American Academy of Neurology AAN
American Heart Association AHA
Antiepileptic drug AED
Arteriovenous malformation AVM
Australian Register of Antiepileptic Drugs in Pregnancy APR
Attention-deficit/hyperactivity disorder ADHD
Autism spectrum disorder ASD
Autosomal-dominant frontal lobe epilepsy ADFLE
Autosomal-dominant temporal lobe epilepsy ADTLE
Centers for Disease Control and Prevention CDC
Central nervous system CNS
Cerebral venous thrombosis CVT
Cerebrospinal fluid CSF
Computed tomography angiography CTA
Computed tomography CT
Disease-modifying agent DMA
Enzyme-inducing antiepileptic drug EIAED
European Medicine Agency EMA
Expanded Disability Status Scale EDSS
U.S. Food and Drug Administration FDA
Idiopathic intracranial hypertension IICH
Intelligence quotient IQ
Intrauterine device IUD
Intrauterine growth restriction IUGR
Liverpool and Manchester Neurodevelopmental Group LMNG
Magnetic resonance imaging MRI
Magnetic resonance angiography MRA
Magnetic resonance venogram MRV
Multiple sclerosis MS
Neural tube defect NTD
Neurodevelopmental disorder NDD
Neurodevelopmental Effects of Antiepileptic Drugs NEAD
North American AED Pregnancy Registry NAAPR
Periventricular nodular heterotopia PVNH
Posterior reversible encephalopathy syndrome PRES
Pregnancy and Multiple Sclerosis study PRIMS
Reversible cerebral vasoconstriction syndrome RCVS
Small for gestational age SGA
Sodium channel, voltage-gated type 1 alpha subunit SCN1A
Subarachnoid hemorrhage SAH
Sudden unexpected death in epilepsy SUDEP
Thymus helper Th
Tissue plasminogen activator tPA
World Health Organization WHO
Epilepsy and Seizures
Epilepsy affects approximately 1% of the general population and is the most frequent major neurologic complication encountered in pregnancy. It is important that the practicing obstetrician becomes familiar with the basic treatment of epilepsy and the implications for the patient and fetus. Many of the antiepileptic drugs (AEDs) used to treat epilepsy are also used to treat psychiatric and pain disorders and are commonly prescribed to women of childbearing age; this makes an understanding of their implications for pregnancy imperative for any clinician managing these patients.
A diagnosis of epilepsy is made in the setting of two unprovoked seizures or one seizure in a patient with clinical features that make a second seizure likely, such as findings on brain magnetic resonance imaging (MRI) or electroencephalogram (EEG) that are consistent with a diagnosis of epilepsy or a family history of epilepsy. Epilepsy syndromes can be divided into generalized and focal epilepsies. An epilepsy syndrome is defined by the constellation of clinical features of a patient’s seizures as well as their imaging and EEG findings. It is important to note that both types of epilepsy syndromes can present with a wide spectrum of seizure types. Convulsions or tonic-clonic seizures, colloquially referred to as “generalized” seizures, can occur in patients with either generalized or focal epilepsies. It is important to work with a patient’s neurologist to have an understanding of the patient’s epilepsy syndrome because this has significant implications for treatment and also sometimes gives insight into the etiology of the patient’s seizure disorder. It may also have a role in predicting the course of the seizure disorder during pregnancy.
Genetic generalized epilepsies, also known as idiopathic generalized epilepsies, are presumed to be genetic in origin, although most cases do not exhibit a mendelian inheritance pattern or have varying degrees of penetrance; first-degree relatives are often not affected. Patients with genetic generalized epilepsy can have myoclonic, absence, or tonic-clonic seizures. They may have only one or a combination of those seizure types. These patients are typically treated with “broad-spectrum” AEDs that include lamotrigine, levetiracetam, topiramate, valproate, and zonisamide. The majority of other AEDs—including, but not limited to, carbamazepine, gabapentin, oxcarbazepine, phenytoin, and pregabalin—are considered “narrow spectrum” and can provoke myoclonic or absence seizures in patients with genetic generalized epilepsies, even if the patient does not have a history of these seizure types. The newest AEDs, such as lacosamide and perampanel, are approved for treatment of focal epilepsies but are being studied for use in generalized epilepsies.
Focal epilepsy is the most common type of epilepsy in adult patients. Whereas the etiology of most focal epilepsies often remains unknown, an underlying cause must be ruled out because they may occur secondary to an acquired abnormality such as a tumor, vascular malformation, brain injury, or infectious or autoimmune disorder that affects the brain. An increasing number of genetic causes of focal epilepsies have also been identified recently, including some with autosomal-dominant inheritance patterns. Patients with focal epilepsy may present with focal seizures with or without loss of consciousness, previously known as simple partial and complex partial seizures, and/or focal seizures that progress to a tonic-clonic seizure, previously known as a secondarily generalized seizure .
The manifestations of focal seizures depend on where in the brain the seizure begins. The most commonly encountered focal epilepsy is temporal lobe epilepsy, which frequently presents with focal seizures with loss of awareness. These seizures are characterized by alteration of awareness that typically lasts 30 seconds to 2 minutes and may be accompanied by semipurposeful movements of the face and hands. The break in awareness is often underreported by patients and even their family members because patients do not remember this part of the seizure, and they may seem to observers to be interacting with their environment. These seizures can be preceded by an aura, such as a feeling of fear or an “epigastric rising,” a sensation that begins in the stomach and that may rise to the chest and head, but an aura also may not be present or remembered. These seizures have the potential to progress to tonic-clonic seizures. Patients with focal epilepsy can be treated with broad- or narrow-spectrum AEDs; however, if the diagnosis is uncertain, it is best to begin with broad-spectrum drugs. The choice of the first AED usually depends on characteristics of the patient and the side effects of the drug. In women of childbearing age, the teratogenic potential of the AEDs should be a strong consideration; this will be discussed below.
Most women with epilepsy will need to remain on AEDs during their childbearing years and throughout pregnancy . Exceptions include patients with childhood epilepsy, which can remit in adulthood. In select cases of adult-onset epilepsy, patients who have been seizure free for 2 to 4 years may attempt to wean from seizure medications under a neurologist’s supervision. Several factors that include the patient’s seizure pattern and MRI and EEG findings affect this decision. Seizure freedom in the 9 months prior to pregnancy predicts a good chance of seizure control during pregnancy. Thus in an appropriate patient who wanted to stop AED therapy before pregnancy, weaning her off seizure medication should be started at least 1 year before becoming pregnant. Unfortunately, women with epilepsy may abruptly stop all medications as soon as they find out that they are pregnant, which puts both the mother and fetus at risk.
Uncontrolled seizures increase the risk of maternal injury and death and potentially expose the infant to transient anoxia. The direct fetal effects of seizures during pregnancy have only been studied in a few case reports. Tonic-clonic seizures during delivery were associated with fetal bradycardia followed by tachycardia in two cases, although the infants were reportedly unaffected on delivery. Fetal death at 33 weeks’ gestation was associated with intraventricular hemorrhage in one patient following a tonic-clonic seizure; the patient had had three tonic-clonic seizures in pregnancy. Focal seizures with loss of consciousness were associated with prolonged uterine contraction in one patient reported by Nei and colleagues. The fetal heart rate also fell from 140 to 78 beats/min. In a population-based study from Taiwan, Chen and colleagues studied 1016 pregnant women with epilepsy. Women with seizures during pregnancy had increased risks of preterm delivery (odds ratio [OR], 1.63), small-for-gestational-age (SGA) infants (OR, 1.37), and low-birthweight infants (OR, 1.36) compared with women without epilepsy. When compared with women with epilepsy but without tonic-clonic seizures during pregnancy, patients with seizures had an increased risk of SGA infants (OR, 1.34).
