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\begin{document}

\title{Pharmacoethics and Pregnancy: Overcoming the drug orphan stigma}



\author[1]{Jamil Kazma}%
\author[2]{Johannes van den Anker (NO FURTHER ASSIGNMENTS)}%
\author[1]{Homa Ahmadzia}%
\affil[1]{The George Washington University}%
\affil[2]{Children’s National Medical Center}%


\vspace{-1em}



  
  \date{May 27, 2024}


\begingroup
\let\center\flushleft
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\selectlanguage{english}
\begin{abstract}
There is paucity of evidence to support clinical decision making and
counseling related to medication use in pregnancy. Despite multiple
efforts from legislative bodies and advocacy groups, the inclusion of
pregnant women in clinical drug trials assessing efficacy and safety
remains scarce. Pregnancy can be complicated by multiple co-morbidities
that require pharmacological intervention; these interventions primarily
target the pregnant women but also sometimes have secondary effects for
the fetus. The U.S. Food and Drug Administration has issued multiple
guidance documents on incorporating pregnant women in clinical trials to
aid pharmaceutical companies in designing a protocol to ensure safety
and adherence to ethical standards. Advances in pediatric pharmacology
studies provide lessons for researchers on the best practice of
designing clinical trials with inclusion of patients from special
populations. In this review, we present the status of pregnant women in
clinical trials, highlighting the ethical stigma and possible future
directives.%
\end{abstract}%



\sloppy


\textbf{Pharmacoethics and Pregnancy: Overcoming the drug orphan stigma}

Jamil M. Kazma\textsuperscript{1}, John Van Den
Anker\textsuperscript{2,3}, Homa K. Ahmadzia\textsuperscript{4}

\textsuperscript{1} Department of Obstetrics \& Gynecology, The George
Washington University School of Medicine and Health Sciences, Washington
D.C., USA

\textsuperscript{2} Division of Clinical Pharmacology, Children's
National Hospital, Washington D.C., USA

\textsuperscript{3} Division of Pediatric Pharmacology and
Pharmacometrics, University Children's Hospital Basel, University of
Basel, Switzerland

\textsubscript{4} Division of Maternal-Fetal Medicine, Department of
Obstetrics \& Gynecology, The George Washington University School of
Medicine and Health Sciences, Washington D.C., USA

*Corresponding author: Homa K. Ahmadzia, MD Division of Maternal Fetal
Medicine Department of Obstetrics and Gynecology The George Washington
University School of Medicine and Health Sciences 2100 Eye Street, NW,
20037 Phone: 202-741-2500 Email: hahmadzia@mfa.gwu.edu

ORCID Jamil M. Kazma 0000-0002-6447-5473 Homa K. Ahmadzia
0000-0003-0341-1086 John Van Den Anker 0000-0002-3585-321X

\textbf{Running head: Pharmacoethics and Pregnancy Keywords: Pregnancy,
Pharmacology, Teratogenicity, Fetotoxicity}

\textbf{Word count:}Abstract 148, Manuscript 3015 words Number of tables
and figures: 2 tables, 1 figures (max 8) Number of references: 66

\textbf{Conflict of interest}

None of the authors have any conflict of interest to disclose

Funding statement

HKA was supported by K23HL141640.



\textbf{Abstract}

There is paucity of evidence to support clinical decision making and
counseling related to medication use in pregnancy. Despite multiple
efforts from legislative bodies and advocacy groups, the inclusion of
pregnant women in clinical drug trials assessing efficacy and safety
remains scarce. Pregnancy can be complicated by multiple co-morbidities
that require pharmacological intervention; these interventions primarily
target the pregnant women but also sometimes have secondary effects for
the fetus. The U.S. Food and Drug Administration has issued multiple
guidance documents on incorporating pregnant women in clinical trials to
aid pharmaceutical companies in designing a protocol to ensure safety
and adherence to ethical standards. Advances in pediatric pharmacology
studies provide lessons for researchers on the best practice of
designing clinical trials with inclusion of patients from special
populations. In this review, we present the status of pregnant women in
clinical trials, highlighting the ethical stigma and possible future
directives.



