996b). Those with early and severe haemolysis showed a reduced or no response to the therapy.

It is easy to recognise the potential benefits of IVIg over exchange transfusion. Administration is less complicated and less labour intensive. As well as being a less invasive therapy, IVIg may also allow treatment of some infants in level two centres or avoid delaying treatment whilst transferring infants to tertiary centres for exchange transfusion. The use of immunoglobulin in neonates has been studied extensively, particularly in the treatment of sepsis, and has been shown to be safe and well tolerated. It is established therapy for alloimmune thrombocytopaenia due to PLA1 incompatibility. The risk of transmission of viral infection is extremely low (Fischer 1988). Haemolysis has been reported as an uncommon complication (Copelan 1986) as has acute renal failure. One 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 conditions for which it is of proven benefit.

Objectives

The primary objective was to assess whether the use of intravenous immunoglobulin, in newborn infants with isoimmune haemolytic jaundice, is effective in reducing the need for exchange transfusion.

The review also assessed complications of therapy, short-term outcomes such as bilirubin levels, duration of phototherapy and hospital stay, simple transfusion requirements, and long term outcomes such as hearing loss, kernicterus and cerebral palsy.

Sub-group analyses were planned to determine if effects depend on:

Population:

  1. Rhesus incompatibility
  2. ABO incompatibility
  3. All other causes of isoimmune haemolytic jaundice
  4. Gestation (less than 37 weeks or 37 weeks and above)

Intervention:

  1. Prophylactic
  2. Treatment of established jaundice
  3. Single versus multiple doses

Criteria for considering studies for this review

Types of studies

All randomised and quasi-randomised controlled trials of intravenous immunoglobulin in the treatment of isoimmune haemolytic disease.

Types of participants

Neonates with isoimmune haemolytic disease.

Types of interventions

Intravenous immunoglobulin given either prophylactically or for treatment of established isoimmune haemolytic jaundice, versus control (placebo or nothing).
Prophylactic IVIg has been defined (for this review) as use in infants with evidence of isoimmune haemolysis within the first few hours of life, before the bilirubin has been shown to rise. Established jaundice has been defined as jaundice reaching a predefined bilirubin level.
Studies should include predefined criteria for both IVIg and transfusion therapy.

Types of outcome measures

Efficacy:

Use of exchange transfusion (proportion of infants receiving one or more exchange transfusions)
Exchange transfusions performed per infant
Maximum serum bilirubin (micromol/litre)
Absolute rise of bilirubin in first 24 hours
Absolute rise of bilirubin in first 48 hours
Percentage change in bilirubin in first 24 hours (%)
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 (%)
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)
Incidence of kernicterus
Incidence of cerebral palsy

Safety: Neonatal mortality

Incidence of adverse reactions requiring cessation of therapy or treatment

Search strategy for identification of studies

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). Search terms were immunoglobulin or gammaglobulin (textwords) and jaundice, hyperbilirubinemia, hemolysis (MeSH terms), haemolytic, hemolytic, haemolysis, hyperbilirubinaemia, rhesus or isoimmune (textwords).

No language restrictions applied.

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Methods of the review

The standard method of the Cochrane Collaboration and its Neonatal Review Group was 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. Criteria used to assess methodological quality were: blinding of randomisation, blinding of intervention, complete follow up and blinding of outcome measurement. Data were extracted from included studies independently by the two reviewers. Any differences of opinion were discussed and a consensus reached. Investigators were contacted for additional or missing information if necessary.

For categorical outcomes, such as the incidence of exchange transfusion, the relative risk and risk difference were calculated. For continuous variables, such as the maximum bilirubin level, weighted mean differences were calculated. The number needed to treat to avoid exchange transfusion was calculated. Ninety-five percent confidence intervals were used and a fixed effects model was assumed for the meta-analysis.

