Risk of adverse pregnancy outcomes following inadvertent exposure to ivermectin during the periconception period: findings from two cluster-randomized trials in Mozambique and Kenya.

Background: Ivermectin is a widely used antiparasitic drug with over 5.9 billion treatments distributed through global programs by 2025, yet its safety during early pregnancy remains uncertain. Early animal studies suggested teratogenicity at doses several-fold higher than the ones used in humans. Inadvertent exposures during mass drug administration campaigns have not shown clear increase in risk of harms. We aim to describe the effect of inadvertent ivermectin exposure during the periconception period on the risk of adverse pregnancy outcomes. Methods: The BOHEMIA trials were open-label, assessor-blinded, cluster-randomized, controlled studies conducted in Mozambique and Kenya to assess the effect of three monthly rounds of 400 mcg/kg of ivermectin mass drug administration versus 400 mg fixed dose of albendazole on malaria transmission. The first implementation took place between mid-March and mid-June 2022 in Mopeia (Mozambique) and the second implementation occurred between October 2023 and December 2023 in Kwale (Kenya). A nested observational prospective cohort sub-study was conducted alongside the main trial to evaluate the safety of drug exposure around the time of conception. This sub-study included women aged 13-49 years who became pregnant between two weeks before and the four weeks following exposure to either ivermectin or albendazole and were excluded from further treatment and monitored monthly until the end of pregnancy. The primary study outcome was incidence of pregnancy outcomes, considering a positive pregnancy outcome all live births without any detectable major congenital anomalies, and adverse pregnancy outcomes defined as a composite of miscarriages, stillbirths, and congenital anomalies. The trial was registered on clinicaltrials.gov (NCT04966702) and on the Pan African Clinical Trial Registry (PACTR202106695877303). Findings: A total of 238 pregnant participants were enrolled in Mozambique and Kenya, 129/238 (54%) were potentially exposed to ivermectin and 109/238 (46%) to albendazole. Adverse pregnancy outcomes occurred in 24/105 (22.9%) women exposed to ivermectin and 15/77 (19.5%) women exposed to albendazole. Among the women with evaluable pregnancy outcomes, the odds of adverse pregnancy outcomes for ivermectin versus albendazole (OR = 1.22, 95% CI 0.59-2.50, p = 0.582) did not differ significantly between treatment arms. Interpretation: Among women exposed to ivermectin or albendazole between two weeks pre-conception and the first four weeks of pregnancy, this study found broad confidence intervals do not exclude a clinically meaningful difference in either direction. It does however add meaningful data to a small cumulative evidence base on inadvertent ivermectin exposure in early pregnancy, even if the number of exposures documented to date remains too small to support policy or regulatory conclusions. Funding: Unitaid.