cerebral cortex or infused intravenously. This effect is at least in part due to altered
calcium permeability of the cell membrane, reduction of chloride influx through the
gamma-aminobutyric acid (GABA)-A receptor, and action of estrogen as a glutamate
agonist in the hippocampus. Progesterone decreases cortical excitability, by enhancing
GABA effects, and increases electroshock seizure threshold in experimental models.
Menarche begins with increases in ovarian hormones, the development of cyclic
fluctuations, and an overall marked increase in pituitary luteinizing hormone (LH) and
follicle-stimulating hormone (FSH). These hormones also fluctuate in pregnancy, during
the perimenopausal period, and with the introduction of exogenous hormones (eg, oral
contraceptives, hormone replacement therapy). All of these hormonal alterations can
result in changes in epilepsy and seizure threshold, although this effect has marked
variability among individuals.
Catamenial epilepsy
Catamenial epilepsy is a general term applied to any exacerbation in seizures with the
menstrual cycle. True catamenial epilepsy requires reproducible and consistent increase
or change in character of seizures at the same point in a regular menstrual cycle.
Anovulatory cycles can make the relationship of seizure to hormones difficult to discern.
Perceived rates of catamenial epilepsy tend to be much higher than true catamenial
epilepsy. Although 10-75% of women in one study noted a cyclic variation in seizure
frequency, it was not reported whether this occurred during regular, ovulatory cycles, or
was confirmed by physiologic hormonal level changes.[9] The breadth of the reported
range itself indicates that seizure exacerbations are influenced by multiple factors, rather
than exclusively hormonal changes. The physiologic processes of menstruation and
ovulation can transiently worsen many medical conditions, and it is likely that, for some
women, physical effects that are only secondarily related to hormones will increase
seizures. Nonetheless, between one third and one half of women report increased cyclic
seizures related primarily to hormonal factors.[11]
Herzog et al described 3 patterns of hormonally based catamenial epilepsy.[12]
Significantly higher numbers of seizures were found when estrogen increased faster than
progesterone: perimenstrually (catamenial type 1) and preovulatory (catamenial type 2).
In patients with anovulatory cycles, seizures more commonly occurred in the second half
of the cycle (catamenial type 3) when progesterone was lower than normal due to failure
to develop a corpus luteum.[12]
Management of patients with catamenial exacerbations must begin with a clear definition
of the clinical situation. An accurate diagnosis of epilepsy is necessary, and may indicate
a need for video-electroencephalogram (EEG) monitoring. Paroxysmal events mimicking
epilepsy (ie, nonepileptic events, or "pseudoseizures") may also worsen at cyclic
intervals.
Clear identification of ovulation at regular intervals is helpful in determining whether
there is any specific higher risk time in the menstrual cycle. A scrupulously maintained
calendar listing seizures and menses for several cycles can suggest a cyclic pattern of
seizures. This can be confirmed by physiologic measures including basal body
temperature and serum hormone levels. Other factors that may contribute to poor seizure
control such as sleep deprivation, suboptimal medication for epilepsy type, and simple
noncompliance must be eliminated, if possible.
Optimization of antiepileptic drug (AED) dosing is often helpful, and increasing doses
each cycle for the duration of the expected exacerbation may be the best-tolerated option.
Some AEDs, however, are poorly suited to this strategy, particularly if they exhibit
nonlinear pharmacokinetics or extensive enzyme induction. Temporary use of adjunctive
therapy such as acetazolamide or benzodiazepines has anecdotally been advocated but
without prospective supportive evidence.
Management strategies using exogenous hormones have not been consistently successful.
If improved control is incidentally noted with hormonal contraceptives, and pregnancy is
not desired, then longer-acting contraceptive agents, such as Depo-Provera, may be
helpful in seizure control. Persistent menstrual irregularity or other suggestions of
spontaneous anovulatory cycles warrants evaluation by an endocrinologist.
Some researchers have had limited success with progesterone to control true catamenial
epilepsy. Continuous progestational supplements reduced catamenial seizures as they
suppressed cycles,[13] and intermittent progesterone suppositories reduced seizures up to
60%, but half of women on these supplements discontinued treatment due to intolerable
side effects.[14] Adverse effects of synthetic and, to a lesser degree, natural progesterones
include sedation, breast tenderness, depression, increased appetite and weight, and
breakthrough menstrual bleeding. In addition, unopposed progesterone has been
implicated in breast cancer, lipid elevations, and hypercoagulability.[15]
Synthesized novel neurosteroids devoid of hormonal side effects (eg, ganaxolone) have
proven promising but also have prohibitive production costs.[16] Overall, natural
progesterones are better tolerated than synthetic agents, but no evidence substantiates the
efficacy of one agent over the other. Further evidence is needed before any hormonal
agent can be recommended for epilepsy management.
