In This article

• While CBT for insomnia is effective for the treatment of sleep problems during pregnancy, some women may require pharmacologic treatment.
• A large population-based cohort study finds no increase in risk of malformations with Z-drug use in early pregnancy.
  
• Zolpidem accounts for most of the pregnancy exposures studied; data are limited for eszopiclone and zaleplon.
  
• Meta-analytic evidence suggests a small increase in risk of preterm birth and low birth weight, but results may reflect confounding.
  
• Insomnia itself has been associated with worse pregnancy outcomes, emphasizing the need for ongoing evaluation and treatment.

Sleep problems are common during pregnancy and are often treated with non-benzodiazepine sedative-hypnotics, also known as “Z-drugs.” These include zolpidem (Ambien), eszopiclone (Lunesta), and zaleplon (Sonata). While widely prescribed for insomnia, data on the reproductive safety of Z-drugs have been limited.

Z-Drugs and Risk of Major Malformations

A new U.S. population-based cohort study provides updated evidence on this topic, evaluating Z-drug use during pregnancy using data from the Medicaid Analytic eXtract (2000–2018) and the Merative MarketScan databases (2003–2020). Participants included pregnant individuals and their liveborn infants.

Exposure was defined as at least one dispensing of a Z-drug during the first trimester. Major congenital malformations were identified using linked maternal and infant claims. The risks of any major malformation, organ-specific malformations, and individual malformations in pregnancies with Z-drug exposure in the first trimester were compared with the risks in unexposed pregnancies. Relative risks (RRs) were estimated using propensity score fine stratification weights to account for potential confounders.

Summary of Findings

• 4,281,579 pregnancies were identified (mean maternal age at delivery: 25.2 years in Medicaid and 31.6 years in MarketScan).
  
• First-trimester Z-drug exposure occurred in 11,652 pregnancies (0.5%) in the Medicaid cohort and in 10,862 (0.6%) pregnancies in the MarketScan cohort.
  
• Zolpidem was the most commonly used agent, accounting for 92.1% of exposures.
  
• The adjusted pooled RR for any major malformation was 1.01 (95% CI, 0.95–1.08).
  
• Slightly increased, but imprecisely estimated, RRs were observed for abdominal wall defects (1.46; 95% CI, 0.89–2.38), tetralogy of Fallot (1.45; 95% CI, 0.86–2.46), and neural tube defects (1.62; 95% CI, 0.96–2.74); however, these signals were driven by the Medicaid cohort and were not replicated in the MarketScan cohort.
  
• Results were consistent across multiple sensitivity analyses.

These findings suggest that first-trimester Z-drug exposure does not meaningfully increase overall risk of congenital malformations, nor was a consistent pattern detected for organ-specific or uncommon defects. Because most exposures involved zolpidem, these findings may not be generalizable to the less commonly used Z-drugs eszopiclone or zaleplon.

Z-Drugs and Other Pregnancy Outcomes

In a recent systematic review and meta-analysis, Wang and colleagues examined associations between Z-drug exposure during pregnancy and risks of preterm birth (PTB), small for gestational age (SGA), and low birth weight (LBW) in nine studies (not including the Fung et al. study above). 

• The majority of exposures across these studies involved zolpidem.
• Z-drug exposure was associated with slightly increased risks of:
  
  • PTB: OR 1.28 (95% CI, 1.05–1.56)
    
  • SGA: OR 1.24 (95% CI, 1.18–1.30)
    
  • LBW: OR 1.51 (95% CI, 1.27–1.78)
• No significant association was observed for congenital malformations (OR 0.90; 95% CI, 0.63–1.28; I² = 56%).
  
• Subgroup analyses suggested that timing of exposure, type of hypnotic, and adjustment for psychiatric comorbidity attenuated some associations.

These modest associations have been observed in other studies as well. However, it is challenging to disentangle the effects of medication from those of underlying insomnia and related psychiatric illness. Prior research indicates that insomnia during pregnancy, even without medication use, may be independently associated with a higher risk of adverse outcomes.

Clinical Implications

Many women experience sleep problems during pregnancy, and more persistent sleep problems have been associated with worse pregnancy outcomes and increased vulnerability to postpartum depression. Because sleep disturbance may be a symptom or may exacerbate mood and anxiety disorders, careful screening for psychiatric symptoms is indicated. Depression or anxiety symptoms may require more targeted interventions. 

While cognitive-behavioral for insomnia (CBT-I) is recommended as a first-line treatment for insomnia, some women may require treatment with a sleep-promoting medication. These research studies provide reassuring information regarding the use of Z-drugs during pregnancy. 

• Current data indicate no increase in risk of major congenital malformations with first-trimester Z-drug exposure.
  
• Slight elevations in PTB, SGA, and LBW risk have been reported, although it is likely that residual confounding by psychiatric illness and concurrent medications may contribute to this finding.
  
• Because insomnia can itself signal or exacerbate perinatal mood and anxiety disorders, careful screening and integrated management of sleep and comorbid psychiatric conditions are essential.
  
• Non-pharmacologic strategies, such as cognitive-behavioral therapy for insomnia (CBT-I), should be considered first-line when feasible.
  
• When medication is indicated, zolpidem appears to have the most reassuring reproductive safety data, though more research is needed for zaleplon and eszopiclone

—Ruta Nonacs, MD PhD