Is use of Unisom (diphenhydramine or doxylamine succinate) safe during pregnancy?

Unisom Use in Pregnancy is Safe

Yes, Unisom is safe to use during pregnancy—both formulations (doxylamine succinate and diphenhydramine) are considered acceptable, though doxylamine is preferred as a first-line option based on current guidelines. 1, 2

Doxylamine Succinate (Preferred Unisom Formulation)

The American College of Obstetricians and Gynecologists (ACOG) recommends doxylamine as a safe first-line pharmacologic treatment for nausea and vomiting in pregnancy when non-pharmacologic measures fail. 1 This is the most strongly endorsed formulation:

• Doxylamine is FDA-approved specifically for treating nausea and vomiting of pregnancy, particularly in combination with pyridoxine (vitamin B6). 1
• Large birth registries, case-control studies, and cohort studies have confirmed the safety of first-generation antihistamines including doxylamine during the first trimester, with no significant increase in congenital malformations. 1
• A randomized placebo-controlled trial demonstrated that doxylamine succinate 10 mg (up to 4 tablets daily) is safe and well-tolerated by pregnant women, with no increased rate of adverse events compared to placebo. 3

Diphenhydramine (Alternative Unisom Formulation)

Diphenhydramine carries slightly more caution but remains acceptable:

• Diphenhydramine has been associated with an increased risk of cleft palate development in some studies; therefore, dimenhydrinate or doxylamine are preferred when an antihistamine is needed. 2
• However, older safety data from 1986 suggest that the risks of using diphenhydramine appear to be low overall. 4
• The FDA label advises pregnant women to "ask a healthcare professional before use" but does not contraindicate its use. 5

Treatment Algorithm for Pregnancy-Related Symptoms

When managing nausea, vomiting, or sleep disturbances in pregnancy, follow this stepwise approach:

Step 1: Non-pharmacologic measures first 1

• Dietary modifications (small, frequent, bland meals)
• Avoidance of triggers
• Ginger 250 mg four times daily
• Pyridoxine (vitamin B6) 10-25 mg every 8 hours

Step 2: First-line pharmacologic options if symptoms persist 1, 2

• Doxylamine (preferred Unisom formulation)
• Dimenhydrinate
• Promethazine

Step 3: Second-line options for inadequate response 1

• Metoclopramide (similar efficacy to promethazine but fewer adverse events such as drowsiness)

Step 4: Severe cases requiring hospitalization 1

• Ondansetron or methylprednisolone on a case-by-case basis

Critical Safety Considerations

• The most critical period for concern about congenital malformations is the first trimester during organogenesis, though both doxylamine and diphenhydramine have demonstrated acceptable safety profiles during this period. 1
• Both formulations cause marked drowsiness; patients should avoid driving, operating machinery, and consuming alcohol. 6, 5
• The FDA labels for both formulations state "if pregnant or breast-feeding, ask a health professional before use," which reflects standard precautionary language rather than a contraindication. 6, 5

Common Pitfalls to Avoid

• Do not confuse Unisom with oral decongestants (phenylephrine, pseudoephedrine), which should be avoided during the first trimester due to associations with gastroschisis and small intestinal atresia. 7, 2
• Avoid using diphenhydramine with any other product containing diphenhydramine to prevent overdose. 5
• Do not use doxylamine with any other product containing doxylamine. 6
• Monitor for rare but serious adverse effects in overdose situations, such as syndrome of inappropriate antidiuresis (SIAD) with severe hyponatremia. 8

Bottom Line for Clinical Practice

Choose doxylamine succinate (Unisom SleepTabs) as the preferred formulation based on ACOG guidelines and FDA approval for pregnancy-related nausea. 1 If only diphenhydramine (Unisom SleepGels/SleepMelts) is available, it remains a reasonable option with slightly more caution regarding cleft palate risk. 2, 4 Both are vastly safer than untreated severe nausea and vomiting, which can lead to dehydration, electrolyte imbalances, and nutritional deficiencies. 1