Epilepsy is the most common neurologic disorder that occurs during pregnancy. Many female patients with epilepsy are of childbearing age and require antiepileptic medications during pregnancy. Antiepileptic drugs are for the most part teratogens and up to 10% of infants exposed to these medications during pregnancy will develop features of fetal anticonvulsant syndrome such as congenital malformations, microcephaly, and intrauterine growth retardation. The issue of effective seizure control during pregnancy to protect the mother and unborn child against adverse impact of breakthrough seizures is a complicated and sensitive issue that poses major therapeutic challenges to the treating neurologists. Treatment of pregnant epileptic patients must focus on monotherapy along with prenatal supplementation of folic acid. This chapter discusses the published literature on epilepsy and pregnancy and aims to assist clinicians in more effective management of this vulnerable group of patients to reduce dangers to the mother and the unborn child.

Introduction

A woman with epilepsy who becomes pregnant or simply wants to have a child poses many questions that are difficult for the physician to answer. The prospective mother’s questions are seemingly more uncomfortable in our evidence-based medicine of today than in bygone days when much less was known about the subject. Can I conceive if I am on antiepileptic medication? What will happen to my seizures if I am pregnant? Will seizures hurt the baby? Will my seizure medication hurt the baby? Can I just stop my seizure medication? I was told I cannot have a baby if I have epilepsy, is that true? There are no simple answers. The physician faces similar, difficult-to-answer questions regarding management that are no less unsettling. What is worse for the baby, seizures or antiepileptic medication? What antiseizure medication is most effective for the mother? What antiseizure medication is safest for the baby? Can birth defects due to antiepileptic drugs be prevented? What else I do not know? In general, these questions cannot be answered by medical studies producing Class I evidence . It is unlikely that such evidence will ever be available due to the ethics of controlled studies on pregnant women.

The fact is that most women with epilepsy will have perfectly healthy children so it is not unreasonable for them to try to do so. Recent evidence suggests that the risk of fetal malformations has been overstated and that the shift to newer antiepileptic drugs and the use of folic acid has reduced the incidence . Medical science has greatly improved the lives of patients with epilepsy over the past 50 years. The repeal of all the eugenic marriage laws in the United States that prohibited marriage (and therefore reproduction) of epileptics is stark evidence of this change in the way society views epilepsy. The medical view of epilepsy has changed as well. Diagnosis of epilepsy is now accurate and relatively rapid. Electroencephalogram-Video (EEG-video) monitoring can clarify events that were only suspected to be seizures and demonstrate clearly those that are not. Improved imaging can identify a treatable cause for seizures in many cases. Tremendous advances in genetics have allowed the elucidation of many syndromes that involve clear molecular abnormalities that predispose a patient to seizures. Treatment has improved dramatically in the past 20 years with many new pharmacologic and nonpharmacologic options that are safer and often more effective than older treatments. However, when all these medical advances come up against the problem of epilepsy in pregnancy, our breathtaking advance slows to a crawl. As with many areas of medicine, the full array of options cannot be used due to concerns about the second patient who does not have a disorder but will be exposed to the effects of treatment. Progress has been slow but definite .

This chapter will examine the available evidence for treatment of epilepsy and will review the most recent guidelines. Issues regarding the patient with epilepsy (meaning the pregnant mother) will be first. The effect of epilepsy and its treatment on conception begins the discussion. The effects of pregnancy on epilepsy and epilepsy on pregnancy will follow. The special case of seizures caused by pregnancy (eclamptic seizures) will be covered separately. Largely due to pregnancy registries, there is a growing body of knowledge regarding the effects of both epilepsy and its treatment on the developing fetus. Birth defects and the fetal anticonvulsant syndrome have been the focus in this area but there is growing evidence that antiseizure medications have more subtle effects on learning and development that should impact medication choice. The chapter will conclude with most recent recommendations for managing a woman with epilepsy through the process from conception to birth and somewhat beyond. Women with epilepsy can have children safely but with higher risk of complications (to both mother and fetus) than in the general population. Minimizing this risk and the responsibility of physicians is the purpose of this chapter.

