Disclosure
Most medical conditions present special issues for women, and epilepsy is no exception. As a chronic and sometimes lifelong disease, epilepsy is particularly intertwined with all aspects of a woman's reproductive health. The concerns are two-edged—epilepsy and antiepileptic medications may have effects on reproductive health, and changes in hormones and reproductive status have implications for epilepsy and seizure control. The phases of a woman's reproductive life, including puberty, reproductive years, and menopause, may influence epilepsy and expression of seizures; for example, seizures may appear or remit at menarche. Hormonal fluctuations during the normal menstrual cycle, especially increases in estrogen, may trigger seizures. Changes in hormones during pregnancy may improve seizure control in some women while in others seizure frequency may increase. Surprisingly, little is known about the effect of menopause on seizures. Antiepileptic medications and seizures affect the various stages of reproductive life and many aspects of reproductive health, including sexual function and fertility, and may influence contraceptive decisions. Provision of excellent care to pregnant women with epilepsy requires an understanding of the emerging and active field of research that addresses teratogenicity, seizure control during pregnancy, breastfeeding, and other issues with important implications for the health of the mother and baby. In older women, concerns have been expressed that long-term use of antiepileptic medications may accelerate bone loss. Many of these effects are poorly understood and are currently under investigation. For excellent patient education resources, visit eMedicine's Women's Health Center. Also, see eMedicine's patient education articles Menopause and Epilepsy.
Transition through both the major reproductive phases of a woman's life (ie, menarche, reproductive years, menopause) and the cyclical hormonal changes of the reproductive years may influence seizures and seizure control. In turn, seizures and antiepileptic medications may affect these normal cycles. Puberty and menarche Little is known about the effects of puberty and menarche on seizures. Expression of seizures frequently changes during this period. Certain genetic epilepsy syndromes may remit, while others may arise or become refractory to medications. Diamantopoulos examined a small number of children retrospectively and concluded that, in general, puberty did not influence epilepsy, but female patients might experience better seizure control in the postmenarche phase of puberty. Thurston et al suggested that puberty may be an opportune time to consider withdrawal of antiepileptic drugs (AEDs) if seizures are well controlled; however, others have reported worsening of partial seizures during puberty. Recent studies by Klein and colleagues suggest that the time period surrounding menarche is associated with a higher than expected incidence of new-onset epilepsy. Different types of epilepsy probably respond differently to changes at menarche; further study of patients who have well-defined epilepsy syndromes may help to clarify responses in specific epilepsy subtypes. The effects of epilepsy on puberty are uncertain. Precocious puberty may suggest a specific etiology of seizures (eg, hypothalamic hamartoma). Delayed puberty in a girl with epilepsy should prompt a standard evaluation that should include a careful medical history, physical examination including Tanner staging, and supportive laboratory testing that may include measurement of follicle-stimulating hormone (FSH), luteinizing hormone (LH), thyroid function, karyotyping, bone age determination, and neuroimaging. Catamenial seizures For many years, a connection between timing of seizure expression and the menses has been observed in women with epilepsy, an observation validated by recent studies. Previously, catamenial seizures have been defined as seizures occurring exclusively or primarily during the perimenstrual period. Catamenial epilepsy now is defined more broadly as a pattern of increased seizures related to cyclical hormonal changes at various stages throughout the menstrual cycle. Several operational definitions of catamenial seizures have been proposed, but none has been universally accepted. This has resulted in widely varying estimates of the prevalence of this condition (12.5-78% of women with epilepsy) depending on whether a strict or liberal criterion for definition of catamenial seizures is used. Most authorities believe that between one third and one half of the affected population may show this pattern. Animal studies have helped to define the neuroendocrine basis of catamenial seizures. These studies generally support the proposition that estrogen compounds are proconvulsant (ie, lower seizure threshold), while progesterone compounds have anticonvulsant properties (ie, raise seizure threshold); however, these mechanisms are not well defined. Neuroactive steroid sex hormones exert an influence on neural function by changing membrane excitability and influencing regulation of gene expression in the nucleus. Intravenous administration of estrogen to