Antiepileptic Drugs, 5th Edition

General Principles


Antiepileptic Drug Use in Women

Martha J. Morrell MD

Professor of Clinical Neurology, Department of Neurology, Columbia University, College of Physicians and Surgeons; and Director, Columbia Comprehensive Epilepsy Center, New York, New York

Women and men with epilepsy share many of the same burdens—the unpredictability of seizures, the need to take daily medications for years or even a lifetime, the social stigma, and the psychological consequences arising from societal misunderstanding. In addition, women with epilepsy must be concerned about the potential effect of reproductive sex steroid hormones on the seizure threshold, about the impact of epilepsy and antiepileptic drugs (AEDs) on reproductive physiology, and about the risks to pregnancy and the fetus from maternal seizures and AEDs. Other considerations include the potential of gender to alter AED pharmacokinetics and pharmacodynamics. As health care providers gain greater sophistication in the treatment of epilepsy and as new therapies become available, gender emerges as a significant consideration in designing the optimal treatment for the whole patient.


Steroid hormones modulate brain excitability. This alters the epilepsy phenotype at puberty, over the menstrual cycle, and at menopause. Physiologic changes in steroid hormones are also likely to influence efficacy of AEDs. As such, ovarian steroids may be considered pharmacoactive compounds that alter the seizure threshold—estrogens acting as proconvulsants and progesterones as anticonvulsants (1).

Steroid Hormone Effects on Neuronal Excitability

The effects of hormones on neuronal excitability are best understood for estrogen and progesterone, the principal ovarian steroid hormones (2, 3, 4). In all experimental models of epilepsy seizure susceptibility alters with fluctuations of these hormones similar to physiologic changes over a reproductive cycle (5,6).

Estrogen has a seizure-activating effect in experimental models of epilepsy and in the human cerebral cortex. Estrogen lowers the electroshock seizure threshold (7, 8, 9), creates new cortical seizure foci when applied topically (10), activates preexisting cortical epileptogenic foci (11), and increases the severity of chemically induced seizures (12). Intravenous estrogen activates electroencephalographic epileptiform activity in some women with partial epilepsy (13).

In contrast to estrogen, progesterone exerts a seizure-protective effect in experimental models of epilepsy. High doses of progesterone and its reduced metabolite pregnenolone induce sedation and anesthesia in rats and in humans. Spontaneous interictal spikes produced by cortical application of penicillin are reduced by progesterone (14). Progesterone also suppresses kindling (15), heightens the seizure threshold to chemical convulsants (16,17), elevates the electroshock seizure threshold (8,18), attenuates ethanol withdrawal convulsions (17), and suppresses focal seizures (19) in animal models of epilepsy.

Steroid hormones modulate cortical excitability by several distinct mechanisms of action (3). In the classic model, the steroid hormone binds to an intracellular receptor (intracytoplasmic for glucocorticoids, intranuclear for estrogen and progesterone). Binding transforms the receptor to an active form that binds to DNA and leads to gene activation and protein synthesis, a process requiring 30 minutes to several hours. Many neuroactive effects of steroids are evident in seconds to minutes, a finding suggesting that some actions are mediated by mechanisms other than the classic model, probably at the level of the neuronal membrane. Sex steroid hormones exert immediate, short-duration effects on neuronal membrane excitability by altering γ-aminobutyric acid (GABA)-mediated inhibition and glutamate-mediated excitation (20) (Table 12.1).




GABAA Receptor

NMDA Receptor in Hippocampus

GABA Concentration

GABAA Receptor Number


Reduces Cl influx



Reduces number


Increases Cl influx



Increases number

GABA, γ-aminobutyric acid; NMDA, N-methyl-D-aspartate.

aEffects of estrogen and progesterone on neuronal excitability are mediated by altering the resting membrane potential. Estrogen reduces inhibition and increases excitation. Progesterone increases inhibition and reduces excitation.

A sex steroid hormone recognition site is present on a recombinantly expressed GABAA receptor complex derived from human complementary DNA (cDNA) (21). Neurosteroids, such as the ovarian steroids, act at two sites on the GABAA receptor complex: directly on the chloride channel and at a distinct site that mediates the action of GABA and benzodiazepines (22, 23, 24, 25).

Estrogen reduces the effectiveness of GABA-mediated neuronal inhibition by reducing chloride conductance through the GABAA receptor complex. Excitatory neurotransmission is modulated by estrogen through agonist binding sites on the N-methyl-D-aspartate (NMDA) receptor complex in the CA-1 region of the hippocampus (26).

Progesterone and progesterone metabolites function as allosteric receptor antagonists or inverse agonists at the GABAA receptor complex (27, 28, 29), thus potentiating GABA-induced chloride conductance by increasing the frequency (benzodiazepine-like effects) and duration (barbiturate-like effect) of channel opening (24,30,31). In addition, progesterone may alter the potency of AEDs. Benzodiazepine binding to the GABAA receptor complex increases by >50% in the presence of pregnenolone, the major reduced metabolite of progesterone (32).

Genomic effects of ovarian steroids alter excitability with a longer latency and for a longer duration. Estrogen increases neuronal excitability by inhibiting GABA synthesis in the arcuate nucleus, in the ventromedial nucleus of the hypothalamus, and in the centromedial group of the amygdala (33), probably through regulation of messenger RNA (mRNA) encoding for glutamic acid decarboxylase, the rate-limiting enzyme for GABA synthesis (34,35). Estrogen affects mRNA encoding for GABAA receptor subunits (36). Progesterone also modulates GABA amino decarboxylase (34), alters expression of mRNA encoding for GABAA receptor subunits (34,36), and reduces glutamate activity (37, 38, 39).

Neuronal morphology is altered with physiologic changes in estrogen. Estrogen exposure profoundly alters the morphology of CA-1 hippocampal neurons taken from ovariectomized animals, by increasing dendritic spines and excitatory synaptic connections within 12 to 24 hours of exposure (40,41). Conversely, when estrogen levels fall, these changes reverse within a similar period.