Description of studies

The search strategy uncovered seven studies. Three studies have been included in the review (Rubo 1992; Dagoglu 1995; Alpay 1999). Details of the studies are given in the table of included studies. Three studies have been excluded until further information is available from the authors (Voto 1995; Silvia 2001; Tanyer 2001). One study contained serious methodological flaws (Rubo 1996). Correspondence with an author indicated that no further information will be available and the study has been excluded.

INCLUDED STUDIES

Population

The three studies which met inclusion criteria included 189 infants. Two studies included only infants with Rh incompatibility (Rubo 1992; Dagoglu 1995). Alpay et al. predominantly enrolled infants with ABO incompatibility (n = 93) but also included infants with Rh incompatibility (n = 16) and both Rh and ABO incompatibility (n = 7), however results were not given for each group separately. One study (Alpay 1999) enrolled only term infants > 37 weeks gestation. One study (Dagoglu 1995) included 29 preterm and 12 term infants but did not define the gestational cut-off for prematurity. Rubo et al. did not give details of the gestation of enrolled infants.

Intervention

The three studies which met inclusion criteria examined the effect of a single dose of IVIg in combination with phototherapy. The control groups received phototherapy alone. None of the studies described the intensity or topography of phototherapy in detail. Two studies used IVIg in a prophylactic approach (Rubo 1992; Dagoglu 1995) and in one study established jaundice (bilirubin > 204 micromol/L) was a necessary criterion for entry (Alpay 1999).

Outcomes

All three included studies reported exchange transfusion as the primary outcome and for two studies (Rubo 1992; Dagoglu 1995) we were able to calculate the number of exchange transfusions per infant and its standard deviation. The maximum bilirubin was reported in two studies (Rubo 1992; Dagoglu 1995). Unpublished data were provided by the authors of the other study (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 predetermined criteria for commencing and ceasing phototherapy. The study by Alpay et al was also the only one to report duration of hospitalisation. All three studies included simple transfusion as an outcome but as predefined criteria for simple transfusion were provided by only one study (Alpay 1999) the results from the other two studies were not included in the analysis. All studies also reported short-term adverse events. No data were reported for changes in bilirubin or on neurodevelopmental outcomes.

STUDIES AWAITING ASSESSMENT

Tanyer 2001
This was not a randomised trial. The methodology did not clearly indicate a quasi-random method, stating only that infants were divided into three groups by "order of admission". No further details were given of the allocation method or whether there were infants eligible for the study who were not enrolled. The study compared groups receiving one dose and three doses of IVIg with control. Further information has been requested from the authors.

Silvia 2001
The study has as yet been published in abstract form only.

Voto 1995
This was an RCT comparing a single dose of IVIg with control. The methods for randomisation and allocation concealment were unclear. Forty infants were enrolled but results are given for only thirty-seven, with no mention of the other three infants. Results were given for total transfusion therapy and not divided into simple and exchange transfusion. Results for bilirubin levels were presented as graphs rather than tables. The only outcomes that could potentially be assessed in the meta-analysis were duration of hospitalisation and phototherapy. Further information has been requested.

EXCLUDED STUDIES

Rubo 1996
This was a multicentre RCT comparing both one dose (group 1) and two doses (group 2) of IVIg used in a prophylactic approach, with control (group 3). 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 74 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. This was the only study to suggest that IVIg was of no clinical benefit in reducing the need for exchange transfusion.

ADDITIONAL DATA

We have attempted to contact the authors of all studies to request both further methodological information and results. We have to date successfully contacted the authors of three papers (Rubo 1992; Rubo 1996; Alpay 1999).

Methodological quality of included studies

See: Table of included studies

None of the studies were of high quality. All three included studies were RCTs but allocation concealment was adequately described in only one study (Dagoglu 1995). The other two studies (Rubo 1992; Alpay 1999) did not describe the method of allocation concealment. None of the studies used a placebo in the control group or described any method of blinding of intervention after allocation. Dagoglu et al. used post randomisation consent. Although follow-up was complete for all infants in whom consent was obtained, two infants randomised to each arm of the study were excluded because consent was withheld. Two infants were also excluded post-randomisation in one other study (Rubo 1992) because of "protocol violations" but no details were given. Blinding of outcome assessment was not mentioned in any study.

