Is ondansetron (Zofran) safe to use during pregnancy?

From the Guidelines

Ondansetron (Zofran) is generally considered safe to use during pregnancy when the benefits outweigh the risks, particularly for managing severe nausea and vomiting of pregnancy (NVP) or hyperemesis gravidarum when other treatments have failed. The typical dosage is 4-8 mg orally every 8 hours as needed, with a maximum daily dose of 24 mg. While ondansetron is not FDA-approved specifically for use during pregnancy, it is often prescribed when first-line treatments like vitamin B6 and doxylamine are ineffective. Current evidence suggests no significant increase in overall birth defects, though some studies have shown a small potential increased risk of oral clefts when used in the first trimester 1. The medication works by blocking serotonin receptors in the brain and gut that trigger nausea and vomiting.

Key Considerations

• The American College of Gastroenterology (ACG) and the European Association for the Study of the Liver (EASL) recommend ondansetron as a second-line treatment for hyperemesis gravidarum 1.
• A recent study published in Gastroenterology found that ondansetron was not associated with an increased risk of stillbirth, spontaneous abortion, or major birth defects, but some studies have reported cases of congenital heart defects when ondansetron is given in the first trimester 1.
• The EASL clinical practice guidelines on the management of liver diseases in pregnancy recommend ondansetron as a second-line treatment for hyperemesis gravidarum, with a note that the absolute risk of orofacial clefting increases from 11 cases per 10,000 births to 14 cases per 10,000 births 1.
• Patients should discuss their specific situation with their healthcare provider, as the decision to use ondansetron during pregnancy should be individualized based on symptom severity and response to other treatments.

Recommendations

• Ondansetron should be used during pregnancy only when the benefits outweigh the risks, and after discussing the potential risks and benefits with a healthcare provider.
• The medication should be used at the lowest effective dose and for the shortest duration necessary to manage symptoms.
• Patients should be closely monitored for any potential side effects or adverse reactions, particularly during the first trimester.

From the FDA Drug Label

Published epidemiological studies on the association between ondansetron use and major birth defects have reported inconsistent findings and have important methodological limitations that preclude conclusions about the safety of ondansetron use in pregnancy (see Data). Available postmarketing data have not identified a drug associated risk of miscarriage or adverse maternal outcomes. Reproductive studies in rats and rabbits did not show evidence of harm to the fetus when ondansetron was administered during organogenesis at approximately 6 and 24 times the maximum recommended human oral dose of 24 mg/day, based on body surface area (BSA), respectively ( see Data)

The safety of ondansetron in pregnancy is uncertain due to inconsistent findings and methodological limitations in epidemiological studies. However, available postmarketing data have not identified a drug-associated risk of miscarriage or adverse maternal outcomes, and reproductive studies in rats and rabbits did not show evidence of harm to the fetus. Caution should be exercised when using ondansetron in pregnant women, and the benefits and risks should be carefully considered 2, 2, 2.

• Key points:
  • Inconsistent findings in epidemiological studies
  • No identified drug-associated risk of miscarriage or adverse maternal outcomes
  • Reproductive studies in rats and rabbits did not show evidence of harm to the fetus
  • Caution should be exercised when using ondansetron in pregnant women

From the Research

Ondansetron Safety in Pregnancy

• The safety of ondansetron during pregnancy has been a topic of debate, with some studies suggesting a potential increased risk of congenital cardiac malformations and oral cleft 3.
• However, other studies have found no significant association between ondansetron use and adverse fetal outcomes, such as spontaneous abortion, stillbirth, major birth defects, preterm delivery, and low birth weight 4, 5, 6, 7.
• A study published in 2013 found that ondansetron was not associated with a significantly increased risk of adverse fetal outcomes, including spontaneous abortion, stillbirth, and major birth defects 4.
• Another study published in 2021 found that ondansetron use in early pregnancy was not associated with an increased risk of miscarriage 5.
• A study published in 2023 found no significant differences in birth defects and adverse obstetric outcomes between women exposed to ondansetron and those who were not 7.
• The European Medicines Agency (EMA) has updated its guidance on the use of ondansetron in pregnancy, stating that it should not be used in the first trimester 3.
• However, some experts argue that the evidence for this guidance is not sufficient and that ondansetron may be a useful and safe alternative for women who suffer from hyperemesis gravidarum and do not respond to other antiemetic drugs 3, 7.

Key Findings

• No significant increase in risk of adverse fetal outcomes associated with ondansetron use 4, 5, 6, 7.
• No significant difference in birth defects and adverse obstetric outcomes between women exposed to ondansetron and those who were not 7.
• EMA guidance recommends against use of ondansetron in the first trimester 3.
• Some experts argue that ondansetron may be a useful and safe alternative for women who suffer from hyperemesis gravidarum and do not respond to other antiemetic drugs 3, 7.