Is ondansetron (Zofran) safe to use during pregnancy?

Ondansetron Use in Pregnancy

Direct Recommendation

Ondansetron can be used during pregnancy as a second-line antiemetic for severe nausea and vomiting, with the understanding that there is a very small absolute increase in risk of orofacial clefts (0.03%) and ventricular septal defects (0.3%), which must be balanced against the significant maternal and fetal risks of inadequately treated hyperemesis gravidarum. 1, 2

Treatment Algorithm

First-Line Therapy

• Begin with metoclopramide 5-10 mg orally every 6-8 hours, which has demonstrated safety in meta-analysis of 33,000 first-trimester exposures with no increased risk of major congenital defects 2, 3
• Metoclopramide remains the preferred initial agent with the most robust safety data according to the American College of Obstetricians and Gynecologists 2

Second-Line Therapy: When to Use Ondansetron

• If metoclopramide is ineffective or not tolerated, initiate ondansetron 8 mg IV every 4-6 hours, particularly for severe nausea and vomiting requiring hospitalization 2, 3
• The American College of Obstetricians and Gynecologists recommends using ondansetron on a case-by-case basis for persistent symptoms before 10 weeks of pregnancy 1
• Use the lowest effective dose 1

Risk Quantification and Context

Specific Birth Defect Risks

• Orofacial clefts: absolute risk increases from 11 per 10,000 births to 14 per 10,000 births (0.03% absolute increase) 4, 1
• Ventricular septal defects: 0.3% absolute increase 1, 2
• No increased risk of stillbirth, spontaneous abortion, or major birth defects overall 1, 5

Critical Context

The FDA label acknowledges that published epidemiological studies have reported inconsistent findings with important methodological limitations that preclude definitive conclusions 6. However, the European Society for Medical Oncology recommends ondansetron as safe for use during pregnancy, representing current international expert opinion 2.

Timing Considerations

First Trimester (Before 10 Weeks)

• Use only after first-line agents have failed 1, 3
• The theoretical concerns about congenital malformations are specific to first-trimester exposure during organogenesis 3

Second Trimester (After 10 Weeks)

• Ondansetron is considered safe and effective after 10 weeks gestation, as organogenesis is complete 3
• The drug can be used more liberally in the second trimester for severe nausea and vomiting 3

Required Monitoring

Before Initiating Ondansetron

• Obtain baseline ECG to assess for QTc prolongation 2, 3
• Check baseline electrolytes, particularly potassium, as abnormalities increase QTc prolongation risk 2, 3

During Treatment

• Monitor hydration status and electrolyte balance closely 2, 3
• Ensure thiamine supplementation to prevent Wernicke encephalopathy in cases of prolonged vomiting 2, 3
• Monitor for adequate hydration and potassium levels, as ondansetron-induced QTc prolongation risk increases with electrolyte abnormalities 3

Critical Caveats and Pitfalls

When NOT to Withhold Ondansetron

• Do not withhold ondansetron when severe nausea and vomiting threatens maternal or fetal health, as the risks of untreated hyperemesis gravidarum (dehydration, malnutrition, electrolyte imbalances, weight loss) often outweigh the small absolute risk increases in birth defects 2, 3
• The absolute risk increase must be contextualized against the background risk and the significant morbidity of untreated disease 4

Medications to Avoid

• Do not prescribe betamethasone or dexamethasone for antiemetic premedication, as these fluorinated corticosteroids cross the placenta almost completely 4, 2
• If steroids are needed, use methylprednisolone or prednisolone instead 1, 3
• Do not use aprepitant or olanzapine as alternatives without careful consideration, as olanzapine has been linked to increased ventricular and septal defects, and aprepitant lacks human safety data 2

Drug-Induced Complications

• Monitor for extrapyramidal symptoms and oculogyric crises with metoclopramide; if these occur, withdraw the drug immediately and initiate appropriate treatment 4

Evidence Quality and Divergence

The evidence shows some divergence between regulatory bodies and clinical practice guidelines. The European Medicines Agency updated their guidance in 2019 stating ondansetron should not be used in the first trimester 7, while the American College of Obstetricians and Gynecologists and European Society for Medical Oncology support case-by-case use 1, 2. The most recent high-quality guidelines (2023-2025) support the use of ondansetron as second-line therapy with appropriate counseling about the small absolute risk increases 4, 1, 2.

Recent research from 2023 found no significant differences in cleft palate, cardiovascular congenital abnormalities, preterm delivery, or small for gestational age outcomes in propensity-score matched analysis 8. The 2021 study on miscarriage risk found no increase in risk (HR 1.21,95% CI 0.77,1.90) 5.