women with epilepsy increases interictal epileptiform discharges. Some have proposed that seizure frequency may vary as a factor of ratio of estrogen to progesterone. This concept has been supported by several studies, including those of Herzog, who defined 3 patterns of catamenial epilepsy based on these theoretical constructs and his observations of seizure patterns in women with epilepsy. Periods of a high estrogen-to-progesterone ratio are seen just prior to and in early menses (C1), just prior to ovulation (C2), and in the second half of the cycle (ie, luteal phase) in patients with anovulatory cycles or an inadequate luteal phase, in whom the expected rise in progesterone from the corpus luteum is not seen (C3) (see section on Fertility and Alterations in Reproductive Hormones). Therefore, careful documentation of seizure frequency in relation to menstrual periods and ovulation (using basal body temperature or mid luteal phase progesterone level to confirm ovulation) is needed to determine the presence or absence of a catamenial pattern of seizures. If a catamenial pattern of seizures can be identified, several possibilities for tailoring AED therapy have been proposed, including cyclic increase in AED doses or intermittent use of benzodiazepines during periods of vulnerability to seizures. Intermittent use of acetazolamide (Diamox) is supported by clinical experience and a small retrospective study. Specific hormonal manipulation has been examined in uncontrolled trials. Use of estrogen antagonists, such as clomiphene citrate, have theoretical as well as some limited clinical support, but concern about long-term effects of estrogen blockade has limited their use. Synthetic and natural progesterone compounds have been studied; preliminary clinical studies suggest benefit from treatment with intermittent natural progesterone in patients with well-defined catamenial seizures. Adverse effects such as sedation, depression, breast tenderness, and breakthrough menstrual bleeding were seen, but these led to cessation of therapy only infrequently in these studies. If hormonal therapies are to be considered, inclusion of the patient's gynecologist in the planning stages and ensuring adequate contraception are important. Randomized prospective clinical trials are needed before these therapies can be recommended more strongly. Menopause The sometimes marked effects of other phases of reproductive life on seizure control would seem to suggest that menopause would have an important effect on the natural history of seizures in a woman with epilepsy. An understanding of changes in seizure control that might occur during menopause becomes increasingly important as the population ages and more women with epilepsy enter into menopause. The perimenopausal period is characterized clinically by irregular menses, "hot flashes" or vasomotor symptoms, and mood changes. Sex hormone levels during this period are in decline; circulating estrogen level decreases gradually and the cyclical progesterone increase in the luteal phase ceases. Menopause usually is defined as 1 year of amenorrhea during which estrogen and progesterone stabilize at low levels. Surprisingly, little research has addressed changes in epilepsy at menopause, and no prospective clinical studies have been done. Available information is derived from clinical experience and retrospective studies based on self-report questionnaires. Epilepsy during the perimenopausal period and menopause Available evidence supports the contention that seizure patterns often change during menopause. Some change in seizures during menopause is reported in 68-72% women, though roughly as many reported improvement as worsening. Overall frequency of seizures did not differ between groups of matched premenopausal and menopausal women. Findings in the perimenopausal group are conflicting—one study reported worsening of seizures during this period, while another reported improvement. Women with catamenial seizures during the reproductive years appeared to fare best, 69% reporting improvement during menopause, while only 23% who did not experience a catamenial pattern reported improvement during menopause. Hormone replacement therapy (HRT) in menopause or the perimenopausal period is in less favor currently but has limited demonstrated benefits in prevention of osteoporosis and improves vasomotor symptoms. The effect of HRT on seizures is unclear. This uncertainty may be partly due to the varied formulations of HRT, including unopposed estrogens or mixed estrogen/progesterone treatments. Abbasi et al reported that women taking progesterone-containing HRT were more likely to report improvement of seizure control during menopause. In contrast, Harden et al noted that 63% of women taking HRT (various formulations) reported worsening of seizure control, while only 12% of women not on HRT reported worsening. He recommended that women with epilepsy who take HRT should be monitored closely for worsening seizure control. These findings are based on studies limited by relatively small sample sizes, retrospective study designs, and potential selection biases; therefore, further work is needed in this area.
