Pregnancy and the Mother with Epilepsy

Mark S. Yerby

Introduction

The management of women with epilepsy is an area that has received increased attention from neurologists. The discrimination and bias of past eras has gradually given way to an atmosphere in which marriage and child rearing is considered acceptable for women with epilepsy (WWE). We therefore tend to forget that in the not too distant past, most states had legislation prohibiting marriage for persons with epilepsy.

The advent of better neurologic training, improved diagnostic techniques, the development of vagal nerve stimulation, and a group of new and effective medications have vastly improved the management of epilepsy. The majority of women with this disorder can have healthy children. The management of women, however, presents unique issues not present for men. To be effective, neurologists need to understand these issues. Fluctuations in sex steroid hormones can have an impact on seizure control. Sexual dysfunction is seen more often in persons with epilepsy. Infertility is more common in women with epilepsy. It is unclear whether this is a function of the treatment or the underlying disorder. Enzyme-inducing antiepileptic drugs (AEDs) may reduce the effectiveness of hormonal contraceptives. Hormonal contraceptives may impact plasma concentrations of specific AEDs. Women with epilepsy are at greater risk for complications of pregnancy and adverse pregnancy outcomes. The following is a practical discussion of the management of these problems.

Infertility and Reproductive Abnormalities

Epidemiologic studies have demonstrated that women with epilepsy have only one fourth to one third as many children as women in the general population.⁸^,³⁵ A variety of hypotheses have been developed to explain this phenomenon. A direct effect of seizures or epileptiform discharges on the pituitary and hypothalamus could disrupt ovulation. Electroconvulsive therapy increases prolactin concentrations over fivefold within 15 to 20 minutes, and in premenopausal women there is an acute increase in luteinizing hormone (LH) and follicle-stimulating hormone (FSH). Generalized seizures also increase prolactin serum concentrations within 15 to 20 minutes by a factor threefold. This fact has been used to assist physicians in differentiating epileptic from nonepileptic seizures.²⁰

Women with epilepsy have higher rates of reproductive and endocrine disorders (REDs) than expected. In a large clinical center, 50% of women with epilepsy were found to have menstrual abnormalities, 20% amenorrheic and 35% anovulatory.²⁴ Herzog et al. were among the first to demonstrate REDs in women with temporal lobe epilepsy.²⁵ Women with primary generalized epilepsies also have REDs. Five of 20 women studied by Bilo et al. had REDs, three with polycystic ovarian disease, and two with hypogonadotropic hypogonadism.⁸

Antiepileptic drugs may also interfere with the hypo-thalamic-pituitary axis. Amenorrhea, oligomenorrhea, and prolonged or irregular cycles have been described in WWE by Isojarvi et al.³⁵ Women with epilepsy taking valproate were overrepresented: 45% of those on valproate monotherapy and 25% on valproate polytherapy had menstrual disturbances. Polycystic ovaries were found in 43% of valproate-treated women and 80% of women treated with valproate before the age of 29 had polycystic ovaries.

Women with epilepsy have more variation in LH pulse frequency and lower LH concentrations than controls.²⁰ In addition, women with left-sided ictal epileptiform foci had polycystic ovarian disease, and those with right-sided foci hypogonadotropic hypogonadism.

Libido is significantly reduced in one third of men and women with epilepsy.⁵⁸ Increasing seizure frequency appears to decrease sexual desire, while there is no difference in libido between treated and untreated women with epilepsy. Hyposexuality and orgasmic dysfunction has been reported in 8% to 68% of women with epilepsy.⁴⁸ Persons with localization-related epilepsies appear to have higher rates of sexual dysfunction compared to those with primarily generalized epilepsies. Shukla et al. have demonstrated that 64% of women with partial epilepsies, compared to 8% with generalized epilepsies, report hyposexuality and sexual dysfunction.⁷⁹

The problem of infertility in WWE is therefore complex. There are multiple factors: Seizure type, frequency, site of ictal onset, and use of AEDs, which may affect an individual patient. Infertility in a couple deserves a careful evaluation of both partners. For WWE, ultrasonography to rule out polycystic ovarian disease, serum LH and FSH concentrations, and an evaluation of AED use will help one narrow the focus of treatment. There is evidence that valproate may adversely impact the fertility of some women. If the patient’s seizures are controlled, discontinuation of valproate is not warranted unless polycystic ovarian disease or hypogonadotropic hypogonadism is found.

