Valproate

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.

Carbamazepine

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.

Lamotrigine

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

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.

Phenytoin

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

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.

Polytherapy

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.

Genetic Counseling

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.

Bilateral periventricular nodular heterotopia (PVNH). Magnetic resonance imaging (MRI) of a 28-year-old primigravida with intractable focal epilepsy who presented for neurologic evaluation at 24 weeks’ gestation. Her prior MRI demonstrated bilateral PNVH ( white arrows point to abnormal cortical tissue lining the ventricles bilaterally). In up to 50% of women, this syndrome is associated with an X-linked dominant mutation in the filamin A gene that is often lethal in male fetuses in the third trimester or the first few postnatal days. In females, this mutation is associated with the above migrational abnormalities and focal seizures. Female patients may have normal or slightly low intelligence quotients (IQs). This case illustrates the importance of early prepregnancy neurologic evaluation and genetic counseling.

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.

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.

Postpartum Safety

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.

Contraception

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.