Two studies have raised significant alarm about the risk of epilepsy in pregnancy. The U.K. confidential inquiry into maternal deaths found that women with epilepsy were 10 times more likely to die during pregnancy or during the postpartum period. Similarly, a recent study by MacDonald and associates evaluated delivery hospitalization records in the United States and also reported a more than tenfold increase in deaths during delivery in women with epilepsy. In the U.K. study, 3 of 14 maternal deaths appeared to be directly related to complications of seizures (drowning, hypoxia, trauma), and the other 11 were attributed to sudden unexpected death in epilepsy (SUDEP), defined as the sudden and unexpected, nontraumatic, and nondrowning death of a person with epilepsy without a detected toxicologic or anatomic cause of death. Mechanisms of SUDEP are uncertain, but risk factors include refractory and tonic-clonic seizures and noncompliance with medications. The U.K. inquiry pointed out that 8 of the 14 women with epilepsy who died in their cohort had not been referred to a provider with knowledge of epilepsy and had not received prepregnancy counseling. Additionally, they noted that one third of the women had difficult social circumstances that may have limited their access to care. Domestic abuse was present in at least two cases, and one patient had schizophrenia. The causes of maternal mortality in the U.S. population study are not known, but it was observed that these patients had an increased risk of major comorbidities that included diabetes, hypertension, psychiatric conditions, and alcohol and substance abuse. They were also at increased risk of preeclampsia, preterm labor, stillbirth, and cesarean delivery.
Whereas these two studies that describe increased mortality in women with epilepsy point to the importance of further research into the optimal management of pregnant women with epilepsy and their comorbidities, they should be put into context for women with epilepsy so as not to deter them from pursuing pregnancy. Although the relative risk was significantly increased, the absolute risk of maternal death in women with epilepsy in the study by MacDonald and colleagues was 80 per 100,000 births (0.08%). Similarly, Edey and colleagues analyzed the U.K. inquiry and estimated the rate of deaths during pregnancy and the postpartum period among women with epilepsy to be 100 per 100,000 births (0.1%). These studies do point to the need for close medical supervision of pregnancies in women with epilepsy and the importance of prepregnancy counseling and planning. The obstetrician and neurologist must work closely together to guide the patient through her pregnancy. Through this cooperation, the majority of pregnant women with seizure disorders can have a successful pregnancy with minimal risk to mother and fetus.
Epilepsy and Fertility
Epilepsy and epilepsy treatment may adversely affect fertility in some women. Several population studies have demonstrated that birth rates are lower in both men and women with epilepsy compared with unaffected individuals. In many studies these decreased birth rates were not explained by lower marriage rates in patients with epilepsy. However, these epidemiologic studies are unable to control for nonbiologic factors that may affect reproduction rates, such as decreased libido, which has been reported in patients with epilepsy, or patients’ concerns about having a child because of fears about the implications of the condition or their medications. Sukumaran and colleagues prospectively followed 375 Indian women trying to conceive and found that 38.4% were infertile after at least 1 year of trying to conceive. Risk factors for infertility include taking AEDs, particularly multiple AEDs. However, age and lower educational level also played a role in the study.
Many lines of evidence suggest that potentially, both epilepsy and AEDs may have adverse effects on reproductive function. Seizures, particularly temporal lobe seizures, are known to disrupt the hypothalamic-pituitary-gonadal axis, and certain AEDs can affect sex steroid metabolism and sex hormone binding globulin concentrations. Increased risks of polycystic ovarian syndrome, premature ovarian insufficiency, and hypogonadotropic hypogonadism have been reported in women with epilepsy. Miscarriage rates, however, do not seem to be increased in women with epilepsy.
Epilepsy and Pregnancy
Teratogenic Effects of Antiepileptic Drugs
Women with epilepsy are at increased risk of having pregnancies complicated by major congenital malformations. This risk appears to be related to exposure to AEDs during pregnancy rather than the epilepsy. Not all AEDs are the same in terms of their teratogenic potential or the patterns of malformations with which they are associated (see Chapter 8 ). Over the past 15 years, prospective studies of the effects of AEDs on teratogenesis have largely replaced older retrospective case series. A few prospective studies of the cognitive effects of AED exposure during pregnancy have also been pivotal in our understanding of AED-associated risks. The most well-studied AEDs in pregnancy are valproate, carbamazepine, and lamotrigine. Of these drugs, valproate has been consistently demonstrated to carry a risk of major congenital malformations significantly greater than that of other AEDs and baseline population rates, typically 1% to 3% depending on the study population. It has also been clearly associated with adverse cognitive and behavioral developmental outcomes.
Lamotrigine has been associated with relatively low rates of teratogenesis, and although cognitive data are mostly reassuring, this still needs further clarification. Levetiracetam is less well studied, but promising early data have led to a dramatic increase in its use in pregnant women and those planning pregnancy. Lamotrigine and levetiracetam are now the most commonly prescribed AEDs for women of childbearing age. Carbamazepine also appears to be a reasonable choice for women who plan to conceive, although its use has been declining in this population.
The section below summarizes the available information on the best-studied and most prescribed AEDs. The majority of the information we have on structural teratogenesis is derived from several international pregnancy registries ( Table 49-1 ). It is important to note that each of these registries uses slightly different methodologies in regard to means of recruitment, infant assessment control groups, and duration of follow-up. These differences account for some of the variability in results; however, when the findings are looked at in aggregate, clear patterns emerge regarding the relative teratogenic risk of individual AEDs.
|REGISTRY||STUDY||RATE OF MAJOR CONGENITAL MALFORMATIONS WITH INDIVIDUAL ANTIEPILEPTIC DRUGS AS MONOTHERAPY *|
|Australian Pregnancy Registry||Vajda, 2014||5.5% |
|Danish Registry||Mølgaard, 2011||1.7% |
|0 % |
|EURAP||Tomson, 2011||5.6% |
|Finland National Birth Registry||Artama, 2005||2.7% |
|GSK Lamotrigine Registry||Cunnington, 2011||2.2% |
|North American AED Pregnancy Registry||Hernandez, 2012||3.0% |
|Norwegian Medical Birth Registry||Veiby, 2014||2.9% |
|Swedish Medical Birth Registry||Tomson, 2012||2.7% |
|U.K./Ireland pregnancy registry||Campbell, 2014 |
Rates of major congenital malformations with first-trimester exposure to valproate monotherapy range from 4.7% to 13.8%. In the two largest prospective cohorts from the United Kingdom and Ireland (1290 valproate exposures) and the European Registry of Antiepileptic Drugs and Pregnancy (EURAP, 1010 valproate exposures), the malformation rates were 6.7% and 9.7%, respectively.
In the European Surveillance of Congenital Anomalies (EUROCAT) database, a population-based database of 14 European countries, valproate exposure was associated with an increased risk of several specific defects. Compared with control pregnancies, those exposed to valproate monotherapy were at statistically increased risk for spina bifida (OR, 12.7), craniosynostosis (OR, 6.8), cleft palate (OR, 5.2), hypospadias (OR, 4.8), atrial septal defects (OR, 2.5), and polydactyly (OR, 2.2). These numbers, however, describe only relative risk and can be hard for a patient to understand. Tomson and Battino compiled the data of 22 prospective studies that reported on specific AED-associated malformations and reported the absolute risks of neural tube defects (NTDs, 1.8%), cardiac malformations (1.7%), hypospadias (1.4%), and oral clefts (0.9%).
