Neurologic Care of Pregnant Women with Epilepsy

Summary: Epilepsy is a common neurologic condition in women of reproductive age. Although their risks are greater than those for women in the general population, the majority of women with epilepsy have a good pregnancy outcome. An understanding of the risks and appropriate management of both the pregnancy and epilepsy in these patients is essential for their physicians. Health-care providers should discuss contraception and reproductive issues with all of their female patients with epilepsy as they enter reproductive age. Optimal care requires prepregnancy counseling, including information about contraception, dietary folate supplementation, and the risks related to pregnancy. Although antiepileptic drugs (AEDs) have been implicated as the major cause of teratogenesis in infants born to mothers with epilepsy, uncontrolled epilepsy is also associated with maternal and fetal risk. Therefore, optimal seizure control during pregnancy remains an important goal for women with epilepsy. Women with epilepsy should be counseled about breast-feeding their infants and supported in their decision. The recommendations in this article reflect those of a Practice Parameter developed by the American Academy of Neurology Quality Standards Subcommittee.     

Clinical Care of Pregnant Women with Epilepsy: Neural Tube Defects and Folic Acid Supplementation

Summary:  Women with epilepsy (WWE) have a risk of bearing children with congenital malformations that is approximately twice that of the general population. Most antiepileptic drugs (AEDs) have been associated with such risk. Valproate and carbamazepine have been associated specifically with the development of neural tube defects (NTDs), especially spina bifida. Other factors may contribute to the risk, including concomitant diseases such as diabetes mellitus, occupational exposure to teratogens, excessive prepregnancy weight, and various nutrient deficiencies. In the general population, maternal folate deficiency, in particular, has been linked with the development of NTDs, and periconceptional folate supplementation with a reduction of risk. It is unclear whether folate supplementation has a comparable protective effect for WWE. Data concerning the risk for congenital malformations associated with the newer AEDs (gabapentin, felbamate, lamotrigine, levetiracetam, oxcarbazepine, tiagabine, topiramate, and zonisamide) are still limited. Several pregnancy registries for women taking AEDs have been established. Comprehensive postmarketing surveillance, regionally or nationally, might be the ideal method of monitoring medication safety, but government support for such an undertaking has for the most part been lacking. Despite uncertainty about the efficacy of periconceptional folate supplementation in WWE, these women should receive such supplementation at dosage levels recommended for the general population of women of childbearing age. Seizure control must not be neglected in a pregnant woman with epilepsy since seizures are associated with harm to the fetus as well as the mother. Risk may be minimized by using a single AED at the lowest effective dosage.     

Malformations in Offspring of Women with Epilepsy: A Prospective Study

PURPOSE: The incidence of malformations among infants of mothers with epilepsy treated with antiepileptic drugs (AEDs) during pregnancy is higher than that found in the general population. The aim of this study was to contribute to providing a definition of the rate of congenital anomalies in the offspring of mothers with epilepsy and to detect possible risk factors. METHODS: Since 1977, 517 pregnancies were followed up at the San Paolo Hospital in Milan by a team of epileptologists and obstetricians. The patients received monthly obstetric and neurologic examinations, and the blood levels of AEDs were tested monthly. During pregnancy the patients underwent ultrasound investigations to evaluate fetal morphology and development. At the time of delivery, the infants were submitted to a standardized examination by a pediatrician, and a more detailed clinical examination was performed on day 5. Malformations were classified as (a) genetic and chromosomic, (b) severe and mild malformations, and (c) deformities. RESULTS: The overall rate of malformations was 9.7%: of these, 5.3% were structurally severe, 2.2% were mild, 0.4% were chromosomic-genetic, and 1.8% were deformities. No malformation was detected in the 25 untreated patients. CONCLUSIONS: The risks of teratogenicity have been regarded as multifactorial, involving such factors as genetic predisposition, although most prospective studies show that AED-related factors are the primary risk factors for an increased incidence of congenital malformations.     