Pregnancy

The majority of WWE can conceive and bear normal, healthy children. The pregnancies of WWE do present a greater risk for complications of pregnancy, they are more likely to have difficulties during labor, and there is a higher risk of adverse pregnancy outcomes.

Increased Seizure Frequency

One quarter to one third of WWE will have an increase in seizure frequency during pregnancy. This increase is unrelated to seizure type, duration of epilepsy, or seizure frequency in a previous pregnancy. While most studies have demonstrated
that the increase tends to occur toward the end of pregnancy, recent reports find that a substantial number (31%) have their increase in the first trimester.¹¹

Plasma concentrations of anticonvulsant drugs decline as pregnancy progresses, even in the face of constant and in some instances increasing doses.⁶³^,⁷²^,⁹²^,⁹³ Plasma concentrations tend to rise postpartum.⁶⁵^,¹⁰³ Although reduction of plasma drug concentration is not always accompanied by an increase in seizure frequency, virtually all women with increased seizures in pregnancy have subtherapeutic drug levels.¹⁵^,³⁶^,⁶⁷^,⁷⁵ The decline of anticonvulsant levels during pregnancy is largely a consequence of decreased plasma protein binding, reduced concentration of albumin, and increased drug clearance.¹⁴^,³⁶^,⁶³^,⁶⁸^,⁶⁹^,⁹³^,¹⁰⁴ The clearance rates are greatest during the third trimester.

Seizures during pregnancy increase the risk of adverse pregnancy outcomes. Generalized, tonic–clonic seizures increase the risk for hypoxia and acidosis as well as injury from blunt trauma.⁸⁵ Canadian researchers have found that maternal seizures during gestation increase the risk of developmental delay.⁵² Although rare, stillbirths have occurred following a single generalized convulsion, or series of seizures.¹⁰^,²⁷^,⁸⁷

Generalized (though not partial) convulsions occurring during labor can have a profound effect on fetal heart rate.⁹⁰ The increased rate of neonatal hypoxia and low Apgar scores may be related to such events.¹⁰⁴ Partial seizures may also have similar effects, if less often.⁷⁴

Complications in the Offspring

The infants of epileptic mothers are at greater risk for a variety of adverse pregnancy outcomes. These include fetal death, congenital malformations, neonatal hemorrhage, low birth weight, developmental delay, feeding difficulties, and childhood epilepsy.

Infant Mortality

Fetal death (defined as fetal loss after 20 weeks’ gestation) appears to be as common and perhaps as great a problem as congenital malformations and anomalies. Studies comparing stillbirth rates found higher rates in infants of mothers with epilepsy (1.3% to 14.0%) compared to infants of mothers without epilepsy (1.2% to 7.8%).

Spontaneous abortions, defined as fetal loss prior to 20 weeks of gestation, do appear to occur more commonly in infants of mothers with epilepsy.¹⁰² Women with localization-related epilepsies appear to be at greater risk for spontaneous abortions than those with other seizure types.⁷⁶ Other studies have demonstrated increased rates of neonatal and perinatal death. Perinatal death rates range from 1.3% to 7.8% compared to 1.0% to 3.9% for controls.

Malformations

Fetal malformations have been associated with in utero exposure to AEDs. Congenital malformations are defined as a physical defect requiring medical or surgical intervention and resulting in a major functional disturbance.

Infants of mothers with epilepsy exposed to anticonvulsant drugs in utero are twice as likely to develop birth defects as infants not exposed to these drugs. Malformation rates in the general population range from 2% to 3%. Reports of malformation rates in various populations of exposed infants range from 1.25% to 12.5%.¹²^,²¹^,³⁷^,⁴⁰^,⁴⁴^,⁵⁹^,⁶²^,⁶⁹^,⁸⁴^,⁹¹^,⁹⁴^,⁹⁹ These combined estimates yield a risk of malformations in a pregnancy of WWE of 4% to 6%. Cleft lip, cleft palate, or both, and congenital heart disease account for many of the reported cases. Orofacial clefts are responsible for 30% of the increased risk of malformations in these infants.¹^,²²^,⁴³

A wide variety of congenital malformations have been reported, and every anticonvulsant drug has been implicated as a cause. No anticonvulsant drug can be considered absolutely safe in pregnancy, yet most of these drugs do not produce any specific pattern of major malformations.

