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Pregnancy and epilepsy-when you're managing both

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Abstract

When a patient with epilepsy is pregnant or planning for pregnancy, you face the challenge of balancing the benefits and teratogenic risks of her antiseizure medication. Here's help.
Pregnancy and epilepsy—when
you’re managing both
When a patient with epilepsy is pregnant or planning
for pregnancy, you face the challenge of balancing
the bene ts and teratogenic risks of her antiseizure
medication. Here’s help.
About 500,000 women in the United States su er from
epilepsy and are of childbearing age.1 For these pa-
tients and their physicians, family planning and
pregnancy are complex and fraught with risk.
e dilemma: Infants born to women with epilepsy have
a 2- to 3-fold risk of congenital malformations compared with
those whose mothers do not have epilepsy, mainly related
to exposure to antiepileptic drugs (AEDs).2 Recent studies
also suggest that children exposed to AEDs such as valpro-
ate, phenobarbital, and phenytoin in utero may have neuro-
cognitive de cits, even when there are no major congenital
malformations.1,3,4
Yet discontinuing the drugs prior to conception or in ear-
ly pregnancy is rarely a viable option. In 1 recent prospective
study, convulsive seizures during the  rst trimester (the type
and timing of seizure thought to have the most harmful e ect
on the developing fetus) were associated with malformations
in 7.4% of pregnancies.2 Seizures also increase the risk of both
fetal and maternal death, although the extent of that risk is
not known.5
Ideally, pregnant women with epilepsy should be under
the care of both an obstetrician experienced in high-risk preg-
nancies and a neurologist or an epileptologist. In reality, those
who live in areas with limited access to such specialized care or
have limited health coverage may be cared for throughout their
pregnancy by a family physician.  is evidence-based review
was developed with this family physician in mind.
Safeguarding mom and fetus
starts before pregnancy
Mechanisms by which AEDs cause fetal and embryonic harm
remain unclear. Possible causes include drug toxicity, drug-
Nitin K. Sethi, MD;
Amy Wasterlain,
MD candidate;
Cynthia L. Harden, MD
Department of Neurology,
New York-Presbyterian
Hospital, Weill Cornell
Medical Center,
New York, NY
sethinitinmd@hotmail.
com
Dr. Sethi and Ms. Wasterlain
reported no potential con ict of
interest relevant to this article.
Dr. Harden reported that she
receives research support from
Forest Pharmaceuticals; serves
as a consultant to H. Lundbeck
A/S, Novartis, Sepracor Inc., and
UCB; and is on the speakers’
bureau of GlaxoSmithKline,
H. Lundbeck A/S, and UCB.
PRACTICE
PRACTICE
RECOMMENDATIONS
RECOMMENDATIONS
Use the dose of antiepilep-
tic drug (AED) at which the
patient is seizure-free prior to
conception as a target level
to adjust dosing during
pregnancy. C
Avoid switching a pregnant
patient to an AED that she
has not taken before. C
Start all women who have
epilepsy and are of childbear-
ing age on ≥0.4 mg folic acid
daily prior to conception. C
Strength of recommendation (SOR)
Good-quality patient-oriented
evidence
Inconsistent or limited-quality
patient-oriented evidence
Consensus, usual practice,
opinion, disease-oriented
evidence, case series
A
B
C
675
JFPONLINE.COM VOL 59, NO 12 | DECEMBER 2010 | THE JOURNAL OF FAMILY PRACTICE
676 THE JOURNAL OF FAMILY PRACTICE | DECEMBER 2010 | VOL 59, NO 12
drug interactions, folic acid de ciency, the
e ect of suboptimally controlled convulsions,
genetic predisposition, enhanced apoptotic
neurodegeneration, and alterations in thyroid
hormone status, among others.6-9 Major con-
genital malformations may occur in a dose-
dependent manner, and physicians should
aim to use the most e ective AED at the lowest
e ective dose for women of childbearing age.2
In reviewing antiseizure therapy for such
patients, here are some considerations to
keep in mind:
Avoid polytherapy, if possible. Ta k i ng
multiple AEDs may increase the risk of major
congenital malformations, especially when
valproate is one of the drugs.1 Hence, an at-
tempt should be made to switch women with
epilepsy who are of childbearing age to mono-
therapy. Ideally, this should be done a year
before planned conception so that good sei-
zure control can be achieved and documented
prior to pregnancy.
