Fetal or neonatal alloimmune thrombocytopenia (FNAIT) is the result of platelet destruction caused by maternal IgG antibodies. The antibodies result from blood contact between mother and a fetus who are respectively negative and positive for a specific platelet antigen. In Caucasians, most cases are affected by the human platelet antigen HPA-1a (PLA1-Zw). Two percent of the Caucasian population is HPA-1a negative (HPA-1bb). Not all patients produce antibodies. Sensitization is present in 6-12% of HPA-1bb mothers. Anti-HPA-1a IgG antibodies cross the placenta, and may destruct fetal platelets. The major complication of the resulting thrombocytopenia is intracranial hemorrhage (ICH) in the fetus or newborn.

Until recently, repeated fetal blood sampling and intrauterine platelet transfusions were the first choice of treatment of fetuses with alloimmune thrombocytopenia. Arial et al were the first to report the effects of maternal administration of IvIG in the treatment of FNAIT. In all seven cases reported, the fetal platelet count increased substantially after treatment with IvIG 1.0 g/kg/wk. In addition, observational studies suggested that IvIG reduced the risk of ICH even in non-responders to IvIG. One randomized placebo-controlled trial was published in 1996 by Bussel et al. in which no effect of adding Dexamethasone to the administered IvIG was observed. The mechanism of action of IvIG in FNAIT is still unclear. Three possible explanations are cited in the literature. Firstly, in the maternal circulation the IvIG will dilute the anti-HPA antibodies, resulting in a lower proportion anti-HPA antibodies among the IgG transferred via the Fc-receptors in the placenta. Secondly, in the placenta, IvIG may block the placenta receptor (Fc-R) and decrease the placental transmission of maternal antibodies including anti-HPA-antibodies. Thirdly, in the fetus, IvIG can block the Fc-receptors on the macrophages and prohibit the destruction of antibody-covered cells. (Radder, 2004) We found evidence for the first mechanism. However, other effects of IvIG, such as anti-idiotypic neutralization of anti-HPA antibodies or suppression of antibody producing B cells, cannot be excluded.

The long-term-side effects for mother and child are still unclear. A recent study on short term follow up, found a possible increase of IgE in children after maternal IvIG administration compared to the normal population. However, no clinically apparent adverse effects in early childhood could be demonstrated (Radder, 2004) Since IvIG is known for its immunomodulating characteristics there is always a chance of long-time side effects for the mother and child.IvIG is widely used in other diseases, such as in prophylaxis and therapy of complications after stem-cell transplantation , autoimmune thrombocytopenic purpura and dermatological and neurological diseases.

The dose of 1.0 g/kg/wk has been commonly used since the first publication of Bussel et al.(1988). In FNAIT, no lower doses of IvIG are published and no dose-effect studies have been done. Results of a recent study suggest that placental antibody transfer is not further increased despite high IgG concentrations in the mother as a result from IvIG treatment. (Radder, 2004) In other immune platelet disorders, the optimal dose of IvIG is still controversial. For example, in treating ITP an effective dose of IvIG appears to be between 0.5 and 1.0 g/kg/day. (Godeau, 1999) If no response is observed, increased doses are suggested to a maximum of 2.0 g/kg/day.

In three reported studies including the Norwegian trial and the study reported from Leiden (Williamson 1998, Jægtvik 2000; Radder 2004), there has been observed a significant correlation between antibody level, detected by different methods, in the mother and the severity of thrombocytopenia in the new-born. Bessos et al (2003) has not been able to find this correlation using an ELISA based method for anti-HPA 1a quantitation. Results of a recent study suggest that placental antibody transfer is not further increased despite high IgG concentrations in the mother as a result from IvIG treatment. This suggests a limitation of the placental Fc-receptor (Radder, 2004). In case of low maternal titers of anti-HPA antibodies, a lower dose of IvIG may be sufficient to reduce transmission of pathogenic HPA-antibodies leading to thrombocytopenia. IvIG therapy is an expensive drug. By halving the dose, costs can be diminished. The present study aims to determine whether 0.5 g/kg/wk of IvIG is as effective as 1.0 g/kg/wk, in the prevention of ICH in FNAIT. During the study period the aim will be to register all pregnant patients with platelet immunization. The web based IT solution will inform if the patient fullfill the inclusion criteria. Thus, parallel with the study we are aiming to establish an international register on patients with this problem. It is also possible to enter retrospective data in the data base.