Infertility
Overall, women with epilepsy have lowered fertility compared with women in the
general population.[17] Menstrual disorders are estimated to occur in 1 of 3 women with
epilepsy compared with 1 in 7 in the general population.[18] Oligomenorrhea and abnormal
cycle length (< 23 d or >35 d) occur in up to one third of women with epilepsy. At least
one third of menstrual cycles in women with generalized seizures are anovulatory.[19]
Seizures themselves can result in abnormal reproductive hormone variations. Fluctuations
of luteinizing hormone (LH) and pulsatile release of prolactin and sex steroids have been
observed in temporal relation to some seizures.[20] Although some clinicians use a failure
of elevation of serum prolactin level to diagnose nonepileptic events, the American
Academy of Neurology guideline for the use of serum prolactin level documents that this
is not a consistent enough relationship for diagnostic purposes.[21]
The type of epilepsy may also have a significant influence on reproductive hormones and
function. The reciprocal feedback of the temporal and limbic structures with the
hypothalamus can alter secretion of hypothalamic, pituitary, and gonadal hormones. A
structural neurologic abnormality of the amygdala or mesial temporal lobe may cause
both epilepsy and altered hypothalamic hormonal function. Different hypothalamic
gonadotropins responses result from right versus left temporal lobe seizure activity have
been observed.[22]
Observed lower birth rates in women with epilepsy may be due to social inhibitions.
There may be fear of rejection due to seizures during social occasions, development of
relationships, or intercourse. Some studies have indicated that reproduction rates in
married women with epilepsy are not less than those in married women without epilepsy,
although marriage rates are lower and occur at older ages, when fertility may be less for
other reasons.[23] Others have reported that the reduced fertility rate in married women
with epilepsy is only partly explained by these social factors.[17]
Fear of effects of epilepsy or its treatments on a pregnancy may cause women with
epilepsy to seek contraception, abortions, and even sterilization. In recent years, attention
has been focused on historical state sterilization programs for reproductive age women
with mental handicaps, often including those with epilepsy. Such programs are no longer
enforced, although caregivers of women with epilepsy not infrequently request healthcare
providers to perform surgical sterilization or prescribe long-acting contraception. The
American College of Obstetrics and Gynecology (ACOG) has issued a committee
opinion that mental capacity in itself does not justify sterilization, and that any such plan
must be agreed upon with the appropriate caregivers or agents to preserve the patient's
best interests and, to the maximum extent possible, her autonomy.[24]
For more information on this topic, see Infertility.
Sexual dysfunction
Studies indicate up to one third of women with epilepsy self-report sexual dysfunction.[32]
Just as with infertility, it is likely that multiple social and psychologic reasons underlie
this difference. However, some studies indicate that physiologic factors may play a
significant part. An outpatient study noting difficulty with sexual arousal also found
increased occurrence of vaginal dryness and vaginismus.[32] Another study of physiologic
responses noted decreased vaginal blood flow in women with epilepsy compared with
controls.[33]
Treatment of sexual dysfunction must begin with identification of potential psychologic
factors and appropriate counseling or therapy. Physiologic factors should be identified by
an overall review of health and medications. Simplifying polytherapy to monotherapy or
changing an antiepileptic drug to another better-tolerated agent may be considered.
failures in their patients taking AEDs, but only 4% of neurologists and none of the
obstetricians knew the effects of the 6 most common AEDs on oral contraceptives.[36]
Subdermal levonorgestrel implants (Norplant) have also been shown to have reduced
efficacy in women taking enzyme-inducing AEDs.[37] It is likely that other forms of
hormonal contraception (eg, transdermal patch, Depo-Provera) have potentially reduced
efficacy with these drugs, but no literature supports this conjecture. Although the
American Academy of Neurology Practice Parameter for Management Issues for Women
with Epilepsy stated that increasing the estrogenic component of a contraceptive to at
least 50 mcg will improve contraceptive effect, reproductive specialists disagreed,
arguing that the progestin component has a greater effect in preventing ovulation than the
estrogen component.[38] The literature is not consistent in identifying whether the estrogen
or progestin component is clinically more important in pregnancy prevention.[39]
Whether gonadotropin-releasing hormone (GnRH) analogues and other nonovarian
hormones have altered efficacy in epilepsy is unknown. Adjunctive contraception either
by nonhormonal methods or changing antiepileptic therapy to those without hormonal
interactions is a reasonable consideration. No impairment of hormonal contraception has
been reported with ethosuximide, felbamate, gabapentin, levetiracetam, pregabalin,
tiagabine, valproate, or zonisamide.[39] No adverse effect on contraception has been
reported with implantable stimulators for epilepsy or with epilepsy surgery.