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Results

EXCHANGE TRANSFUSION (Outcomes 1 & 2)

The results of all three included studies (Rubo 1992; Dagoglu 1995; Alpay 1999) could be entered into the meta-analysis. Two studies used a prophylactic approach (Rubo 1992; Dagoglu 1995) and the other used IVIg to treat established jaundice. Each of the three trials found a statistically significant reduction in the use of exchange transfusion. The meta-analysis supports a statistically significant reduction in the incidence of exchange transfusion in the IVIG 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).

All three studies included infants with Rh incompatibility and in two (Rubo 1992; Dagoglu 1995) there was a statistically significant reduction in the use of exchange transfusion. The overall reduction was also significant (typical RR 0.23, 95%CI 0.12, 0.44; typical RD -0.53, 95%CI -0.70, -0.73: NNT 1.9).

The study by Alpay et al included infants with only ABO incompatibility and for these infants the reduction in the use of exchange transfusion was also significant (RR 0.38, 95%CI 0.16, 0.87; RD -0.22, 95%CI -0.39, -0.05, NNT 4.5).

Statistically significant reductions in the use of exchange transfusion were also found in the two studies in which a prophylactic approach was used (Rubo 1992; Dagoglu 1995) (typical RR 0.21, 95%CI 0.10, 0.45; typical RD -0.59, 95%CI -0.77, -0.40; NNT 1.7) and in the only study which had established jaundice as a necessary criterion of entry (Alpay 1999) (RR 0.36, 95%CI 0.18, 0.75; RD -0.24, 95%CI -0.39, -0.09; NNT 4.2).

Overall, immunoglobulin treatment also led to a reduction in the mean number of exchange transfusions per infant (WMD -0.52, 95%CI -0.70, -0.35). The difference was significant in each individual study and for all subgroups except for those infants with ABO incompatibility only (Mean Difference -0.17, 95%CI -0.37, 0.03)

SIMPLE TRANSFUSION DURING AND AFTER THE FIRST WEEK (Outcomes 3 & 4)

Alpay et al. provided unpublished data for this outcome. Although fewer infants treated with IVIg required simple transfusions during the first week (RR 0.71, 95%CI 0.24, 2.21), more required simple transfusions after the first week (RR 11.00, 95%CI 0.62, 194.50). However these differences were not statistically significant. The number of infants with Rh incompatibility was too small to allow any meaningful conclusion. Results were similarly not significant for those infants with ABO incompatibility only (RR 0.80, 95%CI 0.19, 3.38 and RR 7.46, 95%CI 0.40, 140.45).

MAXIMUM SERUM BILIRUBIN (Outcome 5)

Results were available for all three studies (Rubo 1992; Dagoglu 1995; Alpay 1999). Although only one individual study showed a significant lower maximum serum bilirubin in those receiving 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 one (Alpay 1999) found a significant reduction in maximum serum bilirubin for this subgroup and the overall reduction was not significant (WMD -26.0 micromol/L, 95%CI -58.7, 6.7).

For the subgroup of infants with ABO incompatibility only (Alpay 1999), maximum serum bilirubin was lower in those treated with IVIg (Mean Difference -60.6 micromol/L, 95%CI -83.2, -38.0).

In the two studies using a prophylactic approach (Rubo 1992; Dagoglu 1995) both the individual studies and the combined analysis failed to detect a difference (WMD -3.8 micromol/L, 95%CI -46.0, 38.4).

