First-trimester antibiotic use for urinary tract infections tied to more congenital malformations

A study of more than 70,000 US pregnancies suggests a commonly used antibiotic for urinary tract infections (UTIs) may be tied to increased risk of congenital malformations when taken during the first trimester of pregnancy.

The study, published today in JAMA Network Open, found that exposure to trimethoprim-sulfamethoxazole (TMP-SMX) during the first trimester was associated with increased risk of any malformation, severe cardiac and other cardiac malformations, and cleft lip and palate compared with beta-lactam antibiotics. No increased risk of congenital malformations was observed with nitrofurantoin, which is also commonly used to treat UTIs.

The study partly substantiates the concerns of the American College of Obstetricians and Gynecologists (ACOG), which has suggested that TMP-SMX and nitrofurantoin be avoided during the first trimester when possible because of uncertainty about the risk of congenital malformations, though studies to date have produced mixed results. Despite the ACOG recommendation, the two antibiotics still account for more than half of first-trimester UTI prescriptions, according to the study authors. 

One of the more common infections during pregnancy

For the study, a team of researchers from Vanderbilt University Medical Center, Washington University School of Medicine in St. Louis, and the University of Washington used the Merative MarketScan Commercial Database to identify a cohort of pregnant women who received first-trimester antibiotics (TMP-SMX, nitrofurantoin, fluoroquinolones, and beta-lactams) for uncomplicated UTIs and their live-born infants. 

UTIs are one of the more common infections that occur during pregnancy, affecting roughly 8% of pregnancies.

“Existing evidence on the risk of malformations associated with first-trimester antibiotic therapy for UTI is limited,” the researchers wrote. “To our knowledge, our study is the first large-scale examination restricted to pregnant individuals with UTI.”

The primary outcome of the study was congenital malformations (any and by organ system) identified up to a year after birth. To assess associations with increased risk of congenital malformations, the study used beta-lactams as the active comparator because beta-lactams are widely accepted as safe during pregnancy.

Higher risk of any malformation

Of the 71,604 pregnancies that met the inclusion criteria, 42,402 (59.2%) had first-trimester exposure to nitrofurantoin, 3,494 (4.9%) to TMP-SMX, 3,663 (5.1%) to fluoroquinolones, and 22,045 (30.8%) to beta-lactams. The median age of pregnant individuals was 30, and patient characteristics were similar across agents. The median gestational age differed by antibiotic (nitrofurantoin, 62 days; TMP-SMX, 26 days; fluoroquinolones, 18 days; beta-lactams, 63 days).

A total of 1,518 infants had malformations, including 729 with cardiac malformations. The unadjusted absolute risk of any malformation was 26.9 per 1,000 infants for TMP-SMX, 23.5/1,000 infants for fluoroquinolones, 21.2/1,000 infants for nitrofurantoin, and 19.8/1,000 infants for beta-lactams. 

After adjustments were made for potential confounders—including demographic characteristics, comorbidities, concomitant medications, and measures of healthcare use—TMP-SMX-exposed pregnancies had a 35% higher risk of any malformation compared with those exposed to beta-lactams (risk ratio [RR], 1.35; 95% confidence interval [CI], 1.04 to 1.75). The number needed to harm was 1 additional malformation for every 145 TMP-SMX-exposed pregnancy. The risks for infants exposed to nitrofurantoin (RR, 1.12; 95% CI, 1.00 to 1.26) and fluoroquinolones (RR, 1.18; 95% CI, 0.87 to 1.60) were similar to those exposed to beta-lactams.

In the analysis of organ-specific malformations, TMP-SMX was associated with increased risk of severe cardiac malformations (RR, 2.09; 95% CI, 1.09 to 3.99) and other cardiac malformations (RR, 1.52; 95% CI, 1.02 to 2.25) on a relative scale compared with beta-lactams. The risk of cleft lip and palate was more than triple (RR, 3.23; 95% CI, 1.44 to 7.22) among TMP-SMX-exposed pregnancies. 

The results were generally consistent in sensitivity analyses.

“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,” the authors concluded.