Pregnancy in women who have epilepsy

Ideal, comprehensive care of women who have epilepsy during the reproductive years must include effective preconceptional counseling and preparation. The importance of planned pregnancies with effective birth control should be emphasized, with consideration of the effects of the enzyme-inducing AEDs on lowering efficacy of hormonal contraceptive medications and the need for back-up barrier methods. Before pregnancy occurs, the patient's diagnosis and treatment regimen should be reassessed. Once the diagnosis of epilepsy is confirmed, it is important to verify if the individual patient continues to need medications and if she is taking the most appropriate AED to balance control of her seizures with teratogenic risks. For most women who have epilepsy, withdrawal of all AEDs before pregnancy is not a realistic option. A decision to undergo a trial while not taking AEDs before a planned pregnancy should be based on the same principles used for AED withdrawal in any person who has epilepsy. The taper should be completed at least 6 months before planned conception to provide some reassurance that seizures are not going to recur. If a woman who has epilepsy is in the more prevalent category of needing AEDs for seizure control, then monotherapy at the lowest effective dosage should be used. If large daily doses are needed, then frequent smaller doses or extended-release formulations may be helpful to avoid high peak levels. Some of the newest information about differential risks between AEDs also should be considered. The woman's AED regimen should be optimized and folate supplementation should begin before pregnancy. Given that 50% of pregnancies are unplanned in the United States, folate supplementation should be encouraged in all women of childbearing age who are taking any AED for any indication. Dosing recommendations vary from 0.4 mg/d to 5 mg/d. It is not uncommon for a physician to consider changing AED regimens when the patient first reports that she is pregnant. In many cases, she already is in or past the critical period of organogenesis (Table 3). If a woman who has epilepsy presents after conception and is taking a single AED that is effective, her medication usually should not be changed. Exposing the fetus to a second agent during a crossover period of AEDs only increases the teratogenic risk, and seizures are more likely to occur with any abrupt medication changes. If a woman is on polytherapy, it may be possible to switch to monotherapy safely. Seizure control remains an important goal during pregnancy. In particular, convulsive seizures place the mother and fetus at risk. Nonconvulsive seizures also may be harmful, especially if they involve falling or other forms of trauma. Monitoring serum AED levels during pregnancy can be helpful in optimizing seizure control. Prenatal screening can detect major malformations in the first and second trimesters. Vitamin K1 is given 10 mg/d orally during the last month of pregnancy followed by 1 mg intramuscularly or intravenously to the new-born. Although women who have epilepsy and women who are taking AEDs for other indications do have increased risks for maternal and fetal complications, these risks can be reduced considerably with effective preconceptional planning and careful management during pregnancy and the postpartum period.     

Antiepileptic Drug Therapy: When Is Epilepsy Truly Intractable?

Summary: We define intractable in the first 5 years of epilepsy treatment as an average of at least one seizure every 2 months. For the longer term, we define intractable as at least one seizure per year. Population studies from Chicago, IL, U.S.A., Finland, and Nova Scotia, Canada indicate that with long follow-up, many children with intractable epilepsy eventually have remission of their seizure disorder. Epilepsy is no longer intractable when the seizures stop completely. How often does a new antiepileptic drug (AED) render a child seizure-free when one or more AEDs have failed? Literature on adults with epilepsy suggests that few with chronic epilepsy who have not achieved seizure control with several AEDs will achieve complete seizure control with additional AEDs. The Nova Scotia study suggests that if a child's seizure fails to be controlled with a first AED, there is an increased risk of intractable epilepsy. Nonetheless, the chance of eventual, complete remission of epilepsy (seizure-free without AED treatment) is approximately 40%. We conclude that intractability should not be considered until there has been failure of at least three first-line AEDs. Intractable epilepsy is rare. Careful definition of the characteristics of children with intractable epilepsy who do respond completely to new AEDs will likely provide the only rational approach to treatment of children with three drug failures. Collaboration by multiple epilepsy centers will be required to gain this information.     

