Is Benadryl (diphenhydramine) safe to use during pregnancy?

Benadryl During Pregnancy

Benadryl (diphenhydramine) can be used during pregnancy with caution, particularly avoiding the first trimester when possible, though it has generally good overall safety data despite an unresolved concern about cleft palate risk.

Key Safety Considerations

The evidence presents a nuanced picture of diphenhydramine safety in pregnancy:

First Trimester Concerns

• The FDA drug label explicitly states "do not use if pregnant or breast-feeding" 1, which represents the manufacturer's most conservative position
• Guidelines note that while diphenhydramine is frequently used during pregnancy with good overall safety data, administration has been associated with the development of cleft palate 2
• This cleft palate association comes from a case-control study that "has yet to be sufficiently refuted" 2

Broader Safety Evidence

Despite the cleft palate concern, the overall evidence is reassuring:

• Both first-generation and second-generation antihistamines generally have excellent safety records and do not show a significant increase in congenital malformations when used during the first trimester 2
• Recent large studies have not detected increased risk for congenital malformations 2
• A 2017 meta-analysis found H1 antihistamines were not associated with increased risk of major malformation, spontaneous abortion, prematurity, stillbirth, or low birth weight 3
• A 2020 study of 41,148 pregnancies found lack of strong evidence to conclude birth defects are associated with antihistamine exposure during early pregnancy 4

Clinical Algorithm for Use

When antihistamine therapy is necessary during pregnancy:

1. Preferred alternatives first:

   • Consider second-generation antihistamines (cetirizine, loratadine) which have comparable safety data but better side-effect profiles 2
   • Chlorpheniramine is often chosen by UK clinicians due to its long safety record 5

2. If diphenhydramine is selected:

   • Avoid first trimester use when possible given the unresolved cleft palate signal
   • Use lowest effective dose for shortest duration
   • Document informed discussion of risks vs. benefits

3. For rhinitis specifically:

   • Intranasal corticosteroids (especially budesonide - Category B) are preferred 2
   • Nasal saline rinses are safe and effective 6

Important Caveats

• The most critical time for concern about congenital malformation is the first trimester when organogenesis occurs 2
• The sedative and anticholinergic properties of first-generation antihistamines make them less desirable choices than second-generation agents 2
• Risk of uncontrolled maternal disease (severe allergic reactions, anaphylaxis) must be weighed against medication risks
• Hydroxyzine should be avoided entirely during first trimester based on animal data and is specifically contraindicated in early pregnancy 2, 5

Bottom Line

While diphenhydramine has been widely used in pregnancy without clear evidence of harm in most studies, the persistent cleft palate signal combined with availability of better-studied alternatives (cetirizine, loratadine, chlorpheniramine) and the FDA label warning make it a second-line choice. When antihistamine therapy is needed during pregnancy, prefer second-generation agents or chlorpheniramine over diphenhydramine, especially during the first trimester 2, 5.