A large-scale study published in theJournal of the American Medical Associationfound first-trimester exposure to mRNA COVID-19 vaccines was not associated with an increased risk of major congenital malformations (MCMs), either overall or by specific organ systems. The findings support the safety of mRNA COVID-19 vaccination during early pregnancy. This study used the Mother-Child EPI-MERES Register, and analyzed all live births in France from pregnancies that began between April 1, 2021, and January 31, 2022. This research evaluated 527,564 eligible live-born infants, of whom 130,338 (about 24.7%) were exposed to at least one dose of an mRNA-based COVID-19 vaccine (either Pfizer-BioNTech or Moderna) during their first trimester. To determine whether early vaccination posed any increased risk, this study compared rates of MCMs between infants exposed and unexposed to vaccination in early pregnancy. These malformations were identified according to the European Surveillance of Congenital Anomalies (EUROCAT) guidelines and categorized across 13 organ systems, which encompassed 75 specific birth defects ranging from heart and neural anomalies to limb and abdominal wall malformations. According to the data, the prevalence of MCMs was similar between the groups: 176.6 cases per 10,000 births among vaccinated mothers versus 179.4 per 10,000 among unvaccinated mothers. After adjusting for maternal age, social status, and comorbidities using a propensity score–based model, the weighted odds ratio for any MCM was 0.98 (95% confidence interval [CI], 0.93–1.04), which showed no statistically significant difference. When broken down by organ system, none showed elevated risk associated with vaccination. For example, the odds ratio for digestive system malformations was 0.84 (95% CI, 0.68–1.04), while for abdominal wall defects it was 1.20 (95% CI, 0.75–1.91), both within non-significant ranges. Similarly, no specific congenital condition among the 75 examined displayed any increased incidence linked to first-trimester vaccination. Overall, the study provides strong population-based evidence that mRNA COVID-19 vaccination during early pregnancy does not elevate the risk of congenital abnormalities. These findings offer crucial reassurance to expectant mothers and healthcare providers alike, strengthening the safety profile of mRNA vaccines during all stages of pregnancy. Bernard, C., Duchemin, T., Marty, L., Drouin, J., Miranda, S., Semenzato, L., Botton, J., Chouchana, L., Dray-Spira, R., Weill, A., & Zureik, M. (2025). First-trimester mRNA COVID-19 vaccination and risk of major Congenital Anomalies. JAMA Network Open, 8(10), e2538039.https://doi.org/10.1001/jamanetworkopen.2025.38039