Are ondansetron and pantoprazole (proton pump inhibitor) safe to use during the 1st and 2nd trimesters of pregnancy?

Safety of Ondansetron and Pantoprazole in 1st and 2nd Trimesters

Ondansetron can be used in the second trimester with reasonable safety, and should be considered as second-line therapy in the first trimester when benefits outweigh the very small absolute risk of specific birth defects; pantoprazole has not been associated with adverse pregnancy outcomes and can be used throughout pregnancy when clinically indicated.

Ondansetron Safety Profile

First Trimester Use

Ondansetron is associated with a very small absolute increase in specific birth defects (orofacial clefts: 0.03% increase; ventricular septal defects: 0.3% increase), but these minimal risks must be balanced against the significant maternal and fetal risks of inadequately treated severe nausea and vomiting. 1, 2

• The American College of Obstetricians and Gynecologists recommends using ondansetron on a case-by-case basis for persistent symptoms before 10 weeks of pregnancy, particularly when first-line antiemetics fail 2, 3
• Published epidemiological studies show inconsistent findings, with methodological limitations including uncertainty about actual medication use, concomitant medications, and unadjusted confounders 4
• The FDA label notes that ondansetron exposure has not been associated with overall major congenital malformations in aggregate analyses 4
• Use the lowest effective dose (8 mg IV every 4-6 hours) as second-line therapy after trying metoclopramide or antihistamines 1, 2

Second Trimester Use

Ondansetron is safe and effective in the second trimester, as theoretical concerns about congenital malformations are specific to first-trimester exposure during organogenesis. 1

• The National Comprehensive Cancer Network guidelines state that ondansetron can be used as part of antiemetic regimens during the second and third trimesters 5
• No increased risk of stillbirth, spontaneous abortion, or major birth defects overall has been demonstrated with second-trimester use 1, 2
• Standard dosing of 8 mg IV every 4-6 hours is appropriate for episodes of nausea and vomiting 1

Important Monitoring Considerations

• Baseline ECG monitoring is advised due to potential QTc prolongation 1
• Monitor for adequate hydration and electrolyte balance, particularly potassium, as ondansetron-induced QTc prolongation risk increases with electrolyte abnormalities 1
• Ensure thiamine supplementation (100 mg orally three times daily or intravenous Pabrinex) is provided to prevent Wernicke encephalopathy in cases of prolonged vomiting 1, 3

Pantoprazole Safety Profile

First and Second Trimester Use

Pantoprazole has not been associated with adverse pregnancy outcomes and can be used throughout pregnancy when clinically indicated. 6

• Available data from published observational studies failed to demonstrate an association of major malformations or other adverse pregnancy outcomes with pantoprazole use 6
• A prospective study by the European Network of Teratology Information Services showed no difference in the rate of major malformations between women exposed to PPIs and controls (RR=0.55,95% CI 0.08 to 3.95) 6
• A Danish population-based retrospective cohort study of 549 live births with first-trimester pantoprazole exposure showed no significant increase in major birth defects 6
• A meta-analysis of 1,530 pregnant women exposed to PPIs in at least the first trimester showed no significant increases in risk for congenital malformations (OR=1.12,95% CI 0.86 to 1.45) or spontaneous abortion (OR=1.29,95% CI 0.84 to 1.97) 6

Animal Data Supporting Safety

• Reproduction studies in rats at oral doses up to 450 mg/kg/day (about 88 times the recommended human dose) and rabbits at oral doses up to 40 mg/kg/day (about 16 times the recommended human dose) revealed no evidence of harm to the fetus 6

Treatment Algorithm for Nausea and Vomiting in Pregnancy

First-Line Therapy (Both Trimesters)

1. Start with antihistamines (H1 blockers), phenothiazines, or doxylamine/pyridoxine combination 3
2. Metoclopramide (5-10 mg orally every 6-8 hours) is considered safe with no significant increased risk of major congenital defects based on meta-analysis of over 33,000 first-trimester exposures 1, 3

Second-Line Therapy

1. If first-line agents fail, use ondansetron 8 mg IV every 4-6 hours 1, 2
2. In the first trimester, carefully discuss the very small absolute risk increases (0.03% for orofacial clefts, 0.3% for ventricular septal defects) against the risks of inadequately treated hyperemesis gravidarum 1, 2
3. Combinations of different antiemetics should be used in women who do not respond to a single agent 3

Critical Pitfalls to Avoid

• Do not withhold ondansetron in the second trimester due to first-trimester concerns—the organogenesis period has passed 1
• Do not use metoclopramide as first-line without considering extrapyramidal effects; administer intravenous doses by slow bolus over at least 3 minutes 3
• Do not forget thiamine supplementation before administering dextrose or parenteral nutrition in women with prolonged vomiting 1, 3
• Do not use ketonuria as an indicator of dehydration severity 3

Regulatory Context and Controversy

The European Medicines Agency (EMA) stated in 2019 that ondansetron should not be used in the first trimester 7, 8. However, this decision is controversial and not supported by major obstetric societies, as the absolute risk increases are minimal and must be balanced against the significant risks of untreated severe nausea and vomiting 7, 9, 3. The American College of Obstetricians and Gynecologists and UK guidelines continue to support ondansetron use as second-line therapy when first-line agents fail 2, 3.