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Keywords:

  • Antiepileptic drugs;
  • Contraception;
  • Infertility;
  • Pregnancy;
  • Fetal risks;
  • Metabolic disorders

Abstract

  1. Top of page
  2. Abstract
  3. CONTRACEPTION IN WOMEN WITH EPILEPSY
  4. REPRODUCTIVE HEALTH IN EPILEPSY
  5. PRINCIPLES OF AED USE IN PREGNANCY
  6. NEWER AND OLDER AEDS
  7. DISCUSSION
  8. REFERENCES

Summary:  Epilepsy is a common neurologic disorder affecting women during the reproductive years. Seizures and some antiepileptic drugs (AEDs) can compromise reproductive health, and some AEDs can adversely affect carbohydrate and bone metabolism. Women with epilepsy have lower birth rates and more frequent anovulatory menstrual cycles. This appears to be related to seizure- and AED-associated reproductive endocrine disturbances. Carbamazepine (CBZ), phenytoin (PHT), and phenobarbital (PB) induce hepatic cytochrome P450 enzymes and lower endogenous estrogens, adrenal and ovarian androgens, and contraceptive steroids. Valproate (VPA) inhibits steroid hormone metabolism, elevates androgens, and predisposes to phenotypic signs of hyperandrogenism-hirsutism, obesity, acne, and frequent anovulatory cycles. VPA is associated with weight gain, probably by altering insulin metabolism. CBZ, PHT, and VPA, but not lamotrigine (LTG), are associated with lower levels of calcium. PHT, but not VPA or LTG, appears to accelerate bone turnover. AED effects on bone mineral metabolism may explain the elevated risk of fracture described in women with epilepsy. Prospective pregnancy registries are beginning to provide information about AED-associated teratogenesis. The North American Antiepileptic Drug Pregnancy Registry reports a 12% rate of major malformations after first trimester exposure to PB and an 8.6% rate after first trimester exposure to VPA. A prospective LTG-specific registry reports a 1.8% chance of major malformations after the first trimester. The registries will continue to release information as data become significant. In the meantime, practitioners can be alert to signs and symptoms of reproductive or metabolic health disturbances and participate in pregnancy registry efforts.

Epilepsy is a common neurologic disorder that affects 1 in every 100 individuals, both children and adults. With the exception of epilepsy related to head trauma, the incidence is equal for men and women. All who have epilepsy must live with the concern that a seizure could occur at any time, the need to take medications every day for years or even a lifetime, and the social and economic hardships that accompany this misunderstood condition.

Women with epilepsy face additional challenges. Some antiepileptic drugs (AEDs) reduce levels of physiologic ovarian sex steroid hormones and may reduce the efficacy of contraceptive steroids. Women with epilepsy have a greater risk for syndromes associated with infertility, such as hypothalamic-pituitary axis disruption, polycystic ovary–like syndrome, and anovulatory cycles. Bone loss related to AEDs is more likely to lead to pathological fracture in women. In addition, women with epilepsy taking AEDs are at higher risk for pregnancy complications related to seizures, morphological abnormalities in offspring, and, perhaps, neurodevelopmental compromise. Unfortunately, most physicians are not knowledgeable about these health risks (1).

CONTRACEPTION IN WOMEN WITH EPILEPSY

  1. Top of page
  2. Abstract
  3. CONTRACEPTION IN WOMEN WITH EPILEPSY
  4. REPRODUCTIVE HEALTH IN EPILEPSY
  5. PRINCIPLES OF AED USE IN PREGNANCY
  6. NEWER AND OLDER AEDS
  7. DISCUSSION
  8. REFERENCES

Women taking cytochrome (CY) P450 enzyme–inducing AEDs have perhaps a fivefold increase in the failure rate of oral contraceptive agents (2,3) because the metabolism of the contraceptive steroid is increased. The hormone dosage, particularly with low hormone dose pills (the minipill), may not be sufficient to be effective. Phenytoin (PHT), carbamazepine (CBZ), barbiturates, and topiramate (TPM) induce CYP450 enzymes and increase binding to sex hormone–binding globulin (SHBG) and steroid metabolism (Table 1). Valproate (VPA) and felbamate (FBM) effectively inhibit this enzyme system, thereby slowing metabolism of contraceptive hormones. Gabapentin (GBP) and lamotrigine (LTG) do not interact with hormonal contraceptives.