History

Children born to mothers with epilepsy have an increased risk of an adverse outcome. The risks are relatively small with proper management. It is now recognized that the vast majority of women with epilepsy can have healthy children. This has not always been the case.

Pregnancy is mentioned infrequently in ancient writings regarding epilepsy. Most writing on epilepsy before Hippocrates ascribed epilepsy to magical forces or punishment for sin. The Greek usage of the term “the sacred disease” reflects this. Hippocrates published “The Sacred Disease” in 400 bc as a statement to the general public to combat superstition. “The fact is that the cause of this affliction is in the brain” . He also discussed the role of the uterus which he felt could cause seizures when displaced but little else is mentioned regarding epilepsy and pregnancy . Physicians in the middle ages continued to recognize the uterus as a source of seizures in women. Guainerius in 1516 noted differences between hysterical seizures and “idiopathic” epilepsy based on clinical description of the events and the recognition that patients with hysterical seizures remembered events during the episode . This is one of the earliest writings to recognize the phenomena of psychogenic seizures or pseudoseizures. Vapors arising from the uterus were felt to explain epileptic attacks but some authors felt that these vapors could cause hysterical seizures as well.

The nineteenth century brought about the beginning of our current understanding of epilepsy. In 1795, Boissier de Sauvages determined that epilepsy was a chronic disease and separated it from “acute clonic convulsion with insensibility during the paroxysm” which he termed eclampsia . The main distinction between the two was (and remains) the chronicity of epileptic seizures versus the transient nature of eclampsia, which occurred only during pregnancy. By 1800, medical science recognized that there were epileptic seizures both “grand mal” and “petit mal,” seizures due to eclampsia, and hysterical seizures which we would today call pseudoseizures or psychogenic seizures. All of the understanding of the time is based on clinical grounds. As early as 1843, it was recognized that proteinuria was seen with eclampsia, and in 1896, Schmorl showed that there were fetal cells in the maternal circulation . In 1857, the first effective treatment for epilepsy was discovered with the use of potassium bromide. The drug could cause impotence in males and it was felt that this might be useful in treating menstrual epilepsy, often known as hysterical epilepsy at the time . This was a fairly effective treatment for epilepsy although quite sedating in many patients. Phenobarbital was developed in 1912 and this was somewhat more effective and less sedating. The use of phenobarbital for epilepsy was an accidental discovery as the drug was intended to be used as a tranquilizer . Magnesium was used for the first time to prevent eclampsia in 1906 and was given intrathecally . It was not until 1933 that magnesium was used in large number of patients with both eclampsia and pre-eclampsia at Los Angeles General Hospital .

While there were many developments in the field of epilepsy during the nineteenth and early twentieth centuries, social awareness regarding epilepsy lagged far behind. There was a clear connection between epilepsy, mental retardation, and insanity in the mind of the general public that tended to stigmatize epileptics. Oddly enough, at the time when scientific understanding was growing and effective treatment was becoming available, public policy began to move in a different direction. The first law prohibiting marriage of epileptics (and therefore reproduction) in the United States was passed in Connecticut in 1895 . By 1956, 17 states had laws against marriage for epileptics although, to its credit, Connecticut had repealed their version in 1953. The last state to repeal this type of law did so in 1980. These laws were largely ineffective for several reasons. Persons could cross state lines and marry in states that did not have such laws. Medical evaluation was not required to prove a person was epileptic in most of the states that did have these laws. There was no effective way to identify carriers of epilepsy. These facts made the laws ineffective in preventing the birth of epileptics, which was the intent. There was a growing appreciation at the time that there was a limited genetic component to most epilepsy and this eventually led to a repeal of these laws. Contributing equally to stigmatizing epileptics and relating to their reproductive rights were eugenic sterilization laws. The first such law was passed in Indiana in 1907 . Several other states followed suit but all such laws were held unconstitutional until 1927 with the case of Buck v. Bell . In a decision authored by Justice J. Holmes it was determined that a woman could be sterilized for the greater good of society. “The principle that sustains compulsory vaccination is broad enough to cover cutting the Fallopian tubes” ( Jacobson v. Massachusetts , 197 U.S. 11). As stated by Justice Holmes, “Three generations of imbeciles are enough” . Only 4 of 17 states that had such laws in 1956 applied them to epileptics who were not institutionalized. These laws no longer apply to epileptics in any state. The last such law was repealed in 1980.

