Epilepsy in Pregnancy

Berghella
SEIZURES
KEY POINTS
• Epilepsy is a chronic neurological condition characterized by recurrent unprovoked
seizures. The most important diagnostic tool is the history.
• Approximately 0.3% to 0.5% of all pregnancies are among women with epilepsy.
• For the majority of the patients, seizure frequency remains unchanged during pregnancy.
Status epilepticus is rare during pregnancy.
• Fetal loss, perinatal death, congenital anomalies (4%– 8% or about twice the baseline
risk), low birth weight, prematurity, induction, developmental delay, and childhood
epilepsy have been reported in the past to be more frequent, but more recent data
do not con rm an increase in these complications.
• Supplemental folic acid (0.4 up to 4 mg daily, usually 2–4 mg) may be given to all women
of childbearing age taking antiepileptic drugs (AEDs) prior to conception and
continued during pregnancy. There is insuf - cient published information to address
the dosing of folic acid.
• Counsel women with seizures or epilepsy about the risk of AED-associated teratogenicity
and neurodevelopmental delay, folic acid supplementation, possible changes in
seizure frequency during pregnancy, importance of medication compliance and
AED level monitoring, inheritance risks for seizures, and breast-feeding.
Encourage enrollment in a pregnancy registry.
• In general, the best choice for therapy is the AED that best controls the seizures.
Monotherapy at the lowest possible dose of the AED most ef cient in controlling
seizures should be the goal. All treatment decisions involve a discussion of bene ts and
harms of treatment options.
• Carbamazepine, phenobarbital, primidone, phenytoin, valproate, and topiramate are

FDA category D drugs and should be avoided if possible.
• Optimize AED therapy and complete AED changes if possible at least six months before
planned conception.
• Seizure freedom for at least nine months prior to pregnancy is probably associated with
a high likelihood of remaining seizure-free during pregnancy.
• Stopping or changing an AED during pregnancy for the sole purpose of reducing
teratogenicity is not advised.
• Prenatal testing should include rst-trimester ultrasound, alpha-fetoprotein (AFP) levels,
anatomy, and echocardiographic ultrasounds and, if needed, amniocentesis for
amniotic uid AFP and acetylcholinesterase.
• As pregnancy progresses, both total and nonprotein- bound plasma concentrations of

some AEDs may decline.
• Monitor AED levels through the eighth postpartum week.
• There is insuf cient evidence to support or refute a bene t of prenatal vitamin K

supplementation for reducing the risk of hemorrhagic complications in the newborns of
women with epilepsy.
• There is possibly a substantial increased risk of preterm birth for women with epilepsy who
smoke.
• Encourage breast-feeding and monitor for sedation or feeding dif culties, which can be caused
by certain AEDs, usually those with low protein binding.
• Emphasize that >90% of women with epilepsy have successful pregnancies and deliver
healthy babies.
BACKGROUND
Recommendations and guidelines presented in this chapter are in large part based on the updated
three companion Practice Parameters of the Quality Standards Subcommittee and Therapeutics
and Technology Assessment Subcommittee of the American Academy of Neurology, American
Epilepsy Society, and the updated Epilepsy Quality Measurement Set [1–4].
DIAGNOSES/DEFINITIONS
Seizures result from an abnormal paroxysmal discharge of a group of cerebral neurons. Epilepsy
is a chronic neurological condition. Epilepsy is de ned as at least two unprovoked (or re ex)
seizures occurring greater than 24 hours apart or one unprovoked (or re ex) seizure and a
probability of further seizures similar to the general recurrence risk after two unprovoked
seizures, occurring over the next 10 years [5]. The most important diagnostic tool is the his-
tory. The examination is very often normal unless the patient has a structural brain lesion. The
history should include the following information:
• The presence or absence of an aura, which is a recurrent stereotypic abnormal sensation or
experience. The aura is a simple partial seizure or focal seizure without impairment of
consciousness or awareness according to the newly proposed classi cation of seizures and
epilepsies [6].
• Seizure description by an eyewitness, including duration. • Postictal phase, description, and

duration.• Exacerbating factors.• Birth history, especially when the seizure onset is in the
neonatal period or early childhood.• History of febrile convulsions, central nervous system
infections, head trauma with loss of consciousness or
known structural lesion in the brain. • Family history.
168 MATERNAL-FETAL EVIDENCE BASED GUIDELINES
Ancillary tests include EEG, laboratory tests as indicated by the history, and imaging of the
brain. MRI of the head is more sensitive than CT scan for detecting subtle lesions. EEG poses
no risk to the fetus, so workup for diagnosis should proceed in pregnancy just as in nonpregnant
adults.
SYMPTOMS
In partial onset or focal seizures, some patients may experience a subjective feeling, called an
aura. The particular site of the brain affected determines usually the symptomatology and/or the
clinical expression of the seizure.
EPIDEMIOLOGY/INCIDENCE
Epilepsy occurs in 0.5% to 0.8% of the general population, with 5% of people reporting a seizure
at some time in their life. Approximately one in 26 people will develop epilepsy at some point in
their lives [7]. The prevalence of epilepsy in the United States indicates that approximately one
half million women with epilepsy are of childbearing age. Approxi- mately 0.3% to 0.5% of
all pregnancies are among women with epilepsy [8].
ETIOLOGY/BASIC PATHOPHYSIOLOGY
Paroxysmal discharges of neurons occur when the threshold for ring of neuronal membranes is
reduced. The pathophysiology of epileptic disorders is not very well understood. Structural
abnormalities of neuronal transmitter receptors, channelopathies, excessive excitatory activity,
cortical remod- eling, and loss of inhibitory neuronal activity have all been implicated as
possible mechanisms.
CLASSIFICATION
The International League Against Epilepsy (ILAE) proposed a new classi cation for seizures and
epilepsies in 2010 [6]. Depending on their onset, seizures are classi ed as focal, generalized, or
unknown. Focal seizures can be further subdivided into seizures with or without impairment of
consciousness also known as simple partial or complex partial seizures (CPS). When
awareness is preserved, the patient may either experience focal motor manifestations or
experience a subjective feeling, called an aura. The prototype for generalized seizures is the
generalized tonic clonic (GTC) seizure.
Auras can be olfactory, gustatory, sensory, auditory, visual, vertiginous sensations, or psychic
experiences (such as “deja vu”). Focal seizures with impairment of consciousness can evolve
into bilateral convulsive seizure (also known as secondarily generalized seizure).
RISK FACTORS/ASSOCIATIONS
Risk factors for seizures are numerous and could include malformations of cortical development,
head trauma, central nervous system infections, family history, complicated febrile convulsions,
and possibly history of dif cult birth (anoxia or trauma) or complicated (fetal infections and/or
preterm birth) pregnancy.
COMPLICATIONS
Epileptic women of childbearing age should be informed of the risks associated with
antiepileptic drug (AED) use prior to
conception [3] and that seizures may be harmful to mother and fetus [4]. A recently published
retrospective cohort study evaluated the effect of pregnancy planning in women with epilepsy
on seizure control during pregnancy and on maternal and neonatal outcomes. Planned
pregnancies had a signi cantly greater portion of patients receiving AED monotherapy and of not
using valproic acid. This group also had a lower frequency of seizures during pregnancy as well
as a signi cantly lower likelihood of altering their AED regimen during pregnancy [9].
Maternal Complications
The American Academy of Neurology (AAN) reviewed the scienti c literature and published
practice parameters in 2009, which stated that probably no substantially increased risk exists of
cesarean delivery, late pregnancy bleeding, or preterm labor and delivery in women with
epilepsy who are taking antiepileptic drugs [1–3]. There is insuf cient evidence to support or
refute an increased risk of preeclampsia, gestational hypertension, spontaneous abortion, a
change in seizure frequency or an increased risk of status epilepticus in pregnant women with
epilepsy. Only class IV studies could be found on this subject. On the basis of class II studies,
seizure freedom for at least nine months prior to pregnancy is probably associated with a high
likelihood (84%–92%) of remaining seizure-free during pregnancy. Women can injure
themselves during convulsive seizures.
Fetal Complications
GTC seizures increase the risk of hypoxia and acidosis as well as injury from blunt trauma.
Generalized seizures but not partial seizures occurring during labor can affect fetal heart rate.
According to a recent study, women with epilepsy on AED therapy and experiencing more than
one GTC seizure during pregnancy had an overall ve times higher preterm birth risk, a shorter
gestational age, and a reduced birth weight in boys [10]. Fetal loss (1.3%–14%) and perinatal
death (1.3%–7.8%), congenital malformation anomalies (4%–8%, or about twice the baseline
risk), low birth weight (7%–10%), preterm birth (4%–11%), induction, developmental delay,
and childhood epilepsy can be associated with in utero exposure to AEDs. There is insuf cient
evidence to determine whether the risk of neonatal hemorrhagic complications in the newborns
of women with epilepsy taking AEDs is substantially increased. Evidence is inadequate to
determine whether prenatal vitamin K in women with epilepsy reduces the risk of hemor-
rhagic complications in the newborns.
Congenital malformations are more common among offspring of women on AEDs (5%)
than among offspring of untreated patients (3%). Major congenital malformations include
neural tube defects (NTDs), congenital heart disease, cleft lip/palate, and urogenital
defects. Minor congenital malformations include coarse hair, epicanthal folds, small nail beds,
and skin tags. Most common congenital malformations, which differ for different AEDs, are
cardiac, neural tube, craniofacial, and involving the ngers.
Epilepsy and pregnancy registries have been operational for approximately 15 years and
were developed in order to better understand the risks of birth defects associated with
AED treatment, and more importantly, to system- atically study the range of birth defects
resulting from use of each AED [11]. Two class I studies, including one from the U.K.
Epilepsy and Pregnancy Registry, revealed that exposure
during the rst trimester to valproic acid monotherapy is associated with a greater risk for major
congenital malformations than carbamazepine monotherapy [12,13]. Valproic acid as part of
polytherapy was associated with greater risk than polytherapy without valproic acid [12].
Data from the North American Antiepileptic Drug (NAAED) Pregnancy Registry indicate that
the rate of major malformations is 9% with valproate [14], 6% with phenobarbital, 2%
with lamotrigine, 2.2% with levetiracetam, 4.5% with topiramate, and 3.1% with
carbamazepine. Valproic acid is associated with neural tube defects, oral clefts, hypospadias,
poor cognitive outcome, and cardiac malformations. Exposure to phenytoin, carbamazepine,
topiramte, and lamotrigine was associated with oral clefts. Avoidance of phenobarbital may
reduce the risk of cardiac malformations.
MANAGEMENTPrinciplesEffect of pregnancy on disease: Increase in hepatic cyto-

chrome P450 enzyme activity and renal clearance causes the
concentration of some AEDs to fall. Decreased protein binding results in higher levels of
unbound biologically active AEDs and may cause toxicity (Table 19.1). On the basis of cur-
rent studies, there is insuf cient evidence to support or refute an increased risk of a change in
seizure frequency or status epilepticus during pregnancy.
Preconception Counseling
Also include in rst prenatal visit the following:
a. Conception should be deferred until seizures are well controlled on a minimum dose of
medication.
b.Monotherapy is preferable. Good compliance with AEDs is essential to avoid any seizures.
c. Inform women with epilepsy that infants exposed in utero to AED have a 4% to 8% risk of
congenital malformation, most notably neural tube defects, cardiac, and craniofacial defects,
compared to 2% to 3% for the general population. Epilepsy pregnancy registries have been
operational for more than 15 years and have collected an
170 MATERNAL-FETAL EVIDENCE BASED GUIDELINES
impressive amount of data. Carbamazepine, phenobarbital, primidone, phenytoin,

valproate, and topiramate are FDA category D drugs and should be avoided if possible at
least in the rst trimester. Recent pregnancy data- bases have suggested that valproate is signi
cantly more teratogenic than carbamazepine, and the combination of valproate with lamotrigine
and valproate with carbamazepine is particularly teratogenic [15]. If valproate is used, high
plasma levels (>70 μg/mL) should be avoided unless necessary to control seizures, and the drug
should be given in divided doses three or four times daily. To date, the most comprehensive
prospective study of cognitive development reported IQ in children exposed to low dose of
valproate comparable to IQ in children exposed to other antiepileptic drugs [16]. Lamotrigine has
been associated with facial clefts; however, the lowest rates of MCMs were seen when
lamotrigine dose was <300 mg/ day [17].
d. Seizure freedom for at least nine months prior to pregnancy is probably associated with a
high likelihood of remaining seizure-free during pregnancy.
e. Consider neurological consultation regarding the possibility of tapering off and stopping
anticonvulsant medications if the patient has been seizure-free for greater than two
years and has a normal EEG. The patient should be observed for six to 12 months off
AED before attempting conception.
f. Preconception folic acid supplementation (usually 2–4 mg) may be considered to reduce the
risk of major congenital malformations.
g. Driving privileges should be suspended for several months after a seizure; the exact length
varies depending on the state [18].
h. Home/work: Avoid baths, take showers instead. Avoid manipulation of heavy machinery or
working at heights [18].
i. Enzyme-inducing AEDs (Table 19.1) enhance the metabolism of oral contraceptives,
therefore decreasing their ef cacy. Pregnancies should be planned.
j. Emphasize that 90% of women with epilepsy have successful pregnancies and deliver
healthy babies [19].
Prenatal Counseling
At the rst prenatal visit and during pregnancy as necessary, counsel women with seizures or
epilepsy regarding all of the above preconception issues. In addition, discuss the following:
• There is a possible change in seizure frequency during pregnancy. A recent prospective study
found, however, that pregnancy does not appear to affect seizure frequency in women
with epilepsy [20].
• Although no AED is speci cally indicated for use in pregnant women, the AED that
renders the patient seizure-free and side effect-free should be the drug of choice
during pregnancy.
• The risk-to-bene t ratio must be considered when select- ing a drug.
• There is a risk of AED-associated teratogenicity and neu- rodevelopment delay.
• Importance of medication compliance and AED level monitoring during pregnancy.