Therapy insight: clinical management of pregnant women with epilepsy

In pregnant women with epilepsy who are being treated with antiepileptic drugs (AEDs), careful clinical management is vital because seizure frequency can change during pregnancy, and both seizure activity and AED treatment can have consequences for the developing fetus. Complications of epilepsy and AED treatment include stillbirths, prematurity, low birth weight, major and minor malformations, and cognitive delay later in life. Certain AEDs probably have more adverse effects than others; data from prospective studies indicate that phenobarbital and valproate are associated with significant increases in major malformations, and retrospective studies show lower verbal IQs and greater need for extra assistance in school for children whose mothers received valproate during pregnancy. Monitoring of AED levels and dosage adjustment are warranted throughout pregnancy, and vitamin K(1) at a dose of 10 mg/day should be given in the last month, particularly when cytochrome P450 enzyme-inducing AEDs are being administered. In the postpartum period, breastfeeding is recommended; however, there is differential transfer of individual AEDs in breast milk, and the infant should be observed clinically. For all women of reproductive age, preconceptual counseling is important, and includes optimization of the AED regimen and advising the mother to take supplemental folic acid.     

Fetal antiepileptic drug exposure: motor, adaptive, and emotional/behavioral functioning at age 3 years

The Neurodevelopmental Effects of Antiepileptic Drugs (NEAD) Study is an ongoing prospective observational multicenter study in the United States and United Kingdom that enrolled pregnant women with epilepsy on antiepileptic drug (AED) monotherapy from 1999 to 2004. The study seeks to determine if differential long-term neurodevelopmental effects exist across four commonly used AEDs (carbamazepine, lamotrigine, phenytoin, valproate). In this article, we examine fetal AED exposure effects on motor, adaptive, and emotional/behavioral functioning in 229 children who completed at least one of these tests at 3 years of age. Adjusted mean scores for the four AED groups were in the low average to average range for motor functioning, parental ratings of adaptive functioning, and parental ratings of emotional/behavioral functioning. A significant dose-related performance decline in motor functioning was seen for both valproate and carbamazepine. A significant dose-related performance decline in parental ratings of adaptive functioning was also seen for valproate, with a marginal performance decline evident for carbamazepine. Further, parents endorsed a significant decline in social skills for valproate that was dose related. Finally, on the basis of parent ratings of attention span and hyperactivity, children of mothers who took valproate during their pregnancy appear to be at a significantly greater risk for a future diagnosis of attention-deficit/hyperactivity disorder. Additional research is needed to confirm these findings, examine risks of other AEDs, define the risks in the neonate associated with AEDs for treatment of seizures, and determine the underlying mechanisms of adverse AED effects on the immature brain.     

Oxcarbazepine in pregnancy: clinical experience in Argentina

The potential teratogenicity of antiepileptic drugs (AEDs) is a major concern for women with epilepsy who are considering pregnancy. Traditional AEDs are associated with an at least twofold risk of fetal malformations compared with the general population. The risk of malformations with newer AEDs is unclear. This article reports the multicenter clinical experience in Argentina of pregnant women with epilepsy receiving AEDs. Of 114 pregnancies monitored, 16 newborns had anomalies: 3 cardiac, 3 skull, and 2 gastrointestinal malformations, and 8 facial dysmorphies. Most fetal anomalies were observed following exposure to phenobarbital, valproate, and carbamazepine. Of 55 babies exposed to the new-generation AED oxcarbazepine (20 as combination therapy and 35 as monotherapy), one malformation (cardiac) was reported (in a patient receiving oxcarbazepine and phenobarbital). Thus, newer AEDs may have a lower teratogenic risk than traditional AEDs. These data add to the growing experience with AED therapy in pregnant women with epilepsy.     

Bone health in people with epilepsy: is it impaired and what are the risk factors?