Table 1. Antiepileptic drug effects on oral hormonal contraception
AEDs that induce liver enzymes and may compromise OC efficacy
 Carbamazepine (Tegretol, Carbatrol)
 Phenytoin (Dilantin)
 Phenobarbital
 Mysoline (Primidone)
 Oxcarbazepine (Trileptal) at doses > 1200 mg/day
 Topiramate (Topamax) at doses >200 mg/day
AEDs that do not compromise OC efficacy
 Gabapentin (Neurontin)
 Levetiracetam (Keppra)
 Lamotrigine (Lamictal)
 Valproate (Depakote, Depakene)
 Zonisamide (Zonegran)

Women taking CYP450 enzyme-inducing AEDs who wish to use oral hormonal contraception should consider using a product containing at least 50 μg of the estrogen product (4) to regulate menstrual bleeding rather than the commonly used minipill, which contains 35 μg of estrogen or less. Other forms of hormonal contraception, such as subdermal levonorgestrel (Norplant), a slow-release contraceptive containing only progesterone, may also carry a higher risk for failure (5,6).

REPRODUCTIVE HEALTH IN EPILEPSY

  1. Top of page
  2. Abstract
  3. CONTRACEPTION IN WOMEN WITH EPILEPSY
  4. REPRODUCTIVE HEALTH IN EPILEPSY
  5. PRINCIPLES OF AED USE IN PREGNANCY
  6. NEWER AND OLDER AEDS
  7. DISCUSSION
  8. REFERENCES

Women with epilepsy have a reduction in fertility (7–9) of as much as two thirds of that expected (10), as well as reproductive endocrine disorders, menstrual cycle disturbances, and ovulatory dysfunction (11).

The cause of lower fertility rates is multifactorial. A study in Finland found that persons with epilepsy were less likely to marry and to have offspring (12). In part, this reflects a choice. Much of that choice comes from wrong information suggesting that women with epilepsy are not fit parents, the risk of transmission of epilepsy is very high, or the risk of birth defects in children born to mothers with epilepsy is higher than it really is. A recent survey of healthcare professionals likely to encounter women with epilepsy finds that there is a marked lack of knowledge regarding pregnancy and fetal risks associated with maternal epilepsy and that many physicians would not support the decision of a woman with epilepsy to become pregnant (1).

Infertility

One basis for infertility is physiological. Reproductive health disturbances in women with epilepsy include menstrual cycle abnormalities, anovulatory menstrual cycles, reproductive endocrine disorders, and sexual dysfunction (13–18). About one third of menstrual cycles in women with epilepsy are anovulatory compared with a rate of ∼10% in women without epilepsy (13,19). Women with primary generalized epilepsy were more likely to have anovulatory cycles than women with localization-related epilepsy (11). The antiepileptic medication VPA, unlike CBZ, GBP, LTG, phenobarbital (PB), or PHT, was significantly associated with anovulatory cycles (11,19). Women with primary generalized epilepsy receiving VPA were at highest risk. In fact, 55% of menstrual cycles were anovulatory in this group of women with epilepsy (11).

Ovulatory failure associated with epilepsy and some antiepileptic medications may be a result of endocrine and end-organ disturbances. Hypothalamic-pituitary axis dysfunction is suggested by observations that pituitary release of luteinizing hormone (LH) in women with epilepsy is altered spontaneously and in response to gonadotropin-releasing hormone (GnRH) (14,15,20) (Fig. 1). Women receiving CYP450 enzyme–inducing AEDs have significant reductions in serum concentrations of estradiol, testosterone, and dihydroepiandrostenedione, as well as elevations in SHBG (21–27). Women taking VPA (which does not induce liver cytochrome enzymes) have higher gonadal and adrenal androgen levels (17). Enhanced steroid metabolism and binding reduces the concentration of biologically active steroid. In contrast, adrenal and gonadal androgens are significantly elevated in women receiving the CYP450 enzyme inhibitor VPA. However, women with epilepsy taking GBP or LTG—two AEDs that do not alter CYP450 enzymes—have sex steroid hormone levels that are no different from those of nonepileptic controls not taking medications (21).

image

Figure 1. Reproductive endocrine axis disturbances in persons with epilepsy receiving antiepileptic drugs. Hypothalamic-pituitary axis illustrating amygdala interconnections to the hypothalamus. GnRH, gonadotropin-releasing hormone; FSH, follicle-stimulating hormone; LH, luteinizing hormone; PRL, prolactin; +, excitatory feedback; −, inhibitory feedback.

