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

Clinical Snapshot

Key Findings

• P Value: p = 0.026

• Effect Size: Relative Risk 4.3 for SAB in 31-60 days pre-LMP vaccination window

• Primary Outcome: Spontaneous abortion rate in women receiving HEV239 vs HBV vaccine

• Nnt Or Sensitivity: Number needed to harm not calculable from available data due to subgroup analysis design

• Confidence Interval: 95% CI 1.3-19.3

Clinical Application

Limited applicability as HEV239 vaccine not currently available in Australia Hepatitis E vaccination not part of routine Australian immunisation schedule; TGA approval status unclear. RACGP guidelines do not currently address hepatitis E vaccination in pregnancy planning Women of reproductive age considering hepatitis E vaccination, particularly in endemic areas

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.

References

1. 1.Aziz, A. B., Ahmmed, F., Haile, K., Kering, K., Dudman, S., Julin, C. H., Øverbø, J., Khan, A. I., Akter, A., Ongadi, B. A., Ngugi, B., Mbae, C. K., Mesfin, E., Chowdhury, F., Khanam, F., Lee, J. Y. E., Im, J., Bundi, M. M., Firoj, M. G., Islam, M. T., Mwangi, M., Rickett, N. Y., Ara, S. I., Behute, M. G., Park, S. E., Agampodi, S., Kariuki, S., Kanungo, S., Kim, D. R., Qadri, F., Zaman, K., & Clemens, J. D. (2026). Risk factors for spontaneous abortion following hepatitis E vaccination during and shortly before pregnancy: Further analysis from a cluster-randomized trial. PLoS One. https://doi.org/10.1371/journal.pone.0345974