Intracranial Hemorrhage in Alloimmune Thrombocytopenia: Stratified Management to Prevent Recurrence in the Subsequent Affected Fetus.

Abstract Abstract 894 Introduction: Fetal and neonatal alloimmune thrombocytopenia (AIT) result from parental platelet-specific antigen incompatibility combined with maternal sensitization. AIT is the most common cause of severe thrombocytopenia and intracranial hemorrhage (ICH) in term newborns; if ICH occurs in 1 child then the next affected sibling has a > 90% chance of developing an ICH. Prevention of recurrent ICH is the primary goal of antenatal management of AIT. Methods: Thirty-three women with 37 separate pregnancies were enrolled in 2 consecutive studies of antenatal management of AIT. All patients had a previous child who had suffered an ICH. They were subdivided into 3 groups (Extremely High Risk (EHR), Very High Risk (VHR) and High Risk (HR)) based on the timing of that child's ICH. Therapy was stratified according to the timing of the sibling ICH. The table below lists risk stratification, treatment and outcomes for each treatment arm. In all arms, if fetal blood sampling (FBS) showed a platelet count Results: The mean, on-therapy fetal platelet count was greater than the previous sibling birth platelet count (BPC) in all arms. The first EHR fetus, whose mother received IVIG 1g/kg/wk and prednisone 1mg/kg/d beginning at week 12, suffered an ICH at 19 weeks gestation and died. The EHR protocol was changed to IVIG 2g/kg/wk. None of the 7 other EHR fetuses had an ICH, and all had BPC > 50,000/mL3. Two patients in the VHR group had ICHs, but both occurred at BPC > 100,000/mL3. One was a Grade I (of IV) ICH; the other occurred in a 24-week-old premature infant. Fourteen of the 17 VHR fetuses had BPC > 50,000/mL3. Within the HR group, 2 fetuses (therapy started at 20-24 weeks), suffered an ICH. One patient should have been treated in the VHR arm, but could not receive optimal treatment due to late referral. The other ICH was Grade I, although the BPC was low. All HR fetuses, except for 3 receiving IVIG 1g/kg/wk starting at 20-24 weeks, had BPC > 50,000/mL3. Major complications of the study were FBS-related: 1 case of fetal tachycardia and 8 cases of fetal bradycardia; 3 cases lead to emergent cesarean section, one a result of hemorrhaging from the needle insertion site. Discussion: Fetuses of AIT-affected pregnancies with ICH in a previous affected sibling are at very high risk for ICH. The results of this study demonstrate the success of risk-tailored treatment in prevention of recurrent ICH. Although all or almost all 37 of the fetuses in this study would have developed a recurrent ICH, there were only 5 recurrent ICHs and only 2 of 5 occurred due to failure of therapy. Treatment should be stratified based on the timing of the sibling ICH: the highest risk is second trimester antenatal hemorrhage followed by third trimester followed by perinatal. See the table below for recommended treatments for each group. Since complications due to FBS continued to be substantial, FBS should be avoided until after 32 weeks at which time urgent delivery could be performed if a complication occurred. The intensification of treatment at fixed gestational ages rather than relying on the results of FBS further minimizes the need for early FBS. Risk Stratification, Treatment, Outcome and Recommendations High Risk (n=12) Very High Risk (n=17) Extremely High Risk (n=8) Definition Perinatal ICH in prior sibling ICH 28-36 wk in prior sibling ICH prior to 28 wk in prior sibling Treatments 1 Arm A IVIG 1g/kg/wk (n=6) IVIG 1g/kg/wk (n=15) IVIG 1g/kg/wk + Pred 1mg/kg/d (n=1) Arm B IVIG 2g/kg/wk (n=2) IVIG 2g/kg/wk (n=2) IVIG 2g/kg/wk (n=7) Arm C IVIG 1g/kg/wk + Pred 0.5mg/kg/d (n=4) Mean Sibling BPC (x1,000/mL3) Arm A 11.2 13.3 4 Arm B 5.0 9.5 21.5 Arm C 20.3 Mean BPC (x1,000/mL3) Arm A 47.3 120.7 NA Arm B 112.0 93 124.3 Arm C 137.0 ICH 2 2 1 Expected ICH 10-12 15-17 8 Recommended Treatment 2 1. IVIG 1g/kg/wk + Pred 1mg/kg/d at 20 wk 2. Add 2nd IVIG 1g/kg/wk if FPC at 32 wk 1. IVIG 1g/kg/wk at 12 wk 2. Add Pred 1 mg/kg/d or 2nd IVIG 1g/kg/wk at 20 wk 1. IVIG 2g/kg/wk at 12 wk 2. Add Pred 1mg/kg/d at 24-26 wk ICH, intracranial hemorrhage; IVIG, intravenous immunoglobulin; Pred, prednisone; BPC, birth platelet count; FPC, fetal platelet count; FBS, fetal blood sampling 1 High Risk patients in Study 1 (4 IVIG 1g/kg/wk and 4 IVIG 1g/kg/wk+Pred 0.5mg/kg/d) started therapy at 20-24 weeks. All other patients started therapy at around 12 weeks. 2 All arms should undergo FBS at 32 weeks. Disclosures: Bussel: Amgen, Inc: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cangene: Research Funding; GlaxoSmithKline: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genzyme: Research Funding; Immunomedics: Research Funding; Ligand: Membership on an entity's Board of Directors or advisory committees, Research Funding; Eisai, Inc: Research Funding; Sysmex: Research Funding; Scienta: Speakers Bureau; Shionogi: Membership on an entity's Board of Directors or advisory committees.