TMP-SMX in pregnancy linked to higher risk of infant birth defects

Trimethoprim-sulfamethoxazole (TMP-SMX) exposure increases malformation risks among infants vs β-lactam antibiotic exposure, according to a recent study published in JAMA Network Open.¹

Urinary tract infections (UTIs) present in pregnant patients more often than any other infection, increasing the risk of adverse perinatal outcomes such as low birth weight, preterm birth, pyelonephritis, and maternal sepsis.² Therefore, antibiotic treatments such as TMP-SMX are often used in the first trimester of pregnancy, despite concerns about associated malformations.¹

“Evidence regarding antibiotic safety in pregnancy is needed to guide clinical practice,” wrote investigators. “We evaluated whether nitrofurantoin, TMP-SMX, or fluoroquinolones were associated with congenital malformations (any and by organ system) compared with other antibiotics commonly used to treat UTIs.”

Comparing antibiotic safety during pregnancy

Study participants included pregnant patients provided antibiotic therapy to manage UTI during the first trimester. Infants of these individuals were also included in the analysis.

Additional eligibility criteria included prescription drug coverage from 3 months before the last menstrual period to 1 month after pregnancy, first-trimester outpatient dispensing of an antibiotic against UTIs, and a UTI indication within 7 days of the index indication. Patients with more than 1 UTI-related antibiotic in the first trimester, a supply of index prescription lasting over 14 days, or infection-related hospitalization were excluded.

Oral antibiotic dispensings were identified from outpatient pharmacy claims. These included nitrofurantoin, TMP-SMX, fluoroquinolones, and β-lactams, with β-lactams used as a reference group.

Congenital malformations were reported as the primary outcome, identified using validated algorithms assessing inpatient and outpatient diagnosis codes. Codes for the first month were assessed for the birthing person vs up to 365 days after birth for the infant. Covariates included demographics, comorbidities, suspected teratogenic medications, and nonindex antibiotics.

Antibiotic usage and malformation rates

There were 71,604 pregnancies included in the final analysis. Of pregnant patients, 59.2% used nitrofurantoin in the first trimester, while 4.9% used TMP-SMX, 5.1% fluoroquinolones, and 30.8% β-lactams. Participants were aged a mean of 30 years, and 98.6% had a single pregnancy. Most patient characteristics were similar across agents.

Malformations were identified in 1518 infants, 729 of whom had cardiac malformations. Overall, an unadjusted absolute risk for any malformation of 19.8 per 1000 infants was reported for β-lactams, vs 21.2 per 1000 for nitrofurantoin, 23.5 per 1000 for fluoroquinolones, and 26.9 per 1000 for TMP-SMX.

Similar patterns were found for cardiac malformations. Overall, the weighted risk ratio (RR) for any malformation among infants exposed to TMP-SMX vs β-lactams was 1.35. One additional malformation was indicated for every 145 pregnancies exposed to TMP-SMX.

Nitrofurantoin-exposed infants had a similar risk of any malformation compared to β-lactam–exposed infants, with a weighted RR of 1.12. For fluoroquinolone-exposed infants, the weighted RR was 1.18.

Organ-specific risks and notable findings

TMP-SMX–exposed pregnancies had an RR of 1.45 for cardiac malformation compared to β-lactam–exposed pregnancies, indicating a similar risk. However, orofacial and respiratory malformations had increased risks on a relative scale, with an RR of 2.89.

When restricting analyses to specific malformation groups, increased risks of severe cardiac malformations, other cardiac malformations, and cleft lip and cleft palate were reported in infants exposed to TMP-SMX during pregnancy vs β-lactam. However, these risks were only observed on a relative scale and not an absolute scale.

These results indicated that the use of first-trimester TMP-SMX to treat UTIs increases the risk of any malformation, severe cardiac malformation, other cardiac malformation, and cleft lip and palate in infants vs β-lactam. However, the data indicated no increased risk for nitrofurantoin.

“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,” wrote investigators.

References

1. 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
2. Kazemier BM, Koningstein FN, Schneeberger C, et al. Maternal and neonatal consequences of treated and untreated asymptomatic bacteriuria in pregnancy: a prospective cohort study with an embedded randomised controlled trial.Lancet Infect Dis. 2015;15(11):1324-1333. doi:10.1016/S1473-3099(15)00070-5