One study examined the effects of IVIg in infants with established jaundice (Alpay 1999). Maximum bilirubin levels were significantly lower in those infants receiving IVIg (Mean Difference -62.2 micromol/L, 95%CI -87.7, -36.7)

DURATION OF PHOTOTHERAPY (Outcome 6)

Although criteria for commencing phototherapy were given in all three studies, only two (Rubo 1992; Alpay 1999) used predetermined criteria for ceasing phototherapy. Rubo et al. stated that no significant difference existed in the duration of phototherapy but data were not given. In the other study duration of phototherapy was significantly lower in the IVIg treated infants (Mean Difference -22.4 hours, 95%CI -34.8, -9.9) with an almost identical result for those infants with ABO incompatibility only (Mean Difference -22.8 hours, 95%CI -38.0, -7.7).

DURATION OF HOSPITALISATION (Outcome 7)

Alpay et al, who were the only investigators to measure duration of hospital stay, found a significant decrease (Mean Difference -23.5 hours, 95%CI -37.7, -9.3) for all infants in the study and for the subgroup with ABO incompatibility only (Mean Difference -31.5 hours, 95%CI -49.3, -13.7).

INCIDENCE OF ADVERSE REACTIONS (Outcome 8)

There were no reported adverse reactions as a consequence of IVIg or exchange transfusion in the treatment groups. Three control infants receiving exchange transfusion had adverse reactions. One infant each developed hypoglycaemia, hypocalcaemia and sepsis. There was no mortality in any study.

OTHER COMPARISONS AND OUTCOMES

Data were not available to evaluate treatment by gestation or with multiple doses of IVIg. We were also unable to examine the effects of IVIg on the rate of change of bilirubin or on long term outcomes such as the incidence of hearing loss, kernicterus and cerebral palsy.

HETEROGENEITY

Statistically significant heterogeneity of treatment effect was detected for two outcomes (02 Exchange transfusions per infant and 05 Maximum serum bilirubin), when the results of all three included studies were combined (Comparison 01). The heterogeneity appears to arise from the results of the study by Alpay et al.

Discussion

Seven trials were identified which studied the effects of IVIg in neonatal isoimmune haemolysis. Only three trials, encompassing a total of 189 infants, fulfilled inclusion criteria for the review. Analysis of the data available provides some evidence to support the use of IVIg in isoimmune haemolysis. The trials showed a statistically significant reduction in both the incidence of exchange transfusion and the mean number of exchange transfusions required per infant in those treated with a combination of IVIg and phototherapy, compared to infants treated with phototherapy alone. All the trials used predefined criteria for exchange transfusion. Overall, immunoglobulin treatment was associated with a significantly lower maximum bilirubin level although this finding was not consistent across all subgroups.

The data on other markers of effect such the durations of phototherapy and hospitalisation were reported in only some of the three studies. When reported, there was either no difference or an improvement suggesting that IVIg is, at the least, no worse than conventional treatment.

Despite these positive findings, the conclusions that can be drawn from the review are limited. None of the trials fulfilled criteria for a high quality study and the review included only three trials and 189 infants. An adequate randomisation and allocation concealment method was described for only one study. None of the studies used blinding of the intervention, nor described blinding of the outcome assessors. In two trials eligible infants were excluded after randomisation.

The incidence of late transfusion is an important outcome, especially in areas with a limited supply of safe blood for transfusion. However, as thresholds for simple transfusion in neonates vary widely, this outcome is susceptible to bias, particularly in an unblinded study. Although all the studies reported the incidence of simple transfusion only one provided (unpublished) predefined criteria, thus limiting the conclusions that could be drawn for this outcome.

