Dear Editor

There is one reason why I was initally interested to read the systematic review of intravenous immunoglobulin in haemolytic diseases of the newborn [1] and then concerned by the published responses.

Neither the authors of the systematic review published in Archives nor the respondents to that article cited or discussed the 2002 Cochrane systematic review on exactly the same neonatal topic (Alcock and Liley, 2002).[2] The Cochrane reviewers (who analysed the 1966 to 2002 literature) came to different conclusions. They stated that 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. Alcock and Liley concluded that the number of studies (3) and infants (189) included "is small and none of the three included studies of high quality". Two of the studies mandated the use of early exchange transfusion, limiting the generalizability of the results. The final conclusion was that further well designed studies are needed before routine use of intravenous immunoglobulin can be recommended for the treatment of isoimmune haemolytic jaundice.

Please reassure the readers that Cochrane has not been banished from Archives.

References

(1) Gottstein R, Cooke RWI. Systematic review of intravenous immunoglobulin in haemolytic disease of the newborn. Arch Dis Child Fetal Neonatal Ed 2003;88:F6–F10.

(2) Alcock GS, Liley H. Immunoglobulin infusion for isoimmune haemolytic jaundice in neonates. Cochrane Database Syst Rev 2002;(3):CD003313.

Dear Editor

We are grateful to our colleagues for their interest and responses to our paper.[1] In response to Dr Ovaly’s comments we agree that late anaemia can be a problem in these babies who receive intravenous immunoglobulin (IVIG), as 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, twenty-seven babies with Rhesus, Kell of ABO incompatibility had 28 XTs. Gestation ranged from 28 to 40 completed weeks. Of 26 infants for whom follow-up data was available, 9 (35%) had received top-up red cell transfusions.

We read with interest Dr Ovaly 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. 205 babies had a positive direct Coombes 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 eleven received an XT; thus the XT rate in this group was 13%. After IVIG the RR of requiring an XT is 0.28,[1] 1 thus with IVIG the XT rate would be reduced to 3.6%, decreasing the number of XTs to 3 thus preventing 8. Therefore if IVIG were administered to all babies with moderate or strongly positive DCT, in our population the NNT 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 etc. are followed as for any other blood product. IVIG has been used previously even in preterm and low birthweight infants [4] 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.

References

(1) Gottstein R, Cooke RWI. Systematic review of intravenous immunoglobulin in haemolytic disease of the newborn. Arch Dis Child Fetal Neonatal Ed 2003;88:F6-10.

(2) Ovali F, Samanci N, Daðoðlu T. Management of late anemia in rhesus hemolytic disease: Use of recombinant human erythropoietin (A pilot study). Pediatr Res 1996:39:831-834.

(3) Dunsford I, Bowley CC (1967) Techniques in Blood Grouping, 2nd edn, Vol. II. Edinburgh: Oliver and Boyd, Pp 270, 287.

(4) Ohlsson A, Lacy JB. Intravenous immunoglobulin for preventing infection in preterm and / or low birthweight infants. (Cochrane Review). The Cochrane Library Oxford: Update Software, 2000:issue 3.

(5) http://www.npeu.ox.ac.uk/Inis.htm

Dear Editor

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 presented with clinical features suggestive of Kawasaki’s disease, and the diagnosis was confirmed by echocardiogram which revealed bilateral coronary artery aneurysms (7mm right and left). She 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] after which 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 6.4 g/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. This adverse event was reported to the manufacturer of the IVIG who investigated the batches used. The batch used for the second IVIG dose was confirmed to contain anti-D. She remained well without specific treatment for haemolysis. Her CRP returned to normal and her haemoglobin increased to 12.2 g/dL within 6 weeks. The second patient, a 12-year-old boy with systemic juvenile idiopathic arthritis received IVIG from the same batch. The 5th dose of IVIG he received was from the same batch as the child reported above. 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. His disease is currently quiescent and he receives infusions of IVIG every two months.

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 be more than laboratory phenomena with serious clinical consequences, and may perhaps be more likely in small children receiving large doses. 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 would certainly be 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.

References

(1) Gottstein R, Cooke RWI. Systematic review of intravenous immunoglobulin in haemolytic disease of the newborn. Arch Dis Child Fatal Neonatal Ed 2003;88:F6-F10.

(2) Dale R, Saleem M, Daw S et al. Treatment of severe complicated Kawasaki disease with oral prednisolone and aspirin. J Pediatr 2000;137:723-6.

Dear Editor

As it is clearly stated in the review by Gottstein and Cooke,[1] we consider it unethical to withhold or delay high dose intravenous immunglobulin (IVIG) treatment in infants with haemolytic disease of the newborn. Since the study we have done in 1995,[2] we have treated 129 patients with Coombs positive hemolytic disease of the newborn, with the same method and had to resort to exchange transfusions only in 3 cases. On the other hand, late anaemia is a frequent problem in these cases, necessitating multiple blood transfusions, with well known complications.

The authors suggest that multiple doses of IVIG may reduce late anemia. However, our observation in a limited number of cases is that, even multiple doses of IVIG are inffective in preventing late anemia. In an earlier unpublished study, we had shown that the erythropoietin levels were low in these infants. Thereafter, we had conducted a double blind, randomised pilot study to investigate the effects of recombinant erythropoietin (rHEPO) in these patients.[3] In this study, rHEPO was administered at a dose of 200 units/kg, subcutaneously, 3 times a week, starting at the 14th day of life and lasting for 6 weeks. This protocol reduced the number of erythrocyte transfusions significantly. With the impetus of this pilot study, we have used the same protocol for the subsequent 103 patients and the mean number of transfusions in this group was 1.5, with the majority of patients (55 %) is not needing any transfusions at all. There were no complications, including changes in neutrophil or platelet counts, and hemorrhagic or infectious complications. The administration of rHEPO to patients with haemolytic disease of the newborn, who had received IVIG early in life, not only decreases the infants’ exposure to multiple blood donors, but also diminishes the need for hospitalization and hence the cost that is involved. Therefore, rHEPO treatment is a suitable alternative to erythrocyte transfusions in these infants.

