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\begin{document}

\title{Maternal and neonatal outcomes after benzodiazepine and benzodiazepine
agonist exposure during pregnancy in women with mental disorders}



\author[1]{Hennique Knobbe}%
\author[1]{Elvera Damer}%
\author[1]{Mireille Edens}%
\author[1]{Bas Nij Bijvank}%
\author[1]{Marieke Hemels}%
\author[1]{Peter Ter Horst}%
\affil[1]{Isala klinieken}%


\vspace{-1em}



  
  \date{May 26, 2024}


\begingroup
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\selectlanguage{english}
\begin{abstract}
Abstract Objective To compare the gestational age of neonates in utero
exposed to benzodiazepines (BDZs) with none exposed controls. Secondary
objectives were; birth weight, presence of congenital malformations,
APGAR score, and the need for \textgreater{} 3 months (prolonged)
maternal psychiatric care. Study design A retrospective cohort study of
women and neonates from 2013 to 2021 with univariate and multivariable
analysis to study the associations between BDZs exposure and gestational
age compared to non-exposed women with mental health problems. Results
We found that BDZ exposure was associated with a lower gestational age
of -3.2 days (95\% CI -5.8 , -0.53 days). Women in the exposed group had
an increased risk of psychiatric care (adjusted OR 2.511 (95\% CI 1.675
-- 3.782), p \textless{} 0.001). Conclusion We found that in utero BDZ
exposure was independently associated with a significantly lower
gestational age of the neonates and prolonged psychiatric care of their
mothers.%
\end{abstract}%



\sloppy


\textbf{Maternal and neonatal outcomes after benzodiazepine and
benzodiazepine agonist exposure during pregnancy in women with mental
disorders}

Hennique Knobbe\textsuperscript{1}, Elvera A. Damer\textsuperscript{2},
Mireille A. Edens\textsuperscript{3}, Bas S.W.A. Nij
Bijvank\textsuperscript{4}, Marieke A.C. Hemels\textsuperscript{5},
Peter G.J. ter Horst\textsuperscript{1, 6}

1: Isala, Department of Clinical Pharmacy, E=hennique@hotmail.com ; 2:
Isala, Department of Psychiatry, E=e.a.damer@isala.nl; 3: Isala, Isala
Academie, E=m.a.edens@isala.nl ; 4: Isala, Department of Gynecology and
Obstetrics, E= s.w.a.nijbijvank@isala.nl ; 5: Isala, Department of
Neonatology, E=m.a.c.hemels@isala.nl ; 6: Corresponding author: Dr.
P.G.J. ter Horst, Ph.D., PharmD, hospital pharmacist. Isala; department
of Clinical Pharmacy; dr van Heesweg 2; 8025 AB Zwolle, The Netherlands;
T= 0031 38 424 2469; E=p.g.j.ter.horst@isala.nl

\textbf{Patient Consent}

Consent to publish this cohort study was not obtained, as decided by the
medical ethical review board. This report does not contain any personal
information that could lead to the identification of the patient.

\textbf{Funding}

No funding or grant support

\textbf{Authorship}

All authors attest that they meet the current ICMJE criteria for
Authorship. None of the authors have any conflict of interest.

\textbf{Data availability statement}

The data that support the findings of this study are available from the
corresponding author upon reasonable request.



\textbf{What is already known about this subject?}

Benzodiazepines are thought to decrease the duration of pregnancy, lower
the APGAR scores of the neonate, and decrease birth weight of the
neonate.

\textbf{What this study adds}

The use of benzodiazepines during pregnancy did not negatively affect
maternal and neonatal outcomes after inclusion of possible confounders
in the dataset

Using Directed Acyclic Graphs (DAGs) is of use in the setting of
pregnancies complicated by psychiatric diseases and psychotropic drugs
and other co-morbidities and demographic parameters

\textbf{Abstract}

\textbf{Objective}

To compare the gestational age of neonates in utero exposed to
benzodiazepines (BDZs) with none exposed controls. Secondary objectives
were; birth weight, presence of congenital malformations, APGAR score,
and the need for \textgreater{} 3 months (prolonged) maternal
psychiatric care.

\textbf{Study design}

A retrospective cohort study of women and neonates from 2013 to 2021
with univariate and multivariable analysis to study the associations
between BDZs exposure and gestational age compared to non-exposed women
with mental health problems.