Reproductive Issues
Reproductive counseling and folic acid are discussed in this section.
Reproductive counseling
All physicians treating women of reproductive potential must discuss pregnancy with
these patients, and when appropriate, their caregivers. There are few medical conditions
in which pregnancy and childbirth do not complicate management. It is always preferable
to discuss epilepsy management options before conception occurs. A candid discussion of
whether or when pregnancy is desired can help determine the timing of diagnostic tests
and medication changes. The Physician's Discussion Checklist for Women with Epilepsy
contains helpful clinical printable practice aids for physicians of women with epilepsy in
their reproductive years.
There are several ways to optimize therapy before consideration of pregnancy. First,
establish whether the female patient requires antiepileptic therapy at all. Review of
history and electroencephalographic (EEG) results may show that the diagnosis is
unsubstantiated (due to lack of historical documentation or inadequate diagnostic testing)
or that the patient is now seizure free for several years. Second, determine if the current
regimen is appropriate for the epilepsy syndrome or seizure type. If drug choice or dosing
is in question, referral to a comprehensive epilepsy center for a second opinion should be
considered. Third, advocate simplification of treatment to monotherapy, or consider
whether epilepsy surgery may be beneficial. EEGs and video-EEGs, scrupulously
Folic acid
Low serum or red blood cell folate levels have been associated with spontaneous abortion
and developmental anomalies in animals and humans, especially neural tube defects
(NTDs).[40, 41] All women of reproductive age, with or without epilepsy, should be on
folate supplementation, even if pregnancy is not planned in the near future. Blood folate
levels decline in women taking older antiepileptic drugs (AEDs). Although folate levels
have not been shown to decrease in all AEDs, folate supplementation is recommended for
all patients with epilepsy, both men and women. In addition, a reported association with
the MTHFR (a polymorphism of methylenetetrahydrofolate reductase) genotype appears
to confer increased susceptibility to development of malformations when AED exposure
occurs in utero.[42]
The American Academy of Neurology (AAN) updated their guidelines addressing the
care of women with epilepsy in 2009.[43, 44] recommends use of folate supplementation at a
dosage of no less than 0.4 mg daily for all reproductive-aged women before conception
and throughout gestation.[43] Prenatal multivitamins contain at least 0.8 mg of folate, and
individual folate tablets are available as 1-mg doses. Folate in doses up to 15 mg daily is
safe and usually well-tolerated.[28] Higher doses likely offer more protection against
development of NTDs, and most epileptologists recommend between 1 and 5 mg daily.
The AAN states women who have personal or family history of NTD births should
receive 4 mg daily.[45] This is supported by the recommendation of the American College
of Obstetrics and Gynecology that women with "health risks, including epilepsy" should
take 5 mg folate from 3 months before conception through 3 months after conception,
followed by 0.4-1.0 mg folate daily through lactation.[46] Note, however, that
supplementation with as little as 1 mg daily can be expected to decrease phenytoin serum
concentration and anticonvulsant effect,[47] thus, increased dosing of this AED may be
necessary to maintain therapeutic effect.
Seizures in pregnancy
Approximately 35% of women with epilepsy have more seizures during pregnancy, 10%
have fewer, and 55% remain the same.[48] Multiple factors may contribute to worsening
seizures. Physical and emotional stress may alter AED compliance, gastrointestinal
absorption, or sleep habits. Compliance likely decreases during pregnancy more
commonly than women report to their doctors, in part due to concern for the effects of
Teratogenicity of AEDs
Although genetic influences, medical conditions, or lack of prenatal care may contribute
to an increased incidence of fetal malformations in epilepsy, several lines of evidence
suggest that AEDs play a primary role. Rates of fetal malformations are higher in
pregnant women treated with AEDs than in those who are not treated with these agents.
Higher AED levels have been associated with higher rates of malformation, and
polytherapy carries a higher teratogenic risk than monotherapy. These findings suggest
that optimal therapy for a pregnant woman with epilepsy should be to maintain
monotherapy in the lowest effective dose. This must be balanced by the need to control
convulsive seizures and other types that risk physical injury to the fetus or the infant.
Monitored fetal distress has been documented in labor with both generalized and partial
maternal seizures.[50, 51] Avoiding situations that precipitate seizures (eg, changing AED,
sleep deprivation, noncompliance) is of paramount importance. Thus, it is also
recommended that AED changes should be completed at least 6 months before
conception, and that AEDs should not be changed during pregnancy solely for the
purpose of reducing teratogenicity. Both the American Academy of Neurology (AAN)
and American College of Obstetrics and Gynecology (ACOG) recommend choosing the
AED most appropriate for the patients seizure type, with a goal of monotherapy.
