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\begin{document}

\title{Do pregnant women use pharmacological treatment as prescribed?}



\author[1]{Beau de Korte}%
\author[1]{Nori Smeets}%
\author[1]{Angela Colbers}%
\author[1]{Bart van den Bemt}%
\author[1]{Marleen van Gelder}%
\affil[1]{Radboudumc}%


\vspace{-1em}



  
  \date{May 22, 2024}


\begingroup
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\selectlanguage{english}
\begin{abstract}
Aim: Pregnant women are hypothesized to have low adherence to prescribed
medication, because of concerns about toxicity and harmful effects on
the unborn child. However, very little is known about the actual
adherence to prescribed medication during pregnancy. We determined to
what extent women follow treatment recommendations regarding prescribed
medication use in mid-pregnancy. Methods: Dutch women participating in
the PRIDE Study completed a six-week diary on medication use.
Additionally, pharmacy records were obtained. For each medication
dispensed, we determined three measures of adherence: 1) whether use was
reported in the diary (actual use), 2) difference between dispensing
date and date of first reported use (initiation time), and 3) proportion
of days with at least the correct number of doses taken (implementation
adherence). Results: During the six-weeks study period, 235 of 816 women
(29\%) were prescribed medication. Actual use was highest for
medications used for chronic conditions (88\%; 95\% confidence interval
{[}95\% CI{]} 81-93), followed by medication for pregnancy-related
conditions (79\%; 95\% CI 71-86) and medication for occasional and
short-time use (69\%; 95\% CI 60-77). We observed a [?]1 day delay in
treatment initiation for 42\% of medications dispensed for the first
time in the study period. For medications that were actually used, mean
implementation adherence was 74.2\% (95\% CI 69.3-79.2). Conclusion:
Although actual use of medications dispensed was high, many pregnant
women did not adhere to treatment recommendations. This non-adherence
may impact maternal and child health and lead to exposure
misclassification in studies in perinatal pharmacoepidemiology relying
on administrative databases.%
\end{abstract}%



\sloppy


\textbf{Do pregnant women use pharmacological treatment as prescribed?}

Running title: Adherence to prescribed medication in pregnancy

Beau A C de Korte\textsuperscript{1,2}, Nori J L
Smeets\textsuperscript{3}, Angela Colbers\textsuperscript{4}, Bart J F
van den Bemt\textsuperscript{4,5}, Marleen M H J van
Gelder\textsuperscript{1}

\textsuperscript{1} Department for Health Evidence, Radboud Institute
for Health Sciences, Radboud university medical center, Nijmegen, The
Netherlands

\textsuperscript{2} Department of Gynecology, Canisius Wilhelmina
Hospital, Nijmegen, The Netherlands

\textsuperscript{3} Department of Pharmacology and Toxicology, Radboud
Institute for Health Sciences, Radboud university medical center,
Nijmegen, The Netherlands

\textsuperscript{4} Department of Pharmacy, Radboud Institute for Health
Sciences, Radboud university medical center, Nijmegen, The Netherlands

\textsuperscript{5} Department of Rheumatology Research, Sint
Maartenskliniek, Nijmegen, The Netherlands

\textbf{Corresponding author:} Marleen van Gelder PhD, Department for
Health Evidence (HP133), Radboudumc, P.O. Box 9101, 6500 HB Nijmegen,
The Netherlands. T: +31-24-3666126. E: Marleen.vanGelder@radboudumc.nl.

\textbf{Data availability:} The data from this study are not publicly
available due to privacy and ethical restrictions. For further requests
about access to PRIDE Study data please contact
Marleen.vanGelder@radboudumc.nl.

\textbf{Funding:} No specific funding was received for this paper.

\textbf{Author contributions:} Ms de Korte was the lead author,
responsible for study design, statistical analysis, data interpretation,
and preparation of the draft manuscript. Ms Smeets was responsible for
study design, data collection, data interpretation, and critically
reviewed the manuscript. Dr. Colbers and Prof. van den Bemt were
responsible for study design, data interpretation, and critically
reviewed the manuscript. Dr. van Gelder was responsible for study
design, data collection, statistical analysis, data interpretation, and
critically reviewed the manuscript.