The sensitivity of neurons to the modulating effects of individual steroid hormones may be dynamic, changing after puberty and in response to fluctuations in basal levels of steroid hormones over a reproductive cycle (16,42). The pubertal surge in estrogen appears to have a neuronal priming effect. In contrast to the situation in postpubertal rats, estrogen does not alter the rate of amygdala kindling in prepubertal male and female rats. Rats castrated prepubertally have higher seizure thresholds to minimal and maximal electroshock than do animals castrated after puberty (8). Several experimental models of epilepsy in rodents suggest that the sensitivity of the GABAA receptor complex to neurosteroids varies to maintain homeostatic regulation of brain excitability (6,24,43). In rodents, the threshold dose for seizure onset induced by chemical convulsants (bicuculline, picrotoxin, pentylenetetrazol, and strychnine) changes over the estrus cycle. Female rats in estrus (equivalent to the premenstrual phase in humans) are more sensitive to chemical convulsants than are females in diestrus and males, whereas infusion of progesterone increases the seizure threshold more for females in diestrus (equivalent to human low-progesterone follicular phase) (43). Estrogens also exert differential effects on neuronal excitability, depending on cycling status. Enhanced neuronal excitability occurs when female rats in low-estrogen states are given estrogen, but not when estrogen is given during a highestrogen state (diestrus) (44).

Catamenial Seizures

Women with epilepsy frequently display menstrual cycleassociated seizure patterns. The debate in the literature about whether catamenial (menstrual-associated) seizure patterns exist can be explained by the difference in seizure patterns across ovulatory and anovulatory menstrual cycles. Authors who have not differentiated ovulatory and anovulatory menstrual cycles (45) have not detected catamenial patterns. Authors who have identified cycles as ovulatory or anovulatory find distinct and reproducible seizure patterns in ovulatory cycles (46,47), with seizures more likely to occur in the perimenstrual and ovulatory phases, times when estrogen levels are relatively high and progesterone is relatively low.



The endocrine profile differs in ovulatory and anovulatory cycles. The hypothalamic trophic hormone gonado-tropin-releasing hormone stimulates release of the pituitary gonadotropin, luteinizing hormone (LH), and follicle-stimulating hormone (FSH). FSH stimulates formation of an ovarian follicle. Estrogen is the predominant ovarian sex hormone during the follicular phase (first half) of the menstrual cycle. A midcycle LH surge triggers ovulation and transforms the follicle into the corpus luteum, which secretes progesterone throughout the second, or luteal, phase of the cycle. If fertilization does not occur, the follicle involutes, and progesterone secretion stops. The uterine lining is then shed, to complete a cycle of about 28 days in length. During anovulatory cycles, estrogen levels remain high throughout the cycle, and progesterone remains low.

Hormone-mediated seizure patterns differ across ovulatory and anovulatory cycles. Catamenial seizure patterns may not be evident over all cycles in an individual woman because of the high likelihood of anovulatory cycles in women with epilepsy. During ovulatory cycles, most seizures arise about 3 days before the onset of menstrual flow and persist for a total of 6 days. These seizures may be triggered by the perimenstrual progesterone withdrawal. For women with catamenial seizure patterns, more than three-fourths of all seizures arise in this 6-day window of time (47). Seizures occurring at ovulation may be triggered by the estrogen surge. In contrast to the perimenstrual and ovulatory seizure preponderance over ovulatory cycles, seizures are more dispersed and are often more frequent during an anovulatory cycle, probably because of the relative high and persistent concentration of estrogen unopposed by the luteal surge in progesterone.

Other mechanisms may also contribute to perimenstrual seizure exacerbation. Perimenstrual reductions in serum concentrations of AEDs have been described, perhaps related to increased volume of distribution or increased metabolism (48).

Treatment of Hormonally Sensitive Seizures

The most effective treatment for any type of seizure is usually one of the first-line AEDs used in monotherapy. Women whose seizures display a catamenial association may also respond to adjunctive therapy with a carbonic anhydrase inhibitor or with hormonal therapy.

Acetazolamide (Diamox) is a weak carbonic anhydrase inhibitor with mild diuretic actions. Oral acetazolamide may be helpful as adjunctive therapy for catamenial seizures, although this is not a labeled indication in the United States. One small trial described a ≥50% reduction in seizures in 45% of women taking acetazolamide either intermittently or continuously for catamenial seizures. Fifteen percent of the women reported loss of efficacy over 6 to 24 months (49).

The anticonvulsant properties of acetazolamide may be related to its ability to cause a mild, transient metabolic acidosis. Because tolerance to the anticonvulsant properties of the drug may develop, intermittent therapy may be preferable. In women with catamenial seizures and predictable menstrual cycles, acetazolamide may be used for 10 to 14 days, surrounding the time of seizure vulnerability. The usual dosage is 250 to 1,000 mg in two divided doses. Side effects include gastrointestinal disturbance, sedation, headache, and hypersensitivity reactions, particularly in those sensitive to sulfonamides. Bone marrow depression and renal colic arise rarely, as do electrolyte disturbances such as hypokalemia and hyperglycemia in patients with diabetes mellitus. Acetazolamide has teratogenic and embryocidal effects in rats and mice. This appears to be a species-specific effect; nevertheless, acetazolamide should not be used in pregnant women.

Several small studies have evaluated the effectiveness of progesterones and antiestrogens as AEDs. Synthetic oral progestins have not been helpful (50), although parenteral medroxyprogesterone (Depo-provera) reduces the seizure frequency in some women when it is given in large enough doses to cause amenorrhea (50,51). This can be given as medroxyprogesterone, 120 to 150 mg intramuscularly every 6 to 12 weeks (52). Adverse effects include hot flashes, irregular vaginal breakthrough bleeding, breast tenderness, and a 6- to 12-month delay before the return of menstrual cycles. Natural progesterone is available as extract of soy in suppository and lozenge form. The progesterone may be given over the initial luteal phase of the cycle as 100 to 200 mg three to four times a day, with an average dose of 600 mg to achieve a serum level of 5 to 25 ng/mL (52,53). Natural progesterone comes as 200-mg lozenges and can be given as one-half to one lozenge three times daily on days 14 to 25, one-fourth to one-half lozenge three times daily on days 26 and 27, and one-fourth lozenge three times daily on day 28. Another alternative is prometrium, 100 mg capsules, using a similar dosage schedule. A progesterone topical cream may be helpful for women with ovulatory seizures. This can be used several days before ovulation is anticipated. Reversible side effects include asthenia, emotional depression, breast tenderness, and acne. Progesterone therapy may be most advantageous in women who have inadequate luteal phase cycles, as determined by serum progesterone levels of <5 ng/mL during the midluteal phase (53). Progesterone therapy should be avoided during or in anticipation of pregnancy, and in the absence of scrupulous contraception.