In addition to significantly increasing the risk of birth defects, valproate exposure during pregnancy has also been associated with cognitive and behavioral teratogenesis. Two prospective studies of children exposed to AEDs in utero have recently been published, the Neurodevelopmental Effects of Antiepileptic Drugs (NEAD) study and a study by the Liverpool and Manchester Neurodevelopmental Group (LMNG). Both recruited women with epilepsy in the first trimester of pregnancy and followed the development of their children until age 6. In contrast to many earlier studies of the cognitive effects of AEDs, both of these investigations controlled for several important confounding variables, including maternal intelligence quotient (IQ)—an important predictor of a child’s cognitive performance. Of note, the two studies did overlap: 92 children from the LMNG study were also enrolled in the NEAD study. The NEAD study ultimately evaluated 224 children at age 6 who had been exposed to carbamazepine, lamotrigine, phenytoin, or valproate monotherapy. The LMNG study assessed 198 six-year-old children born to women with epilepsy who took AED monotherapy ( n = 143) or polytherapy ( n = 30) or no medication ( n = 25) during pregnancy and a control group of 210 children of the same age. In the NEAD study, exposure to valproate monotherapy was associated with a significant decrease in mean full-scale IQ (FSIQ) by 7 to 10 points compared with children exposed to carbamazepine, lamotrigine, or phenytoin. The LMNG found that exposure to first-trimester doses of valproate greater than 800 mg/day was associated with a significant decrease in FSIQ by 9.7 points when compared with a control group. The mean FSIQ of children exposed to low valproate doses (≤800 mg/day) was also lower than that of controls, but this did not meet statistical significance. The low-dose group, did, however, have significantly lower verbal IQ scores and an increased need for educational intervention.
A population study that utilized the National Psychiatric Registry and birth registries in Denmark found that school-age children whose mothers were prescribed valproate monotherapy during pregnancy had a significantly increased risk of receiving a formal diagnosis of autism or autism spectrum disorder (ASD). In the valproate-exposed cohort, the absolute risk of autism was 2.5%, whereas the rate in the general population was 0.48%, and the risk of ASD was 4.42%, with a baseline risk of ASD of 1.53%. The rates of autism and ASD in children born to mothers with epilepsy who did not take valproate during pregnancy did not differ from baseline population rates. A recent nested study from the Australian Pregnancy Registry also found that of 26 children between 6 and 8 years of age who were exposed to valproate monotherapy, one tested in the “autistic range” and one tested in the “concern for autistic range” on a standardized assessment. The overall risk of autistic traits was 7.7% in the monotherapy group. In this study, the risk of autistic traits was greatest in the valproate polytherapy group (7/15; 46.7%) and was dose related in the valproate monotherapy group.
The LMNG also found an increased risk of behavioral abnormalities in their antenatally recruited cohort at 6 years of age. Because of the relatively smaller numbers in this cohort, the study examined the aggregate risk of several different neurodevelopmental disorders (NDDs) in exposed children, including autism and ASD, attention-deficit/hyperactivity disorder (ADHD), and dyspraxia as based on diagnoses received from professionals outside of the study. An NDD was diagnosed in 12% of 50 children exposed to valproate monotherapy and in 15% of 20 children exposed to valproate in polytherapy. These rates were significantly elevated compared with an NDD rate of 1.87% in the 214 control children.
In its 2009 guidelines, the American Academy of Neurology (AAN) stated, “Carbamazepine probably does not substantially increase the risk of major congenital malformations in the offspring of women with epilepsy.” This conclusion was based on one class I study from the United Kingdom and the Ireland Pregnancy Registry that did not find a difference between the rate of malformations in carbamazepine-exposed pregnancies and those of an internal control group. At the time, carbamazepine was the only medication that the AAN felt had strong enough evidence to support this conclusion. Across seven pregnancy registries, rates of major malformations in pregnancies exposed to carbamazepine monotherapy have ranged from 2.6% to 5.5%. The two largest studies, the United Kingdom and Ireland Pregnancy Registries ( n = 1657) and the EURAP registry ( n = 1402) reported rates of 2.6% and 5.6%, respectively. Of note, the two registries that reported higher rates of major anomalies with carbamazepine exposure—the Australian and EURAP registries—both follow the exposed infants to 1 year and beyond, whereas the other registries performed the last assessment for malformations at birth or 3 months. In the EURAP registry, malformations that were most likely to be picked up between 2 and 12 months were cardiac, hip, and renal malformations. The rates of anomalies increased for several drugs at the later assessment, but rates with carbamazepine were most affected.
In the EUROCAT database, carbamazepine exposure was specifically associated with an increased risk of NTDs compared with unexposed controls (OR, 2.6; 95% confidence interval [CI], 1.2 to 5.3). However, the risk of spina bifida with carbamazepine exposure was still significantly lower than the risk with valproate (OR, 0.2; 95% CI, 0.1 to 0.6) and was not different from the risk of exposure to other AEDs when valproic acid was excluded. The EUROCAT study did not find a specific association between carbamazepine exposure and other major malformations that included oral clefts, diaphragmatic hernia, hypospadias, and total anomalous venous return. In the compiled registry data prepared by Tomson and Battino, the absolute risks of certain anomalies with exposure to carbamazepine monotherapy were reported for NTDs (0.8%), cardiac malformations (0.3%), hypospadias (0.4%), and oral clefts (0.36%).
Early studies of carbamazepine’s effect on cognitive development were conflicting, and many were limited by retrospective design or did not control for important confounders. A Cochrane review of prospective studies published prior to 2014 concluded that the reported effects of carbamazepine on developmental scores were largely accounted for by variability between studies and identified no clear risk of delayed development in infants and toddlers exposed to carbamazepine. The meta-analysis also reported no evident adverse effect of carbamazepine exposure on the IQ of school-age children. In the NEAD study, no specific effects of carbamazepine exposure on IQ were identified when this group of children was compared with the lamotrigine- and phenytoin-exposed cohorts at age 6. The recent LMNG study also found no difference in the adjusted mean IQ scores between the 6-year-old carbamazepine-exposed children and controls, but verbal IQ was 4.2 points lower in the exposed children. Additionally, the relative risk of having an IQ below 85 was significantly increased in the carbamazepine cohort. Both the NEAD and LMNG studies demonstrated that, compared with valproate exposure, prenatal carbamazepine exposure was less likely to be associated with adverse cognitive effects.
The LMNG found no increased risk for formally diagnosed NDDs at 6 years in the carbamazepine-exposed children when compared with controls. The large Danish population study by Christensen and colleagues also found no increased risk of autism or ASD in teenagers and children with prenatal carbamazepine exposure. An earlier study in Aberdeen, Scotland reported that two of 80 (2.5%) of carbamazepine-exposed children had an ASD, which is above the population rate (0.25%) but lower than that of the valproate group (8.9%). These findings are limited by the small number of cases, the absence of a control group, and retrospective recruitment of only 41% of the original AED-exposed cohort, which potentially introduced a selection bias. The more recent study of autistic traits from the Australian Registry also recruited mothers retrospectively from the prospectively identified cohort (63% enrollment). This study reported scores consistent with autism in one of 34 children exposed to carbamazepine and scores that raised “concern for autism” in another child based on a standardized assessment. The overall rate of autistic traits was 5.9%. The authors advise that this increase should be interpreted with caution because no discernable dose-effect of carbamazepine and no increased risk were seen in pregnancies exposed to polytherapy regimens that excluded valproate. The majority of these polytherapy regimens did include carbamazepine.
