A cohort study of 71,604 pregnancies found that first-trimester exposure to trimethoprim-sulfamethoxazole for urinary tract infection was associated with increased risk of congenital malformations when compared with β-lactam antibiotics, according to a recent study.
The study used data from the Merative MarketScan Commercial Database spanning 2006 to 2022.
Participants included pregnant patients aged 15 to 49 years who filled prescriptions for oral antibiotics to treat urinary tract infections (UTIs) during the first trimester and delivered liveborn singleton infants. Researchers compared outcomes between patients exposed to nitrofurantoin (n = 42,402), trimethoprim-sulfamethoxazole (TMP-SMX) (n = 3,494), fluoroquinolones (n = 3,663), and β-lactams (n = 22,045). Infants were followed for malformations using diagnosis code algorithms through 365 days post-birth.
The absolute risk of any malformation per 1,000 infants was 26.9 for TMP-SMX, 23.5 for fluoroquinolones, 21.2 for nitrofurantoin, and 19.8 for β-lactams.
Compared with β-lactams, TMP-SMX was associated with a 35% higher relative risk (RR) of any congenital malformation (RR, 1.35). This corresponded to a risk difference of 6.88 per 1,000 infants and a number needed to harm of 145. Nitrofurantoin and fluoroquinolones did not show significantly increased risks.
TMP-SMX exposure was also associated with increased RRs for specific malformations:
- Severe cardiac malformations (RR, 2.09)
- Other cardiac malformations (RR, 1.52)
- Cleft lip and palate (RR, 3.23)
However, for these outcomes, the risk difference estimates included the null.
Gestational age at antibiotic exposure differed by agent. TMP-SMX was typically used earlier (median, 26 days after the last menstrual period) than β-lactams (median, 63 days), which may coincide with critical periods of fetal development.
To control for confounding, researchers used propensity score weighting and conducted multiple sensitivity analyses. The associations between TMP-SMX and malformations remained consistent when restricted to symptomatic UTI cases or adjusted for gestational age.
Sarah S. Osmundson, MD, MS, of the Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology, Vanderbilt University Medical Center, Nashville, Tennessee, and colleagues, noted, “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.”
No increased risk was observed with nitrofurantoin, even when exposure occurred during organogenesis windows. This result remained stable across relative and absolute effect estimates.
The study addressed limitations of previous research by focusing exclusively on UTI-related antibiotic exposure and using β-lactams, which are generally considered safe in pregnancy, as the comparator group.
Limitations included the use of administrative claims data, lack of data on medication adherence, and exclusion of non–live birth outcomes, which may underestimate certain risks. Despite these limitations, the study offers large-scale comparative data to inform antibiotic prescribing during early pregnancy.
Full disclosures can be found in the published study.
Source: JAMA Network Open