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Polycystic ovary syndrome

The polycystic ovary syndrome (PCOS) is a gynecologic disorder affecting ∼7% of reproductive-age women. The phenotype includes signs of excess androgen sensitivity such as hirsutism, truncal obesity, and acne. Women with this syndrome have frequent anovulatory cycles and may have elevated androgen levels, elevated cholesterol with abnormal lipid profiles, an abnormal ratio of pituitary LH to follicle-stimulating hormone (FSH), elevated insulin, and glucose intolerance. Some women also have multiple ovarian cysts—a finding in 15–20% of reproductive-age women. The requirement for a diagnosis of PCOS is phenotypic or serologic evidence of androgen excess, as well as anovulatory cycles. Polycystic ovaries, while often present in women with this syndrome, are not required for diagnosis. In fact, asymptomatic polycystic ovaries may be relatively common in normal women of reproductive age, occurring in 21–23% of women (28–30). The health consequences of PCOS include infertility, accelerated atherosclerosis, diabetes, and endometrial carcinoma, underscoring the importance of detection and treatment.

Women with epilepsy appear to be at risk for developing features of this syndrome, although there is no study in a cohort of women with epilepsy that is adequately designed to permit an accurate diagnosis of this syndrome. Polycystic-appearing ovaries and hyperandrogenism are reported to arise in as many as 40% of women with epilepsy receiving VPA (13,17,19) and may be more likely to occur in women who receive VPA at puberty (31). In a random sample of 20 women with epilepsy of temporal lobe origin, five had PCOS, characterized clinically by oligomenorrhea, hirsutism, and androgen and LH elevation, or by ovarian cysts visualized directly or by ultrasonography (32). Another evaluation of 50 women with partial seizures arising from the temporal lobe found that 28 had menstrual cycle disturbance and 19 had reproductive endocrine disorders and polycystic ovaries (20).

In a prospective assessment of 94 reproductive-age women with epilepsy, polycystic ovaries were detected by transvaginal ultrasound in 26% of women with localization-related epilepsy, 41% of women with primary generalized epilepsy, and 16% of nonepileptic controls (11). Women receiving VPA within the preceding 3 years were more likely to have polycystic-appearing ovaries (38%) than women receiving other AEDs. This condition in women receiving VPA may be reversible when medication is changed to LTG (33).

The relative effect of epilepsy versus antiepileptic therapy can be considered by assessing reproductive health in persons receiving AEDs for conditions other than epilepsy. Two studies have assessed menstrual cycle regularity and ovarian morphology in women with bipolar disease. One study of women with bipolar disease treated with either VPA or lithium found no difference in length of the menstrual cycle or appearance of polycystic ovaries, although both groups had a high prevalence of abnormal menstrual cycle length (34). Another study assessed women with bipolar disorder who were treated with VPA or other agents, and reported abnormal menstrual length in 47% of those receiving VPA as compared with 13% of those not receiving VPA and 0% of healthy controls. Polycystic ovaries and elevated androgens were found in 41% of women with bipolar disease given VPA and in none of the other women with bipolar disease or the controls (35).

Additional evidence that these reproductive health disturbances are a consequence of epilepsy, as well as its treatment, comes from a study in female primates (36). Nonepileptic, regularly cycling, healthy primates were treated with VPA for 1 year, and achieved serum concentrations of VPA similar to those of adults with epilepsy. Over prospective 1-year assessment, the primates did not develop abnormalities in menstrual cycle length, ovarian morphology, or response to GnRH stimulation.