Rates of major malformations with lamotrigine exposure have been consistently low and range from 2% to 4.6%, across eight prospective registries. Initially, the North American AED Pregnancy Registry (NAAPR) reported a tenfold increased risk in oral clefts with lamotrigine monotherapy exposure. However, with a larger sample size, this risk was reevaluated and reported as a fourfold increased risk (absolute risk with lamotrigine, 0.45%). A case-control study, however, found no specific increased risk of oral clefting with lamotrigine, and other registries have reported much lower rates of clefting with lamotrigine exposure (0.1% to 0.25%). The absolute risks of clefting reported by Tomson and Battino was 0.15%. The composite risk of other specific malformations in this review were 0.6% for cardiac defects, 0.12% for NTDs, and 0.36% for hypospadias.
In two independent cohorts from the United Kingdom, developmental scores of infants prenatally exposed to lamotrigine did not differ from those of controls. In the LMNG cohort, at 6 years of age, the IQ scores of the lamotrigine-exposed children did not differ from those of controls. Additionally, in the NEAD study, FSIQ scores in children exposed to lamotrigine were significantly higher than those of valproate-exposed children and did not differ from those of carbamazepine- or phenytoin-exposed children. However, both valproate and lamotrigine exposure were associated with decreased verbal IQ relative to nonverbal IQ. In a Norwegian population-based mail survey, parents of lamotrigine-exposed infants also reported impaired language functioning and an increase in autistic traits observed in their children. Parental ratings of the 6-year-old children prenatally exposed to lamotrigine in the NEAD study suggested that they may be at increased risk for ADHD, but the teacher ratings in a subgroup of these children did not substantiate this finding, and no tendency toward social impairment was detected. In contrast to these parental observations, the LMNG found no increased risk of formally diagnosed NDDs in lamotrigine-exposed children, and the population study by Christensen and colleagues found no increased risk of autism or ASD.
Levetiracetam is a relatively new AED, and to date, just over 1000 pregnancies have been reported across eight prospective registries, which have each recruited relatively small cohorts. The major malformation rates across these registries range from 0% to 2.4%. Developmental effects of levetiracetam have been assessed in one study of 51 levetiracetam-exposed children recruited from pregnancies identified in the U.K. Epilepsy and Pregnancy Register. At 36 to 54 months, the developmental scores of the exposed children did not differ from those of controls but were better than a group exposed to valproate. Because this is the only investigation of developmental outcomes with levetiracetam exposure, it will need to be replicated in future studies.
Despite the fact that phenytoin is one of the oldest AEDs still in use, little certainty exists in regard to its teratogenic implications. In 1975, Hanson and Smith described a specific fetal hydantoin syndrome associated with in utero phenytoin exposure. They noted growth and performance delays and craniofacial abnormalities that included clefting and limb anomalies, including hypoplasia of nails and distal phalanges. They later reported that this was present in 11% of 35 exposed infants and that 31% of exposed infants had some aspects of the syndrome. Yet other studies have not substantiated this. In 1988, Gaily and colleagues reported no evidence of the hydantoin syndrome in 82 women exposed in utero to phenytoin. Some of the patients had hypertelorism and hypoplasia of the distal phalanges, but none had the full hydantoin syndrome. The true prevalence of this syndrome and contributing factors has not been established, and it has largely fallen out of current literature.
The more recent pregnancy registries have not focused on the description of syndromes. Of note, the major malformations studied in these registries do not include many of the skeletal abnormalities included in the fetal hydantoin syndrome. Rates of anomalies in these registries have ranged from 2.4% to 6.7% across five registries, but only 761 pregnancies have been enrolled in these studies, and the individual cohorts are small. The largest cohort studied in the NAAPR published a major malformation rate of 2.9% among 416 phenytoin-exposed pregnancies. Tomson and Battino reported the rates of specific malformations with phenytoin exposure: 0.4% for cardiac malformations, 0% for NTDs, 0.2% for oral clefts, and 0.5% for hypospadias.
The cognitive implications of phenytoin exposure have only been evaluated in a few prospective studies. The 2014 Cochrane review found that the methodologies of these studies were too disparate to perform a meta-analysis. The review concluded that phenytoin exposure was associated with better developmental and cognitive outcomes than valproate exposure and that no discernable differences between phenytoin and carbamazepine exposure were present in terms of development and IQ. In the NEAD study, average FSIQ and verbal IQ scores of the phenytoin-exposed children were significantly higher than those of the valproate-exposed cohort and were not different from those of children exposed to carbamazepine or lamotrigine. Because the study did not include an unexposed control group, it is unknown whether the phenytoin group would differ from unexposed children. In terms of behavioral effects, Vinten and associates reported no difference between parentally assessed adaptive behaviors in the phenytoin-exposed Norwegian children when compared with unexposed controls born to mothers with epilepsy.
Phenobarbital is rarely used as a first-line AED in developed countries given its adverse cognitive and metabolic side effects and the availability of alternative medications with fewer adverse effects. It is very difficult to wean patients from phenobarbital, however, and this process often leads to worsened seizure control. Thus, unless pregnancy is planned well in advance, many women previously taking phenobarbital may remain on it. In the NAAPR, phenobarbital was associated with a risk of major malformations of 5.5% in 199 pregnancies, and cardiac malformations were the most frequent malformation reported. In a pooled analysis of 765 barbiturate-exposed pregnancies, Tomson and Battino reported a rate of 3.5% for cardiac malformations and a 1% risk or oral clefts. The absolute risk of NTDs and hypospadias in this analysis was 0.2% for each.
Retrospective studies of the effect of phenobarbital on cognitive and educational outcomes of exposed children have reported mixed results. The largest prospective study of phenobarbital and cognitive outcomes evaluated a cohort of 114 Danish men who had been exposed to phenobarbital in utero between 1959 and 1961. The most common indication for phenobarbital was pregnancy-related hypertension, and mothers with epilepsy were not evaluated. Thus the exposure to phenobarbital was likely shorter in duration than in the children of mothers with epilepsy. The phenobarbital-exposed group had significantly lower IQ scores compared with controls, and children exposed in the third trimester were most affected. In a subset of 33 subjects, this effect was driven by lower verbal IQ compared with children exposed to other AEDs in monotherapy. In a prospective study, Thomas and colleagues also found lower IQs in a group of 12 phenobarbital-exposed children. None of the studies to evaluate the cognitive effects of phenobarbital have accounted for the maternal IQ, which is an important predictor of the child’s IQ.
Other Antiepileptic Drugs
A paucity of data is available to describe the teratogenic risks of other AEDs commonly used to treat epilepsy. The rate of major malformations with oxcarbazepine exposure among 393 prospective cases in the Danish birth registry was 2.8%. Other cohorts are smaller. In the NAAPR study, no major anomalies were reported in a cohort of 98 pregnancies exposed to zonisamide monotherapy, but this was interpreted with caution given the small sample size. The study did demonstrate an increased risk of low birthweight with both zonisamide and topiramate exposure. Recently, concern has been raised that topiramate is a significant teratogen, although sample sizes are still small. In the NAAPR study, the risk of major anomalies was 4.2% in 359 pregnancies. The registry also reported a tenfold increased risk of oral clefts in the topiramate cohort compared with that of an external control group; this corresponded to an absolute risk of 1.4%, which resulted in the U.S. Food and Drug Administration (FDA) reclassification of topiramate from class C to class D for pregnancy. This concern has been corroborated by subsequent cohorts and meta-analyses. Studies of the effect of oxcarbazepine, zonisamide, and topiramate on cognitive and behavioral development are limited.
Little useful information is available on the effect of human in utero exposure to other AEDs that include benzodiazepines, eslicarbazepine, ethosuximide ezogabine, felbamate, gabapentin, lacosamide, perampanel, pregabalin, rufinamide, and vigabatrin. The manufacturers of lacosamide, a recently introduced AED, caution that it is known to antagonize the collapsin response mediator protein 2, which is involved in axonal growth and neuronal differentiation and appears to have adverse effects on brain development in rodents.
