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\begin{document}

\title{Prospective Evaluation of Pregnancy Outcomes after Gestational Exposure
to Prazosin}



\author[1]{Natalie Zitoun}%
\author[1]{M Karen Campbell}%
\author[1]{D Matsui}%
\author[1]{Facundo Garcia-Bournissen}%
\affil[1]{Western University Schulich School of Medicine \& Dentistry}%


\vspace{-1em}



  
  \date{May 15, 2024}


\begingroup
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\selectlanguage{english}
\begin{abstract}
Introduction: Prazosin is an antihypertensive medication which can be
used to help with post-traumatic stress disorder (PTSD) symptoms. Little
data is currently available on its safety in pregnancy. Objective: To
assess the fetal and pregnancy safety associated with Prazosin exposures
in early Pregnancy. Methods: Subjects were 11 patients who took Prazosin
during pregnancy and were counselled at the FRAME clinic in London
Health Sciences Centre (Ontario, Canada) between January 1, 2000 to
December 31, 2021. Data on their other exposures and pregnancy outcomes
were collected from medical records and through telephone
questionnaires. Results: It was found that 6 /11 (54.5\%) subjects did
not report any adverse outcomes and were uneventful pregnancies. There
were 2 miscarriages. Birthweights were within the normal range for the
remaining 9 pregnancies. Adverse events reported were consistent with
background population expectation, including: 1 postpartum hemorrhage, 1
case of preeclampsia, 1 preterm birth, 2 NICU admissions, and 2
caesarean sections. Discussion / Conclusion: For these 11 subjects,
pregnancy outcomes after exposure to Prazosin were consistent with
typical outcomes from unexposed pregnancies. More data are needed to
conclude that Prazosin is safe for use in pregnant subjects. However,
the lack of adverse effects above baseline is reassuring to future
patients who may be unintentionally exposed to Prazosin while pregnant.
Therefore, this study contributes valuable data toward monitoring safety
of Prazosin in Pregnancy.%
\end{abstract}%



\sloppy


\textbf{Title: Prospective Evaluation of Pregnancy Outcomes after
Gestational Exposure to Prazosin}

\textbf{Authors:}

\textbf{Natalie Zitoun\textsuperscript{1}}

\textbf{M. Karen Campbell\textsuperscript{1,2,3,4,5}}

\textbf{Doreen Matsui\textsuperscript{2}}

\textbf{Facundo Garcia-Bournissen\textsuperscript{1,2,4,5}}

\textbf{Affiliations:}

\begin{enumerate}
\tightlist
\item
  \textbf{Department of Epidemiology \& Biostatistics, University of
  Western Ontario, London, ON Canada}
\item
  \textbf{Department of Pediatrics, Schulich School of Medicine \&
  Dentistry, Western University, London, ON Canada}
\item
  \textbf{Department of Obstetrics \& Gynecology, Schulich School of
  Medicine \& Dentistry, Western University, London, ON Canada}
\item
  \textbf{Children's Health Research Institute, London, ON Canada}
\item
  \textbf{Lawson Health Research Institute, London, ON Canada}
\end{enumerate}

\textbf{Keywords: pregnancy, post-traumatic stress disorder, Prazosin,
reproductive clinical pharmacology, drug safety}

\textbf{Funding: Western Graduate Research Scholarship}

\textbf{Abstract:} \textbf{Introduction:} Prazosin is an
antihypertensive medication which can be used to help with
post-traumatic stress disorder (PTSD) symptoms. Little data is currently
available on its safety in pregnancy.\textbf{Objective:} To assess the
fetal and pregnancy safety associated with Prazosin exposures in early
Pregnancy.\textbf{Methods:} Subjects were 11 patients who took Prazosin
during pregnancy and were counselled at the FRAME clinic in London
Health Sciences Centre (Ontario, Canada) between January 1, 2000 to
December 31, 2021. Data on their other exposures and pregnancy outcomes
were collected from medical records and through telephone
questionnaires.\textbf{Results:} It was found that 6 /11 (54.5\%)
subjects did not report any adverse outcomes and were uneventful
pregnancies. There were 2 miscarriages. Birthweights were within the
normal range for the remaining 9 pregnancies. Adverse events reported
were consistent with background population expectation, including: 1
postpartum hemorrhage, 1 case of preeclampsia, 1 preterm birth, 2 NICU
admissions, and 2 caesarean sections.\textbf{Discussion / Conclusion:}
For these 11 subjects, pregnancy outcomes after exposure to Prazosin
were consistent with typical outcomes from unexposed pregnancies. More
data are needed to conclude that Prazosin is safe for use in pregnant
subjects. However, the lack of adverse effects above baseline is
reassuring to future patients who may be unintentionally exposed to
Prazosin while pregnant. Therefore, this study contributes valuable data
toward monitoring safety of Prazosin in Pregnancy.

