Seizure Disorders in Pregnancy

Approximately 1 million women of childbearing age in the United States have seizure disorders. Of these women, approximately 24,000 give birth each year. ^[1] Concerns during these pregnancies include the risk of fetal malformation, miscarriage, perinatal death, and increased seizure frequency. ^[2]

In women who are pregnant, the volume of distribution and the hepatic metabolism of antiepileptic drugs (AEDs) are increased. This, along with decreased compliance with AEDs because of concerns about their effects on the fetus, leads to an increase in seizure frequency, which is observed in as many as 17-33% of pregnancies.

The use of AEDs is associated with a greater baseline risk of fetal malformations during pregnancy. When treating pregnant women who have epilepsy, the risks of increased seizure frequency versus the risks of AED use must be weighed carefully. ^[3]

A population-based study conducted in Norway found that pregnant women with epilepsy had a lower risk of complications but an increased risk of induction, cesarean delivery, and postpartum hemorrhage. ^[4] However, whether this is a result of AEDs or severe epilepsy is unclear.

Go to Women's Health and Epilepsy for complete information on this topic.

Epilepsy management before and after conception

Preconceptual management of women with epilepsy includes the following:

• Attempt to decrease pharmacotherapy to monotherapy

• Taper dosages of AEDs to the lowest possible dose

• In women who have not had a seizure for 2-5 years, attempt complete withdrawal of pharmacotherapy

• Establish the level of total and free AEDs necessary for achieving good clinical control

• Consider preconceptual genetic counseling

• Supplement the diet with folate at 4 mg/d

Management of women with epilepsy during pregnancy includes the following:

• Check total and free levels of AEDs monthly

• Consider early genetic counseling

• Check maternal serum alpha-fetoprotein (MSAFP) levels and perform a level II fetal survey and ultrasonography at 19-20 weeks' gestation

• Consider amniocentesis for alpha-fetoprotein and acetylcholinesterase

Management of women with epilepsy upon labor and delivery includes the following:

• Check levels of AEDs

• Inform all care providers, including nurses, anesthesiologists, and pediatricians that the patient has epilepsy

• Consider seizure prophylaxis with intravenous benzodiazepines or phenytoin

• Manage seizures acutely with intravenous benzodiazepines (1-2 mg of diazepam), then load phenytoin (1 g loaded over 1 h)

• Labor management should be based on routine standards of care

• Start administration of vitamin K for the infant, and send the cord blood for clotting studies

Management of a pregnant patient in status epilepticus includes the following:

• Establish the ABCs, and check vital signs, including oxygenation

• Assess the fetal heart rate or fetal status

• Rule out eclampsia

• Administer a bolus of lorazepam (0.1 mg/kg, ie, 5-10 mg) at a rate of no more than 2 mg/min

• Load phenytoin (20 mg/kg, ie, 1-2 g) at a rate of no more than 50 mg/min, with cardiac monitoring.

• If this is not successful, load phenobarbital (20 mg/kg, ie, 1-2 g) at a rate of no more than 100 mg/min.

• Check laboratory findings, including electrolytes, AED levels, glucose, and toxicology screen.

• If fetal testing results are nonreassuring, move to emergent delivery

For more information, see Epilepsy and Seizures.

The earliest reports of congenital malformations associated with AEDs occurred in the 1960s. Since then, unique malformations and syndromes have been ascribed to phenytoin, phenobarbital, primidone, valproate, carbamazepine, and trimethadione. However, similarities exist among most of the congenital abnormalities caused by the AEDs (see the Table, below).

Table. Fetal Anomalies Associated With AEDs (Open Table in a new window)

Older evidence indicated that women with epilepsy have an increased risk of fetal malformations, even without AED use. However, a systematic review found no statistically different rate of major fetal malformations among patients with epilepsy who were on no medications compared with normal controls. ^[5]

While some studies suggest that monotherapy does not increase the baseline risk of fetal malformations over that in patients not on AEDs, most of the literature suggests that first-trimester use of even a single AED is associated with a 2- to 5-fold increase in major malformations.