\textbf{Conflict of interest:} The authors have stated explicitly that
there are no conflicts of interest in connection with this paper.

\textbf{Ethics approval} : The PRIDE Study was approved by the Regional
Committee on Research Involving Human Subjects Arnhem-Nijmegen (CMO
2009/305).

\textbf{ORCID ID} : Nori Smeets 0000-0002-4927-2459

Angela Colbers 0000-0002-0389-9934

Bart van den Bemt 0000-0002-8560-9514

Marleen van Gelder 0000-0003-4853-4434

\textbf{Key words:} Medication adherence; Implementation; Pregnancy;
PRIDE Study; Treatment initiation

\textbf{Word count:} 3,032

\textbf{Table count:} 4

\textbf{Figure count:} 3

\textbf{BULLET POINT SUMMARY}

\textbf{What is already known about this subject}

\begin{itemize}
\tightlist
\item
  Non-adherence to pharmacological treatment during pregnancy may lead
  to maternal and fetal complications.
\item
  Adherence is considered low during pregnancy, but definitions and
  methods to determine adherence differed between studies.
\item
  Maternal questionnaires and interviews are prone to underreporting,
  resulting in unfairly low estimates of adherence when being compared
  to prescription databases.
\end{itemize}

\textbf{What this study adds}

\begin{itemize}
\tightlist
\item
  Many pregnant women did not adhere to treatment recommendations
  regarding dosage and therapy duration.
\item
  Implementation adherence was high for medications for chronic
  conditions, but substantially lower for medications for short-term use
  and pregnancy-related medication.
\item
  Our findings emphasize the need for identification of reasons for this
  behavior and associated preventive measures.
\end{itemize}

\par\null

\textbf{ABSTRACT}

\textbf{Aim:} Pregnant women are hypothesized to have low adherence to
prescribed medication, because of concerns about toxicity and harmful
effects on the unborn child. However, very little is known about the
actual adherence to prescribed medication during pregnancy. We
determined to what extent women follow treatment recommendations
regarding prescribed medication use in mid-pregnancy.

\textbf{Methods:} Dutch women participating in the PRIDE Study completed
a six-week diary on medication use. Additionally, pharmacy records were
obtained. For each medication dispensed, we determined three measures of
adherence: 1) whether use was reported in the diary (actual use), 2)
difference between dispensing date and date of first reported use
(initiation time), and 3) proportion of days with at least the correct
number of doses taken (implementation adherence).

\textbf{Results:} During the six-weeks study period, 235 of 816 women
(29\%) were prescribed medication. Actual use was highest for
medications used for chronic conditions (88\%; 95\% confidence interval
{[}95\% CI{]} 81-93), followed by medication for pregnancy-related
conditions (79\%; 95\% CI 71-86) and medication for occasional and
short-time use (69\%; 95\% CI 60-77). We observed a [?]1 day delay in
treatment initiation for 42\% of medications dispensed for the first
time in the study period. For medications that were actually used, mean
implementation adherence was 74.2\% (95\% CI 69.3-79.2).

\textbf{Conclusion:} Although actual use of medications dispensed was
high, many pregnant women did not adhere to treatment recommendations.
This non-adherence may impact maternal and child health and lead to
exposure misclassification in studies in perinatal pharmacoepidemiology
relying on administrative databases.



\textbf{INTRODUCTION}

Non-adherence to pharmacological treatment is a significant global
public health issue, as it is estimated that half of patients do not
take their medication as prescribed {[}1, 2{]}. Medication adherence is
defined as the extent to which medication-intake behavior corresponds
with the medication regimen agreed upon with the healthcare professional
{[}1{]}. Among pregnant women, non-adherence can result in or facilitate
the onset of maternal and fetal complications, enhance risks of
hospitalization, and subsequently increase healthcare costs {[}2, 3{]}.
Women tend to overestimate the teratogenic risk of medication {[}4-6{]},
resulting in reluctance to use medication during pregnancy due to these
concerns {[}6-9{]}. Incorrect perception of the safety of medication use
during pregnancy is widespread {[}10{]}, and leads to caution among
treating physicians in prescribing medication as well {[}11-13{]}.

