Is Benadryl (diphenhydramine) safe to use during pregnancy?

Benadryl (Diphenhydramine) Safety in Pregnancy

Diphenhydramine should be used with caution during pregnancy, particularly avoiding the first trimester when possible, and safer alternatives like chlorpheniramine, cetirizine, or loratadine should be strongly preferred. 1, 2

Key Safety Concerns

• Diphenhydramine has been associated with cleft palate development, which is the primary concern that distinguishes it from other antihistamine options 1, 2
• While recent studies have not conclusively confirmed this risk, the association from case-control studies has not been sufficiently refuted to dismiss the concern 2
• The FDA classifies diphenhydramine as Category B or C, indicating incomplete safety data despite widespread historical use 1
• The FDA drug label specifically states "if pregnant or breast-feeding, ask a healthcare professional before use," reflecting these ongoing safety concerns 3

Critical Timing Considerations

• The first trimester poses the highest risk because this is when organogenesis occurs and when cleft palate formation would be affected 2, 4
• If diphenhydramine must be used, avoiding first trimester exposure is the most important risk-reduction strategy 2

Preferred Alternative Antihistamines

When antihistamine treatment is necessary during pregnancy, the following hierarchy should guide selection:

First-Line Options (Better Safety Profiles):

• Chlorpheniramine is the most recommended first-choice antihistamine due to its long safety record and extensive clinical experience 2, 4
• Cetirizine and loratadine are FDA Pregnancy Category B drugs with substantial accumulated safety data from large birth registries and cohort studies 1, 2, 5

Why These Are Preferred:

• Second-generation antihistamines (cetirizine, loratadine) have confirmed safety through extensive epidemiological studies 2
• Meta-analysis of 200,000 first-trimester exposures to first-generation antihistamines showed no increased teratogenic risk overall, but this included safer agents like chlorpheniramine 6

Clinical Decision-Making Algorithm

Step 1: Assess Necessity

• Determine if antihistamine treatment is absolutely necessary, as avoiding all medications during pregnancy is preferable when possible 1
• Weigh the risk of untreated maternal allergic conditions against potential medication risks 1

Step 2: Choose Safest Agent

• First choice: Chlorpheniramine for any trimester 2, 4
• Second choice: Cetirizine or loratadine, particularly after first trimester 2, 5
• Avoid: Diphenhydramine, especially in first trimester 2

Step 3: Optimize Dosing

• Use the lowest effective dose for the shortest duration possible 1
• Monitor fetal development through routine prenatal care if diphenhydramine has already been used 2

Important Caveats and Pitfalls

• Do not assume all antihistamines have equivalent safety profiles—they do not, and this is a common clinical error 2, 4
• Avoid combining antihistamines with oral decongestants during the first trimester due to additional potential risks of congenital malformations 2, 4
• No antihistamine has been proven completely safe during pregnancy, and all should be used with appropriate caution 1, 7
• First-generation antihistamines like diphenhydramine should be avoided as a class during pregnancy according to some expert recommendations, with chlorpheniramine being the notable exception 5

If Diphenhydramine Has Already Been Used

• Recent studies have not detected significant increased risk for congenital malformations with diphenhydramine use, providing some reassurance 2
• Consider switching to safer alternatives (chlorpheniramine, cetirizine, or loratadine) if ongoing treatment is needed 2
• Ensure appropriate prenatal monitoring and ultrasound evaluation 2