CLINICAL OBSTETRICS AND GYNECOLOGY

Volume 56, Number 2, 305–316

r 2013, Lippincott Williams & Wilkins

Pharmacology and
Pharmacogenomics of
Neurological
Medications Used in
Pregnancy
SARAH C. CAMPBELL, PhD and
MICHAEL G. SPIGARELLI, MD, PhD
Department of Pediatrics, Division of Clinical Pharmacology,
Clinical Trials Office, University of Utah, Salt Lake City, Utah

Abstract: Pregnancy increases the pharmacological

management challenge of numerous neurological dis-
eases as a result of complex physiological changes.
Understanding pregnancy-induced changes in phar-
macokinetic and pharmacodynamic parameters can
lead to better outcomes for both the mother and baby.
Although the application of pharmacogenomics in
maternal-fetal medicine is in its infancy, further re-
search and developments will provide important new
developments for managing the efficacy of drug treat-
ments during pregnancy and improving maternal-fetal
safety. Although a wide variety of neurological med-
ications are used during pregnancy, this article will
focus on the drugs with currently known pharmaco-
genomic implications.
Key words: pharmacogenomics, neurological disease,
neurological medications, pharmacology, pharmaco-
kinetics, pharmacodynamics, metabolism
Correspondence: Michael G. Spigarelli, MD, PhD,
Department of Pediatrics, Division of Clinical Pharma-
cology, Clinical Trials Office, University of Utah, Suite
2S010, Salt Lake City, UT. E-mail: michael.spigarelli
@hsc.utah.edu
The authors declare that they have nothing to disclose.
Introduction
Neurological diseases are relatively com-
mon in women of childbearing age and
can contribute to maternal mortality
rates.1,2 Whether the neurological condi-
tion was diagnosed before pregnancy, or
whether neurological symptoms appear
for the first time during pregnancy, many
can be effectively managed therapeuti-
cally with careful preconception, antena-
tal, and postpartum considerations.
Many neurological diseases are af-
fected by the physiological state of preg-
nancy. In addition, the pharmacokinetics
(what the body does to a drug) and phar-
macodynamics (what a drug does to the
body) of the various agents used to treat
those conditions can change drastically.
These pregnancy-induced changes gener-
ally lead to under dosing of patients.
Although a wide variety of neurological
diseases can exist during pregnancy, this
article will focus on those treated with

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www.clinicalobgyn.com | 305
306 Campbell and Spigarelli
drugs that have known pharmacogenom-
ic association(s) and that information can
be found in their drug labels. Antiepileptic
drugs (AEDs), as a class to exemplify the
current state of knowledge with respect to
pharmacology and pharmacogenomics,
will also be discussed.
Pharmacogenomics
A number of regulatory agencies, profes-
sional organizations, and researchers
have proposed definitions for pharmaco-
genomics and pharmacogenetics. The In-
ternational Conference of Harmonization
defines pharmacogenomics as: ‘‘The
study of variations of DNA and RNA
characteristics as related to drug re-
sponse.’’ Pharmacogenetics, a subset of
pharmacogenomics is defined as: ‘‘The
study of variations in DNA sequence as
related to drug response.’’3 Although
both terms often are commonly used in-
terchangeably, the preferred term remains
the more broad pharmacogenomics.
The US Food and Drug Administra-
tion (FDA) currently recommends phar-
macogenomic testing for over 100 drugs
through the drug approval and labeling
process.4 This information, contained
within drug labels, includes pharmaco-
genomic information on a variety of
topics including: clinical response varia-
bility, risk for adverse events, polymor-
phic drug target(s) and disposition genes,
and genotype/phenotype-specific dosing.
It should be noted that all drugs undergo
clearance from the body that is mediated
by enzymatic processes and transporter
dependent processes that are governed by
the underlying genetics, nutritional, and
health status of the individual. This list of
just over 100 drugs with current recom-
mendations represents the humblest of
beginnings when it comes to defining the
interindividual and intraindividual varia-
tion in drug metabolism that fall within
the realm of pharmacogenomics.