Previous studies generally indicate low adherence to prescribed
medication during pregnancy, but methods and definitions differed
substantially between studies. When comparing dispensing data to
self-reported medication use, only 43\% of all medications dispensed
were reported to be used by Danish pregnant women, with notable
differences between medications for chronic conditions (70-100\%) and
medications used for local or short-term treatment (12-77\%) {[}14{]}.
Similarly, in a Dutch cohort study among pregnant women concordance
between self-reported medication use and pharmacy records was moderate
to good for medications used for chronic conditions, whereas concordance
was low for medications that are used occasionally {[}15{]}. Instead of
using a self-administered questionnaire to verify actual use of
prescribed medication, De Jonge et al. conducted telephone interviews,
showing that 84-92\% of mothers confirmed taking the medication, but
slightly more than half of the medications were used at the prescribed
dose and for the duration prescribed {[}16{]}.

Establishing the extent to which pregnant women are adherent to their
medication is challenging. Methods that rely on self-reported medication
use, including questionnaires and interviews, are prone to
underreporting {[}17-22{]}, resulting in unfairly low estimates of
adherence when being compared to prescription databases. More reliable
methods, such as electronic drug monitoring, pill counts, and detection
of medication in biological samples, are often not feasible in
large-scale studies because of high costs and logistical challenges.
Nevertheless, more insight into adherence to pharmacological treatment
among pregnant women is needed not only to improve pharmacotherapy
outcomes, but also to guide studies on medication safety during
pregnancy, which increasingly rely on administrative healthcare
databases and registries {[}23{]}. Therefore, we aimed to determine to
what extent women adhere to treatment recommendations regarding
prescribed medication during pregnancy using diaries as the reference
standard, which are less prone to underreporting compared to methods
that rely on recall over a longer period of time {[}24, 25{]}.

\textbf{METHODS}

\emph{Study population}

This study was imbedded in an ongoing prospective cohort study among
Dutch pregnant women, the PRegnancy and Infant DEvelopment (PRIDE)
Study. The aim of the PRIDE Study is to identify factors that may
influence the health of women and their offspring during and after
pregnancy. In short, pregnant women aged [?]18 years were invited for
participation by their prenatal care providers at their first prenatal
care visit, through the `Moeders voor Moeders' initiative, or online
advertisements. The median gestational age at enrollment was 9.9 weeks.
Participants were asked to complete web-based questionnaires at
enrollment, gestational weeks 17 and 34, and biannually after delivery.
Furthermore, consent was asked to obtain records from prenatal care
providers and pharmacists. A detailed description of the PRIDE Study can
be found elsewhere {[}26{]}. For the current study, we selected all
PRIDE Study participants with ongoing pregnancies who completed the
first follow-up questionnaire at gestational week 17 between September
2013 and February 2018 (N=4,851).

The PRIDE Study was approved by the Regional Committee on Research
Involving Human Subjects Arnhem-Nijmegen (CMO 2009/305). Women were
asked to participate on a completely voluntary basis and gave their
informed consent digitally through the Internet.

\emph{Ascertainment of medication use}

In the first follow-up questionnaire at gestational week 17,
participants were asked to complete a 6-weeks paper-based medication
diary during gestational weeks 19-24 or 26-31 {[}22{]}. Through these
diaries, participants reported on the exact name of the medication used,
daily dose, and specific dates of use. To decrease participant burden,
participants could write down the name of any medication used on a daily
basis on the first page of the diary. A reminder was sent if the diary
was not returned within two weeks after the last day covered by the
diary.

