Ondansetron Pregnancy Risk Category
Ondansetron no longer has an FDA pregnancy risk category under the current labeling system, as the FDA eliminated the A/B/C/D/X classification in 2015. 1 Under the old system that was phased out, ondansetron was classified as Category B. 2
Current FDA Labeling and Safety Information
The current FDA label states that published epidemiological studies have reported inconsistent findings with important methodological limitations that preclude definitive conclusions about ondansetron's safety in pregnancy. 1 The label specifically notes:
No overall increased risk of major congenital malformations has been definitively established, though some studies suggest possible associations with specific defects. 1
Cardiovascular defects: Studies show conflicting results, with relative risks ranging from 0.97 to 1.62 for first-trimester exposure, and one subset analysis suggesting cardiac septal defects (RR 2.05,95% CI 1.19-3.28) that was not confirmed in other studies. 1
Oral clefts: A large US Medicaid database study showed increased risk with oral ondansetron (RR 1.24,95% CI 1.03-1.48) but not with IV ondansetron (RR 0.95% CI 0.63-1.43). 1 Two case-control studies reported conflicting associations with isolated cleft palate. 1
Clinical Practice Guidelines on Ondansetron Use
The most recent high-quality guideline from ESMO (2023) explicitly states that ondansetron is considered safe for treating nausea and vomiting during pregnancy. 2 This represents current international expert consensus for managing severe pregnancy-related nausea.
Risk Quantification from Guidelines
The absolute risk increases are extremely small: 0.03% absolute increase in orofacial clefts (from 11 to 14 per 10,000 births) and 0.3% absolute increase in ventricular septal defects. 2, 3
These small risks must be weighed against the significant maternal and fetal risks of untreated severe nausea and vomiting, including dehydration, malnutrition, and electrolyte abnormalities. 4
Recommended Treatment Algorithm
First-line therapy: Start 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 (OR 1.14,99% CI 0.93-1.38). 2, 3
Second-line therapy: If metoclopramide is ineffective or not tolerated, ondansetron 8 mg orally every 8-12 hours can be used. 3, 4
Timing considerations:
- ACOG recommends case-by-case decision-making for ondansetron use before 10 weeks gestation due to the small absolute risk increases in cleft palate and cardiac defects. 3
- After 10 weeks gestation, ondansetron is considered safer as organogenesis is complete and the theoretical concerns about congenital malformations are specific to first-trimester exposure. 5
Important Clinical Caveats
Do not withhold ondansetron when severe nausea and vomiting threatens maternal or fetal health, as the risks of untreated hyperemesis gravidarum often outweigh the small absolute risk increases in birth defects. 4
Monitor for QTc prolongation: Obtain baseline ECG before initiating ondansetron and monitor electrolytes, particularly potassium, as abnormalities increase QTc prolongation risk. 5, 4
Always provide thiamine supplementation (100 mg daily for minimum 7 days) to prevent Wernicke encephalopathy in cases of prolonged vomiting. 3, 4
Regulatory Controversy
The European Medicines Agency (EMA) updated its guidance in 2019 to state that ondansetron should not be used in the first trimester. 6 However, this decision has been controversial, with the European Network of Teratology Information Services (ENTIS) arguing that it is insufficiently substantiated and does not serve the interests of pregnant women with severe nausea and vomiting. 6 The most recent meta-analysis (2020) found statistically significant but small associations with ventricular septal defects (OR 1.11,95% CI 1.00-1.23) and oral clefts (OR 1.22,95% CI 1.00-1.49). 7