Antiestrogens, such as clomifene, are typically used to treat infertility and as cancer chemotherapeutic agents. Clomifene has been reported to reduce seizures in women with intractable partial epilepsy, but it is associated with potentially significant side effects such as hot flashes, polycystic ovaries, and unplanned pregnancy (52). Many antiestrogens are under development. Some may eventually have a role in the treatment of hormone-sensitive seizures.



Menopause, Epilepsy, and Antiepileptic Drugs

Women with epilepsy may find that seizures improve after menopause, especially if seizures displayed catamenial patterns. However, the perimenopause may be a time of seizure exacerbation. About 2 to 3 years before ovulation stops, cycles become irregular, and there are fluctuations in concentrations of gonadal steroids. This is a time when seizure patterns may change and seizure frequency may worsen (54). One survey suggests that postmenopausal estrogen replacement may exacerbate seizures in some women with epilepsy (55).


AED pharmacokinetics and pharmacodynamics may differ in men and women. Women have smaller body size, higher body fat, lower body water, and less muscle mass. Contraceptive sex steroid hormones and hormone replacement therapy, as well as endogenous ovarian steroid hormones, may also alter AED pharmacology and efficacy.

Since 1993, the U.S. Food and Drug Administration (FDA) and the Department of Health and Human Services (DHHS) have mandated that clinical evaluation of new drugs include study and evaluation of gender differences (56). An efficacy analysis by gender is available for most of the newly marketed AEDs, but not for the older AEDs. Gabapentin, felbamate, lamotrigine, tiagabine, and topiramate were as effective and well tolerated in women as in men during premarketing trials (57). Zonisamide showed equal efficacy by gender but was better tolerated in women (58).


Hormonal contraception may be ineffective in women receiving hepatic cytochrome P450 enzyme-inducing AEDs, with a failure rate exceeding 6% per year (59, 60, 61). A United States-based national survey found that most neurologists and obstetricians were not aware of this significant potential interaction (62). Another survey of more than 3,500 health care providers, including pediatricians, general practitioners, and family practice physicians, confirmed this knowledge deficit (63). Most oral contraceptives contain only sufficient hormone to inhibit ovulation, and even subtle increases in metabolism may lead to contraceptive failure. Some AEDs promote metabolism of contraceptive steroids and also increase production of sex hormone binding globulin, a protein that avidly binds steroid hormones and renders them biologically inactive (64).

Ethinylestradiol and mestranol, a prodrug converted to active ethinylestradiol, are synthetic estrogens contained within oral contraceptives at a usual dose of 35 µg of ethinylestradiol. Ethinylestradiol undergoes significant first-pass metabolism with individual bioavailablity ranging from 10% to 75%. First-pass metabolism occurs by sulfation in the gut, followed by glucuronidation or hydroxylation in the liver. Hydroxylation is catalyzed by the cytochrome CYP3A4. Synthetic progestins contained in oral contraceptives are levonorgestrel, norethindrome, norethisterone, desogestrel, norgestimate, and gestodene. Bioavailablity is ≤80%, and there is no significant first-pass effect. CYP3A4 also appears to be involved in progesterone metabolism.

Phenytoin (PHT), phenobarbital (PB), and carbamazepine (CBZ) are broad-spectrum inducers of hepatic cytochrome P450 enzymes. Enzyme induction increases metabolism of the estrogenic, and probably progestational, component and also increases steroid hormone protein binding, thus reducing the hormone concentration. PHT and CBZ each reduce the concentration of 50 µg of ethinylestradiol by about 50%, and they reduce the concentration of levonorgestrel by about 30% (65). Sodium valproate (VPA) did not change concentrations of ethinylestradiol or levonorgestrel in six women with epilepsy (66).

Felbamate, oxcarbazepine, and topiramate are weak inducers of CYP3A4 only. The effects of felbamate on an oral contraceptive containing 30 µg ethinylestradiol and 75 mg gestodene were assessed in a randomized doubleblind, placebo-controlled study of healthy premenopausal female volunteers. Felbamate was associated with a 42% decrease in gestodene and had a minor effect on ethinylestradiol (67). The effects of oxcarbazepine on oral contraceptives containing 50 µg of ethinylestradiol and 250 µg of levonorgestrel were assessed in healthy women volunteers. Oxcarbazepine was associated with a reduction of 47% in plasma concentrations of both hormones (68). Healthy women volunteers receiving topiramate and oral contraceptives containing norethindrone, 1 mg, and ethinylestradiol, 35 µg, had an 18% to 30% reduction in concentration of ethinylestradiol, with no change in the progesterone norethindrone (69). Table 12.2 provides a list of AEDs categorized by their effect on cytochrome P450 enzymes.

To provide acceptable contraceptive efficacy, women taking cytochrome P450-inducing AEDs must receive at least 50 µg of the estrogen component (70,71). Long-term progesterone-only contraceptive systems such as subdermal levonorgestrel are also prone to failure because of increased steroid metabolism (72,73). Intramuscular medroxyprogesterone has not been evaluated for efficacy in women taking cytochrome P450-inducing AEDs. For women taking these enzyme-inducing AEDs in whom pregnancy is contraindicated, use of a barrier contraceptive should be advised.




Drugs That Induce Cytochrome P450 Enzymes and May Adversely Interact with Hormonal Contraception

Drugs That Inhibit or Have No Effect on Cytochrome P450 Enzymes and Do Not Adversely Interact with Hormonal Contraception















aDrugs that induce this enzyme system may decrease the concentration of biologically active hormone and therefore reduce efficacy of hormonally based contraception. Drugs that inhibit or have no effect on this enzyme system do not affect the efficacy of hormonal contraception.



