Risk factors for spontaneous abortion following hepatitis E vaccination during and shortly before pregnancy: Further analysis from a cluster-randomized trial

Abstract

Background A recent randomized trial of Hepatitis E Vaccine (HEV239) found an elevated risk of spontaneous abortion (SAB) in women given HEV239 during or within ninety days before pregnancy. Here we present additional analyses to better understand this risk. Methods We investigated whether maternal risk profiles of SAB or gestational age at SAB differed between women receiving HEV239 versus control Hepatitis B vaccine (HBV). We also assessed whether HEV239-vaccinated women who experienced SABs had distinct short-term adverse reactions compared to HEV239-vaccinated women who had live births, exploring potential inflammatory mechanisms. Finally, we assessed maternal exposure to HEV239 in narrowly defined pre-last menstrual period (LMP) windows to more precisely demarcate pre-LMP at which HEV-239 vaccination was associated with an elevated risk of SAB. Chi-square tests and Mann-Whitney U tests were performed for bivariate comparisons. Poisson models were used for multivariable analyses. Findings Baseline maternal risk factors for SAB (age, body mass index, parity, and histories of SAB, hypertension, or diabetes) were similar between the SABs in HEV239 and HBV groups. Median gestational age at SAB was comparable (10.5 weeks [IQR 10-13] for HEV239 vs. 11 weeks [IQR 9-12.2] for HBV, p = 0.783). No increased short-term adverse events (pain: 9% vs. 9%; fever: 2% vs. 1%) were observed among HEV239 recipients who experienced SABs compared to those who did not. An elevated risk of SAB was observed in HEV239 recipients vaccinated 31–60 days pre-LMP (Relative Risk 4.3 [95% CI 1.3–19.3], p = 0.026). Interpretation Our analyses did not uncover associations pointing to a biological mechanism underlying the original observation of an increased SAB rate connected to HEV239 vaccination shortly before or during pregnancy. Targeted studies such as placental examinations and genetic testing are needed to investigate potential mechanisms.