(266) First trimester tetracycline use and risk of major congenital malformations: A cohort study

Background: Safety data on tetracycline antibiotic use during pregnancy are limited.

Objectives: To investigate the association between first trimester exposure to tetracyclines and the risk of major congenital malformations

Methods: Cohort study using nationwide Swedish registers for the period from 1 July 2006 to 31 December 2019. From a source cohort of 1245889 eligible singleton live-born infants, 69656 were included in the propensity score-matched analytical cohort. First trimester exposure to tetracycline antibiotics was determined from maternal prescriptions for ATC code J01A filled between the last menstrual period and day 97 of gestation, and compared to no such exposure. The primary outcome was any major congenital malformation diagnosed in the first year of life; secondary outcomes were 12 major malformation organ system subgroups and 16 individual malformations selected based on prior safety signals and/or fulfilment of prespecified statistical power criteria. Anomalies were classified according to the European Surveillance of Congenital Anomalies (EUROCAT guide 1.5). Log binomial regression was used to estimate risk ratios (RRs) with 95% confidence intervals (CIs). Propensity score matching controlled for confounding.

Results: Of 6340 infants exposed to tetracyclines during the first trimester, 252 were diagnosed with any major congenital malformation (39.75 [95% CI, 35.14-44.93] cases per 1000) compared to 2454 of 63316 unexposed infants (38.76 [95% CI, 37.27-40.30] cases per 1000). Tetracycline exposure overall was not associated with any major congenital malformation (RR 1.03 [95% CI, 0.90-1.16]). The RRs for 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 organ system subgroups, nor of any of the 16 individual malformations investigated. Although increased RRs were observed in the main analysis for nervous system anomalies (RR 1.92 [95% CI, 0.98-3.78]) and eye anomalies (RR 1.76 [95% CI, 1.07-2.91]) with tetracycline exposure overall, estimates were attenuated in a sensitivity analysis with follow-up extended up to age three years (RR 1.08 [95% CI, 0.52-2.24] for nervous system anomalies and RR 1.42 [95% CI, 0.88-2.29] for eye anomalies).

Conclusions: In this large population-based study comprising the largest number of tetracycline exposed infants to date, first trimester tetracycline use was not associated with increased risks of major congenital malformations. Additional studies are needed to rule out potential risks owing to power limitations for several malformation subgroups and individual malformations.