Data such as these suggest that epilepsy and some AEDs individually affect fertility and that these effects may be additive. This implies that the most sophisticated therapy for epilepsy will consider disease-treatment effects on reproductive health.

Sexual function

Men and women with epilepsy appear to have a higher incidence of sexual dysfunction than in other chronic neurologic illnesses; the dysfunction manifests primarily as diminished sexual desire and potency. Sexual dysfunction affects 30–66% of men with epilepsy (37–40) and 14–50% of women (38,41,42). More than one third of women with epilepsy report dyspareunia, vaginismus, and lack of vaginal lubrication, with normal sexual desire and experience (43).

Physiological sexual arousal has been quantitatively evaluated in several studies. Fenwick et al. found impaired nocturnal penile tumescence in a group of men with epilepsy and low testosterone (44). Men with localization-related epilepsy arising from the temporal lobe achieved inadequate penile tumescence and rigidity during REM sleep as determined by an in-home monitoring device (45). Both men and women with localization-related epilepsy arising from the temporal lobe had significantly lower increases in genital blood flow in response to an erotic audiovisual stimulus than did control subjects, even given normal subjective sexual arousal (46).

The cause of sexual dysfunction is probably multifactorial (see reference 47 for review). Social development is impaired in some individuals with epilepsy. Poor self-esteem as a result of having seizures may lead an individual to feel sexually unattractive. Sexual arousal may be negatively reinforced, particularly when sexual activity precipitates seizures or when sexual sensations or behaviors become identified as part of the seizure or postictal period. Realistic acceptance of psychosomatic aspects of a chronic illness is positively correlated with sexual function, whereas poor disease acceptance is often associated with sexual dysfunction (48).

Epileptic discharges in limbic structures may also contribute to sexual dysfunction. Sexual dysfunction usually arises after the onset of seizures (38,49,50) and may be more common in patients with partial, rather than generalized, seizures (40,49,51). Some patients treated for partial epilepsy with temporal lobectomy report postoperative improvement in libido and sexual potency, with the greatest improvement seen in those patients with the best seizure control (37,38,52).

Sexuality in people with epilepsy may be adversely affected by alterations in the pituitary gonadotropins and prolactin, and in the sex steroid hormones (20,53,54). Reductions in LH and elevated prolactin are associated with sexual dysfunction (55). Estrogen and progesterone must be present in adequate amounts to support sexual behavior in females (55). Low total and/or free testosterone has been correlated with sexual dysfunction in persons with epilepsy (25,54).

AEDs may contribute to sexual dysfunction by direct cortical effects or secondarily through alterations in the hormones supporting sexual behavior. Occasional or chronic impotence is most likely to arise in men using barbiturate AEDs, such as PB (56). Women with epilepsy receiving the CYP450 enzyme–inducing medications PHT, PB, or CBZ were significantly more likely to have sexual dysfunction than women receiving VPA or LTG (M.J.M, unpublished data, 2003).

When a patient presents with the complaint of sexual dysfunction, the clinician must consider the patient's somatic, psychological, and social well-being, as well as the dynamics of the couple and family (48). The frequency with which patients volunteer sexual complaints may depend to a great extent on the attitude of the physician (48). Given a complaint of sexual dysfunction, the patient should be questioned about precipitating factors, such as acute or chronic life stresses, recent medications, illnesses, surgery, or symptoms of depression. A recommended evaluation strategy includes a thorough physical and neurologic examination; thyroid function tests; testosterone, estrogen, prolactin, and LH levels; complete blood cell count; and fasting blood glucose measurement. Urologic or gynecologic consultation should be obtained.

Effects of AEDs on bone health

Some AEDs may alter bone mineral metabolism and compromise bone health, especially in women who have smaller bone mass. Women using PHT, PB, and perhaps CBZ and VPA are at higher risk for bone disorders such as osteopenia, osteomalacia, and fractures (57–59). A prospective study evaluating the risk of hip fractures in women >65 years found that women taking AEDs were two times more likely to have a hip fracture (60).

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 (60–62). The most severe bone and biochemical abnormalities are found in patients receiving AED polytherapy (60,61) and in patients who have taken AEDs for a longer time (59).

