Objective
We sought to prevent intracranial hemorrhage (ICH) through antenatal management of alloimmune thrombocytopenia.
Study Design
A total of 33 women (37 pregnancies) with alloimmune thrombocytopenia and ICH in a previous child were stratified according to the timing of the previous child’s ICH: extremely high risk (HR) (n = 8) had ICH <28 weeks, very HR (n = 17) between 28-36 weeks, and HR (n = 12) in the perinatal period. Treatment was initiated at 12 weeks with intravenous immunoglobulin 1 or 2 g/kg/wk, and if the fetal platelet count by cordocentesis was <30,000/mL despite treatment, prednisone and/or more intravenous immunoglobulin were added.
Results
Five of 37 fetuses suffered ICHs. Two ICHs had platelet counts >100,000/mL, and 1 was grade I. The other 2 ICHs were unequivocal treatment failures; both were grade III-IV and resulted in fetal demise.
Conclusion
These findings demonstrate the success of stratified treatment in these HR patients, which tailored interventions according to the timing of the sibling’s ICH.
Fetal and neonatal alloimmune thrombocytopenia (AIT) is a result of parental platelet-specific antigen incompatibility combined with maternal sensitization, usually for the antigen Pl A1 (human platelet antigen [HPA]-1a). AIT affects approximately 1 in 1000 live births and is the most common cause of both severe thrombocytopenia in fetuses and neonates and intracranial hemorrhage (ICH) in term newborns. ICH is the most devastating complication of AIT and occurs in up to 10-20% of affected neonates. As many as 75% of ICHs occur antenatally.
The only established predictor for recurrent ICH secondary to AIT is a history of ICH in a previous, affected sibling, especially 1 that occurred antenatally. Small series and case reports have documented a nearly 100% recurrence rate of antenatal ICH in subsequent affected, untreated pregnancies. This is also supported by the finding that antenatal ICH in a previous sibling is a predictor of severe fetal thrombocytopenia in the subsequent affected sibling.
The primary goal of antenatal management of AIT is preventing recurrent ICH by increasing the fetal platelet count through maternally administering treatment(s) until delivery can be safely accomplished. Elective early delivery shortens the time during which the fetus is at risk for ICH; however, too early a delivery can result in complications of prematurity and variable degrees of neuropsychologic sequelae. Because of the morbidity and mortality associated with fetal blood sampling procedures and transfusions in utero, fetal platelet transfusions are held in reserve for failures of maternally administered medical therapy.
In view of these limitations, the main mode of treatment of fetal AIT is maternally administered intravenous immunoglobulin (IVIG) with or without daily steroids. IVIG at 1 g/kg/wk increases the platelet count in most fetuses with AIT. However, IVIG alone at 1 g/kg/wk is insufficient to adequately elevate the platelet counts of fetuses (with siblings who had not suffered an ICH) with platelet counts <20,000/mL prior to therapy. Furthermore, fetuses with a previous sibling who had an antenatal ICH have suffered intracranial bleeding despite having received maternally administered IVIG at this dose.
This article describes the results of stratified therapy of AIT in 37 exceptionally high-risk (HR) pregnancies in which a previous pregnancy was complicated by a fetal or perinatal ICH.
Materials and Methods
The patients in this article represent a specified subset of those who were recruited and treated in 2 consecutive studies of antenatal management of AIT and include all women with previous children who had suffered an ICH. Antenatal, maternally administered treatment with IVIG and steroids was initiated according to protocol, based on the timing of ICH in the previous child. Treatment was subsequently intensified as needed according to the fetal platelet counts acquired by fetal blood sampling.
The institutional review board of all participating institutions approved this protocol, and local informed consent was obtained from each mother (and father when possible) prior to initiation of treatment. There is no ClinicalTrials.gov number for the first study because it was initiated in 1994; the number for the second trial, initiated in 2001, is NCT00194987 .
Patients
From June 20, 1994, through Sept. 29, 2008, 33 women with 37 separate pregnancies were enrolled in 2 consecutive studies at 20 different institutions. Seven patients in the HR group were included in a previous report.
Maternal-fetal pairs were considered for the study if the following conditions were met: there was a history of well-documented AIT in a previous sibling who experienced an antenatal or perinatal ICH, and the fetus in the current pregnancy was affected. Maternal-fetal HPA incompatibility was confirmed by maternal and paternal platelet antigen typing. If the father was heterozygous for the antigen in question or unavailable for testing, the fetal genotype was determined by typing of amniocyte DNA. If the father was a homozygote for the antigen in question and paternity was assured, the fetus was presumed to be affected.
In all, 21 women were enrolled in the first study, and 13 in the second. Four women in this article were included twice for separate pregnancies, 1 of whom enrolled 1 fetus in each study. Patients from both studies were combined for analysis.
Patients were subdivided into 3 stratification groups based on the timing of the previous sibling’s hemorrhage ( Figure ). Ultrasound examination of the fetus was performed at least every 4 weeks commencing at 20 weeks. After delivery an ultrasound was performed within the first 2 days of life and repeated only if there was persistent marked thrombocytopenia. Extremely HR (EHR) patients (n = 8) were those in whom the ICH in a previous pregnancy had occurred in utero <28 weeks ( Supplementary Table 1 ). Very HR (VHR) patients (n = 17) were those in whom the ICH had occurred in utero between 28-36 weeks ( Supplementary Table 2 ). HR patients (n = 12) were those with a perinatal hemorrhage occurring >36 weeks in utero or during the first weeks after birth ( Supplementary Table 3 ). If there was ambiguity as to exactly when an ICH had occurred in a previous fetus, the pregnancy was assigned to the earlier fetal ICH group to avoid suboptimal treatment. One patient was treated in the HR group during her first pregnancy, since the ICH of her previously affected child was thought to be perinatal; however, she was placed into the VHR group for her second pregnancy when it was later discovered that the ICH had occurred at 28 weeks of gestation. One woman who was a late referral should have been enrolled in the EHR group but was enrolled in the HR group instead.
