Maternal use of ondansetron during the first trimester of pregnancy was not found to be associated with cardiac or congenital malformation in offspring; however, ondansetron use may be associated with a slightly increased risk of oral cleft formation, according to a study published in JAMA.

Researchers used the pregnancy cohort of the Medicaid Analytic eXtract dataset from 2000 to 2013 to investigate the association between exposure to ondansetron during the first trimester of pregnancy and the risk of congenital malformation in offspring — specifically cardiac malformation and oral cleft. Women aged 12 to 55 years were included if they had Medicaid coverage from 3 months before their last menstrual period to 1 month after delivery; infants were required to have coverage through Medicaid for the first 3 months of life. Women were considered exposed if they filled at least 1 ondansetron prescription during the first 3 months of pregnancy. A total of 1,816,414 pregnancies provided by 1,502,895 women were included in the cohort.

The primary outcome was a cardiac malformation or oral cleft diagnosed in an infant during the first 90 days after delivery. Secondary outcomes included subgroups of cardiac malformation and oral cleft (palate, lip, or lip and palate) as well as congenital malformations. Confounders included ondansetron treatment indication (nausea and vomiting during pregnancy, hyperemesis gravidarum) and associated conditions (weight loss, electrolyte and laboratory abnormalities, dehydration, gastroesophageal reflux), calendar year, state of residence, age, race, multiple gestation, maternal conditions, concomitant medication, and general markers of the burden of illness.

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Overall, 14,577 of 1,727,947 unexposed and 835 of 88,467 exposed infants were diagnosed with a cardiac malformation resulting in absolute risk of 84.4 (95% CI, 83.0-85.7) and 94.4 (95% CI, 88.0-100.8) per 10,000 births, respectively. For oral clefts, the absolute risk for unexposed infants was 11.1 (95% CI, 10.6-11.6); for exposed infants, the risk was 14.0 (95% CI, 11.6-16.5). In the unadjusted analyses, the increase in risk of cardiac malformations was related to ventricular septal defects (400 exposed and 6826 unexposed cases; relative risk [RR], 1.14) and secundum atrial septal defects (216 exposed and 3080 unexposed cases; RR, 1.37). The increased risk for oral clefts was attributable to cleft palate (65 exposed and 988 unexposed cases; RR, 1.29).

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Based on 3277 exposed and 54,174 unexposed cases, the risk for any congenital malformation was 370.4 (95% CI, 358.0-382.9) vs 313.5 (95% CI, 310.9-316.1), respectively. The adjusted RR for cardiac malformations was 0.99 (95% CI, 0.93-1.06). For oral clefts, the adjusted RR was 1.24 (95% CI, 1.03-1.48).

“Among offspring of mothers enrolled in Medicaid, first trimester exposure to ondansetron was not associated with cardiac malformations or congenital malformations overall after accounting for measured confounders but was associated with a small increased risk of oral clefts,” the authors concluded.


Huybrechts KF, Hernández-Díaz S, Straub L, et al. Association of maternal first-trimester ondansetron use with cardiac malformations and oral clefts in offspring. JAMA. 2018;320(23):2429-2437.