Background
Ten percent of all pregnancies are complicated by hypertension. Eclampsia and preeclampsia account for about half of these cases worldwide, and these conditions have been recognized and described for years despite the general lack of understanding of the disease. [1, 2] In the fifth century, Hippocrates noted that headaches, convulsions, and drowsiness were ominous signs associated with pregnancy. In 1619, Varandaeus coined the term eclampsia in a treatise on gynecology. [3, 4]
Definition
Eclampsia, which is considered a complication of severe preeclampsia, is commonly defined as new onset of grand mal seizure activity and/or unexplained coma during pregnancy or postpartum in a woman with signs or symptoms of preeclampsia. [5, 6] It typically occurs during or after the 20th week of gestation or in the postpartum period. Nonetheless, eclampsia in the absence of hypertension with proteinuria has been demonstrated to occur in 38% of cases reported in the United Kingdom. [7] Similarly, hypertension was absent in 16% of cases reviewed in the United States. [5]
The clinical manifestations of maternal preeclampsia are hypertension and proteinuria with or without coexisting systemic abnormalities involving the kidneys, liver, or blood. There is also a fetal manifestation of preeclampsia involving fetal growth restriction, reduced amniotic fluid, and abnormal fetal oxygenation. [7] HELLP syndrome is a severe form of preeclampsia and involves hemolytic anemia, elevated liver function tests (LFTs), and low platelet count.
Most cases of eclampsia present in the third trimester of pregnancy, with about 80% of eclamptic seizures occurring intrapartum or within the first 48 hours following delivery. Rare cases have been reported before 20 weeks' gestation or as late as 23 days’ postpartum. Although there are numerous studies exploring ultrasound and biomarker prediction of patients at risk of preeclampsia, other than early detection of preeclampsia, no reliable test or symptom complex predicts the development of eclampsia. In developed countries, many reported cases have been classified as unpreventable. [8, 9, 10]
Course of eclamptic seizures
Eclampsia manifests as 1 seizure or more, with each seizure generally lasting 60-75 seconds. The patient’s face initially may become distorted, with protrusion of the eyes, and foaming at the mouth may occur. Respiration ceases for the duration of the seizure.
Eclamptic seizures may be divided into 2 phases. Phase 1 lasts 15-20 seconds and begins with facial twitching. The body becomes rigid, leading to generalized muscular contractions.
Phase 2 lasts about 60 seconds. It starts in the jaw, moves to the muscles of the face and eyelids, and then spreads throughout the body. The muscles begin alternating between contracting and relaxing in rapid sequence.
A coma or period of unconsciousness, lasting for a variable period, follows phase 2. After the coma phase, the patient may regain some consciousness, and she may become combative and very agitated. However, the patient will have no recollection of the seizure.
A period of hyperventilation occurs after the tonic-clonic seizure. This compensates for the respiratory and lactic acidosis that develops during the apneic phase.
Seizure-induced complications can include tongue biting, head trauma, broken bones, and aspiration.
Pathophysiology
Inhibition of uterovascular development
Many uterovascular changes occur when a woman is pregnant. It is believed that these changes are due to the interaction between fetal and maternal allografts and result in systemic and local vascular changes. It has been shown that in patients with eclampsia, the development of uteroplacental arteries is hindered.
Hindrance of cerebral blood flow regulation
It is believed that in eclampsia there is abnormal cerebral blood flow in the setting of extreme hypertension. The regulation of cerebral perfusion is inhibited, vessels become dilated with increased permeability, and cerebral edema occurs, resulting in ischemia and encephalopathy. With increasing blood pressure, cerebral autoregulation is impaired resulting in cerebral regions of ischemia as well as microhemorrhage, each of which may initiate a seizure focus. [11] In extreme hypertension, normal compensatory vasoconstriction may become defective. Several autopsy findings support this model and consistently reveal swelling and fibrinoid necrosis of vessel walls. [3]
Endothelial dysfunction
Factors associated with endothelial dysfunction have been shown to be increased in the systemic circulation of women suffering from eclampsia. These include the following [1] :
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Cellular fibronectin
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Von Willebrand factor
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Cell adhesion molecules (ie, P-selectin, vascular endothelial adhesion molecule-1 [VCAM-1]
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Intercellular adhesion molecule-1 [ICAM-1])
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Cytokines (ie, interleukin-6 [IL-6])
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Tumor necrosis factor-α [TNF-α]
In addition, it is believed that antiangiogenic factors, such as placental protein fms-like tyrosine kinase 1 (sFlt-1) and activin A, antagonize vascular endothelial growth factor (VEGF). [12] Elevated levels of these proteins cause a reduction of VEGF and induce systemic and local endothelial cell dysfunction. [1]
Leakage of proteins from the circulation and generalized edema are sequelae of the endothelial dysfunction and thus a defining factor associated with preeclampsia and eclampsia.
