The choice of antiepileptic medication depends on the seizure type. As the foregoing
literature review has shown, there are studies claiming teratogenesis for each of the major
anticonvulsant medications, yet there are also studies showing that each medication individually
may not be particularly teratogenic. The most important point is to control maternal seizures.
There may be some additional concern for using valproate in pregnancy due to the reported
increased incidence of fetal distress. It is important to note that this finding has not been
corroborated in other studies. Therefore, if valproate is the anticonvulsant that works best for the
patient, it should be used without hesitation. If valproate is used, the dose should be divided over
three to four administrations daily to avoid high peak plasma levels.
In the past, it was thought that carbamazepine was the anticonvulsant of choice and had the least
teratogenic effect. As has been shown in the foregoing literature review, there are studies that
report malformations with the use of carbamazepine. It is important to stress again that the
anticonvulsant that does the best job of controlling seizures is the one that should be used for the
patient. There is little information concerning the newer antiepileptic drugs and teratogenesis. If,
however, they need to be used for good seizure control, they should be implemented as part of
the patient's therapy.
Folic acid supplementation should be begun before or early in pregnancy. Folic acid
supplementation may help to prevent neural tube defects, which are more common in treatment
with carbamazepine and valproate but have been reported in women taking other
anticonvulsants. Studies have shown that folic acid may decrease the incidence of neural tube
defects in at-risk women. It is important that this be implemented early in pregnancy, as open
neural tube defects occur by the end of the fifth week of gestation. Furthermore, low folate levels
have been associated with an increase in adverse pregnancy outcomes in women taking
anticonvulsants. Anticonvulsant levels should be checked frequently after implementing or
increasing folic acid administration, as it leads to lower anticonvulsant levels. A daily dose of 4
mg/day should be more than ample. Patients should also be encouraged to take their prenatal
vitamins, which contain vitamin D. This is because anticonvulsants may interfere with the
conversion of 25-hydroxycholecalciferol to 1-25-dihydroxycholecalciferol, the active form of
vitamin D.
Whether or not they ask, all mothers with idiopathic epilepsy wonder if their child will
develop epilepsy. There is a surprising paucity of studies in this area. Children of parents without
seizures have a 0.5 to 1 percent risk of developing epilepsy. It appears that the infant born to a
mother with a seizure disorder of unknown etiology has a four times greater chance of
developing idiopathic epilepsy than the general population. Furthermore, it appears that epilepsy
in the father does not increase a child's risk of developing a seizure disorder. Many of the rare
seizure disorders have a stronger genetic component.
Care of the Patient During Pregnancy
Once the patient becomes pregnant, it is of the utmost importance to establish accurate
gestational dating. This will prevent any confusion over fetal growth in later gestation. The
patient's anticonvulsant level should be followed as needed and dosages adjusted accordingly to
keep the patient seizure free. It is a common pitfall to monitor levels too frequently and adjust
dosages in a likewise frequent manner. It is important to remember that it takes several half-lives
for a medication to reach a steady state (Table 37-3) . Drugs like phenobarbital have extremely
long half-lives, and the levels should not be checked too frequently. If levels are measured before
the drug reaches a steady state and the dosage is increased, the patient will eventually become
toxic from the medication. Drug levels should be drawn immediately before the next dose
(trough levels) in order to assess if dosing is adequate. If the patient is showing signs of toxicity,
a peak level may be obtained.
TABLE 37-3 -- ANTICONVULSANTS COMMONLY USED DURING PREGNANCY
Therapeutic
Drug
Level (mg/L)
Usual Nonpregnant Dosage
Half-Life
Carbamaz 4–10
600–1,200 mg/day in three or divided doses
Initially 36 h,
epine
(Two doses if extended-release forms are used) chronic therapy
16 h
Phenobarb 15–40
90–180 mg/day in two or three divided doses
100 h
ital
Phenytoin 10–20, total;
300–500 mg/day in single or divided doses *
Avg 24 h
1–2, free
Primidone 5–15
750–1,500 mg/day in three divided doses
8h
Valproic 50–100
550–2,000 mg/day in three or divided doses
Avg 13 h
acid
* If a total dose of more than 300 mg is needed, dividing the dose will result in a more stable
serum concentration.
