Is diphenhydramine (Benadryl) safe to use during the first trimester of pregnancy?

Diphenhydramine Safety in First Trimester

Diphenhydramine can be used during the first trimester of pregnancy, though chlorpheniramine is preferred as the first-choice first-generation antihistamine due to its longer safety record and more robust observational data. 1, 2

Evidence-Based Recommendation

While diphenhydramine is commonly used by pregnant patients and recent large studies have not detected increased risk for congenital malformations, there remains unresolved concern from an older case-control study suggesting a possible association with cleft palate that has not been sufficiently refuted. 1 However, a comprehensive 2009 National Birth Defects Prevention Study examining 364 associations found that diphenhydramine generally showed no meaningful teratogenic risk, though 8 of 24 weak positive associations involved this medication specifically. 3

Preferred Alternatives

• Chlorpheniramine is specifically recommended as the first-choice antihistamine during pregnancy because of its observed safety, longevity of use, and sufficient human observational data demonstrating no significant increase in congenital malformations during first trimester exposure. 2

• Second-generation antihistamines (cetirizine and loratadine) are now confirmed safe through large birth registries, case-control studies, and cohort studies, and offer the advantage of less sedation compared to first-generation agents. 1, 2

Critical Safety Considerations

• Never combine diphenhydramine with oral decongestants during the first trimester, as phenylephrine and pseudoephedrine have conflicting reports of association with gastroschisis and small intestinal atresia. 1, 2

• Risk of malformations increases when decongestants are combined with acetaminophen or salicylates. 1, 2

• The FDA drug label requires asking a healthcare professional before use if pregnant, though it does not provide specific trimester guidance. 4

Strength of Evidence

A 1997 meta-analysis of over 200,000 women found that H1 blockers taken during the first trimester had a summary odds ratio of 0.76 (95% CI: 0.60-0.94) for major malformations, suggesting no increased teratogenic risk and possibly a protective effect. 5 A more recent 2013 case-control study of 13,213 infants with malformations found that previously hypothesized associations between specific antihistamines and birth defects were not supported when adjusted for confounders and multiple comparisons. 6

Practical Algorithm

If antihistamine needed in first trimester:

1. First choice: Chlorpheniramine (longest safety record) 2
2. Second choice: Cetirizine or loratadine (less sedating, confirmed safe) 1, 2
3. Acceptable alternative: Diphenhydramine (widely used, generally safe despite unresolved cleft palate concern) 1, 3
4. Avoid: Hydroxyzine (contraindicated based on animal data) 2

Common Pitfalls

• Assuming all antihistamines have equivalent safety profiles—they do not, with hydroxyzine specifically contraindicated. 2
• Using liquid diphenhydramine preparations without checking alcohol content, as some elixirs contain 15% ethanol. 7
• Combining antihistamines with decongestants during organogenesis increases malformation risk. 1, 2