Background: Although intravenous immunoglobulin G (IVIG) therapy has been reported in hyperbilirubinemia of Rh hemolytic disease, its use in ABO hemolytic disease has been reported in only a few studies. In our institute we have observed that almost 30% of babies with hyperbilirubinemia due to ABO hemolytic disease required exchange transfusion.
Objective: To determine whether administration of IVIG to newborns with significant hyperbilirubinemia due to ABO hemolytic disease would reduce the need for exchange transfusion as a primary goal in these babies.
Design: This was a prospective study involving all newborns with significant hyperbilirubinemia due to direct Coombs-positive ABO hemolytic disease.
Methods: All healthy term babies with ABO hemolytic disease with positive direct Coombs test in the period between 2000 and 2002 were identified. Significant hyperbilirubinemia was defined as hyperbilirubinemia requiring phototherapy and/or rising by 8.5 mol/ l per h (0.5 mg/dl per h) or more to require exchange transfusion. Babies were randomly assigned into two groups: group 1 (study group) received phototherapy plus IVIG (500 mg/kg); and group 2 (control group) received phototherapy alone. Exchange transfusion was carried out in any group if at any time the bilirubin level reached 340 mol/ l (20 mg/dl) or more, or rose by 8.5 mol/l per h (0.5 mg/dl per h) in group 2.
Results: A total of 112 babies were enrolled over 2 years, 56 in each group. Exchange transfusion was carried out in four babies in the study group, while 16 babies in the control group required exchange. Late anemia was not of concern in either group. No adverse effects related to IVIG administration were recorded.
Conclusion: Administration of IVIG to newborns with significant hyperbilirubinemia due to ABO hemolytic disease with positive direct Coomb’s test reduces the need for exchange transfusion without producing immediate adverse effects.
Key words: ABO HEMOLYTIC DISEASE OF THE NEWBORN; INTRAVENOUS IMMUNOGLOBULIN
INTRODUCTION
Intravenous immunoglobulin G (IVIG) has been used in immunological neonatal disorders including alloimmune and autoimmune neonatal thrombocytopaenia1. IVIG is also used as an adjuvant therapy in neonatal sepsis2. Its use in neonatal Rh hemolytic disease has stemmed from its antenatal administration to pregnant women to salvage fetuses with severe Rh isoimmunization3 in addition to its indication in other neonatal immunological disorders. The trials describing the administration of IVIG in hemolytic disease of the newborn have involved mostly babies with Rh hemolytic disease and very few babies with ABO hemolytic disease4-8. Hyperbilirubinemia due to ABO hemolytic disease is the major indicator for exchange transfusion in our institute. Against this background we set out to investigate whether IVIG administration to babies with significant hyperbilirubinemia due to ARO hemolytic disease would reduce the need for exchange transfusion.
PATIENTS AND METHODS
During the period from 2000 to 2002, 112 babies were diagnosed as having significant hyperbilirubinemia due to ABO hemolytic disease confirmed by a positive direct Coombs test. Phototherapy was commenced if the level of serum bilirubin was rising by 8.5 mol/l per h (0.5 mg/dl per h) or if the total bilirubin level exceeded 170 mol/l per h (10 mg/dl per h), 204 mol/l per h (12 mg/dl per h) or 238 mol/l per h (H mg/dl per h) at
The demographic data of both groups are shown in Table 1. There were no differences between the groups in relation to gestational age, birth weight or sex. All babies had been delivered at term and were healthy at the beginning of treatment. Babies were excluded from the trial if they were of low birth weight, had Rh hemolytic disease or other hemolytic anemias, or were sick from other causes such as perinatal asphyxia, or had severe congenital malfomiations.
All babies had 4-hourly serum bilirubin estimation and daily estimation of hemoglobin, red blood cell count, reticulocyte count, white blood cell count and platelet count. Babies were followed in the high-risk clinic at the age of 6 and 12 weeks to check their hemoglobin and red cell count and reticulocyte count for development of late anemia.
Exchange transfusion was performed if at any time the serum bilirubin level was found to be 340/itnol/1 (20 mg/dl) or more, in any of the two groups, or if it was rising by 8.5 mol/l per h (0.5 mg/dl per h) or more in group 2 babies.
Table 1 Demographic data for both groups
Late anemia was considered to be present if the hemoglobin level fell below 120 gl1 on follow-up. Severe late anemia requiring top- up red blood cell transfusion was defined as a hemoglobin level below 70 g/l10.
Any possible adverse effects related to IVIG administration, umbilical venous catheterization or blood transfusion were recorded.
Results are expressed as mean and standard deviation. Statistical significance was set at p
RESULTS
There were no statistically significant differences between the two groups with respect to mode of delivery, Apgar score or the initial values of serum bilirubin, hemoglobin and reticulocyte count.
There were a total of 76 babies with blood group A and 36 babies with blood group B, distributed between the two groups (Table 2). All the mothers were of the O Rh-positive group. Four babies in the study group (group 1) required exchange transfusions compared to 16 babies in the control group (group 2). This was statistically significant (p = 0.007; Table 3).
When comparing the number of babies who had exchange transfusion according to their blood groups, it could be seen that for babies in group 1, only one baby of blood group A was exchanged whereas three babies of blood group B required exchange (Fisher exact test 14, not significant; Table 2). However, for babies in group 2, five of blood group A and 11 of blood group B were exchanged (χ^sup 2^ = 17.23, p
The hospital stay for both groups did not differ significantly (mean of 7.05 days for group 1 versus 7.46 for group 2, p = 0.63). However, in both groups the length of stay was affected by development of clinical or culture-positive sepsis which necessitated a prolonged course of antibiotics.
When followed for late anemia, none of the babies in either group required top-up blood transfusion, because the hemoglobin level remained above 100 g/l.
