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

From the Guidelines

Ondansetron can be safely used during pregnancy when necessary for managing severe nausea and vomiting, particularly in hyperemesis gravidarum when first-line treatments have failed, with a small increased risk of oral clefts if used in the first trimester. The typical dose is 4-8 mg orally every 8 hours as needed, with the lowest effective dose used for the shortest duration possible. While ondansetron is not FDA-approved specifically for use in pregnancy, it is commonly prescribed when the potential benefits outweigh the risks. First-line treatments that should be tried before ondansetron include vitamin B6 (10-25 mg three times daily) combined with doxylamine (12.5 mg three to four times daily) 1. Regarding safety, earlier concerns about potential birth defects have been largely addressed by more recent, larger studies showing no significant increased risk of major congenital malformations, as noted in the European Association for the Study of the Liver Clinical Practice Guidelines 1. However, there may be a small increased risk of oral clefts if used in the first trimester, particularly before 10 weeks gestation, with the absolute risk increasing from 11 cases per 10,000 births to 14 cases per 10,000 births 1. Patients should be informed of this potential risk, though the absolute risk remains very low. Ondansetron works by blocking serotonin 5-HT3 receptors in the chemoreceptor trigger zone and gastrointestinal tract, effectively reducing nausea and vomiting signals to the brain. Key considerations for the use of ondansetron in pregnancy include:

• Using the lowest effective dose for the shortest duration possible
• Informing patients of the potential small increased risk of oral clefts
• Considering alternative treatments, such as metoclopramide, which has not been associated with an increased risk of congenital defects 1
• Monitoring for signs of dehydration, electrolyte imbalances, and nutritional deficiencies in patients with severe nausea and vomiting 1.

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 Available postmarketing data have not identified a drug associated risk of miscarriage or adverse maternal outcomes Ondansetron exposure in utero has not been associated with overall major congenital malformations in aggregate analyses

The safety of ondansetron (Zofran) in pregnancy is uncertain due to inconsistent findings and methodological limitations in epidemiological studies.

• Major birth defects: Studies have reported inconsistent findings, with some showing no association and others suggesting a possible increased risk of specific defects, such as cardiac septal defects or oral clefts.
• Miscarriage and adverse maternal outcomes: Available postmarketing data have not identified a drug-associated risk. Based on the available data, no conclusion can be drawn about the safety of ondansetron use in pregnancy 2.

From the Research

Safety of Ondansetron in Pregnancy

• The safety of ondansetron during pregnancy has been a subject of debate, with some studies suggesting a potential risk of congenital cardiac malformations and oral cleft 3.
• However, other studies have found no increase in risk of miscarriage or other adverse outcomes associated with ondansetron use during pregnancy 4.
• A systematic review of clinical trials found that ondansetron is an effective treatment for nausea and vomiting, including pregnancy-related morning sickness, but further research is needed to fully understand its safety profile 5.
• The American College of Obstetricians and Gynecologists recommends early treatment of nausea and vomiting of pregnancy, and ondansetron is a commonly used treatment option, despite some limitations in the current literature on its safety 6.
• A descriptive analysis of prescription patterns and patient characteristics in UK general practice found that ondansetron is increasingly used off-label to treat nausea and vomiting during pregnancy, including in the first trimester 7.

Risk of Congenital Malformations

• Some studies have suggested a potential risk of congenital cardiac malformations and oral cleft associated with ondansetron use during pregnancy 3.
• However, other studies have found no increase in risk of congenital malformations or other adverse outcomes associated with ondansetron use during pregnancy 4, 5.

Risk of Miscarriage

• A study found no difference in risk of miscarriage between women prescribed ondansetron and those prescribed alternative antiemetics during the first 20 weeks of pregnancy 4.
• The study used electronic health record data and controlled for measured confounding using inverse probability of treatment weights.

Prescription Patterns and Patient Characteristics

• A descriptive analysis of prescription patterns and patient characteristics in UK general practice found that ondansetron is increasingly used off-label to treat nausea and vomiting during pregnancy, including in the first trimester 7.
• The study found that women with mental health disorders, asthma, and/or prescribed folic acid were more likely to experience nausea and vomiting and use antiemetics, including ondansetron.