In the Netherlands, most people visit only one or two pharmacies and all
pharmacies use computerized dispensing records. Through the `Landelijk
Schakelpunt', to which 96\% of Dutch pharmacies are connected {[}27{]},
information on medications dispensed is exchanged between pharmacies,
making their dispensing records virtually complete. For PRIDE Study
participants who provided consent, data on medications dispensed in the
three months before pregnancy until six months after the estimated date
of delivery were requested from the pharmacies the women reported visits
to. From these records, we abstracted data on medications with use in
the 6-weeks covered by the medication diary, including name of the
medication, start and stop dates, frequency of use, and dosage
prescribed.

Medications were coded using the Anatomical Therapeutic Chemical (ATC)
classification system {[}28{]}. We excluded vaccines (ATC code J06 and
J07) and vitamins (A11, A12, B03B), as these may not be considered as
medication by the participants. Furthermore, medications that are
predominantly used over-the counter (acetaminophen {[}N02BE01{]},
antacids {[}A02AD01{]}, and xylometazoline {[}R01AA07{]}) and
medications not indicated for use during pregnancy (contraceptives
{[}G03A{]}, fertility medication {[}G03CA and G03GA{]}, and tranexamic
acid {[}B02AA02{]}) were excluded. We classified the medications in
three mutually exclusive categories after the classification of Bakker
et al. {[}29{]}: (1) medication for chronic conditions, (2) medications
for occasional and short-time use, and (3) pregnancy-related medication
(Supplemental Table 1). Medications for chronic conditions did not
necessarily have to be taken on a regular or daily basis, but may have
been used on an as-needed basis as well.

\emph{Medication adherence}

Adherence to prescribed medications was assessed with three measures.
Actual use was defined as a dispensed medication of which use was
reported in the diary. The definitions of initiation and implementation
as described by the ABC European adherence initiative taxonomy were used
{[}30{]}. For medications first dispensed in the diary period (i.e. no
use in the three months preceding the diary period according to the
pharmacy records), we assessed non-initiation and initiation time
(difference between dispensing date and date of first reported use in
the diary). Implementation adherence was calculated as the proportion of
days with at least the correct number of doses taken, with the pharmacy
records as reference standard. Medications that were prescribed on an
as-needed basis were excluded from the analyses on initiation and
implementation.

\emph{Other variables}

Maternal characteristics included age, level of education, net monthly
household income, chronic conditions (asthma, chronic hypertension,
depression, pre-existing diabetes, and thyroid disorders), pre-pregnancy
body mass index (BMI), parity, smoking in pregnancy, and alcohol
consumption in pregnancy. These data were available from the PRIDE Study
questionnaires.

\emph{Statistical analysis}

We described maternal characteristics of women who were dispensed at
least one of the selected medications during the 6-weeks diary period
and women who did not use medication according to the pharmacy records.
For each medication registered in the pharmacy records with theoretical
use in the diary period, we determined actual use with Wilson score 95\%
confidence intervals (CIs), initiation, and implementation adherence for
the three predefined medication categories, medication groups, and
individual medications with [?]5 prescription dispensings. For
implementation adherence, we calculated the mean proportion of days with
at least the correct number of doses taken as well as the proportion of
users with an implementation adherence [?]80\%. To evaluate whether the
maternal characteristics were associated with implementation adherence,
we used univariable linear regression with robust standard errors to
account for multiple prescriptions per participant in an exploratory
analysis. All statistical analyses were performed using Stata version
16.0 (StataCorp LLC, College Station, TX).

\textbf{RESULTS}

Of the 4,851 PRIDE Study participants who completed the first follow-up
questionnaire in the study period, 1,516 (31.3\%) completed the
medication diary (Figure 1). Among participants with a completed
medication diary, 1,275 (84.1\%) gave permission to request pharmacy
records. Pharmacy records including start and stop dates of medication
were obtained from 816 participants (64.0\%). Characteristics of the
study population and excluded PRIDE Study participants are shown in
Supplemental Table 2.

