Maternal sensitization occurs before delivery in severe cases of fetal alloimmune thrombocytopenia
Authors: Jenny C. Jin, Madhavi M. Lakkaraja, Polina Ferd, Karen Manotas, Julia Gabor, Megan Wissert, Richard L. Berkowitz, Janice G. McFarland, James B. Bussel
Journal: American Journal of Hematology (2019)

Fetal/neonatal alloimmune thrombocytopenia (FNAIT) is the most common cause of severe fetal and neonatal thrombocytopenia and intracranial hemorrhage (ICH) in term newborns. FNAIT occurs in 1:500-1000 to 1:3-10 000 Caucasian pregnancies depending upon method of diagnosis: screening or clinical. Human platelet antigen (HPA)-1a is the most commonly implicated platelet alloantigen, responsible for 75% of FNAIT cases, especially severely thrombocytopenic cases, such as those complicated by ICH.1 Sensitization occurs when the mother produces antibodies against the incompatible paternal platelet antigen (HPA-1a) inherited by the fetus.2, 3 Transplacental passage of fetal platelets leads to maternal sensitization; syncytiotrophoblasts express glycoprotein IIIa, the location of the HPA-1a/1b polymorphism, and might possibly also contribute to sensitization.2 Recent work has demonstrated the critical role of DRB3*0101 in contributing to sensitization to HPA-1a in HPA-1bb women.4 Without universal screening for HPA-1a, FNAIT cannot be anticipated prior to birth of the first affected neonate. In the largest screening study, 75% of FNAIT cases were sensitized at delivery with detection of anti-HPA-1a antibodies only after birth.1 The experience in our study is different since we have often seen severely affected first-born children with FNAIT. This prompted us to explore the birth order in clinically identified FNAIT cases. This IRB-approved study estimated the birth order of the first FNAIT-affected pregnancy by survey of 138 FNAIT-affected mothers who had participated in studies of antenatal treatment carried out over the past approximately 20 years. Responses were obtained in 58 mothers. If an active telephone number was not identified by at least three calls per patient, then surveys were mailed to the addresses recorded in the charts. The 58 patients who could be contacted and received antenatal treatment on protocol comprise the study population in this report and agreed to participate (Figure 1). Mothers were asked if they had experienced miscarriages, elective terminations, received a transfusion, or underwent procedures such as amniocentesis, and if so, during which pregnancy each occurred. Chart reviews verified accuracy and confirmed results; no chart review identified discrepant information. The first affected pregnancy was defined as a pregnancy not preceded by a previous birth, termination, miscarriage, amniocentesis, transfusion, or other procedure that could have resulted in sensitization. If none of these events occurred and the mother was sure she had not had a prior pregnancy, the pregnancy was considered a "true first pregnancy." Mothers with children who had experienced an ICH were included. Statistical analysis was descriptive. Fifty-eight mothers 22 to 43 years old (mean age 32 years) with FNAIT-affected pregnancies were included in this study; 98% were HPA-1a incompatible. Thirty-five of 58 surveyed mothers (60%) were true first pregnancies affected by FNAIT. These 35 mothers specifically denied having had elective terminations, miscarriages, transfusions, amniocenteses, or unaffected children before their first FNAIT-affected pregnancy; these findings were confirmed by chart review. Among the 23 in whom their first FNAIT-affected pregnancy was not their first pregnancy, 17 mothers (29%) had miscarriages or elective terminations before their first FNAIT-affected pregnancy and 6 (10%) had had previous pregnancies. In these six pregnancies, no signs or symptoms of neonatal bleeding were noted and therefore no neonatal platelet counts were obtained. Of the 58 FNAIT-affected mothers, 21 (36%) had a baby with an ICH. In these 21 cases, 15 ICHs (71%) occurred during first-affected pregnancies. Five of 21 pregnancies complicated by resulted in intrauterine fetal deaths due to ICH at 22 weeks (n = 2), 24, 30, and 38 weeks of gestation. Of these five, four were first-affected pregnancies and one was a third pregnancy (intrauterine fetal death at 24 weeks); this mother had had two prior miscarriages before this pregnancy. An ICH in one fetus who survived was first identified at 18 weeks. The other ICHs occurred at the following