Diseases of the bone are becoming increasingly prevalent. Persons with epilepsy treated with antiepileptic drugs (AEDs) are at greater risk as evidenced by changes in bone turnover, osteoporosis, alterations in bone quality, and fracture. Biochemical indices of bone and mineral metabolism including calcium, vitamin D, parathyroid hormone, and bone turnover markers can be affected. AED exposure is a cause of secondary osteoporosis with decreased bone mineral density (BMD) secondary to poor bone accrual in children or accelerated bone loss in adults. Early reports described osteomalacia, a change in bone quality with increased unmineralized bone. Recent studies do not reveal osteomalacia, but there may be more subtle changes in bone quality. Multiple studies have found an increased risk of fractures in association with epilepsy and AED exposure. Cytochrome P450 enzyme inducing AEDs are most commonly associated with a negative impact on bone, but studies also suggest an effect of valproate. There is limited data regarding the newer AEDs. No single mechanism has emerged to explain all the changes in bone in association with epilepsy and AEDs. Although multiple therapies are available for the treatment of bone disease, there is limited study in persons with epilepsy. It is recommended that all persons obtain adequate amounts of calcium and vitamin D. In addition BMD screening is warranted for persons with long-term AED exposure particularly if they have other risk factors for bone disease.     

Teratogenicity of antiepileptic drugs: state of the art

PURPOSE OF REVIEW: Information on the risks associated with antiepileptic drug (AED) use in pregnancy is necessary for a rational approach to the management of women of childbearing potential who have epilepsy. This reviews addresses recent reports on the risk for birth defects and impaired postnatal development attributable to prenatal exposure to AEDs. RECENT FINDINGS: Some studies have indicated greater risk for birth defects as well as for lower verbal IQ in association with exposure to valproic acid, as compared with some other AEDs. The risk appears to be greater at doses above 800-1000 mg/day; lower doses may not carry higher risks than those associated with other AEDs. This observation is a cause of concern but more data are needed from prospective studies to assess the possible impact of confounding factors in order to clarify whether there is a causal relationship. Large-scale pregnancy registries have been launched and are expected to provide more conclusive comparative data on the most frequently used AEDs in the near future. SUMMARY: Although further studies are needed, it appears reasonable to use valproic acid with caution in women with epilepsy who are planning to become pregnant, and to consider prescribing other equally effective and safer AEDs if they are available. The importance of seizure control during pregnancy must not be neglected, and any attempt to change treatment should be done before conception. Drug withdrawal during pregnancy should be avoided, and patients should be made aware that definitive evidence on the relative safety of AEDs is lacking.     

Epilepsy and Pregnancy

Summary:  Since 1963, the association between antiepileptic drugs (AEDs) and congenital malformations in the offspring of women with epilepsy has received attention. A number of articles reported affirmative as well as some negative findings regarding an increased risk of congenital malformations. Although a consensus has not been regarding the presence of the specific malformation syndromes in relation to individual AEDs, such as fetal hydantoin syndrome, it is evident that women taking AEDs carry a two- to sevenfold higher risk of congenital malformations than do the general population. In most recent studies, special attention has been placed on polytherapy, including the specific AED, or AED combinations, and high AED serum concentrations, responsible for the higher risk of congenital malformations. Based on these cumulative results, therapy guidelines for women of childbearing age with epilepsy have been established.     

Impact of early life exposure to antiepileptic drugs on neurobehavioral outcomes based on laboratory animal and clinical research

Epilepsy affects approximately 1% of children under the age of 15, making it a very common neurological disorder in the pediatric population (Russ et al., 2012 [1]). In addition, ~ 0.4–0.8% of all pregnant women have some form of epilepsy (Hauser et al., 1996a,b; Borthen et al., 2009; Krishnamurthy, 2012 [2], [3], [4], [5]). Despite the potential deleterious effects of antiepileptic drugs (AEDs) on the developing brain, their use is still required for seizure control in pregnant women (Krishnamurthy, 2012 [5]), and they represent the standard approach for treating children with epilepsy (Chu-Shore and Thiele, 2010; Quach et al., 2010; Verrotti et al., 2011 [6], [7], [8]). Even when AEDs are effective, there are potential side effects, including cognitive and affective changes or altered sleep and appetite. The consequences of AED exposure in development have been studied extensively (Canger et al., 1999; Modi et al., 2011a,b; Oguni, 2011 [9], [10], [11], [12]). Despite intensive study, there is still debate about the long-term consequences of early life AED exposure. Here, we consider the evidence to date that AED exposure, either prenatally or in early postnatal life, has significant adverse effects on the developing brain and incorporate studies of laboratory animals as well as those of patients. We also note the areas of research where greater clarity seems critical in order to make significant advances. A greater understanding of the impact of AEDs on somatic, cognitive and behavioral development has substantial value because it has the potential to inform clinical practice and guide studies aimed at understanding the genetic and molecular bases of comorbid pathologies associated with common treatment regimens. Understanding these effects has the potential to lead to AEDs with fewer side effects. Such advances would expand treatment options, diminish the risk associated with AED exposure in susceptible populations, and improve the quality of life and health outcomes of children with epilepsy and children born to women who took AEDs during pregnancy.This article is part of a Special Issue entitled “The Future of Translational Epilepsy Research”.     