AEDs may alter bone mineral metabolism by decreasing calcium and by increasing bone turnover. AEDs that interfere with intestinal calcium absorption could directly affect bone cell function, possibly through inhibition of cellular responses to PTH (57,62), but this cannot be the only mechanism. Reproductive-age women taking CBZ, PHT, and VPA had significantly reduced calcium levels compared with women receiving LTG, but only PHT was associated with increased bone turnover (63). Given available data, women with epilepsy should engage in good bone health practices, including adequate daily intake of calcium (1,200 mg/day) and vitamin D, gravity-resisting exercise, and bone density scans if they have taken PHT, CBZ, or VPA for ≥5 years. Bone density scans should be repeated at 3- to 5-year intervals in premenopausal women.

AEDs and lipid metabolism

Changes in lipid metabolism and body weight are associated with some AEDs and may cause long-term adverse health effects. CBZ, PB, and PHT increase high-density lipoproteins, CBZ has cholesterol-lowering effects, and PB and PHT may exert a similar cholesterol-lowering effect (64–67). Counteracting these favorable lipid trends, elevations in low-density lipoproteins are reported with CBZ and PB, and VPA increases LDLs as well as HDLs, leading to an unfavorable lipid profile. VPA-associated obesity and increases in insulin may account for VPA-associated dyslipidemia (33). Until the nature and mechanisms of AED-associated alterations in lipid metabolism are better understood, clinicians should monitor cholesterol and lipid profiles in persons receiving AEDs.

PRINCIPLES OF AED USE IN PREGNANCY

  1. Top of page
  2. Abstract
  3. CONTRACEPTION IN WOMEN WITH EPILEPSY
  4. REPRODUCTIVE HEALTH IN EPILEPSY
  5. PRINCIPLES OF AED USE IN PREGNANCY
  6. NEWER AND OLDER AEDS
  7. DISCUSSION
  8. REFERENCES

Approximately 1% of all pregnancies are in women with epilepsy. The number of women with epilepsy becoming pregnant has grown over the years as marriage rates have increased for women with epilepsy (68), parenting has become more socially supported, and medical management of pregnancy in women with epilepsy has improved. Pregnancy outcome can be maximized if the healthcare 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 (69,70). The factors that are believed to alter seizure frequency include changes in sex hormones, AED metabolism, sleep schedules, and medication compliance.

AED concentrations may change during pregnancy. Changes in AED pharmacokinetics and total AED concentrations are related to an increase in plasma volume of 40–50%, and an increase in renal clearance and hepatic metabolism. The pharmacokinetics of some AEDs is more profoundly affected than that of others, probably because of pregnancy-related differential effects on CYP450 enzymes (71). 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 (70). 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. Significant pregnancy-related reductions can be anticipated in concentrations of CBZ, PHT, PB, LTG, and sometimes VPA.

Potential fetal risks

Women with epilepsy are at greater risk for 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 are more likely to be related to maternal seizures than to fetal exposure to AEDs (10,73). Fetal heart rate decelerations indicate fetal distress and are reported with maternal seizures (74). These observations underscore the importance of seizure control during pregnancy.

The older AEDs (benzodiazepine, PHT, CBZ, PB, and VPA) are associated with a higher risk of major fetal 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) (75–78). The incidence of major malformations in infants born to mothers with epilepsy taking the older AEDs is 4–6%, compared with 2–4% for the general population. The North American Antiepileptic Drug Pregnancy Registry reports a 12% rate of malformations with PB (relative risk 4.8) (78) and an 8.8% rate for women taking VPA [relative risk 5.43, confidence interval (CI) 3.1–9.6] (79). Neural tube defects (NTDs) (spina bifida and anencephaly) occur in 0.5–1% of infants exposed to CBZ (80) and 1–2% of infants exposed to VPA during the first month of gestation (81).

Minor congenital anomalies associated with AED exposure include facial dysmorphism and digital anomalies, which arise in 6–20% of infants exposed to AEDs in utero (82). This represents a twofold increase over the general population. However, these anomalies are usually subtle and often outgrown.

