Macrolide exposure during first trimester not linked to congenital malformations, study finds

A new study published in the journal of PLOS Medicine showed that for the majority of individual major congenital malformations (MCMs), exposure to macrolides during the first trimester is not significantly linked to an elevated risk, which is comforting.

Because macrolides may penetrate the placenta, even at a low rate, the risk of severe congenital malformations linked to exposure to them during pregnancy is usually a cause for worry. Despite being one of the most often given antibiotics for expectant mothers, there is still contradictory information about the safety of macrolides for the fetus. With a focus on certain MCM subtypes, Anh Tran and team sought to assess the risk of major congenital malformations following first-trimester exposure to macrolides as opposed to amoxicillin.

Data from the Mother-Child EPI-MERES Register, which is housed inside the French Health Data System (SNDS), was utilized in this countrywide cohort research. Included were pregnancies associated with their singleton live-born children between January 1, 2010, and December 31, 2020. Pregnancies with one or more prescriptions written for systemic macrolides (erythromycin, roxithromycin, spiramycin, clarithromycin, josamycin, and azithromycin) during the first trimester were included in the macrolide exposure group.

Pregnancies exposed to amoxicillin throughout the first trimester made up the comparative group. Log-binomial regression was used to estimate adjusted relative risks (aRR) and 95% confidence intervals (CI) for any MCM in general and for specific MCMs that had a prevalence of at least one per 10,000 live-born babies in the macrolide exposure group.

1,40,708 pregnancies with macrolide exposure and 592,652 pregnancies with amoxicillin exposure were included in the 7,644,579 eligible pregnancies. When compared to amoxicillin, macrolide exposure during the first trimester was not linked to any MCM overall, even after controlling for observed confounders. In particular, the majority of individual MCMs did not exhibit elevated risk. On the other hand, a higher risk for syndactyly and spina bifida was noted.

For spina bifida and syndactyly, the adjusted risk difference per 10,000 live births was 1.15 and 0.87, respectively. Despite modest numbers of events and broad confidence intervals, sensitivity studies consistently produced increased point estimates for these two MCMs. There is a chance of residual confusion by indication. Overall, the results of this investigation verify that the majority of individual MCMs are not linked to macrolide antibiotics.

Source:

Tran, A., Zureik, M., Sibiude, J., Miranda, S., Drouin, J., Marty, L., Weill, A., Dray-Spira, R., Duval, X., & Tubiana, S. (2025). First-trimester exposure to macrolides and risk of major congenital malformations compared with amoxicillin: A French nationwide cohort study. PLoS Medicine, 22(4), e1004576. https://doi.org/10.1371/journal.pmed.1004576