A recent study suggests the risk of antibiotic use during the first trimester of pregnancy was higher for infants exposed to TMP-SMX versus β-lactam antibiotics.
The finding, which follows earlier research flagging concerns about antibiotic use during the first trimester of pregnancy and risk for congenital malformations, supports a recommendation of the American College of Obstetricians and Gynaecologists (ACOG) to avoid drug during the first trimester but not ACOG’s caution against nitrofurantoin.
The recent analysis of pregnant women found absolute risk of any malformation per 1 000 infants was highest for trimethoprim-sulfamethoxazole (TMP-SMX) at 26.9 (95% CI 21.8-32.8), followed by 23.5 (95% CI 18.8-28.9) for fluoroquinolones, 21.2 (95% CI 19.9-22.7) for nitrofurantoin, and 19.8 (95% CI 18.0-21.8) for β-lactams, reported Anne Butler, PhD, MS, of the Washington University School of Medicine and colleagues.
After accounting for confounding, the risk for any congenital malformation was higher with TMP-SMX (RR 1.35, 95% CI 1.04-1.75), while nitrofurantoin (RR 1.12, 95% CI 1.00-1.26) and fluoroquinolones (RR 1.18, 95% CI 0.87-1.60) had similar risk as β-lactams, they wrote in JAMA Network Open.
TMP-SMX was associated with increased risk of severe cardiac malformations (RR 2.09, 95% CI 1.09-3.99) and other cardiac malformations (RR 1.52, 95% CI 1.02-2.25), as well as cleft lip and palate (RR 3.23, 95% CI 1.44-7.22) compared with β-lactams, though authors noted the corresponding risk difference estimates included the null.
Medpage Today reports that the risk of other types of malformation didn’t differ by antibiotic.
In their 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 versus β-lactam antibiotics”, the authors concluded.
“Our results support the current ACOG recommendation for caution in using TMP-SMX during the first trimester but do not support current recommendations to limit nitrofurantoin use.”
UTIs are common during pregnancy, including asymptomatic bacteriuria and acute cystitis, which are associated with adverse perinatal outcomes like preterm birth, low birth weight, pyelonephritis, and maternal sepsis.
Routine screening often occurs at the initial prenatal appointment, leading to antibiotic treatment during the first trimester when developing foetuses are most susceptible to teratogenic medication effects and potential adverse effects from medication.
Previous research raised concerns about increased risk of congenital malformations associated with TMP-SMX and nitrofurantoin, though authors noted these studies had methodological limitations.
Even though ACOG recommends these two be avoided during the first trimester, they comprise more than half of first-trimester antibiotic prescriptions for UTIs.
“To our knowledge, our study is the first large-scale examination restricted to pregnant women with UTI, rather than heterogeneous indications that may independently increase risk of malformations,” the authors wrote.
Caroline Ovadia, BMBCh, PhD, of the University of Edinburgh in Scotland, who wasn't involved with the research, posted on the UK Science Media Centre website that this study found that “the absolute risk of congenital anomalies with antibiotic treatment for urinary tract infection in pregnancy remains low, supporting the benefit of appropriate clinician-led treatment of urinary tract infection in pregnancy”.
One reassuring result, Ovadia noted, was that the antibiotic nitrofurantoin was not found to be associated with higher risks of foetal anomalies when used in the first trimester for urinary tract infection treatment, which had been previously suggested in some evidence.
Medical claims
The population-based cohort study studied pregnant women who received first-trimester antibiotic therapy for UTI and their live-born infants from 2006 to 2022.
Data came from the Merative MarketScan Commercial Database, which contains longitudinal, patient-level data for people with employer-sponsored commercial insurance and their covered families on all adjudicated medical claims and outpatient pharmacy-dispensed medications.
Patients were between 15 and 49; median maternal age was 30. Median gestational age varied by antibiotic, at 63 days for β-lactams, 62 for nitrofurantoin, 26 for TMP-SMX, and 18 for fluoroquinolones.
The primary exposure was a first-trimester prescription of nitrofurantoin, TMP-SMX, fluoroquinolones (ciprofloxacin, levofloxacin, ofloxacin), and β-lactams to treat UTI. Any congenital malformation overall and by organ system were the primary outcomes.
In the cohort of more than 71 000 pregnancies, 59.2% were nitrofurantoin-exposed, 30.8% were β-lactam-exposed, 5.1% were fluoroquinolone-exposed, and 4.9% were TMP-SMX-exposed. In total there were 1 518 infants with malformations, of which 729 were cardiac related.
Sensitivity analyses using amoxicillin alone or cephalexin rather than all UTI-related β-lactam antibiotics, alternative outcome definition, restriction to symptomatic UTI, and adjustment for gestational age at index “yielded effect estimates consistent with the magnitude and direction of estimates in primary analyses for any malformation”.
Butler and team noted limitations, including the possibility of residual confounding from the non-randomised design. Because the study only looked at live births there was the potential of selection bias.
Outcome misclassification is possible because malformations were identified using claims-based algorithms instead of medical records, and exposure misclassification is also possible if people didn’t actually take the medications they filled.
Last, the findings may not apply to Medicaid and uninsured populations, they said.
Study details
First-Trimester Antibiotic Use for Urinary Tract Infection and Risk of Congenital Malformations
Sarah Osmundson, Katelin Nickel, Susan Shortreed et al.
Published in JAMA Network Open on 9 July 2025
Abstract
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.
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