AED levels decline due to enhanced AED hepatic metabolism, changes in
volume distribution, and increase in glomerular ltra- tion rate, which leads to increased renal
clearance and decreased protein binding. Therefore, levels should be measured on highly protein
bound AEDs (Table 19.1).
• In a retrospective population-based study, a tenfold increase in mortality was noted in

pregnancy in women with epilepsy compared to women without epilepsy. Etiology for mortality
was not found, thus leaving many questions answered. Most of these deaths were Sudden
Unexpected Death in Epilepsy (SUDEP) demonstrating the importance of complete seizure
control and a height- ened clinical attention for these pregnancies [21,22].
• Breast-feeding issues (see below).• Inheritance risks for seizures.• Child care issues [23].•
Educate patients about various pregnancy registries
and encourage enrollment in a registry. The goal of any registry is to gather and publish
information on the rate of major malformations in infants whose mothers had taken AEDs during
pregnancy and to determine the safety of seizure medications. The North American Anti-
Epileptic Drug Pregnancy Registry enrolls pregnant women with epilepsy from the United
States and Canada (http://www.aedpregnancyregistry.org). Likewise, every region has its own
pregnancy registry, and newer AED manufacturers have a registry of their own.
Prenatal Care
• Supplemental folic acid (usually 2–4 mg/day) in women with epilepsy before they become
pregnant is generally recommended to reduce the risk of major congenital malformations.
• A rst-trimester ultrasound is indicated for exact dating. • Anatomic ultrasound at 11 to 13

weeks can identify most
severe defects, such as anencephaly.• Prenatal testing for neural tube defects with alpha-
fetoprotein levels at 15 to 18 weeks gestation (up to 21
weeks).• If appropriate, amniocentesis for amniotic uid alpha-
fetoprotein and acetylcholinesterase levels.• Ultrasound at 16 to 20 weeks gestation can assess

anatomic anomalies, such as orofacial clefts, heart defects,
and caudal neural tube defects.• Fetal echocardiogram at about 22 weeks.• An ultrasound for
growth at >32 weeks is not mandatory. • Neonates should receive vitamin K, 1 mg IM at birth.
The bene t of prenatal maternal vitamin K therapy is unknown with no trial available for
assessment.
THERAPY (TABLE 19.1)

• Multidisciplinary communication between the primary care provider, obstetrician, geneticist,
and neurologist/ epileptologist for counseling and management of seizures and epilepsy during
pregnancy is crucial.
• There is no trial that indicates which AED is safest during pregnancy. The best choice is
the AED that best controls the seizures. All the AEDs are FDA category C except for the
following AEDs that are category D: carbamazepine, phenobarbital, primidone, phenytoin,
valproate, and
topiramate (Table 19.1). These six AEDs should therefore be avoided if possible by using a
different therapy beginning in the preconception period. Switching and abruptly stopping of
AEDs are to be avoided.
• Regarding AED therapy, at the beginning of pregnancy it is recommended that the patient is
on monotherapy with the AED of choice for the seizure type, achieving optimal seizure
control at the lowest effective dose.
• Monitoring the serum levels of lamotrigine, carbamazepine, and phenytoin during
pregnancy should be considered, and monitoring of levetiracetam and oxcar-
bazepine (as monohydroxy derivative) levels may be considered. Free levels (serum
or saliva) are available for carbamazepine, valproic acid, phenobarbital, and phe-
nytoin. Avoid high peak levels by spreading out the total daily dose into multiple
smaller doses. Studies provide some evidence supporting active monitoring of AED
levels during pregnancy, particularly of lamotrigine, as changes in lamotrigine levels
were associated with increased seizure frequency [24]. It seems reasonable to
individualize this monitoring for each patient with the aim of maintaining a level
close to preconception level, presumably the one at which the woman with epilepsy
was doing well with seizure control. One study showed that during pregnancy the
clearance of lamotrigine increases with a peak of 94% in the third trimester; hence,
frequent adjustments of the dose are required during pregnancy [19].
• AEDs have effects on sodium, potassium, or calcium channels. They also can affect
neurotransmitters enhancing the inhibitory neurotransmitter, GABA, or inhibiting the
excitatory glutamate.
• AED Pregnancy Registry: Phone number 1-888-233-2334.

http://www.aedpregnancyregistry.org. DELIVERY AED medication should be
continued in labor and in the immediate postpartum period. Women should be
encour- aged to bring their own AEDs to the delivery, and medications should be taken
at their usual times during labor [25]. Consider intravenous formulations of AEDs if these
cannot be taken orally. A recent study found that women with epilepsy on polytherapy
versus monotherapy had an increased risk of cesarean section [26]. There is possibly a
substantial increased risk of preterm birth or women with epilepsy who smoke [27].
POSTPARTUM/BREAST-FEEDING Breast-feeding is not contraindicated.
The greater the protein binding of the AED (Table 19.1), the lower is its concentration
in breast milk. Breast-feeding is not contraindicated in patients on anticonvulsant
medications unless excess neonatal sedation occurs. Monitor newborns or infants for
sedation when breast-feeding mothers with seizures take low-protein- bound AEDs. The
AED concentration pro led in breast milk follows the plasma concentration curve. The
total amount of drug transferred to infants via breast milk is usually much smaller than
the amount transferred via the placenta during pregnancy. However, as drug elimination
mechanisms are not fully developed in early infancy, repeated administration of a drug
via breast milk may lead to accumulation in the infant. Extended release formulations of
AEDs should be
avoided. It appears that there are no adverse effects of AED exposure via breast milk on
cognition and development observed at three years and six years [28].
Valproic acid, phenobarbital, phenytoin, and carbamazepine may be considered as not
transferring into breast milk to as great an extent as, for example, levetiracetam, gabapentin,
lamotrigine, and topiramate.
For most AEDs, the pharmacokinetics in the mother will return to prepregnancy levels
within 10 to 14 days after delivery. Monitor AED levels through the eighth postpartum week
and adjust doses accordingly to avoid toxicity. Sleep deprivation may exacerbate seizures,
and should therefore be avoided. Women with epilepsy should not bathe their child while they
are alone at home and should avoid stair climbing while carrying the baby; a portable changing
pad placed on the oor should be used. New mothers should avoid using a carrier in front or on
their back. A portable carrier with handles is a safer alternative in the event of a seizure and
subsequent fall [23]. Because enzyme-inducing AEDs (Table 19.1) lower estrogen
concentrations by 40% to 50%, thereby compromising contraceptive effectiveness, hormonal
contraceptives prescribed to women with epilepsy on these AEDs should contain ≥50 μg of
ethinyl estradiol [29]. Oral contraceptives induce lamotrigine metabolism, requiring adjustment
of its dose [30].
WILLIAMS OBSTETRICS
SEIZURE DISORDERS
The Centers for Disease Control and Prevention reported that the prevalence of epilepsy in
adults in 2005 was 1.65 percent (Kobau, 2008). There are 1.1 million American women of
childbearing age who are affected. After headaches, seizures are the next most prevalent
neurological condition encountered in pregnant women, and they complicate 1 in 200
pregnancies (Brodie, 1996; Yerby, 1994). Importantly, epilepsy accounted for 13 percent of
maternal deaths in the United Kingdom for the 2005 to 2007 triennium (Lewis, 2007). Seizure
disorders are also associated with altered fetal development, and they can adversely affect
other pregnancy outcomes. The teratogenic effects of several anticonvulsant medications are
unquestioned. The American Academy of Neurology and the American Epilepsy Society have
developed guidelines regarding treatment in pregnant women, which are discussed
subsequently (Harden, 2009a–c).
Pathophysiology
A seizure is defined as a paroxysmal disorder of the central nervous system characterized by an
abnormal neuronal discharge with or without loss of consciousness. Epilepsy encompasses
different syndromes whose cardinal feature is a predisposition to recurrent unprovoked
seizures. The International League Against Epilepsy Commission on Classification and
Terminology recently updated its terminologies for seizures (Berg, 2010a, 2011; Shorvon, 2011).
This new classification schema is under development, and for now, most adults can be said to
have either focal or generalized seizures.
Focal Seizures
These originate in one localized brain area and affect a correspondingly localized area of
neurological function. They are believed to result from trauma, abscess, tumor, or perinatal
factors, although a specific lesion is rarely demonstrated. Focal seizures without dyscognitive
features start in one region of the body and progress toward other ipsilateral areas of the body,
producing tonic and then clonic movements. Simple seizures can affect sensory function or
produce autonomic dysfunction or psychological changes. Cognitive function is not impaired,
and recovery is rapid. Focal seizures with dyscognitive features are often preceded by an aura
and followed by impaired awareness manifested by sudden behavioral arrest or motionless
stare. Involuntary movements such as picking motions or lip smacking are common.
Generalized Seizures
These involve both brain hemispheres and may be preceded by an aura before an abrupt loss of
consciousness. There is a strong hereditary component. In generalized tonic-clonic seizures, loss
of consciousness is followed by tonic contraction of the young adults include head trauma,
alcohol- and other drug-induced withdrawals, cerebral infections, brain tumors, biochemical
abnormalities, and arteriovenous malformations. A search for these is prudent with a new-
onset seizure disorder in a pregnant woman. The diagnosis of idiopathic epilepsy is one of
exclusion.
Preconceptional Counseling
Women with epilepsy should undergo education and counseling before pregnancy (Chap. 8, p.
158). Folic acid supplementation with 0.4 mg per day is begun at least 1 month before
conception. The dose is increased to 4 mg when the woman taking antiepileptic medication
becomes pregnant. These medications are assessed and adjusted with a goal of monotherapy
using the least teratogenic medication. If this is not feasible, then attempts are made to reduce
the number of medications used and to use them at the lowest effective dose (Dunlop, 2008).
Medication withdrawal should be considered if a woman is seizure free for 2 years or more.
Epilepsy During Pregnancy

The major pregnancy-related risks to women with epilepsy are increased seizure rates with
attendant mortality risks and fetal malformations. Seizure control is the main priority. Earlier
studies described worsening seizure activity during pregnancy, however, this is not as common
nowadays because of more effective levels. These include nausea and vomiting, decreased
gastrointestinal motility, antacid use that diminishes drug absorption, pregnancy hypervolemia
offset by protein binding, induction of hepatic enzymes such as cytochrome oxidases, placental
enzymes that metabolize drugs, and increased glomerular filtration that hastens drug
clearance. Importantly, some women discontinue medication because of teratogenicity
concerns. Finally, the seizure threshold can be affected by pregnancy-related sleep deprivation
as well as hyperventilation and pain during labor.
Pregnancy Complications
Women with epilepsy have a small increased risk of some pregnancy complications (Borthen,
2011; Harden, 2009b). A population-based study from Iceland found that epileptic women had
a twofold increased cesarean delivery rate (Olafsson, 1998). In a cohort study from Montreal,
Richmond and coworkers (2004) reported an increased incidence of nonproteinuric
hypertension and labor induction. From a Swedish study of 1207 epileptic women, Pilo and
colleagues (2006) reported a 1.5-fold increased incidence of cesarean delivery, preeclampsia,
and postpartum hemorrhage. Postpartum depression rates have also been reported to be
increased in epileptic women (Turner, 2009). Finally, children of epileptic mothers have a 10-
percent risk of developing a seizure disorder.
Embryo-Fetal Malformations
For years, it was difficult to separate effects of epilepsy versus its therapy is at least initially
preferable to adding another agent (Buhimschi, 2009).
Specific drugs, when given alone, increase the malformation rate (Chap. 12, p. 246). Some of
these are listed in Table 60-2. Phenytoin and phenobarbital increase the major malformation
rate two- to threefold above baseline (Perucca, 2005; Thomas, 2008). A particularly potent
teratogen is valproate, which has a dose-dependent effect and increases the malformation risk
four- to eightfold (Eadie, 2008; Klein, 2014; Wyszynski, 2005). In general, with polytherapy, the
risk increases with each drug added. At least at this time, the newer antiepileptic medications
are reported to have no associations with a markedly increased risk of major birth defects
(Molgaard-Nielson, 2011).
TABLE 60-2. Teratogenic Effects of Common Anticonvulsant Medications
Management in Pregnancy
The major goal is seizure prevention. To accomplish this, treatment for nausea and vomiting is
provided, seizure-provoking stimuli are avoided, and medication compliance is emphasized. The
fewest necessary anticonvulsants are given at the lowest dosage effective for seizure control.
Although some providers routinely monitor serum drug levels during pregnancy, these
concentrations may be unreliable because of altered protein binding. Free or unbound drug
levels, although perhaps more accurate, are not widely available. Importantly, there is no
evidence that such monitoring improves seizure control (Adab, 2006). For these reasons, drug
levels may be informative if measured following seizures or if noncompliance is suspected.
Some of the newer agents such as lamotrigine and oxcarbazepine may be more amenable to
serum drug level monitoring (Harden, 2009a; Pennell, 2008).
For women taking anticonvulsant drugs, a targeted sonographic examination at midpregnancy
is recommended by some to search for anomalies (Chap. 10, p. 197). Testing to assess fetal
well-being is generally not indicated for women with uncomplicated epilepsy.
Breast Feeding and Contraception

There are limited available data regarding the safety of breast feeding with the various
anticonvulsant medications. That said, no obvious deleterious effects, such as long-term
cognitive issues.
Creasy and Resnik
Epilepsy
Women with epilepsy should be advised about possible interactions between
anticonvulsant drugs and oral contraceptive agents. Certain anticonvulsants, including
phenytoin, phenobarbital, primidone, carbamazepine, oxcarbazepine, topiramate, and
felbamate may interfere with the effectiveness of oral contraceptives and implanted
progestins, leading to unwanted pregnancy.1 The possibility of contraceptive failure must
be discussed with women taking these anticonvulsants and then documented in the
records. Regular counseling of women with epilepsy is necessary during the reproductive
years, because unplanned pregnancy may occur. Valproic acid and the newer
anticonvulsants (e.g., zonisamide, vigabatrin, gabapentin, lamotrigine, levetiracetam,
pregabalin, and tiagabine) have not been reported to cause contraceptive failure. 1,2 When
oral contraception is desired for women taking enzyme-inducing anticonvulsants, a
formulation that includes at least 50 μg of ethinyl estradiol or mestranol is preferred, but
the best way to ensure contraception is to use an alternative method. Combined oral
contraceptives may increase the metabolism of lamotrigine, causing lower lamotrigine
blood levels, and may increase seizure frequency in patients on this medication.
Between 0.3% and 0.6% of pregnant women have epilepsy. Pregnancy may affect the
seizure disorder, and the disorder may affect the course of the pregnancy and the manner
in which it is best managed. Moreover, recurrent seizures and drugs given to the mother
in an attempt to control them may affect fetal development.
EFFECT OF PREGNANCY ON SEIZURE DISORDERS
Pregnancy has unpredictable and variable infuences on epilepsy. When seizure frequency
increases, it most commonly does so in the first trimester and usually reverts to the
pregestational pattern at the conclusion of the pregnancy, although a few patients
experience a permanent deterioration in seizure control. In general, control in patients
with frequent seizures (i.e., more than one a month) before pregnancy is likely to
deteriorate during the gestational period, whereas only about 25% of patients with
infrequent attacks (i.e., less than one every 9 months) experience an exacerbation during
pregnancies.
Several case series have examined changes in seizure frequency during pregnancy, using
pre-pregnancy or postpartum seizure frequency as the control.3 Seizure frequency
remained unchanged in 54% to 80% of patients, with the highest rate of stability in those
with documented medication compliance. Seizure frequency increased in 14% to 32% of
patients and decreased in 3% to 24%. Seizures are more likely to be exacerbated during
pregnancy in women with more frequent seizures before the pregnancy and in those with
focal seizure disorders.4 For those who have been seizure free for at least 9 months prior
to conception, the likelihood of remaining seizure free during pregnancy is 84% to 92%.
It is usually not possible to predict the outcome in individual cases, regardless of the
maternal age, the outcome of previous pregnancies, or any apparent relationship between
seizures and the menstrual cycle. None of these factors provides a guide to the effect that
pregnancy will have on the course of epilepsy. Moreover, attacks may occur during
pregnancy in patients who have been free of seizures for several years.
Epilepsy may appear for the first time during or immediately after pregnancy. It is
uncommon for patients in the latter group to have seizures only in relationship to
pregnancy and at no other time (i.e., gestational epilepsy). Some patients with true
gestational epilepsy experience recurrent seizures during pregnancy, and the remainder
have only a single convulsion. The occurrence of seizures in one pregnancy is no guide to
the course of subsequent pregnancies.
The seizures that occur during pregnancy do not differ clinically from those occurring in
other circumstances. Improved compliance with an anticonvulsant drug regimen may
sometimes account for the reduction in seizure frequency that occasionally occurs
during pregnancy in a woman with epilepsy.
The increase in seizure frequency that occurs in some epileptic patients during pregnancy
may relate to the metabolic, hormonal, or hematologic changes of the gestational period,
or to fatigue or sleep deprivation. A rapid and excessive gain in weight sometimes occurs
before an increase in seizure frequency, providing some support for the belief that uid
retention may occasionally be a factor, perhaps by a dilutional effect on anticonvulsant
drug concentration. It is tempting to relate any change in seizure frequency to hormonal
factors because estrogens are epileptogenic in animals and progesterone has both
convulsant and anticonvulsant properties. Nausea, vomiting, reduced gastric motility, or
use of antacids may also lead to reduced absorption of anticonvulsant drugs.
There is sometimes dificulty in maintaining adequate treatment with anticonvulsant drugs