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The distinction between genotype, phe-
notype, the underlying genetic sequence,
and the externally observable character-
istics, is critically important for the dis-
cussion of pharmacogenomics. For most
drugs understanding of the 4 typical phe-
notypic classifications for polymorphisms
in drug metabolizing enzymes: (1) poor
metabolizers (PM)—no fully functional
copies of the drug metabolizing gene; (2)
intermediate metabolizers (IM)—1 func-
tional copy; (3) extensive metabolizers
(EM)—2 functional copies; and (4) ultra-
rapid metabolizers (UM)—>2 functional
copies of drug metabolizing gene, is im-
portant to accurately apply pharmacoge-
nomics recommendations when and if
they exist. Phenotypes tests utilize plasma
or serum for the detection of parent-to-
metabolite ratios in the determination of
the individual’s status. Genotypic tests
utilize the underlying genetic sequence to
determine individual’s status, although
unknown mutations must be classified
through phenotypic methods. Extensive
metabolizers, despite their name, have
normal enzyme activity, where intermedi-
ate and poor metabolizers have lower
than normal enzyme activity and can
approach no activity. Ultrarapid metab-
olizers excessively metabolize drugs lead-
ing to lack of efficacy for active (parent)
drugs or possibly increased toxicity from
metabolites of prodrugs. The pharmaco-
kinetics or pharmacodynamics of the
drug, as well as influence disease pro-
gression and prognosis, may also be af-
fected.5 Similar classifications exist for
transporters and receptors as well. Com-
plete reviews of pharmacogenomic no-
menclature and concepts are available
elsewhere.6–8
The application of pharmacogenomics
in maternal-fetal medicine is in its early
infancy, further research and develop-
ments will improve the ability to recognize
the risks of drug exposure based on gen-
otype during pregnancy and the ability to
uniquely stratify mothers into risk groups
 Pharmacogenomics of Neurologic Drugs Used in Pregnancy
for adverse drug events and possible birth
defects. Some researchers have hypothe-
sized that AED-induced teratogenicity
has underlying pharmacogenomic impli-
cations.9,10 These researchers have de-
scribed certain families with multiple
exposed affected children, whereas others
with multiple exposures had normal off-
spring.11 These findings strongly suggest
the risk for some pregnant women with a
specific genotype are higher and an alter-
nate drug treatment may be a better op-
tion. Knowing the pregnant patient’s
specific drug metabolizing genotype/phe-
notype may improve efficacy of those
drugs used during pregnancy and improve
fetal/neonatal safety. Understanding the
pharmacogenomics of both mother and
fetus will likely further improve their
safety.
Neurological Medications
With Pharmacogenomic
Implications
Currently, only 5% of the drugs with
pharmacogenomic information in their
drug labels have neurological indica-
tions.4 A list of these drugs can be found
in Table 1. Oncology (23%), psychology
(15%), and cardiology drugs (12%) make
up the majority of the drug classes that
have pharmacogenomics in their drugs
TABLE 1. Drugs Used to Treat
Neurological Diseases With
Pharmacogenomic Information
in Drug Label
Pregnancy Pharmacogenomic
Drugs Category Biomarker
Carbamazepine D HLA-B*1502
Clobazam C CYP2C19
Codeine C CYP2D6
Dextromethorphan C CYP2D6
and quinidine
Phenytoin D HLA-B*1502
Tetrabenazine C CYP2D6
307
labels.4 In the future, the pharmacoge-
nomic implications of many more neuro-
logical medications will be elucidated and
included into their drug labels. Of the 6
neurological medications that currently
have pharmacogenomics information in
their drug labels, 3 are used to treat epi-
lepsy, 1 is used to treat neuropathic pain,
and 2 are for treating neurological con-
ditions not commonly seen in pregnancy.
