Is Zofran (ondansetron) safe to use during pregnancy?

Is Zofran (Ondansetron) Safe in Pregnancy?

Ondansetron is considered safe for treating nausea and vomiting during pregnancy, with only a very small absolute increase in specific birth defects when used in the first trimester. 1, 2

Treatment Algorithm

First-Line Therapy

• Start with metoclopramide 5-10 mg orally every 6-8 hours as the preferred initial antiemetic, as it shows no increased risk of major congenital defects in over 33,000 first-trimester exposures (OR 1.14,99% CI 0.93-1.38). 1, 2

Second-Line Therapy: Ondansetron

• If metoclopramide fails or is not tolerated, ondansetron 8 mg orally every 8-12 hours is appropriate. 2
• The European Society for Medical Oncology (ESMO) 2023 guidelines explicitly state that ondansetron is considered safe for pregnancy-related nausea and vomiting. 1

Risk Quantification: The Numbers Matter

The absolute risks associated with first-trimester ondansetron are extremely small:

• Orofacial clefts: 0.03% absolute increase (from 11 to 14 cases per 10,000 births) 1, 2
• Ventricular septal defects: 0.3% absolute increase 1, 2
• The FDA label notes that published epidemiological studies show inconsistent findings with important methodological limitations that preclude definitive conclusions. 3

Timing Considerations

• Before 10 weeks gestation: Use requires case-by-case decision-making due to the small risks of orofacial clefts and cardiac defects during organogenesis. 2
• After 10 weeks gestation: Ondansetron is safer since organogenesis is complete and palate formation (weeks 6-9) has finished. 1, 2

When Ondansetron Should NOT Be Withheld

Severe nausea and vomiting that threatens maternal or fetal health justifies ondansetron use regardless of gestational age, as the risks of untreated hyperemesis gravidarum—dehydration, malnutrition, electrolyte disturbances, and Wernicke encephalopathy—outweigh the small absolute increase in birth defect risk. 2

Required Safety Monitoring

• Obtain baseline ECG before starting ondansetron to assess QTc interval. 2
• Monitor serum potassium and other electrolytes, as abnormalities increase QTc prolongation risk. 2
• Add thiamine 100 mg daily for at least 7 days in patients with prolonged vomiting to prevent Wernicke encephalopathy. 2

Evidence Quality and Controversies

The largest Danish cohort study of 1,233 exposed pregnancies found no increased risk of any major birth defect (prevalence OR 1.12,95% CI 0.69-1.82), spontaneous abortion, stillbirth, preterm delivery, or low birth weight. 4 A 2023 Israeli propensity-matched study of 774 exposed women similarly found no significant differences in cleft palate, cardiovascular abnormalities, or adverse obstetric outcomes. 5

However, two large studies did report small increases in cardiac septal defects (RR 2.05,95% CI 1.19-3.28 in one subset analysis), though this was not replicated in other investigations. 3, 6 The inconsistency likely reflects methodological limitations including prescription-filling versus actual medication use, recall bias, and unadjusted confounders. 3, 7

Regulatory Divergence

• The European Medicines Agency (EMA) updated its 2019 guidance to state ondansetron "should not be used in the first trimester," a decision that the European Network of Teratology Information Services (ENTIS) argues is insufficiently substantiated and not serving pregnant women's interests. 7
• In contrast, ESMO 2023 and ACOG guidelines support ondansetron use with appropriate counseling. 1, 2

Common Pitfalls to Avoid

• Do not use betamethasone or dexamethasone as premedication for chemotherapy-induced nausea in pregnancy, as they have nearly 100% placental passage; instead use methylprednisolone or prednisolone, which are metabolized in the placenta. 1
• Avoid glucocorticosteroids before 10 weeks gestation due to increased oral cleft incidence; after 10 weeks they are safe. 1
• Do not withhold ondansetron based solely on gestational age when severe symptoms threaten maternal health. 2