Concerns are mounting that exposure to AEDs in utero may confer long-lasting neurodevelopmental or neurocognitive deficit (83,84). Fetal head growth retardation has been associated with maternal use of AEDs (84). 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 (85). Prospective studies are under way to better define the neurodevelopmental risks of AED exposure to the developing brain.

The risk of teratogenicity is partly related to the extent of fetal exposure to the AED (86). The risk is highest in fetuses exposed to higher dosages and to AED polytherapy. Holmes et al. assessed women with a history of seizures on and off AEDs, delivering at one of five maternity hospitals in the Boston area (78). Identified mother–infant pairs were compared with control pairs of nonepileptic mothers and infants. Considering major malformations alone, 4.5% of women with epilepsy taking a single AED gave birth to a child with a major malformation, whereas 8.6% of women taking two or more AEDs had a child with a major malformation. None of the women with a history of seizures 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, and hypoplasia of the midface and fingers were considered, 20.6% of the infants born to mothers with epilepsy taking AEDs had one or more of these birth defects, in contrast to 28% of the infants born to mothers taking two or more AEDs, 6.1% of the infants born to mothers with a history of seizures but not taking AEDs, and 8.5% of controls.

Several mechanisms have been postulated to explain the teratogenicity of AEDs. Some AEDs may be teratogenic because of free radical (arene oxide) intermediates (87,88). CBZ, PB, and PHT are metabolized via CYP450 enzyme-dependent oxidative intermediates, which are further metabolized via hydroxylation by epoxide hydrolase to nonreactive dihydrodiols. PB, PHT, and CBZ induce formation of the epoxide intermediate, and VPA inhibits epoxide hydrolase (89,90). Therefore, polytherapy with an enzyme-inducing AED and VPA would promote epoxide formation and 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 for fetal malformations, and susceptibility to oxidative-related teratogenicity may be genetically determined (91–93). Another putative mechanism for AED-related teratogenicity is alterations in endogenous retinoid concentrations (94).

AEDs and folic acid

Some AEDs cause a deficiency of folic acid (95). PB, PHT, and CBZ are associated with folate malabsorption, while VPA inhibits methionine synthetase, an enzyme promoting the conversion of homocysteine to methionine—a step requiring folic acid as a cofactor (96). Elevation of homocysteine has been associated with higher risk for NTDs (97). Administration of folic acid helps overcome the enzyme inhibition and reduce homocysteine levels.

Folic acid supplementation at conception and throughout pregnancy reduces the risk of giving birth to a child with NTDs in women without epilepsy (98–105). The Medical Research Council Vitamin Study conclusively demonstrated that folic acid supplementation of 4 mg/day reduces the recurrence risk of NTDs in women previously giving birth to a child with an NTD (106). The Czech Cooperative Vitamin Study found that first occurrence rates of NTDs were significantly reduced by periconceptional supplementation of folic acid 0.4 mg/day (107). 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 (108).

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 non-NTDs. In the Czech study, the rate of cleft lip and palate was not reduced in women receiving periconceptional folic acid (107). 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 (109). However, in a recent study, folic acid supplementation provided to women receiving folic acid antagonists during pregnancy (including AEDs) did not reduce the risk of non-NTDs such as cleft lip/palate and cardiovascular and urinary tract malformations (110). One recent report of a child born with an NTD to a mother taking VPA 2,000 mg/day and folic acid suggests that folic acid is not absolutely protective against this malformation (111). However, an ongoing assessment of pregnancy outcomes in children born to mothers with epilepsy reports a recent reduction in children born with major malformations, coincident with more widespread folic acid supplementation (112).

The malformations associated with AEDs are all generated in the first trimester of pregnancy, and NTDs are formed by day 28 after conception. Most women cannot know they are pregnant until a menstrual cycle is missed (day 15). In the United States, >50% of pregnancies are unplanned (113), and >40% of women with planned pregnancies do not consult a healthcare provider prior to pregnancy. Therefore, interventions must be designed to maximize fetal outcome before conception. Many professional societies, including the American Academy of Neurology (114), American College of Obstetric and Gynecologic Physicians (115), and Canadian Society of Medical Geneticists (116), recommend that all women of childbearing age taking AEDs receive folic acid supplementation of 0.4–5.0 mg/day.

