Infants of mothers treated in the first trimester of pregnancy with trimethoprim/sulfamethoxazole (TMP-SMX) antibiotics for urinary tract infection (UTI) appeared to have a higher risk for any malformation, severe cardiac malformation, and cleft lip and palate than those exposed to beta-lactam antibiotics, a large cohort study of commercially insured pharmaceutical claims found.
Recommended routine screening for asymptomatic bacteriuria at the initial prenatal visit often leads to antibiotics being given in the first trimester when the fetus is most susceptible to teratogenic medications and adverse effects from infections.
The study, published in JAMA Network Open found no elevated malformation risk for nitrofurantoin, however, although current American College of Obstetricians and Gynecologists (ACOG) guidance recommends that it be avoided in the first trimester unless there is no other appropriate alternative.
By type of defect, TMP-SMX was associated with an increased risk for severe cardiac malformations (relative risk [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 beta-lactam antibiotics, according to Anne M. Butler, PhD, MS, a pharmacoepidemiologist at Washington University in St. Louis, and colleagues. The findings emerged from an examination of 71,604 pregnancies in women aged 15-49 years with a median age of 30.
Common in pregnancy, UTIs include asymptomatic bacteriuria and acute cystitis; both are associated with adverse perinatal outcomes, including preterm birth, low birth weight, pyelonephritis, and maternal sepsis.
“There is limited guidance on antibiotic selection for UTI treatment in the first trimester due to the potential risk of congenital malformations associated with some antibiotics commonly used to treat UTIs,” Butler told Medscape Medical News. “But outside of the first trimester of pregnancy, nitrofurantoin and TMP-SMX are considered first-line agents for UTI treatment.”
Median gestational age at exposure differed by antibiotic with TMP-SMX prescribed significantly earlier in pregnancy than others: TMP-SMX, 26 (13-59) days; nitrofurantoin, 62 (45-77) days; fluoroquinolones, 18 (9-27) days; and beta-lactams, 63 (48-77) days. Very little TMP-SMX use occurred at 10-13 weeks, when asymptomatic bacteriuria screening typically occurs.
The authors conjectured that TMP-SMX-exposed individuals may have had more unrecognized or unplanned pregnancies than their beta-lactam-exposed counterparts. That could result in residual confounding because such pregnancies may be more exposed to teratogenic prescription medications, tobacco, alcohol, or illicit drugs.
Malformation Risks
Per 1000 infants, the absolute risk for any malformation was 19.8 (95% CI, 18.0-21.8) for beta-lactams; 21.2 (95% CI,19.9-22.7) for nitrofurantoin; 23.5 (95% CI, 18.8-28.9) for fluoroquinolones; and 26.9 (95% CI, 21.8-32.8) for TMP-SMX.
After accounting for confounding, the relative risk for any congenital malformation was highest for TMP-SMX (RR, 1.35; 95% CI, 1.04-1.75). Risk was 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 beta-lactams.
Nitrofurantoin and TMP-SMX are more effective for UTIs than beta-lactams. “TMP-SMX resistance can be high in some geographical areas such that it shouldn’t be used in the absence of culture results,” Butler said. She added that nitrofurantoin works well for lower UTIs such as acute cystitis and asymptomatic bacteriuria but is not recommended for suspected upper UTIs such as pyelonephritis.
Butler said that their 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.
Commenting on the research but not involved in it, Rachel Newman, MD, an assistant professor and maternal-fetal medicine specialist at UTHealth Houston, called it a well-done study that removes the confounding of previous studies. It used an active comparator design and restricted the cohort to individuals treated for UTI rather than for any indication. “It should be generalizable with the caveat that different practice communities have different degrees of resistance to individual antibiotics,” Newman said.
However, the commercial database findings may not be applicable to government-insured and uninsured patients, she noted.
Newman stressed that any antibiotic use in pregnancy should be a thoughtful weighing of risks and benefits, but abundant data have demonstrated the safety of all the antibiotics in this study for pregnant women. “It is reassuring to me that we may be able to use more nitrofurantoin than we’ve been since there is less resistance to this than to beta-lactams,” she said, which provides another option making UTIs easier to treat before they progress to greater morbidity. “But the study points out that antibiotics, though safe in general, should not be used lightly in pregnancy.”
This work was supported by the National Institute of Child Health and Human Development. The Administrative Data Core Services is supported in part by a grant from the Washington University Institute of Clinical and Translational Sciences through the National Center for Advancing Translational Sciences of the National Institutes of Health (NIH). Butler reported receiving grants from NIH during the conduct of the study and grants from Merck outside of the submitted work. Several coauthors reported receiving grants from the NIH and/or grants from various private-sector companies. Newman had no competing interests to disclose.