Effect of Antiepileptic Drug Dose
The risk of major malformations has been shown to be dose related for several AEDs. In the EURAP registry, for example, valproate monotherapy was associated with a malformation risk of 5.6% with preconception doses of less than 750 mg/day and a risk of 24.6% with doses greater than 1500 mg/day. Similar correlations between the risk of birth defects and preconception AED dose were also noted for carbamazepine, lamotrigine, and phenobarbital. Additionally, dose effects on cognitive and behavioral development have been noted for valproate, although more data on the relationship between cognitive teratogenesis and dose of both valproate and other AEDs are needed. Further research is also required on the relevance of serum concentrations, instead of dose, because of the substantial differences in AED metabolism among individuals. For now, preparing a woman with epilepsy for pregnancy involves trying to identify the minimum therapeutic dose and corresponding drug level to control her seizures.
It was previously thought that AED polytherapy always posed more of a teratogenic risk than monotherapy and that polytherapy should be avoided whenever possible. This conclusion was based on several prior studies that demonstrated a higher rate of major malformations with polytherapy. However, a recent study from the NAAPR suggested that the results of these prior studies were largely driven by polytherapy combinations that included valproate. Within the NAAPR, Holmes and colleagues reported that the risk of major anomalies with lamotrigine and valproate therapy was 9.1%, whereas it was 2.9% for the combination of lamotrigine and any other AED. Similarly, they reported that carbamazepine and valproate polytherapy was associated with a major malformation risk of 15.4%, which was much higher than the 2.5% risk seen with the combination of carbamazepine and any other AED. The authors also highlighted similar findings that had been reported in the United Kingdom Epilepsy and Pregnancy Registry and the International Lamotrigine Pregnancy Registry. Studies on cognitive development have suggested the same trend. In an Australian cohort, Nadebaum and colleagues found that in utero exposure to valproate polytherapy was associated with significantly lower FSIQ and verbal comprehension scores than exposure to valproate monotherapy or polytherapy combinations without valproate. The LMNG also reported that only polytherapies that included valproate were linked to decreased mean FSIQ and verbal IQ in school-age children.
The mainstay of epilepsy therapy, especially in women of childbearing age, is still to try to find the one AED that best controls a patient’s seizures at the minimum therapeutic dose or level. However, in certain cases, polytherapy may be preferable to monotherapy. For example, women with idiopathic generalized epilepsies have a limited number of AEDs that are appropriate for their condition. Valproate is an effective option for this type of epilepsy but is a poor choice for these women. When one AED—such as levetiracetam or lamotrigine—is ineffective for these patients, the combination of the two may sometimes be effective and likely carries a reduced risk of teratogenesis when compared with valproate monotherapy. Given the emerging information on the relationship between AED dose and malformation risk for most AEDs, more research is needed to determine whether polytherapy combinations that involve low doses of two AEDs are ever preferable to a single non-valproate AED at a high dose.
Effects of Pregnancy on Anticonvulsant Medications
Although most pregnancy studies to date have focused on AED dose, AED levels are probably far more important and should be studied in the future. Although drug manufacturers and laboratories publish standard therapeutic windows for individual AEDs, these large ranges have little relevance for a given patient with epilepsy. AED metabolism varies greatly by individual, and each patient has her own therapeutic drug level at which seizures are best controlled. This is typically within the standard window but may be above or below it. Therefore it is important to understand and establish this drug level prior to pregnancy whenever possible, because levels of anticonvulsant medications can change dramatically during pregnancy, and in many cases, decreasing AED levels have been associated with loss of seizure control. When prepregnancy levels have not been obtained, they should be drawn as early as possible in the first trimester. Whereas a trough level is ideal, it is usually not practical or safe for women to hold medications for a blood draw. It is more important that they have levels drawn at a convenient and roughly standard time relative to their AED dose. For certain AEDs, including phenytoin and sometimes carbamazepine and valproate, free (unbound) drug levels are available and preferable.
Many factors—including altered protein binding, delayed gastric emptying, nausea and vomiting, changes in plasma volume, changes in the volume of distribution, and even folic acid supplementation—can affect the levels of anticonvulsant medications. Additionally, changes in AED metabolism can be dramatically altered by the pregnant state.
Lamotrigine is the most common AED prescribed in pregnancy, and it is utilized to treat both epilepsy and bipolar disorder. It is also the best example of the substantial effects of pregnancy on AED metabolism. Lamotrigine clearance depends heavily on glucuronidation, a process induced by the increases in estrogen during pregnancy. Over the course of a pregnancy, lamotrigine clearance increases by over 200% in the majority of women with epilepsy. Lamotrigine doses need to be increased substantially over the course of a pregnancy in order to maintain prepregnancy levels and seizure control. Doses of 600 to 900 mg/day are not uncommon by the end of pregnancy. Lamotrigine metabolism decreases rapidly after delivery and returns to baseline within 3 weeks of delivery. To avoid toxicity, it is important to give patients a postpartum dosing plan to taper their dose starting immediately after delivery. A common practice is to decrease the dose by two thirds of the increase over pregnancy in the first week after delivery and then decrease back toward the baseline dose. Leaving a patient on slightly more than her prepregnancy dose is also common, especially in patients with brittle seizure control who may be especially susceptible to the effects of sleep deprivation.
Although less well studied, oxcarbazepine clearance is also dependent on glucuronidation. In the EURAP registry, patients taking oxcarbazepine or lamotrigine during pregnancy were noted to have poorer seizure control than those taking other AEDs. Less than half of those using lamotrigine or oxcarbazepine had their doses adjusted, which suggests therapeutic drug monitoring may not have been regularly performed. In contrast, levels of free and total carbamazepine—as well as a metabolite of carbamazepine—are relatively stable throughout pregnancy, and seizure control appears to be better in patients taking carbamazepine. Given the interindividual variation in AED metabolism and susceptibility to changes during pregnancy, checking AED drug levels monthly is recommended for all AEDs.
Pregnancy and Seizure Frequency
For the majority of women with epilepsy (54% to 80%), seizure frequency will remain similar to their baseline seizure frequency. Across several studies, seizure frequency increased in 15.8% to 32% of women and decreased in 3% to 24%. Seizure freedom for 9 months prior to pregnancy is associated with an 84% to 92% chance of remaining seizure free during pregnancy. Genetic generalized epilepsies seem to be associated with less of a risk of seizures during pregnancy than focal epilepsies, although both groups of patients are at increased risk of seizures in the peripartum and postpartum periods.
A recent study from the Australian Register of Antiepileptic Drugs in Pregnancy (APR) suggested that the AEDs taken during pregnancy might predict seizure control. The authors reported that the risk of seizures was lowest with valproate (27%), levetiracetam (31.8%), and carbamazepine (37.8%), whereas an increased risk of seizures was seen with lamotrigine (51.3%). Phenytoin (51.2%) and topiramate (54.8%) were also associated with a relatively higher risk of seizures, but the sample sizes of these groups were small. As mentioned above, the EURAP registry has also reported a higher risk of seizures in patients taking lamotrigine or oxcarbazepine. In contrast to the APR, a small study by Reisinger and colleagues found a relatively high risk of seizure deterioration in patients treated with levetiracetam monotherapy (47%) when they compared seizures during pregnancy to each patient’s baseline. The NAAPR also notes that rates of seizures during pregnancies managed with levetiracetam were similar to the rates in patients treated with lamotrigine. The increasing metabolism and falling AED levels of many of the newer AEDs including lamotrigine likely play an important role in the variable seizure control reported. Both the APR and EURAP registries reported that lamotrigine dosing had been increased in fewer than 50% of cases analyzed. Future prospective studies, during which therapeutic drug monitoring and appropriate dose adjustments are made, will be necessary to understand whether AED metabolism is the principal reason for worsening seizure control with certain AEDs or if other factors play a role.