NEWER AND OLDER AEDS

  1. Top of page
  2. Abstract
  3. CONTRACEPTION IN WOMEN WITH EPILEPSY
  4. REPRODUCTIVE HEALTH IN EPILEPSY
  5. PRINCIPLES OF AED USE IN PREGNANCY
  6. NEWER AND OLDER AEDS
  7. DISCUSSION
  8. REFERENCES

Since 1993, a number of 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 U.S. Food and Drug Administration on fetal outcome in animals exposed to the newer AEDs are favorable.

Prospective registries have been established to learn more about pregnancy and fetal outcome in women using AEDs. Data of significance are available only for LTG (117). As of September 2001, the registry accumulated data on 168 pregnancies with first-trimester exposure to LTG monotherapy and 166 first-trimester exposures to LTG as part of a multiple AED regimen. In monotherapy, 3 of 166 pregnancies resulting in 168 pregnancy outcomes exposed during the first trimester resulted in a child with a major malformation (1.8%, 95% CI 0.5–5.5%). The malformations were an esophageal defect repaired by surgery, a cleft soft palate, and a right clubfoot.

Data are also available for outcomes after first-trimester exposure to LTG in polytherapy. Five of 50 pregnancies exposed to AED polytherapy that included LTG and VPA had major birth defects (10%, 95% CI 3.7–22.6%), as did 5 of 116 pregnancies exposed to LTG as part of a polytherapy regimen not including VPA (4.3%, 95% CI 1.6–10.3%). No specific patterns of malformation were seen in the registry as a whole or in any subgroup. Although the sample sizes for the individual regimens are too small for small frequencies of major malformations or large frequencies of very rare malformation to be ruled out, this experience is thus far reassuring. Confirmation of these findings comes from experience in a registry maintained in the U.K. (118).

Pregnancy experience with oxcarbazepine (OXC) has been reported in several single-center studies. A report from Argentina on 42 pregnancy exposures to OXC (25 in monotherapy and 17 in combination with other AEDs) found no malformations in the monotherapy group and 1 ventricular septal defect in an infant also exposed to PB (119). A Finnish series that included 740 pregnancies exposed to AEDs during the first trimester found that occurrence of major malformations was independently associated with use of OXC [odds ratio (OR) 10.8%, 95% CI 1.1–106, as well as with CBZ (OR 2.5, 95% CI 1–6), and VPA (4.1, 95% CI 1.6–11)] (120). The wide CIs indicate that these data should not be considered conclusive.

Presently the European Registry (EURAP) is enrolling actively across the globe, while the North American Antiepileptic Drug Registry and pharmaceutical company registries continue to gather data. 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 (114,115,121). This applies to dosage and to 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 present, there is insufficient information to identify any particular AED as the drug of choice during pregnancy. In addition, if there is a family history of NTDs, an agent other than CBZ or VPA might be considered.

Prenatal diagnostic testing includes a maternal serum alpha-fetoprotein and a level II (anatomic) ultrasound at 14–18 weeks. This strategy will identify >95% of infants with neural tube defects. In some instances, an amniocentesis may be indicated, such as if the mother is >35 years of age or if the ultrasound or maternal serum alpha-fetoprotein is concerning.

The older AEDs may be associated with an increased risk for early fetal hemorrhage, due to an AED-related vitamin K deficiency with a reduction in vitamin K-dependent clotting factors (122). Vitamin K deficiency in the newborn is suspected because of reports of proteins induced by vitamin K absence (PIVKAs) detected in cord blood of neonates born to women taking CBZ, PB, and PHT (123). This abnormality is corrected by maternal supplementation with oral vitamin K (124). Therefore, the American Academy of Neurology (114) recommends that vitamin K supplementation be provided (vitamin K1 at 10 mg/day) over the last month of gestation.

