Is there an increased risk of oral clefts associated with the use of amoxicillin (amoxicillin) during pregnancy?

Risk of Oral Clefts Associated with Amoxicillin Use During Pregnancy

Amoxicillin use during pregnancy is not strongly associated with an increased risk of oral clefts, as the FDA drug label indicates there is no evidence of harm to the fetus due to amoxicillin in animal studies, though adequate human studies are limited. 1

Evidence Assessment

FDA Drug Labeling

The FDA drug label for amoxicillin states that reproduction studies in mice and rats at doses up to 3-6 times the human dose showed no evidence of harm to the fetus. However, it notes that "there are no adequate and well-controlled studies in pregnant women" and recommends that amoxicillin "should be used during pregnancy only if clearly needed." 1

Research Evidence

Several studies have examined the potential association between amoxicillin and oral clefts with mixed results:

• A 2012 case-control study found maternal use of amoxicillin was associated with an increased risk of cleft lip with/without cleft palate (adjusted OR = 2.0), with a higher risk for third-gestational-month use (OR = 4.3). 2

• A 2007 Hungarian case-control study suggested a possible association between amoxicillin and orofacial clefts. 3

• However, a larger 2012 Danish nationwide cohort study of over 800,000 births found maternal use of any antibiotics in early pregnancy was not associated with an increased risk of cleft lip with/without cleft palate (POR, 1.08) or cleft palate alone (POR, 1.14). This more robust study did not find a specific association with amoxicillin. 4

• A 2023 systematic review concluded that while no major congenital anomalies were consistently reported with amoxicillin use, there remains a possibility it might be related to some anomalies including cleft palate, suggesting cautious use during pregnancy. 5

Clinical Approach

Risk Assessment

• Amoxicillin is classified as FDA Pregnancy Category B, indicating no evidence of risk in animal studies
• The absolute risk of oral clefts in the general population is low (approximately 1 in 700 births)
• Any potential increased risk from amoxicillin appears to be small based on current evidence

Recommendations for Prescribing

1. Consider alternative antibiotics if appropriate for the infection being treated
2. If amoxicillin is required:
   • Use the lowest effective dose for the shortest duration
   • When possible, avoid use during the critical period for palate formation (weeks 6-9 of gestation)
   • Document the medical necessity for treatment

Patient Counseling

• Explain that untreated bacterial infections during pregnancy may pose greater risks than antibiotic treatment
• Discuss that current evidence does not strongly support a significant increased risk of oral clefts with amoxicillin
• Emphasize the importance of folic acid supplementation during pregnancy, which may reduce the risk of oral clefts

Comparative Context

For perspective, other medications have stronger evidence for oral cleft risk:

• Ondansetron use in pregnancy has been associated with an increased rate of orofacial clefting, with the absolute risk increasing from 11 to 14 cases per 10,000 births 6
• Oral corticosteroids have been associated with a slightly increased risk of cleft lip with or without cleft palate 6
• First-trimester use of certain anticonvulsants like phenytoin has a well-established association with oral clefts 3

In conclusion, while some studies suggest a possible association between amoxicillin and oral clefts, the evidence is inconsistent, and the FDA drug label does not indicate a clear risk. The benefits of treating bacterial infections during pregnancy often outweigh the potential small risk of oral clefts.