\textbf{Introduction}

Pregnant women are poorly represented in clinical drug trials. Around
80\% of pregnant women receive medication during pregnancy, most of
which are used in an off-label manner and lack information on potential
teratogenicity {[}1{]}. In fact, from 2000 to 2010, the U.S. Food and
Drug Administration (FDA) approved 172 new drugs, 98\% of which lack
data on teratogenicity and 73\% had no data on safety for use during
pregnancy {[}2{]}. Many women with pre-existing conditions such as
asthma, chronic hypertension, and diabetes might be taking medication
prior to conception. In addition, the physiologic changes in pregnancy
can exacerbate existing medical conditions or induce new medical
conditions that require treatment. This highlights the importance of the
availability of safety data on drugs prescribed during pregnancy. To
complicate matters further, the doses of drugs used during pregnancy are
extrapolated from clinical drug investigations performed in men and
non-pregnant women and/or from animal models, raising questions about
the pharmacokinetics and pharmacodynamics of these drugs during the
different stages of pregnancy {[}3{]}.

One of the landmark events in obstetric pharmacology was the thalidomide
disaster that occurred in the 1960s. This drug, used for morning
sickness in pregnant women, was found to be teratogenic, causing
devastating skeletal deformities in prenatally exposed fetuses {[}4{]}.
Another drug, diethylstilbestrol, a synthetic estrogen, was initially
prescribed to women with threatened pregnancy loss and then was marketed
as routine for prophylaxis of possible pregnancy loss for all
pregnancies during the 1950s {[}5{]}. Twenty years later after continued
and extensive use, a small study showed an increased risk of clear cell
carcinoma of the vagina in females born to diethylstilbestrol-exposed
pregnant women among other comorbidities before regulatory action was
taken to curtail its use {[}6{]}. Historically, after the thalidomide
and diethylstilbestrol negative outcomes, the US FDA has excluded
pregnant women from phase 1 and phase 2 trials in 1977 over concerns for
the safety of administering drugs in pregnancy, after which the
pharmaceutical companies extended this exclusion into phase 3 and phase
4 {[}7{]}. These examples among many others underscore the importance of
risk and benefit assessment of medication use during pregnancy. However,
the current evidence to support this assessment is sparse. In this
review, we aim to highlight a) the need for inclusion of pregnant women
in clinical trials, b) what legislative actions were taken to curtail
obstacles for their inclusion, and c) possible solutions for clinical
pharmacology researchers.

\textbf{The Ethical Dilemma across history}

Prioritizing protection of the fetus was an important factor that
prevented pregnant women to participate in clinical drug trials. Several
federal regulations now request clarification on inclusion criteria by
defining whether the fetus or the pregnant woman are being targeted, and
whether the study aims to highlight therapeutic or non-therapeutic
outcomes {[}8{]}. In 1974, after the devastating thalidomide disaster,
congress asked the newly established National Commission for the
Protection of Human Subjects of Biomedical and Behavioral Research to
make recommendations for the conduct of research involving pregnant
women and fetuses (Federal regulations at subpart B of 45 CFR 46)
{[}9{]}. Dr. Kelsey, who was the primary reviewer of the thalidomide
application assigned by the FDA, delayed the approval of thalidomide
over concerns of adverse effects and the drug was never approved in the
United States {[}10{]}. The aim of the recommendations thus was to
protect the fetus from unnecessary harm. More than twenty years later
and after much deliberation, the wording was changed in 2001 to include
a more proscriptive approach; stating that pregnant women or fetuses may
be involved in research if all of 10 conditions are met \textbf{(Table
1)} . In 2002, a registry for reporting adverse effects was established.
In 2004, the FDA developed the guidance on pharmacokinetic (PK) studies
in pregnancy, and, in 2005, guidance was provided on clinical lactation
studies and pregnancy {[}11{]}. In 2009, the Second Wave Initiative was
launched aiming to systematically address the knowledge gap on treatment
of pregnant women in a collaborative manner {[}12{]}. The FDA has also
addressed drug labeling to include risk summary and clinical
consideration in an effort to improve patient care decision and
counseling under the Pregnancy and Lactation Labeling Rule (PLLR)
{[}7{]}. This was first proposed in 2008 with the revised version put in
action in 2014. While much has been done to support the moral imperative
of including pregnant women, much more needs to be done to ensure that
we provide pregnant women with beneficence, autonomy, and justice.