Breastfeeding

Breastfeeding is strongly recommended by most health organizations to promote mother–child bonding and reduce the risk of infection and later-life immunological disorders (125,126). AEDs cross into breast milk to variable extents. Passage is usually by simple diffusion, and the ratio is determined by the drug's molecular weight, pKa, lipophilicity, and, most importantly, the extent of protein binding (127,128). For PHT, CBZ, VPA, and tiagabine, the concentration in breast milk is negligible because of their high protein binding. Ethosuximide, PB, and primidone result in measurable concentrations. LTG reaches ∼30% of the maternal serum concentration (129). TPM, OXC, and OXC metabolite levels are similar in maternal serum, cord blood, and placental tissue (130,131), indicating extensive transplacental passage. However, this does not necessarily indicate ultimate exposure for breastfed infants. For TPM, the milk-to-maternal-plasma ratio is 0.69 at 3 months, and breastfed infants have concentrations below the limit of quantification (130).

For most women, the best advice is to seriously consider breastfeeding. 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 breastfeeding continues. When breastfeeding stops, the mother may experience an increase in serum AED concentrations requiring a dosage adjustment.

DISCUSSION

  1. Top of page
  2. Abstract
  3. CONTRACEPTION IN WOMEN WITH EPILEPSY
  4. REPRODUCTIVE HEALTH IN EPILEPSY
  5. PRINCIPLES OF AED USE IN PREGNANCY
  6. NEWER AND OLDER AEDS
  7. DISCUSSION
  8. REFERENCES

Epilepsy raises special issues for women, including challenges to reproductive and metabolic health. Best clinical care considers the impact of both seizures and AEDs. AED selection is optimized when the seizure type, as well as overall health, is considered.

Clinicians selecting an AED should consider its potential impact on reproductive health. CYP450 enzyme-inducing AEDs reduce concentrations of bioavailable sex steroid hormones affecting oral contraceptive regulation of the menstrual cycle and contraceptive efficacy. These agents also reduce endogenous sex steroid hormones, which may contribute to sexual dysfunction.

Clinicians should also be alert to seizure and AED-related reproductive endocrine disorders and ovarian dysfunction. An alteration in the length or regularity of the menstrual cycle is a reliable warning sign of anovulatory cycles. Development of male pattern hair growth, obesity, or acne is a sign of elevated androgens and/or androgen hypersensitivity. Lipid abnormalities and glucose intolerance may accompany hyperandrogenism and confer significant long-term health risks.

AEDs may also affect bone health. Although mechanisms of bone loss and resultant osteopenia and osteoporosis are not elucidated, there are compelling data that the enzyme-inducing AEDs, particularly PHT and PB, are implicated. Bone density should be monitored, and all women with epilepsy are strongly encouraged to observe good bone health practices, including gravity-resisting exercise, calcium (at least 1,200 mg/day) and vitamin D supplementation, and periodic bone density scans.

The rates of major morphological abnormalities after fetal exposure to the older AEDs are confidently established at 4–6% for CBZ and PHT, respectively, and 8% for VPA. Information regarding LTG suggests that there is a low risk for major malformations after monotherapy exposure. Data regarding risks for the other new-generation AEDs are pending. In the meantime, limiting exposure to high dosages and AED polytherapy, supplementing with periconceptional folic acid, and ensuring rigorous prenatal diagnostic testing with an anatomic ultrasound can enhance the odds for a normal pregnancy outcome.

Healthcare providers for women with epilepsy can benefit from the mass of new information coming from the work of a number of investigators, including those involved in the prospective pregnancy registries. Concerns about reproductive health risks for women with epilepsy were recently discussed in a practice parameter developed by the American Academy of Neurology addressing management issues for women with epilepsy (4). This information identifies the unique challenges facing women with epilepsy; it suggests that detection of reproductive and metabolic health disturbances can be accomplished easily, and that there are reasonably simple and effective interventions that can easily be incorporated into clinical practice. The sophisticated treatment of the woman with epilepsy not only provides seizure control but preserves overall long-term health.

REFERENCES

  1. Top of page
  2. Abstract
  3. CONTRACEPTION IN WOMEN WITH EPILEPSY
  4. REPRODUCTIVE HEALTH IN EPILEPSY
  5. PRINCIPLES OF AED USE IN PREGNANCY
  6. NEWER AND OLDER AEDS
  7. DISCUSSION
  8. REFERENCES
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