AED USE DURING PREGNANCY
Epilepsy is the second most common neu-
rological disorder in pregnant women. It
has been estimated that nearly 1 million
American women of childbearing age
have epilepsy12 and approximately
25,000 children are born to these mothers
each year.13 Although commonly used
AEDs are established human teratogens,
infants born to women with untreated
epilepsy in pregnancy have higher rates
of major and minor malformations.9,14
Clinicians face a dual challenge of main-
taining seizure control while minimizing
teratogenic risks of AEDs. Although with
proper preconception, antenatal, and
postpartum management, 95% of preg-
nancies exposed to AEDs show favorable
results,15 the risks associated with in utero
AED exposure are still of considerable
importance. To minimize the teratogenic
risk of AEDs, a high dose of folic acid (up
to 5 mg/d compared with 0.4 to 1 mg/d)
has been recommended for at least 1
month preconception and during the 1st
trimester.16,17 Vitamin K supplementa-
tion is also recommended. The guide-
lines18 for pregnant women on AEDs
call for antenatal maternal vitamin K
supplementation at 20 mg orally through-
out the last 4 weeks of gestation and 1 mg
of vitamin K parenterally to the neonate
immediately after delivery to prevent neo-
natal bleeding.18 Pharmacogenomic test-
ing may also aid clinicians in which
pregnant patients are at an increased risk
of adverse outcomes.
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308 Campbell and Spigarelli
TABLE 2. Pregnancy-induced Pharmacokinetic and Metabolic Changes
Pharmacokinetic and pharmacodynamic changes
Absorption
Volume of distribution
Clearance
Terminal elimination half-life
Peak serum concentrations
Steady-state plasma concentration
Peak serum concentrations
Renal drug elimination
Hepatic drug elimination
Gastric pH
Gastric and intestinal emptying time
Glomerular filtration rate
Protein binding capacity
Intestinal motility
Blood volume
Plasma volume
Total body water
Cardiac output
Tidal volume
Renal plasma blood flow
Hepatic blood flow
Uterine blood flow
Metabolizing enzymes and transporters
Cytochrome P450 1A2 (CYP1A2)
Cytochrome P450 2A6 (CYP2A6)
Cytochrome P450 2C9 (CYP2C9)
Cytochrome P450 2C19 (CYP2C19)
Cytochrome P450 2D6 (CYP2D6)
Cytochrome P450 3A4 (CYP34A)
UDP-glucuronosyltransferases 1A4
(UGT1A4)
UDP-glucuronosyltransferases 2B7
(UGT2B7)
N-acetyltransferase 2 (NAT2)
P-glycoprotein (P-gp)
m indicates increase; k, decrease.
AED pharmacokinetics and pharma-
codynamics can be significantly altered
during pregnancy by many variants in-
cluding: changes in body weight, clear-
ance, protein binding, and metabolism of
drugs (Table 2).27 These pharmacokinetic
changes during pregnancy may escalate
seizure frequency.28–30 Because of the
metabolic induction of the major drug
www.clinicalobgyn.com
Overall Effect in
Pregnancy References
m, k, or unchanged Anderson and colleagues19–21
m Anderson and
colleagues19,20,22
m Anderson and colleagues19,22
m, k, or unchanged Pavek and colleagues20,23
k for many drugs Philipson and colleagues23,24
k Koren and colleagues21,22
k Lobstein and Koren22
m Anderson19
m, k, or unchanged Anderson19
m Anderson and colleagues19,22
m Lobstein and Koren22
m Pavek et al20
k Lobstein and Koren22
k Anderson and colleagues19–22
m Lobstein and Koren22
m Koren21
m Koren21
m Lobstein and Koren22
m Koren and colleagues21,22
m Lobstein and Koren22
m Anderson19
m Thaler et al25
k Anderson and
colleagues19,21,26
m Anderson and colleagues19–21
m Anderson and colleagues19–21
k Anderson and colleagues19–21
m Anderson and colleagues19–21
m Anderson and colleagues19–21
m Anderson19
m Anderson19
m Anderson and colleagues19,26
m Koren21
metabolizing enzymes, the cytochrome
P450s (CYP450s), drug metabolism in
the liver is increased during pregnancy.