Obstetric and Neonatal Outcomes
Women with epilepsy may be at increased risk for obstetric complications . Historically, studies on obstetric complications had yielded mixed results. A 2009 evidence-based review from the AAN reported that insufficient evidence was available to support or refute an increased risk of preeclampsia or gestational hypertension in women with epilepsy. They also stated that preterm labor was probably not increased, at least not to moderate levels (1.5 times the baseline risk) except in women with epilepsy who smoked. Since then, population studies from the United States and Norway have associated epilepsy with a mild to moderate risk of preeclampsia (OR, 1.59 to 1.7) and preterm labor (OR, 1.54 to 1.6) when compared with that of women without epilepsy. Preterm labor was defined as labor before 34 weeks in the Norwegian study and before 37 weeks in the U.S. study. In the Norwegian study by Borthen and colleagues, the risk of these complications in women with epilepsy who did not take AEDs was not increased. However, the possibility that these patients may have had milder epilepsy must be considered. Borthen and colleagues also studied 205 epileptic women from a single Norwegian hospital and found an increased risk of severe preeclampsia in these patients compared with unaffected women.
Epilepsy and AED use are typically not indications for cesarean delivery (CD); however, CD may be more common in women with epilepsy. The reasons for this association are unclear and has not been seen consistently across all studies. In their hospital-based study, Borthen and colleagues found no significant increased risk of CD if preterm labor was accounted for. Induction of labor may also be more common in women with epilepsy. Prospective studies are needed to determine the reasons for labor induction and CD in women with epilepsy. It is unclear if this is related to other complications in these women or physician or patient concern about seizures during late pregnancy or delivery.
Bleeding complications at delivery may also be increased in women with epilepsy, although again studies have been conflicting on this point. Population studies from Norway and the United States both suggest a small but significantly increased risk of postpartum hemorrhage.
According to the 2009 AAN literature review and recommendations, evidence was sufficient to suggest a near twofold increased risk of SGA infants born to epileptic women taking AEDs , but the group felt data were inadequate on the risk of intrauterine growth restriction (IUGR). A recent study from a prospective registry in Norway studied 287 children born to women with epilepsy and found that they had an increased risk of being SGA and having a ponderal index below the tenth percentile. AED exposure was the strongest predictor of a low ponderal index, but seizure frequency was not controlled for. In yet another Norwegian study, topiramate was specifically associated with SGA infants, and in an investigation from the NAAPR, both topiramate and zonisamide were associated with lower birthweights in exposed infants. A Taiwanese study by Chen and colleagues found that seizures during pregnancy were associated with an increased risk of SGA.
The recent U.S. population study found a mild but significantly increased risk of stillbirth in women with epilepsy (OR, 1.27; 95% CI, 1.17 to 1.38). Two other population studies from Denmark and Norway found a trend toward an increased stillbirth risk of similar magnitude, but the effect was not statistically significant. Little else about fetal outcomes of infants born to women with epilepsy is known. The AAN did conclude that the offspring of women using AEDs were at greater risk for a low 1-minute Apgar score.
Preconception Counseling for Women With Epilepsy
Ideally, preconception counseling for a woman with epilepsy should begin at the time of diagnosis and with prescription of the first AED. Unfortunately, this is not always possible. For most patients, the obstetrician must stress that the patient has a greater than 90% chance of having a successful pregnancy that results in a normal newborn. A detailed history of medication use, seizure types, and seizure frequency should be obtained. The patient must be informed that if she has frequent seizures before conception, this pattern will probably continue. Furthermore, if she has frequent seizures, in most cases, she should be encouraged to delay conception until control is optimized. The obstetrician must stress that controlling seizures is of primary importance. For patients with seizures that have been refractory to one to two medications, inpatient video EEG monitoring is often indicated to determine whether the patient is a surgical candidate. Inpatient video EEG monitoring is also recommended in intractable cases or in any patient with atypical features to rule out a diagnosis of nonepileptic seizures. It can be very difficult to diagnose nonepileptic seizures based on clinical history, but some features that should raise suspicion of this diagnosis are closed eyes during a seizure, long duration of seizure activity that waxes and wanes, and a history of abuse.
Valproate is a poor first choice as an AED for any woman of childbearing age. In addition to the adverse effects on pregnancy, valproate is associated with weight gain, hirsutism, and signs of polycystic ovarian syndrome (PCOS). Lamotrigine and levetiracetam are better choices and are quickly becoming the most commonly prescribed drugs for women of childbearing age . They are often used in both focal and generalized epilepsies. Carbamazepine is also a reasonable option for women with focal epilepsy. If these medications are not effective, however, a woman may need to be switched to an AED with higher teratogenic risk or undefined risk. In these cases the patient should be counseled on the available information and unknowns, but again, the importance of seizure control should be stressed. In some women with genetic generalized epilepsies, valproate is the only drug that effectively controls their seizures. Valproate therapy is not a reason to terminate pregnancy, and despite the relatively increased risks of teratogenesis, the majority of women taking valproate will have healthy children. For all AEDs, prepregnancy counseling should include trying to find the minimum therapeutic dose/level needed. This is of utmost importance in women taking valproate.
As discussed above, it is important to establish baseline AED levels prior to pregnancy in order to set a target for dose adjustment during pregnancy. A minimum of two levels taken at a similar time of day is advisable to establish a given individual’s therapeutic range.
Unfortunately, the majority of pregnancies in women with epilepsy are unplanned, which emphasizes the need for appropriate selection of an AED for women of childbearing age and the need for early preconception counseling. Changing AEDs once a woman is already pregnant is usually not recommended. Structural teratogenesis occurs early in the first trimester, and the potential effects of exposure are likely already underway by the time a woman learns she is pregnant. Additionally, switching drugs during the first trimester exposes the fetus to polytherapy and potentially breakthrough seizures during this critical time. Given the increasing knowledge of the adverse cognitive effects of valproate, which are mostly thought to occur in the third trimester, some specialists have switched women off valproate typically to levetiracetam. No available evidence supports or refutes this approach, but it should only be considered in select patients whose history suggests that they may have a good chance of responding to a different drug and are in the care of an epilepsy specialist who can monitor them closely.
If the patient has had no seizures during the past 2 to 4 years, an attempt may be made to withdraw her from anticonvulsant medications. This is usually done over a 1- to 3-month period, slowly reducing the medication, and should not be done close to or during pregnancy. Up to 50% of patients relapse and need to start their medications again. This withdrawal should be attempted only if the patient is completely seizure free and has a normal EEG, and it should only be done with the help of a neurologist. Based on a patient’s history, many neurologists will recommend that the patient refrain from driving for a period of time during and after the wean.
A detailed family history should be taken in the process of counseling women with epilepsy. A history of congenital malformations in the family increases the chances of having an affected child. In particular, in women taking valproate, those who have had prior pregnancies complicated by a malformation have a significantly increased risk of having a second child with a malformation, regardless of whether they were taking valproate at the time of the prior pregnancy.