According to the pharmacy records, 235 (28.8\%) participants used at
least one of the selected medications during the 6-weeks diary period.
These participants were slightly older, more often had a
low/intermediate level of education, a net household income of
\textless{}\textbackslash{}euro3,500 per month, and a chronic condition,
had a higher pre-pregnancy BMI, and were more likely to smoke during
pregnancy compared to participants who were not dispensed medication in
the diary period (Table 1).

\emph{Actual use}

A total of 337 prescriptions containing 93 different ATC codes were
registered in the pharmacy records with use in the 6-weeks diary period.
Table 2 shows the actual use of medications dispensed according to the
diaries. Actual use was highest for medication for chronic conditions
(88\%, 95\% CI 81-93), followed by pregnancy-related medication (79\%,
95\% CI 71-86) and medication for occasional and short-time use (69\%,
95\% CI 60-77). For the medication groups, actual use ranged between
14\% (asthma rescue medication) and 100\% (antidepressants, asthma
maintenance medication, medication for immune-related inflammatory
diseases, and thyroid medication). Similar patterns were observed for
individual medications, with perfect actual use for citalopram,
levothyroxine, and loratadine. Actual use was lowest for combination
preparations with meclizine (45\%), topical hydrocortisone (20\%), and
salbutamol (14\%).

\emph{Initiation}

Prescriptions for 64 pharmacological treatments were dispensed for the
first time in the 6-weeks study period, of which 17 (27\%) were not
initiated. These included 7 prescriptions for pregnancy-related
medication, 6 prescriptions for medication for occasional and short-term
use, and 4 prescriptions for medication for chronic conditions. Of the
medications initiated in the diary period (N=47), 27 (58\%) were started
at the same day of the prescription fill (range 0-7 days; Figure 2). The
median delay in treatment initiation was 0 days (range 0-6 days) for
medication for occasional and short-term use and 1 (range 0-7 days) days
for pregnancy-related medication.

\emph{Implementation adherence}

Implementation adherence was determined for 218 medications dispensed,
of which 66.5\% had [?]80\% days with at least the correct number of doses
taken (Table 3). Overall, implementation adherence was 74.2\% (95\% CI
69.3-79.2). Implementation adherence was high for medication for chronic
conditions (86.0\%, 95\% CI 79.5-92.4), but substantially lower for
pregnancy-related medication (74.3\%, 95\% CI 65.6-83.0) and medication
for occasional and short-term use (53.7\%, 95\% CI 43.0-64.3). A total
of 8 medication groups had [?]80\% days with at least the correct number
of doses taken: antidepressants, antiasthmatics, antihypertensive
agents, antithrombotic agents, iron preparations, medication for
acid-related disorders, medication for immune-related inflammatory
diseases, and thyroid therapy.

We observed a statistically significant difference in implementation
adherence to pregnancy-related medication between women aged [?]30 years
(84.2\%) and women aged \textgreater{}30 years (66.2\%, p=0.04; Table
4). Although not statistically significant, implementation adherence
differed by more than 10\% for pregnancy-related medication between
women with an income \textless{}\textbackslash{}euro3,500 and women with
an income [?]\textbackslash{}euro3,500 (81.3 vs. 64.2\%, p=0.07). Among
women who smoked during pregnancy, implementation was substantially
lower for medication for occasional and short-term use (29.4\%) and
substantially higher for pregnancy-related medication (85.7\%) compared
to women who did not smoke during pregnancy (56.2\% {[}p=0.15{]} and
73.0\% {[}p=0.14{]}, respectively). No other substantial difference in
implementation for the other maternal characteristics we observed.

\emph{Correct dosing}

Of the 112 dispensings of medication for chronic conditions, 78 (70\%)
were used on [?]80\% of days with at least the correct number of doses,
whereas this was the case for 19\% (20/104) of medication for occasional
or short-term use and 38\% (46/121) of pregnancy-related medication
(Figure 3). Correct dosing was most often seen with antidepressants
(100\%), asthma maintenance therapy (92\%), thyroid therapy (86\%), and
antithrombotic agents (80\%). Incorrect dosing frequently occurred with
systemic antibiotics and antimycotics (24\%), topical antibiotics and
antifungals (18\%), decongestants (14\%), ear, eye, nose, and throat
preparations (11\%), antiemetic medication (7\%), gynecological
anti-infectives and antiseptics (7\%), and dermatological
corticosteroids (0\%).

