What is the safety profile of ondansetron (Zofran) in pregnancy and breastfeeding?

Safety Profile of Ondansetron in Pregnancy and Breastfeeding

Ondansetron can be used during pregnancy as a second-line treatment for nausea and vomiting, with a small increased risk of orofacial clefts and cardiac septal defects when used in the first trimester, but is considered safe for use during breastfeeding. 1, 2

Safety During Pregnancy

First Trimester Use

• Ondansetron has been associated with a small absolute risk increase for certain birth defects when used in early pregnancy:
  • 0.03% absolute increase in orofacial clefts 1
  • 0.3% absolute increase in ventricular septal defects 1
  • Some studies show inconsistent findings regarding cardiovascular defects, with relative risks ranging from 0.97 to 1.62 2

Recommendations for Use in Pregnancy

1. First-line treatments for nausea and vomiting in pregnancy should be:

   • Doxylamine and pyridoxine (vitamin B6) combination
   • Phenothiazines 1

2. Second-line therapy (when first-line treatments fail):

   • Metoclopramide
   • Ondansetron 1

3. Timing considerations:

   • The American College of Obstetricians and Gynecologists (ACOG) recommends using ondansetron on a case-by-case basis in patients with persistent symptoms before 10 weeks of pregnancy 1
   • The palate forms between the 6th and 9th weeks of pregnancy, which is the critical period for potential orofacial cleft development 2

Clinical Context

• Ondansetron use for nausea and vomiting in pregnancy has been increasing, from 0.1% in 2005 to 2.5% in 2019 3
• It is primarily used as a second-line therapy but is sometimes prescribed as first-line (2.8% of cases) 3
• 40% of ondansetron prescriptions are initiated during the first trimester 3

Safety During Breastfeeding

• Limited data available: It is not known whether ondansetron is present in human milk 2
• Animal studies: Ondansetron has been demonstrated to be present in rat milk 2
• Recommendation: The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for ondansetron 2
• Clinical guidance: Ondansetron is considered compatible with breastfeeding according to multiple guidelines 1

Risk-Benefit Assessment

Benefits

• Effective treatment for severe nausea and vomiting in pregnancy and hyperemesis gravidarum
• May prevent complications of severe hyperemesis including:
  • Dehydration
  • Electrolyte abnormalities
  • Nutritional deficiencies
  • Weight loss 1

Risks

• Small increased risk of birth defects when used in first trimester
• The absolute risk increases are small:
  • Background risk of orofacial clefts: 11 per 10,000 births
  • With ondansetron: 14 per 10,000 births 1

Practical Recommendations

1. For pregnancy:

   • Use first-line antiemetics (doxylamine/pyridoxine, phenothiazines) before considering ondansetron
   • Reserve ondansetron for cases where first-line treatments have failed
   • When possible, avoid use during weeks 6-9 of pregnancy (palate formation)
   • Consider risk-benefit ratio carefully in the first trimester

2. For breastfeeding:

   • Ondansetron can be used during breastfeeding with minimal concerns
   • No special monitoring of the breastfed infant is required

Common Pitfalls to Avoid

1. Overestimating the risk: While there is a small increased risk of certain birth defects, the absolute risk remains low and should be weighed against the risks of untreated severe nausea and vomiting

2. Undertreatment: Inadequate treatment of severe nausea and vomiting or hyperemesis gravidarum can lead to maternal malnutrition, dehydration, and weight loss, which may pose greater risks to the fetus than medication use

3. Not considering alternative antiemetics: Metoclopramide has not been associated with increased risk of congenital defects and should be considered before ondansetron in the first trimester 1

4. Discontinuing breastfeeding unnecessarily: The benefits of breastfeeding generally outweigh the theoretical risks of ondansetron exposure through breast milk

By following these evidence-based recommendations, clinicians can appropriately manage nausea and vomiting in pregnant and breastfeeding women while minimizing potential risks to the mother and child.