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Systematic review of intravenous immunoglobulin in haemolytic disease of the newborn
  1. A G Cleary1,
  2. B Brown1,
  3. J Minards1,
  4. J Sills1,
  5. P Bolton-Maggs2
  1. 1Royal Liverpool Children’s Hospital, Liverpool, UK; gavin.cleary{at}
  2. 2Manchester Haemophilia Comprehensive Care Centre, Department of Clinical Haematology, Manchester Royal Infirmary, Oxford Road, Manchester M13 9WL, UK

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    We read with interest the recent review of Gottstein and Cooke.1 Their systematic review of trials reporting treatment of infants with proven Rh and/or ABO haemolytic disease of the newborn (HDN) treated with high dose intravenous immunoglobulin (HDIVIG) and phototherapy, with phototherapy alone demonstrated that significantly fewer infants required exchange transfusion in the HDIVIG group. The authors point out that anti-D is the commonest red cell antibody responsible for HDN. We have recently treated two children both of whom developed evidence of immune haemolysis due to anti-D antibodies acquired from IVIG.

    The first patient, a 4 month old infant with Kawasaki’s disease, was treated with intravenous immunoglobulin (2g/kg) with immediate control of fever and irritability. Ten days later her disease became clinically active again and she was therefore given a second dose of IVIG (2g/kg from a different batch), which is a recognised therapeutic option.2 Her clinical condition again improved rapidly. A blood count two days after the second dose of IVIG showed that her haemoglobin had fallen suddenly by 2g/dl to 6.4g/dl, the blood film showed spherocytes and the direct antiglobulin test was positive, evidence of immune haemolysis. Samples that were collected prior to the second dose of IVIG confirmed her blood group to be AB Rh D positive with a negative direct antiglobulin test. Anti-D antibodies were now detected in the patient’s serum; these were not present in her mother whose antibody screen was negative and whose blood group was A Rhesus D positive. The manufacturer of the IVIG investigated the batches used and reported that the IVIG used for the second dose contained anti-D. The second patient, a 12 year old boy with systemic juvenile idiopathic arthritis received a fifth dose of IVIG from the same batch. He was screened for evidence of haemolysis and his antiglobulin test was positive 14 days after treatment. He remained asymptomatic with no fall in haemoglobin.

    IVIG is a pooled blood product not a drug; each batch is made from a pool of plasma collected from several thousand donors. Passive transfer of potentially significant red cell antibodies is a recognised hazard, reported in the company literature but only as a serological phenomenon, not as a clinical warning. The first case is a reminder that such complications may have serious clinical consequences. We would agree with the comment of Gottstein and Cooke that the use of IVIG is not without potential risks, including haemolysis. IVIG is not universally effective in autoimmune haemolysis in older children and adults where steroids are the first choice.

    Indications for the use of IVIG must be clear and evidence based, and as with all pooled blood products, including albumin solutions, the individual batch numbers must be recorded in the case notes, so that adverse events can be appropriately and fully investigated.