Phloroglucinol Exposure During Early Pregnancy and Risk of Major Congenital Malformations: A Nationwide Cohort Study in France.

BACKGROUND AND AIMS: Phloroglucinol is a spasmolytic drug widely prescribed in France for gastrointestinal or pelvic pain, and frequently used during pregnancy despite limited evidence regarding its safety. We aimed to evaluate the association between first-trimester phloroglucinol exposure and the risk of major congenital malformations (MCMs) in a nationwide cohort. METHODS: Using data from the French EPI-MERES cohort based on the national health data system (SNDS), we identified all pregnancies ending after 22 weeks between 2010 and 2022, excluding women with phloroglucinol use in the year before pregnancy. We compared the risks of 68 MCM subtypes according to exposure during gestational weeks 3-12. Adjusted odds ratios (aORs) were estimated using logistic regression controlling for maternal sociodemographic, medical and pregnancy characteristics. Interpretation relied on effect size (aOR > 1.30) and consistency across sensitivity analyses. RESULTS: Among 6,233,539 pregnancies, 1,024,369 (16.4%) were exposed to phloroglucinol. There were 19,635 MCM cases among children exposed to phloroglucinol and 91,693 among those unexposed (overall aOR 1.05, 95% CI 1.04-1.07). Six rare malformations showed isolated elevated risk estimates: tricuspid stenosis (aOR 1.37, 95% CI 0.96-1.94), Ebstein anomaly (aOR 1.43, 95% CI 0.99-2.06), double outlet left ventricle (aOR 1.60, 95% CI 0.83-3.09), indeterminate sex and pseudohermaphroditism (aOR 1.32, 95% CI 1.05-1.66), anencephaly and similar malformations (aOR 1.55, 95% CI 0.95-2.52), and arhinencephaly/holoprosencephaly (aOR 1.90, 95% CI: 0.97-3.72). However, these findings were not consistent across sensitivity analyses. CONCLUSIONS: In this large nationwide cohort, first-trimester exposure to phloroglucinol was not associated with a clinically meaningful increase in the risk of major congenital malformations.