\textbf{Pitfalls of Maternal Physiology and Placental Transfer}

Substantial changes in maternal physiology complicate the extrapolation
of the safety profile and dosing of drugs. Changes in the
cardiovascular, renal, and gastrointestinal systems affect the
absorption, distribution and excretion of certain drugs given to the
pregnant woman during pregnancy {[}13{]}. There is no doubt that drug
pharmacokinetics are different in pregnancy and non-pregnant state and,
ideally, drug properties should be studied in every trimester and in the
postpartum period. However, these trials are challenging to conduct, and
the information is scarce, which is why researchers often rely on
opportunistic studies in which patient are already receiving the
therapeutic agent in question {[}14, 15{]}. In addition to that, the
placenta was thought to be an impenetrable barrier that protected the
fetus from harmful agents including medication. However, after the
thalidomide incident, challenges have been unearthed to explore
mechanisms of transfer of compounds across the lipid membrane {[}16{]}.
Several mechanisms have been proposed to explain the drug transfer
across the placenta including simple diffusion, facilitated diffusion,
pinocytosis, and active transport. Ongoing research is crucial in
identifying potential drugs that follow the trajectory of maternal to
fetal transfer, and the molecular characteristics of compounds.
Uncharged lipophilic drugs tend to transfer readily {[}17{]}, whereas
size does not usually limit transfer as most drugs have a molecular
weight of less than 500 Daltons {[}18{]}.Insulin and enoxaparin are two
examples of drug transfers that are limited due to size {[}19, 20{]}.
Human placental drug transfer studies are often limited to drugs given
near time of delivery. This limitation to study design led to
development of ex vivo perfused human placental models which represented
a non-invasive and effective method of studying transplacental transfer
{[}21{]}.

\textbf{Importance of data on drugs for pregnant women}

\textbf{Physician Counseling}

Counseling is a key concept in any patient encounter, particularly when
it comes to initiate new therapies during pregnancy as it helps
consolidate a patient-centered practice. In fact, informing patients
about the indication, dosage, regimen, side effect(s) and alternatives
can improve adherence and limit therapeutic failure, or help to
recognize adverse effects that otherwise might result in unnecessary
diagnostic tests and hospitalization {[}22{]}. It is imperative for
providers during the prenatal visit to obtain a thorough history about
medical problems and medications used to treat them, and to screen for
herbal medicine use in pregnancy which is particularly important as the
use of complementary and alternative medicine is high globally {[}23{]}.
Some women might have stopped taking their medications prior to the
first visit with a provider after finding out they are pregnant. This
action can sometimes lead to deleterious consequences. For example,
women treated with SSRIs for depression who have discontinued the
medication of fear of fetal concern may have relapses and suicidal
ideation {[}24{]}. On the other hand, counseling may help prevent
unnecessary pregnancy termination because of perceived high fetal risk
not knowing the accurate extent of the risk in question due to lack of
proper information {[}25{]}.

During the counseling, the provider must also distinguish between
teratogenicity which entails structural abnormalities to the fetus in
the first trimester and fetotoxicity referring to functional damage
later in pregnancy {[}26{]}. While the teratogenicity profile of some
drugs has been established through prior animal studies, detecting
fetotoxicity requires more research particularly as some effects
pertaining to neurodevelopment might not be evident until childhood.
Women prefer to seek information about medication use in pregnancy
directly from their healthcare providers. However, the challenge arises
when there is lack of evidence-based data to appropriately display a
risk-benefit assessment for the patient to decide {[}22, 27{]}. Database
such as LactMed\selectlanguage{ngerman}®{[}28{]} and Reprotox®{[}29{]} are some of the common
resources utilized by clinicians when counseling patients, but these
databases can often give inconclusive recommendations given the paucity
of evidence available.

\textbf{Treating life-threatening diseases and those associated with
morbidities}

There is a considerable increase in maternal comorbidity including
obesity, hyperlipidemia, diabetes, and hypertension in recent years
worldwide. Many of these comorbid conditions have been linked to higher
rates of pregnancy-related morbidity and mortality {[}30{]}. Asthma for
example can be common in pregnancy and in some cases worsens due to
physiological changes. In one study, it has been shown that there has
been a reduction in prescriptions of asthma medication during the first
trimester of pregnancy {[}31, 32{]}. However, it is important to control
asthma symptoms during pregnancy despite the safety profile of some
medications used. Uncontrolled asthma can lead to complications
including preeclampsia, preterm delivery and low birth weight {[}33{]}.
This is a compelling example where risks of uncontrolled asthma outweigh
potential risks of neonatal fetotoxicity from exposure. Another example
are oral steroids like prednisone. Prior observational studies have
reported cleft lip and cleft palate when prednisone was used early in
pregnancy but those results were not consistent over time
{[}34{]}.\textbf{Table 2} highlights controversial medications that need
additional counseling given their possible or known adverse effects on
the fetus. There is much controversy in interpreting population-based
studies and animal studies when it comes to teratogenicity and
fetotoxicity. Some drugs that showed adverse effects in animal models
were not matched when studying human population and vice versa. Statins,
which are now being investigated as potential drugs to prevent
preeclampsia have been previously contraindicated in pregnancy. However,
a recent meta-analysis including 16 human studies showed no relationship
between statins and teratogenicity {[}35{]}. More recently, the FDA has
requested removal of the contraindication of statins in pregnancy
{[}36{]}.