Although phototherapy and exchange transfusion are widely used in the management of isoimmune haemolytic jaundice, there is no standard or evidence basis for the thresholds for each intervention. The safe upper limit of bilirubin level is unclear, as is whether bilirubin level alone is a sufficient predictor of the need for exchange transfusion or of neurodevelopmental outcome (Ahlfors 1994). Many practitioners now use intensive phototherapy and defer exchange transfusion until the serum bilirubin has risen above high thresholds, others appear to still use early rate of rise of bilirubin as an indicator for exchange transfusion. The approach used could affect the apparent effectiveness of IVIg, particularly if IVIg were better at slowing the rate of rise of bilirubin than reducing the ultimate peak. The three studies in this review all used different criteria for performing an exchange transfusion and none described their method of phototherapy in detail. The criteria for exchange transfusion in two of the studies (Rubo 1992Rubo 1992, Dagoglu 1995) mandated the use of early transfusion, with 69% and 79% of control infants respectively receiving exchange transfusion. These clinical differences are also reflected in the statistically significant heterogeneity of treatment effect found for two outcomes (02 Exchange transfusions per infant and 05 Maximum serum bilirubin), when the results of all three included studies were combined.

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.

Reviewers' conclusions

Implications for practice

Although the review supports an effect of IVIg in the treatment of isoimmune haemolytic jaundice, the evidence is limited by the small size and weak design of the studies. The role of IVIg remains uncertain, particularly in hospitals that do not use early rate of rise of bilirubin as an indicator for exchange transfusion. Since it appears safe, it may have a role in special circumstances such as parental refusal for exchange transfusion, or where appropriate blood components for exchange transfusion are unavailable. However, routine use of IVIg for the treatment of isoimmune haemolytic jaundice cannot yet be recommended.

Implications for research

Future research into the role of IVIg in the treatment of isoimmune haemolytic jaundice is warranted. Such a trial should examine the safety and efficacy of IVIg by recording both short term outcomes such as the need for transfusion therapy and the incidence of adverse events and also long term neurodevelopmental outcomes. Consideration should also be given to including additional measures to assess the severity of haemolysis such as carboxyhaemoglobin or end tidal carbon monoxide. In view of the declining incidence and severity of isoimmune haemolytic disease, and the reduction in the use of exchange transfusion, the use of IVIg to treat established jaundice will probably require a multicentre randomised controlled trial, incorporating either a placebo or blinding of outcome assessment. Future trials should be well planned and give priority to establishing guidelines for the "conventional" management of isoimmune haemolytic jaundice, focussing on the criteria for performing both simple and exchange transfusions and on the role of intensive phototherapy.

Acknowledgements

The Centre for Clinical Studies, Mater Mothers' Hospital.

Potential conflict of interest

  • None noted.

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Characteristics of studies

Characteristics of Included Studies

Study Methods Participants Interventions Outcomes Notes Allocation concealment
Alpay 1999 RCT
Blinding of randomisation: Unclear
Blinding of intervention: No
Complete follow-up: Yes
Blinding of outcome: Unclear
116 newborn term infants. ABO and/or Rh incompatability. SBR > 204 micromol/l, positive direct Coombs test and reticulocyte count > 10%. 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)

Exchange transfusion, duration of phototherapy, duration of hospitalisation, simple transfusions, maximum 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.

Unpublished data and information supplied. B
Dagoglu 1995 RCT
Blinding of randomisation: Yes
Blinding of intervention: No
Complete follow-up: Yes
Blinding of outcome: Unclear
45 term and preterm infants with Rh incompatability.
Rh +ve infant, Rh -ve mother and +ve direct Coombs test.
Prophylactic approach.
Treatment group: Single doses IVIg 500mg/kg (Sandoglobulin) as soon as possible after birth (most within 2 hours) plus phototherapy.
(n = 22)
Control group: Phototherapy alone. (n = 19)
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)
45 infants eligible. Post-randomisation consent with consent withheld for 2 infants in each group. Further information requested. A
Rubo 1992 RCT
Blinding of randomisation: Unclear
Blinding of intervention: No
Complete follow-up: No
Blinding of outcome: Unclear
34 newborn infants. Rhesus incompatability. Rh -ve infant, Rh +ve mother and +ve direct Coombs test. 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)
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.
Two infants were excluded post randomisation because of unspecified "protocol violatios". Authors contacted. No further information available. B

Characteristics of excluded studies

Study Reason for exclusion
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.

