Does absence of intracranial hemorrhage in the first pregnancy in fetal and neonatal alloimmune thrombocytopenia preclude occurrence in the second?

Abstract

Fetal and neonatal alloimmune thrombocytopenia (FNAIT) can result in intracranial hemorrhage (ICH) resulting in death or neurologic damage to the fetus/newborn. Since FNAIT often recurs in subsequent incompatible pregnancies,1 maternal treatment intravenous immunoglobulin (IVIG) ± prednisone may be administered in the second and subsequent pregnancies to increase the fetal platelet count to prevent ICH.1 Treatment is particularly imperative if the first-affected child has had an intracranial hemorrhage (ICH) because of the high risk of ICH recurrence (Figure 1).2 In contrast, in a second-affected pregnancy in which the first-affected child did not have an ICH, it is unknown how often an ICH might occur; one review estimated a 7% rate of ICH.3 However, a recent study of 64 women with FNAIT secondary to HPA-1a incompatibility accumulated over 20 years without antenatal management in either affected pregnancy (except for delivery at 37 weeks by elective cesarean section) suggested that, if the first-affected baby did not have an ICH, ICH in the second pregnancy would not occur: 0 in 64 in these cases.4 Since treatment is almost always offered in subsequent affected pregnancies, there is very limited pre-existing data that would resolve the question of risk of ICH in a second-affected pregnancy if the first pregnancy was NOT affected by fetal ICH. We performed a de-identified survey among women in NAITbabies.org who had had children affected by FNAIT. One hundred fifty-six survey respondents had had multiple children affected by FNAIT; in 127 cases, the first child did not have an ICH. Among these 127 women, in seven cases, the second child had an ICH (Tables 1 and 2); in one case, the fifth pregnancy had an ICH (after four without ICH but complicated by twin pregnancy, CMV, and maternal pre-eclampsia). In three of the seven cases, a reason other than FNAIT could explain the ICH; three babies with ICH were delivered prematurely at 25, 26, and 26 weeks of gestation following complications of fetal blood sampling. In the other four cases, severe thrombocytopenia secondary to FNAIT presumably caused the ICH in the second baby. Only two of the four first babies underwent cranial ultrasound documenting absence of ICH. Three of the four first babies had no developmental issues. One, product of a 42-week gestation, later developed cerebral palsy not thought to be caused by an ICH. In three of the second babies, the platelet count was 2000, 7000, and “low”; in the fourth, it was not known. Gestational ages were 42, 39, 38, and 36 weeks; the 36-week second child received antenatal treatment with IVIG but had an ICH despite this. The three other second babies with ICH did not receive antenatal treatment. Thus 4 of 127 cases with an ICH is 3.2% (Figure 1). If we exclude the two cases in which the first baby did not have an ultrasound to document the absence of ICH, the ICH rate in the subsequent pregnancy is 1.6%. This estimate is far from definitive and has limitations including participant bias in choosing to complete the survey. Yes 7 at 1 minute 8 at 5 minutes Yes Limited field of vision, high blood pressure, 9 weeks old ICH Yes Shunt placed at 1 month 7 more brain surgeries and delays receiving PT Yes PUBs Yes >4 times a week Yes IVIG Yes Low blood sugar Yes Did not use left hand (noticed at 3 months) Yes 10 days Yes IVIG PUBs Yes 6 months Breathing machine, antibiotics for infection, low blood sugar, slow weight gain (Premature) Yes NEC Yes 4 at 1 minute 7 at 5 minutes Yes PUBs Yes >4 times a week Yes Left side hemiplegia at 10 months. “Autism” Dx Yes 4 at 1 minute 7 at 5 minutes Yes Few hours Yes Eczema, asthma Yes PUBs Yes >4 times a week Yes Left side hemiplegic at 10 months, “Autism” Dx, eczema, asthma Yes 1 Yes Placenta abruption—C section Yes Oxygen, jaundice, stomach pumping, nutrition Yes 1 Yes IVIG PUBs Yes 1 Yes 5 at 1 minute 7 at 5 minutes Yes Pre-eclampsia: emergency C section Yes Difficulty breathing/eating Yes IVIG PUBs Yes 1 Yes 3 at 1 minute 7 at 5 minutes Yes Pre-eclampsia: emergency C section Yes Extreme jaundice, breathing, brain injury, liver and kidney injury, DIC hypotonia from brain injury Yes Liver injury, CMV, hypotonia A separate but also important consideration is the effect of anti-HPA-1a on the placenta and the fetus. Affected babies with FNAIT may be small, especially males.5 This is in line with findings of FNAIT (apparently via anti-HPA-1a) causing inflammation in the placenta (summarized in reference 5) combined with a study showing long-term mild and moderate neurodevelopmental injury not caused by ICH at double the rate (32% compared to 16%) in the normal population.6 Finally, anti_HPA-1a may affect the fetal vasculature. Antenatal treatment protected against placental inflammation in a small study and increased birthweight in a large study.5 In summary, there appears to be a small (1%–4%) but important risk of ICH in the affected second pregnancy with FNAIT even when the first pregnancy was not complicated by an ICH. Furthermore, there may be other emerging effects of FNAIT on the placenta and fetus that are likely ameliorated by antenatal treatment. Katherine A. Knightly was primarily responsible for performing the research and data analysis, including the construction of the table. James B. Bussel was primarily responsible for writing and revising the letter. Margaret McKelvy was primarily involved in developing the NAIT questionnaire from which these results were derived, and piloted attempts to analyze the data. Emilie Vander Haar was primarily responsible for revision and insight for the writing of the letter. Dr. James Bussel is a paid consultant for Rallybio LLC, Janssen Pharmaceuticals, UCB, and Argenx. The remaining authors report no conflict of interest. Data are available on request from the authors.

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