Women with epilepsy are less likely to have children than are other women. Although studies of incident population of persons with seizures or epilepsy do not show a fertility deficit (74,75), all studies of prevalent populations report lower birth rates. Birth rates are reduced by one-third to as much as two-thirds compared with nonepileptic women (76, 77, 78,79, 80). Social factors may contribute to lower birth rates. Women with epilepsy are less likely to marry. Moreover, women with epilepsy may voluntarily choose not to have children. This choice may come about from concern about parenting or concern about transmission of epilepsy, or it may be based on advice provided by family, friends, and health care providers. More important than social pressures is the reproductive dysfunction associated with epilepsy and with AEDs (81).

Hypothalamic-Pituitary Hormone Abnormalities

Disruption of the hypothalamic-pituitary axis is one mechanism for infertility in women with epilepsy (82). The hypothalamic-pituitary axis supports the female reproductive cycle. Hypothalamic gonadotropin-releasing hormone regulates the release of pituitary FSH and LH according to an ultradian cycle of about 28 days (the menstrual cycle) and observing a circadian cycle in addition. Disruption of either of these cycles can lead to ovulatory failure.

Seizures alter hypothalamic hormone release, which then disrupts gonadotropin hormone, and pituitary hormone release (83). In humans, high-frequency epileptic discharges in the hippocampus are associated with a surge in pituitary prolactin (84,85). About 20 minutes after a seizure involving mesial temporal lobe structures (all generalized tonic-clonic and most complex partial seizures), prolactin levels increase by three to five times baseline and remain elevated for 2 hours (86,87). Ictal elevations in LH are also observed.

In addition to ictal perturbations of LH, interictal abnormalities are also described. Elevations in circadian pulsatile secretions of LH in women with generalized epilepsy (88) and reductions in circadian pulsatile LH release in women with temporal lobe epilepsy (89) suggest that epilepsy syndromes may differentially alter LH release. Disturbances in LH release in either direction are associated with anovulatory cycles (Morrell et al., 2002, in press).

Sex Steroid Hormones

Sex steroid hormone concentrations are altered in women receiving AEDs that change the activity of cytochrome P450 liver enzymes. AEDs that induce the hepatic microsomal enzyme system (the cytochrome P450 system) increase metabolism of gonadal and adrenal steroid hormones and induce the synthesis of sex hormone binding globulin, a binding protein for steroid hormones. Increased protein binding decreases the free, biologically active fraction of hormone. Women taking the enzyme-inducing AEDs PHT, CBZ, and PB have significant reductions in estradiol and in gonadal and adrenal androgens, and they have significant elevations in sex hormone binding globulin compared with women without epilepsy who are not taking AEDs (90-95; Morrell et al., 2002, in press). Women taking VPA (which does not induce liver cytochrome enzymes) have higher gonadal and adrenal androgen levels (96). Women with epilepsy who are receiving gabapentin or lamotrigine in monotherapy had no differences in gonadal steroids compared with nonepileptic controls (Morrell et al., 2001).

Polycystic Ovaries

Approximately 30% of women with epilepsy have polycystic-appearing ovaries, compared with about 15% of reproductive-age


women without epilepsy (97). Whether these women have polycystic ovary syndrome is not known (98). Polycystic ovary syndrome is characterized by obesity, acne and hirsutism, elevated LH, elevated androgens, abnormal lipid profile, chronic anovulation, and polycystic ovaries. All these features need not be present. An abnormality in the insulin receptor causing insulin resistance is the basis for this gynecologic syndrome (99). Health consequences of polycystic ovary syndrome include infertility, dyslipidemia, glucose intolerance and diabetes, and endometrial cancer (100).

Women with epilepsy who are taking AEDs may develop some of these features, including anovulatory cycles, menstrual cycle length abnormalities, abnormal LH:FSH ratio, obesity, and polycystic ovaries (96). Twenty-five to 40% of menstrual cycles in women with epilepsy are anovulatory (in contrast to about 10% of cycles in women without epilepsy). Abnormally long or short menstrual cycles (less than 23 days or more than 35 days), significant cycle variability, and midcycle bleeding are signs of ovulatory dysfunction in women with epilepsy. VPA is especially closely associated with polycystic ovaries, hyperandrogenism, and hyperinsulinemia. In part, this may be related to VPA-induced weight gain and obesity (94,101). Whereas 25% to 30% of women with epilepsy who are taking AEDs other than VPA have polycystic-appearing ovaries, this number may be as high as 60% for women receiving VPA (96) (Morrell et al., 2002, in press).

Isojarvi et al. (96) found the prevalence of polycystic ovaries to be highest in women receiving VPA before the age of 20 years. In contrast to a rate of 32% in women receiving VPA after age 20 years and a rate of 18% in women receiving AEDs other than VPA after the age of 20, 60% of women receiving VPA before they were 20 years old and 25% of women receiving other AEDs before age 20 had polycystic-appearing ovaries. Elevations in insulin were reported in the women in this study who were receiving VPA. In addition, VPA-associated elevations in androgens were found in about 20% of these reproductive-age women (96). Androgen elevations have also been reported in prepubertal girls (102).

VPA-associated polycystic ovaries, hyperandrogenism, and hyperinsulinemia appear to be reversible. Sixteen women who had these features when they took VPA were changed to lamotrigine (94). The polycystic-appearing ovaries resolved within 1 year in most of these patients. Testosterone and insulin concentrations normalized within several months. A cross-sectional observational study of 93 women with epilepsy also found an association between current use of VPA and higher prevalence of polycystic ovaries. However, women with epilepsy who were receiving VPA for ≥3 years in the past were no more likely to have polycystic-appearing ovaries than were women who had never taken VPA (Morrell et al., 2002, in press).

Sexual Dysfunction

Sexual dysfunction affects 30% to 40% of persons with epilepsy. Women with epilepsy may have diminished sexual interest and desire (103,104). More than one-third report dyspareunia, vaginismus, and lack of vaginal lubrication, symptoms of a disorder of sexual arousal (105). Direct measurement of genital blood flow showed a diminished genital blood flow response in persons with localization related epilepsy of temporal lobe origin in response to erotic visual stimuli (106).

