Is diphenhydramine (Benadryl) safe for use during pregnancy, and what are its appropriate indications and dosing?

Diphenhydramine Safety in Pregnancy

Diphenhydramine can be used during pregnancy when necessary, but chlorpheniramine, cetirizine, or loratadine are preferred alternatives due to better documented safety profiles, and first-trimester exposure to diphenhydramine should be avoided when possible due to concerns about cleft palate. 1

Safety Profile and Risk Assessment

First Trimester Concerns

• The American College of Allergy, Asthma, and Immunology recommends using diphenhydramine with caution during pregnancy, particularly in the first trimester, due to a possible association with cleft palate, though recent studies have not conclusively confirmed this risk. 1
• The first trimester represents the most critical period for concern about congenital malformations because organogenesis occurs during this time. 1, 2
• An older case-control study suggested an association between first-trimester diphenhydramine exposure and cleft palate, but this finding has not been sufficiently refuted or confirmed by subsequent research. 1, 3

Overall Safety Evidence

• Recent studies have not detected significant increased risk for congenital malformations with diphenhydramine use during pregnancy, but caution remains advised. 1
• Both first-generation and second-generation antihistamines generally have good safety records during pregnancy. 1
• The FDA label advises pregnant women to ask a healthcare professional before use. 4

Preferred Alternative Antihistamines

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

1. Chlorpheniramine (first choice): Recommended as the first-line antihistamine during pregnancy due to its observed safety and longevity of use. 1, 2

2. Cetirizine and Loratadine: FDA Pregnancy Category B drugs with more accumulated safety data than diphenhydramine; these second-generation antihistamines have confirmed safety through large birth registries, case-control studies, and cohort studies. 1, 2

3. Diphenhydramine (use with caution): May be used when preferred alternatives are unavailable or ineffective, but avoid first-trimester exposure when possible. 1

Clinical Indications and Dosing

Approved Uses

• Diphenhydramine is indicated for allergic reactions including anaphylaxis, urticaria, and allergic rhinitis. 5
• In anaphylaxis management, diphenhydramine 1-2 mg/kg or 25-50 mg/dose can be administered parenterally. 6
• The combination of diphenhydramine and ranitidine is superior to diphenhydramine alone in managing anaphylaxis. 6

Dosing Considerations

• Standard adult dosing ranges from 25-50 mg per dose. 6
• Pediatric dosing is 1-2 mg/kg. 6
• Despite over-the-counter availability, adverse physiologic effects and toxicity may occur, especially when administered rapidly intravenously or in large doses. 5

Important Clinical Pitfalls

Combination Products

• Avoid combining diphenhydramine with oral decongestants during the first trimester due to potential risks of congenital malformations including gastroschisis and small intestinal atresia. 2, 3
• Combining decongestants with acetaminophen or salicylates may increase the risk of malformations. 2, 3

Common Misconceptions

• Do not assume all antihistamines have equivalent safety profiles during pregnancy—they do not, and specific agents have better documented safety. 1, 2
• Diphenhydramine is widely used during pregnancy (used by at least 15% of pregnant women in observational studies), but this frequency of use does not equate to superior safety compared to alternatives. 7

Alternative Non-Antihistamine Options

When treating allergic symptoms in pregnancy, consider these safer alternatives:

• Intranasal corticosteroids (e.g., budesonide): May be used with a favorable safety profile. 2
• Sodium cromolyn nasal spray: Considered safe during pregnancy (FDA Category B), though requires frequent dosing. 2
• Montelukast: FDA Pregnancy Category B with reassuring animal reproductive studies. 2

Monitoring Recommendations

• If diphenhydramine must be used during pregnancy, monitor fetal development through routine prenatal care. 1
• Consider switching to safer alternative antihistamines (chlorpheniramine, cetirizine, or loratadine) if treatment is needed throughout pregnancy. 1
• The FDA label warns about marked drowsiness, excitability (especially in children), and advises keeping out of reach of children due to overdose risk. 4