BACKGROUND & AIMS: Limited data are available on the risk of major congenital malformations (MCMs) of thiopurines and anti-tumor necrosis factor (TNF) during pregnancy. In this study, we assess the risk of MCMs associated with maternal exposure to thiopurines and anti-TNF for the treatment of inflammatory bowel disease (IBD) during pregnancy. METHODS: Using the nationwide comprehensive EPI-MERES registry, we identified all births >22 weeks of pregnancy in mothers with IBD in France between April 2010 and December 2021. We compared the risks of 75 individual MCMs according to thiopurines and anti-TNF exposure during the first trimester of pregnancy, accounting for maternal and pregnancy characteristics using propensity score weighting. Sensitivity analyses were conducted to assess estimates robustness. RESULTS: Among a total of 39,515 births (5223 exposed to thiopurines, 6528 to anti-TNF, and 28,827 unexposed), 717 (181.5/10,000) had >/=1 MCM. The overall prevalence of MCMs ranged from 175.2 per 10,000 among unexposed births to 197.2 per 10,000 among those exposed to thiopurine, and 203.7 per 10,000 among those exposed to anti-TNF. None of the 75 MCMs was consistently associated with in utero exposure to thiopurines in the main and sensitivity analyses. However, anti-TNF exposure was associated with an increased risk of talipes equinovarus in the main analysis (adjusted risk ratio, 2.17; 95% confidence interval, 1.04-4.53) and in sensitivity analyses (adjusted risk ratios ranging between 2.15 and 2.40). CONCLUSIONS: This study provides no evidence of substantial risk of MCMs associated with in utero exposure to thiopurines or anti-TNF, except for talipes equinovarus, which appears increased with exposure to anti-TNF. This finding needs to be confirmed in further studies.