An analysis of data from the EURAP epilepsy and pregnancy registry found that the risk of major congenital malformations increased with increasing dose in patients receiving carbamazepine, lamotrigine, valproic acid, or phenobarbital monotherapy. ^[6]

Data from the North American AED pregnancy registry indicate that older AEDs such as valproate and phenobarbital are associated with a higher risk of major malformations than newer AEDS such as levetiracetam and lamotrigine. Compared with a reference population, topiramate was associated with a higher risk of cleft lip. ^[7]

Furthermore, multiple studies present evidence indicating an increase in fetal malformations with AED polytherapy.

Specific increases in congenital abnormalities observed in infants born to mothers with epilepsy include a 4-fold increase in cleft lip and palate and a 3- to 4-fold increase in cardiac anomalies. An increase in the rate of neural tube defects is also observed in the offspring of patients with epilepsy who are using carbamazepine or valproic acid. Long-term studies on neurodevelopment show higher rates of abnormal electroencephalogram (EEG) findings, higher rates of developmentally delayed children, and lower intelligence quotient (IQ) scores.

Results from the Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs (MONEAD) study showed no significant language differences between the 2-year-old children of mothers who took antiseizure medications during pregnancy and the children of healthy matched controls. Most of the women with epilepsy in the MONEAD study used lamotrigine and/or levetiracetam. ^{[8, 9]}

Phenytoin

Fetal hydantoin syndrome was first described in 1973 by Loughnan et al. ^[10] It consists of an array of anomalies, including craniofacial anomalies, distal digital hypoplasia, epicanthal folds, hypertelorism, low-set ears, and developmental delay. The early descriptions of this syndrome were noted in 12 infants, 11 of whom had been exposed to other AEDs, notably barbiturates.

Of infants born to women who used phenytoin during pregnancy, 10-30% are reported to exhibit some of the syndromic findings, most commonly distal digital hypoplasia. However, few infants exposed to monotherapy have the entire constellation of findings.

Of note, in a long-term neurodevelopmental study, 16 patients whose mothers received phenytoin monotherapy during pregnancy demonstrated slightly delayed locomotor development compared with children whose mothers took carbamazepine and with normal controls.

Phenobarbital and primidone

Infants exposed to phenobarbital have been reported to have many of the findings observed in infants with fetal hydantoin syndrome and fetal alcohol syndrome. Furthermore, many of the infants initially described as having fetal hydantoin syndrome were also exposed to phenobarbital.

A drug registry reported 5 (6.5%) of 77 patients who had received phenobarbital monotherapy had fetuses with major malformations, compared with a background rate of 1.6%. ^[11]

Primidone is metabolized to phenobarbital; thus, many of the effects on the fetus are similar. In 1979, Rudd and Freedom reported a specific description of a possible distinct primidone embryopathy, which includes a hirsute forehead, thick nasal roots, a long philtrum, and anteverted nostrils. ^[12] However, many of these findings were similar to those found in association with phenobarbital and phenytoin exposure.

Valproic acid

A syndrome of specific craniofacial abnormalities and long, thin digits with hyperconvex nails has been described in infants exposed to valproic acid during pregnancy. Furthermore, in 1982, an association between valproic acid and neural tube defects was noted at a rate of 1-2%, 20 times greater than the baseline population. ^[13]

In studies comparing valproic acid with carbamazepine, valproic acid appeared to be associated with a higher risk for major congenital malformations, as well as for developmental delay and decreased verbal intelligence. Further, one study demonstrated a dose-response effect, with patients taking the highest doses of valproic acid at greatest risk. ^[14]

In 2009, Meador et al reported that in utero exposure to valproate, as compared with other AEDs, was associated with a lower IQ in children. The study took place over 5 years in 25 epilepsy centers in the United States and the United Kingdom. The design was a prospective, observational, cohort study of pregnant women with epilepsy who took a single agent (carbamazepine, lamotrigine, phenytoin, valproate).

