Major Congenital Malformation Risk After First Trimester Gestational Exposure to Oral or Intravenous Ondansetron

Ondansetron is a 5-HT₃ receptor antagonist that has been approved for the prevention of nausea and vomiting associated with cancer chemotherapy, radiotherapy, and surgery. Ondansetron has also been studied in the treatment of many neuropsychiatric and medical conditions. The drug is commonly used off-label to treat nausea and vomiting of pregnancy (NVP) and hyperemesis gravidarum (HG). Ondansetron crosses the placental barrier, and concerns have been expressed that using ondansetron for NVP/HG during the first trimester of pregnancy may increase the risk of major congenital malformations (MCMs) in the offspring. In this context, findings from a meta-analysis of 6 cohort and 2 case-control studies, read along with the results of subsequently published cohort (n = 3) and case-control (n = 1) studies, suggest that a signal does exist to associate early gestational exposure to ondansetron with an increased risk of heart defects and orofacial defects. Arguments both for and against confounding by indication have been proposed to explain these findings. Nevertheless, even if ondansetron is causally implicated in MCM risk, the absolute increase in risk, such as for orofacial clefts (by 0.03%) and ventricular septal defect (by 0.3%), is small. These small risks should be balanced against the risks associated with inadequately treated NVP/HG, and decision-making must be shared between clinician and patient. Repeated fetal scanning during the second trimester can help in the early detection of malformations, if present.