Today there are successful people in nearly all walks of life who live with epilepsy. There are athletes, members of congress, physicians and lawyers, and persons from nearly every occupation who live normal lives with epilepsy. The disorder has even touched a member of the Supreme Court of the United States . Pregnant women are included in people who have epilepsy but live completely normal lives. Public awareness of epilepsy has improved to the point that the question is now longer if a woman with epilepsy can or should have a child, but rather how best to do it.

Fertility and Epilepsy

A number of studies have shown that women with epilepsy have fewer children than women in the general population. One study involving women with idiopathic epilepsy showed this number to be reduced to one-third the expected number . Other studies show women with temporal lobe epilepsy having 70–85% of the expected number of children . More recent studies show an improvement in these statistics, which is undoubtedly due to a number of factors, both social and medical. With social factors that reduce the chance of a woman with epilepsy having children set aside, it is clear that both seizures and antiepileptic medications have a role in reproductive dysfunction in women with epilepsy.

Generalized seizures increase the level of prolactin by 3 times within less than 30 min of the seizure. Luteinizing hormone (LH) and follicle stimulating hormone (FSH) also increase . This well-known endocrine response to a seizure is useful in the diagnosis of psychogenic seizures (pseudoseizures). These increases may also be the key to understanding why women with epilepsy have reproductive endocrine dysfunction more often than the general population. This effect is probably independent of treatment and is due to the seizures themselves . According to the hypothesis of Herzog , changes in levels of both FSH and LH can be caused by seizure discharges from the limbic lobe, particularly the amygdala. The amygdala has direct connections with the ventromedial hypothalamus via the stria terminalis. Stimulation of the hypothalamus by both seizures and interictal discharges causes changes in the levels of secreted gonadotrophic releasing factors . In turn, this alters the levels of both LH and FSH, which can cause both polycystic ovarian syndrome and hypothalamic amenorrhea. Both of these conditions are found in increased numbers in women with epilepsy, even if untreated. It has been estimated that one-third of the menstrual cycles in women with epilepsy are anovulatory . Women with polycystic ovarian syndrome and hypothalamic amenorrhea have a reduction in progesterone as well as an increase in androgens. These alterations can alter the ratio of estrogen to progesterone (less progesterone) which may increase seizure discharges in the temporal lobe ( Figure 6.1 ) . It is likely that a positive feedback loop is created where seizures worsen the reproductive dysfunction and this in turn worsens the seizures .

Possible mechanisms by which limbic seizure discharges promote reproductive endocrine disorders and how hormonal reproductive hormone levels can influence epilepsy.

Source: Adapted from Herzog AG et al. Reproductive Endocrine Disorders in Men With Partial Seizures of Temporal Lobe Origin. Arch Neurol 1986;43: 347–350, with permission from American Medical Association.