The mechanisms underlying teratogenicity of AEDs remain unclear. Some AEDs may
result in malformations by generating free radical (arene oxide) metabolites that bind
with RNA and alter DNA synthesis and organogenesis.[52] Susceptibility to such oxidative
damage may be genetically determined.[53] Impaired folate absorption or conversion to
tetrahydrofolate (THF) (the biologically active form) is implicated in development of
neural tube defects.
Studies have amply documented the protective effect of folic acid in pregnancies not
exposed to AEDs. However, no conclusive evidence suggests that folic acid
supplementation lowers the risk of neural tube defect in women on AEDs for epilepsy.
Specific recommendations for the amount of folate are variable, but the general
consensus among epileptologists is that 1-4 mg daily is appropriate for pregnant women
with epilepsy. Although one study found that lower serum levels of folic acid predicted a
higher risk of malformation in children of mothers who were treated for AED,[54] data
from the North American Antiepileptic Pregnancy Registry indicated that malformation
rates in women treated with valproate or lamotrigine are not lower even with folate
supplementation of 3 mg daily.[55, 56]
Malformation rates in the general population range from 2% to 3% in most sources, and
4% to 6% in women with epilepsy taking AEDs.[57] Minor malformations such as facial
dysmorphisms and digital hypoplasia occur in 6-20% of pregnancies with in utero
exposure to AEDs.[58] These malformations are often subtle and disappear with maturation
through the first year of life. Evidence for medication-specific syndromes (eg, fetal
hydantoin syndrome, fetal barbiturate syndrome) is lacking; because similar minor
anomalies have been reported with in utero exposure to multiple different AEDs, fetal
anticonvulsant syndrome is a more accurate term.
The most common major malformation in infants of mothers with epilepsy is orofacial
clefting, occurring in 13.8 infants per 1000 births compared with 1.5 infants per 1000
births in the general population.[59] Neural tube defects have been previously reported in
0.5-1% of carbamazepine exposures[60] and 1-2% of valproate exposures.[61] These data,
however, were confounded by polypharmacy; retrospective reporting, which did not
include aborted pregnancies; and predated widespread folic acid supplementation.
Questions about the validity of these numbers and a need to obtain prospective data on
pregnancy exposures to the growing number of AEDs since 1993 prompted the
development of multiple pregnancy registries.
Although additional research is needed to confirm findings, the Neurodevelopmental
Effects of Antiepileptic Drugs study found that children exposed in utero to higher
dosages of valproate and carbamazepine have lower motor and adaptive functioning.[62]
Children exposed in utero to valproate may also be at increased risk for attentiondeficit/hyperactivity disorder.
For more information on this topic, see Antiepileptic Drugs.
Pregnancy registries
Multiple prospective registries track outcomes of AED-exposed pregnancies worldwide.
Although the enrollment methodologies and lengths of follow-up vary, significant
findings have emerged. The North American AED Pregnancy Registry (NAAPR)
identified at least a doubled risk of major malformations with either phenobarbital[63] or
valproate monotherapy.[55]
Phenobarbital was the first AED in monotherapy identified by the NAAPR with a
documented increased risk of major malformations (6.5% compared with background
rate of 1.62%, or a relative risk of 4.2).[63] The United Kingdom Epilepsy and Pregnancy
Register and the Australian Registry of Antiepileptic Drugs in Pregnancy also found
increased risk of major defects with valproate monotherapy.[39] The number of
pregnancies exposed to phenobarbital monotherapy was too small in other registries to
establish the risk found by the NAAPR. Dose-related teratogenicity has been reported in
the European epilepsy and pregnancy registry (EURAP).[64]
The US Food and Drug Administration (FDA) reported to healthcare providers
preliminary evidence in the NAAPR of an increased rate of cleft lip and cleft palate with
lamotrigine exposure in the first 3 months of pregnancy, but this has not been confirmed
by other registries.[56] Current updated information from the NAAPR can be found at
Antiepileptic Drug Pregnancy Registry.
Although pregnancy registries have confirmed concerns regarding the teratogenicity of
specific AEDs, evidence that epilepsy itself confers an increased risk of malformation is
conflicting, except in cases of inherited syndromes and congenital neurologic lesions in
the mother.[65] It is likely that an interdependent combination of AEDs, underlying
epilepsy diagnosis, nutritional issues, and genetic factors contribute to the overall risk of
increased malformations in infants born to mothers with epilepsy. Lindhout et al found
that, contrary to data from older studies, seizures especially during the first trimester are
associated with a marked increased risk of malformations.[66] Whether the rate of
malformation is increased, independent of AEDs, in well-controlled maternal epilepsy is
unknown.