during pregnancy. Serum levels of the older antiepileptic drugs and the newer drug
lamotrigine generally decline in pregnancy and rise in the postpartum period.5 For
phenytoin, carbamazepine, and valproate (but not phenobarbital), the decline is less for
free levels than for total levels. An increase in dosage is frequently required to maintain
plasma levels at pre-pregnancy values; monitoring of drug levels before planned
conception and during pregnancy should be considered, remembering that the free level,
rather than the total level, of the drug correlates best with therapeutic efficacy. The levels
of several newer antiepileptic drugs, including levetiracetam and oxcarbazepine, may also
decline during pregnancy, but the effect of pregnancy on the pharmacokinetics of other
newer agents, such as felbamate, gabapentin, pregabalin, zonisamide, topiramate, and
lacosamide, is unclear.
The reason for the changes in drug requirements is unknown. One possibility is the
dilutional effect of increasing plasma volume and extracellular fluid volume. Poor
compliance with the anticonvulsant drug regimen, perhaps because of nausea and
vomiting or concerns about the effect of medication on the fetus, may also be an
important contributory factor, as may decreased plasma protein binding and changes in
the absorption and excretion of drugs. The increased metabolic capacity of the maternal
liver in pregnancy and possible fetal or placental metabolism of part of the anticonvulsant
dose may influence the changes in anticonvulsant drug requirements that occur in
epileptic women during pregnancy.
Folic acid therapy may lower the plasma phenytoin level, sometimes to below the
therapeutic range, and other drugs taken concomitantly with an anticonvulsant
medication also may lead to reduced plasma levels of the anticonvulsant. Antacids and
antihistamines merit particular mention, because it is not uncommon for them to be taken
during pregnancy.
Status epilepticus sometimes complicates pregnancy and may occur without any
preceding increase in seizure frequency, occasionally because of the injudicious
discontinuation of anticonvulsant drugs. Fortunately, this is a rare occurrence, but it may
lead to a fatal outcome for the mother or fetus. The absence of hypertension, proteinuria,
and edema helps in distinguishing this condition from eclamptic convulsions. As in the
nonpregnant patient, it is essential to obtain control of the seizures as rapidly as possible,
but the formerly accepted practice of terminating pregnancy is usually unnecessary.
Status epilepticus is treated with anticonvulsant drug therapy, with the pregnancy being
allowed to continue to term. Intravenous diazepam (10 to 30 mg) or lorazepam (4 to 8
mg) usually provides temporary control of the seizures, but other anticonvulsant drugs
are needed as well to prevent seizure recurrence. Intravenous phenytoin is usually given
but is best administered in the form of fosphenytoin sodium, the dosage of which is
expressed in terms of phenytoin equivalents. Fosphenytoin sodium is water soluble, may
be infused with dextrose or saline, is better tolerated at the infusion site than phenytoin,
and may be infused three times more rapidly than intravenous phenytoin, with the same
pharmacologic effects. It is converted in the body to phenytoin, which may be
cardiotoxic, and cardiac monitoring is required while the fosphenytoin is given in a
loading dose of 20 mg of phenytoin equivalents per kilogram, infused at a rate of up to
150 mg of phenytoin equivalents per kilogram. Other anticonvulsants may also be
required, including intravenous phenobarbital or midazolam. It is essential to maintain
control of the airway and of glucose and electrolyte balance.
EFFECT OF EPILEPSY ON PREGNANCY AND LACTATION
Only a few studies have attempted to document the effect of epilepsy on pregnancy. The
results are often difficult to evaluate because of the limited number of cases reported; the
lack of comparative data on nonepileptic women attending the same institutions;
differences in the severity of the epilepsy and how it has been treated; differences in age,
medical background, and socioeconomic status of the patients reported; and the lack of
information concerning relevant social habits such as cigarette smoking and alcohol
ingestion.
The incidences of vaginal hemorrhage and of toxemia during pregnancy among epileptic
women were found to be increased in some studies but not others. Whether preterm labor
occurs more commonly in epileptic women, as is sometimes reported, is unclear. 6
Cesarean section is not indicated simply because of maternal epilepsy, except when
seizures occur frequently or during labor, when they are precipitated by physical activity,
or when patients cannot cooperate during labor because of their neurologic disorder or
mental abnormality.7 Fetal death can result from maternal seizures, presumably because
of the accompanying hypoxia and acidosis, but recent evidence suggests that there are no
more stillbirths among epileptic patients than in the general population.7,8 The effect of
maternal seizures on placental blood flow is not established, but changes in fetal heart
rate suggestive of hypoxia have been described9; they may relate to reduced placental
blood flow or to metabolic changes in the mother.
Anticonvulsant drugs taken by the mother may be present in breast milk, but data as to
whether they have any major effect on the infant are limited. There is evidence that
primidone, ethosuxamide, gabapentin, lamotrigine, levetiracetam, and topiramate enter
breast milk in clinically significant quantities; valproic acid, phenytoin, carbamazepine,
and phenobarbital may also do so, but the evidence is less clear. 5 When an infant develops
sedation that is likely to be related to antiepileptic drugs in breast milk, breastfeeding
should be discontinued, and the infant should be observed for signs of drug withdrawal.
However, breastfeeding does not need to be discouraged for reasons related to the milk’s
content of anticonvulsant medication, and current guidelines do not recommend changing
the treatment regimen to a drug that does not penetrate breast milk.5
EFFECT OF MATERNAL EPILEPSY AND ANTICONVULSANT DRUGS ON

THE FETUS AND NEONATE
The epileptic woman who becomes pregnant is usually concerned that her unborn child
may inherit a similar susceptibility to seizures. The risk of epilepsy in the child depends
on the nature of the mother’s seizure disorder, and it is higher in idiopathic than acquired
maternal epilepsy. Although precise quantification of the risk is not possible, it is
probably quite small. The cause of this increased risk to the offspring of epileptic mothers
is unknown. It may relate to genetic factors, seizures arising during pregnancy, or the
metabolic and toxic consequences of seizures or anticonvulsant drugs. In general,
pregnancy in epileptic women does not need to be discouraged on these grounds, but
reassurance and support are necessary.
A major problem in management of epileptic patients during pregnancy is the possibility

that certain anticonvulsant drugs may induce fetal abnormalities. However, epilepsy has a
relatively low prevalence rate, can occur for a multitude of reasons, can vary markedly in
severity, can be treated by a variety of drugs singly or in combination, and can itself be
associated with an increased risk of fetal malformations. Some patients may have a
common genetic predisposition to seizures and to fetal malformation. Environmental
factors may be important in the genesis of congenital abnormalities, and socioeconomic
back- grounds must be matched as much as is possible when comparisons are made of the
incidence of malformations in different patient populations.
All the commonly used older antiepileptic drugs are probably teratogenic to some extent,
and malformation rates are higher for the offspring of mothers taking drug
combinations.6,10 The absolute risk of major congenital malformations based on a large
registry of pregnant women with epilepsy is 2.2% for carbamazepine, 3.2% for
lamotrigine, 3.7% for phenytoin, and 6.2% for valproate.10 Valproic acid has an especially
high (1%) rate of neural tube defects including spina bifida; it may also cause cleft lip or
palate, polydactyly, hypospadias, craniosynostosis, delayed development, and disorders
of the cardiovascular and endocrine systems.10,11 Trimethadione, which is now rarely used
and should be avoided during pregnancy, seems particularly dangerous, as it causes fetal
malformations and mental retardation in more than 50% of exposed infants. It is not clear
that the rates of major congenital malformations seen with antiepileptic drugs other than
valproate differ from rates for women with epilepsy not taking antiepileptic drugs,
although some data suggest that phenytoin and carbamazepine are associated with cleft
palate, that phenobarbital may be associated with cardiac malformations, and that a
dosage-response effect has been noted with lamotrigine.6 Whether newer anticonvulsant
drugs, such as felbamate, gabapentin, pregabalin, levetiracetam, lacosamide, tiagabine,
topiramate, oxcarbazepine, and vigabatrin, are teratogenic is unknown.
Animal studies lend support to the belief that some anticonvulsants are teratogenic. The
mechanism involved is unclear but may include folate deficiency or antagonism. Low
blood folate levels before or early in pregnancy are significantly associated with
spontaneous abortion and the occurrence of developmental anomalies.12 It has also been
suggested that certain oxidative intermediary metabolites of anticonvulsants may affect
cell division and migration.
Although most children born to epileptic mothers are cognitively normal, prenatal
antiepileptic drug exposure may be associated with developmental delay, particularly
when more than one drug has been taken by the mother.6 It appears that exposure to
valproic acid, in particular, carries a higher risk of impaired cognitive outcomes; in one
study, children exposed to valproic acid in utero scored an average of 6 to 9 points lower
on an IQ test at 3 years of age than those exposed to carbamazepine, lamotrigine, or
phenytoin.13
Maternal use of phenytoin during pregnancy has been associated with the fetal hydantoin
syndrome, which is characterized by prenatal and postnatal growth deficiency,
microcephaly, dysmorphic facies, distal phalangeal hypoplasia, and mental deficiency.
Among infants exposed to phenytoin in utero, 11% have enough clinical features to be
classified as having this syndrome, and almost three times as many may show lesser
degrees of impairment of performance or morphogenesis. The syndrome is not unlike that
ascribed to phenobarbital and carbamazepine, and it resembles fetal alcohol syndrome. 14
A consistent facial phenotype has also been reported in children exposed to valproic acid
or sodium valproate in utero.15
Maternal use of barbiturates (60 to 120 mg daily) in late pregnancy may be associated
with neonatal withdrawal symptoms beginning a week after birth. They include restless-
ness, constant crying, irritability, tremulousness, difficulty in sleeping, and vasomotor
instability but not seizures.
Clinical or subclinical coagulopathy may occur in the neonate whose mother received
anticonvulsants during pregnancy. In affected infants, levels of factors II, VII, IX, and X
are decreased, and levels of factors V and VIII and fibrinogen are normal. The
abnormalities are similar to those produced by vitamin K deficiency. As a result, some
experts advocate maternal ingestion of vitamin K1 (10 mg daily) during the last month of
pregnancy. However, it is unclear whether routine prophylaxis in this manner is justiable,
because more recent studies suggest that such hemorrhagic complications are rare, and
even call into question whether maternal antiepileptic use raises the risk of hemorrhage in
neonates at all.5 The routine practice of administering 1 mg of vitamin K to all neonates is
likely to be sufficient to mitigate any risk of hemorrhagic complications that could result
from maternal antiepileptic use.
GENERAL THERAPEUTIC APPROACHES
It is difficult to make more than general therapeutic recommendations about pregnancy in

the epileptic woman. Epilepsy should be treated with the smallest effective dosage of an
anticonvulsant drug, and monotherapy is preferable to polytherapy. Drug selection is
based on seizure type, clinical status, and the maternal and fetal risks. Valproate should
be avoided if possible.6 Folate supplementation (4 mg daily) is usually provided. Because
many pregnancies are unintended and congenital malformations may have already
occurred by the time a woman realizes she is pregnant, consideration can be given to
provide folate supplementation for any woman of childbearing age taking antiepileptic
medications. Similar reasoning suggests that it may be advisable to avoid valproate in
epileptic women of childbearing age.
Prenatal counseling is important. If a nonpregnant epileptic woman asks about

pregnancy, it is appropriate to inform her that there is a small risk of having a malformed
child because of the seizure disorder or the drugs used in its treatment. This risk is
probably about double that for the nonepileptic patient, but there is still a more than 90%
chance that she will have a normal child.
Data concerning the relative safety and therapeutic effectiveness of different

anticonvulsant drugs in the management of pregnant epileptic patients are insufficient to
guide the physician responsible for the care of these patients. It seems clear, however,
that trimethadione should not be used, and that valproic acid should be avoided. If
valproic acid must be used, prenatal testing for maternal serum α-fetoprotein levels or
with ultrasound is advisable to detect neural tube defects, so that therapeutic abortion can
be considered if necessary. Substitution of one anticonvulsant drug for another in
epileptic women whose first medical visit is after the rst trimester should be avoided,
because if a major malformation of the fetus is going to occur, it has probably occurred
already.
The principles of drug management of a seizure disorder in the pregnant woman are the
same as in the nonpregnant woman. Anticonvulsant drugs are as necessary to epileptic
patients during pregnancy as at other times. A detailed account of the drugs used in the
treatment of epilepsy is unnecessary here, but several points are worthy of comment.
A solitary seizure, unrelated to toxemia, should not lead to a diagnosis of epilepsy

because there may be no further attacks. Only time will tell whether an individual who
has a single seizure is going to have further attacks, thereby justifying a diagnosis of
epilepsy and necessitating prophylactic anticonvulsant drug treatment.
Although some physicians start a patient on anticonvulsant medication after one

convulsion, others prefer to withhold medication until the patient has had at least two
seizures, at least in the nonpregnant state. During pregnancy, many physicians initiate
anticonvulsant therapy after even a single seizure and arrange for neurologic reevaluation
after delivery. This approach merits emphasis because many patients with so-called
gestational epilepsy have only a single convulsion, and continued treatment in such
circumstances may be unnecessary. Simple medical and neurologic investigations are
indicated in an adult who has an isolated seizure and is otherwise well with no neurologic
signs: hematologic and biochemical screening tests, electroencephalogram, and,
particularly in the nonpregnant patient, magnetic resonance imaging (MRI) of the head
and a chest radiograph. If the findings of such investigations are unremarkable, discuss
the controversial issue of anticonvulsant drug treatment with the patient but generally
recommend that treatment be withheld unless a future attack occurs.
Pregnant women experiencing two or more seizures merit prophylactic anticonvulsant
drug treatment. In those with a progressive history, abnormal neurologic signs, or a focal
electroencephalographic abnormality, it is necessary to exclude an underlying structural
lesion by means of MRI of the head. The management of such a lesion is described later
in this chapter.
If prophylactic anticonvulsant drug treatment is necessary, it is generally continued until

the patient has been seizure free for at least 2 or 3 years. Treatment is started with a small
dosage of one of the anticonvulsants, depending on the type of seizure experienced by the
patient and the considerations outlined earlier. The dosage is increased until seizures are
controlled, blood concentrations reach the upper end of the optimal therapeutic range, or
side effects limit further increments. If seizures continue despite optimal blood levels of
the anticonvulsant drug selected, a second drug should be substituted for the first.
Patients often respond better to one or another of the various drugs that are available.
Experience during pregnancy with certain newer antiepileptic agents (e.g., felbamate,
gabapentin, topiramate, pregabalin, levetiracetam, zonisamide) is limited, however, and
their effect on the developing fetus is uncertain.
Patients must take medication as prescribed, and treatment should be controlled by