\textbf{Introduction:}

Despite well-justified demands for research to be more inclusive and
equitable, pregnancy-specific prescribing information is still greatly
lacking for many drugs as pregnant women have been, and remain,
consistently underrepresented in clinical research {[}1,2{]}.
Unfortunately, safety of drugs in pregnancy cannot be reliably inferred
from animal studies, or studies in non-pregnant patients {[}3{]}. This
knowlege gap leaves physicians unaware, and unable to inform their
patients, on potential risks or benefits certain medications will have
on the patients or their fetuses if used during pregnancy {[}1{]}. In
the absence of formal clinical trials in pregnancy, alternative data
sources need to be explored to provide accurate pregnancy-specific
information, such as administrative databases or pregnant patient
cohorts. {[}4,5{]}.

A particular condition for which there is a dearth of pregnancy drug
safety information is post-traumatic stress disorder (PTSD), even though
this disorder is prevalent in young people who may get pregnant {[}6{]}.
Prazosin, an antihypertensive medication, has recently gained popularity
in the management of post-traumatic stress disorder (PTSD) symptoms,
particularly vivid nightmares and sleep-related disorders {[}7{]}.
Unfortunately, the use of Prazosin in pregnancy is understudied. One
recent systematic review identified one clinical trial and five cohort
studies to date, {[}8{]} but no data on first trimester exposures.
Prazosin is a well-tolerated generically available medication, but the
lack of pregnancy safety data, especially with regards to first
trimester exposures, leaves physicians and health care providers with
very limited options on how to counsel and monitor pregnant patients
taking this medication {[}5,9{]}.

\textbf{Objective:} The main objective of this study was to evaluate
fetal and pregnancy outcomes in a sample of pregnant patients exposed to
Prazosin during the first trimester of pregnancy.

\textbf{Methods} :

This prospective observational study included a sample of patients
exposed to Prazosin during their pregnancy. The data comes from the
FRAME database of patients who were followed at the Fetal Risk
Assessment from Maternal Exposures (FRAME) clinic at London Health
Sciences Center, London Ontario between January 1, 2000 to December 31,
2021. The FRAME clinic implements a program in which pregnant women
exposed to medications are offered counselling on risks associated with
those exposures and followed, when required, by clinical
pharmacologists. Patients are asked to consent to participate in the
FRAME database, which collects information on the medications they are
exposed to, the outcomes of their pregnancies, and documents any effects
of their medications on their pregnancies or babies. For this study, the
FRAME database was explored to see which patients were taking Prazosin
during pregnancy and, for these, additional data were collected from
retrospective chart review and by telephone interview. For the telephone
interview, initial contact was made by a FRAME physician. Subjects were
informed that they could end the telephone interview at any time and
that the information provided would be included in the FRAME database
for use in potential studies in the future. A total of 20 women who were
taking Prazosin and had attended the FRAME clinic were initially
identified. Of these, 11 became pregnant while taking the medication,
and these formed the final study sample. Data collected included
pregnancy and fetal outcomes, if available, such as: miscarriage,
preterm birth, preeclampsia, hemorrhage, cesarian section, obtained
through electronic chart records and overall pregnancy satisfaction,
obtained through phone-call interviews. To assess fetal growth, birth
weight was recorded. Data analyses were descriptive (means and
frequencies) due to the small sample size. Birthweight corrected for
gestational age was assessed and compared to the Canadian normal
population distributions, as published by Kramer et al {[}10{]} for male
and female singletons. The subject's data was stored as per
institutional guidelines. This study was approved by the Western
Research Ethics Board (Registration \# IRB 00000940).

\textbf{Results:}

The baseline characteristics of the patients, that is, characteristics
of the patients before their pregnancies were confirmed, are shown in
Table 1. Baseline characteristics included PTSD history as well as age,
BMI and location . All of these women were taking Prazosin for PTSD in
the beginning of their pregnancy, 6/11 continued Prazosin use during
pregnancy after finding out they were pregnant and the remainder (5/11)
discontinued prazosin during the first trimester after they found out
they were pregnant. Dose information on Prazosin was not available.
Their mean age (in years) was 33.1 with a standard deviation (SD) of
6.62. Mean BMI (kg/ m\^{}2) was 32.3 with a SD of 5.44. Nine of the 11
patients (81.8\%) came from an urban location, and 2/11(18.2\%) of the
patients came from a rural location.