Pregnancy and epilepsy

The management of women with epilepsy who are planning a pregnancy or who are currently pregnant remains one of the most perplexing and engaging clinical issues for neurologists. A refinement of surveillance methods, along with a greater understanding of teratogenesis, has provided us with better information regarding specific antiepileptic drug (AED)-associated teratogenic risk than in the past. A recent finding from multiple worldwide AED pregnancy registries is an increased teratogenic risk with valproate compared with the other AEDs, supporting previous retrospective reports. Valproate use and independently having more than five convulsive seizures during pregnancy are associated with a risk of decreased verbal intelligence quotient (IQ) in the offspring. The European pregnancy register confirms that most women who are seizure-free early in pregnancy have an excellent chance of maintaining seizure freedom throughout pregnancy. The management of AEDs during pregnancy continues to be explored, and considerations for dosing and therapeutic monitoring are discussed herein. The metabolism of both lamotrigine and oxcarbazepine is induced during pregnancy, and careful clinical monitoring and frequent level assessment are emerging as important for these AEDs.     

First, do no harm: the risks of overtreating children with epilepsy

BACKGROUND: Although overtreatment with antiepileptic drugs contributes to the morbidity associated with epilepsy, many children still are overtreated. OBJECTIVE: To evaluate if the withdrawal of at least one antiepileptic drug (AED) in children with refractory epilepsy using polytherapy enable a better seizure control. METHOD: This was a prospective study. Children with refractory epilepsy using at least two AEDs were included. Once the patient, or guardian, agreed to participate in the study, one or more AED were slowly tapered off. The remaining AEDs dosages could be adjusted as needed, but a new AED could not be introduced. RESULTS: Fifteen patients were evaluated, three girls; ages ranging from 3 to 18 (mean=8.7 years). After at least one AED withdrawal, two (13.5%) patients became seizure free, seizures improved >50% in 5 (33.5%) patients, did not change in 5 (33.5%), and seizure frequency became worse in 3 (20%). Adverse events improved in 12 patients (80%). CONCLUSION: The withdrawal of at least one AED is a valuable option in the treatment of selected children with refractory epilepsy.     

Antiepileptic drugs and neurodevelopment

Clinical studies have documented the teratogenic potential of antiepileptic drugs (AEDs). More recent cohort studies have been trying to sort out which AEDs impose the highest risk of teratogenicity. Currently, there is evidence demonstrating an increased risk of major congenital malformations (MCMs) for valproate, phenobarbital, and polytherapy during pregnancy. Based on the current data from multiple studies, the risk for valproate is the highest. Additional studies are needed to fully delineate if differences exist for other AEDs, especially the newer AEDs. However, although MCMs are easy to recognize and have been shown to be more common after in utero exposure to AEDs, there are insufficient data regarding their long-term effects on cognition and behavior in exposed children. Although most children born to women with epilepsy are healthy, in recent years there has been increasing awareness of the long-term effects of in utero exposure to AEDs. Recent discovery of neuronal apoptosis following in utero AED exposure in animals during a period that corresponds to the third trimester and early infancy in humans raises further concerns. Prospective clinical studies seem necessary in order to better understand the long-term neurodevelopmental effects of in utero exposure to AEDs.     

