Abstract
Ondansetron is frequently used to treat nausea and vomiting during pregnancy. Although some studies reported important safety signals, few studies have been sufficiently large to assess rare pregnancy outcomes. To study the association between ondansetron exposure during pregnancy and the risks of spontaneous abortion, stillbirth, and major congenital malformations. This is a cohort study conducted in 3 countries, with a meta-analysis. Participants included women and girls aged 12 to 55 years who experienced spontaneous abortion, induced abortion, stillbirth, or live birth between April 2002 and March 2016, as recorded in administrative data from 5 Canadian provinces (British Columbia, Alberta, Saskatchewan, Manitoba, and Ontario), the US IBM MarketScan Research Databases, and the UK Clinical Practice Research Datalink. The statistical analysis was completed in October 2020. Exposure to ondansetron during pregnancy was compared with exposure to other commonly used antiemetics to minimize confounding by indication. The primary outcome was fetal death, defined as either spontaneous abortion or stillbirth. Secondary outcomes were the 2 components of the primary outcome and major congenital malformations identified during the year after a live birth. Adjusted hazard ratios were estimated using Cox proportional hazards models with time-dependent drug exposures and were adjusted using high-dimensional propensity scores. For major congenital malformations, adjusted odds ratios were estimated from logistic models. Site-level results were pooled using random-effects meta-analysis. Sensitivity analyses considered second-line antiemetic exposure and exposure specifically during 4 to 10 weeks of gestation. Data from 456 963 pregnancies were included in this study of fetal death (249 787 [54.7%] in Canada, 197 913 [43.3%] in the US, and 9263 [2.0%] in the UK; maternal age, ≤24 years, 93 201 patients [20.4%]; 25-29 years, 149 117 patients [32.6%]; 30-34 years, 142 442 patients [31.2%]; and ≥35 years, 72 203 patients [15.8%]). Fetal death occurred in 12 907 (7.9%) of 163 810 pregnancies exposed to ondansetron, and 17 476 (5.7%) of 306 766 pregnancies exposed to other antiemetics. The adjusted hazard ratios were 0.91 (95% CI, 0.67-1.23) for fetal death with time-dependent ondansetron exposure during pregnancy, 0.82 (95% CI, 0.64-1.04) for spontaneous abortion, and 0.97 (95% CI, 0.79-1.20) for stillbirth. For major congenital malformations, the estimated odds ratio was 1.06 (95% CI, 0.91-1.22). Results of sensitivity analyses were generally consistent with those of the primary analyses. In this large, multicenter cohort study, there was no association between ondansetron exposure during pregnancy and increased risk of fetal death, spontaneous abortion, stillbirth, or major congenital malformations compared with exposure to other antiemetic drugs.
Highlights
80% of women experience nausea and vomiting during pregnancy (NVP),[1] and approximately 20% to 25% of pregnant women use the 5-HT3 receptor antagonist ondansetron off label to treat NVP.[2,3] Several studies have considered adverse outcomes of ondansetron in pregnancy, but few have considered rarer outcomes such as stillbirth
The adjusted hazard ratios were 0.91 for fetal death with timedependent ondansetron exposure during pregnancy, 0.82 for spontaneous abortion, and 0.97 for stillbirth
Pregnancy Outcomes of Patients Treated With Ondansetron vs Alternative Antiemetic Medications. In this large, multicenter cohort study, there was no association between ondansetron exposure during pregnancy and increased risk of fetal death, spontaneous abortion, stillbirth, or major congenital malformations compared with exposure to other antiemetic drugs
Summary
80% of women experience nausea and vomiting during pregnancy (NVP),[1] and approximately 20% to 25% of pregnant women use the 5-HT3 receptor antagonist ondansetron off label to treat NVP.[2,3] Several studies have considered adverse outcomes of ondansetron in pregnancy, but few have considered rarer outcomes such as stillbirth. Among studies[5,6,7,8,9] that investigated major congenital malformations overall, odds ratios (ORs) ranged from 0.57 (95% CI, 0.13-2.49)[7] to 1.04 (95% CI, 0.83-1.30).[8] Oral-facial clefts and cardiac defects have been studied in association with ondansetron exposure compared with nonexposure.[6,9,10,11,12] Estimates in those studies ranged from a risk ratio of 0.95 (95% CI, 0.63-1.43)[9] to an OR of 2.37 (95% CI, 1.18-4.76).[12] In studies[5,6,9,10,11,13] that examined cardiac defects, estimates ranged from a risk ratio of 0.97 (95% CI, 0.86-1.10) for cardiac malformations[9] to a risk ratio of 2.1 (95% CI, 1.1-4.0) for ventricular septal defects.[13]
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