Avoid high-risk AEDs. Overall, an in-
creased risk of major congenital malforma-
tions has been most convincingly found with
valproate and phenobarbital.1 Speci c types
of malformations have also been linked to
certain drugs (TABLE). Cardiac malforma-
tions are associated with carbamazepine,
phenobarbital, and valproate; spina bi da,
hypospadias, porencephaly, and other brain
anomalies, as well as limb reduction defects,
are associated with valproate, particularly at
doses >1100 mg/d.10
Choose newer agents, whenever pos-
sible. e risk of malformations with newer
AEDs—including gabapentin, lamotrigine, le-
vetiracetam, oxcarbazepine, and topiramate—
remains unclear, but preliminary data for
monotherapy with these agents suggest a low-
er teratogenic risk compared with traditional
AEDs, such as phenobarbital and valproate.10
Initiate folic acid supplementation.
Drug-induced folate de ciency has been pro-
posed as a contributing factor in the terato-
genicity of AEDs, so diligence is essential in
ensuring that patients who have epilepsy and
are of childbearing age take folic acid.11 Stud-
ies have demonstrated a signi cant reduction
in spontaneous abortion in women who are
receiving AED therapy and taking folic acid
supplements, and the bene ts of folic acid
have been found to be especially notable for
women taking valproate.12
Folic acid supplementation, of course, is
important for all women of childbearing age.
At a dose of 0.8 mg/d, folate has been shown to
reduce the risk of neural tube and ventricular
septal defects in the general population.  e
American Academy of Neurology/American
Epilepsy Society (AAN/AES) Practice Param-
eters recommend that all women of child-
bearing age taking AEDs also take folate sup-
plements (0.4-4 mg/d).13 An optimal dose has
not been determined for this patient popula-
tion, but we routinely recommend 1 mg/d for
women with epilepsy of childbearing age and
increase the dose to 4 mg/d after conception.
Switching (or stopping) AEDs
before conception
Changes in AEDs are rarely made after concep-
tion. Any switches that patients may desire—
from a potentially unsafe drug to a “safer” AED,
for example—should be considered at least a
year prior to planned pregnancy so good sei-
zure control can be achieved before then.
In attempting a change in medication,
start by checking the serum drug level of
the patient’s e ective, yet potentially unsafe,
antiseizure drug.  at allows you to deter-
mine the baseline therapeutic drug level and
dose at which the patient is seizure-free.  en
add the second, safer AED and taper it up to
its therapeutic dose, guided by serum drug
levels and the manufacturer’s recommended
titration schedule. Once the new medication
has reached the therapeutic serum level, be-
gin titrating the older AED down. If the pa-
tient su ers a breakthrough seizure during
the cross-taper, we recommend aborting the
process and rapidly titrating the  rst drug
back to the predetermined therapeutic level.
What about stopping AED therapy en-
tirely if your patient wants to get pregnant?
Stopping AEDs is a clinical decision made by
the treating physician in accordance with the
patient’s wishes on a case-by-case basis, and
should be considered only when it is highly
likely that seizures will not recur as a result. If
the patient has a history of poorly controlled
epilepsy despite adequate AED trials, a struc-
tural brain lesion, persistently abnormal elec-
troencephalograms, or any other  nding that
Monotherapy
with a newer
antiepileptic
drug appears
to be the
safest and
best-tolerated
option for
women of
childbearing
age, provided
adequate seizure
control can be
obtained.
PREGNANCY AND EPILEPSY
677
JFPONLINE.COM VOL 59, NO 12 | DECEMBER 2010 | THE JOURNAL OF FAMILY PRACTICE
suggests she may have recurrent seizures, ex-
plain that the risk of discontinuing the medi-
cation is greater than the risk of fetal exposure
to AEDs. It is also important to point out that
more than 90% of women with epilepsy have
normal, healthy children14—and that there are
other steps to take to mitigate risk.13
What to consider
in the  rst trimester
Registries that aim to gather data on the out-
comes of a large number of AED-exposed
pregnancies are a source of reliable infor-
mation regarding the risks associated with
various antiseizure agents.  e primary
US-based registry is the AED Pregnancy
Registry, available at http://aedpregnancy
registry.org. We recommend that physicians
caring for pregnant women with epilepsy en-
courage them to enroll early on, before any
prenatal tests are performed. Explain to your
patient that by joining the registry, she will be
helping others like her make informed deci-
sions about prenatal care.