At approximately 16 weeks' gestation, the patient should undergo blood testing for
maternal serum marker screening in an attempt to detect neural tube defect. This, coupled with
ultrasonography, gives a more than 90 percent detection rate for open neural tube defects. If the
patient is difficult to scan or if she wants to be even more certain that there is no neural tube
defect, amniocentesis can be undertaken. This should be considered if the patient is taking
valproate or carbamazepine, as these medications appear to carry almost the same risk as if the
patient had a family history of a neural tube defect.[ At 18 to 22 weeks, the patient should
undergo a comprehensive, targeted, ultrasound examination by an experienced obstetric
sonographer to look for congenital malformations. A fetal echocardiogram can be obtained at 20
to 22 weeks to look for cardiac malformations, which are among the more common
malformations of women taking any antiepileptic medications. If fetal echocardiography is not
readily available, it is reassuring to remember that an adequate "four-chamber view" of the heart
on ultrasound will identify 68 to 95 percent of major cardiac anomalies.[ As previously noted,
there appears to be an increased risk for intrauterine growth restriction for fetuses exposed in
utero to anticonvulsant medications. If the patient's weight gain and fundal growth appear
appropriate, regular ultrasound examinations for fetal weight assessment are probably
unnecessary. If, however, there is a question of fundal growth or if the patient's habitus precludes
adequate assessment of this clinical parameter, serial ultrasonography for fetal weight assessment
can be performed.
In older and retrospective studies, there appears to be an increased risk of stillbirth
in mothers taking anticonvulsant medications.[] In a prospective study, however, this
complication was not seen.[As previously noted, in the studies that showed an increase in
stillbirths, factors such as intrauterine growth restriction or oligohydramnios were not prenatally
identified. With modern surveillance and the more common use of ultrasonography, many of
these risk factors can be detected before the fetus faces imminent risk. Non-stress testing,
therefore, is not necessary in all mothers with seizure disorders. It should be limited to those who
have other medical or obstetric complications that place the patient at increased risk of stillbirth.
If at all possible, the patient should be maintained on a single medication, and drug levels should
be drawn at appropriate intervals to make certain that the patient is receiving enough medication.
If the patient is taking phenytoin, free levels should be obtained if possible. A drug dosage
should not be increased only because the total level of drug is falling. The free level of drug may
still be therapeutic. If, however, the patient develops any seizure activity, dosages should then be
adjusted upward. A brief seizure during pregnancy does not appear to be deleterious to the fetus.
It is best to use the lowest dose of a single medication possible that will keep the patient seizure
free. This, however, must be individualized. For instance, if the patient usually experiences
seizures during the day and drives, it is important to make certain that the patient remains seizure
free. For this type of patient, drug dosages should be increased if levels fall. If, on the other hand,
the patient only has brief partial complex seizures that do not generalize and occur only during
her sleep, it is optimal to keep the medications at the lowest serum concentration that will keep
her seizure free. An occasional seizure of this type would not harm either patient or fetus. The
key to managing anticonvulsants in pregnancy is individualization of therapy.
Early hemorrhagic disease of the newborn can occur in infants exposed to
anticonvulsants in utero, and this appears to be a deficiency of the vitamin K-dependent clotting
factors II, VII, IX, and X. The use of vitamin K in the third trimester to prevent hemorrhagic
disease is somewhat controversial. Although some advocate administering 10 to 20 mg of
vitamin K orally, daily, to mothers during the final few weeks of pregnancy, this is certainly not
the standard of care. There appears to be no adverse effect of administering this vitamin, but, on
the other hand, its utility has not been clearly demonstrated. Very little hemorrhagic disease of
the newborn is seen today, and this is probably because most infants receive 1 mg of vitamin K
intramuscularly at birth. This certainly should be given to all infants of mothers receiving
anticonvulsants. Because of early discharges and the shortened time of neonatal observation, it
might be prudent to check a prothrombin time on the cord blood at birth. This can be done by
taking fresh cord blood and placing it in a citrated blood tube and having it sent immediately for
prothrombin time. This might be especially prudent if the child is to undergo a very early
circumcision.
