{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T15:15:25Z","timestamp":1790176525510,"version":"4.1.0"},"update-to":[{"DOI":"10.1371\/journal.pmed.1004576","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2025,4,24]],"date-time":"2025-04-24T00:00:00Z","timestamp":1745452800000}}],"reference-count":40,"publisher":"Public Library of Science (PLoS)","issue":"4","license":[{"start":{"date-parts":[[2025,4,15]],"date-time":"2025-04-15T00:00:00Z","timestamp":1744675200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["www.plosmedicine.org"],"crossmark-restriction":false},"short-container-title":["PLoS Med"],"abstract":"<jats:sec id=\"sec019\">\n<jats:title>Background<\/jats:title>\n<jats:p>While macrolides are among the frequently prescribed antibiotics for pregnant women, evidence of their fetal safety remains conflicting. This study aimed to evaluate the risk of major congenital malformations (MCM) after first-trimester exposure to macrolides compared with amoxicillin, focusing on specific MCM subtypes.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec020\">\n<jats:title>Methods and findings<\/jats:title>\n<jats:p>This nationwide cohort study used data from the Mother-Child EPI-MERES Register nested in the French Health Data System (SNDS). Pregnancies linked with their singleton live-born infants from January 1, 2010, and December 31, 2020, were included. The macrolide exposure group comprised pregnancies with one or more prescriptions filled for systemic macrolides (erythromycin, spiramycin, roxithromycin, josamycin, clarithromycin, and azithromycin) during the first trimester. The comparator group comprised pregnancies exposed to amoxicillin during the first trimester. Adjusted relative risks (aRR) and 95% CI were estimated by log-binomial regression for any MCM overall and individual MCMs with a prevalence of at least one per 10,000 live-born infants in the macrolide exposure group. Among 7,644,579 eligible pregnancies, 140,708 exposed to macrolides and 592,652 exposed to amoxicillin were included. After adjustment for measured confounders, macrolide exposure during the first trimester was not associated with any MCM overall (aRR 1.00, 95% CI 0.96 to 1.05) compared with amoxicillin. Specifically, no increased risk was found for most individual MCMs. However, an increase in the risk for spina bifida (aRR 1.82, 95% CI 1.22 to 2.71) and syndactyly (aRR 1.65, 95% CI 1.06 to 2.58) was observed. The adjusted risk difference per 10,000 live-born infants was 1.15 (95% CI 0.26 to 2.05) for spina bifida and 0.87 (95% CI 0.01 to 1.72) for syndactyly. Sensitivity analyses consistently yielded elevated point estimates for these two MCMs, despite wide confidence intervals and small numbers of events. Residual confounding by indication is possible.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec021\">\n<jats:title>Conclusions<\/jats:title>\n<jats:p>The findings indicate that macrolide exposure during the first trimester is not strongly associated with an increased risk for most individual MCMs, which is reassuring. However, an increased risk of spina bifida and syndactyly remains possible. Future studies are required to investigate these observations further as evidence continues to grow.<\/jats:p>\n<\/jats:sec>","DOI":"10.1371\/journal.pmed.1004576","type":"journal-article","created":{"date-parts":[[2025,4,15]],"date-time":"2025-04-15T17:33:38Z","timestamp":1744738418000},"page":"e1004576","update-policy":"https:\/\/doi.org\/10.1371\/journal.pmed.corrections_policy","source":"Crossref","is-referenced-by-count":11,"title":["First-trimester exposure to macrolides and risk of major congenital malformations compared with amoxicillin: A French nationwide cohort study"],"prefix":"10.1371","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3541-5524","authenticated-orcid":true,"given":"Anh","family":"Tran","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mahmoud","family":"Zureik","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeanne","family":"Sibiude","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara","family":"Miranda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J\u00e9r\u00f4me","family":"Drouin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lise","family":"Marty","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alain","family":"Weill","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rosemary","family":"Dray-Spira","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xavier","family":"Duval","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah","family":"Tubiana","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2025,4,15]]},"reference":[{"issue":"10","key":"pmed.1004576.ref001","doi-asserted-by":"crossref","first-page":"2238","DOI":"10.1093\/jac\/dkq307","article-title":"Oral antibiotic prescribing during pregnancy in primary care: UK population-based study","volume":"65","author":"I Petersen","year":"2010","journal-title":"J Antimicrob Chemother"},{"issue":"6","key":"pmed.1004576.ref002","doi-asserted-by":"crossref","first-page":"648.e1-648.e15","DOI":"10.1016\/j.ajog.2019.06.050","article-title":"In utero exposure to antibiotics and risk of congenital malformations: a population-based study","volume":"221","author":"P Damkier","year":"2019","journal-title":"Am J Obstet Gynecol"},{"issue":"5","key":"pmed.1004576.ref003","doi-asserted-by":"crossref","first-page":"1629","DOI":"10.1111\/bcp.15638","article-title":"Trends in anti-infective use during pregnancy in France between 2010 and 2019: a nationwide population-based study","volume":"89","author":"S Tubiana","year":"2023","journal-title":"Br J Clin Pharmacol"},{"issue":"2","key":"pmed.1004576.ref004","doi-asserted-by":"crossref","first-page":"250.e1","DOI":"10.1016\/j.ajog.2023.12.020","article-title":"Prescription medication use during pregnancy in the United States from 2011 to 2020: trends and safety evidence","volume":"231","author":"O Mansour","year":"2024","journal-title":"Am J Obstet Gynecol"},{"key":"pmed.1004576.ref005","first-page":"1052","volume-title":"A Review of Antibiotic Use in Pregnancy. 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