AEDs may contribute to sexual dysfunction by direct cortical effects or secondarily through alterations in the hormones supporting sexual behavior. Occasional or chronic impotence occurred in 12% of men beginning treatment of epilepsy with a single drug, and it was most likely to be associated with barbiturate use (107). Decreased libido or impotence occurred in 22% of men receiving primidone. AEDs also reduce the biologically active fraction of steroid hormones by increasing steroid hormone protein binding and metabolism (108, 109,110). Reductions in androgens by enzyme-inducing AEDs may impair erectile function in men (111) and may reduce sexual desire in men and in women. Reductions in estrogen contribute to the physiologic arousal dysfunction experienced by women with epilepsy.

Detecting Reproductive Dysfunction in the Woman with Epilepsy

Until the relationship of epilepsy, AEDs, and these reproductive endocrine and ovarian abnormalities is better understood, clinicians must be alert to signs of reproductive dysfunction. These signs are listed in Table 12.3. Keeping a diary with length of the menstrual cycle and the timing and duration of menstrual flow is the most sensitive indicator for most reproductive cycle disorders. Women with menstrual dysfunction should be referred for gynecologic evaluation and care. A suggested evaluation is provided in Table 12.4.


Weight gain of more than 10% or body mass index of more than 27 kg/m2

Hirsutism (increased body and facial hair and scalp hair loss)


Menstrual cycle shorter than 23 days or longer than 35 days

Menstrual cycle with more than 5 days' variability from cycle to cycle

Midcycle menstrual bleeding

History of difficulty conceiving or first trimester miscarriage

Disorder of sexual desire or sexual arousal




Physical, gynecologic, and neurologic examinations

Complete blood count, liver function tests, fasting glucose, and lipid panel

Thyroid function tests

Pituitary hormones


Luteinizing hormone and follicle-stimulating hormone



Gonadal and adrenal steroids


Estradiol, progesterone, testosterone, dihydroepiandrostenedione (DHEA)

Transvaginal ovarian ultrasound


AEDs may alter bone mineral metabolism and may compromise bone health, especially in women who have smaller bone mass. Women using the established AEDs are at higher risk of bone disorders such as osteopenia, osteomalacia, and fractures (112, 113, 114). A prospective study evaluating the risk of hip fractures in women >65 years of age found that women taking AEDs were twice as likely to have a hip fracture (115).

Bone biochemical abnormalities described in people with epilepsy include hypocalcemia, hypophosphatemia, elevated serum alkaline phosphatase, elevated parathyroid hormone (PTH), and reduced levels of vitamin D and its active metabolites (116, 117, 118). The most severe bone and biochemical abnormalities are found in patients taking AED polytherapy (116,117) and in patients who have taken AEDs for a longer period (112).

AEDs may alter bone mineral metabolism by inducing vitamin D metabolism (61,117). Decreased Vitamin D leads to decreased intestinal calcium absorption, hypocalcemia and a compensatory increase in circulating PTH, resulting in increased mobilization of bone calcium stores. Because VPA does not induce the hepatic cytochrome P450 enzyme system, this mechanism does not explain the reduction in bone density associated with the drug (114). AEDs may also interfere directly with intestinal calcium absorption and could directly affect bone cell function, possibly through inhibition of cellular responses to PTH (113,118). Research is currently under way to define effects of individual AEDs on bone metabolism. In the meantime, women with epilepsy should receive adequate daily calcium and vitamin D and should engage regularly in gravity-resisting exercise.


Increased total cholesterol and low-density lipoproteins (LDLs) are associated with cardiovascular disease in women as well as men. Changes in lipid metabolism and body weight associated with use of some AEDs may create a longterm adverse health effect. Some AEDs are associated with abnormalities in cholesterol and lipid profiles (119, 120, 121, 122). CBZ, PB and PHT increase high density lipoproteins. CBZ has cholesterol lowering effects, and PB and PHT may exert a similar cholesterol lowering action. Counteracting these favorable lipid trends, elevations in low density lipoproteins are reported with CBZ and PB. VPA increases low- and high-density lipoproteins and leads to an unfavorable lipid profile. VPA-associated obesity and increases in insulin may account for VPA-associated dyslipidemia (94). Until the nature and mechanisms of AED-associated alterations in lipid metabolism are better understood, clinicians should monitor cholesterol and lipid profiles in women and men receiving AEDs.


Approximately 1% of all pregnancies are in women with epilepsy. The number of women with epilepsy who become pregnant has grown over the years, as marriage rates have increased for women with epilepsy (123), as parenting has become more socially supported, and as the medical management of pregnancy in women with epilepsy has improved. Pregnancy outcome can be maximized if the health care provider is alert to the following concerns: the importance of maintaining seizure control during pregnancy, the potential for fetal loss, and the risk of AED-associated teratogenicity and neurodevelopmental delay. Counseling and relatively minor treatment modifications can reduce the risk of an adverse pregnancy outcome.

Seizure frequency may change during pregnancy. Approximately 35% of pregnant women with epilepsy experience an increase in seizure frequency, 55% have no change, and 10% have a decrease in seizure frequency (124,125). The factors that are believed to alter seizure frequency include changes in sex hormones, in AED metabolism, in sleep schedules, and in medication compliance.

AED concentrations may change during pregnancy. Physiologic changes during pregnancy that can alter AED pharmacokinetics and total AED concentrations include decreased gastric tone and motility, nausea and vomiting, which arise in 40% of women during the first trimester, an increase in plasma volume of 40% to 50%, and an increase in renal clearance. The pharmacokinetics of some AEDs is more profoundly affected than is that of others, probably because of the pregnancy-related differential effects on cytochrome P450 enzymes. Two cytochrome P450 enzymes, CYP2C9 and CYP2C19, are induced to a greater extent than is CYP3A4. This could account for the greater reduction in PHT compared with CBZ, which is principally metabolized by CYP3A4, and VPA, which is predominantly


eliminated by glucuronidation and β-oxidation (64,126). Although the total concentration falls for many AEDs, there tends to be an increase in the percentage of unbound or free drug because of a reduction in albumin and, thus, in protein binding (127). Therefore, it is necessary to follow the non-protein-bound drug concentration, especially for AEDs that are highly protein bound, such as CBZ, PHT, and VPA. Dose adjustments should aim to maintain a stable non-protein-bound fraction. The concentration of AED in fetal serum is proportional to the free (non-protein-bound) maternal concentration (128).