Improving the infrastructure of research seems to be something that
would benefit the moral imperative to incorporate pregnant women into
clinical drug trials. Pharmacoepidemiologic studies are limited by the
fact that often disease and severity are related to exposure and adverse
outcome and that systematic bias is not usually accounted for when the
pharmacologic exposure or the disease itself was the cause of
fetotoxicity. For example, autoimmune diseases like rheumatoid
arthritis, inflammatory bowel disease or lupus might exacerbate during
pregnancy. In these diseases it has been noted that there is an
increased risk of low birth weight, preterm birth and associated
morbidities with current treatment options, but whether this is in an
effect of the treatment per se or the disease itself is hard to decipher
{[}37-39{]}.

\textbf{The effect of the regulatory bodies on clinical trials in
pregnancy}

Pregnant women have previously been categorized as a ``vulnerable
population' with special consideration enforced by regulatory bodies
when including them in research. The American College of Obstetrics and
Gynecology instead recommended that pregnant women be categorized under
``scientifically complex,'' and recently the Common Rule, the federal
policy for the protection of human subjects, has been revised in 2019 to
remove pregnant women from the vulnerable population category {[}40{]}.
However, despite that, some institutional review boards (IRB) may still
feel reluctant given that there is no practical guide to address the
risk and benefits of enrolling pregnant women into clinical trials
{[}41{]}. Two important steps to curtail this is to involve experts in
the field of maternal-fetal medicine and obstetrics pharmacology in
board meetings and to require justification for exclusion of pregnant
women and that this justification may be questioned during review
{[}42{]}. IRB interpretation of the regulatory process has some flaws
{[}11{]}, particularly when it comes to the wording of ``minimal risk of
the fetus.'' When submitting to the IRB of the academic institution or
other regulatory bodies, researchers may present preclinical and animal
studies corroborating the risk to the fetus, but with concern that these
studies are evaluated by the IRB regulatory staff and due to the dearth
of available data may not be sufficiently supportive or
convincing{[}11{]}. For that reason, there is wide agreement to clarify
regulations for enrolling pregnant women in trials and develop practical
guidelines that can be universally implemented {[}15{]}.

The FDA previously had regulatory rules in place that restricted
inclusion of pregnant women in clinical trials, citing that woman should
only be included if there is direct benefit to the woman or fetus with
minimal risk or if risk is solely related to the intervention in
question {[}43{]}. In their revised guideline in 2018, they have
recommended excluding pregnant women from phase 1 and phase 2 trials and
allow enrollment later. Federal regulations require investigators to
consider the interest of the pregnant woman and fetus, raising the
ethical question of whether the fetus is considered a patient. One
argument involves a dependent moral status to be deemed on the fetus,
which is based on the expectation of whether the fetus is to achieve the
moral status of becoming a child and a person {[}44{]}. It is only when
the pregnant woman considered the previable fetus a patient and
therefore invoke the dependent moral status, then the healthcare
provider and patient should have a thorough discussion about the
beneficence of protecting the fetus from harm.

Pharmaceutical companies have long feared including pregnant women in
clinical trials even during the phase 3 and phase 4 of the process. In
response to that, the FDA has issued a guidance for industries to better
design clinical trials. It highlights emphasis on pharmacokinetic and
pharmacodynamic studies of drugs in pregnant women, particularly if that
population is to benefit from the drug. In addition, in 2002, the FDA
also issued a guidance on reporting adverse effects of medication in
pregnancy and that surveillance should not be limited to the
post-marketing phase. The recent events of the COVID-19 pandemic have
highlighted the deficiency and reluctance posed on including pregnant
women in trials. In a recent analysis, it has been shown that pregnant
women have been excluded from the therapeutic clinical trials involving
the COVID-19 infection, despite most medications used showing low or
non-significant safety concerns, except for remdesivir {[}45{]}. This
only increases the concerns that despite guidance and call to action
initiatives, there is no legal framework to enforce its implementation.

