25
Epilepsy in Women of Childbearing Age
Introduction
Throughout their reproductive lives, women with epilepsy (WWE) face challenges that place them and their unborn offspring at risk of adverse events. The estimated epilepsy prevalence in women of childbearing age is 0.3–0.5%. Juvenile absence epilepsy and juvenile myoclonic epilepsy are particularly common in women of this age. While it is important to choose an antiepileptic drug (AED) that is appropriate for the patient’s particular epilepsy syndrome, this chapter will also review considerations for AED choice that are specific to WWE.
Catamenial epilepsy
Catamenial epilepsy is defined as a twofold increase in daily seizure frequency during specific phases of the menstrual cycle. This may occur during (1) menses (perimenstrual), (2) ovulation (periovulatory), or (3) the entire second half of the cycle (luteal phase). Approximately one-third of women with temporal lobe epilepsy have a catamenial pattern. Diagnosis of catamenial epilepsy requires careful documentation of seizure patterns related to the menstrual cycle.
The perimenstrual pattern is the most common. During this phase, the estrogen to progesterone balance favors estrogen, which has pro-convulsant properties. Fluctuations in metabolism of certain AEDs around the time of menses might also predispose patients to seizures if levels fall, although this theory is not strongly substantiated.
Treatment options include targeted AED therapy at the most vulnerable times of the cycle; select use of contraception; and use of medroxyprogesterone acetate, natural progesterone, or other hormonal treatments such as the investigational agent ganaxolone or clomiphene citrate. The use of natural progesterone lozenges for perimenstrual catamenial epilepsy has the best evidence of efficacy.
Contraception
The choice of contraception for a WWE prescribed AED therapy can be challenging. As the best AED and oral contraceptive pill (OCP) combination is not known, many physicians and WWE choose alternate contraceptive options, some not as reliable as OCPs.
TIPS AND TRICKSThe cytochrome P450 system, specifically CYP3A4, is the primary metabolic pathway of ethinyl estradiol and other sex hormones. Because AED induction of this pathway will accelerate hormone clearance, it will also reduce OCP efficacy. Some enzyme-inducing AEDs may also lead to an increase in sex hormone-binding globulin, which reduces free levels of reproductive hormones. Therefore, when using an enzyme-inducing AED, an OCP containing 30 µg or more of estrogen should be used, although there is no direct evidence supporting this suggestion. The CDC Medical Eligibility Criteria for contraception classifies phenytoin, carbamazepine, phenobarbital, primidone, topiramate, and oxcarbazepine as increasing the risk of birth control failure in individuals who use OCPs.
Preconception counseling
As up to a half of pregnancies are unplanned, WWE of reproductive age should be prescribed an AED with low risk to offspring.
TIPS AND TRICKSConsider stopping AEDs in WWE who are entering their reproductive years. Factors to be considered when deciding whether to stop AEDs are discussed in Chapter 17. For those who need to be maintained on an AED, one with the lowest possible rate of major congenital malformations should be used, at the lowest dose necessary for seizure control. In addition, all WWE of childbearing age should take a daily prenatal vitamin and additional folic acid. Although the ideal dose of folic acid is not actually known, a total daily dose of about 5 mg/day is frequently recommended. In the USA, this equals four 1 mg folic acid tablets and one prenatal vitamin, which typically has 800 µg of folic acid.
Once it has been determined that a WWE is on the best AED for childbearing and seizure control, a baseline AED level will be helpful for medication titration during pregnancy. Patients should be attentive to the earliest signs of pregnancy (missed menses, nausea, fatigue) and notify their neurologist immediately if they conceive. Serum blood levels can change dramatically within the first trimester, prior to the first obstetrical visit, so immediate monitoring and adjusting may be needed.
Infertility
Infertility is the inability to conceive after 1 year of regular unprotected sexual intercourse in women younger than 35 years of age and for 6 months in women older than 35 years. The national infertility rate is estimated at 10–15% of all couples. The infertility rate is higher in WWE, with a pregnancy rate approximately 60–75% of that of the general population.
The reasons for this lower pregnancy rate are multiple. In the past, WWE might not have been allowed to marry or have children. Recently, lower marriage rates have also been documented. Some WWE may have cognitive impairment, which leads to a lower chance of living independently. They may also not be as socially engaged as their peers. Understandably, they can be concerned about the effects of medications on their offspring, the inheritance of disease, and the difficulty of raising children. In addition to depression, WWE frequently have impaired sexual function and lower self-reported arousal – those on enzyme-inducing medications are usually the most affected.
There is some evidence that WWE have endocrine abnormalities at a higher rate than the general population, which may contribute to infertility. These endocrine abnormalities include polycystic ovarian syndrome (PCOS), hyperprolactinemia, and premature menopause. PCOS, characterized by polycystic ovaries, hirsutism, obesity, and infertility, occurs in about 5% of the general population but in approximately 20% of women with temporal lobe epilepsy.
Seizures themselves, especially convulsions, can lead to prolonged increases in prolactin levels. Prolactin at sustained high levels is known to suppress ovulation and therefore may affect fertility in women with frequent seizures. Finally, for unknown reasons, WWE have higher rates of premature ovarian failure, defined as primary gonadal failure, high gonadotropin levels, and amenorrhea before 40 years of age.
Antiepileptic drugs
Antiepileptic drug choice is critical for pregnancy outcome but should really be determined before conception. Most choices are governed by the rates of major congenital malformations associated with first-trimester exposure. Several large international pregnancy and pharmaceutical company registries track these malformations. Unfortunately, studies are underpowered for many AEDs. These registries agree that first-trimester valproic acid exposure is associated with an increased rate of major congenital malformations, while lamotrigine and levetiracetam are associated with some of the lowest rates of malformations. The American Academy of Neurology (AAN) guidelines recommend avoiding use of valproic acid during the first trimester to reduce risk of malformations. In addition, they suggest avoiding polytherapy of any AED and, if possible, avoiding phenytoin and phenobarbital to prevent reduced cognitive outcomes.
A recent publication by the North American Antiepileptic Drug Pregnancy Registry reviewed findings on malformations and monotherapy AED exposure in pregnancy (Table 25.1). In this study, valproate was associated with neural tube defects, hypospadias, cardiac defects, and oral clefts, while phenobarbital had a higher risk of cardiac defects and oral clefts. In addition, a prospective investigation of AED exposure during pregnancy confirmed a high rate of fetal malformation with valproate exposure and also demonstrated a lower IQ measured at age six. Given the findings from these studies, lamotrigine and levetiracetam are becoming more commonly used AEDs in women of childbearing age
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