Women with epilepsy are at greater risk of fetal loss. Early or late miscarriage and preterm delivery are three to five times more likely than in women without epilepsy. The reasons for fetal loss are not entirely understood, but they are more likely to be related to maternal seizures than to fetal exposure to AEDs (129,130). Fetal heart rate decelerations indicate fetal distress and are reported with maternal seizures (131). These observations underscore the importance of seizure control during pregnancy.

The first reports of birth defects associated with fetal exposure to AEDs came from small, retrospective case series that described drug-specific syndromes after exposure to trimethadione, PHT, PB, CBZ, VPA, and benzodiazepines. However, the features of these syndromes were more similar than dissimilar, with typical features being cleft lip and palate, cardiac septal defects, urogenital defects, and dysmorphisms of the face and digits. The effects of individual AEDs were further obscured in the early studies because women were likely to be receiving AED polypharmacy.

The older AEDs (benzodiazepines, PHT, CBZ, PB, and VPA) are associated with a higher risk of fetal major malformations, including cleft lip and palate and cardiac defects (atrial septal defect, tetralogy of Fallot, ventricular septal defect, coarctation of the aorta, patent ductus arteriosus, and pulmonary stenosis) (132, 133, 134). The incidence of these major malformations in infants born to mothers with epilepsy taking any one of these AEDs is 4% to 6 %, compared with 2% to 4% for the general population. Neural tube defects (spina bifida and anencephaly) occur in 0.5% to 1% of infants exposed to CBZ (135) and in 1% to 2% of infants exposed to VPA during the first month of gestation (136). Risks of malformations are highest in fetuses exposed to multiple AEDs and those exposed to higher doses.



No. of Malformations and Rate



Data Collection Period

Children of Women with Epilepsy on AEDs

Control Subjects

Additional Findings

Netherlands (188,189)


52 (3.7%)

29 (1.5%)

Additional risk with polytherapy

Japan, Italy, Canada (144)


80 (9.0%)

3 (3.1%)

Valproate dose correlated with malformations

United Kingdom (190)


10 (3.4%)

6 (1%)

No cases of spina bifida

Iceland (74)


13 (5.9%)


Denmark (142)


4 (4.6%)

280 (1%)


United States (146)


18 (5.7%)

9 (1.8%)

Major malformations, microcephaly, growth retardation, midface hypoplasia or hypoplasia of fingers in 20.6% of AED-exposed infants vs. 8.5% of control subjects

AED, antiepileptic drug.

Minor congenital anomalies associated with AED exposure include facial dysmorphism and digital anomalies, which arise in 6% to 20 % of infants exposed to antiepileptic drugs in utero(137). This represents a twofold increase over the general population. However, these anomalies are usually subtle and are often outgrown.

Concerns are mounting that exposure to AEDs in utero may confer a long-lasting neurodevelopmental or neurocognitive deficit (138,139). Fetal head growth retardation has been associated with maternal use of AEDs (140). Although prospective trials are lacking, retrospective studies show that children exposed in utero to VPA in monotherapy or polytherapy are more likely to require special educational resources (141). Prospective studies are under way to define more clearly the neurodevelopmental risks of AED exposure to the developing brain.

As outlined in Table 12.5, several large, observational studies confirm that fetuses exposed to AEDs in utero are at risk of morphologic abnormalities: 193 pregnancies from 145 women with epilepsy were compared with 24,094 pregnancies in women without epilepsy. Children born to women with epilepsy who took AEDs during pregnancy had low birth weight, decreased body length, and decreased head circumference (142). Another prospective multicenter study also found reduced birth weight and body length in children born to mothers with epilepsy who were taking AEDs (143). A prospective study of 983 babies born to women with epilepsy in Japan, Italy, and Canada found a 7% rate of malformations for exposed children compared


with a 3.1% rate for children not exposed to an AED in utero (144). There was no difference in incidence of malformation by exposure to any one AED.

The risk of teratogenicity is partly related to the extent of fetal exposure to the AED (145). The risk is highest in fetuses exposed to higher dosages and to AED polytherapy. Holmes et al. (146) assessed women with a history of seizures on and off AEDs delivering at one of five maternity hospitals in the Boston area. Identified mother-infant pairs were compared with control pairs of nonepileptic mothers and infants. Considering major malformations alone, 4.5% of women with epilepsy who were taking a single AED gave birth to a child with a major malformation, whereas 8.6% of women who were taking two or more AEDs had a child with a major malformation. No women with a history of seizures who were not taking an AED gave birth to a child with a major malformation. Major malformations were detected in 1.8% of infants born to controls. When major malformations, growth retardation, microcephaly, hypoplasia of the midface, and hypoplasia of the fingers were considered, 20.6% of the infants born to mothers with epilepsy who were taking AEDs had one or more of these birth defects, in contrast to 28% of the infants born to mothers who were taking two or more AEDs, 6.1% of the infants born to mothers with a history of seizures but who were not taking AEDs, and 8.5% of controls.

This study confirms observations made in the 1990s. AEDs increase the risk of major malformations and anomalies, and the risk increases with exposure to multiple AEDs. There is no study yet that provides the answer to the question “Which drug is best to use in pregnancy?” The design of the Holmes study was not able to capture the difference in incident versus prevalent epilepsy, nor was it able to assess the effects of ethnicity and preventive health behaviors such as folic acid supplementation.

Several mechanisms have been postulated to explain the teratogenicity of AEDs. Some AEDs may be teratogenic because of free radical (arene oxide) intermediates (147,148). CBZ, PB, and PHT are metabolized by cytochrome P450 enzyme-dependent oxidative intermediates, which are further metabolized by hydroxylation by epoxide hydrolase to nonreactive dihydrodiols. PB, PHT, and CBZ induce formation of the epoxide intermediate, and VPA inhibits epoxide hydrolase (149,150). Therefore, polytherapy with an enzyme-inducing AED and VPA would promote epoxide formation and would inhibit epoxide breakdown. These unstable intermediates bind with RNA and disrupt DNA synthesis and organogenesis. Higher concentrations of oxide metabolites are associated with a greater risk of fetal malformations, and susceptibility to oxidative-related teratogenicity may be genetically determined (151, 152, 153). Another putative mechanism for AED-related teratogenicity is alteration in endogenous retinoid concentrations (154).