The cohort study assessed the neurodevelopmental outcomes of children who were exposed in utero to several different AEDs. A planned interim analysis conducted when the children were 3 years of age reported lower mean IQ scores in children with in utero valproic acid exposure compared with the other AEDs. This association was dose-dependent. The investigators concluded that valproate should not be used as a first-line agent in women with childbearing potential. ^[15]

This interim analysis was updated in 2013 with data from children completing 6 years of follow-up. The final results of the Neurodevelopmental Effects of Antiepileptic Drugs (NEAD) study showed that children exposed to valproate products while their mothers were pregnant had decreased IQs at age 6 compared to children exposed to other antiepileptic drugs. ^[16]

The prescribing information was changed to reflect this risk including a Black Box Warning stating not to use valproate derivatives in women of childbearing age unless the drug is essential to the management of seizures, or for manic episodes associated with bipolar disorder (FDA fetal risk category D). It should not be used for migraine headache prophylaxis during pregnancy (FDA fetal risk category X).

Carbamazepine

In 1989, a syndrome that included craniofacial abnormalities and hypoplastic nails was described in infants exposed to carbamazepine monotherapy in utero. ^[17]

In a 1996 cohort study, 6 of 47 infants demonstrated this syndrome. ^[18] These infants also had lower IQ scores than did controls.

However, an analysis of 86 patients on carbamazepine monotherapy showed no difference in IQ scores compared with normal controls.

Carbamazepine is also associated with an increased risk of neural tube defects in as many as 0.5-1% of births (ie, 10 times the baseline risk).

A cohort study by Jentink et al suggests that carbamazepine monotherapy in the first trimester produces fetal malformations specific to spina bifida; however, the risk is lower than for valproic acid. ^[19]

In addition, carbamazepine is also associated with a risk of cardiac anomalies; thus, for patients taking this drug, a fetal echocardiogram is recommended at 20-22 weeks' gestation.

Trimethadione

In 1975, a cluster of findings, including epicanthal folds, low-set ears, microcephaly, short stature, and irregular teeth, was ascribed to trimethadione. ^[20]

A review of 57 pregnancies published in 1977 revealed either malformations or fetal loss 87% of the time. ^[21]

Currently, trimethadione is rarely used in the treatment of epilepsy and should certainly be discontinued during pregnancy.

Gabapentin, lamotrigine, felbamate, topiramate, and oxcarbazepine

These newer anticonvulsants have not been studied extensively in pregnancy, although the use of pregnancy registries for AEDs are providing larger sample sizes.

Several studies of in utero exposure reported either case reports of anomalies or no effects on the fetus. None of the existing studies revealed a rate of congenital malformations greater than that for a woman with epilepsy who is not taking AEDs.

However, a large, randomized trial did demonstrate that valproate leads to better seizure control than do several of these newer AEDs. ^[22] Thus, the benefits and risks between congenital anomalies and seizure control need to be considered when preparing women with epilepsy for pregnancy. The new anticonvulsants generally have a better pharmokinetic profile and are not metabolized to known teratogens.

All of these anticonvulsants are considered US Food and Drug Administration pregnancy category C. Of note, they are still known to cross the placenta and into breast milk.

The mechanisms of teratogenicity of the AEDs have not been fully characterized. Phenobarbital, primidone, and phenytoin act as folate antagonists. Certainly, a folate deficiency appears to lead to an increase in congenital malformations, particularly neural tube defects; thus, folate administration prior to conception has been recommended for prophylaxis.

Because AEDs all have a similar central mechanism to control seizures, a common pathway that is disrupted during embryogenesis may lead to the similarities in the syndromes described, and this may be why an additive effect is observed with polytherapy.

Studies in teratogenesis, particularly fetal hydantoin syndrome, point to a genetic predilection for the generation of epoxides. These anomalies have been observed at an increased rate in children whose enzyme activity of epoxide hydrolase is one third less than the reference range. Anomalies have also been observed in children with low epoxide hydrolase activity who were exposed to carbamazepine.

Regarding the cognitive and neurodevelopmental differences seen, one interesting study demonstrated that among rats treated with AEDs to achieve therapeutic levels, apoptosis of neural tissue occurred. This is consistent with smaller brains demonstrated in animal studies and may be a causal mechanism in the lower IQs and developmental delay seen in a minority of these patients.

Because exposure to multiple AEDs seems to be more teratogenic than monotherapy, patients are advised to switch to a single AED prior to conception and to taper to the lowest possible dose. An attempt to switch to one of the newer AEDs might offer lower fetal/embryonic risk, although this has not been studied in a prospective, randomized clinical trial.