Labor and Delivery
Vaginal delivery is the route of choice for the mother with a seizure disorder. If the
mother has frequent seizures brought on by the stress of labor, she may undergo cesarean
delivery after stabilization. Furthermore, seizures during labor may cause transient fetal
bradycardia.[ The fetal heart rate should be given time to recover. If it does not, then one must
assume fetal distress and/or placental abruption and deliver by cesarean section. Because stress
often exacerbates seizure disorders, an epidural anesthetic can benefit many laboring patients
with epilepsy.
Management of anticonvulsant medications during a prolonged labor presents a
challenge. During labor, oral absorption of medications is erratic and, if the patient vomits,
almost negligible. If the patient is taking phenytoin or phenobarbital, these medications may be
administered parenterally. An anticonvulsant level should be obtained first to help ascertain the
appropriate dosage. Phenobarbital may be given intramuscularly, and phenytoin may be given
intravenously. Fosphenytoin, although expensive, is available and makes the administration of
intravenous phenytoin much easier. If the patient's phenytoin level is normal, the usual daily
dose may be administered intravenously. The medication may only be mixed in normal saline
and must be administered at a rate no faster than 50 mg/min. Fosphenytoin is easier to use.
Because of the long half-life of phenobarbital, if the patient's serum level is therapeutic, a 60- to
90-mg intramuscular dose will probably be sufficient to maintain the patient throughout labor
and delivery. The main problem arises if the patient is taking carbamazepine. This medication is
not manufactured in a parenteral form, although extended-release forms now exist. Oral
administration may be attempted, but, if the patient has seizures or a pre-seizure aura, she may be
loaded with a therapeutic dose of phenytoin to carry her through labor. The usual loading dose is
10 to 15 mg/kg administered intravenously at a rate no faster than 50 mg/min. This should be
effective in controlling seizures. Benzodiazepines may also be used for acute seizures, but one
must remember that they can cause early neonatal depression as well as maternal apnea. Prenatal
diagnostic techniques are not perfect. Even if the infant appears to have no anomalies, an
experienced pediatrician should be present at the delivery of the infant born to a mother taking
anticonvulsant medications.
New Onset of Seizures in Pregnancy and the Puerperium
Occasionally, seizures will be diagnosed for the first time during pregnancy. This
may present a diagnostic dilemma (Table 37-4) . If the seizures occur in the third trimester, they
are eclampsia until proven otherwise and should be treated as such until the attending physician
can perform a proper evaluation. The treatment of eclampsia is delivery, but the patient must first
be stabilized. It is often difficult, however, to distinguish eclampsia from an epileptic seizure.
The patient may be hypertensive initially after an epileptic seizure and may
TABLE 37-4 -- DIFFERENTIAL DIAGNOSIS OF PERIPARTUM SEIZURES
Blood
Protein Seizure
Pressure
uria
s
Timing
CSF
Other Features
Eclampsia
+++
+++
+++
Third
Early: RBC, Platelets normal
trimester
0–1,000;
or ↓ RBC
protein, 50– normal
150 mg/dl
Late: grossly
bloody
Epilepsy
Normal
Normal +++
Any
Normal
Low
to +
trimester
anticonvulsant
levels
Subarachnoid
+ to +++
0 to +
+
Any
Grossly
hemorrhage
(labile)
trimester
bloody
Thrombotic
Normal to
++
++
Third
RBC 0–100 Platelets ↓ ↓
thrombocytopen +++
trimester
ic purpura
RBC
fragmented
Amniotic fluid Shock
−
+
Intrapartum Normal
Hypoxia,
embolus
cyanosis
Platelets ↓ ↓
RBC normal
Cerebral vein
thrombosis
Water
intoxication
+
Normal
−
−
Pheochromocyto +++ (labile) +
ma
Autonomic
+++ with
−
stress syndrome labor pains
++
Postpartum
Normal
(early)
++
Intrapartum Normal
+
Any
Normal
trimester
Intrapartum Normal
−
Headache
Occasional
pelvic phlebitis
Oxytocin
infusion rate
>45 mU/min
Serum Na <124
mEq/L
Neurofibromato
sis
Cardiac
arrhythmia
of high
paraplegics
Toxicity of local Variable
−
++
Intrapartum Normal
anesthetics
Modified from Donaldson JO: Peripartum convulsions. In Donaldson JO (ed): Neurology of
Pregnancy. Philadelphia, WB Saunders, 1989, p 312.
