Pregnancy Exposure Registry

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antidepressants during pregnancy. Healthcare providers are encouraged to register patients by calling the National Pregnancy Registry for Antidepressants at 1-844-405-6185 or visiting online at https://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/antidepressants/ .

Risk Summary 

Based on findings from animal studies of other drugs that enhance GABAergic inhibition, ZULRESSO may cause fetal harm. Available data from case reports with ZULRESSO use in pregnant women are insufficient to establish a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. In animal reproduction studies, malformations were not seen in rats or rabbits at plasma levels up to 5 and 6 times the maximum recommended human dose (MRHD), respectively. Developmental toxicities were seen in the fetuses of rats and rabbits at 5 and ≥3 times the plasma levels at the MRHD, respectively. Reproductive toxicities were seen in rabbits at ≥3 times the plasma levels at the MRHD. These effects were not seen in rats and rabbits at 2 and 1.2 times the plasma levels at the MRHD. Brexanolone administered to pregnant rats during pregnancy and lactation resulted in lower pup survival at doses which were associated with ≥2 times the plasma levels at the MRHD and a neurobehavioral deficit in female offspring at 5 times the plasma levels at the MRHD. These effects were not seen at 0.8 times and 2 times the plasma levels at the MRHD, respectively (see Data). 

In published animal studies, administration of other drugs that enhance GABAergic inhibition to neonatal rats caused widespread apoptotic neurodegeneration in the developing brain. The window of vulnerability to these changes in rats (postnatal days 0-14) corresponds to the period of brain development that takes place during the third trimester of pregnancy in humans.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

Data

Animal Data

In pregnant rats and rabbits, no malformations were seen when brexanolone was given during the period of organogenesis at continuous intravenous doses up to 60 and 30 mg/kg/day, respectively. These doses were associated with maternal plasma levels 5 and 6 times the plasma levels at the MRHD of 90 mcg/kg/hour, in rats and rabbits, respectively. In rats, a decrease in fetal body weights was seen at 60 mg/kg/day (5 times the plasma level at the MRHD). In rabbits, increased numbers of late resorptions and a decrease in fetal body weights were seen at doses equal to and greater than 15 mg/kg/day (3 times the plasma levels at the MRHD) with fewer live fetuses and a higher post implantation loss seen at 30 mg/kg/day (6 times the plasma levels at the MRHD) in the presence of maternal toxicity (decreased food consumption and decreased body weight gain and/or body weight loss). Effects in rats and rabbits were not seen at 2 and 1.2 times the plasma levels at the MRHD, respectively.

When brexanolone was administered to pregnant rats by continuous intravenous administration at 30 and 60 mg/kg/day (2 and 5 times plasma levels at the MRHD, respectively) during the period of organogenesis and throughout pregnancy and lactation, increased numbers of dead pups and fewer live pups at birth were seen. This effect was not seen at 0.8 times the plasma levels at the MRHD. Decreased pup viability between postnatal day 0 and 4 in the presence of maternal toxicity (decreased body weight gain and food consumption during lactation) was seen at 5 times the plasma levels at the MRHD. These effects were not seen at 2 times the plasma levels at the MRHD. A neurobehavioral deficit, characterized by slower habituation in the maximal startle response in the auditory startle test, was seen in female offspring of dams dosed at 5 times the plasma levels at the MRHD. This effect was not seen at 2 times the plasma levels at the MRHD.