Is ondansetron (Zofran) safe to use during pregnancy?

Ondansetron Safety During Pregnancy

Ondansetron should be used as a second-line treatment for nausea and vomiting in pregnancy only after 10 weeks gestation, with careful consideration of its small increased risk of orofacial clefts. 1, 2

Risk Assessment

Ondansetron use in pregnancy has been associated with a small absolute increase in risk of orofacial clefting, with the background risk increasing from 11 cases per 10,000 births to 14 cases per 10,000 births (0.03% absolute increase) 2, 1. Some studies have also suggested a possible association with cardiac septal defects, though findings across studies have been inconsistent 3.

The FDA label notes that available data on ondansetron use in pregnant women from several published epidemiological studies have methodological limitations that preclude definitive conclusions about safety 3. Studies have shown inconsistent findings regarding:

• Overall major congenital malformations (no significant increase in aggregate analyses)
• Cardiovascular defects (relative risks ranging from 0.97 to 1.62)
• Oral clefts (some studies showing increased risk, others not)

Treatment Algorithm for Nausea and Vomiting in Pregnancy

1. First-line treatments (should be tried before ondansetron):

   • Vitamin B6 (pyridoxine) supplementation
   • Doxylamine-pyridoxine combination
   • Phenothiazines 1

2. Second-line treatments (if first-line fails):

   • Metoclopramide (has better established safety profile in pregnancy)
   • Ondansetron (only after 10 weeks gestation) 1

3. For severe hyperemesis gravidarum:

   • IV hydration and electrolyte replacement
   • Consider combination of ondansetron and metoclopramide for enhanced effect
   • Methylprednisolone as last resort 1

Dosing and Administration

If ondansetron is deemed necessary after 10 weeks:

• Dose: 4-8 mg orally or intravenously every 8-12 hours 1
• Obtain baseline ECG before initiating therapy due to risk of QT prolongation 1
• Monitor for adverse effects

Special Considerations

• Timing: The European Association for the Study of the Liver Clinical Practice Guidelines specifically note that ondansetron should only be used after 10 weeks gestation 2, 1
• Cancer patients: For pregnant cancer patients receiving chemotherapy, ondansetron may be considered for managing chemotherapy-induced nausea and vomiting, particularly after the first trimester 2, 1
• Monitoring: If ondansetron is used, careful monitoring is recommended, and the lowest effective dose should be employed 2

Important Caveats

• Despite its increasing off-label use for nausea and vomiting in pregnancy, ondansetron's safety profile remains controversial 4, 5
• The European Medicines Agency's Pharmacovigilance Risk Assessment Committee has recommended against ondansetron use in the first trimester, though this position has been challenged by some experts 4
• Animal studies at doses 6-24 times the maximum recommended human dose did not show evidence of harm to the fetus 3
• When weighing risks and benefits, consider that untreated severe nausea and vomiting can lead to significant maternal morbidity and potential complications 1, 6

Conclusion

While ondansetron appears to pose a small absolute risk of congenital anomalies, it remains a valuable second-line option for treating nausea and vomiting in pregnancy after 10 weeks gestation when first-line treatments have failed. The decision to use ondansetron should weigh the small increased risk against the potential benefits of treating significant maternal symptoms.