It is also important to take a family history that includes seizure disorders, including febrile seizures, and intellectual disability. Many patients are concerned about the risk of passing epilepsy on to their child. Only a few epidemiologic studies have looked at the inheritance patterns of epilepsy. For most patients with epilepsy, the risk of passing it on to their children is higher than the approximate 1% to 2% risk in the general population; however, the absolute risk remains low. Factors associated with a low risk are late onset of epilepsy in the parent and a known acquired cause of epilepsy such as a vascular malformation, stroke, or trauma. Patients with an early onset of epilepsy, epilepsy of unknown cause, and a family history of epilepsy—particularly in a first-degree relative—have a higher risk. Epilepsy associated with intellectual disability may also be more likely to be genetic. Across many studies, the “genetic” generalized epilepsies or idiopathic generalized epilepsies have a higher risk of inheritance than focal epilepsy. Interestingly, a consistent finding in several epidemiologic studies is that mothers with epilepsy have a much higher chance of having a child with epilepsy than do fathers with epilepsy. The most recent large population study from Rochester, Minnesota reviewed the medical records of all 660 probands with epilepsy born between 1935 and 1994 and all their first-degree relatives. This study also found that epilepsy was more likely to be inherited from the mother, although when analyzed separately, this effect was only true for focal epilepsies, not generalized epilepsies. When all types of epilepsy were considered, the cumulative incidence to age 40 of epilepsy in a child of a woman with epilepsy was 5.39%, which correlates to a fivefold increased risk from the baseline population. The authors recommended taking the standard error into account and counseling women that on average, the risk of passing on epilepsy is 2.69% to 8% . In children of women with generalized epilepsy, the incidence was 8.34% (1.36% to 15.36% risk, considering standard error), and if the mother had focal epilepsy, the incidence was 4.43% (1.43% to 7.43%).
This type of epidemiologic data can be useful for patients with epilepsy of unknown cause, but they should not be used to counsel all patients indiscriminately. It is critical that the neurologist and obstetrician take a patient’s individual clinical and family history into account before advising on the risks of passing on epilepsy.
An increasing number of epilepsy genes and familial syndromes have been discovered that can substantially alter the risk of inheriting an epileptic disorder. Autosomal-dominant forms of epilepsy, such as autosomal-dominant frontal lobe epilepsy (ADFLE) and autosomal-dominant temporal lobe epilepsy (ADTLE), are highly penetrant familial epilepsies that should be considered in a patient with one or more first-degree relatives with a similar epilepsy syndrome. Mutations in the sodium channel, voltage gated, type 1 alpha subunit ( SCN1A ) gene have variable penetrance and expressivity, and they can present with a range of manifestations. Even within one family, some individuals with the mutation will be unaffected, some will have simple febrile seizures or a mild epilepsy syndrome that persists into adulthood, whereas others can have Dravet syndrome, a severe epileptic encephalopathy. Preimplantation genetic testing for these disorders is available only for some syndromes and is controversial. However, recognizing these family syndromes definitely changes the counseling on the risk of inheriting epilepsy. Other genetic syndromes associated with epilepsy have more serious complications. For example, bilateral periventricular nodular heterotopia (PVNH; Fig. 49-1 ) is an uncommon cause of focal epilepsy. Approximately 50% of female patients with PVNH will have a mutation in the filamin A gene. This is an X-linked–dominant mutation that is typically lethal in males in the third trimester or in the immediate postnatal period. Female patients may have no manifestations other than the periventricular nodules, which represent aberrant neuronal migration, and epilepsy. An echocardiogram is recommended in these women, because they can have cardiac anomalies. Other examples of critical genetic diagnoses are mitochondrial disorders that can present with epilepsy. Whereas a comprehensive review of the genetics of epilepsy is beyond the scope of this chapter, genetic counseling is an important option for many prospective parents with epilepsy, and certain clinical findings or key features in a family history, such as other affected relatives or frequent miscarriages, make specialized counseling essential.
Folic Acid Supplementation
The 2009 AAN practice guidelines recommend folic acid supplementation of 0.4 to 4 mg/day for all women of childbearing age who take AEDs. These recommendations are largely extrapolated from studies that have demonstrated that folic acid supplementation reduces the risk for NTDs in the general population. Additionally, low first-trimester serum folic acid levels have been correlated with an increased risk for congenital malformations in the offspring of women with epilepsy, and several AEDs are known to lower folic acid levels. Little direct evidence is available to suggest that folic acid reduces the risk of major anomalies in women taking AEDs, although the AAN practice guidelines state that prior studies might have been underpowered to detect a benefit. One study by Pittschieler and colleagues suggested that folic acid may reduce the risks of miscarriage in women with epilepsy. The NEAD study also found an association between higher IQs in children of mothers with epilepsy who took periconceptional folic acid supplementation (≥0.4 mg). It is unclear whether this effect was specific to AED use because similar beneficial effects on cognitive development have been noted in the general population. The optimal dose of folic acid for women taking AEDs is not known. A recent study of women without epilepsy found delayed psychomotor development in children of women exposed to doses greater than 5 mg compared with women who took doses of 0.4 to 1 mg, which raises concerns about the practice of high-dose supplementation. More research is needed to determine the optimal dose of folic acid in women with epilepsy. In the meantime, supplementation with 0.4 to 1 mg in all women of childbearing age taking AEDs should be recommended. Many clinicians increase the dose to 4 mg of folic acid when a patient is trying to conceive or is pregnant.
Vitamin D deficiency is also common in women with epilepsy. This occurs because anticonvulsants may interfere with the conversion of 25-hydroxycholecalciferol to 1,25-dihydroxycholecalciferol, the active form of vitamin D. Ideally, 25-hydroxyvitamin D levels should be checked and optimized prior to pregnancy. A supplemental dose of 1000 to 2000 IU of vitamin D 3 in addition to a prenatal vitamin is reasonable during pregnancy. Additionally, because folic acid supplementation can mask the hematologic effects of vitamin B 12 deficiency, B 12 levels should also be checked in women with epilepsy.
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 . AED levels should be checked as soon as possible and then monthly. Adjustments should be made to keep the patient’s AED level around her prepregnancy or early pregnancy level.
An early anatomic ultrasound at 14 to 15 weeks’ gestation can identify signs suggestive of NTDs in women at high risk (see Chapter 9 ). At approximately 16 weeks’ gestation, the patient should undergo blood testing with maternal serum alpha-fetoprotein screening in an attempt to detect any NTD. Coupled with ultrasonography, these data result in a detection rate of more than 90% for open NTDs (see Chapter 10 ). At 18 to 22 weeks, the patient should undergo a specialized, detailed anatomic ultrasound to determine whether congenital malformations, including NTDs, are present. If adequate views of the fetal heart are not obtained, a fetal echocardiogram can be performed at 20 to 22 weeks’ gestation to detect cardiac malformations, which are among the more common malformations in women taking any antiepileptic medications. In the United States, no official recommendations have been made on the use of fetal cardiac echo studies in women with epilepsy, but the 2009 Italian guidelines do advise this examination for all women taking AEDs.
As previously noted, there appears to be an increased risk for IUGR in fetuses exposed in utero to anticonvulsant medications. If the patient’s weight gain and fundal growth appear appropriate, regular ultrasound examinations to assess fetal weight are probably unnecessary. If, however, if poor fundal growth is suspected or if the patient’s habitus precludes adequate assessment of this clinical parameter, serial ultrasonography for fetal weight discernment can be performed.
Antepartum fetal evaluation with nonstress testing is not necessary in all mothers with seizure disorders, but it should be considered for patients who have active seizures in the third trimester.