\textbf{Results}

We found that BDZ exposure was associated with a lower gestational age
of -3.2 days (95\% CI -5.8 , -0.53 days). Women in the exposed group had
an increased risk of psychiatric care (adjusted OR 2.511 (95\% CI 1.675
-- 3.782), p \textless{} 0.001).

\textbf{Conclusion}

We found that in utero BDZ exposure was independently associated with a
significantly lower gestational age of the neonates and prolonged
psychiatric care of their mothers.

\textbf{Keywords}

\begin{itemize}
\tightlist
\item
  Benzodiazepines
\item
  Pregnancy
\item
  Neonatal complications
\item
  Maternal complications
\item
  Retrospective cohort study
\end{itemize}



\textbf{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 \emph{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.

\textbf{Materials, subjects and methods}

\emph{Study design and setting}

This explorative retrospective cohort study was conducted in Isala, a
large teaching hospital in Zwolle, the Netherlands. Pregnant women
treated in our hospital and women who were referred from primary care or
regional hospitals to our hospital were included. The period of
inclusion was from the introduction of national guidelines on the use of
BDZs during pregnancy on 01-01-2013 until 31-12-2020 with a
(poli)clinical delivery or puerperium in our hospital.

\emph{Participants}

We included pregnant women between 18 and 45 years with a diagnosed
mental disorder using psychotropic drugs and/or having at least two
(poli)clinical consults from a mental care provider in our hospital. We
divided the included patients into two groups, a BDZs-exposed and a
reference group not using BDZs.

\emph{Exposure}

The exposed group consisted of pregnant women exposed to BDZs and/or
hypnotic benzodiazepine receptor agonists (BDZs), BDZs exposure was
defined as using chronic BDZs any time from the first day of the last
menstrual period (LMP) until the end of the pregnancy. The LMP was
estimated from the gestational age reported in the patient file.

Exclusion criteria for both groups were a stillbirth delivery
(\textgreater{} 24 weeks of gestation) and multiple births. Also,
pregnancies with exposure to teratogenic drugs according to the
Teratology Information Centre (TIS) were excluded. However, we included
lithium because of its indication in bipolar disorders. Mother-child
couples were excluded in the case of paternal or maternal congenital
malformations according to ICD-10 codes class XVII (Q00-Q99) or in the
case of an actual maternal diagnosis of epilepsy (ICD-10 G40-G41),
because of the possibility of using teratogenic anti-epileptic drugs.
Further, mother-child couples with missing primary or secondary outcomes
were also excluded. Women with short-term use of BDZs only used during
hospital admission were excluded as these might bias the results because
it's not related to psychiatric disease. In the presence of more than
one pregnancy concerning the same mother, we randomly selected one
pregnancy in our dataset. For statistical reasons, we included a double
number of pregnancies in the reference group at random compared to the
exposed group.

\emph{Outcomes}

We compared the exposed and reference group using gestational age (days)
as the primary outcome. Secondary outcomes were birth weight, APGAR
scores at 1 and 5 minutes, presence of congenital malformations, and
prolonged psychiatric care defined as \textgreater{} 3 months postpartum
psychiatric care.

Congenital malformations were divided into minor and major malformations
according to EUROCAT guidelines if an ICD-10 codes class XVII (Q00-99)
was recorded in the EPF. Prolonged psychiatric care of the mother was
defined as more than 3 months postpartum, which is the normal follow-up
time. The severity of the underlying mental disorder was estimated by
the total number of registered mental disorders.

The reference group consisted of pregnancies of women with any mental
disorder not using a BDZ at any time during pregnancy.

\emph{Covariates}

The primary and secondary outcomes may be a priori confounded by other
factors, like gender because of higher birth weights in male infants
compared to female infants. Maternal age at the time of conception, BMI
before pregnancy, educational level (low/middle/high), presence of
support system (defined as an in-house living partner) and smoking,
drugs, and alcohol use during pregnancy, may be associated with birth
weight and complications during delivery. The number and type of actual
and historical mental disorders mentioned in the patient file and the
use of concomitant other psychotropic drugs during pregnancy may affect
primary and secondary outcomes, and so were recorded. Other possible
confounders may be chronic comorbid disorders, such as thyroid disease
and asthma, and pregnancy-related disorders, like (gestational)
diabetes, hypertension, pre-eclampsia/HELLP, and infections during
pregnancy. Further, information about the parity (0/1+), a previous
miscarriage/abortion, and the use of IVF/ICSI were collected. The use of
epidural/spinal anesthesia during delivery, position during delivery,
gender of the newborn, and presence of meconium may influence the
primary and secondary outcomes, and were also recorded.