\textbf{Extrapolating innovations from pediatric clinical trials}

While neonates and children have been lumped with pregnant women under
the umbrella of vulnerable populations, numerous advances have led to
success in conducting pediatric clinical trials {[}46{]}. Quality of
clinical data in pediatrics has stemmed from the fact that investigators
tend to include multiple drugs in a single protocol, extensive
pharmacokinetic and pharmacodynamic modeling and incorporation of
multiple sites {[}47{]}. As for legislative processes, the Best
Pharmaceuticals for Children Act (BPCA) and Pediatric Research Equity
Act (PREA) contributed to the development of drug trials in the
pediatric population. The BPCA provided incentive for drug development
and PREA enforces pediatric studies to be conducted of medication that
would help the health of children. Incentives included exclusive
marketing by manufacturers for an additional six month for conducting
pediatric-focused studies, which can translate to up to 500 million
dollars in revenue for each drug {[}48{]}. Unfortunately, these do not
yet apply to the pregnant population.

Recent innovations in clinical trial design allowed the development and
use of population-based pharmacokinetic and pharmacodynamic modeling to
better understand the mechanism of drugs within the physiologic milieu
{[}49, 50{]}. These advances will likely help optimize selected drug
doses and understand interaction with tissues in an attempt to minimize
unwanted adverse effects to the fetus. These models have been described
by Mendes and Zhang {[}49, 50{]}. Population
pharmacokinetics-pharmacodynamics studies have been used in pediatric
clinical trials and have been found to be very helpful as they
incorporate drug properties, physiologic variables, and target tissues
to determine effect {[}51{]}. Despite its success in pediatric
populations, its use in the pregnant population seems underutilized.

A multi-disciplinary collaboration is necessary to optimally design and
conduct clinical drug trials in pregnant women. For example, if a
rheumatologist wishes to conduct a trial on effective treatment of
rheumatoid arthritis flare and include pregnant women, a collaboration
with maternal-fetal medicine and neonatology specialists should be
considered to optimize outcome of the study and avoid adverse effect of
treatment or disease on the fetus.

\textbf{A complex twist: treating the fetus through the pregnant woman}

Some fetal conditions are treated through transplacental transfer of
drugs adding a complex layer on the safety of drugs. While the drug is
administered to the pregnant woman and has known maternal side effects,
the primary indication is to treat the underlying fetal condition. One
important condition is fetal arrythmia (i.e. supraventricular
tachycardia) in which studies have shown benefit in administering
digoxin, sotalol, and flecainide among other antiarrhythmic medications
{[}52{]}. In this unique circumstance often added maternal monitoring by
electrocardiogram is advised to balance maternal/fetal well-being.
Another example is prevention of congenital toxoplasmosis. Spiramycin, a
well-known macrolide, has shown to decrease transmission of
toxoplasmosis in a seropositive pregnant woman by 60\%. Due to its
chemical properties, it tends to concentrate in the placenta and rarely
transfer to the fetus mitigating adverse effects and fetotoxicity
{[}53{]}.

\textbf{Conclusion}

The Belmont Report originally published in 1979 enforces the adherence
to the basic ethical principles in research including beneficence,
justice, and respect to persons. We need a call to action by all
stakeholders (i.e. legislative agencies, pharmaceutical companies,
funders and academic researchers) to prioritize including pregnant women
in clinical trials. It helps not only make a better risk-benefit
assessment, but also help prevent adverse effects in the fetus or the
pregnant woman when it is medically needed to give medications. We
should strengthen the pregnant woman's autonomy to be able to
participate in clinical trials if she wishes and that this should not be
a predicament; at the same time monitoring for fetotoxicity should be
standardized and required in clinical research. If pregnant women are
not included in future drug research studies, they will lag behind in
terms of receiving benefits of therapeutic advancement compared to the
general population. Learning from pediatric drug advances, clinical
research involving pregnant women has a promising road ahead.