frequent monitoring of the plasma concentration of the anticonvulsant drug. Monthly
follow-up visits during pregnancy usually permit satisfactory supervision of the patient.
At the initial visit, trough values of total and free concentrations of each drug should be
measured. Total levels should then be measured each month in patients whose seizures
are well controlled; free levels should be monitored monthly in those with poor seizure
control, seizures during pregnancy, or a marked (>50%) decline in total level. Poor
compliance with an anticonvulsant drug regimen can often be improved by
encouragement and by explaining the importance of taking medication regularly.
Simplifying the dosage schedule so that medication is taken just once or twice daily may
be helpful.
As the pregnancy continues, the dosage of the anticonvulsant drug may need to be
increased if seizures become more common, or the free level of the anticonvulsant drug
declines by more than about 30%. In some instances, the required dosage may reach a
level that would probably cause toxic side effects in a nonpregnant patient. If the
anticonvulsant dosage is increased during the pregnancy, reductions will probably be
necessary in the puerperium to prevent toxicity, but this change must be based on clinical
evaluation and measurement of the plasma concentration of the drug, because the period
over which drug requirements decline varies considerably. Because of the poorly de ned
risks of increased obstetric complications among pregnant epileptic women, close
supervision of these patients by the obstetrician is mandatory, and delivery in a hospital is
advised.
After delivery, the infant must be inspected for congenital malformations and given an
injection of vitamin K1 (1 mg/kg intramuscularly). Clotting factors may be studied after
about 4 hours, and further injections of vitamin K1 can be given if necessary. If
hemorrhage occurs, infusions of fresh-frozen plasma or of factors II, VII, IX, and X may
also be necessary. Breastfeeding of a healthy infant by an epileptic mother should not be
discouraged. The effect of enzyme-inducing anticonvulsants on oral contraceptives and
implantable progestins should be discussed.
Queenan
Epilepsy
Men-Jean Lee
Department of Obstetrics & Gynecology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
Overview
Women of childbearing age with epilepsy should be offered preconception and early pregnancy
consultation with a neurologist and perinatologist to evaluate their need for antiepileptic drugs
(AED), determine the minimum number of agents needed and dosage(s) required to prevent
seizures, and discuss the teratogenic potential of the drugs. In addition, folate supplementation
is recommended prior to conception to potentially decrease risk for fetal neural tube defects. To
optimize pregnancy outcomes, the patient should be treated with the lowest effective dosage and,
if possible, a single AED prior to attempting pregnancy; however, the frequency of seizures
tends to increase during pregnancy so careful monitoring of AED levels in the blood is
recommended to minimize seizure activity.
Pathophysiology
Epilepsy complicates approximately 0.3–0.5% of pregnancies. Between 14% and 32% of these
patients will experience an increase in seizure frequency during pregnancy, which is most often
attributable to a reduction in the plasma concentration of anticonvulsant drugs. In addition,
pregnancy hormone levels, emotional stress, and sleep deprivation also lower neuronal seizure
thresholds. In general, the reasons for changes in plasma AED levels include increased plasma
volume, electrolyte changes, physiological respiratory alkalosis, and reduced plasma protein
binding. Additionally, factors known to affect the pharmacokinetics of AED in pregnancy
include: (1) decreased motility of the gastrointestinal tract may change the bioavailability of
orally administered dosage forms; (2) increases in glomerular filtration rate and creatinine
clearance during pregnancy influence the renal clearance rates of many drugs; and (3) hormonal
changes increase hepatic enzyme systems responsible for the metabolism and clearance of many
AEDs.
Whatever the underlying cause of the increase in seizure frequency during pregnancy, the
potential for seizure-induced fetal damage secondary to hypoxia, and the added maternal risk of
seizures (e.g., aspiration pneumonia) necessitate close observation and careful management by a
neurologist and perinatologist. Women who continue to have seizures during pregnancy tend to
be at increased risk for preterm birth and fetuses with growth restriction compared to women
with epilepsy who have no seizures.
Teratogenicity of anticonvulsants
There is considerable controversy concerning the teratogenicity of anticonvulsant drugs. The
overall rate of congenital abnormalities in association with maternal intake of AEDs is 5–6%.
This is twice the expected rate of 2.5–3.0% in the general unaffected population. In addition,
children of mothers with epilepsy, even when untreated with AEDs, tend to have slightly more
minor anomalies than do children of women without epilepsy.
Trimethadione has been shown to result in spontaneous abortions and fetal malformations in
over 80% pregnancies. Its use is, therefore, contraindicated during pregnancy and it probably
should not be given to women of childbearing age. Valproic acid is also considered a highly
teratogenic AED that should be avoided during pregnancy, if at all possible. Valproate
monotherapy during the first trimester of pregnancy contributes to the development of major
congenital malformations (MCMs) in the offspring of women using this medication. Valproate
as a part of polytherapy in the first trimester of pregnancy probably contributes to the
development of MCMs when compared to polytherapy that does not include valproate. There
appears to be a relationship between the dose of valproate and the risk of development of MCMs
in the offspring of women with epilepsy. In addition to structural defects, valproate use during
pregnancy is associated with the development of fetal valproate syndrome (similar to fetal
alcohol syndrome), which includes developmental delay and neurobehavioral issues. The
cognitive and behavioral impairments have been attributed to prolonged intrauterine exposure of
the developing fetus to valproate even after embryogenesis has been completed. Therefore,
valproic acid is one AED that should be discontinued even after the first trimester if an
alternative effective AED can be used. Carbamazepine does not appear to substantially increase
the risk of MCMs when used as monotherapy. Data from a number of pregnancy registries
suggest that lamotrigine, levetiracetam, oxcarbazepine, topiramate, and gabapentin are not
significantly associated with an increased risk of MCMs in pregnancy. However, topiramate and
zonizamide use in pregnancy is associated with lower birth-weight newborns than lamotrigine.
The incidence of MCMs increases with increasing number of anticonvulsant medications used to
control seizures. As noted, if possible, only one AED should be used during pregnancy and the
lowest effective dose of each AED is recommended. Exposure to polytherapy and valproate
during pregnancy are associated with significantly reduced verbal intelligence in the offspring.
Carbamazepine monotherapy with maternal serum levels within the recommended range does
not impair intelligence in prenatally exposed offspring. It should be remembered that 95% of
infants born to mothers receiving AED treatment will be normal.
Serum levels
Pregnancy appears to cause an increase in clearance and a significant decrease in the levels of
lamotrigine, carbamazepine, and phenytoin. Sufficient data are not available to provide evidence
for a change in clearance or levels during pregnancy for valproate. In general, the unbound
concentration of the AED is the pharmacologically active level of the medication that should be
monitored during pregnancy.
Breast feeding
Primidone probably enters breast milk in potentially clinically important amounts, whereas
valproate, phenytoin, and carbamazepine probably do not. Lamotrigine may penetrate into breast
milk in clinically important amounts. There is insufficient evidence to determine if indirect
exposure to maternally ingested AEDs has symptomatic effects on the newborns. In general,
nursing mothers receiving ethosuximide, phenobarbital, primidone, or lamotrigine should be
advised to closely monitor the infant for sedation, poor suckling, and lethargy. Phenytoin,
carbamazepine, and valproate are probably safe to take if the woman chooses to breastfeed.
These AEDs are all moderately to highly protein-bound, and are not transferred in high
concentrations in breast milk.
Management
The treatment of the pregnant epileptic patient should ideally begin preconceptionally. At this
time, her seizure status should be assessed to ascertain whether or not she truly needs an
anticonvulsant drug. If she has been seizure-free for a long interval (at least 9 months) on
minimal doses of anticonvulsant drugs and has a negative electroencephalogram (EEG), it may
be reasonable to attempt anticonvulsant withdrawal before conception. Women who report
seizure activity within 2 years of pregnancy are significantly more likely to experience antenatal,
intrapartum, and postpartum seizures when compared with women whose last seizure occurred
more than 2 years before pregnancy. Given the potential teratogenic risks of AED exposure in
early pregnancy, discontinuation or decreasing the dosage of AED in those women who have not
had a seizure in the past 2 years under the direct supervision of a neurologist can be considered
prior to pregnancy.
Risk for relapse increases when the history includes clonic–tonic grand mal convulsions,
prolonged seizures, failure of AED treatment, or seizure control achieved with a combination of
two or three drugs. One should, therefore, hesitate in withdrawing AED treatment from women
who are planning pregnancy if their history includes the above risks for relapse. The current
recommendation is that AEDs, if withdrawn, should be withdrawn at least 6 months prior to
pregnancy. When possible, monotherapy should be used rather than polytherapy. After
monotherapy is established, the lowest plasma AED level that prevents seizures should be
determined.
Counseling pregnant women with epilepsy later in pregnancy is also important. Women who are
late registrants to prenatal care or do not realize that they are pregnant until after the first
trimester of pregnancy often self-discontinue AEDs without realizing that embryogenesis has
already been completed and the risk of seizures during pregnancy out- weighs any further risk
for developing any new anomalies. Women with intractable seizures or drug-resistant epilepsy
should be referred to an epilepsy center and evaluated for noncompliance with medications and
to rule out structural intracranial pathology. Women with treatable seizures should be counseled
to continue taking the lowest effective dose of AED to control seizure activity. A single seizure
is unlikely to induce birth defects; however five or more seizures during pregnancy have been
associated with impaired cognitive development of the offspring.
Several observations can serve as guidelines for management throughout pregnancy:
• 1 Steady-state plasma concentrations of most anticonvulsants decrease as pregnancy

progresses.
• 2 These changes may be associated with breakthrough seizures, requiring an increase in

anticonvulsant medications.
• 3 Patients appear to have a threshold concentration of drug below which seizure control is
lost. In other words, some patients may be adequately controlled by drug concentrations
below the quoted therapeutic range.
• 4 The use of divided doses or slow-release preparations results in lower peak levels and may
reduce the risk of malformations.
• 5 For valproate, the use of a single daily dose is not advisable because the adverse effects are
believed to be the result of high peak serum level.
• 6 Total serum AED levels and, if possible, free AED fractions should be measured at regular
intervals throughout pregnancy, particularly for lamotrigine, phenytoin, and
carbamazepine.
Treatment
Preconceptional
1 Ascertain the patient’s need for anticonvulsant medications.
2 Determine the fewest agents (ideally monotherapy) and lowest effective level of
anticonvulsant medication at which the patient is seizure-free.
3 The use of divided doses or slow-release preparations results in lower peak levels and may
reduce the risk of malformations.
4 Discuss the risks of anticonvulsant medications to the fetus.
5 Recommend folate supplementation (1mg/day) beginning before conception.
Antenatal
• 1 Maintain the concentration of anticonvulsant medication(s) at the level(s) required by the

patient.
• 2 Obtain plasma anticonvulsant levels every 3 to 4 weeks, or if a seizure occurs, if potential

drug interaction is suspected, or if signs of toxicity develop.
• 3 Raise doses if necessary to maintain effective anticonvulsant activity. Dosage increments

may need to be small (e.g., the use of 30 mg rather than 100 mg phenytoin capsules).
• 4 Assess drug toxicity clinically after an appropriate interval based on the estimated time to
reach a steady state.
• 5 Ifseizurecontrolisnotmaintainedandtheanticonvulsantdosehasbeen increased until toxic

effects are apparent (Table 24.1), add additional anticonvulsant medication.
• 6 Prescribe supplements containing at least 0.4 mg folic acid to all patients on anticonvulsant
medication and follow their complete blood counts (CBCs), since folic acid deficiency
anemia is frequent in this group of patients.
• 7 Offer prenatal diagnosis to patients receiving AEDs (Level 2 sonogram, MSAFP, and fetal
echocardiogram).
• 8 Consider Vitamin K, 10 mg/day orally after 36 weeks of pregnancy until delivery to prevent
neonatal hemorrhage.
• 9 Epilepsy is not usually considered an indication for early delivery.
First seizure during pregnancy

For the patient who develops new onset seizures during pregnancy, eclamptic seizures must
be ruled out. A detailed neurological history and examination are essential. Diagnostic
studies, including electroencephalography, magnetic resonance imaging, serum electrolytes
and metabolic studies including serum calcium level, urine protein, and fasting and
postprandial blood glucose determinations, should be performed on all patients. A lumbar
puncture following computed tomography or magnetic resonance imaging may be indicated
to rule out intracranial bleed or mass. Based on these studies and evidence of other
neurological signs or symptoms, angiographic studies may be helpful.
Postpartum
1 Administer 1 mg of vitamin K intramuscularly to all newborns of patients receiving AEDs.
2 Examine the newborn carefully for signs of fetal teratogenic effects.
3 Reduction of anticonvulsant medication may be required in the postpartum period. Check the
patient every 2 or 3 weeks after delivery.
Uptodate
Management of epilepsy and pregnancy
Author:
Steven C Schachter, MD
Section Editors:
Charles J Lockwood, MD, MHCM
Paul Garcia, MD
Deputy Editor:
April F Eichler, MD, MPH
Contributor Disclosures
All topics are updated as new evidence becomes available and our peer review process is
complete.
Literature review current through: Aug 2017. | This topic last updated: Dec 06, 2016.
INTRODUCTION — Over 90 percent of women with epilepsy have a normal pregnancy. This

point should be emphasized to the patient who is likely to have many fears and anxieties
regarding the risks. Nonetheless, women with epilepsy are at increased risk for a range of
perinatal complications compared with the general population, including preeclampsia, preterm
labor, and fetal and maternal mortality [1]. It is important for physicians and women with
epilepsy to be aware of these as careful planning and management of pregnancy can increase
the odds of a favorable outcome.
There are a number of important issues to be addressed by the physician when a woman with
epilepsy becomes pregnant; these include:
●Are antiseizure drugs necessary?

●What effect do antiseizure drugs have on the fetus?
●What effect does maternal epilepsy have on the fetus?
●What effect does pregnancy have on seizures?
●How should the patient be managed during pregnancy and delivery?
●How should the patient be managed during the postpartum period?
This topic will discuss the management of pregnancy and epilepsy. The risks associated with
epilepsy and pregnancy are discussed separately. (See "Risks associated with epilepsy and
pregnancy".)
PRECONCEPTION MANAGEMENT — Epilepsy is not a contraindication for pregnancy. Over

90 percent of women with epilepsy will have good outcomes [2]. Preconception counseling is
important for all women of child bearing years because many pregnancies are unplanned and
the risks of complications can be minimized by interventions before and early on in pregnancy
[3]; in addition, many women with epilepsy report limited knowledge about key issues and
unmet informational needs regarding pregnancy and childbirth [4]. Counseling should include
information regarding risks associated with epilepsy and pregnancy, potential interactions with
oral contraceptive therapy, and recommended folate supplementation.
Contraception — Women with epilepsy should be aware that hormonal contraceptive failure
may occur with antiseizure drugs which are inducers of the hepatic cytochrome P-450 system
(carbamazepine, phenytoin, phenobarbital, primidone, topiramate, and oxcarbazepine).
Long-acting reversible contraceptives (LARC), including copper or levonogestrel intrauterine

devices and etonogestrel implants, are highly effective alternatives that carry no or much less
potential for drug-drug interactions, depending on the method. This topic is discussed in more
detail separately. (See "Overview of the management of epilepsy in adults", section on
'Contraception'.)
Folic acid supplementation — Preconception folic acid supplementation (0.4 to 0.8 mg daily)