2005 AES Annual Course: Evidence Used to Treat Women with Epilepsy

Summary:  Although most female-specific considerations for treatment of epilepsy cannot be answered by Class I evidence, significant progress in our knowledge base has occurred in the past few years. Open-label studies of progesterone supplementation showed promising results; an ongoing randomized trial may provide definitive evidence for therapeutic use of progesterone in women. A randomized trial of hormone replacement therapy demonstrated a dose-related increase in seizure frequency in postmenopausal women with epilepsy. The use of different AED regimens during pregnancy cannot be explored with randomized, controlled trials; we must rely on the best available evidence from ongoing observational studies. The consistent findings of large prospective pregnancy registries reveal a consistent pattern of amplified risk for major congenital malformations in pregnancies exposed to valproate. These registries have also highlighted the concern for the effect of shifting hormones on AED concentrations. An increased frequency of seizures during pregnancy has been noted with lamotrigine (LTG) and oxcarabazepine, both of which undergo glucuronidation. Other studies have demonstrated an increased clearance of LTG during pregnancy and with exogenous estrogen use. It may be prudent to closely monitor serum concentrations of these AEDs with hormonal changes. An increased risk for neurodevelopmental consequences has been demonstrated for the fetus exposed to AED polytherapy, valproic acid, or frequent maternal convulsive seizures. Preliminary information about breastfeeding with LTG and levetiracetam is available. These newly released findings provide the tools to begin to practice evidence-based medicine when treating our female patients during their reproductive and postmenopausal years.     

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.     

Obstetric and Gynecologic Care of Women with Epilepsy

Summary: Optimal gynecologic and obstetric care for women with epilepsy requires a multidisciplinary approach throughout the various life stages. Epilepsy has important effects on puberty, contraceptive efficacy, pregnancy and fetal development, and menopause. This article discusses these effects and makes recommendations for gynecologic and obstetric care of patients with epilepsy, with particular focus on pregnancy. Despite very real risks to both the developing fetus and the mother, the majority of women with epilepsy—with appropriate pregnancy planning and management—have good pregnancy outcomes.     

Contraception for women with epilepsy

Antiepileptic drugs that induce hepatic enzyme activity may alter the metabolism of most hormonal methods of contraception, and this affects the contraceptive regime. This effect should be considered in the choice of both the treatment of the epilepsy and the choice of contraceptive method. This review considers these interactions and offers advice about their management.     

Epilepsy, Antiepileptic Drugs, and the Risk of Spontaneous Abortion

The possible effect of in utero antiepileptic drug (AED) exposure on the incidence of spontaneous abortion was evaluated among pregnancies of women with epilepsy and the wives of men with epilepsy. The proportion of pregnancy outcomes terminating in spontaneous abortion, the gestational age-specific rates of spontaneous abortion, and the cumulative risks of spontaneous abortion were determined. The gestational age-adjusted rate ratio for spontaneous abortion of 0.80 (95% confidence interval 0.45-1.40) was not increased for the pregnancies of women with epilepsy compared with those of the wives of men with epilepsy. Among women with epilepsy the rate ratio for in utero exposure to AED exposure was 1.14 (0.52-1.47) and was consistent with no effect of AED on fetal loss. The cumulative risk of spontaneous abortion of 18% for AED exposed pregnancies was also similar to risks reported in nonepilepsy populations. Thus, neither epilepsy nor in utero AED exposure was found to be associated with recognized fetal loss.     

Epilepsy, Pregnancy, and the Child

Women with epilepsy have many legitimate concerns regarding the effects of their condition and the use of antiepileptic drugs (AEDs) on their unborn children. These concerns fall into 4 areas: increased seizure frequency during pregnancy, risk of birth defects, risks associated with breast- feeding, and psychomotor retardation in offspring. Studies have shown that many of these risks can be minimized with appropriate management and counseling. Data also show that psychomotor retardation in offspring of mothers with epilepsy is generally transitory. In this article, associations between maternal use of AEDs, birth defects, intrauterine growth retardation, and the psychomotor development are discussed together with how best to alter AED therapy to minimize them.     

Sexual Function in Women with Epilepsy

Summary: Purpose: To examine certain aspects of sexual behaviour and attitudes in a group of women with epilepsy using a validated questionnaire (Sexuality Experience Scales), and effects of antiepileptic drugs (AEDs) on sex hormone binding globulin (SHBG), total testosterone (TT), and free testosterone (FT). Methods: One hundred ninety-five women all attending a hospital-based epilepsy clinic were recruited. One hundred fifty-nine received AED therapy and 36 women did not. A control group of 48 women was also recruited. All women completed the first two Sexuality Experience Scales (SES 1 and SES 2), and those women in stable heterosexual relationships completed SES 3 and SES 4. At the same time blood was taken for TT and SHBG levels. FT was calculated using the method of Nanjee and Wheeler (22). Results: Women receiving AED therapy achieved significantly higher SES 1 and SES 2 scores than the rest of the women, suggesting that they adhered to a stricter sexual morality and were less open to psychosexual stimulation than the rest of the women treated. Women in the treated group were less likely to have received further education than the controls, a factor that influences SES 1 and SES 2 scores. There were no significant differences between the three groups on SES 3 or SES 4, with the exception of the orgasmic adequacy (OE) scale of SES 3 where those women in the treated group attained a higher mean score than the controls, suggesting that they found orgasm less satisfying. Women receiving AEDs had significantly higher SHBG and TT than controls and untreated patients. There were no differences in FT between the groups. Those women receiving AEDs also exhibited the expected mid-cycle rise in FT. There was no significant correlation between FT and the desired frequency of intercourse or enjoyment of it for the three groups. Conclusions: Women in the treated group appeared to be more “moral” and less open to sexual approach, but those who had regular partners appeared to desire and enjoy intercourse as much as the control and untreated groups. This could be explained by differences in demographic characteristics of the study groups or be indicative of a bimodal distribution of sexual interest in these women. As FT was within physiological norms for each study group this cannot be cited as a cause for hyposexuality.     