It is now well established that AED use may promote bone loss and osteoporosis. This is an active area of research, increasing in magnitude as the population ages and the number of older women with epilepsy grows. The importance of this topic is compounded by the fact that seizures increase the risk of falls and other injuries. Several AEDs are implicated in producing accelerated bone loss: phenobarbital, primidone, phenytoin, carbamazepine, and valproate. Long-term data on most of the newer AEDs are too limited to make definite recommendations; however, many of these have more favorable pharmacologic properties and may prove safer with respect to bone health. The mechanism or mechanisms of accelerated osteoporosis secondary to AED use are under active investigation and are likely multiple. Hepatic microsomal enzyme induction, producing vitamin D catabolism, is a major mechanism; however, additional mechanisms (eg, direct effects on bone cells, impaired calcium absorption) must be invoked to explain bone loss from non–enzyme-inducing medications such as valproate. Bone mineral density studies (dual energy x-ray absorptiometry [DXA] scans) should be obtained in individuals at risk, especially, but not limited to, patients who are institutionalized and older women taking AEDs. The optimal prevention and treatment strategies for AED-related bone loss remain to be defined. Supplemental vitamin D and calcium supplementation is recommended for patients taking the older AEDs (phenobarbital, primidone, phenytoin, carbamazepine, valproate). Recommended doses are at least 1000 mg of calcium/400 IU vitamin D in premenopausal women and 1500 mg calcium/600 IU vitamin D in postmenopausal women, and some authorities recommend even higher dose supplementation. Whether this supplementation strategy is adequate in the face of strong hepatic enzyme inducers, such as phenytoin, is not clear. Crossover to one of the newer, non–enzyme-inducing AEDs may be an advisable strategy, especially as more information about the bone effects of these medications becomes known. In patients with known osteoporosis, treatment with bisphosphonates should be considered, although in young patients some questions are still unanswered about the effects of long-term use of these medications. |
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Sexual dysfunction in women with epilepsy Sexual dysfunction is a common problem in the general population, and recent studies confirm that women with epilepsy are affected even more frequently. The literature is replete with descriptions of sexual dysfunction in epilepsy; in early reports, psychological and psychosocial factors were emphasized. Early studies often focused on sexual dysfunction in men; many were uncontrolled retrospective hospital- or institution-based studies that did not control adequately for seizure type, medications, and other important factors. Several recent studies in women with epilepsy have indicated that 18-42% women in this population self-report sexual dysfunction; results probably depend to a great extent on the population studied. The most recent of these studies have implicated physiological more than psychological factors. Multiple endocrinologic and neuroanatomic systems support each of the various components of sexuality. Sexual desire depends on frontal lobe function and requires adequate androgen hormones, particularly testosterone. Physiologic sexual arousal is dependent on intact cerebral cortex (including limbic), spinal cord, the sympathetic and parasympathetic divisions of the autonomic nervous system, androgens (in both men and women), and estrogens (in women). Disruption of any of these systems as a result of seizures or structural or functional deficits related to epileptogenic region may lead to sexual dysfunction. Mechanisms of sexual dysfunction in epilepsy The causes of sexual dysfunction in people with epilepsy are not well defined and are probably multifactorial. Psychosocial disability, including restricted social opportunities to meet partners, has been believed in the past to play an important role; however, recent studies suggest that the level of sexual experience in patients with epilepsy is not significantly different from that of the general population. Poor self-esteem as a result of having seizures may be a factor in self-perception of sexual