Although ondansetron is not specifically approved by the FDA to treat nausea and vomiting during pregnancy (NVP), its use is common, and approximately 25% of pregnant women are prescribed ondansetron to treat NVP. Overall, studies show the use of ondansetron appears to be associated with an additional 3 instances of oral cleft defects (such as cleft lip or cleft palate) for every 10,000 women exposed to ondansetron during their first trimester. There may also be a very slight increased risk of a type of heart defect called a ventricular septal defect, but no apparent increased risk of other birth defects, miscarriage, or fetal death.

Within these studies, it is impossible to rule out confounding variables – such as metabolic changes and severe nutritional deficiencies that are common in pregnant women with severe NVP. Any of these can also increase the risk of oral cleft defects. In addition, prolonged severe NVP is associated with increased anxiety and depression which has led to the termination of pregnancy in some cases. Physicians must weigh up all the risks and benefits for each pregnancy before deciding to prescribe ondansetron.

The main studies that investigated the use of ondansetron during pregnancy have included:

• Dormuth et al, 2021: A meta-analysis of 456 963 pregnancies in 3 countries reported that the use of ondansetron was not associated with an increased risk of miscarriage, fetal death, or major birth deformities compared with using other antiemetics (such as metoclopramide, promethazine, doxylamine) during pregnancy.
• Andrade 2020: A review of previously published cohort and case-control studies suggests early exposure to ondansetron does increase the risk of orofacial defects (absolute increased risk 0.03%) and ventricular septal defects (absolute increased risk 0.3%).
• Huybrechts et al, 2018: A retrospective Medicaid data analyses of 1,816,414 pregnancies from 2000 to 2013; 88,467 (4.9 percent) of which were associated with ondansetron exposure during the first trimester. Oral cleft defects occurred in 14 per 10,000 exposed infants compared to 11.1 per 10,000 unexposed infants (ARR 1.24, 95% CI: 1.03–1.48)
• Zambelli-Weiner et al, 2018: A retrospective analysis of medical claims data from 864,083 mother-child pairs registered from 2000 to 2014 of whom 5,557 mother-child pairs were administered ondansetron in the first trimester. There was a non-significant increase in orofacial cleft defects (OR: 1.30, 95% CI: 0.76–2.28) and an increased risk of cardiac defects (OR: 1.52, 95% CI: 1.35-1.70).

Repeated fetal scanning during the second trimester can help with the early detection of malformations if needed.