Some AEDs may cause a deficiency of folic acid (155). PB, PHT, and CBZ are associated with folate malabsorption, whereas VPA inhibits methionine synthetase, an enzyme promoting the conversion of homocysteine to methionine, a step requiring folic acid as a cofactor (156). Elevation of homocysteine has been associated with higher risk of neural tube defects (157). Administration of folic acid helps to overcome the enzyme inhibition and reduce homocysteine levels.

Folic acid supplementation at conception and through pregnancy reduces the risk of giving birth to a child with neural tube defects in women without epilepsy (158, 159, 160, 161,162, 163, 164, 165). The Medical Research Council (166) vitamin study conclusively demonstrated that folic acid supplementation of 4 mg/day reduces the recurrence risk of neural tube defects in women who had previously given birth to a child with a neural tube defect. The Czech Cooperative Vitamin Study found that first occurrence rates of neural tube defects were significantly reduced by periconceptional supplementation of folic acid, 0.4 mg/day (167). The U.S. Centers for Disease Control and Prevention recommends that all women of childbearing potential receive routine supplementation of folic acid of at least 0.4 mg/day (168).

The protective effect of folic acid in pregnant women without epilepsy has led to the recommendation that folic acid be provided to women with epilepsy, although there are no studies as yet conclusively demonstrating the relevance of this mechanism in AED-mediated teratogenicity. In fact, folic acid supplementation does not necessarily protect against nonneural tube defects. In the Czech study, the rate of cleft lip and palate was not reduced in women receiving periconceptional folic acid (167). How relevant these observations are to women with epilepsy is not yet established. One study associated lower serum levels of folic acid with a higher risk of malformations in children of mothers taking AEDs during pregnancy (169). However, in a more recent study, folic acid supplementation provided to women receiving folic acid antagonists during pregnancy (including AEDs) did not reduce the risk of nonneural tube defects such as cleft lip or palate and cardiovascular and urinary tract malformations (170). One report of a child born with a neural tube defect to a mother taking VPA, 2,000 mg/day, and folic acid suggests that folic acid is not absolutely protective against this malformation (171). However, an ongoing assessment of pregnancy outcomes in children born to mothers with epilepsy reports a reduction in children born with major malformations, coincident with more widespread folic acid supplementation (172).

The malformations associated with AEDs are all generated in the first trimester of pregnancy, and neural tube defects are formed by day 28 after conception. Most women cannot know whether they are pregnant until a menstrual cycle is missed (day 15). In the United States, more than 50% of pregnancies are unplanned (173), and more than 40% of women with planned pregnancies do not consult a health care provider before pregnancy. Therefore, interventions must be designed to maximize fetal outcome


before conception. Many professional societies, including the American Academy of Neurology (70), the American College of Obstetric and Gynecologic Physicians (174), and the Canadian Society of Medical Geneticists (175) recommend that all women of childbearing age taking AEDs receive supplemental folic acid supplementation at 0.4 to 5.0 mg/day.





Orofacial Clefts



















































Valproic acid













AED, antiepileptic drug; IUGR, intrauterine growth retardation; NTDs, neural tube defects.

a Delayed ossification.

b Teratogenic at maternal toxic dose.

c Limb agenesis at high dose in rodents.

Since 1993, some new AEDs have been introduced. There is little information regarding effects of some of these drugs on the developing human fetus. Animal reproductive toxicology studies for AEDs provide some useful information but may not be specifically predictive of the human experience. Data from the FDA on fetal outcome in animals exposed to the AEDs is presented in Table 12.6.

The U.S. Institute of Medicine has advocated for inclusion of pregnant and lactating women in clinical drug trials (176). However, the DHHS still places severe restrictions on participation in drug trials for pregnant and lactating women (177). Therefore, prospective, widely inclusive registries are the best means for obtaining information on pregnancy outcome after AED exposure. Information about pregnancy outcomes for fetuses exposed to the newer AEDs is provided in Table 12.7.


Antiepileptic Drug

Premarketing and Postmarketing Experience


10 pregnancies: 1 SAb, 2 Tab, 7 normal outcomes


16 pregnancies: 5 Tab, 3 births with defects on polytherapy


No information available


289 pregnancy reports with 293 outcomes (2 sets if twins, 1 set of triplets): 12 SAb (no defects), 27 TAb (2 with defects, both polytherapy); 242 normal outcomes


13 births with defects: 10 polytherapy, 3 monotherapy


12 pregnancies: 3 SAb, 9 normal outcomes


23 pregnancies: 4 SAb, 8 TAb, 1 birth with defects on polytherapy


8 pregnancies: 5 TAb, 3 normal outcomes




9 pregnancies: 3 SAb, 3 TAb, 1 birth with hypospadias on polytherapy


26 births in Japan: 2 births with defects on polytherapy (1 anencephaly, 1 atrial septal defect)

SAb, spontaneous abortion; TAb, therapeutic abortion.

a Premarketing data.

b Premarketing and postmarketing data.

c Named patient distribution.

Prospective registries have been established to learn more about pregnancy and fetal outcome in women using AEDs, as discussed later. A registry should be contacted regarding any woman who becomes pregnant while taking AEDs.

Management of epilepsy in reproductive-age women should focus on maintaining effective control of seizures while minimizing fetal AED exposure (70,174,178). This applies to dosage and to the number of AEDs. Medication reduction or substitution should take place before conception.


Altering medication during pregnancy increases the risk of breakthrough seizures and exposes the fetus to an additional AED. The recommended management during pregnancy is AED monotherapy at the lowest effective dose. The best drug to choose is the drug most likely to be effective and well tolerated for that woman's seizure type. At this time, there is not sufficient information to identify any particular AED as the drug of choice during pregnancy. In addition, if there is a family history of neural tube defects, an agent other than CBZ or VPA may be considered. The FDA use in pregnancy categories for the marketed AEDs are provided in Table 12.8.

Once a patient is pregnant, prenatal diagnostic testing includes a maternal serum α-fetoprotein and a level II (anatomic) ultrasound at 14 to 18 weeks. This strategy identifies >95% of infants with neural tube defects. In some instances, amniocentesis may be indicated.