attractiveness. Misunderstanding or poor acceptance of the diagnosis of epilepsy by the patient and partner may lead to inaccurate or unrealistic perceptions (either underestimation or overestimation of difficulties), leading to sexual dysfunction. The importance of this factor has been established in other chronic diseases, including cardiovascular disease. Although psychological factors are likely to play a role, physiologic factors may be more important. Immediately following seizures, elevations occur in inhibitory neurochemicals, including GABA, which transiently depress sexual desire and arousal. Brain dysfunction related to the epileptogenic region may cause sexual dysfunction, particularly if brain disease affects the limbic system, and, in temporal lobe epilepsy, right-sided epileptic foci are more strongly associated with sexual dysfunction. Sexual dysfunction appears to be more common in localization-related than generalized epilepsy. It commonly appears after the onset of seizures and may be ameliorated by successful anterior temporal lobectomy, even with continued AED therapy. Limbic pathology and seizures also are tied closely to hormone disturbances. Although most studies have shown that gonadotropin hormone levels are normal or moderately low in people with epilepsy, the occurrence of seizures also may disrupt the pulsatile release of these hormones, which is known to be critical for normal function. Finally, AEDs may cause sexual dysfunction. Depressant drugs such as barbiturates and benzodiazepines may be the worst offenders, but nearly all anticonvulsant medications have been implicated. Direct cortical depressant effects of the medication, secondary disturbances in the hormone levels via protein binding, or hepatic microsomal enzyme-induction interactions could be important. This is an area that requires more study. Evaluation of sexual dysfunction in patients with epilepsy The first step in evaluation of sexual dysfunction is identification of the problem. This often requires direct questioning by the clinician. Studies have shown that patients are often reluctant to raise issues of sexuality with their health care providers; frequency of sexual complaints depends on the individual physician and on explicit history taking. Sexual dysfunction is a common problem and has a broad differential diagnosis. Other causes unrelated to epilepsy or antiepileptic medications should be sought. Psychological factors are identified frequently. These may be related to overt psychiatric disease such as psychosis or affective disorders, or may be related to previous negative relationship, family, or social/religious experiences or taboos. Physiologic or medical etiologies also should be investigated. Commonly implicated medical conditions include those associated with small-vessel vascular disease (eg, diabetes mellitus, hypertension), endocrine disorders (eg, hyperthyroidism or hypothyroidism, altered gonadotropic hormones, hyperprolactinemia), and other systemic diseases, including nearly any major organ system dysfunction. Specific neurological causes of sexual dysfunction include injury to the autonomic nervous system (ie, neuropathy) or spinal cord, or frontal or temporal lobe injury (even in the absence of epilepsy). The evaluation always should begin with a careful sexual, medical, and neurological history and include a complete medical and neurologic examination. Screening laboratory tests may include CBC, serum chemistries, lipid screening, glucose tolerance test, and hormone levels (eg, testosterone, prolactin, FSH, LH, thyroid). Strong consideration should be given to referral to a urologist or gynecologist who is expert in this area. Treatment of sexual dysfunction Specific treatment depends on identification of the cause of sexual dysfunction. If psychological factors are believed to play an important role, psychotherapy for the individual or the couple may be useful. Specific physiologic treatments also may be available. Contributing medical conditions should be identified and treated, and offending medications should be reduced or eliminated. Exercises, relaxation techniques, and vaginal lubricants may be useful, especially if vaginismus or dyspareunia is reported. If no other cause is identified, a trial of reduced anticonvulsant medication or a change to another AED may be considered.
