Is Zofran (ondansetron) teratogenic during pregnancy?

Is Zofran (Ondansetron) Teratogenic During Pregnancy?

Ondansetron should be used with caution during pregnancy, particularly in the first trimester, as there is a marginal increased risk of cleft palate and cardiovascular malformations, especially ventricular septal defects. 1, 2

Safety Profile of Ondansetron in Pregnancy

First Trimester Concerns

• Ondansetron exposure in early pregnancy has been associated with a small absolute increase in risk of:
  • Orofacial clefts (0.03% absolute increase)
  • Ventricular septal defects (0.3% absolute increase) 2
• FDA labeling notes inconsistent findings in epidemiological studies regarding major birth defects 3
• Large retrospective cohort studies have shown conflicting results with relative risks ranging from 0.97 to 1.62 for cardiovascular defects 3

Safety in Later Pregnancy

• Ondansetron is considered safer after 10 weeks of gestation when organogenesis (particularly palate formation) is complete 1
• The American College of Obstetricians and Gynecologists (ACOG) recommends using ondansetron on a case-by-case basis only for persistent symptoms, preferably after 10 weeks of pregnancy 1

Recommendations for Antiemetic Use in Pregnancy

First-Line Options (Safer Alternatives)

• Vitamin B6 (pyridoxine) supplementation
• Doxylamine-pyridoxine combination
• Phenothiazines 1
• Metoclopramide (5-10 mg orally every 6-8 hours) has a better established safety profile with no significant increase in major congenital defects in meta-analyses of large cohort studies 2, 1

When to Consider Ondansetron

• Second-line therapy when first-line treatments fail
• Preferably after 10 weeks gestation
• For severe hyperemesis gravidarum when benefits may outweigh potential risks 1

Recent Evidence on Safety

• A 2023 propensity-score matched study found no significant differences in cleft palate, cardiovascular congenital abnormalities, spina bifida occulta, preterm delivery, or small for gestational age between women exposed to ondansetron and those who were not 4
• However, sample sizes in many studies are limited, and methodological issues exist in the current literature 5

Special Considerations for Cancer Patients

• For pregnant cancer patients receiving chemotherapy, ondansetron can be considered for managing chemotherapy-induced nausea and vomiting (CINV), particularly after the first trimester 2
• In these cases, the benefits of preventing severe nausea and vomiting may outweigh the small potential risks, as severe dehydration and malnutrition also pose significant risks to both mother and fetus 1

Clinical Approach

1. First attempt treatment with safer first-line antiemetics (pyridoxine, doxylamine, phenothiazines, metoclopramide)
2. Consider ondansetron only if first-line treatments fail, preferably after 10 weeks gestation
3. Weigh benefits against risks, particularly in cases of severe nausea and vomiting that threaten maternal nutritional status
4. Monitor fetal development with appropriate ultrasound surveillance if ondansetron is used

While ondansetron is widely used for nausea and vomiting in pregnancy, the evidence suggests caution, particularly in the first trimester when organogenesis occurs. The small increased risk of specific birth defects must be balanced against the potential maternal and fetal risks of untreated severe nausea and vomiting.