Introduction
The risk for mental disorders during life is high, especially for women at fertile age, with a prevalence of 20-44% for any mental disorder during pregnancy and a relapse rate during pregnancy of 43-50%. Prior studies indicate that mental disorders during pregnancy are associated with an increased risk of preterm birth, low birth weight, and low APGAR scores.
Benzodiazepines including the agonist zopiclone and zolpidem, (together BDZs) are commonly used psychotropic drugs for mental disorders during pregnancy. BDZs act on the GABA-A receptor by increasing the inhibitory effect of y-aminobutyric acid (GABA), which leads to the opening of chloride channels, hyperpolarization of the cell membrane, and inhibition of excitation of the central nervous system. A systematic review and meta-analysis conducted by Bais et al in 2019 in 28 countries showed that the use of BDZs during pregnancy is common, with a prevalence of 3.1% (95% CI 1.8% , 4.5%). BDZs cross the placenta and may accumulate in fetal tissues. A recent systematic review and meta-analysis from Grigoriadis in 2020 included 14 cohort studies and showed that exposure to BDZs in pregnancy was significantly associated with an increased risk of spontaneous abortion (OR 1.86, 95% CI 1.43, 2.42), low birth weight (OR 2.24, 95% CI 1.41, 3.88), low APGAR score (OR 2.19, 95% CI 1.94, 2.47), preterm birth (OR 1.96, 95% CI 1.25, 3.08), induced abortion (OR 2.04 CI 95% 1.23 , 3.40) and admission to the NICU (OR 2.61 95% CI 1.64, 4.14).
The teratogenicity of BDZs is however still under debate. A meta-analysis from Enato et al in 2011 showed no increased risk for major malformations and oral cleft in cohort studies (OR 1.07 (95% CI 0.9, 1.25)), while analysis of case-control studies showed an association between major malformations (OR 3.01 95% (CI 1.32, 6.84)) and oral clefts alone (OR 1.79 95% (CI 1.13, 2.82)) after BDZ exposure in the first trimester. In case-control studies, cardiac malformations were not significantly increased. A more recent meta-analysis of Grigoriadis in 2020 with only cohort studies confirms these results and showed no significant association with congenital malformations (OR 1.13 95% (CI 0.99, 1.30)) and cardiac malformations (OR 1.27 (95% CI 0.98, 1.65)) after BDZ exposure. However, a combination of BDZs and antidepressants increased the risk of congenital malformations significantly (OR 1.40 95% (CI 1.09, 1.80)). In the Netherlands, the use of BDZs during pregnancy is carefully considered, as described in the guidelines for benzodiazepines in pregnancy and childbirth of the Dutch Association of Obstetrics and Gynaecology (NVOG).
Studies on BDZs during pregnancy often used large databases without overseeing the indication or diagnosis of use and often lack determination of possible confounding variables. To our knowledge, this is the first study on the effect of BDZs exposure in pregnancy on neonatal and maternal outcomes, including possible confounders. Our primary aim was to investigate the potential association of BDZs exposure during pregnancy with gestational age, and our secondary aims are to determine the potential association with birth weight, presence of congenital malformations, APGAR score, and the need for prolonged psychiatric care.