Patients who have not had a seizure for 2-5 years may wish to attempt complete withdrawal from AEDs prior to conception.

Valproic acid

Because evidence indicates that high peak plasma levels of valproic acid may be more teratogenic, this drug should be dosed at 3-4 times per day rather than the standard twice-per-day dosing in patients with seizures whom valproate is considered essential treatment. However, patients with epilepsy should be counseled that they are still at a greater risk (ie, 4-6% vs 2-3%) for fetal anomalies than is the baseline population. For more information, see Fetal Congenital Abnormalities and Adverse Outcomes.

Folate

Supplemental folate has been shown to decrease neural tube defects in patients without epilepsy and to decrease other congenital anomalies in women with epilepsy. ^[23] Thus, all women on AEDs, and particularly those using either valproic acid or carbamazepine, should be advised to take supplemental folate prior to conception.

Vitamin K-dependent clotting factors

Reports of increased risk of spontaneous hemorrhage in newborns suggest that the inhibition of vitamin K–dependent clotting factors (ie, II, VII, IX, X) secondary to increased vitamin K metabolism and the inhibition of placental transport of vitamin K results from AED use.

Historically, most patients on AEDs received oral vitamin K supplementation at the end of pregnancy. However, a study of 204 neonates born to mothers taking AEDs who did not received vitamin K supplementation showed no evidence of coagulopathy. ^[24] Upon delivery, clotting studies can be performed on the cord blood, and vitamin K can be administered to the infant. If the cord blood is deficient in clotting factors, fresh frozen plasma may be required to protect the newborn.

Testing

Because of the increased risk of anomalies, a level II fetal survey should be performed at 19-20 weeks' gestation, with careful attention to the face, central nervous system, and heart. A fetal echocardiogram should also be considered to diagnose potential cardiac anomalies. Because of the increased risk of neural tube defects, an MSAFP screening test should be offered.

Whether to perform an amniocentesis routinely for alpha-fetoprotein and acetylcholinesterase is controversial. Many authors recommend it in the setting of a family history of neural tube defects or with the use of valproic acid or carbamazepine, because the sensitivity of amniocentesis is higher than either MSAFP screening tests or ultrasonography for detecting neural tube defects.

Generalized tonic-clonic seizures during pregnancy can lead to increased maternal trauma. If the maternal trauma involves the abdomen, a theoretical risk of abruption exists, possibly leading to fetal hypoxia or death. Furthermore, the risk of maternal aspiration can lead to maternal hypoxia, which can also lead to fetal hypoxia.

Evidence indicates seizure frequency increases during 17-33% of pregnancies. Several possible etiologies have been proposed for this occurrence. Increased renal and hepatic metabolism of AEDs, increased volume of distribution, and changes in serum-binding proteins all impact circulating levels of AEDs. The increased stress, hormonal changes, and decreased sleep during pregnancy likely lower the seizure threshold and have been shown to increase seizure frequency in patients who are not pregnant. Finally, many women may have decreased compliance with taking AEDs because of concerns regarding the effects on their fetus.

Increased levels of circulating estrogen during pregnancy increase the function of the P-450 enzymes, which leads to more rapid hepatic metabolism of the AEDs. Also, renal function increases during pregnancy, with a 50% rise in creatinine clearance, which impacts the metabolism of carbamazepine, primidone, and benzodiazepines. The increase in total blood volume and a concomitant rise in the volume of distribution also lead to decreased levels of circulating AEDs. In contrast, the decrease in albumin and circulating plasma proteins likely increases the free component of the AEDs in serum.

The increased levels of estrogen and progesterone may have a direct impact on seizure activity during pregnancy. Estrogen has been shown to be epileptogenic, decreasing the seizure threshold. Thus, the rising estrogen levels in pregnancy, which peak in the third trimester, may have some impact on the observed increase in seizure frequency. Conversely, progesterone seems to have an antiepileptic effect, and women with seizure disorders have been observed to have fewer seizures during the luteal phase of the menstrual cycle.

