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Exposure to Macrolide Antibiotics During the First Trimester of Pregnancy with Risk of Major Congenital Malformations: A French Nationwide Cohort Study
27 Pages Posted: 16 Sep 2024
More...Abstract
Background: 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 (MCMs) after first-trimester exposure to macrolides compared with amoxicillin, focusing on specific malformation subtypes.
Methods: This nationwide cohort study used data from the Mother-Child EPI-MERES Register nested in the French Health Data System (SNDS). We included all pregnancies linked with their singleton live-born infants from January 1, 2010, and December 31, 2020. The macrolide exposure group comprised pregnancies with one or more prescriptions filled for macrolides (erythromycin, spiramycin, roxithromycin, josamycin, clarithromycin, and azithromycin) during the first trimester. The comparator group comprised pregnancies exposed to amoxicillin during the first trimester. MCMs were identified during the first year after delivery. Adjusted relative risks (RRs) and 95%CI were estimated by log-binomial regression for MCMs with a prevalence of at least one per 10,000 live-born infants exposed to macrolides in utero.
Findings: Among 7,644,579 eligible pregnancies, 140,708 exposed to macrolides and 592,652 exposed to amoxicillin during the first trimester were included. Exposure to macrolides was associated with an increased risk for syndactyly (RR 1.68, 95%CI 1.11 to 2.55, based on 31 events in the macrolide exposure group) and spina bifida (1.80, 1.22 to 2.67, 36 events) compared with amoxicillin. We found no increased risk for other specific MCMs. Sensitivity and subgroup analyses for individual macrolides consistently yielded elevated point estimates for syndactyly and spina bifida, despite wide confidence intervals and small numbers of events. Possible residual confounding by indication.
Interpretation: Although macrolide exposure in early pregnancy is not associated with an increased risk for most MCMs considered, an increase in the risks of syndactyly and spina bifida associated with their exposure is still possible. Further studies are needed to confirm as evidence continues to grow.
Funding: None.
Declaration of Interest: All authors declare no competing interests.
Ethical Approval: Our research team (EPI-PHARE) has permanent regulatory access to the data from the SNDS. This study thus did not require specific authorization from the French data protection authority (CNIL). Informed consent was waived as the data were anonymized. This study was approved by the scientific committee of EPI-PHARE (under the reference T-2023-04-512).
Keywords: Macrolides, Pregnancy, Major Congenital Malformations, French Health Data System, SNDS
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