Researchers have found in a new study involving over 70,000 pregnancies in the U.S. that using trimethoprim-sulfamethoxazole (TMP-SMX) during the first trimester is associated with a higher risk of congenital malformations. The malformations include especially cardiac defects and cleft lip/palate, compared to beta-lactam antibiotics. In contrast, nitrofurantoin, another commonly used UTI antibiotic, showed no increased risk of birth defects. The study has been published in JAMA Network Open by Sarah S. and colleagues.
The research used data from the Merative MarketScan Commercial Database for the 2006-2022 period. It comprised 71,604 pregnant women aged 15-49 years who were commercially insured and treated for UTI in the first trimester. The participants were matched with their liveborn offspring, and congenital malformations were monitored through diagnosis codes up to 365 days post-delivery. The analysis was done by comparing results across participants exposed to the four primary groups of antibiotics: nitrofurantoin (59.2%), TMP-SMX (4.9%), fluoroquinolones (5.1%), and β-lactams (30.8%). Risk ratios (RRs) and risk differences for overall and certain malformations were estimated using log-binomial regression models, with propensity score weights.
Main Findings
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The median maternal age was 30 years, and gestation at exposure differed by antibiotics: nitrofurantoin (62 days), β-lactams (63 days), TMP-SMX (26 days), and fluoroquinolones (18 days).
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The absolute risk for any congenital malformation per 1,000 infants was greatest with TMP-SMX at 26.9 (95% CI, 21.8-32.8), followed by fluoroquinolones at 23.5 (95% CI, 18.8-28.9), nitrofurantoin at 21.2 (95% CI, 19.9-22.7), and β-lactams at 19.8 (95% CI, 18.0-21.8).
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Following adjustment for potential confounding factors, TMP-SMX was significantly related to any congenital malformation (RR, 1.35; 95% CI, 1.04-1.75) when compared with β-lactams.
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In addition, TMP-SMX use was associated with particularly severe malformations. Risk for severe cardiac malformations was more than doubled (RR, 2.09; 95% CI, 1.09-3.99), and other cardiac defects (RR, 1.52; 95% CI, 1.02-2.25) and cleft lip and palate (RR, 3.23; 95% CI, 1.44-7.22) also demonstrated increased risks.
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Nitrofurantoin and fluoroquinolones, however, did not demonstrate statistically significant elevated risks compared with β-lactams (nitrofurantoin RR, 1.12; 95% CI, 1.00-1.26; fluoroquinolones RR, 1.18; 95% CI, 0.87-1.60).
Researchers determined that first-trimester TMP-SMX exposure was linked to a greater risk of total congenital malformations, especially severe cardiac abnormalities and cleft lip and palate, compared to β-lactam antibiotics. These results reiterate the need for prudent antibiotic choice in early pregnancy and potentially guide prescribing practice to enhance fetal and maternal outcomes.
Reference:
Osmundson SS, Nickel KB, Shortreed SM, et al. First-Trimester Antibiotic Use for Urinary Tract Infection and Risk of Congenital Malformations. JAMA Netw Open. 2025;8(7):e2519544. doi:10.1001/jamanetworkopen.2025.19544