AEDs have also been associated with an increased risk of early fetal hemorrhage. This may result from an AED-related vitamin K deficiency with a reduction in vitamin K-dependent clotting factors (179). Vitamin K deficiency in the newborn is suspected because of reports of PIVKAs (proteins induced by vitamin K absence) detected in umbilical cord blood of neonates born to women taking CBZ, PB, and PHT (180). This abnormality is corrected by maternal supplementation with oral vitamin K (181). Therefore, the American Academy of Neurology (70) recommends that vitamin K supplementation be provided (vitamin K1 at 10 mg/ day) over the last month of gestation.


Category C: Either studies in animals have revealed adverse effects on the fetus (teratogenic or embryocidal effects, or others) and there are no controlled studies in women, or studies in women and animals are not available. Drugs should be given only if the potential benefits justify the potential risk to the fetus.

















Category D: There is positive evidence of human fetal risk, but the benefits from use in pregnant women may be acceptable despite the risk (e.g., if the drug is needed in a life-threatening situation or for a serious disease for which safer drugs cannot be used or are ineffective).










Valproic acid, Divalproce sodium


Information about the teratogenic potential of an AED is obtained in animals as part of preclinical development. These animal studies do not necessarily predict the human response, although the animal studies did indicate the teratogenic potential of the older AEDs.

Information about the frequency and specific type of teratogenic risk of a pharmaceutical compound is difficult to acquire in humans. Pregnant women are excluded from investigational drug trials, even many phase IV trials. Therefore, information about reproductive toxicology is obtained from preclinical animal studies, from unintended pregnancies occurring during human premarketing trials, and from spontaneous postmarketing reports. Governmental efforts in the United States include the FDA MedWatch effort and the human birth defects surveillance program of the Centers for Disease Control and Prevention. Individual pharmaceutical companies collect reports of adverse fetal outcomes, and some have sponsored drug specific registries. The scientific community has, until recently, relied on retrospective (and usually small) series evaluating fetal outcome after gestational AED exposure.

More than 2,000 prospective pregnancies are needed to detect a drug effect that occurs in 4% to 8% of exposed fetuses. To detect both the frequency and the type of birth defects associated with exposure to an agent, data must be acquired on all pregnancy exposures, and the number of normal as well as abnormal outcomes must be determined. Retrospective registries do not supply the numerator needed to determine incidence.

A review of the literature on AED-associated teratogenesis underscores the importance of obtaining prospective information on human pregnancies. The time and duration of gestational exposure to the AED were often unknown, nor were other risks for adverse fetal outcome assessed, such as tobacco and alcohol use during pregnancy. Ultimately, it is difficult to associate a pharmaceutical agent with adverse fetal outcome without considering the independent and interactive effects of other variables contributing to fetal outcome, such as genetics and environmental factors.

The ideal pregnancy registry is prospective and population based, uses predefined methods of data collection, contains data on timing of AED exposure and a detailed treatment schedule, uses standard definitions for pregnancy outcome, malformations, and anomalies, and includes prolonged follow-up after birth. Registries must include a large number of patients to evaluate less frequent exposures and ideally compares treated and untreated women with


epilepsy and nonepileptic controls. Variables collected should include family history of birth defects, classification of maternal epilepsy, exposure to other pharmaceutical compounds, high-risk behavior, and maternal age. At this time, the European Registry comes closest to this ideal and has been very successful in recruiting subjects.


Breast-feeding is strongly recommended by most health organizations to promote maternal-child bonding and to reduce the risk of infection and immunologic disorders later in the child's life (182,183). AEDs cross into breast milk to variable extents. Passage is by simple diffusion, and the ratio is determined by the drug's molecular weight, the negative log of the dissociation constant, lipophilicity, and the extent of protein binding. Protein binding is the most important variable in determining the concentration of AED in breast milk in relation to the maternal serum concentration (184,185). For PHT, CBZ, VPA, and TGB, the concentration in breast milk is negligible because of their high protein binding. Ethosuximide, PB, and PRM result in measurable concentrations. Lamotrigine reaches approximately 30% of the maternal serum concentration (186). AED protein binding and concentrations in breast milk are listed in Table 12.9.

For most women, the best advice is seriously to consider breast-feeding. Once started, the infant can be observed for proper weight gain and sleep cycles. The mother must also be advised that AED metabolism and clearance will remain elevated as long as breast-feeding continues. When breastfeeding stops, the mother may experience an increase in serum AED concentrations requiring a dosage adjustment.


Antiepileptic Drug

Percentage Protein Bound

Milk:Plasma Ratio

Concentrations in Infants




Not therapeutic











Not known

Not known




Not known







Not known

Not known




Not known







Not therapeutic







Not known

Not known



Not known

Not known




Not therapeutic




Not known



Not known

Not known

MHD, monohydroxy derivative.


As multiple AEDs become available, selection of a treatment regimen considers medication effectiveness, which is a combination of efficacy and tolerability. Epilepsy phenotype may vary according to cycles of ovarian steroid hormones. Although the efficacy of marketed AEDs appears to be equivalent across gender, tolerability may differ. AED-related bone loss may affect men and women equally, but women, because of their lower bone mass, may be at greater risk of symptomatic bone disease. Lipid abnormalities related to VPA may be more profound in women than in men because women appear to be more susceptible to VPA-associated weight gain. Women may also suffer more significant consequences of AED-related alterations in steroid hormones, manifesting as failure of hormonal contraceptive or as ovulatory dysfunction. Women face the fear of AED-related birth defects. The teratogenic potential of AEDs will be better defined as global registries develop to record pregnancy outcomes after AED exposure.

Reproductive and metabolic health may be compromised in persons with epilepsy, and women appear to be at particular risk. Because the health care provider appreciates these risks, early diagnosis and intervention in patients with dyslipidemia, bone disease, and reproductive health dysfunction is possible, and interventions to maximize metabolic and reproductive health can be instituted. Interventions include changing to an alternative AED or implementing symptomatic treatment. More recent assessments of care delivered to women with epilepsy demonstrate that health care practices are often not in accordance with recommended best practice (63,187). Appreciating gender differences in epilepsy presentation and treatment response is essential to ensure the best care for the woman with epilepsy.




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