Breastfeeding
AEDs cross into maternal milk to varying extents. Highly protein-bound AEDs have low
concentrations in breast milk, whereas AEDs that have no protein binding are present in
similar concentrations between milk and serum. As long as AEDs are not changed after
delivery, this is simply an enteral continuation of the same parenteral AED exposed to
while in utero.
Breastfeeding is strongly recommended to promote maternal-infant bonding and to
reduce the risk of infectious and immune disorders later in life. The mother must be
aware that the infant may not like the flavor imparted to milk at certain times after taking
her AED, and she should be advised to consider timing feeding or pumping milk to
optimize nursing.
Most AEDs have an extensive transplacental transfer rates and low to moderate excretion
into breast milk. Levetiracetam, however, can have higher excretion into breast milk.[67]
The benefits of breastfeeding likely outweigh the risk of most AED exposure in the
neonate; however, some drugs with age-specific side effects may warrant consideration.
For example, whether lamotrigine has the same high risk of rash with exposure from
breast milk or whether valproate has the same increased risk of hepatotoxicity is
unknown. Presumably, because the infant tolerated the drug in utero, the risk for these
age-specific toxicities is likely to be low.
The mother must be advised that her metabolism and clearance of AEDs will remain
higher while she is lactating. Her levels may increase when she stops breastfeeding,
requiring a dose adjustment.
Menopause
Menopause and seizures and bone health are discussed in this section.
Bone health
Antiepileptic drugs (AEDs) may decrease bone mineral density (BMD) and result in
osteopenia, osteoporosis, and fractures. Although these risks are present in both men and
women treated with AEDs for more than several years, postmenopausal women are
especially susceptible due to the added risk factor of hormonal depletion. A prospective
study of women older than 65 years found that those taking AEDs were twice as likely to
develop hip fractures.[70] Patients with epilepsy have been reported to suffer osteopenic
fractures due to falls and tonic events associated with convulsions.
Several mechanisms have been proposed for bone loss with AED treatment. Cytochrome
p-450 enzyme-inducing agents (phenytoin, phenobarbital, primidone, carbamazepine)
increase vitamin-D metabolism, leading to decreased calcium absorption in the intestine,
and increased parathyroid hormone, causing bone calcium stores to be mobilized. Reports
suggest that nonenzyme-inducing AEDs, such as valproate, may also result in decreased
bone mineral density, although to a lesser degree.[71] Little information is available about
the effects of agents approved since 1993.
Testing for bone loss can be performed by using chemical or structural methods.
Measuring biochemical serum levels for low calcium and phosphate, reduced vitamin D
and its metabolites, and elevated serum alkaline phosphatase (ALP) and parathyroid
hormone (PTH) levels may provide insight into risks for bone loss. However, such testing
should not be used as the sole measure of bone health, because structural integrity and
fracture resistance may be impaired even when laboratory tests are in the normal range.
Markers of bone formation and resorption can also be monitored. Severity of these
abnormalities can correlate with duration of AED exposure as well as the number and
types of AEDs used.[72]
Bone mineral density testing is the preferred method to quantify risk of osteoporosis.
Dual energy x-ray absorptiometry (DXA or DEXA) can be performed centrally (hip,
spine) or peripherally (finger, wrist, heel, tibia) and are not always directly comparable,
due to the different normal composition of these bones. The test defines a T-score with
zero or greater as normal bone mass, and negative numbers define osteopenia (T score
between -1 and -2.5) or osteoporosis (T <-2.5). Testing bone structure by bone mineral
density should be conducted in all patients taking AEDs longer than 5 years and repeated
at biannual intervals to assess adequacy of therapy.[73]
Therapy to prevent bone loss should begin well before menopause and is a consideration
for any patient (male or female) treated with AEDs. Calcium supplements are most
helpful when used in conjunction with vitamin C (which promotes absorption of calcium)
and vitamin D. The recommended daily allowance of calcium varies from 1000 to 1500
mg in adults, and increased doses are suggested for those with evidence or risk of bone
loss. The recommended daily intake of vitamin D is 400-800 IU, but doses up to 15,000
IU may be necessary in patients with evidence of bone loss.[74] Judicious sunlight
exposure to the skin helps provide vitamin D for calcium metabolism. Weight-bearing
exercise (even walking) also significantly reduces the risk of bone loss in the general
population. Pharmacologic intervention with bisphosphonates or other agents is
recommended for T scores of -2 or less. Such therapy should usually be managed by an
internist or endocrinologist.