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References to studies

Included studies

Alpay 1999

{published and unpublished data}

Alpay F, Sarici SU, Okutan V, Erdem G, Ozcan O, Gokcay E. High-dose intravenous immunoglobulin therapy in neonatal immune haemolytic jaundice. Acta Paediatr 1999:216-219.

Dagoglu 1995

{published data only}

Dagoglu T, Ovali F, Samanci N, Bengisu E. High-dose intravenous immunoglobulin therapy for rhesus haemolytic disease. J Int Med Res 1995;23:264-271.

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 hyperbilirubinaemia caused by Rh hemolytic disease. J Pediatr 1992;121:93-97.

Excluded studies

Rubo 1996

{published data only}

Rubo J, Wahn V and Studiengruppe Rhesusinkompatabilitat. Kooperative studie zum einfluss einer hochdosierten immunglobulintherapie auf die hyperbilirubinamie bei rhesusinkompatibilitat [Influence of high dose immuno-globulin therapy on hyperbilirubinemia in rhesus-hemolytic disease. A cooperative study.]. Monatsschr Kinderheilkd 1996;144:516-519.

References to studies awaiting assessment

Silvia 2001

{published data only}

Silvia L, Spinelli I, Lydia E, Otheguy I, Miguel A, Larguia I. Postnatal use of high-dose intravenous immunoglobulin therapy in rhesus hemolytic disease treatment. J Perinatal Med 2001;29 Suppl 1:683.

Tanyer 2001

{published data only}

Tanyer G, Siklar Z, Dallar Y, Yildirmak Y, Tiras U. Multiple dose IVIG treatment in neonatal immune hemolytic jaundice. J Trop Pediatr 2001;47:50-53.

Voto 1995

{published data only}

Voto L, Sexer H, Ferreiro G, Tavosnanska J, Orti J, Mathet E et al. Neonatal administration of high dose intravenous immunoglobulin in rhesus hemolytic disease. J Perinat Med 1995;23:443-451.

* indicates the primary reference for the study

Other references

Additional references

Boggs 1960

Boggs TR, Westphal MC Jr. Mortality of exchange transfusion. Pediatrics 1960;26:745-55.

Bowman 1998

Bowman JM. RhD hemolytic disease of the newborn. N Eng J Med 1998;339:1775 - 1777.

Copelan 1986

Copelan EA, Strohm PL, Kennedy MS, Tutschka PJ. Hemolysis following intravenous immune globulin therapy. Transfusion 1986;26:410-12.

Ergaz 1993

Ergaz Z, Arad I. Intravenous immunoglobulin therapy in neonatal immune hemolytic jaundice. J Perinat Med 1993;21:183-7.

Ergaz 1995

Ergaz Z, Gross D, Bar-Oz B, Peleg O, Arad I. Carboxyhemoglobin levels in neonatal immune hemolytic jaundice treated with intravenous gammaglobulin. Vox Sang 1995;69:95-9.

Fischer 1988

Fischer GW. Therapeutic uses of intravenous gammaglobulin for pediatric infections. Pediatr Clin North Am 1988;35:517-33.

Guaran 1992

Guaran RL, Drew JH, Watkins AM. Jaundice: Clinical practice in 88, 000 liveborn infants. Aust NZ J Obstet Gynaecol 1992;32:186-92.

Hammerman 1996a

Hammerman C, Vreman HJ, Kaplan M, Stevenson DK. Intravenous immune globulin in neonatal immune hemolytic disease: Does it reduce hemolysis? Acta Paediatr 1996;85:1351-3.

Hammerman 1996b

Hammerman C, Kaplan M, Vreman HJ, Stevenson DK. Intravenous immune globulin in neonatal isoimmunization: factors associated with clinical efficacy. Biol Neonate 1996;70:69-74.