References

(1) Gottstein R, Cooke RWI. Systematic review of intravenous immunoglobulin in haemolytic disease of the newborn. Arch Dis Child Fetal Neonatal Ed 2003;88:F6-F10.

(2) Daðoðlu T, Ovalý F, Samancý N, Bengisu E. High dose intravenous immunoglobulin therapy for rhesus hemolytic disease. J Int Med Res 1995;23:264-271.

(3) Ovalý F, Samancý N, Daðoðlu T. Management of late anemia in rhesus hemolytic disease: Use of recombinant human erythropoietin (A pilot study). Ped Res 1996;39:831-834.

Dear Editor

It has been encouraging to read article of Gottstein et al.[1] on use of high dose Intravenous Immunoglobulin (HDIVIG), in case of hemolytic disease of newborns (HDN) & the conclusion showing effectiveness of HDIVIG. I have following observations to make with respect to implication to practice & future research. All the references mentioned [2-6] were 3-10 years old. These trials have not taken into consideration the Irradiance of Phototherapy used, though they had observed the number of exchange transfusions performed. In the present era, when 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 of exchange transfusion almost completely, even in severe cases of HDN. The irradiance of the phototherapy can further be effectively increased by decreasing the distance of phototherapy unit to the patient, especially of the undersurface phototherapy unit keeping the thermal & nursing issues under consideration. The second issue which has not been addressed is the enterohepatic recirculation of bilirubin from the gut. The inexpensive measures which decrease the back entry of bilirubin from gut, like early enteral feeds, oral administration of agar agar, Isbagol husk etc will further reduce the serum bilirubin levels. Therefore, before HDIVIG is being administered as a routine in HDN, there is need to have RCTs which compare the use of current effective phototherapy combinations with highest possible irradiance along with agents which decrease enterohepatic recirculation of bilirubin with or with out HDIVIG & need for exchange transfusion in HDN. These trials should also address the cost effectiveness & safety realizing the cost of HDIVIG in developing world.

References

(1) Gottstein R,Cooke RWI. Systematic review of intravenous immunoglobulin in haemolytic disease of the newborn. Arch Dis Child Fetal Neonatal Ed 2003;88:F6–F10.

(2) Alpay F, Sarici SÜ, Okutan V, et al. High-dose intravenous immunoglobulin therapy in neonatal immune haemolytic jaundice. ActaPaediatr 1999;88:216–19.

(3) Dagoglu T, Ovali F, Samaci N, et al High-dose intravenous immunoglobulin therapy for rhesus haemolytic disease. J Int Med Res 1995;23:264–71.

(4) Rübo J, Albrecht K, Lasch P, et al. High-dose intravenous immune globulin therapy for hyperbilirubinemia caused by Rh hemolytic disease. J Pediatr 1992;121:93–7.

(5) Voto LS, Sexer H, Ferreiro G, et al Neonatal administration of high-dose intravenous immunoglobulin in rhesus hemolytic disease . J Perinat Med 1995;23:443–51.

(6) Rübo J, Wahn V, et al Influence of high dosage immuno-globulin therapy on hyperbilirubinemia in rhesus hemolytic disease. A co-operative study. Monatsschr Kinderheilk 1996;144:516–19.

Dear Editor

The systematic review of intravenous immunoglobulin (ivIgG) in haemolytic disease of the newborn (HDN) by Gottstein and Cooke[1] raises some interesting points. The first fascinating observation is just how tiny is the number of babes, worldwide, entered into published randomised (or quasi-randomised) studies suitable for this sort of systematic review.

I too was struck by the apparently unusually high rate of exchange transfusions in Rhesus (Rh) disease; 26 of all 35 babes (74%, 95% CI 56.7 – 87.5%) with Rh HDN not given ivIgG needed exchanging. In the Northeast of England only 60%[2] of all 822 affected babes presenting between 1952 and 1957 required transfusion of any sort at all, and this was in the days when sibships (and thus severity of HDN) were greater and phototherapy was not used. These figures lend some perspective to the problem of interpreting these trials.

I too considered the possible contributory factors mentioned by Gottstein and Cooke and wonder if amongst the different practices there might be great variations in sibship sizes. However, I can not help but wonder if , in the absence of other information about antenatal and postnatal diagnostic and management practices, Rh HDN in the countries from which these data originated really might be rather different from that which we see in the United Kingdom; and Rh HDN is relatively easy to diagnose, unlike ABO HDN. Gottstein and Cooke may well be right that were we to reserve ivIgG treatment for infants with severe haemolysis the number needed to treat (to prevent one exchange transfusion) might be low. This is a hypothesis, not a fact, and it has not been tested in most regions of the world.

Leading on from this, their suggestion that it may be unethical to delay wider use of ivIgG while carrying out further research begs the question that ivIgG has any beneficial role at all in less severe HDN. At what level of severity will it become clinically valuable to use it? I rather think that more research is indeed needed if we are to use this form of treatment in a rational way. The alternative, and not a particularly appealing one (to me at least), is for a committee of ‘experts’ to decide (in the absence of data) what level of severity of HDN justifies use of ivIgG.

References

(1) Gottstein R, Cooke RW. Systematic review of intravenous immunoglobulin in haemolytic disease of the newborn. Arch Dis Childh Fetal Neonatal Ed 2003;88: F6-F10.

(2) Walker W. The changing pattern of haemolytic disease of the newborn (1948-1957).