\emph{Data source and data collection}

Women eligible for the study were found using CTcue\selectlanguage{ngerman}\textsuperscript{®},
an Artificial Intelligence searching program developed to collect data
from Electronic Patient Files (EPF) of our clinic
(CTcue\textsuperscript{®}, version 2.1.1.10, Amsterdam, Netherlands).
Data were collected in CTcue® and further processed in Rstudio.

\emph{Statistical methods}

A directed acyclic graph (DAG) was constructed by using the online
DAGitty software (http://www.dagitty.net/) to select covariates for
inclusion in the statistical models.

The relationships between each of the variables were assigned based on
knowledge of the publications regarding these associations. Concerning
assumptions described in the DAG theory, a minimal sufficient set of
adjustment variables was identified for estimating the effect of BDZs
use on maternal and neonatal risks.

\emph{Descriptive statistics}

Continuous data were presented as mean (±sd) or median (\ldots{} -
\ldots{}), depending on the distribution. Normality of the data was
tested with a visual inspection of the data, the Shapiro-Wilk test, and
comparing means with medians. Categorical data were presented as n(\%).

\emph{Inferential statistics}

Variables concerning the exposed and reference group were compared using
the independent samples T-test, Pearson's Chi-square test, or Fisher's
exact test whenever applicable.

Regression analyses on the primary (gestational age) and secondary
outcomes (birth weight, APGAR scores, congenital malformations, and
prolonged psychiatric care) were performed to adjust the study group
(BDZ-exposed versus reference group) for confounding variables.

Comparison of baseline characteristics (p\textless{}0.05) and univariate
regression analyses were performed to select potential confounders.
Variables with a p-value \textless{}0.1 by univariate analysis were
entered in the multivariable regression model for backward regression
analysis. Variables with a non-obvious time relationship with the
investigated outcome (e.g. epidural/spinal anesthesia and gestational
age), were excluded from the multivariable model. All statistical tests
were performed using Rstudio.

\emph{Ethical approval}

The Daily Board of the Medical Ethics Committee Isala Zwolle, The
Netherlands, has reviewed this study. As a result, the rules laid down
in the Medical Research Involving Human Subjects Act (also known by its
Dutch abbreviation WMO), do not apply to this research proposal.

Our findings are reported according to the Strengthening the Reporting
of Observational Studies in Epidemiology (STROBE) guideline.

\textbf{Results}

\emph{Participants}

We identified 201 pregnancies exposed to the BDZ group and 386
pregnancies not exposed to BDZ in the period of interest. In the exposed
group, six pregnancies were excluded because of multiple births and one
for a stillbirth. Of the remaining 194 singleton live birth pregnancies
in the exposed group, a total of 25 pregnancies were excluded for the
following reasons: pregnancies with an actual diagnosis of epilepsy,
pregnancies with congenital malformations in one of the parents, or
exposure to teratogenic drugs. For the same reasons and due to missing
data about the primary and secondary outcomes, 42 pregnancies were
excluded and nine multiple births pregnancies from the reference group.

As a result, 169 pregnancies in the exposed group and 335 pregnancies in
the reference group were eligible. In presence of more than one
pregnancy from the same mother we randomly selected a pregnancy in our
dataset. See figure 1 for the details on patient selection. The final
dataset consisted of 147 pregnancies in the exposed group and 294
pregnancies in the reference group.

Both groups differed in maternal and clinical characteristics, see table
1. In the BDZs exposed women used more alcohol during pregnancy (4.1\%
vs 0.7\%, p = 0.019), had lower number of mental disorders (p=0.010), a
higher number of concomitant psychotropics (p\textless{}0.001), and
needed longer psychiatric care after delivery (p\textless{}0.001), see
table 1. Duration of pregnancy was shorter in the BDZs exposed group,
269 days for the exposed group and 274 days for the non-exposed group,
p\textless{}0.001.

\emph{BDZ-exposure}

In 26.5\% of the pregnancies, exposure to BDZ was in at least the first
trimester, while the exposure was in at least the third trimester
(91.8\%). In 20.4\%, exposure occurred in all trimesters.

