(241) Association of First Trimester Macrolide Use With Congenital Malformations in the Offspring

Background: Macrolide antibiotics are commonly used during pregnancy. Safety data are conflicting, however, with some studies suggesting increased risks of cardiac malformations and major congenital malformation overall. Methodological challenges, including lack of adjustment for treatment indication and heterogenous reference populations, complicate interpretation of the available evidence.

Objectives: To evaluate the association between macrolide use during the first trimester of pregnancy and risk of congenital malformations.

Methods: We conducted a cohort study including pregnancies ending in live births from nationwide US Medicaid data (2000-18) who were exposed to macrolides (exposed) or amoxicillin (referent), defined as ≥1 filled prescriptions between the date of last menstrual period (LMP) and LMP+90 days. Outcomes of interest included major congenital malformations overall (MCM), cardiac malformations, and other organ system malformations. Relative risks (RR) with 95% confidence intervals (CI) were estimated for all macrolides combined and for individual macrolides (azithromycin, clarithromycin, and erythromycin) using log-binomial models, with propensity score overlap weights to control for treatment indications and other potential confounders.

Results: We identified 99,062 pregnancies exposed to macrolides and 95,918 exposed to amoxicillin in the first trimester. Among these, 3,278 (3.31%) infants exposed to macrolides and 3,144 (3.28%) infants exposed to amoxicillin were diagnosed with MCM. The weighted RRs were 0.98 (95% CI 0.93-1.03) for MCM overall and 0.96 (0.86-1.06) for cardiac malformations. There was no association between macrolides and specific cardiac defects or other organ system malformations. Among macrolide exposed pregnancies, 90,869 were exposed to azithromycin only, 5,180 to erythromycin only, and 1,565 to clarithromycin only. The weighted RRs for MCM overall were 0.98 (0.93-1.04) for azithromycin, 0.91 (0.76-1.08) for erythromycin, and 1.14 (0.87-1.49) for clarithromycin. The weighted RRs for cardiac malformations were 0.95 (0.86-1.06), 0.93 (0.68-1.29), and 1.41 (0.89-2.23) respectively. Associations between individual macrolides and other organ specific malformations were either null or imprecisely estimated due to the relatively small number of pregnancies with exposure to erythromycin and clarithromycin.

Conclusions: First trimester exposure to macrolides overall was not associated with congenital malformations in the offspring compared with amoxicillin. The elevated point estimate for cardiac malformations with clarithromycin observed in the context of multiple testing and small numbers requires further evaluation.