Nausea and vomiting affect more than 50% of all pregnant women. Although ondansetron is often used for treatment, data on its safety for the fetus are limited. The drug is administered during the period the fetus is most susceptible to teratogenic effects (7–12 weeks’ gestation). This historical cohort study was performed to determine whether use of ondansetron during pregnancy led to an increased risk of adverse fetal outcomes.
Danish registries were used to establish a nationwide cohort of all pregnancies that resulted in a singleton live birth or stillbirth or ended with any abortive outcome during 2004 to 2011. Data were extracted for women given ondansetron. Specific exposure times were defined as the first trimester through 12 weeks’ gestation for any major birth defect, any time before 37 completed weeks for preterm delivery, any time during pregnancy for analyses involving birth weight, weeks 7 to 22 for spontaneous abortion, and week 7 until birth for stillbirth. Women who did not receive ondansetron were categorized as “unexposed.” Outcomes were spontaneous abortion, stillbirth, any major birth defects, preterm delivery, and infants of low birth weight or small for gestational age (SGA). Cox proportional hazards regression models were used to estimate hazard ratios (HRs) for the comparison of pregnancies in which women were and were not exposed to ondansetron. The analyses of birth defects, preterm delivery, and birth weight were based on live births; logistic regression was used to estimate prevalence odds ratios (ORs). Women exposed to ondansetron were matched, in a 1:4 ratio, to unexposed women in accordance with the nearest-neighbor–matching algorithm.
Exposure to ondansetron occurred in 1970 (0.3%) of 608,385 women in the cohort. The first prescription was filled at a median of 70 gestational days (interquartile range, 57–88 days). In unadjusted analyses conducted before propensity score matching, the risk of spontaneous abortion was significantly decreased among women who were exposed to ondansetron compared with unexposed women. No increased risk of stillbirth, any major birth defects, infant born at low birth weight, or infant born SGA was associated with ondansetron exposure, whereas the risk of preterm delivery was significantly increased. The propensity score–matched analyses included spontaneous abortion (1849 exposed vs 7396 unexposed women), stillbirth (1915 vs 7660), any major birth defect (1233 vs 4932), preterm delivery (1792 vs 7168), and birth of infants at low birth weight and SGA (1784 vs 7136). The matched groups were similar in baseline characteristics. More than 50% of women given ondansetron were hospitalized for hyperemesis or nausea and vomiting, and almost half received another antiemetic. An analysis that included 215 cases occurring in weeks 7 to 12 and 139 cases in weeks 13 to 22 found that women exposed to ondansetron were not at increased risk for spontaneous abortion compared with unexposed women, with an adjusted HR of 0.49 (95% confidence interval [CI], 0.27–0.91) in weeks 7 to 12 and of 0.60 (95% CI, 0.29–1.21) in weeks 13 to 22. Six stillbirths occurred among 1915 women exposed to ondansetron (0.3%) and 27 among 7660 women not exposed (0.4%; adjusted HR, 0.42; 95% CI, 0.10–1.73). Among 1233 women given ondansetron in the first trimester, 36 infants (2.9%) had a major birth defect compared with 141 of 4932 unexposed infants (2.9%; adjusted prevalence OR, 1.12; 95% CI, 0.69–1.82). No cases of cleft palate occurred in the exposed group. Among 1792 women exposed to ondansetron before 37 weeks’ gestation, 111 had preterm deliveries (6.2%) compared with 374 among 7168 unexposed women (5.2%; adjusted prevalence OR, 0.90; 95% CI, 0.66–1.25). Exposure to ondansetron at any time during pregnancy was not associated with low birth weight (4.1% exposed vs 3.7% unexposed; adjusted prevalence OR, 0.76; 95% CI, 0.51–1.13) or with infants who were SGA (10.4% exposed vs 9.2% unexposed; adjusted prevalence OR, 1.13; 95% CI, 0.89–1.44). Compared with pregnancies with exposure to antihistamine antiemetics, those having exposure to ondansetron had no significantly different risk of spontaneous abortion.
These results indicate that ondansetron exposure in pregnancy is not associated with a significantly increased risk of major adverse fetal outcomes, including spontaneous abortion, stillbirth, any major birth defects, preterm delivery, or low birth weight or SGA. These results may offer some reassurance for using ondansetron as treatment for nausea and vomiting during pregnancy.
Department of Epidemiology Research, Statens Serum Institut, Copenhagen, Denmark