is recommended for all women of child bearing potential to minimize the risk of neural tube
defects. A higher dose (4 mg daily) is suggested in women considered to be at increased risk of
neural tube defects (eg, previous child with a neural tube defect, those taking antiseizure drugs,
especially carbamazepine or valproate). (See "Folic acid supplementation in pregnancy".)
Low serum folate levels in women with epilepsy are independently associated with an increased
risk of major fetal malformations [5]. It has not yet been conclusively determined if folic
acid supplementation prevents neural tube defects in women receiving antiseizure drugs.
However, animal studies have shown that valproate and phenytoin decrease the concentration
of certain forms of folate and are associated with neural tube defects [6,7]. A limited number of
observational studies in women with epilepsy have failed to demonstrate a reduction in the risk
of neural tube defects with preconceptual use of folic acid compared with folic acid
supplementation beginning later in pregnancy [8,9].
Published clinical guidelines regarding the dose of folate supplementation in women with
epilepsy vary and are not definitive. The 2009 American Academy of Neurology and American
Epilepsy Society guidelines state that data are insufficient to determine whether doses higher
than 0.4 mg offer greater protective benefits [10]. In contrast, the American College of
Obstetricians and Gynecologists recommends 4 mg of folic acid daily for women at risk of
having offspring with neural tube defects (including women taking antiseizure drugs) [11]. The
higher dose of folic acid has not been associated with adverse effects.
In the absence of randomized clinical trial evidence in women taking antiseizure drugs, and
extrapolating from other high risk patients [12], we suggest that women with epilepsy
on valproate or carbamazepine who are planning to become pregnant should receive daily high
dose folic acid supplementation (4 mg) for one to three months prior to conception and
throughout the first trimester in order to reduce the risk of neural tube defects [13]. If possible,
valproate should be avoided in pregnancy. (See "Risks associated with epilepsy and
pregnancy", section on 'Valproate'.)
Women who are taking other antiseizure drugs, which have not been associated with as high a
risk of neural tube defect, and sexually active women of reproductive age who are not actively
planning pregnancy, may take the more standard lower dose of folic acid (0.4 to 0.8 mg per day)
[14]. (See "Folic acid supplementation in pregnancy".)
Maternal supplementation with multivitamins containing folic acid has not been associated with
a reduction in the risk of congenital anomalies (cardiovascular defects, oral clefts, urinary tract
defects) in women taking antiseizure drugs during pregnancy [8,15].
Necessity for antiseizure drugs — There are two issues that must be considered concerning
the administration of antiseizure drugs in any woman with a seizure disorder who wants to
become pregnant:
●Is the diagnosis of epilepsy well established? In some patients, routine EEG recordings or
continuous video/EEG monitoring may be warranted to confirm the diagnosis.
●Does the patient require antiseizure drugs and if so, is she on the most appropriate
medication(s) and at the minimum dose to maintain seizure control?
The frequency of seizure recurrence within six and twelve months of discontinuing therapy is
approximately 15 and 30 percent, respectively [16]. The risk may vary according to the specific
epilepsy syndrome and other factors, however, and these estimates should be individualized.
(See "Overview of the management of epilepsy in adults", section on 'Discontinuing antiseizure
drug therapy'.)
If a woman has been seizure-free for a satisfactory period and the decision is made to
discontinue antiseizure drugs, we suggest doing so at least six to twelve months prior to
becoming pregnant, as the risk of seizure recurrence after withdrawal is highest during this
period.
Choice of antiseizure drug — If it is felt that medications cannot be withdrawn, the patient
should take the most suitable medication for the seizure type, with the exception of valproate,
which should be avoided whenever possible. (See "Overview of the management of epilepsy in
adults".)
The optimal treatment of women with epilepsy who are of childbearing age is unclear because
of a lack of conclusive data on the comparative teratogenicity of different antiseizure drugs. A
number of pregnancy registries are beginning to accumulate data that should help guide therapy
in the coming years. (See "Risks associated with epilepsy and pregnancy", section on 'Effect of
antiseizure drugs on the fetus'.)
Data on the comparative efficacy of various antiseizure drugs for controlling seizures during
pregnancy are also quite limited, and there are no randomized trials in this setting. Most
pregnancy registry studies collect only crude information on seizure outcomes, or none at all. In
an Australian registry study that included over 1000 pregnancies in women with epilepsy treated
with antiseizure drug monotherapy, seizure control was better among women treated with
"older" antiseizure drugs (eg, carbamazepine, phenytoin, valproic acid) compared with "newer"
antiseizure drugs such as lamotrigine, levetiracetam, or topiramate (35 versus 48 percent of
pregnancies affected by at least one seizure) [17]. Among the "newer" antiseizure drugs,
levetiracetam was associated with fewer seizure-affected pregnancies than lamotrigine (32
versus 51 percent), although the number of levetiracetam-exposed pregnancies was relatively
small (n = 82). One other large registry study also observed that lamotrigine was associated
with worse seizure control compared with other antiseizure drugs despite a mean dose increase
of 26 percent from the first to third trimesters [18]. Lamotrigine clearance is known to increase
two- to threefold during pregnancy, and close monitoring of clinical status and drug levels is
indicated in women treated with lamotrigine as well as other antiseizure drugs. (See 'Drug levels
and dose adjustment' below.)
At present, we recommend the following approach. Antiseizure drug therapy should be

optimized prior to conception, if possible, before exposure of the fetus to potential teratogenic
effects of antiseizure drugs [2]. Since there is no agreement as to which antiseizure drug is most
or least teratogenic, the antiseizure drug that stops seizures in a given patient is the one that
should be used.
An exception is valproate. Results from pregnancy registries and cohort studies suggest higher
teratogenicity and adverse neurodevelopmental outcomes with valproate than with other
antiseizure drugs [19]. Also, while concentrations of most antiseizure drugs are generally lower
in umbilical compared with maternal serum, valproate is associated with higher umbilical than
maternal concentrations, perhaps because of increased placental transfer [20]. The risks
associated with in utero exposure to valproate and other antiseizure drugs are reviewed
separately. (See "Risks associated with epilepsy and pregnancy", section on 'Long-term
effects'.)
For these reasons, we generally avoid valproate in women planning to become pregnant if

seizures can be adequately controlled with other antiseizure drugs. If valproate is used, it should
be prescribed at the lowest effective dose. If possible, aim for doses of 500 to 600 mg/day [19]
and avoid high plasma levels (>70 µg/mL) unless absolutely necessary to control seizures [21].
The drug should be given in divided doses three or four times daily [21].
Other recommendations concerning the use of antiseizure drugs include [13,21-23]:
●The antiseizure drug should be administered at the lowest dose and lowest plasma level
that protects against tonic-clonic and/orcomplex partial seizures.
●The plasma drug level should be monitored regularly during pregnancy including, if
available, the physiologically important free or unbound drug concentration. (See 'Drug
levels and dose adjustment' below.)
●The use of multiple agents should be avoided, if possible, especially combinations
involving valproate, carbamazepine, and phenobarbital.
●If there is a family history of neural tube defects,
both valproate and carbamazepine should be avoided, unless a patient's seizures cannot
otherwise be controlled.
●In established pregnancy, changes to alternate antiseizure drug therapy should not be
undertaken solely to reduce teratogenic risk for several reasons [2]:
•Changing antiseizure drugs may precipitate seizures.
•Overlapping antiseizure drugs during the change exposes the fetus to effects of an
additional antiseizure drug.
•There is limited advantage to changing antiseizure drugs if pregnancy has already
been established for several weeks.
Antiepileptic Drug Pregnancy Registry — The Antiepileptic Drug Pregnancy Registry (Toll-

free:1-888-233-2334; online at http://www.aedpregnancyregistry.org/) is a North American
registry for pregnant women who are taking any antiseizure drug. The registry's purpose is to
collect data to assess the fetal risk from antiseizure drugs and to provide information about
pregnancy issues to patients with epilepsy and their physicians.
MANAGEMENT DURING PREGNANCY AND DELIVERY — Management during pregnancy

consists of folic acid supplementation, screening for major malformations, monitoring plasma
antiseizure drug levels, and the administration of vitamin K late in pregnancy.
Women may experience increased seizure frequency during pregnancy because they are sleep-
deprived or noncompliant with antiseizure medications due to concerns about the effects of the
medication on the developing fetus. Preconception counseling may play a role in minimizing this
risk [3]. It is important to emphasize the importance of adequate sleep, medical compliance, and
minimizing stress and other factors known to precipitate seizures.
In a study that included 95 women with epilepsy followed at a single tertiary care epilepsy clinic,
38 percent of pregnancies were associated with increased seizure frequency compared with the
pre-pregnancy baseline [24]. The risk of worsened seizure frequency was highest in those with
seizures in the 12 months prior to conception and in those with focal epilepsy.
Although the mechanisms are not yet clear, there appears to be a significant increase in the risk
of maternal mortality around the time of delivery in women with epilepsy, along with a more
modest increase in the risk of a range of obstetric complications [1]. This highlights the
importance of close intrapartum care and the need for a better understanding of the
mechanisms underlying these risks, so that preventive interventions can be devised.
(See "Risks associated with epilepsy and pregnancy", section on 'Perinatal morbidity and
mortality' and "Management of normal labor and delivery".)
Continued folic acid supplementation — Preconception doses of folate are recommended

through the first trimester and are generally continued throughout pregnancy. (See "Folic acid
supplementation in pregnancy".)
Although serum and red cell folate levels can be monitored, the utility of this practice is not
known, and serum levels do not reflect total body saturation levels. While at least one
retrospective study found that serum folic acid levels of mothers of malformed offspring were
significant lower than those of mothers of normal offspring during the first and second trimesters
of pregnancy [25], no prospective studies have been performed to evaluate whether monitoring
levels during pregnancy improves outcomes.
Screening for malformations — Screening for major anomalies provides the patient with the
opportunity to terminate the pregnancy if a malformation is present. Even if the patient would not
consider termination, it may be helpful to know if a major defect is present in order to plan the
optimum mode of delivery and to refer the patient to a center with specialty pediatric services for
delivery. There are two major screening modalities: serum alpha-fetoprotein (AFP)
concentration and ultrasonography:
●Elevated serum AFP is associated with neural tube defects and other fetal abnormalities
(eg ventral wall defects, congenital nephrosis). Measurement of the serum AFP
concentration or amniocentesis for alpha-fetoprotein should be performed between 14 and
16 weeks, especially in women treated with valproate and carbamazepine [26-28].
Amniocentesis is associated with a 0.5 percent risk of miscarriage. (See "Open neural tube
defects: Risk factors, prenatal screening and diagnosis, and pregnancy management".)
●Real-time ultrasonography should be performed at 18 to 20 weeks to evaluate for neural
tube defects, cleft lip and palate, heart anomalies, and for a general fetal anatomical survey
[28].
Measurement of the serum alpha-fetoprotein level alone will detect most, but not all, cases of
open spina bifida and anencephaly (80 and 90 percent of cases respectively). The detection
rate increases to 94 to 100 percent if the serum level is measured in combination with high-
resolution ultrasonography by an experienced ultrasonographer [28]. The highest degree of
accuracy is obtained by using amniocentesis for determination of amniotic fluid AFP and
acetylcholinesterase (AChE). If both levels are elevated, there is greater than a 99 percent
chance of an open neural tube defect. However, amniocentesis is associated with a small (0.5
percent) risk of miscarriage.
Patient preference is important to consider in women with an elevated AFP level and a normal
ultrasonographic examination. One study estimated that the probability of an affected fetus
ranges from 0.01 to 0.15 percent in women with a serum AFP concentration 2.0 to 3.5 times the
median and normal ultrasonography [28]. This risk is below the one-half percent rate of fetal
loss with amniocentesis and some women may decide not to proceed with amniocentesis in this
setting.
It seems reasonable to reserve amniocentesis for women:
●With elevated serum AFP levels in whom the ultrasound examination is unable to reliably
exclude a neural-tube defect.
●Who desire a fetal karyotype because of an abnormality on ultrasound examination and
an elevated serum AFP.
Drug levels and dose adjustment — Pregnancy is accompanied by many alterations in drug
metabolism, including increased liver metabolism, renal clearance, and volume of distribution,
and decreased gastrointestinal absorption and plasma protein binding [20,29-31]. As an
example, for antiseizure drugs that are highly protein bound (eg, phenytoin, valproate), the total
plasma drug level may decrease with impaired protein binding, but the physiologically important
free or unbound drug concentration may not change. As a result, free drug levels for these
antiseizure drugs may be more reliable during pregnancy. However, medication dosage should
be adjusted if the patient's seizures are not controlled, not because the free or total level has
decreased.
Both total and free plasma drug levels, where available, should be checked at weeks five to six
and week 10, and then at least once each trimester. Trough levels, drawn first thing in the
morning, are preferred. If trough levels are not possible, then levels should be consistently
checked at approximately the same interval since the most recent dose.
Antiseizure drugs that may warrant closer monitoring

include lamotrigine, levetiracetam, oxcarbazepine, phenytoin and topiramate[10]:
●Lamotrigine clearance increases by a factor of about two to three during pregnancy,

peaking in the second trimester [10,24,32-36]. Drug levels should therefore be monitored
more frequently during the second and third trimesters, to reduce the possibility of
increased seizures, as well as in the early postpartum period, to avert toxicity [10,24,32-
36]. Combination treatment with lamotrigine and valproate appears to attenuate the
increased clearance of lamotrigine in pregnancy [37]. In one series, a ratio to target
concentration (ie, current lamotrigine level/nonpregnant baseline lamotrigine level) of less
than 0.65 was a predictor of seizure worsening [35]. Another center found that monthly
monitoring of lamotrigine levels was associated with a rate of breakthrough seizures similar
to that reported with other antiseizure drugs [38].
●Levetiracetam clearance also increases during pregnancy [24,39,40]. In a study that
included 15 women treated with levetiracetam monotherapy, clearance increased by 200
percent during the second trimester compared with the pre-pregnancy baseline [24]; in
another small study, levetiracetam plasma concentrations declined to 40 percent of
baseline concentrations in the third trimester [39]. In the former study, approximately half of
the women on levetiracetam experienced an increase in seizure frequency during
pregnancy, suggesting the need for close clinical monitoring of patients taking
levetiracetam in pregnancy.
●In one large pregnancy registry, oxcarbazepine monotherapy increased the risk of
seizure, suggesting the possibility that it, too, is associated with pharmacokinetic changes
in pregnancy, and requires more frequent monitoring [41]. In twelve women monitored in
pregnancy, the concentration of an active oxcarbazepine metabolite, 10-monohydroxy
metabolite (MHD), decreased significantly in gestation and increased after delivery [42,43].
These and other reports support close clinical monitoring of women taking oxcarbazepine
during pregnancy [44].
●A study describing 12 women on topiramate therapy during pregnancy reported that
serum concentrations declined by about 30 percent [45]. Increased seizure frequency in
pregnancy was also observed in this series.
Vitamin K supplementation — Most physicians recommend administration of prophylactic

vitamin K1 (10 to 20 mg/day) during the last month of pregnancy to women treated with
antiseizure drugs to protect the child against severe postnatal bleeding due to a deficiency in
vitamin K-dependent clotting factors [10]. This practice is based upon limited data from multiple
case reports and small case series that have suggested an increased risk of bleeding in the
neonates of mothers taking antiseizure drugs [46-50]. Enzyme-inducing antiseizure drugs, such
as phenobarbital, phenytoin, and carbamazepine, cross the placenta and may increase the rate
of oxidative degradation of vitamin K in the fetus, an effect that can be overcome by large doses
of vitamin K.
Despite the reports of excess bleeding and theoretical rationale for vitamin K administration,
there has been limited systematic study of this issue [10]. Findings of a large epidemiologic
study do not support routine antenatal administration of vitamin K [51]. In this report, 662
pregnancies (667 neonates) in women with epilepsy who used enzyme inducing antiseizure
drugs (463 carbamazepine, 212 phenytoin, 44 phenobarbital, 11 primidone, and
7 oxcarbazepine) were prospectively followed and compared with pregnancies of matched
controls. No mother received vitamin K during pregnancy, but all infants received 1 mg vitamin
K intramuscularly at birth. The incidence of bleeding complications in neonates was not
significantly different between mothers with epilepsy and controls (0.7 versus 0.4 percent,
respectively). Furthermore, in the five infants who had bleeding complications in the epilepsy
group, all had other possible explanations for bleeding (prematurity, traumatic delivery, sepsis,
fetal alcohol syndrome, or intrauterine asphyxia).
The authors provide several possible explanations for the contrasting findings of this study
compared with prior case reports and series [51]. First, most case reports occurred in an era
when polytherapy was more prevalent and regular monitoring of drug levels less common;
higher drug levels may increase bleeding risk. In addition, use
of phenobarbital and phenytoin was more common in the past, while most patients in this study
were on monotherapy and took carbamazepine. Finally, the incidence of birth trauma may be
lower with the current increase in cesarean section rates worldwide.
Regardless of the reasons for the discrepancy, these findings suggest that antenatal vitamin
K prophylaxis may not be necessary in all women on antiseizure drugs. On the other hand, oral
vitamin K is relatively cheap and harmless. The 2009 AAN AES guidelines concluded that there
was not sufficient evidence to recommend for or against this practice [10]. We suggest oral
vitamin K supplementation (10 to 20 mg per day for the last month of pregnancy) in women with
risk factors for premature delivery, in women taking multiple antiseizure drugs, enzyme-inducing
antiseizure drugs (eg, phenobarbital, carbamazepine, phenytoin, topiramate, oxcarbazepine),
and in women who abuse alcohol during pregnancy.
All newborns receive 1 mg of vitamin K intramuscularly at birth. Fresh frozen plasma can be
given if bleeding occurs.
At delivery — Most women have a normal vaginal delivery [47,52,53]. However, elective

