Topical retinoid use in women of reproductive age and risk of major congenital malformations in exposed pregnancies – a Nordic cohort study

Background Topical retinoids are used to treat mild to moderate acne and should be avoided during pregnancy as a precaution given the teratogenic effect of systemic isotretinoin, despite limited safety data. Objectives To describe recent trends in prevalence of topical retinoid use in women of reproductive age and to estimate risk of major congenital malformations (MCMs) associated with exposure of topical retinoids in early pregnancy. Methods Using publicly available nationwide data we estimated the annual prevalence of topical retinoid use in women of reproductive age (15-44 years) 2006-2024 in Denmark, Iceland, Norway, and Sweden. We subsequently used linked individual-level data to perform a population-based cohort study using nationwide registers to estimate prevalence of use during pregnancy and risk of MCM. We included all infants with a gestational age of at least 22 weeks in Denmark, Iceland, Norway, and Sweden from 1996 to 2020. We compared risks of non-genetic MCM among infants with first trimester exposure to topical retinoids with: 1) unexposed infants and 2) infants with first trimester exposure to topical azelaic acid or topical clindamycin. We estimated risk ratios (aRR) with log-binomial regression, adjusting for country of birth, maternal age, and birth year. Results The prevalence of topical retinoid use among women of reproductive age in Denmark, Iceland, Norway, and Sweden increased from 8.7 per 1000 in 2006 to 28.5 per 1000 in 2024. Of 3,869,586 infants included in the cohort, 0.86 per 1000 were exposed to topical retinoids in the first trimester. Among infants exposed to topical retinoids, 3.3% had any MCM (71 of 2172), compared with 3.0% among unexposed (111,404 of 3,671,023), aRR 1.1 (95% CI 0.87-1.38), and 2.6% among infants exposed to azelaic acid or clindamycin (295 of 11,139), aRR 1.1 (95% CI 0.87-1.47). Conclusion We observed a 3.3-fold increase in topical retinoid use over the past 18 years among women of reproductive age in the Nordic countries. We did not observe an increased risk of MCM associated with use of topical retinoids. Limiting to pregnancies resulting in a birth could underestimate both the prevalence of topical retinoid exposure and MCM risk.