exhibit some myoglobinuria secondary to muscle breakdown. The diagnosis becomes clearer
over time, but in either case, rapid, thoughtful action must be undertaken. The first physician to
attend a patient after a seizure may not be an obstetrician/gynecologist, and magnesium sulfate
may not be started acutely. This should be remedied as soon as possible.
If the patient at an earlier gestational age develops seizures for the first time, she should be
evaluated and started on the proper medication. The physician must be alert to look for acquired
causes of seizures including trauma, infection, metabolic disorders, space-occupying lesions,
central nervous system bleeding, and ingestion of drugs such as cocaine and amphetamines. The
patient must be stabilized, and the physician must make certain that an adequate airway is
established for the protection of both mother and fetus. The physician should also look for focal
signs that may be more suggestive of a space-occupying lesion, central nervous system bleeding,
or abscess.
Blood should be obtained for electrolytes, glucose, calcium, magnesium, renal
function studies, and toxicologic studies, while intravenous access is being established. If the
patient had a tonic-clonic seizure, and the attending physician feels that this is probably newonset epilepsy, she should be started on the appropriate anticonvulsant medication while
awaiting results of laboratory studies. If she is not in status epilepticus, this medication may be
given orally.
If the patient presents with recurrent generalized seizures, status epilepticus,
immediate therapeutic action must be taken. The drug of choice is intravenous phenytoin, as it is
highly effective, has a long duration of action, and a low incidence of serious side effects. This
medication should be administered in a loading dose of 18 to 20 mg/kg at a rate not exceeding 50
mg/min. Rapid infusion may cause transient hypotension and heart block. If possible, the patient
should be placed on a cardiac monitor while receiving a loading dose of phenytoin. Also, this
medication must be given in a glucose-free solution to avoid precipitation.[ Fosphenytoin, if
available, can be given more rapidly with fewer side effects. If phenytoin is unavailable, a
benzodiazepine may be used as a first-line drug for status epilepticus. These drugs, however,
cause respiratory depression, and the physician must have the ability to intubate the patient if
necessary when these medications are used. If these measures are ineffective, an anesthesiologist
and neurologist should be immediately consulted if they are not already involved in the patient's
care.
Any patient experiencing seizures for the first time during pregnancy without a
known cause should undergo an EEG and some type of intracranial imaging. In looking only at
eclamptic patients, Sibai et al. found that EEGs were initially abnormal in 75 percent of patients
but normalized within 6 months in all patients studied. While this group found no uniform
computed tomography (CT) abnormalities in this set of eclamptics, they did find that 46 and 33
percent of eclamptics had some abnormalities in the magnetic resonance imaging (MRI) and CT,
respectively. Most of the findings were nonspecific and were not helpful in diagnosis or
treatment. If the physician is not certain that the patient has eclampsia, an imaging study should
be part of the evaluation described above.