Prenatal testing. We also recommend
that pregnant women taking AEDs—par-
ticularly those on higher-risk drugs such as
TABLE
Commonly used antiepileptic drugs: Major teratogenic risks1,10,19
AED
FDA pregnancy
category* Associated risks Recommendations for use during pregnancy
Carbamazepine C Cardiac malformations Lower teratogenic potential compared with
phenobarbital and valproate
Gabapentin C No MCMs associated with
monotherapy
Limited data suggest lower teratogenic risk
compared with traditional AEDs
Lamotrigine C No distinctive pattern of MCMs Limited data suggest lower teratogenic risk
compared with traditional AEDs
Levetiracetam C Pyloric stenosis (in polytherapy
with lamotrigine); spina bi da (in
polytherapy with carbamazepine
and valproate)
Limited data suggest lower teratogenic risk
compared with traditional AEDs
Oxcarbazepine C Urogenital malformations Limited data suggest lower teratogenic risk
compared with traditional AEDs
Phenobarbital D Cardiac malformations
Increases risk of MCMs to at least
double that of general population
Best avoided in women of childbearing age
Phenytoin D Bradycardia and hypotension; fetal
hydantoin syndrome
Best avoided in women of childbearing age
Topiramate C Hypospadias; oral clefts Limited data suggest lower teratogenic risk
compared with traditional AEDs
Valproate D Cardiac malformations; hypospadias;
limb reduction defects; neural tube
defects; porencephaly; spina bi da
Increases risk of MCMs to at least
double that of general population
Best avoided in women of childbearing age
AED, antiepileptic drug; FDA, US Food and Drug Administration; MCMs, major congenital malformations.
*Category C indicates that human data are lacking and animal studies were positive OR not done; Category D indicates that human data have shown a teratogenic
risk but the bene ts may outweigh the risk.
Traditional AEDs include carbamazepine, phenobarbital, phenytoin, and valproate.
678 THE JOURNAL OF FAMILY PRACTICE | DECEMBER 2010 | VOL 59, NO 12
More than 90%
of women with
epilepsy have
normal, healthy
children.
valproate—undergo a detailed  rst trimester
ultrasound study between 16 and 20 weeks’
gestation. Amniocentesis should be avoid-
ed, if possible; if needed, however, amniotic
alpha-fetoprotein levels may be determined
for additional risk assessment.15
Medication changes. Once a woman
is pregnant, stopping or switching AEDs re-
quires a higher level of caution and is usually
ill advised. We generally avoid medication
switches after conception. But if a patient ex-
plicitly requests a change to a “safer” agent,
we may attempt a cross-taper, as we would
before pregnancy. Evidence suggests, how-
ever, that it may be too late to avoid the risk
for major congenital malformations, which
typically develop very early in pregnancy.1,3
Avoid untried AEDs. We advise against
changing a pregnant woman’s seizure medi-
cation to an agent she has not tried before,
because of the risks of both common adverse
e ects, such as allergies, and rare idiosyn-
cratic reactions leading to aplastic anemia
and Stevens-Johnson syndrome.
AED dosing throughout pregnancy
When seizures are well controlled prior to
conception, they usually remain controlled
during pregnancy, although both increases
and decreases in seizure frequency have been
reported.16 Seizure exacerbations are usually
due to decreased AED levels; this may be the
result of decreased plasma protein bind-
ing, decreased albumin concentration, or
increased drug clearance,16 although stress,
sleep deprivation, and noncompliance may
be contributing factors, as well.  e changes
in pharmacokinetics make it imperative that
seizure frequency as well as AED levels be
carefully monitored throughout pregnancy.