NEW TOPIC
Author: Aaron B Caughey, MD, PhD, MPH; Chief Editor: Thomas Chih Cheng
Peng, MD
Overview
Approximately 1 million women of childbearing age in the United States have seizure
disorders. Of these women, approximately 20,000 give birth each year. Concerns during
these pregnancies include the risk of fetal malformation, miscarriage, perinatal death, and
increased seizure frequency.[1]
In women who are pregnant, the volume of distribution and the hepatic metabolism of
AEDs are increased. This, along with decreased compliance with AEDs because of
concerns about their effects on the fetus, leads to an increase in seizure frequency, which
is observed in as many as 17-33% of pregnancies.
The use of antiepileptic drugs (AEDs) is associated with a greater baseline risk of fetal
malformations during pregnancy. When treating pregnant women who have epilepsy, the
risks of increased seizure frequency versus the risks of AED use must be weighed
carefully.
A population-based study conducted in Norway found that pregnant women with epilepsy
had a lower risk of complications but an increased risk of induction, cesarean delivery,
and postpartum hemorrhage.[2] However, whether this is a result of AEDs or severe
epilepsy is unclear.
Go to Women's Health and Epilepsy for complete information on this topic.
Management of women with epilepsy upon labor and delivery includes the following:
Administer a bolus of lorazepam (0.1 mg/kg, ie, 5-10 mg) at a rate of no more
than 2 mg/min
Load phenytoin (20 mg/kg, ie, 1-2 g) at a rate of no more than 50 mg/min, with
cardiac monitoring.
If this is not successful, load phenobarbital (20 mg/kg, ie, 1-2 g) at a rate of no
more than 100 mg/min.
Check laboratory findings, including electrolytes, AED levels, glucose, and
toxicology screen.
If fetal testing results are nonreassuring, move to emergent delivery
X
X
defects
Intrauterine X
growth
restriction
Microcephaly
X
Low IQ
X
Distal digital X
X
X
hypoplasia
Low-set ears X
X
Epicanthal
X
X
X
X
fold
Short nose
X
X
X
X
Long
X
philtrum
Lip
X
X
X
X
abnormalities
Hyperteloris X
X
m
Development
X
X
al delay
Trimethadion
e
X
X
X
X
Other
Ptosis
Ptosis
Hirsute
forehead
Hypoplastic
nails
Cardiac
anomalies
Older evidence indicated that women with epilepsy have an increased risk of fetal
malformations, even without AED use. However, a systematic review found no
statistically different rate of major fetal malformations among patients with epilepsy who
were on no medications compared with normal controls.[3]
While some studies suggest that monotherapy does not increase the baseline risk of fetal
malformations over that in patients not on AEDs, most of the literature suggests that firsttrimester use of even a single AED is associated with a 2- to 5-fold increase in major
malformations.
An analysis of data from the EURAP epilepsy and pregnancy registry found that the risk
of major congenital malformations increased with increasing dose in patients receiving
carbamazepine, lamotrigine, valproic acid, or phenobarbital monotherapy.[4]
Data from the North American AED pregnancy registry indicate that older AEDs such as
valproate and phenobarbital are associated with a higher risk of major malformations than
newer AEDS such as levetiracetam and lamotrigine. Compared with a reference
population, topiramate was associated with a higher risk of cleft lip.[5]
Furthermore, multiple studies present evidence indicating an increase in fetal
malformations with AED polytherapy.
Specific increases in congenital abnormalities observed in infants born to mothers with
epilepsy include a 4-fold increase in cleft lip and palate and a 3- to 4-fold increase in
cardiac anomalies. An increase in the rate of neural tube defects is also observed in the
offspring of patients with epilepsy who are using carbamazepine or valproic acid. Longterm studies on neurodevelopment show higher rates of abnormal electroencephalogram
(EEG) findings, higher rates of developmentally delayed children, and lower intelligence
quotient (IQ) scores.
Phenytoin
Fetal hydantoin syndrome was first described in 1973 by Loughnan et al.[6] It consists of
an array of anomalies, including craniofacial anomalies, distal digital hypoplasia,
epicanthal folds, hypertelorism, low-set ears, and developmental delay. The early
descriptions of this syndrome were noted in 12 infants, 11 of whom had been exposed to
other AEDs, notably barbiturates.
Of infants born to women who used phenytoin during pregnancy, 10-30% are reported to
exhibit some of the syndromic findings, most commonly distal digital hypoplasia.
However, few infants exposed to monotherapy have the entire constellation of findings.
Valproic acid
A syndrome of specific craniofacial abnormalities and long, thin digits with hyperconvex
nails has been described in infants exposed to valproic acid during pregnancy.
