Is Zofran (ondansetron) safe to use during pregnancy?

Safety of Ondansetron (Zofran) During Pregnancy

Ondansetron (Zofran) should be used during pregnancy only as a second-line therapy for severe nausea and vomiting that is unresponsive to first-line treatments, and the decision should be made on a case-by-case basis after weighing potential benefits against risks.

First-Line Treatment Options for Nausea and Vomiting in Pregnancy

• Vitamin B6 (pyridoxine) supplementation is recommended as the first-line treatment for hyperemesis gravidarum or severe nausea and vomiting in pregnancy 1
• Doxylamine and pyridoxine combination is considered another first-line option for nausea and vomiting in pregnancy 1, 2
• Metoclopramide can be given as a second-line option for patients requiring additional medication, with no reported increased risk of congenital defects 1, 2

Ondansetron Use and Safety in Pregnancy

• Ondansetron should primarily be used in severe nausea and vomiting that requires hospitalization, and only as a second-line therapy 1
• The FDA pregnancy labeling for ondansetron notes that "published epidemiological studies on the association between ondansetron use and major birth defects have reported inconsistent findings and have important methodological limitations that preclude conclusions about the safety of ondansetron use in pregnancy" 3
• The FDA label further states that "available postmarketing data have not identified a drug associated risk of miscarriage or adverse maternal outcomes" 3
• A large Danish study found that ondansetron taken during pregnancy was not associated with significantly increased risk of adverse fetal outcomes including spontaneous abortion, stillbirth, major birth defects, preterm delivery, or low birth weight 4
• More recent research has shown modest increases in risk for cleft palate (adjusted OR 1.6,95% CI 1.1-2.3) and renal agenesis-dysgenesis (adjusted OR 1.8,95% CI 1.1-3.0), though these findings may be due to chance 5

Treatment Algorithm for Nausea and Vomiting in Pregnancy

1. Start with vitamin B6 supplementation as first-line therapy 1
2. Add doxylamine if vitamin B6 alone is insufficient 1, 2
3. Consider metoclopramide as a second-line option if symptoms persist 1, 2
4. Reserve ondansetron for severe cases unresponsive to first-line and second-line therapies 1

Important Considerations and Caveats

• The American College of Obstetricians and Gynecologists recommends using ondansetron on a case-by-case basis in patients with persistent symptoms, particularly before 10 weeks of pregnancy 1
• Risk-benefit assessment should weigh potential fetal risks against maternal risks of untreated severe nausea and vomiting, including dehydration, electrolyte imbalances, and nutritional deficiencies 1
• A recent study found no increased risk of miscarriage with ondansetron use compared to other antiemetics (metoclopramide or promethazine) during early pregnancy 6
• The European Medicines Agency's Pharmacovigilance Risk Assessment Committee has taken a more cautious stance, stating that ondansetron should not be used in the first trimester of pregnancy, though this position has been questioned by some experts 7
• Thiamine supplementation should be considered in severe cases to prevent Wernicke encephalopathy, starting at 100 mg daily for at least 7 days 1