cesarean section may be justified in women with frequent seizures during the third trimester or a
history of status epilepticus during severe stress [54,55].
A tonic-clonic seizure occurs during labor in 1 to 2 percent of women with epilepsy, and in
another 1 to 2 percent 24 hours after delivery. It is therefore essential to maintain a plasma
antiseizure drug level known to protect against seizures during the third trimester and during
delivery. Doses must not be missed during the period of labor.
Convulsive seizures during labor and delivery should be treated promptly with intravenous
benzodiazepines; lorazepam is considered the drug of choice [47] (see "Convulsive status
epilepticus in adults: Classification, clinical features, and diagnosis"). Intravenous phenytoin is
also highly effective and has a longer duration of action [13]. After
delivery, phenobarbital, primidone, and benzodiazepines remain in neonatal plasma for several
days. This can cause sedation and possibly a neonatal withdrawal syndrome [56].
Magnesium sulfate is not an appropriate alternative for epileptic seizures. However, when
seizures first present during the third trimester of pregnancy or the early postpartum period, it
may be difficult to distinguish eclampsia from a new onset or late relapse of epilepsy. In these
cases, treatment of eclampsia and evaluation of other etiologies for the seizure is warranted.
(See "Eclampsia".)
Generalized tonic clonic seizures can be associated with hypoxia; continuous fetal heart rate
monitoring is recommended in the event of a seizure, as well as for a period of at least an hour
after administration of benzodiazepines [57]. (See "Eclampsia", section on 'Fetal resuscitation'.)
MANAGEMENT IN THE POSTPARTUM PERIOD — There are several basic principles of

management of women with a history of seizures during the postpartum period [57].
●If the antiseizure drug dose has been altered during pregnancy, a return to prepregnancy
levels should be considered during the first few weeks after delivery. Lamotrigine clearance
decreases quickly in the first week postpartum, and dose adjustments should be made
sooner. In one case series, postpartum taper schedules of lamotrigine appeared to reduce
the likelihood of maternal lamotrigine toxicity [35]. The dose was incrementally reduced at
postpartum days 3, 7, and 10, with return to preconception dose or preconception dose
plus 50 mg to help counteract the effects of sleep deprivation.
●The mother needs to be advised of the importance of adequate rest, sleep and
compliance with drug therapy.
●Precautions need to be taken to protect the infant if the mother has a seizure. It is
prudent, for example, to have another person present when the mother bathes the child. In
addition, the baby should be changed on the floor or an alternative safe position.
Breast feeding — All of the antiseizure drugs are measurable in breast milk [58,59]. The
reported percentage of maternal plasma levels in breast milk varies from 5 to 10 percent
with valproate [60] to 90 percent with ethosuximide [61]. There is no evidence to determine
whether this form of antiseizure drug exposure has clinical effects on the newborn [10]. Most
experts believe that taking antiseizure drugs does not generally contraindicate breast feeding,
as probable benefits outweigh risks [2].
Neurodevelopmental outcomes at age three years were examined in 199 children exposed to
either carbamazepine, lamotrigine, phenytoin, or valproate in utero; IQs for breastfed children
did not differ from non-breastfed children for all antiseizure drugs combined and for each of four
individual antiseizure drug groups [62]. The mean duration of breastfeeding was 7 months.
Similarly reassuring results were seen at six years, with breastfed children performing better
than nonbreastfed children on IQ and verbal domain testing, even after adjusting for potential
confounding through propensity score matching [63]. Another study that included 223 children
exposed to antiseizure drugs in utero found that prenatal exposure was associated with adverse
developmental outcomes regardless of breastfeeding status during the first year of life, but that
infants who were breastfed continuously for more than six months had slightly better outcomes
than those who were not breastfed [64]. In all of these studies, it is difficult to exclude residual
confounding by maternal intelligence and socioeconomic status as an explanation for the
improved outcomes among breastfed infants; nonetheless, results provide reassurance about
the lack of net harm.
Clinical experience generally suggests that problems tend to occur only with the sedative drugs,
such as phenobarbital, primidone, or benzodiazepines. Exposure to these drugs may cause the
child to become irritable, fall asleep shortly after beginning to nurse, or fail to thrive. If this
occurs, breast feeding may need to be discontinued but can be retried one week later.
One of the newer antiseizure drugs, lamotrigine, can be excreted extensively in breast milk
[65,66]. One study in 30 infants found that plasma concentrations were highly variable, but that
overall, lamotrigine exposure during lactation was at most marginally higher than that of other
antiseizure drugs and as with all other antiseizure drugs, considerably less than placental
transfer [67]. No adverse events in these infants were observed in the first postnatal year.
Small studies of levetiracetam, topiramate, and gabapentin have found that while present in

breast milk in concentrations similar to maternal plasma, the concentrations in infant plasma
were low, suggesting rapid elimination [68-70].
APPROACH TO A FIRST SEIZURE IN PREGNANCY — Occasionally, a woman presents with

a first seizure in pregnancy. With a few exceptions, the approach to diagnosis and management
of a first seizure is the same as in a nonpregnant individual. (See "Evaluation and management
of the first seizure in adults" and "Initial treatment of epilepsy in adults".)
Additional considerations in a pregnant woman include:

●Additional diagnostic considerations for new seizures might include pregnancy-associated
conditions, such as eclampsia and cerebral venous thrombosis.
(See "Eclampsia" and "Etiology, clinical features, and diagnosis of cerebral venous
thrombosis".)
●Depending on the stage of pregnancy, there may be safety concerns regarding the use of
neuroimaging procedures. Concern about the possible fetal effects of ionizing radiation
should not prevent medically indicated diagnostic procedures using the best available
modality for the clinical situation. The National Radiological Protection Board advises that
magnetic resonance imaging (MRI) be avoided in the first trimester since there is limited
experience assessing safety during organogenesis; however, MRI should be considered in
the first trimester when the benefit exceeds the theoretic risk. Gadolinium is generally
avoided because of adverse fetal effects in animal studies. (See "Diagnostic imaging
procedures during pregnancy".)
●Choice of antiseizure drug treatment is complicated by concerns of fetal safety. While no
antiseizure drug has been definitively shown to be safe in pregnancy, the evidence
linking valproate to fetal malformations is sufficiently convincing to recommend avoiding its
initiation in pregnancy. (See "Risks associated with epilepsy and pregnancy".)
●Other management issues follow those of individuals with established epilepsy in
pregnancy. (See 'Management during pregnancy and delivery' above.)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from

selected countries and regions around the world are provided separately. (See "Society
guideline links: Seizures and epilepsy in adults".)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials,

"The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain
language, at the 5th to 6th grade reading level, and they answer the four or five key questions a
patient might have about a given condition. These articles are best for patients who want a
general overview and who prefer short, easy-to-read materials. Beyond the Basics patient
education pieces are longer, more sophisticated, and more detailed. These articles are written
at the 10th to 12th grade reading level and are best for patients who want in-depth information and
are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print
or e-mail these topics to your patients. (You can also locate patient education articles on a
variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Basics topic (see "Patient education: Epilepsy and pregnancy (The Basics)")
SUMMARY AND RECOMMENDATIONS — Risks associated with pregnancy and epilepsy may

be minimized by interventions before and during pregnancy.
●Women of child bearing years should be counseled regarding the interactions between
antiseizure drugs and oral contraceptive therapy and the potential risks associated with
epilepsy and pregnancy. (See 'Preconception management' above.)
●The diagnosis of epilepsy and the need for ongoing antiseizure drug therapy should be
assessed before conception. Some women who have been seizure free for a prolonged
period may reasonably choose to discontinue antiseizure drug therapy prior to conception.
The risk of recurrent seizures varies based on the specific epilepsy syndrome and other
factors, and the decision should be individualized. (See 'Necessity for antiseizure
drugs' above.)
●Because there are no clear data indicating that any drug is without risk in pregnancy, we
suggest that patients planning pregnancy should be managed on the most effective
antiseizure drug for their seizures (Grade 2C). As an exception, valproateshould be
avoided if an alternate effective antiseizure drug regimen can be found (Grade 1B).
Monotherapy and the lowest possible drug dose may limit risk of teratogenicity. The
antiseizure drug regimen should be optimized six months prior to planned conception.
(See 'Choice of antiseizure drug' above.)
●We suggest NOT making changes to antiseizure drug regimen for the purpose of
reducing teratogenic risk in established pregnancy (Grade 2C). (See 'Choice of antiseizure
drug' above.)
●Folic acid supplementation (0.4 to 0.8 mg per day) is recommended for all women of child
bearing potential (Grade 1A). (See "Folic acid supplementation in pregnancy".)
●For women taking carbamazepine or valproate, or with a previously affected child, we
suggest higher dose folate supplementation, 4 mg per day, prior to conception (Grade 2B).
(See 'Folic acid supplementation' above.)
●We recommend monitoring both total and free plasma antiseizure drug levels during
pregnancy. A suggested schedule is: at weeks five to six, at week 10, and then at least
once each trimester, and again in the first or second postpartum
week. Lamotrigine and levetiracetam may need to be monitored more frequently.
(See 'Drug levels and dose adjustment' above.)
●For patients being treated with antiseizure drugs, we recommend offering prenatal
screening. (See 'Screening for malformations'above.)
●We suggest oral vitamin K supplementation, 10 to 20 mg/day, in the last month of
pregnancy for women taking enzyme-inducing antiseizure drugs
(eg, phenobarbital, carbamazepine, phenytoin, topiramate, oxcarbazepine) (Grade 2C).
(See 'Vitamin K supplementation' above.)
●Antiseizure drug therapy is generally not considered a contraindication to breast feeding.
(See 'Breast feeding' above.)
Risks associated with epilepsy and pregnancy

Author:
Steven C Schachter, MD
Section Editors:
Paul Garcia, MD
Charles J Lockwood, MD, MHCM
Deputy Editor:
April F Eichler, MD, MPH
Contributor Disclosures
All topics are updated as new evidence becomes available and our peer review process is
complete.
Literature review current through: Aug 2017. | This topic last updated: Aug 01, 2017.
INTRODUCTION — Over 90 percent of women with epilepsy have a normal pregnancy. This

point should be emphasized to the patient who is likely to have many fears and anxieties
regarding the risks. Nonetheless, women with epilepsy are at increased risk for a range of
perinatal complications compared with the general population, including preeclampsia, preterm
labor, and fetal and maternal mortality. It is important for physicians and women with epilepsy to
be aware of these as careful planning and management of pregnancy can increase the odds of
a favorable outcome.
There are a number of important issues to be addressed by the physician when a woman with
epilepsy becomes pregnant; these include:
●Are antiseizure drugs necessary?

●What effect do antiseizure drugs have on the fetus?
●What effect does maternal epilepsy have on the fetus?
●What effect does pregnancy have on seizures?
●How should the patient be managed during pregnancy and delivery?
●How should the patient be managed during the postpartum period?
This topic will discuss the risks associated with epilepsy and pregnancy. The management of
pregnancy and epilepsy is discussed separately. (See "Management of epilepsy and
pregnancy".)
PERINATAL MORBIDITY AND MORTALITY — A growing body of literature indicates that

perinatal morbidity and mortality are increased among women with epilepsy compared with the
general population; complications range from mild to severe and include preeclampsia, preterm
labor, bleeding, placental abruption, poor fetal growth, prematurity, fetal death, and maternal
mortality [1-10]. The magnitude of the increase in risk appears to be relatively small for most
complications (ie, between 1 and 1.5 times expected rates), with the exception of maternal
mortality, which may be as much as 10-fold higher among women with epilepsy during the
delivery hospitalization [9].
Risk estimates derived from a population-based cohort study of delivery hospitalizations in

69,383 pregnant women with epilepsy and over 20 million pregnant women without epilepsy in
US hospitals between 2007 and 2011 [9] are generally similar to those derived from a meta-
analysis of previous smaller studies [10]. Risk was significantly higher among women with
epilepsy across a wide range of perinatal outcomes, including [9]:
●Maternal death: 80 deaths per 100,000 pregnancies among women with epilepsy,
compared with 6 deaths per 100,000 pregnancies among women without epilepsy
(adjusted odds ratio [OR] 11.5, 95% CI 8.6-15.1)
●Cesarean delivery: 41 versus 33 percent (OR 2.5)
●Pregnancy-related hypertension (11 versus 8 percent; OR 1.3) and preeclampsia (7
versus 4 percent; OR 1.6)
●Antepartum hemorrhage (2.1 versus 1.5 percent; OR 1.4) and postpartum hemorrhage,
including severe postpartum hemorrhage (0.7 versus 0.4, OR 1.8)
●Preterm labor (11 versus 7 percent; OR 1.5)
●Poor fetal growth (4 versus 2 percent; OR 1.7)
●Stillbirth (0.8 versus 0.6; OR 1.3)
The specific causes of maternal death could not be determined by this study. There are a
number of possibilities, including an increase in medical comorbidities among women with
epilepsy, an increase in life-threatening complications of pregnancy, and an increase in seizure-
related complications, including sudden unexpected death in epilepsy (SUDEP). Previous,
smaller studies have also raised concern that mortality rates may be higher in women with
epilepsy compared with the general population of pregnant women and provided some insight
into the contribution of SUDEP [11,12].
●A study that examined all epilepsy-related deaths in a United Kingdom population-based

registry for maternal deaths during pregnancy found 14 deaths in women with epilepsy out
of a total of over two million pregnancies [12]. Eleven out of fourteen deaths (80 percent)
were attributed to SUDEP in the period from 2006 to 2008. Using these numbers and an
estimate of the expected rate of epilepsy in the overall population of pregnant women in the
United Kingdom (0.6 percent), the authors estimated a death rate from epilepsy of 1 in
1,000 among women with epilepsy, which was tenfold higher than the estimated rate in the
overall study population (11 per 100,000).
●This rate is similar in magnitude to estimates of SUDEP risk in the chronic epilepsy
population, and therefore the pregnancy-attributable risk of SUDEP among women with
epilepsy is not certain. Two-thirds of the deaths were in women treated with lamotrigine;
additional details of seizure control and other potential risk factors for SUDEP were not
available from the study [12]. SUDEP is discussed in more detail separately. (See "Sudden
unexpected death in epilepsy".)
There appears to be a modest increase in the risk of fetal death or stillbirth among women with
epilepsy, although studies are not entirely consistent [9,10]. The mechanism of an increased
risk of fetal death among women with epilepsy is also not well understood. Some studies have
found that treated versus untreated epilepsy carried a higher risk of miscarriage or stillbirth; but
treatment may have been a marker for more serious epilepsy rather than the cause of mortality
[13]. In a large European registry, only 1 of 165 reported miscarriages or stillbirths was
associated with seizures or status epilepticus (SE); two-thirds of these pregnancies were
seizure free [14].
Data on whether antiseizure drug exposure contributes to risk of spontaneous miscarriage are
mixed, but in aggregate the contribution appears to be minimal [10]. In a large population-based
observational study that included nearly one million pregnancies, women using antiseizure
drugs during pregnancy had a slightly higher risk of spontaneous abortion compared with
women not using antiseizure drugs (adjusted risk ratio [aRR] 1.13, 95% CI 1.04-1.24); however,
when limited to women with an epilepsy diagnosis, the use of antiseizure drugs was not
associated with increased risk (aRR 0.98, 95% CI 0.87-1.09) [15].
EFFECT OF PREGNANCY ON SEIZURES — The frequency of seizures does not increase