Furthermore, in 1982, an association between valproic acid and neural tube defects was
noted at a rate of 1-2%, 20 times greater than the baseline population.[9]
In studies comparing valproic acid with carbamazepine, valproic acid appeared to be
associated with a higher risk for major congenital malformations, as well as for
developmental delay and decreased verbal intelligence. Further, one study demonstrated a
dose-response effect, with patients taking the highest doses of valproic acid at greatest
risk.[10]
In 2009, Meador et al reported that in utero exposure to valproate, as compared with
other AEDs, was associated with a lower IQ in children. The study took place over 5
years in 25 epilepsy centers in the United States and the United Kingdom. The design
was a prospective, observational, cohort study of pregnant women with epilepsy who
took a single agent (carbamazepine, lamotrigine, phenytoin, valproate).
The cohort study assessed the neurodevelopmental outcomes of children who were
exposed in utero to several different AEDs. A planned interim analysis conducted when
the children were 3 years of age reported lower mean IQ scores in children with in utero
valproic acid exposure compared with the other AEDs. This association was dose
dependent. The investigators concluded that valproate should not be used as a first-line
agent in women with childbearing potential.[11]
Carbamazepine
In 1989, a syndrome that included craniofacial abnormalities and hypoplastic nails was
described in infants exposed to carbamazepine monotherapy in utero.[12]
In a 1996 cohort study, 6 of 47 infants demonstrated this syndrome.[13] These infants also
had lower IQ scores than did controls.
However, an analysis of 86 patients on carbamazepine monotherapy showed no
difference in IQ scores compared with normal controls.
Carbamazepine is also associated with an increased risk of neural tube defects in as many
as 0.5-1% of births (ie, 10 times the baseline risk).
A cohort study by Jentink et al suggests that carbamazepine monotherapy in the first
trimester produces fetal malformations specific to spina bifida; however, the risk is lower
than for valproic acid.[14]
In addition, carbamazepine is also associated with a risk of cardiac anomalies; thus, for
patients taking this drug, a fetal echocardiogram is recommended at 20-22 weeks'
gestation.
Trimethadione
In 1975, a cluster of findings, including epicanthal folds, low-set ears, microcephaly,
short stature, and irregular teeth, was ascribed to trimethadione.[15]
A review of 57 pregnancies published in 1977 revealed either malformations or fetal loss
87% of the time.[16]
Currently, trimethadione is rarely used in the treatment of epilepsy and should certainly
be discontinued during pregnancy.
However, a large, randomized trial did demonstrate that valproate leads to better seizure
control than do several of these newer AEDs.[17] Thus, the benefits and risks between
congenital anomalies and seizure control need to be considered when preparing women
with epilepsy for pregnancy. The new anticonvulsants generally have a better
pharmokinetic profile and are not metabolized to known teratogens.
All of these anticonvulsants are considered US Food and Drug Administration pregnancy
category C. Of note, they are still known to cross the placenta and into breast milk.
Mechanisms of Teratogenicity
The mechanisms of teratogenicity of the AEDs have not been fully characterized.
Phenobarbital, primidone, and phenytoin act as folate antagonists. Certainly, a folate
deficiency appears to lead to an increase in congenital malformations, particularly neural
tube defects; thus, folate administration prior to conception has been recommended for
prophylaxis.
Because AEDs all have a similar central mechanism to control seizures, a common
pathway that is disrupted during embryogenesis may lead to the similarities in the
syndromes described, and this may be why an additive effect is observed with
polytherapy.
Studies in teratogenesis, particularly fetal hydantoin syndrome, point to a genetic
predilection for the generation of epoxides. These anomalies have been observed at an
increased rate in children whose enzyme activity of epoxide hydrolase is one third less
than the reference range. Anomalies have also been observed in children with low
epoxide hydrolase activity who were exposed to carbamazepine.
Regarding the cognitive and neurodevelopmental differences seen, one interesting study
demonstrated that among rats treated with AEDs to achieve therapeutic levels, apoptosis
of neural tissue occurred. This is consistent with smaller brains demonstrated in animal
studies and may be a causal mechanism in the lower IQs and developmental delay seen in
a minority of these patients.
Valproic acid
Because evidence indicates that high peak plasma levels of valproic acid may be more
teratogenic, this drug should be dosed at 3-4 times per day rather than the standard twiceper-day dosing. However, patients with epilepsy should be counseled that they are still at
a greater risk (ie, 4-6% vs 2-3%) for fetal anomalies than is the baseline population.
Folate
Supplemental folate has been shown to decrease neural tube defects in patients without
epilepsy and to decrease other congenital anomalies in women with epilepsy.[18] Thus, all
women on AEDs, and particularly those using either valproic acid or carbamazepine,
should be advised to take supplemental folate prior to conception.