Contraception Antiepileptic medications may affect hormonal contraceptives. For instance, certain medications increase the metabolism of contraceptives, rendering them less effective. The choice of contraceptive in women with epilepsy must take into account these known interactions. The importance of these issues is heightened by the increased risk of teratogenicity in children born to women with epilepsy. Despite the known risks, these interactions are not well understood by neurologists or obstetricians. Currently, most oral contraceptives contain some combination of an estrogen (often ethinyl estradiol) and a progesterone. Other hormone-based contraceptive formulations include medroxyprogesterone (Depo-Provera) or levonorgestrel (Norplant). To avoid the potential thromboembolic or other complications of high-dose exogenous estrogens, most modern oral contraceptives contain 35 mcg or less of estrogen, reduced from formulations popular in the 1970s that contained 50-100 mcg. The cause of increased hormonal contraceptive failures in women with epilepsy on certain medications is thought to be due primarily to hepatic microsomal enzyme induction and increased metabolism of hormones. The hepatic enzyme-inducing AEDs (eg, barbiturates, carbamazepine, oxcarbazepine, phenytoin, ethosuximide, and to some extent topiramate) may reduce oral contraceptive hormone levels by as much as 40-50%, and several reports have documented increased risk of oral contraceptive failure in women taking these medications. Mid-cycle breakthrough bleeding may herald contraceptive failure but is not a reliable sign; contraceptive failure may occur without this warning. These AEDs also increase sex hormone binding globulins, leading to decreased free hormone levels, a possible contributing mechanism. No evidence exists of increased failure rates in women taking newer generation, non–enzyme-inducing AEDs. If women on hepatic enzyme-inducing AEDs wish to use oral contraceptives, formulations using the equivalent of 50-100 mcg of ethinyl estradiol are recommended, ideally in conjunction with a barrier or other method of contraception. Despite the increased rate of oral contraceptive failures in women taking enzyme-inducing AEDs, the success of higher estrogen dose pills is as good as or superior to barrier methods alone. In spite of the known proconvulsant effects of estrogen, no definite adverse effects of hormonal contraception on seizure control have been established, perhaps because of the concurrent administration of progesterones. Levonorgestrel is less effective if given concurrently with hepatic enzyme-inducing AEDs; intramuscular medroxyprogesterone may need to be administered more frequently, although this has not been studied carefully. Fertility and alterations in reproductive hormones
Interaction between epilepsy and the reproductive hormones is bidirectional. Hormone levels may influence seizure thresholds, as discussed earlier, but ongoing seizure activity and epileptogenic brain lesions also may affect the tightly regulated hormone systems of the hypothalamic-pituitary axis. That prolactin levels frequently are elevated postictally is well known, and this finding sometimes is used diagnostically to distinguish epileptic and nonepileptic seizures.
Significant alterations in levels of gonadotropin hormones (FSH, LH) are not reported frequently in women with epilepsy, but intermittent seizures may alter the carefully regulated pulsatile release of hormones from the hypothalamic-pituitary system and lead to dysregulation of ovulation and decrease in fertility. AED-induced changes in hormone metabolism and protein binding also may disrupt this carefully regulated system. The end result is that epilepsy is associated with increased menstrual and ovulatory dysfunction and decreased fertility.
Women with epilepsy experience higher rates of menstrual and ovulatory dysfunction than do women in the general population. Menstrual irregularities include either abnormally short or long cycles and abnormally heavy bleeding. A condition similar to the polycystic ovarian syndrome, comprising amenorrhea, multiple ovarian cysts, and elevated androgen levels, is seen frequently in women with epilepsy. One medication, valproate, has been linked to weight gain, hyperandrogenism, and polycystic ovaries. Whether other medications also cause this problem is under investigation. Moreover, that anovulatory cycles are more frequent in women with epilepsy than in controls is well known. One study found a 4-fold greater number of anovulatory cycles in women with temporal lobe epilepsy than in controls. In short, both seizures and antiepileptic medications may contribute to this problem.
Infertility usually is defined as inability to conceive after 1 year of intercourse without contraception. Fertility in women with epilepsy may be reduced to one third or less than that in the general population. A higher infertility rate has been reported in localization-related epilepsy than in idiopathic generalized epilepsies. The reasons for this decreased fertility rate are unknown. Although social factors may contribute, physiologic factors, as already discussed, related to both seizures and AEDs probably predominate.
Evaluation of infertility usually involves referral to a specialist in this area. Often the couple is evaluated; frequently performed tests include semen analysis, assessment of ovulatory cycles, a postcoital test, and evaluation of tubal patency.