Italian Consensus Conference on Epilepsy and Pregnancy, Labor and Puerperium

To facilitate an integrated and rational approach to the care of women with epilepsy of childbearing potential, a group of experts appointed by Italian scientific societies in the fields of epileptology, neonatology, pediatrics, neuropediatrics, child neuropsychiatry, obstetrics, and gynecology held a joint meeting in Santa Trada di Cannitello, Reggio Calabria, Italy, on October 15–16, 2004, with the aim of reaching consensus on the optimal management of these women. An ad hoc system for the classification of available published evidence and the opinions of experts was developed and used to grade recommendations on different aspects related to counseling, diagnostic, and treatment issues. The present document summarizes available evidence on the reciprocal interactions between epilepsy, antiepileptic drugs, fertility, contraception, pregnancy, delivery, breastfeeding, and the offspring. Recommendations are made concerning the information and counseling that should be provided to women with epilepsy with respect to issues related to contraception, conception, pregnancy, labour, and puerperium. More detailed recommendations on the same issues are provided to physicians and other healthcare professionals involved in the care of these women, with special reference to choice of effective contraception, optimization of antiepileptic drug therapy, use of prenatal diagnostic tests and other monitoring procedures, and appropriate management practices in relation to childbirth, puerperium, and the care of the child.     

Polycystic Ovarian Syndrome in Women with Epilepsy: A Review

Summary: Polycystic ovarian syndrome (PCOS) remains a controversial issue in women with epilepsy. The syndrome is characterized by clinical signs of endocrine dysfunction, such as irregular menstruation, hirsutism, and infertility, but its pathogenesis and presentation are heterogeneous. There are few data on the relationship between epilepsy and PCOS. Studies by a Finnish group have raised the issue of an association between valproate (VPA) and PCOS in young women with epilepsy. These studies, however, were retrospective, laid emphasis on polycystic ovary morphology rather than on clinical endocrine dysfunction, and were undertaken in selected populations. Further studies, both in Italy and Germany, failed to replicate the findings of the Finnish group. Future research should ideally be prospective and include baseline data in untreated women. No compelling data lead to a specific contraindication of the use of VPA in young women, and the drug remains a first-line treatment option.     

Hormonal Effects on Epilepsy in Women

Summary: Some female gonadal and adrenal steroid hor-mones and their related pituitary peptides have neuroactive effects that can influence seizures. These effects may play a significant role in the pathophysiology of epilepsy, the pattern of seizure occurrence, therapeutic interventions using naturally occurring hormones, and the development of hormone-based neuroactive synthetic analogues with potent antiepileptic properties.     

Counseling Women with Epilepsy

Summary: All persons with epilepsy have a right to timely, accurate, culturally sensitive information that will help them manage their seizures and their lives successfully. The goals of counseling are to provide guidance for women with epilepsy in making informed choices, to promote self-management practices that will decrease health risks, and to provide comprehensive answers about relevant issues. Four broad areas that should be covered in counseling women with epilepsy include access to care, unique health needs of women with epilepsy, personal care and safety, and social and community relationships. These are described here in more detail.     

Therapy for Neurobehavioral Disorders in Epilepsy

Summary:  Neurobehavioral disorders commonly affect patients with epilepsy. In addition to the behavioral changes during and immediately after seizures, the epileptogenic disorder of function often extends further into the postictal and interictal period. Cognitive impairments commonly affect attention, memory, mental speed, and language, as well as executive and social functions. Reducing seizure frequency and the antiepileptic drug burden can reduce these problems. Attentional deficits may respond to therapies for attention-deficit/hyperactivity disorder, but apart from patients with this comorbid disorder, their efficacy is unproven in other epilepsy patients. No effective therapies are established for other cognitive problems, but pragmatic, compensatory strategies can be helpful. Behavioral disorders include fatigue, depression, anxiety, and psychosis. Many of these disorders usually respond well to pharmacotherapy, which can be supplemented by psychotherapy. Cognitive and behavioral disorders can be the greatest cause of morbidity and impaired quality of life, often overshadowing seizures. Yet these problems often go unrecognized and, even when identified, are often undertreated or untreated.