Fetal and Neonatal Alloimmune Thrombocytopenia: Risk of ICH in Second Pregnancy and Treatments to Maintain an Adequate Platelet Count

Background:

Fetal and Neonatal AlloImmune Thrombocytopenia (FNAIT) results from parental platelet antigen incompatibility and maternal sensitization leading to often severe fetal thrombocytopenia and possibly intracranial hemorrhage (ICH). Studies have shown that if the first FNAIT-affected baby of a mother has an ICH, the 2nd affected offspring is highly likely to have an ICH. However, the risk of ICH in a 2nd offspring if the first affected baby did NOT have an ICH is unknown; one estimate was 7%. In 2022, the Norwegian group reported no ICH in a 2nd FNAIT-affected child in 64 pregnancies when the first affected child did not have one. In the United States, standard practice is to treat the 2nd pregnancy to ameliorate fetal thrombocytopenia and prevent ICH.

Methodology and Results:

Part 1: To evaluate risk of ICH, we sent an IRB-approved Qualtrics-based survey asking for FNAIT information to affected women of NAITbabies, a group of women with FNAIT. 324 women responded: 156 had 2 (or more) affected children. 29 of the 156 had a first child with an ICH and 127 did not have an ICH in the first child. For the 127 with no ICH in the first child, there were 3 ICHs not directly related to FNAIT in the 2^nd child: 3 infants born at 25-26 weeks after complications of fetal blood sampling (FBS) with good fetal platelet counts (FPC). 4 ICHs were related to FNAIT: 3 (10%) were among 30 women who had no antenatal treatment in their 2^nd affected pregnancy. 1 was among the 93 (1.1%) women who had received antenatal management with IVIG, steroids, and/or weekly fetal platelet transfusion.

Among the 29 patients who had had an ICH in their first pregnancy, only 1 had an ICH in their 2^nd pregnancy: 24 women received antenatal treatment, 1 of whom had an ICH, while 5 received no treatment, none of whom had an ICH.

Part 2: Given that the survey showed a 10% incidence of ICH in the second pregnancy if untreated, we explored what treatment was needed to prevent ICH using a fetal/neonatal platelet count of 30,000 as a surrogate marker and performing additional analyses on data from our published randomized study of intravenous immunoglobulin (IVIG)x2/week (wk) vs. IVIG + prednisone 0.5 mg/kg. In that study, FBS was planned at 32 weeks so if the FPC was < 50,000, treatment would be intensified to 2 gram/kilogram/wk (g/kg/wk) of IVIG and prednisone 0.5 milligram/kilogram/day; if FBS was omitted, intensification would proceed automatically.

In Arm A (IVIG x 2/wk), 9/42 fetuses had FPC < 30,000: 6were < 20,000 with 2 < 10,000. For Arm B (IVIG+ prednisone), 6/39 FPC were < 30,000 with 4 < 20,000 and none < 10,000. No ICHs occurred in fetuses with low counts. 3/95 had grade 1 ICHs all with platelet counts > 100,000; 2 had received IVIGx2/wk and 1 IVIG+Prednisone. Among 13 fetuses with FPC < 30,000, treatment was intensified in 11 and 9 were born with count > 50,000. For 4 with low FPC but not intensifying treatment, 3 had birth counts <30,000.

For 22 who did not undergo fetal sampling, 10 mothers were from Arm A (IVIGx2) with two pairs of affected twins. 5 mothers (6 babies) intensified treatment and all were born with counts >50,000. The other 5 mothers (6 babies) in Arm A not receiving salvage were all born with counts > 200,000 except 1 of 42,000. In Arm B (IVIG+Pred), 10 mothers did not undergo FBS and 8 intensified treatment. All 8 had birth platelet counts > 30,000 with 1 having counts between 30 and 50,000/ul (none < 30,000). The 2 not receiving intensified treatment both had birth platelet counts > 75,000.

Conclusions:

Part 1 suggests that there is a real risk of ICH in a second pregnancy and that treatment apparently prevents ICH as previously demonstrated when treatment beyond IVIG 1 g/kg/wk was administered. Part 2 provides a way to optimize treatment in order to minimize the risk of ICH by trying to maintain an adequate platelet count defined as > 30,000. There were 15 with FPC < 30,000 at 32 weeks emphasizing that even IVIGX2 or IVIG+Pred was not always effective at maintaining a safe FPC. 11/13 of these were “rescued” by treatment intensification. Thus, it appears that IVIG+ pred or IVIGx2/wk are sufficient starting treatments but approximately 15% of mothers will nonetheless have birth counts < 30,000. To avoid this, intensifying treatment at 32 weeks (IVIGx2+Pred) until delivery improves outcomes by substantially lessening the risk of ICH. Clearly a biomarker (to be developed) would restore a balance of not overtreating many patients who do not need it and not undertreating those at highest risk of ICH.

Bussel:Janssens: Consultancy; Alpine-Vertex: Consultancy; RallyBio: Consultancy, Research Funding; Argenx: Consultancy; UCB: Membership on an entity's Board of Directors or advisory committees; Sobi: Consultancy.