Antiepileptic drugs can interfere with normal endocrine function but it is unlikely that they are a direct cause. Some animal studies have failed to show structural changes in the ovaries in animals exposed to valproate that did not have epilepsy . In contrast, the studies of Isojarvi showed a high incidence of polycystic ovarian syndrome in women who used valproate. The incidence was higher than in women with epilepsy who took other antiepileptic drugs and also higher among women who had started valproate before 20 years of age . Evidence suggests that there is an interaction between valproate and epilepsy in women that produces reproductive dysfunction in women. Studies of women taking valproate for bipolar disorder find a lower rate of polycystic ovarian syndrome than in women taking valproate for epilepsy . As an enzyme inhibitor, valproate can inhibit the conversion of testosterone to estradiol, leading to increased androgen levels that are part of the reproductive dysfunction in women with polycystic ovarian syndrome . It is noted that evaluation of women with bipolar disorder has shown that this population also has a higher incidence of reproductive endocrine dysfunction that makes interpretation of data including the treatment with valproate difficult. Herzog has suggested that enzyme-inducing antiepileptic drugs may promote the metabolism of testosterone and thus minimize the effects of epileptic seizures on reproductive function . This of course is in addition to the effect of reducing seizures which also would reduce the incidence of polycystic ovarian syndrome. An effective way to block the effects of valproate in promoting polycystic ovarian syndrome in women with epilepsy has not yet been found. In addition, the question of whether valproic acid produces the same degree of reproductive endocrine dysfunction in women whose seizures are very well controlled has not clearly been answered.

Libido is reduced in women with epilepsy. Studies suggest that one-third of women with epilepsy experience sexual dysfunction . There have been few studies that directly address this problem. While most of the evidence for this has been collected by self-report, studies over many years show fairly consistent results in women which contrasts with reporting of sexual dysfunction in men. The incidence of sexual dysfunction in men is estimated at 20%, which is a significantly lower number than previously reported. Some of the discrepancy may ultimately have to do with methods of data collection . In women with temporal lobe epilepsy, sexual dysfunction more often is associated with right-sided lesions as opposed to left-sided lesions . This finding suggests that the problem involves more than the common finding of depression in patients with epilepsy which can produce sexual dysfunction on its own. It appears that lesions of the amygdala and hippocampus can lead to problems with sexuality. Connections from the amygdala to the hypothalamus may play a significant role. It appears that seizures themselves play the major role, as several studies have shown that women with epilepsy had no sexual dysfunction before the onset of the seizures .

Contraception and Epilepsy

Seizures do not appear to have any significant effect on the effectiveness of birth control, but antiepileptic medications clearly reduce the effectiveness of oral contraceptive pills. According to a recent survey, many physicians are not knowledgeable about this problem, even if they had patients that had experienced oral contraceptive failure . The failure rate for standard oral contraceptive pills is estimated at 0.7 per 100 years in the general population and 3.1 per 100 years in women taking antiepileptic drugs . With the more recent, low-estrogen birth control pills, popular because they reduce side effects, the rate of failure is almost certainly higher. In 1998, the American Academy of Neurology recommended an estradiol dose of 50 μg for 21 days for patients using enzyme-inducing antiepileptic drugs . The original formulation of oral contraceptive pills was 80 μg of estrogen with 1 mg of progestin . It appears that 50 μg of estradiol is inadequate and there are more failures than was initially thought.

The main hepatic system that processes the steroid sex hormones is the P-450 system. Many antiepileptic drugs induce this system ( Table 6.1 ). There is also likely an increase in sex steroid hormone conjugation in the intestinal tract. The result of reducing levels of these hormones is failure to prevent ovulation. Crawford finds that 10% of women have unregulated cycles on low-dose estrogen oral contraceptives . It should be noted that lack of breakthrough bleeding does not guarantee that the birth control is effective . In view of this, it is recommended that a higher dose of estradiol be considered (≫50 μg for 21 days) and barrier methods also should be employed. Other methods such as subdermal levonorgestrel (Norplant) and intramuscular medroxyprogesterone are other options, but there is an increase in failure to prevent pregnancy with these methods as well in women taking antiepileptic drugs . Whether these methods are more successful and safer for women with epilepsy wishing to avoid pregnancy has not yet been determined.

