Enhancing Therapy To Avoid Fetal Blood Sampling (FBS) In Antenatal Management Of Alloimmune Thrombocytopenia (AIT)

Neonatal AIT (NAIT) is a potentially life-threatening, often severe thrombocytopenia caused by a parental human platelet antigen (HPA) incompatibility resulting in maternal alloantibodies attacking fetal platelets. NAIT affects approximately 1 in 1000 live births and may be accompanied by intracranial hemorrhage (ICH) in 10-20% of cases. Since there is no routine screening for NAIT, it is usually diagnosed after birth of the first affected thrombocytopenic fetus. Mothers of NAIT babies can be treated during subsequent affected pregnancies with IVIG and corticosteroids to increase fetal platelet counts and avoid fetal/neonatal ICH, using fetal blood sampling (FBS) to monitor treatment. Using this approach in previous studies IVIG 1g/kg alone (no steroids) was shown to not be effective in severely thrombocytopenic fetuses with AIT. While FBS allows enhancing therapy (salvage) in poor responders, it is a high-risk procedure associated with adverse fetal outcomes (eg premature delivery and fatal umbilical cord hemorrhage). This study assessed the efficacy, benefits and pitfalls of: a) 2 different regimens in treatment of fetal AIT, both of which are “more” than IVIG 1g/kg alone, and b) an alternative approach, omitting FBS in affected women without a history of ICH in a prior affected sibling and enhancing treatment empirically at 32 weeks, ie treating mothers as if they had undergone FBS and had a low fetal platelet count (FPC).

Antenatal treatment in this study compared IVIG 2g/kg/wk (arm A) to IVIG 1g/kg/wk + prednisone (arm B) starting at 20-30 weeks of gestation until delivery, with FBS at 32 weeks. In the alternative treatment arm which was added at the end of the study, all women were treated with IVIG 2g/kg/wk + prednisone 0.5mg/kg (Salvage) after 32 weeks. This prospective multicenter study included 99 mothers and 102 fetuses enrolled from May 2001 to November 2012. All mothers had documented NAIT and those with ICH in a previous child were excluded. FPC, birth platelet count (BPC) and ICH were compared among the 3 treatment regimens outlined above: 1) arm A, 2) arm B, and 3) either Arm A or Arm B followed by empiric salvage without FBS.

There was no difference in efficacy of treatment between arm A versus arm B; both increased BPC to greater than or equal to 50k in the fetus/neonate in 85% or so of cases (table 1). In 30 pregnancies in which Salvage was used, there were 16 fetuses who did not undergo FBS and 14 who did. Only 2 of the 30 receiving Salvage had BPC < 50,000/uL (50k); whereas, 9 of 72 neonates not receiving salvage therapy had a BPC < 50k. When only fetuses with an FPC < 50k were included, 13/14 receiving Salvage had a BPC > 50k whereas only 1 of 5 not on Salvage did (table 2; p=0.006). Overall, of 102 fetuses, 11 had a BPC ≤ 50 (poor responders). Among these 11 poor responders, 0 resulted in ICH, 9 did not receive Salvage treatment (5 in arm A; 4 in Arm B), and 1 of 2 receiving Salvage was only on it for 1.5 weeks.

Common adverse effects related to IVIG include headaches, skin rashes, flushing and nausea; these were self-reported by treated mothers and obtained by chart review including nursing records. Also increased hemolysis in mothers with blood type A occurred and was presumed to be caused by anti-A present in IVIG (see separate abstract at this meeting).

Arms A and B were approximately equally effective; however, both resulted in approximately 15% of low FPC at 32 weeks. These findings support the hypothesis that empiric addition of salvage treatment at approximately 32 weeks of gestation is needed in treating affected cases of NAIT to avoid fetal blood sampling and its substantial attendant complications. The addition of Salvage is highly effective in treating fetal AIT and eliminates risks associated with FBS and greatly reduces the chance of a BPC < 50k. However, adverse events have been seen from the increased dosage of IVIG and prolonged prednisone and require careful monitoring.

Bussel:Sysmex: Research Funding; Shionogi: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Eisai: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Ligand: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Immunomedics: Research Funding; IgG of America: Research Funding; Genzyme: Research Funding; Cangene: Research Funding; GlaxoSmithKline: Equity Ownership, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Amgen: Equity Ownership, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Symphogen: Membership on an entity’s Board of Directors or advisory committees.