Abstract
IMPORTANCE: Although messenger RNA (mRNA) COVID-19 vaccines are widely recommended during pregnancy, data on their fetal safety during the teratogenic window remain limited. OBJECTIVE: To evaluate the association between first-trimester exposure to mRNA COVID-19 vaccines and the risk of major congenital malformations (MCMs), across 75 individual MCMs grouped by 13 organ systems. DESIGN, SETTING, AND PARTICIPANTS: This nationwide, population-based cohort study was conducted using the comprehensive Mother-Child EPI-MERES Register, including all live-born infants in France from pregnancies starting April 1, 2021, to January 31, 2022. Follow-up data were available up to December 2024. EXPOSURE: Exposure was defined as receiving at least 1 dose of mRNA-based COVID-19 vaccine during the first trimester of pregnancy. MAIN OUTCOMES AND MEASURES: MCMs were identified following European Surveillance of Congenital Anomalies guidelines. The main analyses compared exposed and nonexposed infants, and sensitivity analyses used alternative comparison groups based on maternal vaccination status and timing. Confounders were adjusted for using a propensity score-based standardized mortality ratio weighting method. Weighted odds ratios (ORs) were estimated using logistic regression. RESULTS: Among 527 564 eligible live-born infants, 130 338 (24.7%) were exposed to at least 1 vaccine dose during the first trimester. Mothers of exposed infants were slightly older than mothers of unexposed infants (mean [SD] age, 30.4 [5.3] years vs 30.1 [5.1] years), were less socially deprived, and presented slightly more often with a comorbidity. The prevalence of MCMs was 176.6 per 10 000 (2302 infants) among exposed infants and 179.4 per 10 000 (7128 infants) among nonexposed infants. No increased risk of MCMs was observed overall (weighted OR, 0.98 [95% CI, 0.93-1.04]), by organ system (weighted ORs ranging from 0.84 [95% CI, 0.68-1.04] for digestive system MCMs to 1.20 [95% CI, 0.75-1.91] for abdominal wall defects), or for any of the 75 individual MCMs. Sensitivity and stratified analyses confirmed these findings. CONCLUSIONS AND RELEVANCE: In this cohort study of pregnancies exposed to mRNA COVID-19 vaccines in the first trimester, exposure was not associated with an increased risk of any MCMs, overall, by organ group, or by individual MCM, supporting the safety of mRNA COVID-19 vaccines in early pregnancy.