Postpartum Period
The levels of anticonvulsant medications must be monitored frequently during the
first few weeks postpartum, as they can rapidly rise. If the patient's medication dosages were
increased during pregnancy, they will need to be decreased rather rapidly after delivery to
prepregnancy levels. All of the major anticonvulsant medications cross into breast milk. The
levels vary in breast milk from 18 to 79 percent of the plasma levels.[] The use of these
medications, however, is not a contraindication to breast-feeding. Primidone, phenobarbital, and
benzodiazepines may have a sedative effect on the fetus with later withdrawal symptoms. Should
the infant exhibit these types of symptoms, breast-feeding should be discontinued.
All methods of contraception are available to women with idiopathic seizure disorders. The
majority of women are able to take oral contraceptives without any adverse side effects. Oral
contraceptive failures are more common in women taking anticonvulsants. This is due to the fact
that all of the major anticonvulsant medications induce hepatic enzymes, which metabolize
estrogen faster.[ These patients may, therefore, require oral contraceptives with higher dosages of
estrogens. The amount of enzyme induction, however, varies and oral contraceptive doses must
be individualized.
In conclusion, the majority of women with idiopathic epilepsy will have an
uneventful pregnancy with an excellent outcome. To optimize neonatal outcome, the patient
should take only one medication and, when possible, use the lowest dose effective in keeping her
free of seizures. It is important, though, for the patient to realize that prevention of seizures is the
most important goal during pregnancy. Simple interventions such as taking folic acid prior to
conception, taking prenatal vitamins containing vitamin D, and giving the infant vitamin K at
birth will help to optimize the outcome. There is an increase in congenital malformations in
infants exposed to anticonvulsant medications in utero. The majority of infants exposed to these
medications, however, will have no malformations. With modern techniques for prenatal
diagnosis, including ultrasound and α-fetoprotein determination, many of these malformations
can be detected early. The majority of women with epilepsy will labor normally and have
spontaneous vaginal deliveries. In short, with close cooperation and excellent communication
among the obstetrician, neurologist, and pediatrician, the vast majority of these patients will have
a safe pregnancy with an excellent outcome.
Anticonvulsants
Epileptic women taking anticonvulsants during pregnancy have approximately
double the general population risk of malformations. Compared with the general risk of 2 to 3
percent, the risk of major malformations in epileptic women on anticonvulsants is about 5
percent, especially cleft lip with or without cleft palate and congenital heart disease. Valproic
acid (Depakene) and carbamazepine (Tegretol) each carry approximately a 1 percent risk of
neural tube defects and possibly other anomalies. In addition, the offspring of epileptic women
have a 2 to 3 percent incidence of epilepsy, five times that in the general population.
Whenever a drug is claimed to be a teratogen, one always can raise the issue of whether the drug
actually is a teratogen or the disease for which the drug was prescribed in some way contributed
to the defect. Even when they take no anticonvulsant drug, women with a convulsive disorder
have an increased risk of delivering infants with malformations; this information supports a role
for the epilepsy itself rather than the anticonvulsant drug as a contributor to the birth defect.[Of
infants born to 305 epileptic women on medication in the Collaborative Perinatal Project, 10.5
percent had a birth defect. Of the offspring of women who had a convulsive disorder and who
had taken no phenytoin at all, 11.3 percent had a malformation. In contrast, the total
malformation rate was 6.4 percent for the control group of women who did not have a convulsive
disorder and who therefore did not take any antiepileptic drugs. The issue remains unresolved, as
patients who take more drugs during pregnancy usually have more severe convulsive disorders
than do those who do not take any anticonvulsants. A combination of more than three drugs or a
high daily dose increases the chance of malformations.
Possible causes of anomalies in epileptic women on anticonvulsants include the
disease itself, a genetic predisposition to both epilepsy and malformations, genetic differences in
drug metabolism, the specific drugs themselves, and deficiency states induced by drugs such as
decreased serum folate. Phenytoin (Dilantin) decreases folate absorption and lowers the serum
folate, which has been implicated in birth defects. Therefore, folic acid supplementation should
be given to these mothers, but may require adjustment of the anticonvulsant dose. Although
epileptic women were not included in the Medical Research Council study, most authorities
would recommend 4 mg/day folic acid for high-risk women. One study suggested that folic acid
at doses of 2.5 to 5 mg daily could reduce birth defects in women on anticonvulsant drugs.