Oxidative stress
Evidence indicates that leptin molecules increase in the circulation of women with eclampsia, inducing oxidative stress, another factor in eclampsia, on cells. (The leptin increase also results in platelet aggregation, most likely contributing to the coagulopathy associated with eclampsia.) [3, 13]
Oxidative stress has been found to stimulate the production and secretion of the antiangiogenic factor activin A from placental and endothelial cells. [12] Studies in pregnant mouse models have proposed that there is a dysregulation in the reactive oxygen species (ROS) signaling pathway. [13, 14]
Studies also suggest that increased systemic leukocyte activity plays a role in the mediation of oxidative stress, inflammation, and endothelial cell dysfunction. Histochemistry studies indicate that there is predominantly an increase in neutrophil infiltration of vasculature in patients with eclampsia. [14]
Etiology
The mechanism(s) responsible for the development of eclampsia remain(s) unclear. [6] Genetic predisposition, immunology, endocrinology, nutrition, abnormal trophoblastic invasion, coagulation abnormalities, vascular endothelial damage, cardiovascular maladaptation, dietary deficiencies or excess, and infection have been proposed as etiologic factors for preeclampsia/eclampsia. [3] Imbalanced prostanoid production and increased plasma antiphospholipids have also been implicated in eclampsia. [3, 15] In murine models, placental ischemia appears to be associated with an increased susceptibility to seizures and cerebrospinal fluid (CSF) inflammation. [6]
Risk factors for eclampsia
The following are considered risk factors for eclampsia:
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Nulliparity
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Family history of preeclampsia, previous preeclampsia and eclampsia [3]
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Poor outcome of previous pregnancy, including intrauterine growth restriction, abruptio placentae, or fetal death
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Multifetal gestations, hydatid mole, fetal hydrops, primigravida
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Teen pregnancy
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Primigravida
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Patient older than 35 years
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Lower socioeconomic status
The following preexisting medical conditions are also considered risk factors [5] :
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Obesity
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Chronic hypertension
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Renal disease
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Thrombophilias-antiphospholipid antibody syndrome
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Protein C deficiency and protein S deficiency
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Antithrombin deficiency
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Vascular and connective tissue disorders
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Gestational diabetes
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Systemic lupus erythematosus
Multiorgan System Effects
Preeclampsia/eclampsia produces multiple systemic derangements that can involve a diversity of organ systems including hematologic, hepatic, renal, and cardiovascular systems as well as the central nervous system. The severity of these derangements often correlates with maternal medical (eg, preexisting renal or vascular pathology) or obstetric factors (eg, multifetal gestations or molar pregnancy).
Cardiovascular concerns
Eclampsia is associated with cardiovascular derangements such as generalized vasospasm, increased peripheral vascular resistance, and increased left ventricular stroke work index. Pulmonary capillary wedge pressure (PCWP) may vary from low to elevated. Importantly, central venous pressure (CVP) may not correlate with PCWP in patients with severe preeclampsia or eclampsia. [16]
A prospective observational study by Vaught that included 63 women with pre-eclampsia with severe features reported higher systolic pressure, higher rates of abnormal diastolic function, decreased global right ventricular longitudinal systolic strain, increased left-sided chamber remodeling, and higher rates of peripartum pulmonary edema in these women when compared with healthy pregnant women. [17]
Hematologic concerns
Hematologic problems associated with eclampsia can include decreased plasma volume, increased blood viscosity, hemoconcentration, and coagulopathy.
Renal concerns
Eclampsia-associated renal abnormalities can include decreases in glomerular filtration rate, renal plasma flow, and uric acid clearance as well as proteinuria.
Hepatic concerns
Hepatic derangements associated with eclampsia can include periportal necrosis, hepatocellular damage, and subcapsular hematoma.
Central nervous system concerns
Eclampsia can result in central nervous system (CNS) abnormalities such as cerebral overperfusion due to loss of autoregulation, cerebral edema, and cerebral hemorrhage.
