Is Zofran (ondansetron) safe 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 when first-line treatments have failed, due to inconsistent safety data and potential risks of congenital heart defects when used in the first trimester. 1

Evidence on Safety Profile

The FDA label for ondansetron states that published epidemiological studies on its use during pregnancy have reported inconsistent findings and have important methodological limitations that preclude definitive conclusions about safety 2. Specifically:

• Some studies have found no association between ondansetron exposure and major birth defects 3, 4
• Other studies have suggested a possible increased risk of:
  • Cardiac septal defects (relative risk 2.05,95% CI 1.19-3.28) in one cohort study 2
  • Oral clefts (RR 1.24,95% CI 1.03-1.48) with oral ondansetron in first trimester 2

Treatment Algorithm for Nausea and Vomiting in Pregnancy

First-Line Treatments (Try These First)

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

Second-Line Treatments (If First-Line Fails)

• Metoclopramide (has shown similar efficacy to ondansetron with fewer safety concerns) 1
• Ondansetron - only when other options have failed and after 10 weeks gestation 1

Third-Line Treatment (Last Resort)

• Methylprednisolone (for severe hyperemesis gravidarum) - given IV at 16 mg every 8 hours for up to 3 days, then tapered 1

Key Clinical Recommendations

1. Timing considerations: The American College of Obstetricians and Gynecologists (ACOG) recommends using ondansetron on a case-by-case basis only in patients with persistent symptoms, and preferably after 10 weeks of pregnancy 1

2. Risk-benefit assessment: For severe nausea and vomiting of pregnancy (hyperemesis gravidarum) that doesn't respond to first-line treatments, the benefits of ondansetron may outweigh the potential risks, as severe dehydration and malnutrition also pose significant risks to both mother and fetus 1

3. Monitoring: If ondansetron is used, patients should be informed about the inconsistent safety data and potential risks, particularly regarding cardiac defects and oral clefts 2, 5

Limitations of Current Evidence

• Most safety data for ondansetron in pregnancy are based on fewer than 200 births, whereas safety data for doxylamine-pyridoxine are based on more than 250,000 pregnancies 5

• A systematic review of ondansetron use in pregnancy found inconsistent results across studies, with most showing no increased risk of malformations, but some suggesting possible cardiac defects 6

• The European Association for the Study of the Liver Clinical Practice Guidelines specifically recommend doxylamine-pyridoxine and phenothiazines as first-line treatments for hyperemesis gravidarum, with metoclopramide and ondansetron as second-line therapies 1

In conclusion, while ondansetron has been increasingly used for nausea and vomiting in pregnancy, its safety profile remains uncertain. The most prudent approach is to reserve it as a second-line agent when first-line therapies have failed, and to use it preferably after the first trimester when organogenesis is complete.