Although detailed information about
changes in serum levels of the newer AEDs
during pregnancy is not available, it can be
assumed that they will decline somewhat
even if the dose remains the same. Carbam-
azepine has the least alteration in metabolism
during pregnancy,17 while a widely dispa-
rate e ect on lamotrigine metabolism during
pregnancy has been noted. In some women,
serum levels of lamotrigine have been shown
to decrease by as much as 60% to 90% due to
induction of UDP-glucuronosyltransferase
(UGT) enzymes,18 the drug’s main metabolic
enzymes. Increased clearance of lamotrigine
typically occurs within the  rst several weeks
of pregnancy and returns to baseline within
2 weeks after birth.
As a result, incremental dosing of la-
motrigine is usually required early in the
pregnancy. In some cases, dramatic increas-
es—several multiples of the preconception
dose—may be needed, followed by a rapid
decrease after delivery.18
Monitoring drug levels
Our approach to monitoring AED levels in a
pregnant woman with epilepsy includes the
following:
Check levels at baseline—prior to concep-
tion, whenever possible—and monthly
throughout the pregnancy, with more fre-
quent checks for women with recurrent
seizures and those taking lamotrigine.
Use the dose at which the patient was
seizure-free prior to conception as a target
level during pregnancy.
Adjust the dose as needed to maintain the
preconception serum drug level.
Drug-speci c considerations. As phe-
nytoin and valproate are highly protein-
bound, we follow free levels during pregnancy
rather than total levels alone. (If your facility
is not equipped to track free drug levels, it is
important to realize that total levels of these
AEDs may not accurately re ect the drug
level.) If your patient is taking phenytoin and
you’re unable to obtain this information, you
can use the patient’s albumin level and the to-
tal phenytoin level to estimate the free level of
the drug with the following formula:
Free phenytoin = measured level/
[(0.2 × albumin level) + 0.1].
Provide vitamin K augmentation late
in pregnancy. In addition to routinely prescrib-
ing 4 mg/d folic acid for pregnant women with
epilepsy, we recommend oral augmentation of
vitamin K as another protective measure.
AEDs that induce hepatic CYP enzymes
also induce vitamin K metabolism, thereby
reducing the e ectiveness of vitamin K-
dependent clotting factors and predispos-
ing newborns to hemorrhagic disease.13 It
remains unclear whether only women who
PREGNANCY AND EPILEPSY
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During
pregnancy,
changes in
pharmaco-
kinetics may
affect dosing
requirements,
and serum levels
of antiepileptic
drugs should be
monitored at
least monthly.
are taking CYP enzyme-inducing AEDs or all
women taking AEDs should receive oral vita-
min K supplementation in the last few weeks
of pregnancy. We recommend oral vitamin
K supplementation for all pregnant women
with epilepsy (phytonadione 10 mg/d) start-
ing at 36 weeks’ gestation and continuing un-
til delivery despite the lack of a proven bene t
because it is safe and carries little, if any, risk.
An intramuscular injection of 1 mg
vitamin K is generally given to all new-
borns—regardless of whether the mother
has epilepsy and takes AEDs—to prevent
hemorrhagic disease.13
Should women taking AEDs
breastfeed?
e advantages of breastfeeding are largely
undisputed, but women being treated with
AEDs are generally concerned about the pos-
sibility of contaminated breast milk. While
antiepileptic agents such as gabapentin, la-
motrigine, levetiracetam, and topiramate are
excreted in breast milk in potentially clinical-
ly important amounts, no short-term adverse
e ects have been observed in nursing infants
of women being treated with AEDs.13 Little
information is available regarding long-term
e ects, and the AAN and AES state that fur-
ther study is needed. Nonetheless, breast-
feeding is generally believed to be a relatively
safe option for patients with epilepsy who are
being treated with AEDs, and is not contra-
indicated by the AAN/AES guidelines.13
Indeed, pregnancy itself is relatively safe
for women with epilepsy. When you’re involved
in their care, your awareness of the teratoge-
nicity of various AEDs, the factors to consider
in managing epilepsy and pregnancy, and the
steps to take to mitigate risk will help you maxi-
mize the chance of a positive outcome.
