Is Zofran (ondansetron) safe to use during pregnancy?

Safety of Ondansetron (Zofran) During Pregnancy

Ondansetron should be used during pregnancy only as a second-line therapy for severe nausea and vomiting that has not responded to first-line treatments, and the risk-benefit assessment should be made on a case-by-case basis. 1

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
• Metoclopramide can be given as a second-line option for patients requiring additional medication, with no reported increased risk of congenital defects 1, 2

Evidence on Ondansetron Safety During Pregnancy

• The FDA label states that published epidemiological studies on ondansetron use and major birth defects have reported inconsistent findings with important methodological limitations 3
• Available postmarketing data have not identified a drug-associated risk of miscarriage or adverse maternal outcomes 3
• Several studies have assessed ondansetron and the risk of oral clefts with inconsistent findings:
  • A retrospective cohort study showed an increased risk of oral clefts with oral ondansetron in the first trimester (RR 1.24,95% CI 1.03,1.48) 3
  • No such association was reported with intravenous ondansetron (RR 0.95% CI 0.63,1.43) 3
• Studies on cardiovascular defects have shown inconsistent results:
  • Relative risks ranged from 0.97 to 1.62 3
  • One cohort study found an association with cardiac septal defects (RR 2.05,95% CI 1.19,3.28), but this was not confirmed in other studies 3
• A 2013 Danish study of 1,915 women exposed to ondansetron found no significantly increased risk of:
  • Spontaneous abortion 4
  • Stillbirth 4
  • Major birth defects 4
  • Preterm delivery 4
  • Low birth weight or small for gestational age infants 4
• A 2021 study found no difference in risk of miscarriage between pregnancies exposed to ondansetron versus comparator antiemetics (HR 1.21,95% CI 0.77,1.90) 5

Recommended Treatment Algorithm for Nausea and Vomiting in Pregnancy

1. First-line therapy: Start with vitamin B6 supplementation and/or doxylamine-pyridoxine combination 1
2. Second-line therapy: Consider metoclopramide if first-line therapy is ineffective 1, 2
3. Third-line therapy: Consider ondansetron only for severe cases that have not responded to first and second-line therapies, particularly if hospitalization is required 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 when teratogenic risk is highest 1
• The European Medicines Agency's Pharmacovigilance Risk Assessment Committee (PRAC) has taken a more cautious approach, stating that ondansetron should not be used in the first trimester of pregnancy 6
• Animal studies did not show evidence of harm to the fetus when ondansetron was administered during organogenesis at doses 6-24 times the maximum recommended human dose 3
• The 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
• Despite increasing off-label use of ondansetron for nausea and vomiting in pregnancy, several studies have shown no clear benefits over other treatments such as doxylamine 7

In clinical practice, ondansetron should be reserved for cases where first-line therapies have failed and the benefits of treating severe symptoms outweigh the potential risks, especially considering the inconsistent evidence regarding birth defects.