Interested readers should refer to the recently published American Academy of Neurology practice parameter discussing management issues for women with epilepsy for further specific recommendations on management of epilepsy during pregnancy. Family planning in women with epilepsy Because of the many important issues surrounding epilepsy and pregnancy, a discussion of family planning is necessary before discussing pregnancy-related issues. Early discussion and education are particularly important because as many as 50% pregnancies in the United States may be unplanned, and prenatal medical care may not begin during the critical early phase of pregnancy when neural tube formation and organogenesis occur. These discussions should include information about contraception, folate supplementation, and accurate information about risks to mother and fetus from seizures and antiepileptic medications during pregnancy. For women who have experienced excellent seizure control for several years, discontinuation of medication may be a consideration. These decisions can be aided by information available in recently published practice parameters for discontinuation of antiepileptic medication and ideally would take place more than 6 months prior to conception, since most seizure recurrences will occur during the first 6 months after stopping AEDs. For other patients, the goal should be AED monotherapy in the lowest effective dose, since both polytherapy and high AED drug levels have been associated with increased risk of teratogenesis. Discussion with a genetic counselor may be desirable, particularly if epilepsy results from an inherited condition. If possible, the patient should be referred to an obstetrician/gynecologist physician experienced in the treatment of women with epilepsy. Folate supplementation is of clearly established benefit in pregnancy. Studies in animal models and in humans have demonstrated that neural tube defects are associated with maternal folate deficiency and that dietary supplementation with folic acid reduces the risk of neural tube defects. For this reason alone, folic acid supplements should be recommended to women with epilepsy. In addition, risk of neural tube defects is increased in women with epilepsy taking anticonvulsant medications, an effect most clearly established with valproate and carbamazepine. Although this increased risk has not been linked definitely to folate deficiency, some AEDs have been demonstrated to block folate absorption or activation; therefore, most epilepsy specialists recommend additional folate supplementation for their patients taking AEDs. This practice has not been proven to reduce the risk of neural tube defects, but folate supplementation is felt to be extremely safe. No consensus exists on appropriate dose; recommendations range from 1-5 mg/day folic acid. Because the critical phase for neural tube formation is at 3-4 weeks gestation, shortly after first missed menstrual period and prior to the time that most women see a health care provider, preconception discussion about folic acid supplementation is critical. Most authorities recommend treating all women of childbearing potential with folic acid supplements as a routine measure. Seizure control during pregnancy Seizure control may worsen during pregnancy in some patients, though they constitute a minority. While rare isolated seizures carry uncertain risks, uncontrolled convulsive seizures place both mother and baby at risk: increased risk of injury or other complications of seizures in the mother, and increased risk of bradycardia, placental abruption, premature labor, intracranial hemorrhage, or even fetal death in the baby; this risk is particularly high if seizures progress to status epilepticus. Effects of nonconvulsive seizures on developing fetuses are not well documented. Any of several factors may be associated with loss of seizure control during pregnancy. Increased stress and sleep deprivation may contribute. Physiologic changes of pregnancy that may alter seizure threshold include increase in sex hormone levels and sodium and water retention. Altered physiology of pregnancy also can change previously stable AED levels owing to changes in absorption (either through gastric motility changes or nausea and vomiting), changes in volume of distribution, alterations in protein binding, and increase in hepatic metabolism. Providers also must be sensitive to the possibility that lower AED levels reflect noncompliance with medication due to fear of teratogenic effects. AED levels should be monitored more closely than usual during pregnancy. Pharmacokinetic changes demand monitoring of free levels of highly protein bound AEDs to avoid confusion with increased seizures (or symptoms of toxicity) despite therapeutic total serum drug levels. Levels should be monitored at least each trimester and for 2-3 months following delivery. If dose was increased during pregnancy, medication dose tapering should be anticipated in the postpartum period to avoid medication toxicity. Teratogenicity Women with epilepsy taking AEDs have an increased risk of having a child with major congenital malformations. Risk is roughly 2 times that in the general population (ie, 4-6% in women with epilepsy vs 2-3% in the general population). Fetal abnormalities can be classified as malformations (ie, defects that lead to a significant functional impairment) or anomalies (ie, minor variations of normal morphology without significant functional impact). Malformations commonly involve cardiac, neurological, and genitourinary systems and are seen with all older AEDs. Minor