JFP
JFP
CORRESPONDENCE
Nitin K. Sethi, MD, Comprehensive Epilepsy Center, New
York-Presbyterian Hospital, Weill Cornell Medical Center,
525 East 68th Street, Room K-615, New York, NY 10021;
sethinitinmd@hotmail.com
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3. Holmes GL, Harden C, Liporace J, et al. Postnatal concerns
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... This recommendation does not apply to women who have had previous NTD affected pregnancy and women on some antiseizure drugs [3]. Certain antiseizure drugs are known to cause folate deficiency and higher dose of folic acid is recommended for all women of childbearing age and pregnant women [88]. Although there has not been any study that determined the optimal dose of folic acid for women on antiseizure drugs, it is usually recommended that women of childbearing potential take 1mg/day of folic acid and the dose be increased to 4 mg/day following conception [88]. ...
... Certain antiseizure drugs are known to cause folate deficiency and higher dose of folic acid is recommended for all women of childbearing age and pregnant women [88]. Although there has not been any study that determined the optimal dose of folic acid for women on antiseizure drugs, it is usually recommended that women of childbearing potential take 1mg/day of folic acid and the dose be increased to 4 mg/day following conception [88]. The American College of Obstetricians and Gynecologists recommends a folic acid supplement of 0.4 mg/day for women at low risk of NTDs and 4 mg/day for women at high risk of NTDs or who have had a previous pregnancy with an NTD [89]. ...
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Maternal folate supplementation is critical for fetal development. Women with MTHFR (methylenetetrahydrofolate reductase) gene polymorphisms may not be getting the proper folate form to support fetal development. The objectives of this review were to: (1) undertake a comprehensive review on the association of MTHFR polymorphisms with the risk for various congenital diseases and other adverse pregnancy outcomes, (2) assess the efficacy and safety of current folic acid and other supplementations in women with the MTHFR polymorphism, and (3) provide guidance on the appropriate supplementation for women of childbearing potential with the MTHFR gene polymorphism in order to decrease these adverse pregnancy outcomes. Our assessments show that women with MTHFR gene polymorphism cannot efficiently convert folic acid to L-5-methyl-tetrahydofolate, the predominant active form of folic acid, due to reduced MTHFR enzymatic activity. L-5-methyl-tetrahydrofolate is currently commercially available under several brand names. Based on our comprehensive review and knowledge of the biochemistry of the folates, we recommend that L-5-methyltetrahydrofolate be given in combination with folic acid to women with MTHFR polymorphism that are pregnant or planning to become pregnant. Further study is needed to determine the optimal dose.
... Given these complex considerations, WWE need information about epilepsy and pregnancy prior to conception. A particular emphasis has been placed on effective birth control, planned pregnancies, AED optimization, and vitamin supplementation [8,9]. There is some suggestion that folic acid and vitamin K supplementation are particularly important for WWE as there is some evidence that AEDs can increase the risk of negative outcomes that can be prevented by supplementation (e.g., neural tube defects and hemorrhagic disease) [10]. ...
... Despite the absence of randomized control trials (RCTs) of preconception counseling [11], several studies with retrospective designs suggest that pregnancy planning, including preconception AED optimization, can improve pregnancy outcomes [12][13][14]. Practice guidelines for managing pregnancy in WWE consistently promote the need for effective preconception counseling for WWE throughout the reproductive years [8][9][10]15,16]. Epilepsy & Behavior 31 (2014) [246][247][248][249][250][251][252][253][254][255] Nevertheless, findings from qualitative research suggest that many WWE remain uninformed about key issues regarding epilepsy and pregnancy [17][18][19][20]. ...
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For women with epilepsy (WWE), pregnancy is complicated by considerations such as the potential teratogenicity of antiepileptic drugs (AEDs) versus the risks of having seizures during pregnancy. However, qualitative research suggests that many WWE remain uninformed about the risks associated with epilepsy and pregnancy and may, therefore, be making uninformed decisions about their families. The objectives of this review were to determine the level of patient knowledge, their informational needs, and whether these needs concerning pregnancy and childbirth issues are met among WWE. Electronic databases searched were PsycINFO, MEDLINE, Embase, CINAHL, and Web of Science. Studies were included if they used quantitative methods to survey WWE aged 16years or older about their knowledge, access to information, or informational needs specifically regarding epilepsy and pregnancy. Twelve studies were identified and assessed for research standards using the Quality Index. Overall Quality Index score was only 7.1 out of 14, indicating significant design limitations of many included studies, including highly selective sampling methods and the use of unvalidated outcome measures. There was a paucity of studies investigating specific areas of women's knowledge and information needs. Overall, WWE reported adequate awareness, but limited knowledge, of key issues regarding pregnancy and childbirth. Across studies, many women reported not receiving information about these issues. Evidence suggested that many WWE wanted to receive more information - particularly about the risks of AEDs for their offspring - well in advance of choosing an AED or planning pregnancy. Women aged under 35years wanted the most information. Preconception counseling received by many WWE appears insufficient, risking uninformed decision-making about pregnancy. Further research is needed to investigate the barriers that WWE face in accessing, receiving, and retaining appropriate information.