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Table 1. The ten requirements for inclusion of pregnant women in
clinical trials outlined by the FDA {[}43{]}\selectlanguage{english}
\begin{longtable}[]{@{}ll@{}}
\toprule
1 & Where scientifically appropriate, preclinical studies, including
studies on pregnant animals, and clinical studies, including studies
on~nonpregnant~women, have been conducted and provide data for assessing
potential risks to pregnant women and fetuses;\tabularnewline
\midrule
\endhead
2 & The risk to the fetus is caused solely by interventions or
procedures that hold out the prospect of direct benefit for the woman or
the fetus; or, if there is no such prospect of benefit, the risk to the
fetus is not greater than minimal and the purpose of the research is the
development of important biomedical knowledge which cannot be obtained
by any other means;\tabularnewline
3 & Any risk is the least possible for achieving the objectives of the
research;\tabularnewline
4 & If the research holds out the prospect of direct benefit to the
pregnant woman, the prospect of a direct benefit both to the pregnant
woman and the fetus, or no prospect of benefit for the woman nor the
fetus when risk to the fetus is not greater than minimal and the purpose
of the research is the development of important biomedical knowledge
that cannot be obtained by any other means, her consent is obtained in
accord with the informed consent provisions of~subpart A~of this
part;\tabularnewline
5 & If the research holds out the prospect of direct benefit solely to
the fetus then the consent of the pregnant woman and the father is
obtained in accord with the informed consent provisions of~subpart
A~of~this part, except that the father's consent need not be obtained if
he is unable to consent because of unavailability, incompetence, or
temporary incapacity or the pregnancy resulted from rape or
incest.\tabularnewline
6 & Each individual providing consent under paragraph~4 or 5~of this
section is fully informed regarding the reasonably foreseeable impact of
the research on the fetus or neonate;\tabularnewline
7 & For children as defined in~\selectlanguage{ngerman}§46.402(a)~who are pregnant, assent and
permission are obtained in accord with the provisions of~subpart
D\tabularnewline
8 & No inducements, monetary or otherwise, will be offered to terminate
a pregnancy;\tabularnewline
9 & Individuals engaged in the research will have no part in any
decisions as to the timing, method, or procedures used to terminate a
pregnancy; and\tabularnewline
10 & Individuals engaged in the research will have no part in
determining the viability of a neonate.\tabularnewline
\bottomrule
\end{longtable}

Table 2. Some medications with controversial use in pregnancy\selectlanguage{english}
\begin{longtable}[]{@{}lllll@{}}
\toprule
Medication & Condition & Research Study Design & Proposed
Teratogenicity/Fetotoxicity & Recommendations\tabularnewline
\midrule
\endhead
\textbf{~Amitriptyline} & Major depressive disorder; Migraine
prophylaxis & Observational and animal studies {[}54-57{]} & Interferes
with embryo development in animals; no confirmed teratogenicity in
humans & Can be used in pregnancy\tabularnewline
Lithium & Bipolar disorder & Observational and animal studies {[}58,
59{]} & Ebstein anomaly characterized by abnormal development of the
tricuspid valve & Do not offer lithium for women who are planning to get
pregnant\tabularnewline
Paroxetine; Fluoxetine & Major Depressive Disorder & Observational and
animal studies {[}60-62{]} & Cardiac defects, anencephaly and atrial
septal defects. No adverse effects in animal studies & Avoid paroxetine
and fluoxetine or if no alternative agent, get fetal echocardiogram
22-24 weeks\tabularnewline
Prednisone & Inflammatory conditions including rheumatoid arthritis,
lupus nephritis, inflammatory bowel disease, asthma & Observational and
animal studies {[}35, 63, 64{]} & Oral clefts, low birth weight, preterm
birth, preeclampsia, and gestational diabetes mellitus & Use with
caution as limited evidence supports association with observed
fetotoxicity and pregnancy morbidity\tabularnewline
Statins & Dyslipidemia & Observational and animal studies {[}35{]} & No
clear teratogenicity identified in recent studies & Contraindicated,
with recent shift to labeling it as being safe by the FDA\tabularnewline
Warfarin & Thromboprophylaxis in patients with mechanical heart valve &
Observational and animal studies {[}61, 65, 66{]} & Skeletal defects
including nasal hypoplasia and stippled epiphyses & Contraindicated
especially in first trimester; Switch to alternative closer to
delivery\tabularnewline
\bottomrule
\end{longtable}

Figure 1. Timeline of advancements in policy making towards drug trials
in pregnancy\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Fig-1-Ethics/Fig-1-Ethics}

\end{center}
\end{figure}

\selectlanguage{english}
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