While there are more side effects with higher-dose oral contraceptives that make the newer, lower-dose formulations popular, there also is an effect on antiepileptic drugs. In particular, lamotrigine has been shown to have its levels reduced by oral contraceptive pills. One study showed a 50% reduction in lamotrigine levels after the introduction of birth control . Another study showed a 100% increase in lamotrigine levels during the pill-free period . The mechanism appears to be that oral contraceptive pills increase glucuronidation in the liver, which is the main metabolic pathway for elimination of lamotrigine and several other antiepileptic drugs . Lowering serum anticonvulsant levels by increasing the dose of oral contraceptive pills can increase the risk of breakthrough seizures, but the risk may be overstated . Fortunately, if the problem is anticipated, careful monitoring of serum anticonvulsant levels can allow for adjustment in dosage.

The Effect of Pregnancy on Epilepsy

There are a number of factors that can affect seizure frequency in women with epilepsy who are pregnant. The major factors are hormonal changes that accompany the pregnant state, changes in behavior, and changes in metabolism that alter the concentrations of antiepileptic drugs. These will be discussed separately.

Perhaps one-third of women with epilepsy will have an increase in seizures during pregnancy. Ten to twenty percent will have a decrease in seizure frequency. A small number of women will have one or two seizures during pregnancy and never have them at any other time in their life . The majority of women with epilepsy will not have their seizure frequency altered . Studies show that changes in seizure frequency do not depend on the seizure type, age of the mother, duration of epilepsy, or the number of seizures that occurred in a previous pregnancy . In general, it is believed that most seizures will occur toward the end of the pregnancy; however, one-third of seizures can occur in the first trimester . A small percentage of women will have a permanent increase in their seizure frequency following pregnancy . A recent evaluation of previous studies found no clear evidence to state if seizures were increased or decreased in general in pregnant women with epilepsy. For now, women must be treated on a case-by-case basis. The only clear recommendation is that if a woman’s seizures are well controlled for a year before pregnancy, there is a 90% chance this will remain during the pregnancy .

Maintenance of the placenta requires major changes in the levels of hormones. Estrogens and progesterone increase by 10 times their normal levels during pregnancy. The relationship between these hormones and epilepsy has been fairly well delineated. Estrogens are pro-convulsant in both animal models and human studies while progesterone appears to increase seizure threshold, making seizures less likely . There are several mechanisms for estrogen to decrease seizure threshold. It can increase activity at both N -methyl- d -aspartate (NMDA) and non-NMDA glutamate receptors . In the hippocampus, the density of dendritic spines increases in neurons exposed to estrogen. Specifically these are NMDA synapses and the net effect appears to be an increase of excitability . Finally, estrogens affect the expression of neurotransmitters in neurons that contain estrogen receptors (highly concentrated in the amygdala) . Progesterone seems to have the exact opposite effect as estrogen on neurons . The effects of estrogen and progesterone begin with menarche. Some previous epidemiologic studies have not been able to show a clear increase in seizures at the time of puberty for women although this has long been suspected. The data on seizure onset and seizure exacerbation related to menarche has been difficult to interpret for a number of reasons. The process of sexual maturation occurs over many years making it difficult to pinpoint a particular vulnerable time. Some epilepsies that have a genetic origin (absence epilepsy) remit during puberty, masking both the incidence of new-onset seizures in the general population or recurrence of previously controlled seizures. Several studies however show that there is an increase in seizure frequency with menarche . This appears to be more likely with focal epilepsies. The changes in puberty correlate to rises in hormone levels. Initially there is an increase in the levels of dihydroepiandrosterone sulfate (DHEAS) followed by an increase in estrogens roughly 2 years later. The increase in progesterone levels does not occur until ovulation begins, usually 2–4 years after the increase in estrogen levels . While women during puberty are exposed to high levels of estrogen for a prolonged period, there is no clear data that this fact alone produces epilepsy. Instead, the high estrogen levels may act as a second injury that leads to the development of seizures. Because most focal epilepsy is the result of some type of cerebral insult, it may explain why focal epilepsy is more likely than primary generalized epilepsy to be exacerbated by menarche. This is the “two-hit hypothesis” described by Dichter in 1997 . This possible effect is elegantly demonstrated in animal studies. Female rats castrated before puberty have a lower incidence of seizures than the general population and there is no effect if castration is performed after puberty . More evidence for the effects of sex hormones on seizure frequency is provided by studies on catamenial epilepsy. Herzog suggests that if the baseline seizure frequency doubles during a woman’s menstrual cycle (the phase may differ), this qualifies as catamenial epilepsy. Perhaps one-third of women will fit this definition. What appears to be significant is not the absolute levels of estrogen and progesterone, both of which rise at different times during the menstrual cycle, but their ratio. In spite of all this information, little is known about the direct effect of increased hormone levels during pregnancy on seizures. Ramsey did not find any association between seizure frequency and levels of estrogen, progesterone, or their ratios . In most cases, the effects of increased hormone levels do not translate into more seizures. At this point, there are no practical recommendations regarding management of hormone levels for the purpose of treating seizures.