This condition along with the other variants
mentioned can lead to serum concentra-
tions of AEDs falling during pregnancy.31
Therapeutic drug monitoring, the con-
cept of following serum/plasma concentra-
tions of drugs to ensure adequate dosing, is
 Pharmacogenomics of Neurologic Drugs Used in Pregnancy 309

therefore an important component to anticonvulsant polytherapy.32 An in-

maintain seizure control throughout preg-
nancy and is recommended at least once per
trimester and monthly for patients with
complicated epilepsy or breakthrough
seizures.
USE OF CARBAMAZEPINE AND
PHENYOIN IN PREGNANCY
Newer AEDs are not preferred due to the
lack of research or utilization knowledge
proving their safety during pregnancy.
Therefore, the most common AEDs used
during pregnancy are older drugs such as
carbamazepine and phenytoin (Table 3).32
Carbamazepine is used for partial seizures
with complex symptomatology, general-
ized tonic-clonic seizures, mixed seizure
patterns and trigeminal neuralgia. It is
also used in an off-label manner for rest-
less leg syndrome and posttraumatic
stress disorder. Carbamazepine may be
associated with teratogenic effects includ-
ing cardiovascular malformations, cra-
niofacial defects, hypospadias, and spina
bifida.33 These risks increase with
crease in daily folic acid may mitigate
some of these risks.34 As hepatic metabo-
lism is the main route of elimination for
carbamazepine (also responsible for in-
ducing CYP450 isoforms 1A2, 2B6, C9,
and 3A4) an increase in dose may be
necessary. Therapeutic drug monitoring
is recommended and can aid in determin-
ing dose increases of carbamazepine.
Phenytoin is used for the management
of generalized tonic-clonic, complex parti-
al seizures, and prevention of seizures after
neurosurgery. Phenytoin has a narrow
therapeutic window, indicating that the
safe and effective blood concentration
range of a phenytoin is close to its toxic
blood concentration range. Phenytoin
is highly bound to protein (90% to 93%)
and is cleared mainly by saturable hepatic
metabolism.35,36 A substantial increase
in 8-hydroxylated phenytoin during preg-
nancy has been demonstrated,31 indicating
increased hepatic metabolism. This in-
crease in metabolism is partially responsi-
ble for the decreased serum concentrations
and decreased seizure control seen during

TABLE 3. Antiepileptic Drugs Used in Pregnancy and Associated Pharmacogenomics

Pregnancy Information in
Category Drug Label? Biomarker Testing Rationale
Older AEDs
Carbamazepine D Yes HLA- Susceptibility to SJS or TEN
B*1502
Phenobarbital D No Unknown NA
Phenytoin D Yes HLA- Susceptibility to SJS or TEN
B*1502
Valproic acid D No Unknown NA
Newer AEDs
Clobazam C Yes CYP2C19 Initial dose adjustments for
CYP2C19 PMs
Felbamate C No Unknown NA
Gabapentin C No Unknown NA
Lamotrigine C No HLA- Possible susceptibility to SJS
B*1502 or TEN
Oxcarbazepine C No Unknown NA
Topiramate D No Unknown NA
Vigabatrin C No Unknown NA

AEDs indicates antiepileptic drugs; NA, not applicable; PMs, poor metabolizers, SJS, Steven-Johnson syndrome; TEN, toxic
epidermal necrolysis.

www.clinicalobgyn.com
310 Campbell and Spigarelli
pregnancy. A fall in total serum phenytoin
concentration may also be the result of
decreased phenytoin protein binding as
more free drug is available for metabolism
and thus cleared more rapidly during
pregnancy.