\textbf{Table 1. Baseline and Exposure Characteristics for Patients
pre-confirmed pregnancy (n =11)}\selectlanguage{english}
\begin{longtable}[]{@{}ll@{}}
\toprule
\textbf{Age (years)} & \textbf{33.1\textsuperscript{a}
(6.62)\textsuperscript{b}}\tabularnewline
\textbf{BMI (kg/m\^{}2)} &
\textbf{32.3\textsuperscript{a}(5.44)\textsuperscript{b}}\tabularnewline
\textbf{Prazosin for PTSD} & \textbf{11 (100\%)}\tabularnewline
\textbf{Urban Location} & \textbf{9 (81.8\%)}\tabularnewline
\textbf{Rural Location} & \textbf{2 (18.2\%)}\tabularnewline
\textbf{a= average, b =s.d Remaining data is in n (\%)} & \textbf{a=
average, b =s.d Remaining data is in n (\%)}\tabularnewline
\bottomrule
\end{longtable}

Previous exposure, prior to pregnancy diagnosis, and continued exposure
during pregancy to alcohol, tobacco, cannabis, and other prescription
medication are provided in Table 2. Eight (72.7\%) of these 11 women had
a history of being on other prescription drugs,with the most commonly
co-prescribed drugs being Sertraline and Quetiapine. Five of the l1
(45.5\%) had a history of smoking,1/11 (9.10\%) had a history of alcohol
consumption, and 2/11(18.2\%) had a history of marijuana use. The
majority of patients lived in an urban location {[}9/11(81.8\%){]}
rather than a rural area {[}2/11 (18.2\%){]}. Five out of the 11
patients (45.5\%) indicated that they continued to smoke tobacco
throughout their pregnancies, and 2/11(18.2\%) indicated that they
continued to use cannabis. No patient indicated drinking alcohol once
they found out about the pregnancy. Six of the 11 subject (54.5\%)
reported that they had continued to take other prescription drugs after
their pregancy was confirmed, namely Escitalopram (1 patient),
Lisdexamfetamine (1 patient), Aripiprazole (1 patient), Duloxetine (1
patient) , Trazadone (1 patient) , and Sertraline (2 patients) during
their pregnancies.

\textbf{Table 2. Exposures Documented Throughout Pregnancy for the 11
subjects (n(\%))}\selectlanguage{english}
\begin{longtable}[]{@{}lll@{}}
\toprule
& \textbf{Past Use} & \textbf{Use Throughout Pregnancy}\tabularnewline
\textbf{Smoking} & \textbf{5 (45.5\%)} & \textbf{5
(45.5\%)}\tabularnewline
\textbf{Alcohol Consumption} & \textbf{1 (9.10\%)} & \textbf{0
(0\%)}\tabularnewline
\textbf{Recreational Drugs (Marijuana)} & \textbf{2 (18.2\%)} &
\textbf{2 (18.2\%)}\tabularnewline
\textbf{Other Prescription Medications} & \textbf{8 (72.7\%)} &
\textbf{6 (54.5\%)}\tabularnewline
\bottomrule
\end{longtable}

It was found that 6 /11 (54.5\%) subjects did not report any adverse
outcomes and were uneventful pregnancies. There were 2 miscarriages.
Adverse events reported were consistent with background population
expectation, including: 1 postpartum hemorrhage, 1 case of preeclampsia,
1 preterm birth, 2 NICU admissions, and 2 caesarean sections. None of
the subjects gave birth to low birthweight (bwt) infants (Table 3A).
Overall, birthweights for gestational age (GA) fell between the
10\textsuperscript{th} and 90\textsuperscript{th} percentiles (\%ile),
so all subjects in the Prazosin cohort exhibited fetal growth within the
normal population distribution. Looking at individual patient data as
shown in Table 3B, patient 1 experienced hemorrhaging (9.1\%) and
required NICU (18.2\%), patient 3 required a c-section (18.2\%),
patients 4 and 7 experienced a miscarriage (18.2\%), and patient 9
experienced pre-eclampsia (9.1\%), required a c-section (18.2\%),
required NICU (18.2\%), and had a preterm baby (9.1\%).

When the patients were asked about Pregnancy satisfaction, 8/11 (72.7\%)
reported that they were satisfied and thought their pregnancies had gone
as smoothly as possible.