Treatment: initial therapy
All therapies (except in 1 patient), were administered to the mother, other than in utero platelet transfusions, which were administered at the time of fetal sampling. One HR patient received salvage therapy with fetal platelet transfusions weekly. All patients, except for HR patients in the first study, started therapy as close to 12 weeks as possible and underwent fetal blood sampling at 20-24 weeks ( Figure ). HR patients from the first study underwent initial sampling at 20-24 weeks prior to starting treatment.
The first EHR patient started on IVIG 1 g/kg/wk plus prednisone 1 mg/kg/d. After the failure of therapy in this patient resulted in fetal demise, the 7 subsequent EHR pregnancies were treated with IVIG 2 g/kg/wk in 2 divided doses each week. All 12 VHR patients from the first study received IVIG 1 g/kg/wk. The 5 VHR patients in the second study were randomized to receive either IVIG 1 g/kg/wk (n = 3) or IVIG 2 g/kg/wk (n = 2). The 8 HR patients in the first study were randomized to receive IVIG 1 g/kg/wk plus prednisone 1 mg/kg/d (n = 4) or IVIG 1 g/kg/wk alone (n = 4) after their initial sampling. The 4 HR patients in the second study were randomized to receive either IVIG 1 g/kg/wk (n = 2) or IVIG 2 g/kg/wk (n = 2) starting at 12 weeks.
Definition of response
Maternally administered treatment was initiated at least 4 weeks prior to the first fetal blood sampling in all groups, except in the HR group in the first study. An initial response was defined as a fetal platelet count >30,000/mL at the time of sampling. For the HR group in the first study, an initial response was defined as a platelet count >30,000/mL at the time of the second sampling and a platelet increase of >10,000/mL compared to the pretreatment platelet count.
Intensification of therapy
Therapy was intensified (salvage therapy) in all groups of both studies, if the prescribed therapy did not provide a satisfactory response. Patients initially receiving 2 g/kg/wk IVIG added prednisone 1 mg/kg/d to their regimen. Patients on IVIG 1 g/kg/wk either increased their dosage of IVIG to 2 g/kg/wk or added prednisone 1 mg/kg/d. Empiric salvage therapy was instituted in those patients for whom fetal blood sampling was not possible (n = 6), not attempted for medical reasons (n = 1), or did not provide a reliable fetal platelet count for technical reasons (n = 1).
Fetal blood sampling
Fifty-nine samplings were performed in 29 of 37 pregnancies ≤25 weeks’ gestation. Since the platelet count in an untreated, AIT-affected infant has been estimated to decrease by as much as 20,000-25,000/mL/wk, fetal blood sampling procedures were scheduled according to the obtained fetal platelet count, ie, the lower the count, the sooner the next sampling was performed.
Fetal blood sampling was performed as described in previous reports. Under ultrasonographic guidance a 20- or 22-gauge spinal needle was inserted through the anterior abdominal wall of the mother and into an umbilical vessel. The mean corpuscular volume of the red blood cells was used to confirm that the blood was of fetal origin, and the platelet count was determined prior to removal of the needle. If the fetal platelet count was found to be <50,000/mL, 10 mL of concentrated, maternal platelets were infused through the sampling needle prior to its removal from the fetal vessel.
Analysis of data
Data were analyzed descriptively using means and SD, medians and ranges.
Results
All 33 women had a previous child with an antenatal or perinatal ICH. Thirty-five (95%) of the 37 pregnancies, involved Pl A1 (HPA-1a) incompatibility. One patient had an incompatibility of Bak-a (HPA-3a), and 1 patient’s incompatibility was unknown; she was diagnosed with AIT because of having >1 child with (transient) fetal and neonatal thrombocytopenia.
The Figure summarizes the overall results for each group. Among the treated fetuses in this report, there were 5 recurrent ICHs, 3 of which were failures of antenatal therapy (1 of the 3 was a grade I ICH).
EHR group
Eight women were treated in the EHR group ( Supplementary Table 4 ). The fetus of the first woman in the EHR group, receiving IVIG 1 g/kg/wk and prednisone 1 mg/kg/d starting at 13 weeks, suffered an ICH at 19 weeks’ gestation and was electively terminated at 21 weeks ( Table 1 ). The EHR protocol was then changed to initiate therapy at 12 weeks’ gestation with IVIG 2 g/kg/wk, and no other ICHs occurred in this group. Five of the 7 pregnancies on the adjusted regimen added prednisone 1 mg/kg/d by 28 weeks’ gestation as salvage therapy. The 7 neonates were healthy and had birth platelet counts >50,000/mL; 4 were >100,000/mL. In the 8 previous siblings, 5 died in utero and the remaining 3 infants had serious neurologic sequelae; the mean platelet count for the available previous siblings was 18,000/mL ( Figure ). The prenatal and postnatal cranial ultrasound examination findings were all normal in the treated fetuses.