Hara 1987

Hara T, Mizuno Y, Kawano M, Ueki Y, Ueda K. Treatment of immune hemolytic anaemia with gammaglobulin. J Pediatr 1987;110:817-8.

Jackson 1997

Jackson JC. Adverse events associated with exchange transfusion in healthy and ill newborns. Pediatrics 1997;99:E7.

Keenan 1985

Keenan WJ, Novak KK, Sutherland JM, Bryla DA, Fetterly KL. Morbidity and mortality associated with exchange transfusion. Pediatrics 1985;75(suppl):422-6.

Kubo 1991

Kubo S, Ariga T, Tsuneta H, Ishii T. Can high-dose immunoglobulin therapy be indicated in neonatal rhesus haemolysis? A successful case of haemolytic disease due to rhesus (c+E) incompatibility. Eur J Pediatr 1991;150:507-8.

Liley 1997

Liley HG. Rescue in inner space: management of Rh hemolytic disease. J Pediatr 1997;131:340-342.

Magny 1991

Magny JF, Bremard-Oury C, Brault D, Menguy C, Voyer M, Landais P et al. Intravenous immunoglobulin therapy for prevention of infection in high-risk premature infants: report of a multicenter, double blind study. Pediatrics 1991;88:437-443.

Panagopoulos 1969

Panagopoulos G, Valaes T, Doxiadis SA. Morbidity and mortality related to exchange transfusion. J Pediatr 1969;74:247-54.

Peterec 1995

Peterec SM. Management of neonatal Rh disease. Clin Perinatol 1995;22:561-593.

Sato 1991

Sato K, Hara T, Kondo T, Iwoa H, Honda S, Ueda K. High-dose intravenous gammaglobulin therapy for neonatal immune haemolytic jaundice due to blood group incompatability. Acta Paediatr Scand 1991;80:163-6.

Urbaniak 1979

Urbaniak SJ. ADCC (K-cell) lysis of human erythrocytes sensitized with rhesus alloantibodies. II. Investigation into the mechanism of lysis. Br J Haematol 1979;42:315-25.

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Comparisons and data

01 IVIg plus phototherapy vs phototherapy

Comparison or outcome Studies Participants Statistical method Effect size
01.01 Use of exchange transfusion (one or more) 3 189 RR (fixed), 95% CI 0.28 [0.17, 0.47]
01.02 Exchange transfusions per infant 3 189 WMD (fixed), 95% CI -0.52 [-0.70, -0.35]
01.03 Use of simple transfusion in 1st week 1 116 RR (fixed), 95% CI 0.71 [0.24, 2.12]
01.04 Use of simple transfusion after 1st week 1 116 RR (fixed), 95% CI 11.00 [0.62, 194.49]
01.05 Maximum serum bilirubin (micromol/L) 3 189 WMD (fixed), 95% CI -46.55 [-68.39, -24.71]
01.06 Duration of phototherapy (hours) 1 116 WMD (fixed), 95% CI -22.37 [-34.83, -9.91]
01.07 Duration of hospitalisation (hours) 1 116 WMD (fixed), 95% CI -23.48 [-37.71, -9.25]
01.08 Incidence of adverse reaction 2 189 RR (fixed), 95% CI 0.25 [0.03, 2.17]

02 IVIg plus phototherapy vs phototherapy. Rh incompatibility

Comparison or outcome Studies Participants Statistical method Effect size
02.01 Use of exchange transfusion (one or more) 3 96 RR (fixed), 95% CI 0.23 [0.12, 0.44]
02.02 Exchange transfusions per infant 3 96 WMD (fixed), 95% CI -0.90 [-1.17, -0.63]
02.03 Use simple transfusion in 1st week 1 23 RR (fixed), 95% CI 0.51 [0.10, 2.51]
02.04 Use of simple transfusion after 1st week 1 23 RR (fixed), 95% CI 3.93 [0.21, 73.71]
02.05 Maximum serum bilirubin (micromol/L) 3 96 WMD (fixed), 95% CI -25.98 [-58.69, 6.73]
02.06 Duration of phototherapy (hours) 1 23 WMD (fixed), 95% CI -10.32 [-37.78, 17.14]
02.07 Duration of hospitalisation (hours) 1 23 WMD (fixed), 95% CI -20.22 [-48.17, 7.73]