gestational ages: 34, 34, 35, 35, 36, 36, 36, 37, 37, 37, 38, 38, 40, 40, and 41 weeks. Fifteen of the 16 mothers whose live-born infant had suffered an ICH had platelet counts <20 000/μL at birth (the other infant's platelet count was 24 000/μL). Most clinically identified newborns with FNAIT present with signs of bleeding such as petechiae and ecchymoses on the first day of life, although fetal and neonatal ICH are known.2 As in our 16 cases, thrombocytopenia in neonates with clinically identified FNAIT is usually severe, with 90% of neonates with FNAIT having platelet counts of <50 000/μL on the first day of life and 50% having counts <20 000/μL. ICH, the most severe complication of FNAIT, occurs in 10% to 20% of such clinically identified cases, resulting in death or substantial neurologic sequelae in at least 50% of cases.1 Most cases of ICH in FNAIT occur in utero as seen in the cases in this report. Ten to 20% of such clinically identified cases suffer an ICH and most of these ICH occur prior to birth, as was seen here. This study demonstrates that in clinically identified FNAIT, sensitization occurred in at least 60% of mothers during their first pregnancy. This included almost three quarters of cases complicated by ICH. The ICHs in this study occurred as early as at 18 weeks, with the earliest intrauterine deaths occurring at 22 weeks. Although a number of ICHs occurred late in the third trimester, presumably the underlying thrombocytopenia developed weeks to months earlier than when the ICH was identified. Finally, only 6 of the 58 mothers had a previous live-born infant who could have been identified by screening at delivery. FNAIT is pathophysiologically analogous to hemolytic disease of the fetus and newborn (HDFN), in which parental antigen incompatibility results in maternal antibody production. In contrast to what we report in FNAIT, the first pregnancy in HDFN very infrequently results in an anemic or jaundiced baby, as sensitization primarily occurs at the time of the first birth. Nonetheless, screening for maternal blood type is performed at the time of the first prenatal visit in the first pregnancy and in RhD-negative women, anti-D prophylaxis is administered at 26 weeks of gestation, as well as after delivery to RhD-negative women if they have had an RhD+ infant.5 The successful use of screening and subsequent prophylaxis with anti-D has led to near disappearance of HDFN, a disease that in the past affected as many as 1 in 100 pregnancies. This is one of the major medical achievements of the 20th century. Currently, Norway is the only country that has adopted universal platelet antigen screening. Screening would be feasible as demonstrated in three large studies.3, 4, 6 The success of screening and prophylaxis in HDFN, the similarities in the pathophysiology of HDFN and FNAIT, and the possibility of platelet antigen screening suggest that prophylaxis of FNAIT would be possible if an appropriate agent was available.5 This has led to the first steps in the development of "NAITGAM," a hyperimmune IVIG made from donors expressing high titers of anti-HPA-1a. The mechanism of prophylaxis with "NAITGAM" would likely be analogous to that seen with anti-D, which, while clinically very effective, remains poorly understood.6 The findings of this report suggest that if prophylaxis were to become available, it would need to be administered by approximately 12 weeks of gestation, since the earliest ICHs occurred at 18 weeks and fetal platelet antigen expression is thought to be initiated by 12 weeks of gestation. One limitation in our study of FNAIT is that mothers were enrolled in these studies over two decades, and thus only about half of the targeted women could be contacted. However, this is a large study of this population. Another limitation is our reliance on maternal history; but it is general consensus among obstetrical providers that a woman's history regarding her first pregnancy is reliable and confirmation of findings by chart review was available for nearly all cases. FNAIT is a serious disease. It is the most common cause of profound thrombocytopenia in neonates of all gestational ages and the leading cause of ICH in full term infants. If universal screening for HPA-1a/1b platelet antigen typing and effective prophylaxis can be instituted, this could realize a similarly substantial breakthrough for FNAIT as was achieved with HDFN many years ago. Partially supported by the Children's Cancer and Blood Foundation.