\textbf{DISCUSSION}

In this prospective study with medication diaries as the reference
standard, we observed that majority of medications dispensed were
reported to be used, ranging from 69\% (medication for occasional and
short-term use) to 88\% (medication for chronic conditions). A
substantial proportion of women, however, did not take the medication as
prescribed: the overall implementation adherence was 74.2\%. Achieving
an implementation adherence of [?]80\% ranged between 19\% for medication
for occasional and short-term use and 70\% for medication for chronic
conditions. Implementation adherence of pregnancy-related medication
seemed lower for women aged \textgreater{}30 years, women with an income
[?]\textbackslash{}euro3,500, and non-smoking women, whereas women who
smoked during pregnancy seemed to have a lower implementation for
medication for occasional and short-term use.

Self-report based on interviews or questionnaires is generally
acknowledged to result in underreporting of medication use during
pregnancy {[}17-22{]}. This may explain why the proportion of
medications dispensed that is actually reported to be taken is higher in
the current study compared with previous studies, in which this measure
ranged between 43 and 57\% {[}14, 19{]}. However, consistent patterns of
actual use are observed between studies when focusing on individual
medications or groups of medications, with high levels of actual use for
medication for chronic conditions, and substantially lower for
medication for occasional and short-term use {[}14, 15, 19-21, 31-34{]}.
Part of these lower levels of actual use for medication for occasional
and short-term use may be explained by forgetfulness when using
interviews or questionnaires that cover a prolonged period of pregnancy
{[}22{]}, but remained when using diaries as reference standard
{[}21{]}. This disagreement may be worrisome for some maternal
conditions, including infections (antibiotics) and fever (antipyretics),
in which pharmacological treatment is often recommended to prevent
maternal and infant morbidity and mortality {[}35-38{]}. In an Italian
cross-sectional study, 3.2\% of women reported intentionally avoiding a
prescribed antibiotic in pregnancy {[}39{]}.

Although actual use gives an indication of medication adherence among
pregnant women, it does not assess whether medication is actually used
as prescribed in terms of timing and dosage. As human fetal development
is strictly sequenced with specific organ systems being formed at
particular stages of pregnancy, timing of exposure is of utmost
importance when assessing medication safety in pregnancy. In the current
study, 42\% of medications were not initiated on the date of
prescription fill, but 1-7 days afterwards. These relatively small
differences may result in exposure misclassification for the
etiologically relevant time window when relying on prescription
databases.

In our study, suboptimal implementation adherence could result from two
distinct deviations of prescription instructions: an incorrect dosage
and a shorter duration of use (persistence). Comparable to our study, de
Jonge et al. {[}16{]} observed that a substantial proportion of women
(30\%) did not adhere to treatment recommendations, often using a lower
dose or for a shorter duration than prescribed. Inadequate treatment of
infections and pregnancy-related and chronic conditions, such as
hypothyroidism {[}40{]}, asthma {[}41{]}, and diabetes {[}42{]}, is
associated with increased risk of adverse birth outcomes. Therefore,
adequate and continuous dosage should be aimed for during pregnancy.

To date, there is no strong evidence for certain maternal and pregnancy
characteristics to be associated with not following treatment
recommendations. In addition to the associations with maternal age,
household income, and smoking observed in this study, others identified
associations with educational level, marital status, disease severity,
and alcohol consumption {[}19-21, 31, 39, 43{]}. None of these findings
have consistently been reported; only smoking status has been implicated
in multiple studies {[}19, 20{]}. Identification of characteristics
linked to non-adherence may facilitate the implementation of
personalized preventive measures.

