First-Trimester UTI Antibiotic Use Tied to Congenital Malformation Risks

 

• Earlier research raised concerns about antibiotic use during the first trimester of pregnancy and risk for congenital malformations.
• In this study, the risk of malformation was higher for infants exposed to TMP-SMX versus β-lactam antibiotics.
• Findings support ACOG's recommendation to avoid TMP-SMX during the first trimester but not ACOG's caution against nitrofurantoin.

Taking certain antibiotics for urinary tract infection (UTI) during the first trimester of pregnancy was linked to increased risk for some congenital malformations, an analysis of commercially insured 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 in St. Louis, 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 Openopens in a new tab or window.

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. The risk of other types of malformation didn't differ by antibiotic.

"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 versus β-lactam antibiotics," the authors concluded. "Our results support the current ACOG [American College of Obstetricians and Gynecologists] 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 fetuses 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 make up more than half of first-trimester antibiotic prescriptions for UTIs.

"To our knowledge, our study is the first large-scale examination restricted to pregnant individuals 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 U.K. Science Media Centeropens in a new tab or window 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 fetal anomalies when used in the first trimester for urinary tract infection treatment, which had been previously suggested in some evidence."

This 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 ages 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 fill 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 nonrandomized 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. Lastly, the findings may not apply to Medicaid and uninsured populations.

Disclosures

This work was supported by the National Institute of Child Health and Human Development (NICHD) of the NIH

Butler reported receiving grants from NIH and Merck.

Co-authors disclosed relationships with NICHD, GSK, Pfizer, Syneos Health, Opioid Pharmaceutical Consortium via Syneos, GSK, AbbVie, Bristol-Myers Squibb, and Exact Sciences.

Ovadia reported relationships with Mirum Pharmaceuticals and Dr. Falk Pharma.

Primary Source

JAMA Network Open

Source Reference: opens in a new tab or windowOsmundson SS, et al "First-trimester antibiotic use for urinary tract infection and risk of congenital malformations" JAMA Netw Open 2025; DOI: 10.1001/jamanetworkopen.2025.19544.

https://www.medpagetoday.com/obgyn/pregnancy/116477