Are hypnotic benzodiazepine receptor agonists teratogenic in humans?

Hypnotic benzodiazepine receptor agonists (HBRAs; zolpidem, zopiclone, and zaleplon) are used in the treatment of insomnia. Little is known about the safety of HBRAs during pregnancy.

Data from the Swedish Medical Birth Registry from July 1, 1995, up to 2007 were used to identify 1318 women who reported the use of HBRAs in early pregnancy. They gave birth to 1341 infants. Maternal characteristics and the presence of congenital malformations were compared with all other women who gave birth (n = 1,106,001) and all other infants (n = 1,125,734) born during the study period.

Use and/or reporting of HBRAs increased with maternal age and were higher at first than higher parity. Maternal smoking was strongly associated with reported use of HBRAs. The probability of using HBRAs increased in women who had had 3 or more earlier miscarriages or 5 or more years of involuntary childlessness. An excess use of other drugs and above all psychoactive drugs were seen in women reporting use of HBRAs.Hypnotic benzodiazepine receptor agonists were not associated with an increased risk for congenital malformations. A statistically significant high risk for other intestinal malformations than atresias/stenosis was based on only 4 infants.

Maternal use of HBRAs does not seem to increase malformation risk. The tentative association with some intestinal malformations may be due to chance because of multiple testing and needs confirmation.