Testing
Because of the increased risk of anomalies, a level II fetal survey should be performed at
19-20 weeks' gestation, with careful attention to the face, central nervous system, and
heart. A fetal echocardiogram should also be considered to diagnose potential cardiac
anomalies. Because of the increased risk of neural tube defects, an MSAFP screening test
should be offered.
Whether to perform an amniocentesis routinely for alpha-fetoprotein and
acetylcholinesterase is controversial. Many authors recommend it in the setting of a
family history of neural tube defects or with the use of valproic acid or carbamazepine,
because the sensitivity of amniocentesis is higher than either MSAFP screening tests or
ultrasonography for detecting neural tube defects.
Seizure Frequency
Generalized tonic-clonic seizures during pregnancy can lead to increased maternal
trauma. If the maternal trauma involves the abdomen, a theoretical risk of abruption
exists, possibly leading to fetal hypoxia or death. Furthermore, the risk of maternal
aspiration can lead to maternal hypoxia, which can also lead to fetal hypoxia.
Evidence indicates seizure frequency increases during 17-33% of pregnancies. Several
possible etiologies have been proposed for this occurrence. Increased renal and hepatic
metabolism of AEDs, increased volume of distribution, and changes in serum-binding
proteins all impact circulating levels of AEDs. The increased stress, hormonal changes,
and decreased sleep during pregnancy likely lower the seizure threshold and have been
shown to increase seizure frequency in patients who are not pregnant. Finally, many
women may have decreased compliance with taking AEDs because of concerns regarding
the effects on their fetus.
Increased levels of circulating estrogen during pregnancy increase the function of the P450 enzymes, which leads to more rapid hepatic metabolism of the AEDs. Also, renal
function increases during pregnancy, with a 50% rise in creatinine clearance, which
impacts the metabolism of carbamazepine, primidone, and benzodiazepines. The increase
in total blood volume and a concomitant rise in the volume of distribution also lead to
decreased levels of circulating AEDs. In contrast, the decrease in albumin and circulating
plasma proteins likely increases the free component of the AEDs in serum.
The increased levels of estrogen and progesterone may have a direct impact on seizure
activity during pregnancy. Estrogen has been shown to be epileptogenic, decreasing the
seizure threshold. Thus, the rising estrogen levels in pregnancy, which peak in the third
trimester, may have some impact on the observed increase in seizure frequency.
Conversely, progesterone seems to have an antiepileptic effect, and women with seizure
disorders have been observed to have fewer seizures during the luteal phase of the
menstrual cycle.
Rarely, some patients experience their first seizure during pregnancy. This can be a result
of true gestational epilepsy, a rare syndrome of seizures occurring only during pregnancy.
Patients with this syndrome have a variable presentation, with single or multiple seizures
occurring in 1 or more of their pregnancies. The seizures can also be a manifestation of
epilepsy that may extend beyond the patients pregnancy.
Workup
The workup of these patients should involve a neurologic examination, consultation with
a neurologist, a complete blood count (CBC), a chemistry panel (particularly for
electrolytes), head magnetic resonance imaging (MRI) versus computed tomography
(CT) scans, and electroencephalographic examination.
Differentials
The differential diagnosis should include eclampsia and any possible etiology considered
in the nonpregnant patient, including stroke, electrolyte abnormalities, tumor, trauma,
drugs/withdrawal, and epilepsy.
Status epilepticus
Rarely, a patient has intractable seizures upon labor and delivery. When these last longer
than 30 minutes with either (1) a continuous seizure or (2) a lack of full recovery between
seizures, the patient is considered to be in status epilepticus. Assuming that preeclampsia
and eclampsia have been excluded, the protocol for managing status epilepticus is similar
to the management of any seizure, ie, using benzodiazepines, phenytoin, and, rarely,
phenobarbital.
During this situation, the fetus must be monitored. In the setting of nonreassuring fetal
testing results, establish an airway and attempt intrauterine resuscitation. If the seizure is
not treated easily and the fetal testing results continue to be nonreassuring for longer than
Conclusion
Pregnancy in patients with seizure disorders can be complicated by a variety of maternal
and fetal issues. Patients can experience higher rates of seizures because of the lower
serum plasma levels of their AEDs. The fetus is likely to be at increased risk for
congenital abnormalities, most notably facial clefts, cardiac anomalies, and neural tube
defects.
Long-term outcomes show that children of patients with seizure disorders may have
lower IQs and higher rates of developmental delay. Syndromes related to several of the
AEDs and to specific abnormalities observed in patients with seizure disorders are not
known to affect rates of chromosomal abnormalities.
Women with epilepsy should be treated during pregnancy by a team of providers,
including a perinatologist and a neurologist, that can focus on balancing the risks of
seizures versus the administration of AEDs. Preconceptual