PHARMACOGENOMICS OF
CARBAMAZEPINE AND PHENYTOIN
Human leukocyte antigen, major histo-
compatibility complex, class I, B (HLA-
B*1502) genotyping predicts susceptibility
to carbamazepine-induced or phenytoin-
induced Steven-Johnson syndrome or toxic
epidermal necrolysis, which are life-threat-
ening dermatologic reactions. Patients
demonstrating an absence of the HLA-
B*1502 allele are at substantially lower risk
of these adverse reactions. Published
population frequencies for HLA-B*1502
are greatest in Han Chinese 8% to 15%,
followed by Asian (unspecified; 5%), white
(1% to 2%), Hispanic (1% to 2%),
and African-American (0.2%).37,38 Cur-
rent regulatory guidance recommends
that patients with the HLA-B*1502
allele should only be treated with carbama-
zepine or phenytoin when the benefit
clearly outweighs the risk. The FDA rec-
ommends genetic testing for HLA-B*1502
before initiating treatment with carbama-
zepine or phenytoin. Pharmacogenomic
testing of HLA-B*1502 is not recom-
mended for patients currently on these
drugs. Recommendations for loading and
maintenance doses for phenytoin based on
cytochrome P450 isoform 2C9 (CYP2C9)
genotype have been evaluated by the Royal
Dutch Pharmacists Association Pharma-
cogenetics Working Group, however, the
FDA currently only recommends HLA-
B*1502 pharmacogenomic testing.39
CLOBAZAM USE IN PREGNANCY
Clobazam, a benzodiazepine long used for
epilepsy in Canada, was not approved in
the US until October 25, 2011. Although its
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approved for use of seizures associated with
Lennox-Gastaut syndrome, a rare child-
onset form of epilepsy, it has been found
to be the most common AED polytherapy
combination with carbamazepine in a
Canadian survey of pregnant women on
AEDs.40 Only 1 human study of clobazam
use during pregnancy has been reported
that demonstrated its ability to cross the
placenta41 and its use during pregnancy is
not advised.
PHARMACOGENOMICS OF
CLOBAZAM
More than 25 variant alleles have been
reported for the principal metabolic en-
zyme, CYP2C19. These include ones that
are associated with reduced enzyme func-
tion (ie, poor metabolizers; CYP2C19*2,
CYP2C19*3, CYP2C19*4, CYP2C19*5,
CYP2C19*6, CYP2C19*7, CYP2C19*8)
and one which is associated with a gain-
of-function and increased metabolism (ie,
ultrarapid metabolizer; CYP2C19*17).
There are known pharmacokinetic differ-
ences among these variants; however, only
modifications in clobazam dose have been
recommended for CYP2C19 poor metabo-
lizers (see below). The population distribu-
tion for the most common reduced function
allele (CYP2C19*2), is greatest in Chinese
(27%), followed by Africans (14%) and
European-Americans (14%). The popula-
tion distribution for the next most common
reduced function allele (CYP2C19*3) in
order of prevalence is Japanese (13%),
followed by Chinese (5%), African-Ameri-
cans, and whites (<1%).42 The gain-of-
function allele (CYP2C19*17) occurs most
frequently in Africans (29%), followed by
European-Americans (23%), and Chinese
(2%).43 The FDA recommends genotyping
CYP2C19 in patients before initiating or
reinitiating treatment with clobazam.
Clobazam’s active metabolite, N-desme-
thylclobazam, is also the major circulating
metabolite in humans. Concentrations of N-
desmethylclobazam in plasma, are 3 to 5
 Pharmacogenomics of Neurologic Drugs Used in Pregnancy
times higher in CYP2C19 poor metabo-
lizers, and 2 times higher in intermediate
metabolizers compared with extensive
metabolizers (eg, normal metabolizers).
For this reason, the initial dose should
be 5 mg/d (instead of 5 mg/BID) in
CYP2C19 poor metabolizers. Currently,
no dosage recommendations have been
made for the CYP2C19*17 gain-of func-
tion allele.