We found no differences in both groups regarding birth weight, APGAR
scores at 1, 5 and 10 minutes and the number of minor and major
malformations. BDZs exposure was associated with a decreased number of
gestational days (duration of pregnancy) of -3.2 days, 95\% CI -5.8 -
-0.53, p = 0.019. In the final regression model, also gestational
diabetes, preeclampsia or HELLP syndrome, maternal infections, placental
disease, meconium containing amnion fluid, lower birth weight and
appearance of minor malformations were relevant factors for decreased
number of gestational days. See table 2 for details. The factors APGAR
score at 1 and 5 minutes seems not logically related to number of
gestational days.

BDZs exposure was associated with prolonged psychiatric care, which was
defined as more than 3 months psychiatric care after delivery, OR 2.511,
95\% CI 1.675-3.782, p\textless{}0.001. Other factors in the model were
maternal age, male gender of the newborn and birthweight, see table 3
for details.

We found no differences between minor malformations between the exposed
and control group with a crude OR = 1.852 (95\% CI 0.897, 3.822), and
also no differences in major malformations with a crude OR = 0.652 (95\%
CI 0.253, 1.680).

\textbf{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
of\emph{Grigoriadis 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.

\emph{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.

\textbf{Conclusion}

We found that neonates in utero exposed to BDZs had a statistically
significant lower gestational age of -3.2 days compared to neonates not
exposed to BDZs in mothers with mental disorders. This difference seems
not clinically relevant. We also found that the use of BDZs during
pregnancy is associated with prolonged psychiatric care after delivery
concerning the mother. We found no differences between exposed or none
exposed to BDZs regarding birth weight, the number of congenital
malformations, APGAR score, and the need for prolonged psychiatric care.

\textbf{References}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image1/image1}

\end{center}
\end{figure}

\textsuperscript{*See for more details of the inclusion criteria and
exclusion criteria in the method section}