anomalies usually are noted in facial features, most often in mid face structures, or digits (eg, distal phalangeal hypoplasia, nail hypoplasia). Evidence for medication-specific syndromes (eg, "fetal hydantoin syndrome") is lacking; perhaps more striking is similarity of defects seen in children of mothers using different AEDs. An exception is neural tube defects, which are more common with maternal use of valproate or carbamazepine. While genetic influences or other factors such as socioeconomic status may contribute to increased incidence of fetal malformations, several lines of evidence suggest that antiepileptic medications play a primary role. Rates of fetal malformations are higher in pregnant women treated with antiepileptic medications than in those who are not treated. Higher AED levels are associated with higher rates of malformation, and polytherapy carries a higher risk than monotherapy. The mechanisms underlying teratogenicity of AEDs are still poorly defined. Interference with folate absorption or activation is suspected in production of neural tube defects. Reactive products of oxidative metabolism have been implicated, but not all AEDs produce these intermediate products. Nonetheless, similar types and rates of malformations appear with different antiepileptic medications, including newer AEDs that do not induce hepatic enzymes and do not undergo oxidative metabolism, suggesting some common risk to women with epilepsy independent of medication type. Because all major AEDs are teratogenic, the best therapy is generally that which is appropriate and effective for epilepsy type and confers the most effective seizure control. Information about teratogenic risks specific to individual AEDs, especially the newer AEDs is currently limited. The AED Pregnancy Registry is collecting information regarding epilepsy, AED use, and pregnancy outcome. Clinicians should ask their female patients with epilepsy who become pregnant to register by calling 1-888-233-2334 or online at Antiepileptic Drug Pregnancy Registry. Thus far, the registry has released data demonstrating that maternal exposure to phenobarbital and valproate during pregnancy significantly increases the risk of fetal malformations over background risk. Greater numbers of subjects will be needed to make definitive comment on other specific AEDs. No consistent evidence is available from large-scale studies to link first trimester maternal seizures with increased risk of fetal malformations. One study reported increased malformations in women with first trimester seizures; however, a recent large study from Finland did not support this finding. Limited studies suggest that children of women with epilepsy may have increased risk of cognitive problems; however, many studies have not controlled carefully for factors such as parental intelligence quotient and socioeconomic status. A large multicenter trial to address this issue is in progress. Obstetrical complications Studies are conflicting regarding the risk of perinatal complications in children born to mothers with epilepsy. Some reports have suggested increased risk for preeclampsia, vaginal bleeding, preterm labor, low birth weight, low Apgar scores, and asphyxia. Other studies contradicted these findings and demonstrated no difference in rates of preeclampsia, vaginal bleeding, preterm labor, low birth weight, or perinatal mortality. One problem may be that studies commonly have failed to control for socioeconomic or other confounding factors; however, they uniformly support an increased risk for hemorrhagic disease of the newborn in children of women with epilepsy. Hemorrhagic disease of the newborn This syndrome consists of a neonatal bleeding diathesis (including intracranial hemorrhage of various types), typically appearing 2-7 days postpartum, although early and late forms also are described. Hemorrhagic disease of the newborn in children of women with epilepsy was first described by Mountain et al in patients treated with phenobarbital and primidone; however, many AEDs have been implicated. The putative mechanism is deficiency of vitamin K-dependent clotting factors, possibly via hepatic microsomal enzyme induction in fetal liver with normal coagulation tests in mother. The syndrome can be treated by maternal ingestion of vitamin K supplements in the last month of pregnancy, although transplacental transfer of vitamin K has been difficult to establish. Most clinicians recommend treating with vitamin K 10 mg PO per day during the last month of pregnancy, in addition to routine administration of 1 mg of vitamin K to the neonates at birth. Lactation Breastfeeding has many benefits for the infant and the mother-child relationship. Antiepileptic medications are present in breast milk. Transmission via breast milk depends on protein binding; highly protein bound AEDs are present in low concentrations in breast milk. Anticonvulsant exposure from breast milk is lower than exposure in utero. However, AED levels may reach therapeutic range in the infant for some medications and this could theoretically place the child at risk for dose-related or idiosyncratic side effects of the AEDs, though these problems have not been widely reported. Children of women taking sedating AEDs, such as barbiturates, should be monitored for sedation, poor feeding, or behavioral changes. In general, maternal anticonvulsant use is not a contraindication to breastfeeding, and risks and benefits should be discussed so that each mother can make an informed decision based on the available information.
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