... Consequently, dose reduction after birth is necessary. 1,2 Balanced medicines information regarding the risks and benefits of AEDs is important to reduce unnecessary concerns regarding drug treatment and for pregnant women's participation in therapeutic decisions. 1 Others have documented that pregnant women, including those with epilepsy, have needs for information about teratogenic risks of medicines. ...
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Aim To assess the relative risk of major congenital malformations (MCM) from exposure to anti-epileptic drugs (AEDs) during pregnancy. Methods 15 year prospective observational study from 1996 until 2009. The outcome measure is the MCM rate. Results Informative outcomes were available for 5802 cases. The risk of MCM was significantly higher in women on AEDs during pregnancy (n=5376) in comparison to those on no treatment (n=426), RR: 1.55 (95% CI 1.13 to 2.14), and significantly higher in polytherapy (n=1183) than monotherapy (n=4193), RR: 1.60 (95% CI 1.19 to 2.15). The risk to those on valproate monotherapy was more than double that for those on either carbamazepine (RR 2.35, 95% CI 1.55 to 3.57) or lamotrigene (RR 2.40, 95% CI 1.57 to 3.68). 245 and 362 informative outcomes were obtained for topiramate and levetiracetam respectively, with MCM rates of 7.1% (95% CI 4.5 to 11.0%) and 2.5% (95% CI 1.3 to 4.7%). There were 3/83 cases of MCM in Topiramate monotherapy and 14/162 cases in polytherapy. There were no cases of MCMs in levetiracetam monotherapy and 9/229 cases levetiracetam polytherapy. Conclusions AED exposure during pregnancy increases the risk of MCM in the babies of women with epilepsy. Polytherapy exposure has a higher risk than monotherapy. Valproate exposure carries higher MCM risk than any other AED. Lowest risk is associated with carbamazepine or lamotrigene monotherapy. Results for levetiracetam, although numbers are small, look promising.
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To reassess the evidence for management issues related to the care of women with epilepsy (WWE) during pregnancy, including preconceptional folic acid use, prenatal vitamin K use, risk of hemorrhagic disease of the newborn, clinical implications of placental and breast milk transfer of antiepileptic drugs (AEDs), risks of breastfeeding, and change in AED levels during pregnancy. A 20-member committee evaluated the available evidence based on a structured literature review and classification of relevant articles published between 1985 and October 2007. Preconceptional folic acid supplementation is possibly effective in preventing major congenital malformations in the newborns of WWE taking AEDs. There is inadequate evidence to determine if the newborns of WWE taking AEDs have a substantially increased risk of hemorrhagic complications. Primidone and levetiracetam probably transfer into breast milk in amounts that may be clinically important. Valproate, phenobarbital, phenytoin, and carbamazepine probably are not transferred into breast milk in clinically important amounts. Pregnancy probably causes an increase in the clearance and a decrease in the concentration of lamotrigine, phenytoin, and to a lesser extent carbamazepine, and possibly decreases the level of levetiracetam and the active oxcarbazepine metabolite, the monohydroxy derivative. Recommendations: Supplementing women with epilepsy with at least 0.4 mg of folic acid before they become pregnant may be considered (Level C). Monitoring of lamotrigine, carbamazepine, and phenytoin levels during pregnancy should be considered (Level B) and monitoring of levetiracetam and oxcarbazepine (as monohydroxy derivative) levels may be considered (Level C). A paucity of evidence limited the strength of many recommendations.
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