Table 1: Patient characteristics of the exposed and control group\selectlanguage{english}
\begin{longtable}[]{@{}lllll@{}}
\toprule
& \textbf{Characteristic} & \textbf{No benzodiazepine exposure}, N = 294
& \textbf{Benzodiazepine exposure}, N = 147 &
\textbf{p-value\emph{\textsuperscript{1}}}\tabularnewline
Maternal & Benzodiazepine exposure only in first trimester, n (\%) & 0
(NA) & 39 (27) &\tabularnewline
& Benzodiazepine exposure only in second trimester, n (\%) & 0 (NA) & 84
(57) &\tabularnewline
& Benzodiazepine exposure only in third trimester, n (\%) & 0 (NA) & 135
(92) & \textgreater{}0.999\tabularnewline
& Maternalage, Median (IQR) & 31.0 (26.2 -- 34.0) & 31.0 (28.0 -- 35.0)
& 0.217\tabularnewline
& Body Mass Index (BMI), Median (IQR) & 24.8 (21.8 -- 28.4) & 24.7 (21.9
-- 29.1) & 0.905\tabularnewline
& Primiparous, n (\%) & 156 (53) & 92 (63) & 0.057\tabularnewline
& Use of Assisted Reproductive Technique, n (\%) & 17 (5.8) & 14 (9.5) &
0.147\tabularnewline
& Smoking during pregnancy, n (\%) & 60 (20) & 41 (28) &
0.078\tabularnewline
& Alcohol use during pregnancy, n (\%) & 2 (0.7) & 6 (4.1) &
\textbf{0.019}\tabularnewline
& Drugs use during pregnancy, n (\%) & 18 (6.1) & 10 (6.8) &
0.782\tabularnewline
& Educational level, n (\%) & & & 0.192\tabularnewline
& High & 98 (33) & 35 (24) &\tabularnewline
& Low & 54 (18) & 31 (21) &\tabularnewline
& Middle & 122 (41) & 73 (50) &\tabularnewline
& Presence of support, n (\%) & 275 (94) & 135 (92) &
0.510\tabularnewline
& Number of concomitant mental disorders, n (\%) & & &
\textbf{0.010}\tabularnewline
& 1 & 101 (34) & 32 (22) &\tabularnewline
& 2 & 99 (34) & 43 (29) &\tabularnewline
& 3 & 67 (23) & 48 (33) &\tabularnewline
& 4 & 19 (6.5) & 18 (12) &\tabularnewline
& 5 & 6 (2.0) & 5 (3.4) &\tabularnewline
& 6 & 2 (0.7) & 1 (0.7) &\tabularnewline
& Number of other psychotropic drugs, n (\%) & & &
\textbf{\textless{}0.001}\tabularnewline
& 0 & 120 (41) & 33 (22) &\tabularnewline
& 1 & 145 (49) & 90 (61) &\tabularnewline
& 2 & 26 (8.8) & 21 (14) &\tabularnewline
& 3 & 3 (1.0) & 2 (1.4) &\tabularnewline
& 4 & 0 (0) & 1 (0.7) &\tabularnewline
& Need for prolonged psychiatric care (\textgreater{}3 months post
partum, n (\%) & 93 (32) & 79 (54) &
\textbf{\textless{}0.001}\tabularnewline
& Having gestational diabetes, n (\%) & 27 (9.2) & 11 (7.5) &
0.549\tabularnewline
& Having thyroid disease, n (\%) & 13 (4.4) & 10 (6.8) &
0.289\tabularnewline
& Having hypertension, n (\%) & 30 (10) & 9 (6.1) & 0.155\tabularnewline
& Preeclampsia or HELLP during pregnancy, n (\%) & 8 (2.7) & 8 (5.4) &
0.150\tabularnewline
& Maternal infections, n (\%) & 53 (18) & 38 (26) & 0.056\tabularnewline
& Having astma, n (\%) & 41 (14) & 23 (16) & 0.633\tabularnewline
& Having Placentaldisease, n (\%) & 37 (13) & 18 (12) &
0.919\tabularnewline
& Use of epiduraal anesthesia during delivery, n (\%) & 160 (54) & 80
(54) & \textgreater{}0.999\tabularnewline
& Unknown & 294 & 147 &\tabularnewline
& Breech position of the child , n (\%) & 11 (3.7) & 8 (5.4) &
0.231\tabularnewline
& Meconium containing amnion fluid, n (\%) & 44 (15) & 17 (12) &
0.329\tabularnewline
Neonatal & gender, n (\%) & & & 0.544\tabularnewline
& f & 151 (51) & 71 (48) &\tabularnewline
& m & 143 (49) & 76 (52) &\tabularnewline
& Number of gestational days, Median (IQR) & 274 (267 -- 282) & 269 (266
-- 276) & \textbf{\textless{}0.001}\tabularnewline
& Birth weight, Median (IQR) & 3,390 (3,090 -- 3,689) & 3,350 (3,005 --
3,630) & 0.128\tabularnewline
& APGAR score at 1 minute, Median (IQR) & 9.00 (8.00 -- 9.00) & 9.00
(8.00 -- 9.00) & 0.160\tabularnewline
& APGAR score at 5 minutes, n (\%) & & & 0.164\tabularnewline
& 3 & 1 (0.3) & 0 (0) &\tabularnewline
& 5 & 1 (0.3) & 2 (1.4) &\tabularnewline
& 6 & 3 (1.0) & 2 (1.4) &\tabularnewline
& 7 & 8 (2.7) & 5 (3.5) &\tabularnewline
& 8 & 12 (4.1) & 14 (9.9) &\tabularnewline
& 9 & 59 (20) & 24 (17) &\tabularnewline
& 10 & 207 (71) & 95 (67) &\tabularnewline
& Unknown & 3 & 5 &\tabularnewline
& APGAR score at 10 minutes, n (\%) & & & 0.442\tabularnewline
& 3 & 1 (0.8) & 1 (1.4) &\tabularnewline
& 5 & 1 (0.8) & 0 (0) &\tabularnewline
& 6 & 1 (0.8) & 0 (0) &\tabularnewline
& 7 & 2 (1.5) & 0 (0) &\tabularnewline
& 8 & 5 (3.8) & 7 (9.7) &\tabularnewline
& 9 & 16 (12) & 11 (15) &\tabularnewline
& 10 & 106 (80) & 53 (74) &\tabularnewline
& Unknown & 162 & 75 &\tabularnewline
& Minor malformations, n (\%) & 17 (5.8) & 15 (10) &
0.092\tabularnewline
& Major malforomations, n (\%) & 18 (6.1) & 6 (4.1) &
0.373\tabularnewline
& \emph{\textsuperscript{1}}Wilcoxon rank sum test; Fisher's exact test;
Pearson's Chi-squared test & \emph{\textsuperscript{1}}Wilcoxon rank sum
test; Fisher's exact test; Pearson's Chi-squared test &
\emph{\textsuperscript{1}}Wilcoxon rank sum test; Fisher's exact test;
Pearson's Chi-squared test & \emph{\textsuperscript{1}}Wilcoxon rank sum
test; Fisher's exact test; Pearson's Chi-squared test\tabularnewline
\bottomrule
\end{longtable}

