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\begin{document}

\title{Drug Therapy during Pregnancy}



\author[1]{Dongmei Sun}%
\author[1]{Janine Hutson}%
\author[1]{Facundo Garcia-Bournissen}%
\affil[1]{Western University Schulich School of Medicine and Dentistry}%


\vspace{-1em}



  
  \date{March 17, 2025}


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\textbf{}

Drug therapy in pregnancy may cause anxiety to both physicians and
patients due to uncertainty regarding dosing and safety. Nevertheless,
the need for medication is high given that maternal chronic illnesses
such as hypertension or diabetes are on the rise\textsuperscript{1}. In
a national study in the United States over 33 years, the prevalence of
prescription medication use by pregnant women in the first trimester
increased by 62.5\% between the first 2 years of the study and the last
2 years\textsuperscript{2}. Furthermore, the average number of
medications used anytime in pregnancy has increased two-fold
\textsuperscript{2}. More recent research from different countries has
found that medications are widely used in pregnancy, with the prevalence
of using at least one drug ranging from 60 to 90 percent, excluding
vitamins and minerals \textsuperscript{3-5}. Prescription of drugs with
potential teratogenicity has also increased in pregnancy, including
folate antagonists or angiotensin converting enzyme
inhibitors\textsuperscript{3,4}. This suggests that many women go into
pregnancy with chronic conditions that require medications, including
those may pose some degrees of risk to the fetus, since the maternal
benefit may outweigh the risk or if the pregnancy is unplanned.
Successful treatment of pregnant patients requires a correct diagnosis
and providing treatment that not only is effective but also balances
risks and benefits, as maternal health is the best defense for fetal
health. However, concomitant health conditions, and the intrinsic
complex physiological changes associated to pregnancy can make
prescribing in this population a particularly challenging balancing act.
Very few drugs have specific pregnancy dosing regimens supported by
scientific evidence in spite of well-known pharmacokinetics changes
during pregnancy affecting a large proportion of medications (Table
1)\textsuperscript{6-10}. Data on drug efficacy and safety is sorely
lacking for pregnant women, even for drugs that have been available for
decades. Pregnant patients are commonly excluded from clinical trials
during the drug development process due to ethical and safety concerns,
which implies that the majority of drug therapy data in pregnancy have
been extrapolated from males and to a much lesser extent, from
non-pregnant females\textsuperscript{11}. However, using extrapolated
data in pregnancy has a number of major drawbacks such as that the
extrapolation commonly fails to account for the changes in drug
metabolism related to pregnancy \textsuperscript{6}. Multiple
physiological changes in pregnancy, including those affecting
pharmacokinetics, must be considered when prescribing. Furthermore,
these changes can also be affected by genetic
variability\textsuperscript{10}. Some drugs need to be used at higher
doses in pregnancy due to increasing metabolic demand. A classic example
is thyroid hormone, which requires a 30 to 45 percent higher dose in
order to maintain euthyroid state due to limited compensation in
pregnant patients with underlying thyroid disease \textsuperscript{12}.
One of the biggest physiologic changes in pregnancy is the expansion of
plasma volume by approximately 50 percent due to hormone-mediated
vasodilation, leading to activation of the renin-angiotensin-aldosterone
system\textsuperscript{10}. This change results in and increased volume
of distribution for hydrophilic drugs and reduced peak concentrations
\textsuperscript{6}. Increased glomerular filtration rate in pregnancy
also increases elimination of renally cleared drugs; a classic example
of this effect is lithium\textsuperscript{13}. Changes in hepatic enzyme
activity in pregnancy, including upregulation of cytochrome P450 and
glucuronidation, are another cause of increased metabolism and
elimination of drugs\textsuperscript{14}. Increased metabolism of
lamotrigine by glucuronidation results in low drug levels in pregnancy
and this can be further affected by polymorphism of
UDP-glucuronosyltransferases \textsuperscript{15}. One strategy to
address changes in drug metabolism is to use therapeutic drug monitoring
(TDM) with blood levels; however, TDM analysis is not readily available
for the majority of drugs used in pregnancy, limiting the usefulness of
this strategy in clinical practice. Furthermore, lower total drug levels
do not necessarily translate to less free drug due to volume expansion
in pregnancy leading to relative hypoalbuminemia \textsuperscript{6}.
For some drugs, many clinicians modify the dosing regimen on their own
based on limited pharmacokinetic data. For example, labelatol, a common
antihypertensive used in pregnancy, has a half-life of only 1.7 \selectlanguage{ngerman}± 0.27
hours in patients in the 3rd trimester of pregnancy, compared to 6-8
hours outside of pregnancy\textsuperscript{16}. This difference leads
many clinicians to prescribe labelatol three times per day based on
patient response instead of twice-per-day as per drug
