First-Trimester Antibiotic Use for Urinary Tract Infection and Risk of Congenital Malformations

Importance Clinical guidelines recommend screening and treating bacteriuria in early pregnancy given that urinary tract infections (UTIs) can cause serious maternal and neonatal consequences. Evidence regarding antibiotic exposure during early pregnancy and risk of congenital malformations is limited and inconsistent. Objective To compare the risk of congenital malformations following first-trimester exposure to different antibiotic agents used to treat UTI. Design, Setting, and Participants This population-based cohort study included commercially insured pregnant individuals aged 15 to 49 years who were treated for UTI and linked liveborn infants in the Merative MarketScan Commercial Database (2006-2022). Exposure First-trimester antibiotic prescription fill of nitrofurantoin, trimethoprim-sulfamethoxazole (TMP-SMX), fluoroquinolones (ciprofloxacin, levofloxacin, ofloxacin), and β-lactams to treat UTI. Main Outcomes and Measures Congenital malformations (any and by organ system) were identified using validated algorithms based on diagnosis codes up to 365 days after birth. Log-binomial regression models were used to estimate propensity score–weighted risk ratios (RRs) and risk differences. Results The cohort of 71 604 eligible pregnancies (median maternal [IQR] age, 30 [27-34] years) included 42 402 (59.2%) nitrofurantoin-exposed, 3494 (4.9%) TMP-SMX–exposed, 3663 (5.1%) fluoroquinolone-exposed, and 22 045 (30.8%) β-lactam–exposed individuals. Median (IQR) gestational age differed by antibiotic (nitrofurantoin, 62 [45-77] days; TMP-SMX, 26 [13-59] days; fluoroquinolones, 18 [9-27] days; β-lactams, 63 [48-77] days). The absolute risk of any malformation was 19.8 (95% CI, 18.0-21.8) per 1000 infants for β-lactams, 21.2 (95% CI, 19.9-22.7) per 1000 infants for nitrofurantoin, 23.5 (95% CI, 18.8-28.9) per 1000 infants for fluoroquinolones, and 26.9 (95% CI, 21.8-32.8) per 1000 infants for TMP-SMX. After accounting for confounding, risk of any congenital malformation was higher for TMP-SMX (RR, 1.35; 95% CI, 1.04-1.75) but similar for nitrofurantoin (RR, 1.12; 95% CI, 1.00-1.26) and fluoroquinolones (RR, 1.18; 95% CI, 0.87-1.60) compared with β-lactams. TMP-SMX was associated with increased risk of severe cardiac malformations (RR, 2.09; 95% CI, 1.09-3.99), other cardiac malformations (RR, 1.52; 95% CI, 1.02-2.25), and cleft lip and palate (RR, 3.23; 95% CI, 1.44-7.22) compared with β-lactams; however, for these specific malformations, the corresponding risk difference estimates included the null. Risk of other malformation types did not differ by agent, although some estimates were imprecise. Results were generally consistent across sensitivity analyses. Conclusions and Relevance In this cohort study of first-trimester antibiotic exposure, the risk of any malformation, severe cardiac malformation, other cardiac malformation, and cleft lip and palate was higher for infants exposed to TMP-SMX vs β-lactam antibiotics. No elevated risk was observed for nitrofurantoin.