during pregnancy in the majority of women with epilepsy [2,6,16-18]. A large European registry
of epilepsy in pregnancy confirmed the statistics related to seizure control in pregnancy which
had been previously reported in an aggregate of smaller studies [14]. Among 1956 pregnancies
in 1882 women with epilepsy, seizure frequency and antiseizure drug treatment remained
unchanged in 62 to 64 percent; 58 percent were seizure free during pregnancy. Risk factors for
seizures during pregnancy included localization-related (focal) epilepsy as compared with
generalized epilepsy and antiseizure drug polytherapy. SE occurred in 1.8 percent, one-third of
which were convulsive type. No risk factors for SE were identified. In a cohort of 1297
pregnancies in women with epilepsy, seizures during the month prior to pregnancy was the
most important predictor of seizures during pregnancy; other independent predictors included
partial (versus generalized) seizures and polytherapy [19]. (See "Localization-related (focal)
epilepsy: Causes and clinical features".)
Women with catamenial epilepsy may have improved seizure control during pregnancy, possibly
attributable to the absence of cyclical hormone variations and increased progesterone levels. In
a prospective study of 274 women with epilepsy, women with catamenial epilepsy (n=59) were
more likely to be seizure-free than those with non-catamenial epilepsy (80 versus 22 percent)
[20].
Many women who experience increased seizure frequency are sleep deprived or noncompliant
because of concerns about the effects of the medication on the developing fetus [21,22]. Altered
antiseizure drug pharmacokinetics may also contribute to change in seizure frequency during
pregnancy. (See "Management of epilepsy and pregnancy", section on 'Drug levels and dose
adjustment'.)
Seizures rarely occur at the time of delivery, in only 3.5 percent of the European cohort [14].
Labor and delivery are not usually associated with increased complications.
OTHER MATERNAL RISKS — Individuals with epilepsy have an increased prevalence of

comorbid depression and anxiety compared with individuals without epilepsy, and this appears
to be true during pregnancy and the postpartum period as well. In a population-based study that
included 706 pregnancies in women with epilepsy and over 100,000 pregnancies in those
without epilepsy, peripartum depression affected 27 percent of women with epilepsy compared
with 23 percent of women with other chronic diseases and 19 percent of the entire non-epilepsy
population [23]. Rates of anxiety were similarly elevated in women with epilepsy compared with
all others (22 versus 15 percent). Risk factors for depression or anxiety among women with
epilepsy included high seizure frequency, history of physical and/or sexual abuse, adverse
socioeconomic factors, previous loss of a child, antiseizure drug use, unplanned pregnancy, and
prepregnancy depression or anxiety.
Detection of depression during pregnancy is important because both pharmacologic and

nonpharmacologic treatments are available, and untreated illness may have consequences for
both mother and child. Several studies have suggested that women with epilepsy may be
undertreated compared with women without epilepsy [23,24], emphasizing the importance of
screening and appropriate treatment. (See "Unipolar major depression during pregnancy:
Epidemiology, clinical features, assessment, and diagnosis", section on 'Potential adverse
outcomes' and "Mild to moderate antenatal unipolar depression: Treatment" and "Severe
antenatal unipolar major depression: Treatment".)
EFFECT OF ANTISEIZURE DRUGS ON THE FETUS
Fetal and neonatal effects
Overview and risk factors — There is an increased risk of both major and minor
malformations in fetuses exposed to the antiseizure drugs. The reported risk of major fetal
malformations in women taking antiseizure drugs is 4 to 6 percent, compared with a population
estimate of 2 to 3 percent [16,25-29].
The most common major congenital malformations associated with antiseizure drugs are neural
tube, congenital heart and urinary tract defects, skeletal abnormalities, and cleft palate
[25,30,31]. The risk of certain dysmorphic features (generally considered minor malformations)
associated with the administration of antiseizure drugs is less clear [32,33]. Many of these drugs
appear to be implicated in dysmorphisms, such as hypoplasia of the nails and distal phalanges,
hypertelorism, and the "anticonvulsant face" (broad or depressed nasal bridge, short nose with
anteverted nostrils, long upper lip, maxillary hypoplasia) [32,34]. In a retrospective review of
children born to mothers with epilepsy, 74 percent of children exposed to antiseizure drugs in
utero were identified by a panel of expert dysmorphologists as having facial features that were
either mildly, moderately, or obviously suggestive of fetal anticonvulsant syndrome; however, 61
percent of unexposed children also had these facial features, suggesting that these can be
nonspecific [35,36]. The term fetal anticonvulsant syndrome is often used to describe infants
exposed to antiseizure drugs in utero who are born with congenital malformations. However,
none of these malformations are specific to antiseizure drug exposure.
Some groups may be at higher risk than others:

●The risk of fetal malformations is strongly influenced by antiseizure drug therapy, in
particular valproate exposure [28,29,31]. Phenytoin, carbamazepine, phenobarbital,
and topiramate have also been associated with higher baseline rates of fetal malformations
[2,7,13,27,31,37-41]. The risks associated with other antiseizure drugs are not yet certain.
●Polytherapy with more than one antiseizure drug is a risk factor for fetal malformation as
identified in a number of prospective, registry studies, with a risk of major malformation
increasing to 6 to 8.6 percent [27,29]. Polytherapy with a regimen that
includes valproate or topiramate represents a particularly high risk for fetal malformation
[42,43].
●A family history of birth defects, low folate levels, and a low maternal level of education
have been identified as additional risk factors for fetal malformations, at least in some
studies [27,28,31,40,44-47].
●In addition to the specific antiseizure drug used alone or in combination, the gestational
timing of the exposure and the dose of the antiseizure drug used are also likely to be
important. These have been best associated with valproate [28,31,41,47,48].
●Women with one antiseizure drug-exposed pregnancy resulting in major congenital
malformation are at increased risk in subsequent pregnancies [49,50]. The risk appears to
be particularly high for valproate and topiramate, but may also be increased for other
antiseizure drugs and in pregnancies exposed to polypharmacy. In two different registry
studies, women taking valproate who had a previous child with a major congenital
malformation had a recurrence risk of approximately 50 percent if they continued valproate
during the subsequent pregnancy [49,50].
The mechanism for antiseizure drug-induced teratogenicity has not been determined. One
possibility is that some fetuses have low or deficient epoxide hydrolase activity that results in
increased levels of teratogenic oxidative metabolites when they are exposed to antiseizure
drugs [51]. Another mechanism involves oxidative damage to DNA from free radical
intermediates produced by prostaglandin H synthase bioactivation of antiseizure drugs [52].
Deficiency of folic acid has also been implicated in teratogenicity associated with antiseizure
drugs, which are folic acid antagonists.
Valproate — One to 2 percent of fetuses exposed to valproate in utero develop neural-tube like

defects (spina bifida aperta, open lumbosacral myelocele), a 10- to 20-fold increase over the
general population [38,53,54]. There also may be a pattern of major malformations consisting of
meningomyelocele, cardiovascular, and urogenital malformations with minor craniofacial,
skeletal, and genital anomalies [54]. One retrospective review of children exposed to valproate
in utero examined by expert dysmorphologists found that abnormal facial features were seen in
more than 90 percent, compared with 61 percent of unexposed children and 48 to 79 percent of
children exposed to other antiseizure drugs. Higher valproate doses are associated with more
frequent and more severe dysmorphia [31,35,36].
First trimester maternal exposure to valproic acid (VPA) increases the risk of major
malformations, independent of any contribution of the epilepsy syndrome itself [4,7,55]:
●The North American Antiepileptic Drug Pregnancy Registry followed 323 valproate-
exposed pregnancies to completion [56,57]. The prevalence of major birth defects in
offspring of women who received valproate monotherapy was 9.3 percent, as compared
with 2.9 percent in offspring of women receiving other antiseizure drugs and 1.1 percent in
an antiseizure drug unexposed control group. Thus, the relative risk of major malformation
in VPA-exposed women was 9.0 (95% CI 3.4-23.3). Increased dose of VPA was also
associated with increased risk (OR = 3.7 for VPA ≤1500 mg/day versus OR=10.9 for VPA
>1500 mg/day) [28], a finding also seen in other studies [31,47].
●A case-control study using the European Surveillance of Congenital Anomalies database
(registering a combined total of 98,075 major congenital malformations) found that VPA
was associated with an increased risk for several congenital malformations [58]. Compared
with no antiseizure drug use, adjusted odds ratios for specific malformations were: spina
bifida (12.7), atrial septal defect (2.5), cleft palate (5.2), hypospadias (4.8), polydactyly
(2.2), and craniosynostosis (6.8). Odds ratios were similarly elevated for the comparison of
VPA use to other antiseizure drug use.
The effect of VPA on malformation risk is dose-dependent, but a lowest safe dose has not been
established [41,48,59,60]. In the Australian registry of Antiepileptic Drugs in Pregnancy, 17
percent of 110 infants exposed to valproate had malformations, a higher incidence than for
infants exposed to other antiseizure drugs alone or in combination (OR = 8.56; 95% CI 3.52-
21.2) [48]. Valproate doses ≤1400 mg per day were associated with lower rates of
malformations than higher doses (OR = 0.109; 95% CI 0.04-0.30). Data from the same registry
also suggests that while the risk of spina bifida and hypospadias decreases with lower doses,
the risk of other malformations (eg, cleft lip/palate, atrial septal defects) does not [59].
In rare patients, neonatal coagulopathy, due to hypofibrinogenemia caused by VPA, has been
reported [61,62].
Phenytoin — Orofacial clefts, cardiac malformations, and genitourinary defects are the major
anomalies described with phenytoin[7,30,37,41,63,64].
In utero exposure to phenytoin has been associated with the development of neuroblastoma in

several case reports [65]. (See "Epidemiology, pathogenesis, and pathology of
neuroblastoma".)
Phenobarbital — Malformations of the heart, orofacial, and urogenital structures occur with

increased frequency with phenobarbital [7,30,63,64,66,67].
Findings from the North American Antiepileptic Drug Pregnancy Registry found a 5.5 percent
incidence of major malformations among 199 pregnancies associated with phenobarbital use, a
rate that was somewhat higher than for unexposed pregnancies and for those exposed
to lamotrigine. [57].
Carbamazepine — Carbamazepine has been associated with major malformations, in
particular, spina bifida [7,54,68]. As many as 0.9 percent of fetuses exposed in utero to
carbamazepine have spina bifida aperta (a seven-fold increase) [30,54,69,70]. However, in the
United Kingdom Epilepsy and Pregnancy Registry, compared with other antiseizure drugs,
carbamazepine was associated with the lowest rate of major congenital malformations: 2.2
percent of 900 pregnancies [29]. The incidence of neural tube defects in carbamazepine-
exposed pregnancies was 0.2 percent in this study. Similarly, in the North American
Antiepileptic Drug pregnancy and in the EUROCAT Antiepileptic Study Database, the risk of
fetal malformations associated with carbamazepine monotherapy was 2.9 percent and 3.3
percent respectively [42,57,68]. Another registry reported a 4.5 percent incidence of
genitourinary malformations in infants born to mothers on carbamazepine monotherapy [41].
Topiramate — Data from the North American Antiepileptic Drug Pregnancy registry and the
United Kingdom Epilepsy and Pregnancy registry indicate that topiramate is associated with an
increased incidence of oral clefts in infants of exposed mothers [71]. In the North American
study, a 1.4 percent prevalence of oral clefts in topiramate-exposed infants was associated with
a 21.3 relative risk (95% CI: 7.9 to 57.1) compared with a background population of untreated
women [57]. In the United Kingdom population, the 3.2 percent prevalence of oral clefts in
newborns exposed to topiramate was 16 times higher than their background population. Across
multiple studies to date, the estimated absolute risk of oral clefts in a topiramate-exposed
pregnancy has ranged from 5 to 29 per 1000 births, compared with an expected unexposed risk
in the background population of 1 to 2 per 1000 births [57,72-74].
The risk of fetal malformations is increased further in association with polytherapy regimens that
include topiramate. In an Australian registry cohort study, for example, the fetal malformation
rate was more than two times higher in polytherapy pregnancies that included topiramate
compared with those that did not (14.9 versus 6.6 percent) [75].
Topiramate use in pregnancy may also increase the risk for low birth weight. In a study from the
North American Antiepileptic Drug Pregnancy Registry, the prevalence of small-for-gestational-
age (SGA) was 18 percent in 347 topiramate-exposed neonates and 12 percent in 98
zonisamide-exposed neonates, compared with 7 and 5 percent in lamotrigine-exposed
neonates and unexposed controls, respectively [76]. The risk of SGA was significantly elevated
for both topiramate (RR 3.5, 95% CI 2.1-5.7) and zonisamide(RR 2.2, 95% CI 1.1-4.4)
compared with controls after adjusting for multiple factors, including maternal age, parity,
smoking status, education, and periconceptional folic acid intake.
Lamotrigine — Data on lamotrigine exposure are mostly reassuring, although studies have not

been entirely consistent:
●Multiple registry studies have reported a 1.9 to 3.2 percent incidence of major
malformations after first trimester exposure to lamotrigine monotherapy, rates that are not
elevated compared with unexposed controls and estimates from population-based cohorts
[29,42,57,72,77-79]. Similarly, in a US cohort of >1.3 million pregnancies that included
1945 women with lamotrigine exposure during the first trimester, there was no increase in
the rate of cardiac, noncardiac, and overall malformations in lamotrigine-exposed infants
compared with unexposed infants after adjusting for multiple potential confounders [80].
The daily dose of lamotrigine in exposed infants was relatively low (≤200 mg/day in 78
percent of women), and the indication for lamotrigine (eg, bipolar disorder, pain, epilepsy)
was not specified. Women with exposure to any other antiseizure drugs were excluded
from the study.
●The data regarding risk and dose of lamotrigine has been conflicting. The International
Lamotrigine Pregnancy Registry found no effect of lamotrigine dose, up to 400 mg/day, on
the incidence of major malformations [79,81]. However, the United Kingdom Epilepsy and
Pregnancy Registry did observe a dose-relationship and suggested that doses higher than
200 mg per day might present a risk similar to that of valproate [29]. In the EURAP
Epilepsy and Pregnancy Registry, the incidence of fetal malformations with lamotrigine at
any dose was low, but was significantly higher for patients taking 300mg or more each day
than for patients taking lower doses (2.0 versus 4.5 percent) [31].
●Data released from the manufacturer's pregnancy registry in January 2008 reported that
the risk of major malformations after exposure to lamotrigine used in polytherapy with other
antiseizure drugs, not including VPA, was similar to that of lamotrigine monotherapy, but
was increased in those exposed to lamotrigine and VPA, (16 of 143 pregnancies, 11.2
percent) [78]. These findings were similar in the final report of the International Lamotrigine
Pregnancy registry [79].
●A report from the North American Antiepileptic Drug Pregnancy Registry noted a higher
than expected prevalence of cleft palate and/or cleft lip in infants exposed to lamotrigine in
the first trimester, of 8.9 per 1000 compared with the expected 0.7 to 2.5 per 1000 [82].
However, population-based case control studies derived from a European congenital
anomaly register found that lamotrigine monotherapy did not specifically increase the risk
of isolated orofacial clefts relative to other malformations [83,84]. These studies were not
designed to study whether lamotrigine was associated with a generalized risk of
malformations, and therefore could not determine an association.
Levetiracetam — Levetiracetam use in pregnancy appears to be associated with a low risk of

