Topical retinoids and risk of major congenital malformations and spontaneous abortion: a systematic review and meta-analysis.

Abstract

Background: Topical retinoids are commonly prescribed for dermatological conditions during reproductive years; however, concerns regarding teratogenicity have persisted due to the established risks associated with oral retinoids. This systematic review and meta-analysis aimed to evaluate the association between first-trimester topical retinoid exposure and risks of major congenital malformations (MCM) and spontaneous abortion (SAB).

Methods: Following PRISMA 2020 guidelines, we searched PubMed, Scopus, Cochrane Library, Web of Science, and Google Scholar up to November 25, 2025. Studies comparing pregnancy outcomes in women exposed to topical retinoids versus unexposed controls were included. Random-effects meta-analysis, Bayesian hierarchical modeling with multiple prior specifications, and Robust Bayesian Model-Averaged (RoBMA) analysis were performed.

Results: Eight studies with total of 3,632,118 pregnancies were included. Topical retinoid exposure was not significantly associated with MCM risk (risk ratio [RR] 0.83, 95% CI 0.64-1.07, P-value = 0.14, I² = 0%) or SAB risk (RR 0.99, 95% CI 0.68-1.43, P-value = 0.94, I² = 0%). Bayesian analysis with three prior specifications yielded posterior estimates ranging from RR 0.86 to 0.89, all with credible intervals crossing unity. RoBMA demonstrated 74.1% posterior probability favoring the null hypothesis (BF₁₀ = 0.35). Leave-one-out sensitivity analysis identified Refsum et al., 2025 as influential for MCM (+29.6% change when omitted). E-value analysis indicated findings were not significant to unmeasured confounding.

Conclusion: Topical retinoid exposure during the first trimester was not associated with increased risks of MCM or SAB. These findings support the relative safety of topical retinoids in early pregnancy; however the results were driven mainly by a single large registry study.