\textbf{Table 3A. Pregnancy and Fetal Outcomes for 11 subjects (n (\%))}\selectlanguage{english}
\begin{longtable}[]{@{}ll@{}}
\toprule
\textbf{Miscarriage} & \textbf{2/11 (18.2\%)}\tabularnewline
\textbf{Preterm Birth} & \textbf{1/11(9.1\%)}\tabularnewline
\textbf{NICU Admission} & \textbf{2/11 (18.2\%)}\tabularnewline
\textbf{Preeclampsia} & \textbf{1/11 (9.1\%)}\tabularnewline
\textbf{Hemorrhaging} & \textbf{1/11 (9.1\%)}\tabularnewline
\textbf{Caesarean Section} & \textbf{2/11 (18.2\%)}\tabularnewline
\textbf{Prazosin Use Continued During Entire Duration of First
Trimester} & \textbf{6/11 (54.5\%)}\tabularnewline
\textbf{Pregnancy Satisfaction} & \textbf{8/11 (72.7\%)}\tabularnewline
\textbf{note: there we no fetal malformations, no infants had a low
birthweight} & \textbf{note: there we no fetal malformations, no infants
had a low birthweight}\tabularnewline
\bottomrule
\end{longtable}

\textbf{Table 3B. Pregnancy and Fetal Outcomes for Individual Patients}\selectlanguage{english}
\begin{longtable}[]{@{}ll@{}}
\toprule
\textbf{Patient} & \textbf{Pregnancy / Fetal Outcome}\tabularnewline
\textbf{1} & NICU, Hemorrhaging\tabularnewline
\textbf{2} & No adverse outcome reported\tabularnewline
\textbf{3} & C-section\tabularnewline
\textbf{4} & Miscarriage\tabularnewline
\textbf{5} & No adverse outcome reported\tabularnewline
\textbf{6} & No adverse outcome reported\tabularnewline
\textbf{7} & Miscarriage\tabularnewline
\textbf{8} & No adverse outcome reported\tabularnewline
\textbf{9} & Preterm, C-Section, Pre-eclampsia, NICU\tabularnewline
\textbf{10} & No adverse outcome reported\tabularnewline
\textbf{11} & No adverse outcome reported\tabularnewline
\bottomrule
\end{longtable}

\textbf{Discussion:}

Currently, not enough data exists on the safety of many medications in
pregnancy {[}11{]}. This lack of safety information in practice leads to
patients having access to only a limited number of medications when they
get pregnant, which are often old, less safe, and less effective
{[}5{]}.

Unfortunately, information on whether a medication is safe to use in
pregnancy is difficult to come by and is mostly obtained from following
patients who unexpectedly get pregnant while taking a certain
medication, thus already exposing the fetus to the medication {[}12{]}.
These cases are not easy to find, which is why the group of patients
counseled and followed by our FRAME program provides us with invaluable
knowledge on what happens when pregnant patients are exposed to
medications.

The US Food and Drug Administration (FDA) and the National Institutes of
Health (NIH) released new requirements to encourage inclusion of female
participants in clinical research {[}13,14{]}. Despite these guidelines,
the enrollment of pregnant populations and women of reproductive age in
clinical trials continues to be poor, leading to a lack of accurate
pregnancy-specific prescribing information. {[}4,5,6,1,2,15,16,17{]}.
Even if a medication is believed to not represent a risk for the
developing fetus, many questions on the pharmacology of drugs in
pregnancy remain, which can affect drug response and risk for toxicity.
During pregnancy, a variety of physiological changes take place which
can impact drug metabolism {[}18{]} and can lead to drug serum
concentrations outside of their therapeutic windows. In these instances,
utilizing standard dosing regimens (which were defined in non-pregnant
people) can produce unexpected therapeutic failures or toxicities.

Various studies show that PTSD is prevalent in pregnancy {[}6{]} and
that maternal PTSD is associated with negative birth or child outcomes,
like low birthweight, preterm birth, and less mother-infant bonding
{[}19{]}. Well controlled studies in non-pregnant subjects have reported
that Prazosin results in significant improvement in the number of PTSD
symptoms, including PTSD-associated nightmares {[} 20,21, 22{]}. Despite
this finding, there are still very few and adequate studies that exist
for the safety of Prazosin use in pregnancy, and virtually no data
available on safety of exposure to this drug in the first trimester.