CODEINE USE IN PREGNANCY
Codeine is one of the most common med-
ications used to decrease acute pain in
pregnant women.44–46 Codeine is a m-opioid
receptor agonists and elicit its therapeutic
effect by depressing the central nervous
system. Codeine is metabolized by cyto-
chrome P450 isoform 2D6 (CYP2D6) to
morphine, its active metabolite. This en-
zyme is responsible for the metabolism of
approximately 25% of all medications by
the human liver, yet only comprises of a
small percentage of the total liver CYP450
content. Therefore, any decreases in its
activity or presence of any inhibitor can
lead to significant changes in blood concen-
trations and has the potential to greatly
impact efficacy for pro-drugs and toxicity
for active parent drugs. Unlike other
CYP450s, there are no known CYP2D6
inducing substrates. The unique condition
of pregnancy, however, is the only time in
which CYP2D6 induction has been dem-
onstrated. The mechanism of this induction
remains to be elucidated.47 No pharmaco-
kinetic studies have been reported with
codeine use in pregnancy. Association be-
tween first trimester use of codeine and
various congenital anomalies have been
observed.48,49 With extended use in late
pregnancy, codeine can result in neonatal
withdrawal.50,51
PHARMACOGENOMICS OF CODEINE
CYP2D6 is highly polymorphic and ap-
proximately 115 distinct alleles have been
311
described, yet many have not been func-
tionally characterized. The characterized
CYP2D6*1n and CYP2D6*2n alleles have
increased enzymatic activity, CYP2D6*10
and *17 have reduced activity, whereas
CYP2D6*3, CYP2D6*4, and CYP2D6*5
have diminished or absent activity.
CYP2D6*6, CYP2D*7, CYP2D*8 are
known to have absent activity. Low
CYP2D6 activity can lead to reduced active
metabolite formation and loss of drug ef-
fect, or reduced metabolism and detoxifi-
cation from normal dosages of codeine.
Between 1% and 5% of Americans and
Europeans are ultrarapid metabolizers (by
carrying 2 or more copies of the
CYP2D6*2 allele).52,53 The reduced func-
tion allele CYP2D6*10 has a frequency of
about 50% in Asians.54 In the other known
reduced function allele, CYP2D6*17,
frequency is greatest in Africans (34%).55
The alleles associated with absent
activity are found in approximately 7% of
white, <3% of Africans, and 1% of
Asians.
A standard starting dose of codeine is
recommended in patients with an exten-
sive metabolizer phenotype (eg, normal
metabolizer). In patients identified as a
CYP2D6 ultrarapid metabolizer, the
choice of an alternative analgesic (other
than the CYP2D6 substrate) should be
made to avoid the risk of severe toxicity
associated standard doses of codeine.
There is insufficient evidence in the liter-
ature to recommend a higher dose of
codeine in poor metabolizers, which may
be necessary to overcome the inability to
convert to the active metabolite mor-
phine. The therapeutic recommendations
for codeine based on CYP2D6 phenotype
are summarized in Table 4.
Studies have shown that ultrarapid and
extensive metabolizers (eg, normal metab-
olizers) steadily increase metabolic capacity
throughout pregnancy, whereas intermedi-
ate and poor metabolizers steadily decrease
in metabolic capacity throughout preg-
nancy.47,56,57 Studies on the implications
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312 Campbell and Spigarelli
TABLE 4. Codeine Pharmacogenomic Recommendations
Phenotype Codeine Metabolism
Ultrarapid Increased metabolism to
metabolizer morphine. Risk of toxicity
Extensive Normal metabolism to
metabolizer morphine
Intermediate Reduced metabolism to
metabolizer morphine
Poor Greatly reduced metabolism
metabolizer to morphine
on effective management of codeine
through gestation are warranted.
