First-trimester exposure to nonbenzodiazepine sedative hypnotics (Z-drugs) was not associated with an increased risk for overall or organ-specific congenital malformations, in a large US cohort study spanning more than 4 million pregnancies. 

Modest effects for some rare, severe malformations, such as tetralogy of Fallot and neural tube defects, could not be ruled out, but the “signals” were not consistently identified, the researchers noted. 

Overall, the findings provide “reassurance” on the use of Z-drugs for sleep problems during pregnancy, the investigators, with first author Kelly Fung, MS, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, write. 

The study was published online December 23 in JAMA Psychiatry. 

Filling a Data Gap

Sleep disturbances are common in pregnancy and often treated with Z-drugs (zolpidem, eszopiclone, or zaleplon) when first-line behavioral interventions fail. 

However, there is limited data on the safety of Z-drugs for the developing fetus. Some previous reports have suggested possible associations with cardiac, gastrointestinal, and neural tube defects based on small numbers of exposed pregnancies.

To investigate further, Fung and colleagues analyzed Medicaid data from 2000 to 2018 as well as data from the Merative MarketScan Commercial Claims Database from 2003 to 2020. 

Among nearly 4.3 million pregnancies, first-trimester Z-drug exposure was documented in roughly 0.5%-0.6% of pregnancies, with zolpidem accounting for 92% of exposures.

After adjusting for confounding factors, there was no difference in risk for congenital malformations overall among infants exposed to Z-drugs in the first trimester compared with unexposed infants (pooled relative risk [RR], 1.01). 

Although adjusted pooled relative risks were elevated for certain rare outcomes, including abdominal wall defects (RR, 1.46), tetralogy of Fallot (RR, 1.45), and neural tube defects (RR, 1.62), these estimates were “imprecise” and only seen in the Medicaid cohort. Further, the absolute increase in risk for these malformations was small — roughly 1 case per 5000 treated pregnancies, the investigators reported. 

The results were generally consistent across multiple sensitivity analyses. 

“These findings suggest that Z-drug exposure in the first trimester of pregnancy is not associated with a meaningful elevation in the risk of congenital malformations overall, nor was there a consistent signal observed for organ-specific or uncommon, individual malformations examined,” the authors conclude. 

The study was funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development. Fung reported no relevant financial relationships.