A systematic review conducted by Davidson et al. (2021) {[}8{]} looked
at pregnancy Prazosin exposures, but could only locate one
randomized-control trial (conducted in the third trimester of pregnancy)
and 5 cohort studies studying Prazosin use during late pregnancy and
lactation. As the indication for use of Prazosin was mostly for maternal
hypertension, the role of the underlying condition should be considered
in adverse outcomes. The authors of this review noted that Prazosin may
have a greater bioavailability and slower elimination in pregnant
patients and may possibly lead to hypotension when given to patients who
are normotensive and taking Prazosin for PTSD, which may cause fetal
effects. This systematic review failed to find any reports for the use
of Prazosin for the indication of PTSD, and provided few reports with
regards to Prazosin's use for other indications in the perinatal time
period. The authors concluded that it is best to avoid this drug in
pregnant patients due to the lack of safety information{[}8{]}.

One of the studies cited in the Davidson review {[}8{]} was a 1983 study
that looked at Prazosin use in 8 sujects in the last trimester of
pregnancy {[}23{]}. This study found that Prazosin was effective for
blood pressure control and outcomes suggested safety when used in the
last trimester in these women. These data, although older, is still been
used for reference when looking at Prazosin safety. The fact that a
study with a small sample size conducted in 1983 is still one of the
only studies that can be referred to when looking at Prazosin exposure
during pregnancy illustrates the lack of data that currently exists.
However, it is important to highlight that there are no data on the
safety (or effectiveness) of Prazosin use in the first trimester of
pregnancy.

The data presented in our study is the first case series to evaluate
this topic. We did not observe any malformations in the newborns, and
the babies that required brief NICU admission were reported to be doing
well according to mothers who were contacted at follow up, with mothers
reporting normal development of these babies and the NICU admissions
being required as a precaution. There was no indication that the
neonatal complications were related to Prazosin exposure, or that the
rate of NICU admissions differed from that of the general population.
Overall, birthweights in the population studied were within normal
ranges for gestational age, and none were classified as low birthweight
(i.e. \textless{}2500g). With regards to additional fetal outcomes, the
proportion of miscarriages (18.2\%) did not exceed expected rates based
on normal population proportions {[}24{]}.

It should be acknowledged that PTSD itself may lead to an elevated risk
of poor outcomes. Ferri at al. (2007) found that PTSD during pregnancy
was significantly associated with low birth weight {[}25{]}. A study
conducted by Seng et al (2011) study also found that maternal PTSD was
significantly associated with obstetrical complications such as shorter
gestation and lower birthweight {[}26{]}. This is something to keep in
mind with regards to the adverse outcomes reported in our study, given
that there may be reason to expect elevated risk for reasons other than
Prazosin exposure.

Limitations of the present study include a small sample size, thus
limiting analysis to descriptive findings, and the absence of a
comparison group of women not exposed to Prazosin during pregnancy.
Another limitation is the use of self-reported data, collected via phone
call questionnaires, which could be subject to recall bias and social
desirability bias. The above could limit the ability to make any
conclusions regarding safety based on this one small case series. This
study provides preliminary data on the effects of use of Prazosin for
the treatment of PTSD during pregnancy; however, further research is
definitely needed. Future studies of the use of this medication for this
indication in pregnant women are warranted given the prevalence of this
disorder in this population. With larger datasets, accompanied by
statistical analyses and replicated studies, it may be possible to make
more solid safety conclusions. If possible, this medication should still
be avoided during pregnancy, due to its unknown safety profile. However,
if a pregnant woman is exposed to this medication, the lack of adverse
effects or pregnancy complications in this study is reassuring.

\textbf{Conclusion:} There is a lack of current research evidence
regarding drug safety for pregnant women with PTSD. Our study addresses
this lack of information by providing incremental data regarding first
trimester exposure in a more recent time period to inform the literature
and to guide future studies. Although a small sample, this study
contributes observational data on the use of Prazosin for PTSD during
pregnancy and represents an important starting point for amassing more
data to improve the care of pregnant women experiencing this condition.
Furthermore, our results also showed that there were no major congenital
malformations in the cohort that would have raised concern with regards
to this drug's safety.

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\textbf{Bullet Points}

\textbf{What is already known:}

\textbf{Prazosin is used to treat PTSD symptoms}

\textbf{PTSD is prevalent in pregnant populations}

\textbf{What this study adds:}

\textbf{The first observational data on the use of Prazosin for PTSD
during pregnancy}

\textbf{Clinical significance}

\textbf{Provides clinicians and patients with preliminary data for drug
safety for Prazosin in Pregnancy}

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