Is ondansetron (Zofran) safe to administer during the first trimester of pregnancy?

From the Guidelines

Ondansetron (Zofran) should be used with caution during the first trimester of pregnancy, as it may be associated with a small increased risk of congenital defects, particularly heart defects and cleft palate, and its use should be carefully weighed against the potential benefits in managing severe nausea and vomiting. The most recent and highest quality study on this topic is from 2024, which suggests that ondansetron should only be administered as a second-line therapy for severe nausea and vomiting in pregnancy, after first-line treatments such as vitamin B6 and doxylamine have failed 1. This study also notes that some studies have reported cases of congenital heart defects when ondansetron is given in the first trimester, which supports the need for caution when using this medication during early pregnancy. Some key points to consider when deciding whether to use ondansetron during the first trimester of pregnancy include:

• The potential benefits of using ondansetron to manage severe nausea and vomiting, which can help prevent dehydration and weight loss, and support adequate maternal and fetal nutrition.
• The potential risks of using ondansetron, including the small increased risk of congenital defects, particularly heart defects and cleft palate.
• The availability of alternative treatments, such as vitamin B6 and doxylamine, which may be effective in managing mild to moderate nausea and vomiting, and can be used as first-line therapies.
• The importance of careful discussion between the patient and healthcare provider, weighing the severity of symptoms against potential risks to the developing fetus, before deciding to use ondansetron during the first trimester of pregnancy, as recommended by the American College of Obstetricians and Gynecologists (ACOG) 1. It's also worth noting that other studies have reported similar findings, including a study from 2023 which found that the use of ondansetron in early pregnancy has not been linked to a high risk of congenital defects, but a marginal relative increase in cleft palate and cardiovascular malformations has been described 2. However, the 2024 study is the most recent and highest quality study on this topic, and its findings should be given the most weight when making decisions about the use of ondansetron during the first trimester of pregnancy.

From the FDA Drug Label

Available data on ondansetron use in pregnant women from several published epidemiological studies preclude an assessment of a drug-associated risk of adverse fetal outcomes due to important methodological limitations, including the uncertainty of whether women who filled a prescription actually took the medication, the concomitant use of other medications or treatments, recall bias, and other unadjusted confounders. Two large retrospective cohort studies and one case-control study have assessed ondansetron exposure in the first trimester and risk of cardiovascular defects with inconsistent findings. Several studies have assessed ondansetron and the risk of oral clefts with inconsistent findings.

The safety of ondansetron administration during the first trimester of pregnancy is uncertain due to inconsistent findings and methodological limitations in available studies 3. While some studies suggest no increased risk of major congenital malformations, others report potential associations with cardiovascular defects and oral clefts. Therefore, a conservative clinical decision would be to exercise caution when considering ondansetron use in pregnant women, especially during the first trimester. Key points to consider include:

• Inconsistent study findings: Available data do not provide a clear assessment of the risk of adverse fetal outcomes.
• Methodological limitations: Studies are limited by factors such as recall bias, concomitant medication use, and unadjusted confounders.
• Potential risks: Some studies suggest potential associations with cardiovascular defects and oral clefts.

From the Research

Safety of Ondansetron in Pregnancy

The safety of ondansetron during the first trimester of pregnancy is a topic of ongoing debate. Some studies suggest that ondansetron may be associated with an increased risk of congenital malformations, such as orofacial clefts and heart defects 4, 5. However, other studies have found no significant increase in risk 6, 7.

Risks and Benefits

The European Medicines Agency has stated that ondansetron should not be used during the first trimester of pregnancy due to the potential risks 4, 8. However, some experts argue that the benefits of ondansetron in treating severe nausea and vomiting of pregnancy may outweigh the potential risks 7, 8. Key points to consider include:

• The absolute increase in risk of congenital malformations associated with ondansetron is small 5
• Untreated nausea and vomiting of pregnancy can have significant consequences for the mother and fetus 6
• Ondansetron is an effective treatment for nausea and vomiting of pregnancy 6, 7

Clinical Decision-Making

The decision to use ondansetron during pregnancy should be made on a case-by-case basis, taking into account the individual patient's circumstances and the potential risks and benefits 7, 5. Clinicians should discuss the potential risks and benefits with their patients and make informed decisions together 5.