Senior Researcher Department of Chronic Diseases & Centre for Fertility and Health, Norwegian Institute of Public Health Oslo, Norway
Background: Isotretinoin is a systemic retinoid used to treat severe acne and recognized as a potent teratogen. Topical retinoids are used to treat milder forms of acne and are contraindicated during pregnancy as a precaution, despite limited safety data.
Objectives: To describe the prevalence of prescription topical retinoid use in women of fertile age, overall and in the first trimester of pregnancy, and estimate risk of major congenital malformations (MCMs) associated with use in the first trimester.
Methods: Using publicly available data, we calculated the prevalence of topical retinoid use in women of fertile age (15-44 years) from 2006 to 2020 in Norway and Sweden. We also conducted a population-based cohort study using national health register data with individual linkage to prescription drug databases. We included all registered births with a gestational age of at least 22 weeks in Iceland, Norway, and Sweden from 2003 to 2020. The main exposure of interest was first trimester use of topical retinoids (ATC codes D10AD), defined as having filled a prescription from the date of last menstrual period (LMP)+14 days, to LMP+97 days. In sensitivity analyses, we defined exposure as use during gestational weeks 5-8 (LMP+35 to LMP+70), the period most sensitive to teratogenic effects. We compared pregnancies with first trimester use of topical retinoids to unexposed pregnancies and to pregnancies with first trimester use of topical azelaic acid or clindamycin (active comparators). We excluded pregnancies with exposure to isotretinoin and other known teratogens. The main outcome was any nongenetic MCM, diagnosed up to a year after birth. We estimated risk ratios (aRR) and 95% confidence intervals (CIs) with log-binomial regression, adjusted for country, maternal age, and birth year.
Results: From 2006 to 2020, the prevalence of topical retinoid use increased from 8.7 to 22.1 per 1000 women of fertile age. Of 2,464,047 births included in the cohort, 103 per 100,000 were exposed to topical retinoids in the first trimester (LMP to LMP+97). First trimester prevalence increased by 2.4 per 100,000 per year (p=0.101). Among pregnancies exposed to topical retinoids, 3.8% resulted in an MCM (65 of 1,732), compared to 3.1% of unexposed (76,306 of 2,436,693), aRR 1.2 (95% CI 0.94-1.52), and 3.1% of pregnancies exposed to azelaic acid or clindamycin (176 of 5,913), aRR 1.2 (95% CI 0. 92-1.63). Sensitivity analysis showed similar results.
Conclusions: Despite an increase in use among women of fertile age, use of topical retinoids in pregnancy remained at a low level. We found no excess risk of MCM associated with use of topical retinoids in the first trimester. Limiting to pregnancies resulting in a birth could underestimate both the prevalence and MCM risk.