Prognosis
Although the incidence of eclampsia has declined in recent years, mainly due to the improvement of healthcare, serious adverse outcomes still exist. [18] Five percent of patients with hypertension develop severe preeclampsia, and about 25% of women with eclampsia have hypertension in subsequent pregnancies. About 2% of women with eclampsia develop eclampsia with future pregnancies. [2]
Multiparous women with eclampsia have a higher risk for the development of essential hypertension; they also have a higher mortality rate in subsequent pregnancies than do primiparous women.
Maternal morbidity
Maternal complications from eclampsia include the following:
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Permanent CNS damage from recurrent seizures or intracranial bleeds
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Disseminated intravascular coagulopathy
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Renal insufficiency
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Pulmonary edema
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Cardiopulmonary arrest
The most significant maternal complication of eclampsia is permanent CNS damage secondary to recurrent seizures or intracranial bleeding. The maternal mortality rate is 8-36% in these cases. A loading dose of magnesium sulfate followed by maintenance doses for 12-24 hours may be effective in preventing recurrent seizures. [19]
Maternal mortality
Eclampsia and preeclampsia account for approximately 63,000 maternal deaths annually worldwide. [20] In developed countries, the maternal death rate is reportedly 0-1.8%. The perinatal mortality rate from eclampsia in the United States and Great Britain ranges from 5.6% to 11.8%. The maternal mortality rate is as high as 14% in developing countries. [7, 21, 22]
A study from the US Centers for Disease Control and Prevention (CDC) found an overall preeclampsia/eclampsia case-fatality rate of 6.4 per 10,000 cases at delivery. The study also found a particularly high risk of maternal death at 20-28 weeks’ gestation. [23]
Black woman have twice the risk that White women have for mortality associated with preeclampsia/eclampsia. This is most likely due to inadequate access to prenatal care among Black women, as well as to increased incidences in Black women of genetic diseases associated with circulating antiphospholipids. It has been proven that patients with elevated antiphospholipid plasma levels have a higher incidence of preeclampsia and eclampsia. [3] However, whether this is due to the antiphospholipids themselves or to some other underlying process is not clear. [15]
A majority of women who suffer eclampsia-associated death have concurrent HELLP syndrome. [20]
An international study demonstrated that serious complications among patients with eclampsia (including maternal mortality) may be predicted by the use of a model that incorporates gestational age, chest pain or dyspnea, oxygen saturation, platelet count, and creatinine and aspartate transaminase concentrations. Although clinical use of the model awaits future validation, the identification of the predictive variables may aid in management decisions. [24]
Fetal/neonatal morbidity/mortality
Fetal bradycardia is associated with eclamptic seizures. A retrospective study reported fetal heart rate decelerations during 79% of intrapartum seizures, and the mean duration of bradycardia was 5.8 minutes. [25]
The fetal mortality rate varies from 13-30% due to premature delivery and its complications. Placental infarcts, abruptio placentae, intrauterine growth restriction, and fetal hypoxia also contribute to fetal demise. [3]
Complications
As many as 56% of patients with eclampsia may have transient deficits, including cortical blindness. Although earlier studies failed to demonstrate persistent neurologic deficits after uncomplicated eclamptic seizures, [22] a subsequent Swedish study found that patients with eclampsia have a 70% increased risk of developing a neurologic disorder during the years after a first pregnancy, including a fivefold increased risk of epilepsy. [26]
Additionally, the risk of cerebrovascular accidents (CVAs) and coronary artery disease (CAD) may be increased in eclamptic mothers later in life.
Other potential complications of eclampsia include the following:
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Permanent neurologic damage from recurrent seizures or intracranial bleeding
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Renal insufficiency and acute renal failure
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Fetal changes: Intrauterine growth restriction, abruptio placentae, oligohydramnios
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Hepatic damage and rarely hepatic rupture
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Hematologic compromise and disseminated intravascular coagulation (DIC)
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Increased risk of recurrent preeclampsia/eclampsia with subsequent pregnancy
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Maternal or fetal death: Eclampsia is associated with approximately 13% of maternal deaths worldwide [6]
Although some women who have had eclampsia or preeclampsia have reported subsequent cognitive difficulties even years later, a long-term follow-up study by Postma et al found no objective evidence of such problems. In this study, 46 women who had been eclamptic and 51 who had been preeclamptic were given neurocognitive tests an average of about 7 years after the index pregnancy; 48 controls, who had normotensive pregnancies, were also included. [27]
The eclamptic and preeclamptic women did not perform as well as the controls on motor-function tests or on the Hospital Anxiety and Depression Scale. However, they scored similarly to the control subjects with regard to attention, executive functioning, visual perception, and working and long-term memory. [27]