There are nonhormonal factors that increase the likelihood of seizures during pregnancy. Sleep deprivation is known to be a potential trigger for epileptic seizures and is clearly occurs more frequently during pregnancy. There are physical discomforts that produce this including frequent urination, often at night, fetal movements, and general discomfort that occurs with pregnancy, particularly in the late stages. Stress and anxiety over the health of the infant, marital relationships which are altered during pregnancy, and changes in body image all contribute to anxiety and therefore, insomnia. Related to this is an increase in noncompliance with medication. Many pregnant women are concerned about the effects of antiepileptic medication on the fetus. Particularly if control of seizures is good, there is an increased likelihood that women will discontinue their antiepileptic medication.

A final consideration is the effects of pregnancy on metabolism of antiepileptic drugs. The metabolism of nearly every antiepileptic drug is increased resulting in lower blood levels if adjustments are not made ( Table 6.2 ). The effects of the various changes in maternal metabolism tend to occur after the first trimester but the effect on antiepileptic drug levels is unpredictable and depends on the drug being used. For example, highly protein-bound drugs are likely to have their levels altered whereas minimally protein-bound drugs will be little affected by changes in albumin levels. Many neurologists recommend monthly antiepileptic drug levels during pregnancy as changes in blood levels can occur rapidly . Appropriate adjustment for the desired levels can then be achieved. Highly protein-bound antiepileptic drugs should have free drug levels obtained, whereas minimally protein-bound drugs can have total levels obtained. Because the various changes in maternal metabolism do not have predictable results on drug levels except that the levels are nearly always reduced, no formula can be given for adjusting antiepileptic drug levels during pregnancy. Normal metabolism returns 2–3 months after delivery so antiepileptic drug doses have to be adjusted again to avoid overdosing. An exception to this is lamotrigine. Its metabolism returns back to normal within a few weeks requiring a more rapid adjustment (downward) of the dosage .

The Effects of Epilepsy on Pregnancy

There are a number of complications of pregnancy that are more common in women who have epilepsy. Issues regarding the fetus will be discussed further on. The chance for vaginal bleeding, hyperemesis, eclampsia, and placental abruption are all increased by double over the general population. There is an increased chance of preterm labor and cesarean section as well . Some of these effects are the direct result of seizures while others may be a combination of the effects of antiepileptic drugs and seizures. Maintaining seizure control is still the best way to prevent these complications.

