Is Benadryl (diphenhydramine) 50mg safe for pregnant women to use as a sleep aid?

Diphenhydramine 50mg Safety in Pregnancy for Sleep

Diphenhydramine (Benadryl) 50mg can be used for sleep in pregnant women, but it should be used with caution due to a potential association with cleft palate, and second-generation antihistamines like loratadine or cetirizine are preferable first-line options. 1

Key Safety Considerations

Risk Profile of Diphenhydramine

• Diphenhydramine has been associated with the development of cleft palate when administered during pregnancy, which is a significant concern that must be weighed against treatment benefits 1
• Despite this specific risk, diphenhydramine has generally good overall safety data from extensive historical use 1
• The FDA classifies diphenhydramine as Category B or C, indicating limited evidence of harm but incomplete safety data 1

General Antihistamine Safety in Pregnancy

• The National Institute of Child Health and Human Development recommends avoiding all antihistamines if possible during pregnancy, especially in the first trimester 1
• No antihistamine has been proven completely safe during pregnancy, and all should be used with caution 1
• A comprehensive review of sleep-promoting medications found no correlation with increased risk of congenital malformations overall for antihistamines, though data remain limited 2

Preferred Alternatives to Diphenhydramine

Second-Generation Antihistamines

• Second-generation antihistamines (loratadine, cetirizine) are preferable to first-generation antihistamines like diphenhydramine due to their superior safety profile 1
• Loratadine and cetirizine are classified as FDA Pregnancy Category B drugs, implying no evidence of harm to the fetus, though well-controlled human studies remain limited 1
• Chlorphenamine is often chosen by clinicians when antihistamine therapy is necessary during pregnancy because of its long safety record 1

Other Sleep Medication Considerations

• Benzodiazepines and hypnotic benzodiazepine receptor agonists may increase rates of preterm birth, low birthweight, and/or small-for-gestational-age infants, making them less desirable options 2
• The small number of studies and subjects prohibits definitive interpretation regarding consequences of hypnotic or sedating medication use in pregnancy 2

Clinical Decision-Making Algorithm

Step 1: Assess Necessity

• Determine if pharmacologic treatment is absolutely necessary, as avoiding medication during pregnancy is preferable when possible 1
• Consider the risk of untreated maternal sleep disturbance (which can affect maternal and fetal health) against potential medication risks 1

Step 2: Choose Appropriate Agent

• If antihistamine treatment is deemed necessary, prioritize second-generation antihistamines (loratadine 10mg or cetirizine 10mg) before considering diphenhydramine 1
• If second-generation antihistamines are ineffective or unavailable, chlorphenamine may be considered before diphenhydramine 1
• Diphenhydramine 25-50mg can be used if other options fail, with awareness of the cleft palate association 1

Step 3: Dosing Strategy

• Use the lowest effective dose for the shortest duration possible 1
• For diphenhydramine specifically, consider starting at 25mg rather than 50mg to minimize fetal exposure while assessing efficacy 1

Important Caveats

Timing Considerations

• First trimester exposure carries the highest theoretical risk for structural malformations, including cleft palate with diphenhydramine 1
• Pregnancy-related factors that disrupt sleep include heartburn, nocturnal oxytocin secretion, nocturia, and fetal movement, which may respond to non-pharmacologic interventions 3

Documentation and Counseling

• Always document the risk-benefit discussion with the patient, including the specific concern about cleft palate with diphenhydramine 1
• Approximately 90% of pregnant women use medications during pregnancy, with 10% of birth defects directly linked to medications, emphasizing the importance of judicious prescribing 4

Research Limitations

• Much information about medication safety in pregnancy comes from registries, case studies, and animal studies rather than randomized controlled trials due to ethical concerns 4, 5
• The paucity of randomized controlled trials in pregnant populations restricts clinicians' ability to make fully informed decisions 2