Rarely, some patients experience their first seizure during pregnancy. This can be a result of true gestational epilepsy, a rare syndrome of seizures occurring only during pregnancy. Patients with this syndrome have a variable presentation, with single or multiple seizures occurring in 1 or more of their pregnancies. The seizures can also be a manifestation of epilepsy that may extend beyond the patient’s pregnancy.

Workup

The workup of these patients should involve a neurologic examination, consultation with a neurologist, a complete blood count (CBC), a chemistry panel (particularly for electrolytes), head magnetic resonance imaging (MRI) versus computed tomography (CT) scans, and electroencephalographic examination.

Differentials

The differential diagnosis should include eclampsia and any possible etiology considered in the nonpregnant patient, including stroke, electrolyte abnormalities, tumor, trauma, drugs/withdrawal, and epilepsy.

Studies of seizure frequency have shown a smaller increase in seizure frequency than have older studies, which suggests that the practice of closer monitoring of AED dosing and levels may have some impact on the number of seizures during pregnancy. One study showed that 38% of pregnant patients with epilepsy required changes in their AED dosing to achieve seizure control. Assuming that successful monotherapy with one of the AEDs has been achieved preconceptually, the same total and free levels of the AED that keep the patient from having seizures should be maintained.

In most patients with epilepsy, total levels of AEDs are followed; however, because of the aforementioned physiologic changes of pregnancy, checking free levels in patients who are difficult to treat may be more useful. Most authors suggest that these AED levels should be monitored monthly during pregnancy, with adjustment of dosing based on these levels and the clinical manifestations of seizure frequency. Of note, one study found that the newer AEDs needed even more frequent adjustments than did valproate during pregnancy.

Treating a patient with epilepsy during labor and delivery should include preparation and close monitoring. All care providers, including obstetricians, neurologists, nurses, anesthesiologists, and pediatricians, should be informed during labor and delivery that the patient has epilepsy.

Because trauma and hypoxia from a seizure can put the mother and fetus at risk, treatment of seizures should be discussed a priori with the group of practitioners who are caring for the patient.

AED levels should be checked upon admission. If the serum drug level is low, patients may be administered extra doses or may be switched over to intravenous benzodiazepines or phenytoin, although benzodiazepines can cause respiratory depression in the mother and the newborn.

Status epilepticus

Rarely, a patient has intractable seizures upon labor and delivery. When these last longer than 30 minutes with either (1) a continuous seizure or (2) a lack of full recovery between seizures, the patient is considered to be in status epilepticus. Assuming that preeclampsia and eclampsia have been excluded, the protocol for managing status epilepticus is similar to the management of any seizure, ie, using benzodiazepines, phenytoin, and, rarely, phenobarbital.

During this situation, the fetus must be monitored. In the setting of nonreassuring fetal testing results, establish an airway and attempt intrauterine resuscitation. If the seizure is not treated easily and the fetal testing results continue to be nonreassuring for longer than 10 minutes, a neuromuscular blocking agent can be administered and emergent cesarean delivery can be performed.

Pregnancy in patients with seizure disorders can be complicated by a variety of maternal and fetal issues. Patients can experience higher rates of seizures because of the lower serum plasma levels of their AEDs. The fetus is likely to be at increased risk for congenital abnormalities, most notably facial clefts, cardiac anomalies, and neural tube defects.

Long-term outcomes show that children of patients with seizure disorders may have lower IQs and higher rates of developmental delay. Syndromes related to several of the AEDs and to specific abnormalities observed in patients with seizure disorders are not known to affect rates of chromosomal abnormalities.

Women with epilepsy should be treated during pregnancy by a team of providers, including a perinatologist and a neurologist, that can focus on balancing the risks of seizures versus the administration of AEDs. Preconceptual management with tapering to AED monotherapy and folate supplementation are recommended. During pregnancy, AED levels should be monitored closely, and the fetus should be carefully screened for anomalies with serum testing, ultrasonography, and, possibly, amniocentesis. Vitamin K supplementation for the patient and then for the newborn at the end of the pregnancy is controversial; the risks and benefits of this aspect of management should be discussed by the entire team of providers caring for the patient. With careful treatment of these patients, more than 90% have an entirely uncomplicated pregnancy.