Seizures can be a problem during labor and delivery. Generalized tonic–clonic seizures are particularly troublesome. They can produce acidosis and hypoxia in the mother with subsequent risk to the baby. The fetal heart rate can be lowered by a convulsive seizure, which probably contributes to statistics showing low Apgar scores and other evidence of hypoxia . Nonconvulsive seizures do not carry the same risks but may interfere with a woman’s ability to cooperate with a vaginal delivery . Fortunately, convulsive seizures are relatively rare during labor, occurring in only 1% of women who are in labor . These seizures carry with them the risk of stillbirth or developmental delay in the infant . Several factors can contribute to the timing of seizures at the time of delivery. Prolonged labor may be accompanied by sleep deprivation. Drug levels may be low during prolonged labor due to a combination of emesis and impaired absorption. Several studies have shown that most women who do have seizures during pregnancy have subtherapeutic levels of antiepileptic drugs . If patients are taking antiepileptic drugs with an intravenous formulation can be switched at an equivalent dose. Levels should be followed during prolonged labor. Seizures can be treated rapidly with benzodiazepines but with a potential risk of respiratory depression in the neonate. There are recent concerns about the use of older anticonvulsants that will cross into the fetal circulation, causing apoptotic cell death , but this is generally in the population of asphyxiated babies. There is no clear data on whether these drugs can cause this when given to a mother during labor. Newer antiepileptic drugs such as levetiracetam appear not to have this complication but there is little data on their use for seizures during labor. Women with generalized seizures during labor should be placed on the left side to reduce the chance of aspiration and increase uterine blood flow . They also should be treated with oxygen. The goal of treatment is to avoid convulsive status epilepticus. If the seizures cannot be managed, a cesarean section should be performed rapidly.

A number of antiepileptic drugs can cause vitamin K deficiency in the neonate by inhibiting its transport across the placenta . These drugs include phenobarbital, phenytoin, carbamazepine, ethosuximide, primidone, and diazepam . The newer antiepileptic drugs have not been studied. The potential hemorrhagic complications in the newborn can be serious with a 30% mortality reported . Women taking anticonvulsants that cause this problem should be treated with 10 mg/day of oral vitamin K beginning at 36 weeks of gestation. The newborn should receive 1 mg of intravenous or intramuscular vitamin K at the time of delivery . The mother should receive parenteral vitamin K if she has not been treated in the month preceding labor. If two of the vitamin K dependent coagulation factors in the neonate (II, VII, IX, or X) are below 5% of normal, then fresh frozen plasma should be given .

Eclampsia

Eclampsia and pre-eclampsia are disorders that occur only in pregnant women. Pre-eclampsia usually occurs during a woman’s first pregnancy. It is a disorder of multiple systems that includes hypertension, proteinuria, generalized edema, hypoalbuminemia, hemoconcentration, abnormalities of hepatic function which can include coagulopathy, and increased levels of urate . Eclampsia is one of several potential complications of this state and involves the development of seizures or unexplained coma in a patient with pre-eclampsia. Most cases occur after 28 weeks of gestation but this is not always the case. Eclampsia has been reported as early as 20 weeks of gestation with 1% of cases occurring even before then. It occurs most frequently antepartum but frequently occurs during labor . It can occur within 48 h after delivery and a few cases have been reported within 4 weeks after delivery. The estimated incidence of eclampsia in Europe and the United States is 1 in 2000 deliveries . Eclampsia is a serious condition with a mortality rate of 1.8–5% . The criteria for pre-eclampsia are listed in Table 6.3 .