Prognostic Significance of Failure of the Initial Antiepileptic Drug in Children with Absence Epilepsy

PURPOSE: In children with childhood absence epilepsy (CAE) and juvenile absence epilepsy (JAE), to determine the impact of failure of initial antiepileptic drug (AED) for lack of efficacy in eventual seizure control and long-term remission of epilepsy. METHODS: Centralized EEG records for the province of Nova Scotia allowed identification of all children seen with CAE or JAE between 1977 and 1985. Information regarding success or failure of initial AED in fully controlling seizures and long-term seizure control and remission of epilepsy was collected by patient questionnaire and chart review. RESULTS: Eighty-six of 92 eligible patients were followed up (75 CAE, 11 JAE). Initial AED treatment was successful in 52 (60%) of 86. Success tended to be greater for valproate (VPA) than for other AEDs (p = 0.07), and lower if generalized tonic-clonic or myoclonic seizures coexisted (p < 0.004 and p < 0.03). Terminal remission was more likely if the initial AED was successful than if it had failed (69% vs. 41%; p < 0.02). Compared with those in whom the initial AED was successful, subjects whose initial AED had failed were more likely to progress to juvenile myoclonic epilepsy (JME) at last follow-up (32% vs. 10%; p < 0.02) and to develop intractable epilepsy (17% vs. 2%; p < 0.04). CONCLUSIONS: Initial AED was successful in 60% of children with AE. If the first AED failed, the outcome was less favorable, with a lower rate of terminal remission and a higher rate of progression to JME and intractable epilepsy.     

The Australian registry of anti-epileptic drugs in pregnancy: experience after 30 months.

BACKGROUND: Most women with epilepsy need to take antiepileptic drugs (AEDs) in pregnancy to prevent the potentially harmful effects of seizures. Retrospective studies have demonstrated an increased chance of having a child with a birth defect (BD) in women with epilepsy taking AEDs. It is uncertain how much of this risk is directly caused by the AEDs and whether certain drugs or combinations are associated with a greater risk. AIMS: To establish a register to evaluate prospectively the incidence of adverse pregnancy outcomes in women exposed to specific AEDs; to determine whether certain AEDs or combinations were associated with a greater risk; and to determine whether other factors influenced the risk. METHODS: An Australia-wide, prospective, voluntary, telephone-interview based, observational register. Three groups of pregnant women were enrolled: those with epilepsy taking AEDs, those with epilepsy not taking AEDs, and those taking AEDs for a non-epileptic indication. The pregnancy outcomes were evaluated by follow-up interviews and by reference to hospital and treating doctors' records. RESULTS: Over the first 30 months of the study (till December 2001) 334 eligible women were enrolled, with all states and territories being represented. Two hundred and ninety two pregnancies had been completed, of which 256 (88%) resulted in a healthy live birth, 19 (6.5%) a live birth with a birth defect, four an induced abortion because of a detected malformation on ultrasound, one premature labour with a stillbirth and 12 (4%) spontaneous abortions. Of the completed pregnancies, 269 were exposed to at least one AED during the first trimester. The incidence of birth defects in relation to specific AEDs was: valproate (16.7%), phenytoin (10.5%), lamotrigine (7.7%) and carbamazepine (3.3%), none of which was significantly different from that in women with epilepsy not taking an AED (4.3%, n.s.). The dose of valproate taken was higher in pregnancies with BD compared to those without (mean 2081 mg vs. 1149 mg, p<0.0001). The incidence of folate supplementation being taken prior to conception did not differ for pregnancy outcomes with or without BD (70% vs. 66%, n.s.). CONCLUSIONS: The model for the Australian Pregnancy Register appears to be successful, with strong enrolment from all regions over the first 30 months. The study is prospective and includes reference to all new AEDs approved in Australia over the past decade. Analysis of the pregnancy outcomes to date may reveal early trends, but numbers are still to small for any definitive conclusions to be made regarding the relative risk in pregnancy of individual AEDs.     

