First Trimester Tetracycline Exposure and Risk of Major Congenital Malformations.

Importance: Safety data on tetracycline antibiotic use during pregnancy are limited. Objective: To investigate the association between first trimester exposure to tetracyclines and the risk of major congenital malformations (MCMs). Design, Setting, and Participants: This cohort study used data from nationwide registers for singleton infants live-born in Sweden from July 1, 2006, to December 31, 2018, with follow-up through December 2019. Tetracycline-exposed and unexposed infants were matched on propensity scores (ratio 1:10). Data analysis was performed from June 2023 to May 2024. Exposure: First trimester exposure to tetracyclines determined from maternal prescription fills, compared with no exposure. Main Outcomes and Measures: The primary outcome was any MCM diagnosed in the first year of life; secondary outcomes were 12 major malformation organ system subgroups and 16 individual malformations selected on the basis of prior safety signals and/or fulfillment of prespecified statistical power criteria. Malformations were identified by International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (ICD-10) codes aligned to the European Surveillance of Congenital Anomalies (EUROCAT) classification. Log binomial regression was used to estimate relative risks (RRs) with 95% CIs. Results: From a source cohort of 1 245 889 eligible infants (640 892 male [51.4%]), a propensity score-matched analytical cohort of 69 656 infants (35 903 male [51.5%]) was generated. Of 6340 infants exposed to tetracyclines during the first trimester (3325 male [52.4%]), 252 received a diagnosis of any MCM (39.75 cases per 1000 infants; 95% CI, 35.14-44.93 cases per 1000 infants) compared with 2454 of 63 316 unexposed infants (38.76 cases per 1000 infants; 95% CI, 37.27-40.30 cases per 1000 infants). Tetracycline exposure was not associated with any MCM (RR, 1.03; 95% CI, 0.90-1.16). The RRs for specific tetracycline substances were 1.07 (95% CI, 0.93-1.23) for doxycycline, 0.83 (95% CI, 0.60-1.15) for lymecycline, and 0.78 (95% CI, 0.32-1.92) for tetracycline-oxytetracycline. There was no increased risk for 10 of 12 malformation subgroups or for any of the 16 individual malformations analyzed. The higher RRs in the main analysis for nervous system anomalies (1.92; 95% CI, 0.98-3.78) and eye anomalies (1.76; 95% CI, 1.07-2.91) were attenuated in a sensitivity analysis with follow-up extended to age 3 years (nervous system anomalies, RR, 1.08; 95% CI, 0.52-2.24; eye anomalies, RR, 1.42; 95% CI, 0.88-2.29). Conclusions and Relevance: In this cohort study, first trimester tetracycline exposure was not associated with increased risks of any MCMs. Additional studies are needed to rule out potential risks owing to power limitations for several MCM subgroups and individual malformations.