Is trazodone safe during pregnancy at low doses for insomnia?

Trazodone Use During Pregnancy for Insomnia

Trazodone can be used during pregnancy at low doses for insomnia when behavioral interventions have failed, though it should be avoided in the first trimester when possible, and FDA-approved hypnotics or cognitive behavioral therapy should be considered first. 1, 2

Safety Profile in Pregnancy

Reassuring Evidence on Birth Defects

• 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 with trazodone use during pregnancy 2
• A systematic review of 14 studies found no consistent evidence linking trazodone to increased risks of congenital malformations, stillbirths, or low birth weight 3
• A multicentre prospective study of 147 pregnant women exposed to trazodone or nefazodone found major malformation rates of 1.6%, which did not exceed baseline rates of 1-3% 4

Potential Concerns

• Some studies suggest a possible association with increased risk of spontaneous and therapeutic abortions, though data are limited and varied 3
• Animal studies showed increased fetal resorption in rats at 7.3-11 times the maximum recommended human dose and increased congenital anomalies in rabbits at 7.3-22 times the maximum recommended human dose 2

Placental and Breast Milk Transfer

• Trazodone and its active metabolite (mCPP) cross the placenta, with cord blood concentrations comparable to maternal serum levels 5
• Trazodone transfers into breast milk at lower concentrations than serum (50.2 ng/mL in milk vs 267.6 ng/mL in cord blood) 5
• Limited postmarketing reports have not identified adverse effects on breastfed infants 2

Clinical Efficacy During Pregnancy

• A randomized clinical trial in 54 pregnant women during the third trimester showed trazodone improved sleep quality compared to placebo after 6 weeks of treatment 6
• The same study demonstrated that trazodone treatment reduced postpartum depression symptoms at 2 and 6 weeks after delivery 6

Treatment Algorithm for Pregnant Patients

First-Line Approach

• Cognitive behavioral therapy for insomnia (CBT-I) should be the initial treatment before any pharmacological intervention 1, 7

Second-Line Pharmacological Options

• Short-intermediate acting benzodiazepine receptor agonists (zolpidem, eszopiclone, zaleplon) or ramelteon are preferred over trazodone 1, 7

Third-Line: When to Consider Trazodone

• After first and second-line treatments have failed 1
• When comorbid depression or anxiety is present (though low doses used for insomnia are inadequate for treating major depression) 1
• Consider the risk of untreated depression and insomnia, as women who discontinue antidepressants during pregnancy are more likely to experience relapse of major depression 2

Dosing Recommendations

Starting Dose

• Begin with 25-50 mg taken at bedtime 7
• Use the lowest effective dose possible 1

Timing Considerations

• Avoid use in the first trimester when possible, as this is when the risk of congenital malformations is greatest (though trazodone has not been shown to increase this risk) 2
• If used throughout pregnancy, 35% of women in one study continued trazodone use without adverse outcomes 4

Monitoring Requirements

• Assess sleep onset, maintenance, and overall quality after initiating treatment 7
• Monitor for common side effects including sedation, dizziness, and dry mouth 7
• Be aware of rare but serious side effects such as priapism 1, 7
• Regular follow-up every few weeks initially to assess effectiveness and adverse effects 1

Critical Caveats

Pregnancy Registry

• Healthcare providers should register patients by calling the National Pregnancy Registry for Antidepressants at 1-844-405-6185 2

Risk-Benefit Considerations

• The developmental and health benefits of treating insomnia should be weighed against potential risks 2
• Untreated insomnia during pregnancy is associated with postpartum depression, which itself carries significant morbidity 6
• The American Academy of Sleep Medicine recommends against trazodone for primary insomnia in non-pregnant adults due to limited efficacy evidence, but this must be balanced against the unique risks of untreated insomnia in pregnancy 1

Administration Guidelines

• Take on an empty stomach to maximize effectiveness 1
• Caution if signs/symptoms of compromised respiratory function, hepatic dysfunction, or heart failure are present 1, 2