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It was encouraging to read article of Gottstein et al,1 on the use of high dose intravenous immunoglobulin (HDIVIG) in cases of haemolytic disease of newborns (HDN) with their conclusion showing the effectiveness of HDIVIG. I have the following observations to make with respect to implications on practice and future research.
Firstly, all the references mentioned were between three and ten years old.2–6 These trials did not take into consideration the irradiance of the phototherapy used, although they did observe the number of exchange transfusions performed. Presently, a combination of blue and white fluorescent light double surface phototherapy, with effective higher irradiances of 20–40 uW/cm2/nm, can practically eliminate the need for exchange transfusion, even in severe cases of HDN. Irradiance of phototherapy can be increased further by decreasing the distance between the phototherapy unit and the patient, especially with an undersurface phototherapy unit, keeping thermal and nursing issues under consideration.
Secondly, the authors did not address enterohepatic recirculation of bilirubin from the gut. Inexpensive measures can decrease the back entry of bilirubin from gut, like early enteral feeds, oral administration of agar agar, isbagol husk and so forth, and further reduce serum bilirubin levels. Further randomised controlled trials are required before administration of HDIVIG becomes routine in HDN. These trials should compare use of current effective phototherapy combinations with the highest possible irradiance, agents that decrease enterohepatic recirculation of bilirubin with or without HDIVIG, and the need for exchange transfusion in HDN. They should also address cost effectiveness and safety, considering the cost of HDIVIG in the developing world.
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Authors’ reply
We are grateful to our colleagues for their interest and responses to our paper.1 In response to Dr Ovalý’s comments we agree that late anaemia can be a problem in babies who receive intravenous immunoglobulin (IVIG), as is also demonstrated in our systematic review. Even when infants have received exchange transfusions (XTs) top up red cell transfusions may be required. In a recent local audit of XTs, 35% of babies received top up red cell transfusions after one or more exchange transfusions. During a five year period from 1998–2002, 27 babies with Rhesus, Kell, or ABO incompatibility had 28 XTs. Gestation ranged from 28 to 40 completed weeks. Of 26 infants for whom follow up data was available, nine (35%) had received top up red cell transfusions.
We read with interest Dr Ovalý and colleagues paper describing a double blind randomised controlled trial of subcutaneous recombinant human erythropoietin (rHEPO) and its use in this situation.2
We await with interest the outcome of a Cochrane meta-analysis of this therapy in newborn infants (currently at the protocol stage).
We reviewed our computer database for a three year period from December 1999 to December 2002 to postulate what impact IVIG might have on our population of babies with haemolytic disease of the newborn. Two hundred and five babies had a positive direct Coombs test (DCT) result. Of these infants, 12 received XTs. There is a degree of under ascertainment with this database as there were four additional babies who required an XT during this time period. However, we make the assumption that the proportions of those missed requiring XTs is similar to the proportions of DCT positive babies who were missed from the database. Eighty five babies had moderate or strongly positive DCT. Of these 11 received an XT, giving an XT rate in this group of 13%. After IVIG the relative risk of requiring an XT is 0.28,1 thus with IVIG the XT rate would be reduced to 3.6%, decreasing the number of XTs to three and therefore preventing eight. If IVIG were administered to all babies with moderate or strongly positive DCT, in our population the number needed to treat would be 10.6 to prevent one XT. The degree of positivity of the DCT is an objective validated assessment of the strength of antigen/antibody reaction, determined by the degree of agglutination in the laboratory.3 During the three year period of this database there was only one infant who had only a weakly positive DCT and required an XT.
We were interested to read Dr Cleary and colleagues case reports. We recognise that IVIG is not specific for a particular type of haemolysis and that it is a pooled blood product. We therefore agree that all the usual procedures regarding documentation of batch number and so on are followed as for any other blood product. IVIG has been used previously even in preterm and low birthweight infants4 and is currently being used in the INIS Trial.5 As with any drug or blood product we will need to remain vigilant for the occurrence of any adverse events.