03 IVIg plus phototherapy vs phototherapy. ABO incompatibility only

Comparison or outcome Studies Participants Statistical method Effect size
03.01 Use of exchange transfusion (one or more) 1 93 RR (fixed), 95% CI 0.38 [0.16, 0.87]
03.02 Exchange transfusions per infant 1 93 WMD (fixed), 95% CI -0.17 [-0.37, 0.03]
03.03 Use of simple transfusion in 1st week 1 93 RR (fixed), 95% CI 0.80 [0.19, 3.38]
03.04 Use of simple transfusion after 1st week 1 93 RR (fixed), 95% CI 7.46 [0.40, 140.45]
03.05 Maximum serum bilirubin (micromol/L) 1 93 WMD (fixed), 95% CI -60.58 [-83.21, -37.95]
03.06 Duration of phototherapy (hours) 1 93 WMD (fixed), 95% CI -22.84 [-37.99, -7.69]
03.07 Duration of hospitalisation (hours) 1 93 WMD (fixed), 95% CI -31.51 [-49.30, -13.72]

04 IVIg plus phototherapy vs phototherapy. Prophylaxis

Comparison or outcome Studies Participants Statistical method Effect size
04.01 Use of exchange transfusion (one or more) 2 73 RR (fixed), 95% CI 0.21 [0.10, 0.45]
04.02 Exchange transfusions per infant 2 73 WMD (fixed), 95% CI -0.89 [-1.18, -0.60]
04.05 Maximum serum bilirubin (micromol/L) 2 73 WMD (fixed), 95% CI -3.83 [-46.01, 38.35]

05 IVIg plus phototherapy vs phototherapy. Established jaundce

Comparison or outcome Studies Participants Statistical method Effect size
01 Use of exchange transfusion (one or more) 1 116 RR (fixed), 95% CI 0.36 [0.18, 0.75]
05.02 Exchange transfusions per infant 1 116 WMD (fixed), 95% CI -0.31 [-0.53, -0.09]
05.03 Use of simple transfusion in 1st week 1 116 RR (fixed), 95% CI 0.71 [0.24, 2.12]
05.04 Use of simple transfusion after 1st week 1 116 RR (fixed), 95% CI 11.00 [0.62, 194.49]
05.05 Maximum serum bilirubin (micromol/L) 1 116 WMD (fixed), 95% CI -62.20 [-87.73, -36.67]
05.06 Duration of phototherapy (hours) 1 116 WMD (fixed), 95% CI -22.37 [-34.83, -9.91]
05.07 Duration of hospitalisation (hours) 1 116 WMD (fixed), 95% CI -23.48 [-37.71, -9.25]

Additional tables

  • None noted.

Amended sections

Cover sheet
Background
Description of studies
Methodological quality of included studies
Results
Discussion

Contact details for co-reviewers

Dr Helen G Liley

Consultant Neonatologist
Neonatology
Mater Mothers Hospital, Brisbane
c/o Kevin Ryan Centre, Mater Mothers Hospital
Raymond Terrace
South Brisbane
Queensland AUSTRALIA
4101
Telephone 1: 07 3840 8250
Facsimile: 07 3840 1949

E-mail: 3neomh@mater.org.au


This review is published as a Cochrane review in The Cochrane Library, Issue 3, 2003 (see http://www.thecochranelibrary.com External Web Site Policy for information). Cochrane reviews are regularly updated as new evidence emerges and in response to comments and criticisms, and The Cochrane Library should be consulted for the most recent recent version of the review.