Ondansetron (Zofran) Use in First Trimester
Ondansetron can be used during the first trimester of pregnancy, as the available evidence does not demonstrate a significantly increased risk of major birth defects, though some studies suggest possible modest associations with specific defects that require clinical judgment.
FDA Labeling and Safety Data
The FDA drug label for ondansetron states that published epidemiological studies have reported inconsistent findings with important methodological limitations that preclude definitive conclusions about safety in pregnancy 1. The label notes that available postmarketing data have not identified a drug-associated risk of miscarriage or adverse maternal outcomes 1.
Evidence from Large Epidemiological Studies
Overall Safety Profile
A large Danish cohort study of 608,385 pregnancies found no significantly increased risk of spontaneous abortion, stillbirth, major birth defects, preterm delivery, low birth weight, or small-for-gestational-age infants with ondansetron exposure during pregnancy 2.
The Danish study specifically showed that ondansetron was not associated with major birth defects overall (2.9% in exposed vs 2.9% in unexposed women; prevalence odds ratio 1.12,95% CI 0.69-1.82) 2.
Specific Birth Defects: Areas of Concern
Cleft Palate:
- The National Birth Defects Prevention Study found a modest increased risk of cleft palate (adjusted OR 1.6,95% CI 1.1-2.3) 3.
- Another analysis reported an association between ondansetron and cleft palate (adjusted OR 2.37,95% CI 1.18-4.76) 4.
- However, a large US Medicaid database study showed conflicting results, with increased risk for oral ondansetron (RR 1.24,95% CI 1.03-1.48) but not intravenous ondansetron (RR 0.95% CI 0.63-1.43) 1.
Cardiac Defects:
- Studies examining cardiovascular defects have shown inconsistent findings, with relative risks ranging from 0.97 to 1.62 1.
- One subset analysis suggested an association with cardiac septal defects (RR 2.05,95% CI 1.19-3.28), but this was not confirmed in other studies 1.
Renal Defects:
- The Slone Birth Defects Study found a modest association with renal agenesis-dysgenesis (adjusted OR 1.8,95% CI 1.1-3.0) 3.
Clinical Context and Usage Trends
- Ondansetron use for nausea and vomiting of pregnancy increased dramatically from less than 1% before 2000 to 13% by 2013-2014 3.
- This represents off-label use, as ondansetron is not FDA-approved specifically for nausea and vomiting of pregnancy 3.
Important Methodological Limitations
The FDA label emphasizes that existing studies have critical limitations including:
- Uncertainty about whether women who filled prescriptions actually took the medication 1
- Concomitant use of other medications or treatments 1
- Recall bias and unadjusted confounders 1
- Unknown timing of exposure relative to critical developmental windows (e.g., palate formation occurs between weeks 6-9) 1
Clinical Recommendation
For severe nausea and vomiting of pregnancy requiring pharmacologic treatment, ondansetron can be used when other first-line agents are ineffective or contraindicated, recognizing that:
- The absolute risk of any specific birth defect remains low even if the modest associations are real 2, 3.
- The majority of birth defects studied (51 defect groups analyzed) showed no increased risk 3.
- Untreated severe nausea and vomiting can lead to maternal morbidity including dehydration, electrolyte imbalances, and need for hospitalization 5.
Common pitfall: Avoid using ondansetron as a first-line agent when other established treatments for nausea and vomiting of pregnancy (such as doxylamine-pyridoxine) have not been tried, given the inconsistent but concerning signals for cleft palate in some studies 3, 4.