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.