The clinical implications of non-adherence are relatively
straightforward: it may endanger maternal and child health and increase
healthcare costs {[}2, 3{]}. Enhancing adherence among pregnant women,
however, is not straightforward. Improved counseling may attenuate some
of the incorrect risk perceptions of medication safety among pregnant
women, but for many medications, robust data on fetal safety are lacking
{[}44-48{]}. This may hamper evidence-based decisions on whether the
potential risks of pharmacological treatment outweigh the burden of the
underlying maternal condition. Non-adherence also affects research on
medication safety in pregnancy, as many studies rely on administrative
databases for exposure assessment {[}23{]}. Not taking medication as
prescribed, or not taking the medication at all, will lead to exposure
misclassification and may bias studies determining associations with
infant outcomes {[}49{]}.

A major strength of the current study is the use of a diary to assess
actual medication use, thereby reducing the probability of
underreporting due to forgetfulness {[}24, 25{]}. The amount of details
collected with these diaries enabled us to look beyond actual use by
assessing initiation and implementation. Furthermore, the study
population was considered large compared to some earlier studies, but
still limited in the ability to assess adherence to individual
medications and associations between maternal characteristics and
implementation. Another limitation includes the relatively short time
frame of only 6 weeks in mid-pregnancy. Adherence is expected to be
lower in the first trimester of pregnancy because of fear for
teratogenicity, but it was considered not feasible to administer diaries
immediately after inclusion in the PRIDE Study until delivery due to
participant burden. Mobile applications to daily record medication
intake may improve the feasibility of intensive long-term data
collection {[}50{]}. Social desirability might have increased reporting
of medication use when not actually taken, but was considered unlikely
as participants were unaware of the aim of this study. Also, we were
unable to distinguish between intentional and unintentional avoidance of
medication use. Some women may have discontinued treatment or
implemented dose changes following consultation with a healthcare
professional before the registered end date of the prescription, which
may have decreased implementation adherence unjustly.

In conclusion, actual use of medication dispensed during pregnancy was
high in this study compared with previous studies, but many women did
not adhere to treatment recommendations regarding dosage and therapy
duration. As this behavior may be detrimental to maternal and fetal
health, future efforts should focus on identifying reasons for
non-adherence and associated preventive measures. Furthermore, the
results of this studies may inform and facilitate quantitative bias
analyses in studies on medication safety in pregnancy relying on
administrative databases or registries.



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\textbf{FIGURE CAPTIONS}

\textbf{Fig. 1} Flow chart of participation

\textbf{Fig. 2} Delay in treatment initiation after a medication
dispensing (N=47)

\textbf{Fig. 3} Adherence to prescribed medication among pregnant women
in the six weeks diary period. Only medication groups with \selectlanguage{english}[?]10
prescriptions are shown. No actual use indicates that use was not
reported in the medication diary. Implementation is represented as
proportion of days with at least the correct number of doses taken.
Implementation adherence was not assessed when medication was prescribed
on an as-needed basis or when the dosage was not registered in the
pharmacy record

\textbf{Hosted file}

\verb`Adherence_Table 1.docx`  available at \url{https://authorea.com/users/460064/articles/556140-do-pregnant-women-use-pharmacological-treatment-as-prescribed}

\textbf{Hosted file}

\verb`Adherence_Table 2.docx`  available at \url{https://authorea.com/users/460064/articles/556140-do-pregnant-women-use-pharmacological-treatment-as-prescribed}

\textbf{Hosted file}

\verb`Adherence_Table 3.docx`  available at \url{https://authorea.com/users/460064/articles/556140-do-pregnant-women-use-pharmacological-treatment-as-prescribed}

\textbf{Hosted file}

\verb`Adherence_Table 4.docx`  available at \url{https://authorea.com/users/460064/articles/556140-do-pregnant-women-use-pharmacological-treatment-as-prescribed}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Adherence-Fig1/Adherence-Fig1}

\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Adherence-Fig2/Adherence-Fig2}

\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Adherence-Fig3/Adherence-Fig3}

\end{center}
\end{figure}

\selectlanguage{english}
\FloatBarrier
\end{document}