An exception to this is the association of sodium valproate with neural tube defects (NTDs). Methodologic problems make frequency estimates imprecise since most published data are case reports, case series, or very small cohorts from registries that were not designed to evaluate pregnancy outcomes. The prevalence of spina bifida (SB) with valproate exposure is approximately 1% to 2%, and with carbamazepine 0.5%.²⁸^,⁵³^,⁷³ However, a prospective study in the Netherlands found that infants of mothers with epilepsy (IMEs) exposed to valproate had a 5.4% prevalence rate of SB. Average daily valproate doses were higher in the IMEs with SB (1,640 ± 136 mg/day) than in the unaffected IMEs (941 ± 48 mg/day). Another group of investigators has found that valproate doses of 1,000 mg/day or plasma concentrations of 70 μg/mL or less are unlikely to cause malformations.⁴⁰^,⁹⁴

Women with epilepsy should, as should all women of childbearing age, take folate supplementation. The dose recommended by the Centers for Disease Control and Prevention of 400 μg/day may not be high enough for many women who do not metabolize folate effectively. Even with folate supplementation, women taking valproate or carbamazepine should avail themselves of prenatal diagnostic ultrasound to rule out NTDs.

Neonatal Hemorrhage

For many years, it has been believed that infants of mothers with epilepsy are at greater risk of neonatal hemorrhage. This was reported first by Van Creveld, who suggested that vitamin K deficiency might be the cause.⁹⁵ Since then, there have been numerous reports that in utero exposure to AEDs is associated with neonatal hemorrhage.⁹^,¹⁹^,⁴⁶^,⁵⁰^,⁸¹^,⁸³^,⁸⁶ Early reports attributed this to phenobarbital or primidone, but a hemorrhagic diathesis has subsequently also been described in children exposed to phenytoin, carbamazepine, diazepam, mephobarbital, amobarbital, and ethosuximide.

This has been differentiated from other hemorrhagic disorders in infancy in that the bleeding occurs internally, during the first 24 hours of life. Accurate prevalence figures are lacking.

The hemorrhage appears to be a result of a deficiency of vitamin K–dependent clotting factors II, VII, IX, and X. Maternal coagulation parameters are invariably normal. The fetus, however, will demonstrate diminished clotting factors and prolonged prothrombin and partial thromboplastin times. A prothrombin precursor, protein induced by vitamin K absence (PIVKA), has been discovered in the serum of mothers taking anticonvulsants.¹⁶ Assays for PIVKA may permit prenatal identification of infants at risk for hemorrhage.⁶^,⁹⁷

The historical demonstration of an increased risk of neonatal hemorrhage coupled with a demonstrated deficiency of vitamin K and PIVKA led clinicians to believe that the relative lack of vitamin K and the presence of PIVKA was the cause of this particular neonatal hemorrhage. Three studies demonstrated that oral maternal supplementation increased neonatal vitamin K and reduced hemorrhage.⁴^,¹³^,¹⁸ However, this practice has been challenged. Kaaja et al. found no difference in the rates of neonatal hemorrhage in 667 infants of mothers with epilepsy (0.7%) and 1,334 control infants (0.4%).³⁹ No
mothers in either group were supplemented with vitamin K, but all infants received intramuscular vitamin K at delivery. They concluded that on the basis of their experience, no evidence of a difference in clinical bleeding could be found; hence, supplementation was not recommended. Hey measured cord blood from 137 infants of mothers with epilepsy taking phenobarbital, phenytoin, or carbamazepine and found that 14 of 105 had prolonged prothrombin times but none had any clinical bleeding.²⁶ He believed that the lack of clinical bleeding in his series made supplementation with vitamin K inappropriate.

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