The times at which IVIG was given varied between 2 h and 72 h with 68% of the babies receiving IVIG before or at the age of 24 h and 94.6% receiving IVIG by the age of 48 h (Table 4) The four babies who were exchanged in the IVIG group all underwent exchange before the age of 24 h.
No immediate adverse effects related to IVIG were noted, including fever, allergic reactions, volume overload or hemolysis.
The duration of phototherapy for both groups showed that group 1 babies had phototherapy for 2-7 days (average 3.848 days) while group 2 babies had phototherapy for 2-9 days (average 4-402 days). This was statistically significant (p = 0.036; Table 5).
Table 2 Exchange transfusion according to blood group
Table 3 Babies requiring or not requiring exchange transfusions (total 112)
Table 4 Age of administration of IVIG
Table 5 Duration of phototherapy (days)
DISCUSSION
The clinical significance of hyperbilirubinemia in newborn infants lies in its historical association with kernicterus, where significant unconjugated bilirubin appears to produce an encephalopathy with a specific clinical neurological syndrome”.
One of the most important causes of hyperbilirubinemia in the newborn is immune hemolytic anemia due to antibodies acquired from the mother transplacentally. With the wide use of anti-D to prevent Rh hemolytic disease, other blood group incompatibilities now assume a major role in the causation of neonatal hyperbilirubinemia which may require exchange transfusion.
Initial reports describing the use of IVIG for Rh isoimmunization in pregnant women in the third trimester have indicated a reduction in maternal antibody titers and severity of fetal hemolysis, and hence a reduction in severity of neonatal Rh isoimmune disease’. The mechanism by which IVIG is thought to reduce the degree of hemolysis is by blocking the reticuloendothelial Fc receptor sites and hence preventing the extravascular destruction of neonatal red blood cells by transplacentally acquired maternal isoantibodies12,13. This competitive action of IVIG with isoantibodies has led to the suggestion that, in order for IVIG to be ef\fective, it must be administered as soon as the diagnosis of isoimmune hemolytic anemia is made4,14.
Our study has shown that ABO hemolytic disease is an important cause of significant hyperbilirubinemia, which may necessitate exchange transfusion, and that IVIG administration significantly reduces the need for exchange transfusion. Although advocates of IVIG suggest administering it early4,14, we were able to show that IVIG administration can still be effective if given as late as the age of 72 h of life. Although the majority of babies in our study were of blood group A, rather than blood group B (76 vs. 36), more babies with blood group B tended to require exchange transfusion than babies with blood group A. This was significant in babies who did not receive IVIG, indicating that ABO hemolytic disease tends to be severe in our babies with blood group B. Our study suggests that administering IVIG has resulted in significantly fewer babies of blood group B needing exchange transfusion compared to babies who received phototherapy alone (Table 2). Therefore, it is justifiable to suggest that a family history of a previous baby of blood group B requiring exchange transfusion for significant hyperbilirubinemia due to ABO hemolytic disease should be treated with IVIG as soon as the diagnosis is made. All babies who were given IVIG received one dose; in our opinion, this will be effective without the need for a repeat dose.
Exchange transfusion is not without risks. In fact, ten of the babies who had exchange, from both groups, had to be treated for blood culture-positive or clinical sepsis, needing to extend their length of stay to complete the antibiotic course. This was the main reason why the length of stay in our babies who received IVIG was not significantly shortened in comparison with other studies, which reported significant reduction in the length of hospital stay when IVIG was administered6. Given the risks of exchange transfusion, we found that IVIG treatment was effective and non-invasive. Although the length of stay for both groups was not significantly different, we were able to show that the duration of phototherapy was significantly shortened in the IVIG group compared with the control group. In our opinion, this difference reflects the continuing effect of IVIG in controlling the hemolytic process and hence the need for longer use of phototherapy.
Transfusions for late anemia have been reported to be increased in babies who received IVIG4,6,7. This is explained by the fact that antibody-sensitized neonatal erythrocytes will bind to the Fc sites on the surface of the reticuloendothelial cells which have become free after the effect of IVIG had faded, causing late hemolysis. In our patients, severe late anemia requiring blood transfusion was not encountered. This may be related to the sparse distribution of A and B sites on the red cells of the newborn, leading to a minimal effect on the erythrocyte life span, in ABO hemolytic disease. This is in contradistinction to Rh hemolytic disease, where the surface of the red cell becomes coated with antibodies, leading to its rapid destruction and marked shortening of its life span.
Mild adverse effects related to IVIG include fever, allergic reactions, hemolysis and fluid overload. Serious adverse effects are rare and include anaphylaxis and possible transmission of infections. We did not encounter any of the mild adverse effects in our babies. With improvements in the processing of IVIG the serious adverse effects will be avoided. We conclude that IVIG is a safe and effective therapy for reducing the need for exchange transfusion in significant hyperbilirubinemia of ABO hemolytic disease.
Acknowledgements
We are especially grateful to the medical and nursing staff in the neonatal intensive care unit at Security Forces Hospital who helped us to finish this study. We thank Mrs Bing Borromeo for typing this manuscript and for secretarial support.
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A. M. Miqdad, O. B. Abdelbasit, M. M. Shaheed, M. Z. Seidahmed, A. M. Abomelha and O. P. Arcala
Department of Pediatrics, Security Forces Hospital, Riyadh, Saudi Arabia
Correspondence: Dr O. B. Abdelbasit, Department of Pediatrics, Security Forces Hospital, P. O. Box 3643, Riyadh 1 1 481, Kingdom of Saudi Arabia
2004 Parthenon Publishing. A member of the Taylor & Francis Group
DOI: 10.1080/14767050400009873
Received 23-12-03 Revised 20-04-04 Accepted 21-04-04
Copyright CRC Press Sep 2004
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