Fewer than 10 percent of offspring show the fetal hydantoin syndrome, which consists of
microcephaly, growth deficiency, developmental delays, mental retardation, and dysmorphic
craniofacial features (Fig. 9-3) . In fact, the risk may be as low as 1 to 2 percent. While several of
these features are also found in other syndromes, such as fetal alcohol syndrome, more common
in the fetal hydantoin syndrome are hypoplasia of the nails and distal phalanges (Fig. 9-4) , and
hypertelorism. Carbamazepine (Tegretol) is also associated with an increased risk of a
dysmorphic syndrome.
A genetic metabolic defect in arene oxide detoxification in the infant may increase
the risk of a major birth defect. Epoxide hydrolase deficiency may indicate susceptibility to fetal
hydantoin syndrome.
Figure 9-3 Facial features of the fetal hydantoin syndrome. Note broad, flat nasal ridge,
epicanthic folds, mild hypertelorism, and wide mouth with prominent upper lip. (Courtesy of Dr.
Thaddeus Kelly, Charlottesville, VA.)
Figure 9-4 Hypoplasia of toenails and distal phalanges. (From Hanson JWM: Fetal hydantoin
syndrome. Teratology 13:186, 1976, with permission.)
In a follow-up study of long-term effects of antenatal exposure to phenobarbital and
carbamazepine, anomalies were not related to specific maternal medication exposure. There were
no neurologic or behavioral differences between the two groups.[23] However, children exposed
in utero to phenytoin scored 10 points lower on IQ tests than children exposed to carbamazepine
or nonexposed controls.[24] Also, prenatal exposure to phenobarbitol decreased verbal IQ scores
in adult men.[25]
Newer Antiepileptic Drugs
Lamotrigine (Lamictal) has been studied in a registry established by the
manufacturer, Glaxo Wellcome. Eight of 123 infants (6.5 percent; 95 percent confidence interval
[CI] 3.1 to 12.8 percent) born to women treated with lamotrigine during the first trimester and
followed prospectively to birth were found to have congenital anomalies. All of the mothers of
children with malformations had a seizure disorder and some took at least one other medication
during the pregnancy.
Lamotrigine is an inhibitor of dihydrofolate reductase and decreases embryonic
folate levels in experimental animals, so it is theoretically possible that this drug would be
associated with an increased malformation risk like the other antiepileptic drugs. The limited
human data to date do not appear to indicate a major risk for congenital malformations or fetal
loss following first-trimester exposure to lamotrigine.
There are no epidemiologic studies of congenital anomalies among children born to
women treated with felbamate, gabapentin, oxcarbazepine, tiagabine, topiramate, or vigabatrin.
Some women may have taken anticonvulsant drugs for a long period without reevaluation of the
need for continuation of the drugs. For patients with idiopathic epilepsy who have been seizure
free for 2 years and who have a normal electroencephalogram (EEG), it may be safe to attempt a
trial of withdrawal of the drug before pregnancy.
Most authorities agree that the benefits of anticonvulsant therapy during pregnancy
outweigh the risks of discontinuation of the drug if the patient is first seen during pregnancy. The
blood level of drug should be monitored to ensure a therapeutic level but minimize the dosage. If
the patient has not been taking her drug regularly, a low blood level may demonstrate her lack of
compliance and she may not need the drug. Because the albumin concentration falls in
pregnancy, the total amount of phenytoin measured is decreased, as it is highly protein bound.
However, the level of free phenytoin, which is the pharmacologically active portion, is
unchanged. Neonatologists need to be notified when a patient is on anticonvulsants, because this
therapy can affect vitamin K-dependent clotting factors in the newborn. Vitamin K
supplementation at 10 mg daily for these mothers has been recommended for the last month of
pregnancy.
Ref : Gabbe: Obstetrics - Normal and Problem Pregnancies, 4th ed., Copyright © 2002
Churchill Livingstone, Inc.