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 rise1. 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 years2. Furthermore, the
average number of medications used anytime in pregnancy has increased
two-fold 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 3-5. Prescription of
drugs with potential teratogenicity has also increased in pregnancy,
including folate antagonists or angiotensin converting enzyme inhibitors3,4.
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)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 females11. 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 6. Multiple
physiological changes in pregnancy, including those affecting
pharmacokinetics, must be considered when prescribing. Furthermore,
these changes can also be affected by genetic variability10.
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 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 system10. This change results
in and increased volume of distribution for hydrophilic drugs and
reduced peak concentrations 6. Increased glomerular
filtration rate in pregnancy also increases elimination of renally
cleared drugs; a classic example of this effect is lithium13. Changes in hepatic enzyme activity in pregnancy,
including upregulation of cytochrome P450 and glucuronidation, are
another cause of increased metabolism and elimination of drugs14. Increased
metabolism of lamotrigine by glucuronidation results in low drug levels
in pregnancy and this can be further affected by polymorphism of
UDP-glucuronosyltransferases 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 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 ± 0.27
hours in patients in the 3rd trimester of pregnancy, compared to 6-8
hours outside of pregnancy16. This difference
leads many clinicians to prescribe labelatol three times per day based
on patient response instead of twice-per-day as per drug monograph16. 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 17. Enoxaparin
once-per-day versus twice-per-day in a population pharmacokinetics study
both achieved target plasma concentration in pregnancy18; 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 19.
Treatment with beta-blockers are the mainstay of therapy during
pregnancy and in the post-partum period19. 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 hemorrhage20,21.
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 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 consistently23, the risk of
maternal corticosteroid use with increased risk of cleft lip and palate
has not been consistent among studies24,25.
In addition, long term corticosteroid use is also linked to increased
risk of preeclampsia which needs to be taken into consideration for
treatment and monitoring26.
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 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 data22.
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.
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