Is Augmentin (amoxicillin/clavulanate) and Zofran (ondansetron) safe during pregnancy?

Safety of Augmentin and Zofran in Pregnancy

Both Augmentin (amoxicillin/clavulanate) and Zofran (ondansetron) can be used during pregnancy when clinically indicated, though ondansetron should be used with awareness of conflicting regulatory guidance and the evidence supporting its safety. 1, 2, 3

Augmentin (Amoxicillin/Clavulanate) Safety Profile

Augmentin is considered safe throughout pregnancy and is classified as "Compatible" for use during pregnancy. 2

Key Evidence Supporting Safety:

• Amoxicillin-clavulanic acid is explicitly stated as safe for use during pregnancy in multiple high-quality gastroenterology guidelines. 1
• Reproduction studies have shown no increased occurrence of fetal malformations or harmful effects. 2
• The FDA classifies this combination as Pregnancy Category B, meaning animal studies show no fetal harm and there are no adequate human studies showing risk. 4
• The benefit of treating maternal bacterial infections generally outweighs theoretical risks to the fetus. 2

Important Caveat:

• Augmentin is NOT recommended in women at risk of preterm delivery due to a very low risk of necrotizing enterocolitis in the fetus. 2, 4
• This specific contraindication was reported in a single study of women with premature rupture of fetal membranes. 4

Clinical Algorithm for Augmentin Use:

1. Confirm bacterial infection requiring antibiotic therapy 2
2. Assess if patient is at risk for preterm delivery 2, 4
   • If YES: Consider alternative antibiotics
   • If NO: Augmentin is a safe first-line option
3. Use throughout pregnancy when indicated 2
4. Compatible with breastfeeding 2

Zofran (Ondansetron) Safety Profile

Ondansetron can be used during pregnancy for chemotherapy-induced nausea/vomiting and is considered safe based on the strongest epidemiological evidence, though regulatory guidance has created confusion. 1, 3, 5

Evidence Supporting Safety:

The highest quality study—a large Danish cohort of 608,385 pregnancies with propensity-score matching—found ondansetron was NOT associated with increased risk of:

• Spontaneous abortion 5
• Stillbirth 5
• Major birth defects 5
• Preterm delivery 5
• Low birth weight 5
• Small for gestational age infants 5

Conflicting Evidence and Regulatory Confusion:

Published epidemiological studies have reported inconsistent findings with important methodological limitations that preclude definitive conclusions. 3

• Some studies suggested associations with cardiac septal defects (RR 2.05) and oral clefts (RR 1.24), but these findings were NOT confirmed in other studies. 3
• A systematic review of 10 epidemiologic studies found paucity of evidence linking ondansetron to congenital malformations. 6
• The European Medicines Agency (EMA) updated guidance in 2019 stating ondansetron should NOT be used in first trimester, but this decision has been criticized as insufficiently substantiated by the European Network of Teratology Information Services (ENTIS). 7

FDA Labeling:

• FDA classifies ondansetron as having "inconsistent findings" with "important methodological limitations that preclude conclusions about safety." 3
• The FDA label notes ondansetron crosses the placenta and is present in all embryonic compartments. 3, 8

Clinical Guideline Support:

High-quality oncology guidelines explicitly state that ondansetron, metoclopramide, and steroids can be used to treat nausea and vomiting during pregnancy and are considered safe. 1

Clinical Algorithm for Ondansetron Use:

1. For severe nausea/vomiting requiring antiemetic therapy:

   • First-line: Consider metoclopramide or vitamin B6/doxylamine combinations
   • Second-line: Ondansetron can be used when first-line agents fail 1

2. For chemotherapy-induced nausea/vomiting in pregnant cancer patients:

   • Ondansetron is appropriate and considered safe 1

3. Counseling points:

   • Inform patients that the largest and highest-quality study found no increased risks 5
   • Acknowledge that some smaller studies suggested possible associations with cardiac defects and clefts, but these were not confirmed 3
   • Explain that regulatory warnings exist but are controversial and not well-supported by the strongest evidence 7

4. Use throughout pregnancy when benefits outweigh theoretical risks 1, 5

Common Pitfalls to Avoid

• Avoiding Augmentin in all pregnant women: This is unnecessary except in those at risk for preterm delivery. 2, 4
• Refusing ondansetron based solely on EMA guidance: The strongest epidemiological evidence supports safety, and clinical guidelines from major societies endorse its use. 1, 7, 5
• Failing to treat severe nausea/vomiting: Untreated hyperemesis can lead to maternal dehydration, electrolyte imbalances, and poor fetal outcomes. 6
• Not considering alternative antibiotics in preterm labor risk: This specific population should avoid Augmentin. 2, 4

Breastfeeding Compatibility

• Augmentin is compatible with breastfeeding. 2
• Ondansetron presence in breast milk is unknown, but it is present in rat milk, suggesting likely human milk presence. 3