The pathophysiology of pre-eclampsia is complex, but it appears to be related to the placenta as the symptoms resolve promptly after delivery. In a normal placenta, trophoblast cells invade the spiral arteries of the uterus and destroy the media of the arteries. This transforms relatively small, muscular arteries into large sinusoidal vessels that allow increased perfusion of the placenta . With pre-eclampsia, this process of trophoblast invasion of the spiral arteries is incomplete leaving the vessels with a relatively reduced diameter and thicker, more muscular walls than normal. This produces hypertension, a reduction of plasma volume, and hypoperfusion of all vital organs . Inadequate perfusion of the placenta due to the abnormal arteries causes abnormalities in the maternal vascular endothelium with the release of numerous mediators that have widespread effects on circulation in other tissues. This includes thromboxane, endothelin, and superoxide with reductions in nitric oxide and prostacyclin, which function as vasodilators. In addition to widespread vasospasm and activation of both platelets and the coagulation system, there is widespread endothelial dysfunction in the systemic circulation that results in renal dysfunction with increased vascular resistance and hypertension . Immune mechanisms may contribute as well . Finally, there is a certain degree of apoptosis involved in maintenance of normal placental function and it appears that this increases as the pregnancy progresses. If there is inadequate apoptosis it can cause a maternal immune response against the fetus. If there is excessive apoptosis this will damage the normal function of the placenta resulting in placental ischemia .

The exact pathogenesis of seizures in eclampsia remains uncertain. The most likely theory centers on abnormal cerebral circulation. It is noted that many of the symptoms of eclampsia and much of the imaging and pathologic data show a marked similarity to hypertensive encephalopathy. In hypertensive encephalopathy there is disruption of the blood–brain barrier in response to rapid, severe elevations in systemic blood pressure. The normal autoregulation of cerebral pressure is overcome and the increased pressure in the cerebral vessels causes breakdown of the blood–brain barrier. During pregnancy there may be changes that predispose cerebral arterioles to dilate at lower than normal pressures, making the brain more susceptible to hyperperfusion with rapid increases in cerebral blood pressure . It has been noted that brain imaging studies usually show abnormalities in the posterior white matter consistent with vasogenic cerebral edema. Pathologic studies of the brain in patients who died with eclampsia show petechial hemorrhages which tend to occur in the parieto-occipital and occipital lobes . The predilection for white matter changes appears related to the structure of this tissue. There is a matrix of glial cells traversed by myelinated fiber tracts and arteries, which is less dense than gray matter. This allows for accumulation of fluid in the extracellular space . White matter in the posterior parietal and occipital regions is supplied by the vertebrobasilar arterial system and this is less well supplied with adrenergic sympathetic input than the carotid system. This may explain why the posterior white matter is more affected in pre-eclampsia than the frontal and central white matter.

The treatment of seizures due to eclampsia has historically been with magnesium. This clearly reduces morbidity and mortality of both the infant and the mother . This has always puzzled neurologists as magnesium was not an anticonvulsant. EEG abnormalities during eclamptic seizures do not resolve with successful treatment with magnesium and often take a week to resolve . Magnesium is a potent vasodilator. It is felt that patients with leukoencephalopathy develop intense vasospasm with sudden, severe elevations in systemic blood pressure and this vasospasm can produce cerebral ischemia. Relief of this vasospasm may be the mechanism of action of magnesium in treating eclamptic seizures and the improvement in perfusion of the placenta may improve the outcome of the infant.

Eclampsia should be suspected in any pregnant woman with new-onset seizures. There is a considerable differential diagnosis for new-onset seizures during pregnancy listed in Table 6.4 . Many of the conditions listed can be caused by pre-eclampsia. An example would be a cerebral infarct caused by a venous thrombosis secondary to a hypercoagulable state, not uncommon in pregnancy and often seen in severe pre-eclampsia. Because the seizures with eclampsia are potentially life threatening, it is best to recognize pre-eclampsia early and try to prevent its complications. It should be noted that some women who experience seizures postpartum do not have signs of pre-eclampsia that precede eclampsia, so eclampsia must be considered for several weeks postpartum with new-onset seizures. There is evidence that there are markers that may predict pre-eclampsia. Fms-like tyrosine kinase-1 can bind both placental and vascular endothelial growth factor and may have a role in the pathogenesis. Increased levels can be a marker for pre-eclampsia. Urinary placental growth factor can be decreased and this finding also strongly predicts pre-eclapmsia . Careful monitoring of blood pressure and urine protein are routine in the management of pregnant women.

Table 6.4

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