major congenital malformations when used as monotherapy. The United Kingdom Epilepsy and
Ireland Pregnancy registry reported a risk of 0.7 percent in 304 pregnancies exposed to
levetiracetam monotherapy [85], which is lower than the 2.4 percent risk reported in 450
pregnancies followed by the North American Antiepileptic Drug Pregnancy Registry [57] and
similar to rates in the unexposed nonepilepsy population. Higher rates have been reported in
pregnancies exposed to levetiracetam as part of a polytherapy regimen [85]. Limited data
suggest that intrauterine exposure to levetiracetam monotherapy does not adversely affect early
developmental outcomes, in contrast with drugs such as valproate [86,87]. (See 'Long-term
effects' below.)
Pregabalin — Animal studies and at least one prospective cohort study have raised concern
about possible risk of major birth defects related to first trimester exposure to pregabalin [88,89].
In a multicenter observational study, first trimester exposure to pregabalin (mostly for indications
other than seizure disorder) was associated with an increased rate of major birth defects
compared with no exposure (6 versus 2 percent) [89]. Limitations of this study included the
small number of exposed pregnancies (n = 164), high rates of polypharmacy and tobacco use
among women taking pregabalin, as well as differences in medical comorbidities between
exposed and unexposed women [90]. In a subsequent larger retrospective study that included
477 exposed infants among more than 1.3 million pregnancies, the association between
pregabalin exposure and major congenital malformation was no longer significant when
propensity-score matching was used to control for potential confounding (RR 1.18, 95% CI 0.81-
1.67) [91].
Other drugs — There is limited human information on the fetal risks of other antiseizure drugs
(eg, gabapentin, felbamate, tiagabine). While animal and other preliminary data are reassuring
[92], patients should be counseled that the actual risks are largely unknown at this time.
In a registry-based study in Denmark, major birth defects were detected in 11 of 393 infants
exposed to oxcarbazepine, a rate that was not significantly higher than in nonexposed infants
[72]. Several small case-control studies as well as larger registry-based studies that include a
limited number of gabapentin-exposed pregnancies have found no association
between gabapentin and major birth defects [57,72,93,94].
As described above, zonisamide use during pregnancy may be associated with an increased

risk for low birth weight. (See 'Topiramate' above.)
Long-term effects — There is accumulating evidence from observational studies that

anticonvulsant treatment during pregnancy may have deleterious effects on the cognitive and
neurologic function of the offspring that may manifest later in life [25,95-101].
Valproate is the most strongly associated with adverse cognitive and developmental outcomes
[7,102-113]. Several studies illustrate these risks:
●A prospective study of 309 children who had been exposed to antiseizure drugs in utero
found that at age three years, children exposed to valproate had IQ scores that were on
average six to nine points lower than those exposed to lamotrigine, phenytoin,
or carbamazepine [104]. These findings persisted at six years [110]. Further support for
this association are the findings that the relationship between IQ score and valproate
exposure was dose related, and that children's IQ scores were related to maternal IQ
scores in all exposure groups except for valproate [105].
●A prospective blinded study of 182 children of mothers with epilepsy and 141 controls
found significantly lower verbal intelligence associated with exposure to valproate and
antiseizure drug polytherapy but not to carbamazepine monotherapy [106]. In another
registry-based study, 102 school-aged children exposed to valproate in utero had lower
than mean average language test scores on blinded assessments [107]. Similarly, in a
prospective study of 172 infants (mean age of 15 months), in utero exposure to valproate
monotherapy was associated with lower mental and motor developmental quotients
compared with carbamazepine monotherapy [108].
In utero exposure to valproate also appears to increase the risk of autism spectrum disorders
[109,114-117]. In a population-based study of more than 650,000 children born in Denmark from
1996 through 2006 that included 6584 women with epilepsy, 2655 antiseizure drug-exposed
pregnancies and 508 valproate-exposed pregnancies, the risk of autism spectrum disorder was
increased in children exposed to valproate in the overall study population (HR 2.9, 95% CI 1.7 –
4.9; absolute risk 4.42%) as well as in valproate-exposed children born to mothers with epilepsy
(HR 1.7, 95% CI 0.9 – 3.2; absolute risk 4.15%) [117]. For the more narrowly-defined diagnostic
code of childhood autism, the relative risk was increased fivefold (absolute risk, 2.5%). Analyses
were adjusted for parental age at conception, parental psychiatric history, gestational age, birth
weight, sex of the child, congenital malformations, and parity. An increased risk of autism
spectrum disorders was also observed in children exposed to valproate whose mothers had
diagnoses other than epilepsy, but not in children of women who were previous users of
valproate but stopped at least 30 days before conception; both of these factors increase
confidence in the association. An increased risk was not observed in association with other
antiseizure drugs, including carbamazepine, oxcarbazepine, lamotrigine, and clonazepam,
although the number of events in these subgroups was low.
Reports from other studies also implicate phenytoin, carbamazepine, primidone,

and phenobarbital exposures with impaired cognitive performance later in life [7,101,105,118-
120]. Polytherapy may present a higher risk than monotherapy [7,100,118], and verbal abilities
may be particularly affected [105,121]. Some studies find that the risk of cognitive impairments
is highest in those who also have one or more of the congenital malformations described above
[35,36,122]. In one prospective comparative study, intellectual quotient at 4.5 years was lower
for children exposed to valproate compared with carbamazepine, phenytoin or lamotrigine, but
verbal abilities were impaired compared with nonverbal skills for all four drugs [105].
(See "Management of epilepsy and pregnancy", section on 'Choice of antiseizure drug'.)
Limited available data on cognitive outcomes in children exposed

to levetiracetam or topiramate in utero are reassuring [113].
EFFECT OF EPILEPSY ON THE FETUS — In addition to concerns about fetal exposure to

antiseizure drugs, there are risks to the fetus from maternal seizures and maternal epilepsy. As
mentioned above, a history of epilepsy alone does not appear to increase the risk of fetal
malformations [27]. However, this study did not directly assess the risk associated with maternal
seizures during pregnancy.
Risk to the fetus of maternal seizures — Few studies have been performed on the direct
effects of maternal seizures on the fetus. Fetal hypoxia may occur as a result of decreased
placental blood flow or postictal apnea; but no information is available on the number or length
of seizures that may jeopardize the fetus [123,124]. One report of fetal heart rate monitoring
during a maternal generalized tonic-clonic seizure lasting 2.5 minutes revealed significant fetal
heart rate deceleration lasting up to 30 minutes after the seizure [123]. While nonconvulsive
seizures are believed to be less dangerous, another case report has documented significant
fetal bradycardia during a one-minute, complex partial seizure [124].
Additional risks of maternal seizures include injury to the fetus, abruption, or miscarriage due to
maternal trauma sustained during a seizure.
One prospective study found no association between first trimester seizures and major fetal
malformations, but the confidence intervals were wide (odds ratio 0.6, 95% CI 0.1-2.9) [40].
Another cohort study reported that the occurrence of one or more major antepartum seizures in
63 epileptic women did not significantly increase the rate of antepartum complications,
congenital anomalies, stillbirth, fetal growth restriction, or microcephaly compared with epileptic
women without antepartum seizures; however, long-term outcome data were not provided [3].
Finally, in a population-based data set in Taiwan, epileptic seizures during pregnancy were
marginally associated with small for gestational age infants compared with women with epilepsy
who did not suffer seizures during pregnancy (HR 1.37; 95% CI:1.01-1.84) [125].
Even for SE, the risks to the fetus are unclear. In a large European registry of 1956 pregnancies
in 1882 women with epilepsy, SE occurred in 1.8 percent, one-third of which were convulsive
type [14]. Only one case of SE was associated with stillbirth; the remaining cases were not
clearly associated with fetal or maternal complications.
Inheritance of epilepsy — Epilepsy affects approximately 0.5 to 1 percent of the general

population; the risk of a seizure disorder is greater among the children of with a parent with
epilepsy [126-130].
The best estimates of familial risk come from a population-based study that included 660
individuals with epilepsy and nearly 2500 first-degree relatives living in a single county in the
northern US [130]. The cumulative incidence of any form of epilepsy by age 40 years was 4.5
percent among individuals with a first-degree relative with epilepsy, which was threefold higher
than the incidence in the general population. The risk was highest for relatives of individuals
with generalized epilepsy (standardized incidence ratio [SIR] 8.3) and lowest for relatives of
those with focal epilepsy (SIR 2.6).
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from

selected countries and regions around the world are provided separately. (See "Society
guideline links: Seizures and epilepsy in adults".)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials,

"The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain
language, at the 5th to 6th grade reading level, and they answer the four or five key questions a
patient might have about a given condition. These articles are best for patients who want a
general overview and who prefer short, easy-to-read materials. Beyond the Basics patient
education pieces are longer, more sophisticated, and more detailed. These articles are written
at the 10th to 12th grade reading level and are best for patients who want in-depth information and
are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print
or e-mail these topics to your patients. (You can also locate patient education articles on a
variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Basics topic (see "Patient education: Epilepsy and pregnancy (The Basics)")
SUMMARY — While the majority of women with epilepsy will have uncomplicated pregnancies,
there is a higher risk of certain complications in this population.
●Perinatal morbidity and mortality appear to be increased among women with epilepsy
compared with the general population across a range of outcomes. The magnitude of the
increase in risk appears to be relatively small for most complications (ie, between 1 and 1.5
times expected rates), with the exception of maternal mortality, which may be as much as
10-fold higher among women with epilepsy during the delivery hospitalization.
(See 'Perinatal morbidity and mortality' above.)
●Most women will have no alteration of their seizure pattern during pregnancy, especially if
noncompliance and sleep deprivation are minimized. Altered pharmacokinetics of
antiseizure drugs during pregnancy may also contribute to increased seizure frequency in a
small number of women (see 'Effect of pregnancy on seizures' above).
●Both major and minor malformations are more common in fetuses exposed to antiseizure
drugs in utero compared with offspring of untreated women with epilepsy and women
without epilepsy. The overall risk of major malformations is 4 to 6 percent; valproate is a
major contributor to this risk. Polypharmacy and higher antiseizure drug dose increase the
risk. The timing (early versus late in gestation) and dose of exposure are also likely to be
important. Valproate should be avoided in pregnancy, if possible. (See 'Fetal and neonatal
effects' above.)
●There is increasing evidence that antiseizure drug exposure in utero may be associated
with impaired cognitive development. The evidence for this association is strongest
with valproate, which has been associated with impaired cognitive and motor development
as well as an increased risk of autism spectrum disorders. (See 'Long-term effects' above.)
●Seizures, particularly convulsive seizures, are believed to be harmful to the fetus. Fetal
bradycardia has been documented during maternal seizures. However, studies
documenting the risk that seizures pose to the fetus are lacking. (See 'Risk to the fetus of
maternal seizures' above.)
●Risks associated with pregnancy and epilepsy can be minimized by preconception
planning and careful management during pregnancy. (See "Management of epilepsy and
pregnancy".)

Epilepsy in Pregnancy

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Epilepsy in Pregnancy

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Berghella

• Carbamazepine, phenobarbital, primidone, phenyt- oin, valproate, and topiramate are

• As pregnancy progresses, both total and nonprotein- bound plasma concentrations of

• Monitor AED levels through the eighth postpartum week.

• There is insuf cient evidence to support or refute a bene t of prenatal vitamin K

• Seizure description by an eyewitness, including duration. • Postictal phase, description, and

infections, head trauma with loss of consciousness or

known structural lesion in the brain. • Family history.

168 MATERNAL-FETAL EVIDENCE BASED GUIDELINES

MANAGEMENTPrinciplesEffect of pregnancy on disease: Increase in hepatic cyto-

Also include in rst prenatal visit the following:

impressive amount of data. Carbamazepine, phenobar- bital, primidone, phenytoin,

• The risk-to-bene t ratio must be considered when select- ing a drug.

• There is a risk of AED-associated teratogenicity and neu- rodevelopment delay.

• Importance of medication compliance and AED level monitoring during pregnancy.

• In a retrospective population-based study, a tenfold increase in mortality was noted in

• A rst-trimester ultrasound is indicated for exact dating. • Anatomic ultrasound at 11 to 13

fetoprotein levels at 15 to 18 weeks gestation (up to 21

weeks).• If appropriate, amniocentesis for amniotic uid alpha-

fetoprotein and acetylcholinesterase levels.• Ultrasound at 16 to 20 weeks gestation can assess

THERAPY (TABLE 19.1)

• AED Pregnancy Registry: Phone number 1-888-233-2334.

Epilepsy During Pregnancy

TABLE 60-2. Teratogenic Effects of Common Anticonvulsant Medications

Breast Feeding and Contraception

Creasy and Resnik

EFFECT OF PREGNANCY ON SEIZURE DISORDERS

There is sometimes dificulty in maintaining adequate treatment with anticonvulsant drugs

EFFECT OF EPILEPSY ON PREGNANCY AND LACTATION

EFFECT OF MATERNAL EPILEPSY AND ANTICONVULSANT DRUGS ON

A major problem in management of epileptic patients during pregnancy is the possibility

GENERAL THERAPEUTIC APPROACHES

It is difficult to make more than general therapeutic recommendations about pregnancy in

Prenatal counseling is important. If a nonpregnant epileptic woman asks about

Data concerning the relative safety and therapeutic effectiveness of different

A solitary seizure, unrelated to toxemia, should not lead to a diagnosis of epilepsy

Although some physicians start a patient on anticonvulsant medication after one

If prophylactic anticonvulsant drug treatment is necessary, it is generally continued until

Patients must take medication as prescribed, and treatment should be controlled by

Several observations can serve as guidelines for management throughout pregnancy:

• 1 Steady-state plasma concentrations of most anticonvulsants decrease as pregnancy

• 2 These changes may be associated with breakthrough seizures, requiring an increase in

1 Ascertain the patient’s need for anticonvulsant medications.

4 Discuss the risks of anticonvulsant medications to the fetus.

5 Recommend folate supplementation (1mg/day) beginning before conception.

• 1 Maintain the concentration of anticonvulsant medication(s) at the level(s) required by the

• 2 Obtain plasma anticonvulsant levels every 3 to 4 weeks, or if a seizure occurs, if potential

• 3 Raise doses if necessary to maintain effective anticonvulsant activity. Dosage increments

• 5 Ifseizurecontrolisnotmaintainedandtheanticonvulsantdosehasbeen increased until toxic

• 9 Epilepsy is not usually considered an indication for early delivery.

First seizure during pregnancy

2 Examine the newborn carefully for signs of fetal teratogenic effects.

INTRODUCTION — Over 90 percent of women with epilepsy have a normal pregnancy. This

●Are antiseizure drugs necessary?

PRECONCEPTION MANAGEMENT — Epilepsy is not a contraindication for pregnancy. Over

Long-acting reversible contraceptives (LARC), including copper or levonogestrel intrauterine

Folic acid supplementation — Preconception folic acid supplementation (0.4 to 0.8 mg daily)

At present, we recommend the following approach. Antiseizure drug therapy should be

For these reasons, we generally avoid valproate in women planning to become pregnant if

Other recommendations concerning the use of antiseizure drugs include [13,21-23]:

Antiepileptic Drug Pregnancy Registry — The Antiepileptic Drug Pregnancy Registry (Toll-

MANAGEMENT DURING PREGNANCY AND DELIVERY — Management during pregnancy

Continued folic acid supplementation — Preconception doses of folate are recommended