In 2006, the clinical application of co-
deine pharmacogenomics was described
after a case of fatal respiratory depression
in a breastfed newborn whose mother was
prescribed codeine.58 The mother was
found after the fact to be an ultrarapid
metabolizer, which led to opioid intoxica-
tion in the newborn. The postmortem
blood from the neonate revealed high
concentrations of morphine and the
breast milk morphine concentrations
were 4-fold higher than previous litera-
ture reports.58 As a result of this case, the
FDA and Health Canada have issued
public health advisories and proposed
labeling updates. Since then, other
breastfed infants who experience life-
threatening central nervous system de-
pression whose mothers were CYP2D6
ultrarapid metabolizers have been re-
ported.59 The Royal Dutch Pharmacists
Association Pharmacogenetics Working
Group has evaluated therapeutic dose
recommendations for codeine based on
CYP2D6 genotypes and recommend al-
ternative drug treatment for analgesia in
patients carrying poor metabolizer alleles
and ultrarapid metabolizer alleles.39 A
summary of these recommendations can
be found in Table 4.
DEXTROMETHORPHAN AND
QUINIDINE USE IN PREGNANCY
This combination of drugs is used for
the treatment of pseudobulbar affect by
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Recommendations
Avoid codeine use. Possibility for codeine toxicity.
Consider analgesic that is a not a CYP2D6 substrate
15-50 mg every 4 h as needed for pain
Begin with 15-60 mg every 4 h as needed for pain.
Consider alternative analgesic if there is no response
Avoid codeine use. Lack of efficacy. Consider alternative
analgesic
N-methyl-D-aspartate receptor antago-
nism. Pseudobulbar affect is a nervous
system disorder described as emotional
incontinence. Symptoms can include: in-
voluntary crying, uncontrollable episodes
of crying/laughing, and uncontrollable
and exaggerated emotional outbursts,
typically without inner feelings of sad-
ness, depression, or happiness. Pseudo-
bulbar affect can cause severe distress
and embarrassment, and social and occu-
pational dysfunction. The US prevalence
of pseudobulbar affect has been estimated
to be about 10% across common neuro-
logical conditions.60–65 Pseudobulbar affect
is generally thought to be a underrecog-
nized and undertreated disorder.60,66 There
have been no human or animal pregnancy
studies with this drug combination and its
use during pregnancy is not advised.
PHARMACOGENOMICS OF
DEXTROMETHORPHAN AND
QUINIDINE
Dextromethorphan is metabolized by
CYP2D6, which is the underlying ration-
ale for quinidine as the combination
agent. In this drug combination quinidine
is intended to inhibit CYP2D6 to achieve
higher dextromethorphan exposure, com-
pared to when dextromethorphan is given
alone. As a result, genotyping CYP2D6 to
determine whether patients who are poor
metabolizers should be considered before
treating with this drug combination. The
quinidine component is not expected to
contribute to the effectiveness of this drug
 Pharmacogenomics of Neurologic Drugs Used in Pregnancy
combination in CYP2D6 poor metabolizers,
although if the patient is taking other agents
metabolized by CYP2D6 may experience
untoward adverse reactions. CYP2D6 gen-
otyping may predict patients who may be at
risk of significant toxicity due to quinidine.
Approximately 7% to 10% of whites and
3% to 8% of African Americans are classi-
fied as poor metabolizers.
TETRABENAZINE USE IN PREGNACY
Tetrabenazine is a central monoamine-
depleting agent for the treatment of chor-
ea associated with Huntington disease.
The mean age of onset is 35 to 44 years,67
however, 5% to 10% of cases are juvenile
Huntington disease in which onset occurs
before 20 years of age.68,69 The prevalence
of Huntington disease worldwide has
been estimated between 3 and 6 per
100,000.70 Tetrabenazine was used for-
merly as an antipsychotic but now is used
primarily in the treatment of various
movement disorders including tardive
dyskinesia. There have been no controlled
studies in human pregnancy and animal
pregnancy studies have not been reported.
Tetrabenazine is only recommended for
use in pregnancy when there are no alter-
natives and benefits outweigh risk.
