Is trazodone safe for use during pregnancy, even at low doses, for treating insomnia?

Trazodone Use During Pregnancy for Insomnia

Trazodone can be used cautiously during pregnancy for insomnia, particularly in the third trimester, as available human data have not identified consistent associations with major birth defects or adverse maternal-fetal outcomes, though it should be avoided as first-line therapy and used at the lowest effective dose.

Evidence from FDA Drug Labeling

The FDA label for trazodone provides reassuring human pregnancy data:

• Published prospective cohort studies, case series, and case reports over several decades have not identified drug-associated risks of major birth defects, miscarriage, or adverse maternal or fetal outcomes 1
• The estimated background risk in the U.S. general population for major birth defects is 2-4% and miscarriage is 15-20% 1
• A pregnancy exposure registry exists for monitoring outcomes (National Pregnancy Registry for Antidepressants: 1-844-405-6185) 1

Important caveat: Animal studies showed increased fetal resorption in rats at 7.3-11 times the maximum recommended human dose and congenital anomalies in rabbits at 7.3-22 times the human dose 1

Systematic Review Evidence

The most recent systematic review (2025) analyzing 14 studies found:

• No consistent evidence linking trazodone to increased risks of congenital malformations, stillbirths, or low birth weight 2
• Possible association with increased risk of spontaneous and therapeutic abortions, though data were limited and varied 2
• The review concluded that further research with larger, well-controlled studies is needed 2

Clinical Trial Evidence for Third Trimester Use

A randomized clinical trial specifically evaluated trazodone for insomnia in the third trimester:

• 54 pregnant women with insomnia were randomized to trazodone, diphenhydramine, or placebo 3
• Trazodone improved sleep profile compared to placebo after 6 weeks of treatment 3
• Importantly, trazodone treatment reduced postpartum depression symptoms at 2 and 6 weeks after delivery compared to placebo 3
• This suggests potential benefit beyond just treating insomnia 3

Concerning Preclinical Data

Recent research (2021) raises potential concerns about neurodevelopmental effects:

• Trazodone interferes with sterol biosynthesis, causing elevated 7-dehydrocholesterol (7-DHC) levels 4
• In animal models, maternal trazodone exposure increased 7-DHC and decreased desmosterol in newborn pup brains 4
• The most elevated toxic oxysterols occurred in offspring with DHCR7+/- genotype exposed to maternal trazodone 4
• This suggests trazodone might be a risk factor for neurodevelopmental disorders, especially in DHCR7+/- fetuses 4

However, this preclinical finding has not been confirmed in human studies and requires further investigation 4

Pharmacokinetic Data

Trazodone and its active metabolite (mCPP) cross the placenta and enter breast milk:

• Cord blood concentrations at 7.4 hours post-dose were comparable to maternal serum levels (267.6 ng/mL trazodone, 22.8 ng/mL mCPP) 5
• Breast milk concentrations were lower (50.2 ng/mL trazodone, 3.2 ng/mL mCPP) 5
• One infant exposed in utero and via breast milk developed normally with no adverse effects at 6-month follow-up 5

Clinical Recommendations for Use

When trazodone is considered necessary during pregnancy:

• Avoid first trimester use when possible, as this is the period of highest risk for congenital malformations (general principle for all medications) 1
• Use the lowest effective dose (typically 25-50 mg for insomnia, well below the 400 mg maximum recommended dose) 1, 3
• Consider that low doses used for insomnia (25-50 mg) are substantially below doses that caused animal toxicity (7.3-22 times human maximum dose) 1
• Third trimester use appears to have the most favorable risk-benefit profile based on the clinical trial showing benefits for both insomnia and postpartum depression prevention 3

Preferred Alternatives

Before using trazodone, consider:

• Cognitive behavioral therapy for insomnia (CBT-I) as first-line treatment 6, 7
• The American Academy of Sleep Medicine recommends against trazodone for general insomnia treatment (though this recommendation is not pregnancy-specific) 6, 7
• Other medications have not been well-studied in pregnancy for insomnia, and many carry their own risks 8

Critical Clinical Context

The decision must weigh untreated insomnia risks:

• Untreated depression and insomnia during pregnancy increase risk of postpartum depression 1
• Women who discontinued antidepressants during pregnancy were more likely to experience relapse of major depression 1
• Insomnia may be an early warning sign or trigger for psychiatric illness relapse 8

Practical Algorithm

1. First-line: Attempt CBT-I and sleep hygiene measures
2. If pharmacotherapy needed:
   • Avoid first trimester if possible
   • Third trimester: Trazodone 25-50 mg can be used with informed consent about limited but generally reassuring human data
   • Second trimester: Use only if benefits clearly outweigh risks
3. Monitoring: Enroll in pregnancy registry, monitor fetal development, assess for postpartum depression
4. Breastfeeding: Can continue with caution, as trazodone transfers into breast milk but limited data show no adverse infant effects 1, 5