Vitamin K Supplementation
Third-trimester vitamin K supplementation in women taking certain enzyme-inducing AEDs (EIAEDs) is a historic practice based on a concern for an increased risk of intracranial neonatal hemorrhage and clotting factor deficiencies associated with EIAED exposure reported in early case studies. EIAEDs include phenobarbital, phenytoin, carbamazepine, and oxcarbazepine. A more recent study of 662 women with epilepsy taking EIAEDs did not find any increased risk of bleeding in the neonate if the infant received 1 mg of vitamin K intramuscularly at birth. This problem is rare today because most neonates are given vitamin K at birth. The 2009 AAN guidelines state that evidence is insufficient to recommend for or against the practice of peripartum vitamin K supplementation. Another recent study evaluated the risk of maternal postpartum hemorrhage in women with epilepsy and also found no significant difference in the risk of bleeding in women taking EIAEDs versus controls. There was also no difference in the risk of bleeding in women taking EIAEDs who supplemented with vitamin K and those who did not.
Labor and Delivery
Although epidemiologically there may be an increased risk of induction of labor and CD in women with epilepsy, these interventions should not be recommended to women with epilepsy without specific additional obstetric, medical, or neurologic indications. Most women with epilepsy have successful vaginal deliveries. Although no evidence exists to support or challenge epidural analgesia in patients with epilepsy, it is typically utilized to decrease stress and allow the mother to rest during a long labor.
The risk of seizures during labor in women with epilepsy is 3.5% or less, and seizures are most common in patients who have had seizures during pregnancy. Whenever a seizure occurs, acute seizure management involves assessing the patient’s clinical stability, including respiratory and circulatory function. Nothing should be put in the mouth of a seizing patient, but supplemental oxygen should be provided, and suctioning of secretions can be performed if possible. Ideally, the patient should be turned on her left side to increase blood supply to the fetus. Short-acting benzodiazepines, typically lorazepam 0.1 mg/kg to 0.2 mg/kg with a maximum of 10 mg, are the mainstay of acute seizure treatment. If the seizure does not resolve within 2 minutes, lorazepam should be given. In most cases this is followed by intravenous (IV) fosphenytoin or phenytoin if seizures persist. Status epilepticus is defined by seizures that last more than 5 minutes. In the rare case of tonic-clonic status in pregnancy, intubation and stabilization with anesthesia may be required. Fetal monitoring should begin as soon as possible after a seizure, if it is not already in place. Transient fetal heart rate changes may be seen and can be tolerated temporarily, but if fetal bradycardia persists, the clinician must assume fetal compromise or placental abruption and must proceed with CD.
New Onset of Seizures in Pregnancy and in the Puerperium
Occasionally, seizures are diagnosed for the first time during pregnancy, which may present a diagnostic dilemma. If the seizures occur in the third trimester, they are eclampsia until proven otherwise and should be treated as such until the physician can perform a proper evaluation. The treatment of eclampsia is delivery, but the patient must first be stabilized (see Chapter 31 ). Magnesium sulfate, instead of AEDs, is the treatment of choice for eclamptic seizures. It is often difficult, however, to distinguish eclampsia from an epileptic seizure. The patient may be hypertensive initially after an epileptic seizure and may exhibit some myoglobinuria secondary to muscle breakdown, which will test as proteinuria on a routine urinalysis. 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 develops seizures for the first time at an earlier gestational age, she should be evaluated and started on the proper medication. The physician must look for acquired causes of seizures that include trauma, infection, metabolic disorders, space-occupying lesions, central nervous system (CNS) bleeding, and ingestion of drugs such as cocaine and amphetamines. Blood samples should be obtained for electrolytes, glucose, ionized calcium, magnesium, renal function studies, and toxicologic studies while IV access is being established. If the patient experienced a tonic-clonic seizure and the attending physician believes, based on clinical history, that this is probably new-onset epilepsy with a high likelihood of recurrence, she should be started on the appropriate anticonvulsant medication while awaiting the results of any laboratory studies. Although lamotrigine is one of the most commonly prescribed drugs for women planning pregnancy, it is typically not practical to start it when epilepsy presents in pregnancy. The lamotrigine titration schedule is at least 6 weeks because of an increased risk of a Stevens-Johnson reaction in patients taking this drug, especially if it is titrated quickly. In addition, accelerated lamotrigine metabolism in pregnancy makes it virtually impossible to achieve a therapeutic level in a pregnant woman over a reasonable time period. Similar considerations apply to oxcarbazepine. For new-onset epilepsy, levetiracetam is often used first because it can be started quickly and does not carry a high risk of rash. An unfortunate side effect of levetiracetam, however, is an increase in depressed mood or irritability; this should be assessed in women starting this drug.
Any patient who experiences seizures for the first time during pregnancy without a known cause should undergo an EEG and intracranial imaging. In studying only eclamptic patients, Sibai and colleagues found that EEGs were initially abnormal in 75% of patients but normalized within 6 months in all women studied. Although this group found no uniform abnormalities on computed tomography (CT) in this series of eclamptic patients, they did find that 46% and 33% had some abnormal findings on EEG and CT, respectively. Most of the findings were nonspecific and were not helpful in diagnosis or treatment. An MRI is indicated in most cases of new-onset seizures and may be helpful if eclampsia is suspected.
Breastfeeding and the Postpartum Period
The levels of anticonvulsant medications must be monitored frequently during the first few weeks postpartum (see Chapter 23 ) because they can rise rapidly. If the patient’s medication dosages were increased during pregnancy, they will need to be decreased over the 3 weeks after delivery to levels at or slightly higher than that of the prepregnancy period. As discussed above, this is especially important for lamotrigine.
The benefits of breastfeeding have been well established and include the promotion of mother-infant bonding (see Chapter 24 ). Whereas AEDs taken by the mother are present in breast milk to varying degrees, few data suggest neonatal harm from exposure through breast milk. The NEAD study found that infants exposed to carbamazepine, lamotrigine, phenytoin, and valproate in breast milk had higher IQs and language scores at 6 years than those infants whose mothers did not breastfeed. An improvement in parent-reported developmental abilities of children was also noted in breastfed infants in a Norwegian cohort of AED-exposed children at 6 and 18 months, although the effect was not sustained at 36 months. Neither study found adverse effects on developmental outcomes related to breast milk exposure for the studied drugs (carbamazepine, lamotrigine, phenytoin, and valproate). Although further prospective studies of AED exposure via breast milk are necessary, for most AEDs, the theoretic concern of prolonged infant exposure likely does not outweigh the known benefits of breastfeeding. Some experts advise caution with AEDs with longer half-lives, such as phenobarbital and zonisamide, although again the concern is largely theoretic.
Breastfeeding should be supported and encouraged for most women with epilepsy; however the sleep deprivation associated with trying to feed a newborn may put her at risk for seizures. A key part of managing a pregnancy in women with epilepsy is discussing seizure safety with her and her family. Partners or other members of a patient’s support system should assist with night feedings with either pumped milk or formula so that the patient can get a stretch of uninterrupted sleep, typically 6 to 8 hours depending on the patient. The patient may have to pump milk additional times during the day to maintain this supply. Other safety recommendations include giving baths only in the presence of another adult and changing diapers on a pad on the floor instead of on a changing table. Avoiding stairs when possible and using a stroller, rather than an infant carrier strapped to the mother, should also be considered. The importance of not allowing infants to sleep in the parents’ bed should also be emphasized. Lastly, women with epilepsy are at increased risk for postpartum depression, a topic that should be discussed with the patient and her family prior to delivery and after.
Contraceptive counseling is an important part of preconception and postpartum planning in women with epilepsy, and drug-drug interactions are numerous between AEDs and hormonal contraception. Both the Centers for Disease Control and Prevention (CDC) and the World Health Organization (WHO) have released evidence-based reviews on the use of specific types of contraception in women taking AEDs. The most reliable form of reversible contraception is the intrauterine device (IUD), and this is considered the contraceptive method of choice for most women with epilepsy. Both the copper and levonorgestrel IUD are appropriate. If hormonal methods are considered, the physician should review the considerations laid out by the CDC and WHO before initiating treatment.