monograph\textsuperscript{16}. However, there is considerable variation
among clinicians due to lack of scientific evidence. For example, in
patients diagnosed with acute pulmonary embolism, twice-per-day dosing
and once-per-day dosing of low molecular weight heparin are both
commonly used \textsuperscript{17}. Enoxaparin once-per-day versus
twice-per-day in a population pharmacokinetics study both achieved
target plasma concentration in pregnancy\textsuperscript{18}; however,
once daily regimen has not been universally adopted in clinical practice
and no similar data are available for other low molecular weight
heparins. Pregnancy is also a vulnerable period for the occurrence of
cardiac events. In particular consideration must be given to patients
known to have long QT syndrome or on QT prolonging drugs. The adrenergic
nature of labor and delivery may lead to catecholaminergic polymorphic
ventricular tachycardia in these patients. Furthermore, patients with
congenital long QT syndrome are also at risk during a nine-month
post-partum period \textsuperscript{19}. Treatment with beta-blockers
are the mainstay of therapy during pregnancy and in the post-partum
period\textsuperscript{19}. There is a lack of data for therapeutics
that may be urgently needed intrapartum that may prolong the QT interval
in susceptible patients. For example, oxytocin and carbetocin are both
known to prolong the QT interval but may be required for prevention or
treatment of postpartum hemorrhage\textsuperscript{20,21}. Clinical
guidelines for using oxytocin for augmentation or induction of labour
are lacking and some obstetricians may choose to do an elective
Caesarian section to avoid prolonged oxytocin in these patients although
this is not evidence based due to lack of studies. In addition to the
challenges in proper prescribing in pregnancy, the information on
teratogenicity of drugs is also limited. Management of the care of a
pregnant patient must balance the benefits of treating the maternal
medical condition with possible adverse effects on the fetus. Clinicians
must rely on animal data, data from pregnancy registries, and published
case control studies and case reports to make these risk/benefit
assessments. These resources are by no means ideal as results are
confounded by recall bias, selection bias, and inconsistency, as well as
lack of ability to extrapolate safety between species
\textsuperscript{22}. Other than a few specific drugs with clear
evidence of harm, many drugs have limited information, leading to
variable practice among clinicians and inconsistent information provided
to patients. For example, while angiotensin-converting enzyme inhibitor
induced fetopathy has been described since the 1990s and accepted by
medical community consistently\textsuperscript{23}, the risk of maternal
corticosteroid use with increased risk of cleft lip and palate has not
been consistent among studies\textsuperscript{24,25}. In addition, long
term corticosteroid use is also linked to increased risk of preeclampsia
which needs to be taken into consideration for treatment and
monitoring\textsuperscript{26}. The US Food and Drug Administration
recognized the limitation of the prior FDA classifications for
medication use in pregnancy (A, B, C, D, X category system). Thus, the
``Pregnancy and Lactation Labeling Rule'' went into effect by the FDA in
June 2015, requesting manufacturers to provide available information
regarding risks in pregnancy and lactation in a narrative summary;
however, according to a recent survey, less than 50 percent of
prescribers were aware of this change, while more than half deemed the
narrative summary not helpful \textsuperscript{27}. Lack of quality data
is one of the barriers identified in this survey. In addition to the
rating systems used in various jurisdictions, an evidence-based medicine
classification system has been developed by toxicologists, which can be
used to assist clinical decision making. Unfortunately, all of the
currently available systems are of limited utility due to reliance on
small studies and inability to be updated frequently with new
data\textsuperscript{22}. Since the thalidomide story in the 1960s, much
advancement has been made in medical therapy in pregnant women. However
there remains a significant knowledge gap in pharmacological information
which may expose patients to either toxicity or under treatment with
reduced efficacy. In addition, numerous commonly used medications lack
concrete data on teratogenicity. Supported by the NIH, the Pediatric
Trials Network is currently conducting a multicentre trial studying the
pharmacokinetics and safety of commonly used drugs in lactating women
and breastfeeding infants in North America (NCT03511118); similar
studies in pregnancy are also warranted to guide appropriate dosing.
Long term data on children with fetal exposure for developmental
toxicity are also urgently needed, and while some data for newer
medications is systematically collected by international registries, in
general information on fetal risks of maternal exposures is limited to
incidental data obtained from accidental exposures. Finally, making all
up-to-date information readily available to clinicians should also be a
priority.

\textbf{References}

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In practice.} Feb 18 2020.

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