PHARMACOGENOMICS OF
TETRABENAZINE
As with several other agents, tetrabena-
zine is metabolized by CYP2D6 that gives
rise to its primary metabolites. Patients
should be genotyped for CYP2D6 before
treatment with single doses of tetrabena-
zine over 25 mg and daily doses over
50 mg. Patients who are poor metaboliz-
ers should not be given daily doses
>50 mg. Exposures to metabolites are
substantially higher in poor metabolizers
(about 3-fold for a-hydroxytetrabenzine
and 9-fold for b-hydroxytetrabenzine)
compared with extensive metabolizers
(eg, normal metabolizers) that can lead
to increased adverse events.
313
Future Directions/Limitations
Increased availability of analytical meth-
ods for determining neurological drug con-
centration will aid in the ability to utilize
therapeutic drug monitoring to improve
effectiveness and limit toxicity in pregnant
patients. Use of blood spots cards and
other techniques that utilize more conven-
ient samples can improve accessibility to
patient samples decreasing the need for
larger volumes of blood. Testing for
DNA from noninvasive buccal swabs is
also available and can provide DNA sam-
pling without the need for blood collec-
tion. For some applications, the timeline
for obtaining pharmacogenomic test re-
sults may seem to be too long to serve a
therapeutic advantage (especially for drugs
given short term). With newer technolo-
gies, pharmacogenomic test results can be
acquired in the timeframe needed. Com-
panies are currently working toward bed-
side tests that could provide results for
specific CYP450s within 1 hour. The avail-
ability of genetic testing is growing, includ-
ing several tests that are offered directly to
the consumer, and the cost for the tests
themselves are decreasing (around $100
for some CYP450 tests). However, further
assessing the clinical utility of pharmaco-
genomics testing in maternal-fetal medi-
cine and its cost-effectiveness still needs to
be determined. Providing pharmacoge-
nomic education to health care providers
is another important step for the future of
this type of personalized medicine.
Although small studies exist for how
individuals with various CYP2D6 geno-
types respond to pregnancy and drug ther-
apy, this is not the case for most other drug-
metabolizing enzymes and transporter
genotypes. Studies on the duration of in-
duction for metabolizing enzymes and
transporters postpartum are still needed.
Pharmacokinetic modeling can improve
the understanding of maternal-fetal metab-
olism, the contribution of maternal geno-
types, and developments of adverse drug
reactions in this unique population.
www.clinicalobgyn.com
314 Campbell and Spigarelli
Other potential interferences involved
in drug treatment during pregnancy, such
as decreased patient adherence due to
concern about teratogenicity and the ef-
fects of nausea and vomiting on decreased
drug absorption have not been discussed.
These are very real conditions that can
have substantial effects on drug treatment
during pregnancy.
Summary and Conclusions
Pregnancy can affect many neurological
diseases and make the pharmacological
management of these diseases challenging.
Knowing the pregnancy-induced pharma-
cokinetic and pharmacodynamic changes
during pregnancy can aid in the effective
management of these patients. Although
currently only a few of the neurological
medications have information regarding
the pharmacogenomic implications of
treatment, as research progresses, many
more biomarkers will be discovered to
guide improvements in maternal-fetal
medicine. Adverse drug events such as
Steven-Johnson syndrome or toxic epider-
mal necrolysis can be prevented by aware-
ness of the HLA-B*1502 genotyping
results in patients starting carbamazepine
or phenytoin. Other examples of current
pharmacogenomic applications have re-
sulted in modifications in dosing of cloba-
zam for CYP2C19 poor metabolizers.
Genotyping for CYP2D6 is recommended
for codeine, dextromethorphan/quinidine
combination therapy, and tetrabenazine,
which allows for improvements in efficacy
and avoidance of possible adverse drug
effects. Genotyping of CYP2D6 in breast-
feeding mothers prescribed codeine for
postpartum pain is strongly advised to
improve neonatal safety.
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