Discussion
In this study, we found that in utero exposure to BDZs in women with a
mental disorder(s) was associated with a significantly lower gestational
age 3.2 days, 95% CI -5.8 - -0.53, p = 0.019. We also found that the
use of BDZs during pregnancy is associated with prolonged psychiatric
care after delivery concerning the mother. Other parameters like birth
weightthe presence of congenital malformations, and the APGAR scores,
were not different compared to non-exposure of BDZs.
Concerning the lower gestational age, our results are in line with
Huitfeldt et al. and Grigoriadis et al. Huitfeldt et al reported in 2020
a reduction of gestational age of 2.1 days ((95% CI -3.3 - -0.9 days)
after in utero exposure of BDZs. The recent systematic review and
meta-analysis by Grigoridaris et al in 2020 included studies with
prospectively collected data concerning a BDZ exposed and non-exposed
cohort, regardless of psychiatric disease, and excluded co-exposure with
other psychotropic drugs. They found that exposure to BDZs was
associated with a reduction of 6.2 in gestational age (MD – 6.2 days
weeks (95% CI -11.2 days - 0.01), P = 0.02). These results, together
with our results, a significant shorter gestational age, seems not to be
of clinical relevance. Other studies lack information about the
indication of use, which might have biased the results. Our cohort
comprises BDZs exposure with exposure to other psychotropic drugs, also
possible/usable in general clinical care. We found that co-administered
psychotropic drugs did not contribute to the lower gestational age. An
explanation from a clinical perspective could be that women using BDZs
at the end of pregnancy, are more prone to inducing birth and so a
shorter duration of pregnancy, possibly because of fatigue symptoms in
this vulnerable population and the associated risks of post-partum
depression.
We found no association of BDZs exposure with birthweight which
indicates that BDZs exposure in utero does not alter the intrauterine
growth of the fetus. Our results are conflicting with the results ofGrigoriadis et al. in 2020 who found that SGA differed
significantly between BDZ exposed and non-exposed cohorts after
correction for publication bias (OR 1.38 (95% CI 1.04, 1.85), P =
0.03), however, the indication for use was not given. Wang et al in 2010
found also an increase in the proportion of SGA among women using BDZs.
We found no significant association between BDZs exposure and the risk
for minor and major congenital malformations in our study, where 26.5%
of the women in our cohort were exposed to BDZs during the first
trimester. Our results are in line with a meta-analysis of Eneto et al
(2011). They included studies with BDZ exposure in at least the first
trimester with an unexposed control group with only live births and
found no association with major malformations (OR 1.06 (95% CI 0.91,
1.25)) or oral clefts (OR 1.19 (95% CI 0.34, 4.15)) in cohort studies.
However, in case-control studies, they found an association between
major malformations (OR 3.01 (95% CI 1.32, 6.84)) or oral clefts (OR
1.79 (95% CI 1.13, 2.82)) and BDZ exposure. The included case-control
studies may be hampered by recall bias from exposed neonates and the use
of concomitant co-medication. A recent meta-analysis by Grigoriadis et
al (2019) included cohort studies with prospectively collected data
about major congenital malformations and cardiac malformations in BDZ
exposed and unexposed pregnancies with live births. They found no
association with congenital (OR 1.08 (985% CI 0.93, 1.25)) and cardiac
malformations (OR 1.27 (95% CI 0.98, 1.65)) and BDZ exposure alone.
However, the risk of malformations increased in a sub-group of women
using BDZ and antidepressants with an OR of 1.40 (95% CI 1.09, 1.80)).
It is not clear whether these results were due to combined exposure to
BDZ and antidepressants or antidepressants exposure alone, which is
associated with cardiac malformations.
We found no differences in major malformations in the exposed group
(4.1%) compared to the reference group (6.1%) after exclusion of some
risk factors for the development of congenital malformations, such as
teratogenic drugs. EUROCAT reported a prevalence of 2.33% of major
congenital malformations in live births in the Netherlands between 2011
and 2018, which seems lower compared to our study population. An
explanation could be that our cohort consists of women with a high-risk
pregnancy and delivery or puerperium in the hospital, which could
increase the selection and surveillance for congenital malformations.
All women in our study had a mental disorder, which is also a risk
factor and related to other risk factors for congenital malformations,
such as smoking or drug use.
Previous studies reported that the percentage of minor malformations
ranged from 14.7% to 40.7%. We found 7.3% minor malformations in our
cohort, however, minor malformations were also not consequently
reported, screened, and diagnosed. Minor malformations can be used to
detect different syndromes or major congenital malformations, especially
related to teratogenics which we did not find. However, these data must
be interpreted cautiously because of methodological issues about their
variation in definition, diagnosis, and reporting.
Strengths and limitations
Observational studies are, by their nature, limited in their ability to
establish causation with certainty. Consequently, our results are not
necessarily reflective of a causal relationship.
It could be that the effects we found, were due to the severity of
illness, which we didn’t measure. That is, women with more severe
illness may have stayed on the drug, and thus, the illness, and not
necessarily the drug, may have affected the effects. This limitation is
a result of confounding, that is, the BZD association is distorted
because other factors that the study groups differ on, such as diagnosis
or indication, can also be associated with adverse outcomes. Effects of
confounding by indication can explain a portion or all of the
associations found.
However, we tried to reduce selection and confounding bias by using a
DAG and using potential confounders published in literature.
Our results are limited by relatively small sample size, and so our
findings should be interpreted with caution. Unfortunately, we could not
register the use of drugs by trimester of pregnancy. Therefore, any
influence of drugs during the organogenesis and the prevalence of
congenital malformations in our population could not be directly related
to the use of drugs, including BDZs.
In the exposed group the use of BDZs was grouped, regardless of
indication, dosage, or half-life of individual drugs. These factors were
accounted for by introducing the severity of illness (intermittent
versus continuous use of BDZs (data not shown); the number of registered
mental illnesses; use of other psychotropic drugs), introducing risk
factors for mental disease (educational level; presence of support
system), however, we did not find differences between both groups.
Although residual confounding could be possible.
Further, it could be that we underestimated the number of congenital
malformations, as we only considered live births in our cohort.
Therefore, miscarriages and planned abortions may have contributed to
the number of malformations.
From the literature, we know that there may be an association between
BDZ exposure and miscarriages, but this needs further study. and it
could be that children with specific malformations were lost to
follow-up because of their specific malformations and further treatment
in a tertiary clinic.
Finally, the study population is a high-risk population of pregnant
women with severe mental disorders who are referred to our hospital.
Women using BDZ while pregnant and treated by their general practitioner
were not included. This might overestimate the risks we found and limit
our study’s generalizability.
One of the strengths of our study is that only women are included with a
defined BDZ-exposure for a mental disorder, determined by a manual
review of the EPD. We used a rich dataset, including all main possible
confounders, to analyze our data, including dosage of BDZ, the
indication of use, frequency and duration of use, and excluding
occasional use of BDZ at the end of pregnancy during hospitalization.
This may prevent misclassification.
Also, our reference group were women with mental disorders not using
BDZs. We know that mental disorders themselves can also lead to
different adverse neonatal and maternal outcomes. So confounding by
indication might therefore be limited in our study.