School performance at age 16 in children exposed to antiepileptic drugs in utero--a population-based study

Purpose: In order to evaluate long‐term effects on neurodevelopment in children born to women with epilepsy during pregnancy we studied the children’s school grades at age 16. Methods: We used the Patient Register, the Medical Birth Register, and a local study at South Hospital, Stockholm, to identify women with epilepsy in Sweden who had given birth between 1973 and 1986. The Swedish School Mark Registry was used to obtain information about school grades from the last year of compulsory school, at age 16. Exposed children were compared to all other children born in Sweden between 1973 and 1986. Key Findings: Medical records were analyzed for 1,235 children. Six hundred forty‐one children had been exposed in utero to antiepileptic drugs (AEDs) in monotherapy, 429 in polytherapy, and 165 to no known AED. Children exposed to polytherapy had an increased risk of not receiving a final grade—odds ratio (OR) 2.99 [95% confidence interval (CI) 2.14–4.17]. Children exposed to monotherapy, mainly carbamazepine or phenytoin, did not have a significantly increased risk of not receiving a final grade—OR 1.19 (95% CI 0.79–1.80). Children born to women with epilepsy had a decreased chance of getting a “pass with excellence.” Significance: Exposure to several AEDs in utero may have negative effects on neurodevelopment, and polytherapy should, if possible, be avoided in pregnant women.     

Use of antiepileptic drugs in pregnancy

Babies born to mothers exposed to antiepileptic drugs (AEDs) are at increased risk for major congenital malformations, cognitive impairment and fetal death. For the millions of women with epilepsy, maintaining the safest drug that will successfully prevent seizures during pregnancy remains a primary consideration. The recent development of collaborative international registries to examine the differential and dose-dependent effects of the expanding number of old and new AEDs, have shed light upon potential differences during pregnancy. Valproic acid appears to be associated with the highest risk of overall, as well as AED-specific, birth defects, becoming more evident as doses exceed 1000 mg/day. Lamotrigine may be less teratogenic to humans than other AEDs, although orofacial clefts have recently been reported. The effects of polytherapy appear to carry greater risks compared with monotherapy. Limited data exist for many of the newer AEDs. Furthermore, AED effects may persist during postnatal development. Although no class 1 outcome data are available, prepregnancy counseling to optimize patient-specific treatment is recommended for women of childbearing potential with epilepsy.     

Overtreatment in children with epilepsy

Children with epilepsy are at risk for overtreatment, defined as the use of an excessive number or amount of antiepiletic drugs (AEDs). While the extent of overtreatment of epilepsy in children is not known, there is increasing awareness that overtreatment with AEDs contributes to the morbidity associated with childhood epilepsy. Reasons for overtreatment include using AEDs in a child with seizures who does not require therapy, choosing an inappropriate AED for the seizure type or syndrome; treating non-epileptic behaviors as seizures, use of polytherapy when monotherapy would suffice, and inadequate therapeutic options. Despite the introduction of eight new AEDs in the United States during the last decade, many children continue to be treated with the older generation sedative AEDs. Numerous investigators have now demonstrated that sedative AEDs can be safely removed from the drug regimen of children with epilepsy with resultant improvement in behavior, alertness, and improved seizure control. However, the biggest obstacle to overtreatment is the lack of effective therapies for many of the childhood epileptic syndromes. Until there are more effective therapies developed it is highly likely that children will continue to be over-medicated on ineffective and detrimental AEDs.     

EURAP: the European Registry of Antiepileptic Drugs and Pregnancy

All old-generation antiepileptic drugs (AEDs) are considered to be teratogenic. In Germany, one out of 200 pregnant women (0.5%) is treated with AEDs for epilepsy. The risk of major malformations following exposure to AEDs during the first trimester of pregnancy is two to three times the rate reported in the general population, which is estimated at 2-3%. The risks associated with the treatment of epilepsy during pregnancy are therefore of major concern to all women of childbearing potential with epilepsy. Data on the comparative teratogenicity of these AEDs in humans are, however, conflicting, mainly due to inadequate sample sizes and other methodological shortcomings of previous studies. The teratogenic potential of newer AEDs is even less well known, which prevents a rational approach to AED treatment in women of childbearing potential. The European Registry of Antiepileptic Drugs and Pregnancy is a prospective international multicentre study of pregnancies with AEDs. In Germany the project was started in 2001 and so far more than 500 pregnancies have been enrolled. The enrollment rate is 4% of 4,000 pregnancies with AEDs reported annually.