Table 2: Factors associated with number of gestational days\selectlanguage{english}
\begin{longtable}[]{@{}lllll@{}}
\toprule
\textbf{Characteristic} & \textbf{N} & \textbf{Beta} & \textbf{95\%
CI\emph{\textsuperscript{1}}} & \textbf{p-value}\tabularnewline
Benzodiazepine exposure during pregnancy & 441 & -3.2 & -5.8 to -0.53 &
0.019\tabularnewline
Benzodiazepine exposure only in first trimester & 147 & -4.4 & -8.8 to
0.00 & 0.050\tabularnewline
Having gestational diabetes & 441 & -7.4 & -12 to -2.9 &
0.001\tabularnewline
Having preeclampsia or HELLP & 441 & -12 & -19 to -5.8 &
\textless{}0.001\tabularnewline
Maternal infections & 441 & -6.1 & -9.2 to -3.0 &
\textless{}0.001\tabularnewline
Having placental disease & 441 & -6.3 & -10 to -2.5 &
0.001\tabularnewline
Meconium containing amnion fluid & 441 & 7.3 & 3.7 to 11 &
\textless{}0.001\tabularnewline
Birth weight & 441 & 0.02 & 0.01 to 0.02 &
\textless{}0.001\tabularnewline
\emph{APGAR score at 1 minute} & \emph{433} & \emph{1.2} & \emph{0.23 to
2.1} & \emph{0.015}\tabularnewline
\emph{APGAR score at 5 minutes} & \emph{433} & \emph{2.2} & \emph{0.89
to 3.5} & \emph{0.001}\tabularnewline
Minor malformations & 441 & -5.2 & -10 to -0.41 & 0.034\tabularnewline
\emph{\textsuperscript{1}}CI = Confidence Interval &
\emph{\textsuperscript{1}}CI = Confidence Interval &
\emph{\textsuperscript{1}}CI = Confidence Interval &
\emph{\textsuperscript{1}}CI = Confidence Interval &
\emph{\textsuperscript{1}}CI = Confidence Interval\tabularnewline
\bottomrule
\end{longtable}

Table 3: factors associated with prolonged psychiatric care
(\textgreater{} 3 months post partum)\selectlanguage{english}
\begin{longtable}[]{@{}llllll@{}}
\toprule
\textbf{Characteristic} & \textbf{N} &
\textbf{OR\emph{\textsuperscript{1}}} & \textbf{95\%
CI\emph{\textsuperscript{1}}} & \textbf{p-value} &
\textbf{p-value}\tabularnewline
Benzodiazepine exposure during pregnancy & 441 & 2.511 & 1.675 to 3.782
& 0.000 & 0.000\tabularnewline
Maternal age & 441 & 1.047 & 1.008 to 1.089 & 0.019 &
0.019\tabularnewline
Gender of the neonate & 441 & & & &\tabularnewline
Male & & 1.499 & 1.021 to 2.207 & 0.039 & 0.039\tabularnewline
Birth weight & 441 & 1.000 & 1.000 to 1.001 & 0.038 &
0.038\tabularnewline
\emph{\textsuperscript{1}}OR = Odds Ratio, CI = Confidence Interval &
\emph{\textsuperscript{1}}OR = Odds Ratio, CI = Confidence Interval &
\emph{\textsuperscript{1}}OR = Odds Ratio, CI = Confidence Interval &
\emph{\textsuperscript{1}}OR = Odds Ratio, CI = Confidence Interval &
\emph{\textsuperscript{1}}OR = Odds Ratio, CI = Confidence Interval
&\tabularnewline
\bottomrule
\end{longtable}

\textbf{Hosted file}

\verb`figure 1.docx`  available at \url{https://authorea.com/users/568235/articles/614187-maternal-and-neonatal-outcomes-after-benzodiazepine-and-benzodiazepine-agonist-exposure-during-pregnancy-in-women-with-mental-disorders}

\selectlanguage{english}
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\end{document}

