Introduction
Background
Preeclampsia is defined as gestational blood pressure (BP) elevation with proteinuria that develops after 20 weeks' gestation. Preeclampsia is one of 4 major hypertensive disorders of pregnancy. The other 3 conditions that comprise these hypertensive complications of pregnancy include gestational hypertension, chronic hypertension, and chronic hypertension with superimposed preeclampsia. Preeclampsia occurs in 5-8% of pregnancies. Preeclampsia is a multisystem, heterogeneous disorder with early onset and late (term) presentations that result from failed placental vascular remodeling and maternal constitutional factors (genetic, environmental, and behavioral). Variability in the relative contribution of aberrant placental vascular remodeling and maternal factors determine the timing of onset, disease spectrum, and severity. Although its pathogenesis is incompletely understood, it is a major cause of maternal and neonatal morbidity and mortality.1
Eclampsia; the occurrence of seizures, coma, or both in the setting of preeclampsia; and hemolysis, elevated liver enzymes, and low platelets (HELLP) syndrome are manifestations of severe preeclampsia. The outcome for infants born to women with preeclampsia depends on the infant's gestational age and condition at delivery, the severity of the maternal hypertensive disease, end-organ involvement, and any other associated comorbid maternal conditions. Preterm birth is more common among pregnancies complicated by preeclampsia, which accounts for as many as 15% of preterm deliveries.
As the understanding of the hypertensive disorders of pregnancy has evolved, the term pregnancy-induced hypertension (PIH) is no longer recommended to describe preeclampsia.2,3,4
Although preeclampsia is primarily a disease of primigravidas, multiple clinical risk factors that increase the predisposition to develop this disease have been identified. Risk factors include black race, past obstetric history, genetic predisposition, maternal obesity, blood pressure at the initiation of pregnancy, multifetal gestation, advanced maternal age, age younger than 18 years, and preexisting vascular insufficiency, insulin resistance, or thrombophilia.5,6,7,8 Emerging information suggests a link between maternal low birth weight (<5%) and the development of preeclampsia before 34 weeks' gestation and the existence of a strong relationship between preeclampsia and intrauterine growth restriction. The risk for later cardiovascular disease among women who develop preeclampsia is increased. Fetal outcomes include stillbirth, intrauterine growth restriction, low birth weight, and prematurity.
Pathophysiology
Current concepts regarding the pathophysiology of preeclampsia recognize that preeclampsia is a multisystem disorder characterized by vasoconstriction, metabolic changes, endothelial dysfunction, and activation of the coagulation cascade in conjunction with an inflammatory response. A 2-stage model of preeclampsia has been proposed in which failure of placental vascular remodeling results in reduced placental perfusion and initiates a cascade of events that result in serious maternal illness with the potential for significant perinatal morbidity and death.9,10
Release of various placental factors in response to placental ischemia alter blood flow and arterial pressure regulation causing impaired vascular endothelial function. Women with underlying microvascular disease, such as diabetes, hypertension, and collagen vascular disease, have a higher incidence of preeclampsia. Investigation into the pathogenesis of preeclampsia has revealed a strong relationship between preeclampsia and intrauterine growth restriction. Thus, preeclampsia may encompass more than one disease; women who experience a pregnancy complicated by fetal growth restriction without associated hypertension are more likely to have a subsequent pregnancy affected by preeclampsia.11,12
Normal placental development involves progressive loss of the musculoelastic tissue in the spiral arteries that feed the intervillous space vessels. This causes a nearly 25% increase in uterine blood flow during the first trimester. The process of placental spiral artery remodeling is typically completed by 18-20 weeks' gestation. Endothelium-derived relaxing and contracting factors have an important regulatory role in maintaining vascular resistance and blood pressure. An imbalance between factors promoting angiogenesis (vascular endothelial growth factor [VEGF], placental growth factor [PlGF]) and antagonizing factors (such as soluble fms-like tyrosine kinase 1 [sFlt1] and soluble endoglin) has been proposed to have a major role in the pathogenesis of preeclampsia.13,14
Circulating sFlt1 levels have been found to be significantly elevated before the onset of clinical symptoms in women who develop preeclampsia. Placental growth factor has also been shown to significantly decrease mid pregnancy, concurrent with increasing sFlt1 levels. Excess soluble endoglin is released into the circulation of preeclamptic women and has been shown to exacerbate the vascular damage induced by sFlt1. In animal studies, this process results in the development of a HELLPlike syndrome and fetal growth restriction. Studies evaluating the use of the angiogenic molecules, sFlt1, soluble endoglin, and PlGF as a composite biomarker to identify women at risk for preeclampsia are ongoing.
In women at high risk for development of preeclampsia (and in infants who are small for gestational age or whose mothers have diabetes mellitus), this physiologic dilatation of the spiral arteries does not occur because the placental trophoblast cells do not invade the spiral arteries, resulting in maintenance of narrow vessels with resultant placental hypoperfusion and ischemia. In severe cases, not only do the spiral arteries maintain their muscular structure, but other pathologic changes also occur.3,10,15,16 Accumulation of fat-laden macrophages with fibrinoid necrosis (ie, acute atherosis), disruption of the basement membranes, platelet deposition, mural thrombi, and proliferation of intimal and smooth muscle cells all decrease the luminal diameter.
The narrowed and damaged spiral arteries become thrombosed, resulting in placental infarction and necrosis. Uteroplacental blood flow is then reduced by 50-75%. The anatomical reduction in blood flow may be complicated by vasospasm of the uteroplacental bed.
The primary defect in preeclampsia appears to originate at the maternal-fetal interface (the placenta). Decreased placental perfusion is thought to lead to fetoplacental ischemia. The ischemic placenta may produce circulating antiangiogenic factors that promote generalized maternal vascular endothelium dysfunction, leading to systemic manifestations of preeclampsia. Associated abnormalities in clotting and platelet function contribute to vasoconstriction and platelet adhesion and aggregation, as well as to the activation of coagulation factors that increase the risk of thromboembolic formation.
The primary feature of preeclampsia, development of hypertension, occurs when normally extreme vasodilatation does not occur. Although cardiac output increases 30-50%, the decreased peripheral vascular resistance (PVR) results in decreased BP, even in women with chronic hypertension. Women who develop preeclampsia experience an increase in PVR and alterations in vascular sensitivity to endogenous hormones (eg, angiotensin II, catecholamines, vasopressin). This increase in vascular reactivity to pressor hormones may be mediated, at least in part, through damage to vascular endothelial cells, disrupting the normal prostaglandin balance.
The normal expansion of blood volume by 50% that occurs with pregnancy is decreased by 15-20% in patients with preeclampsia. This is the result of diminished plasma volume, leading to the relative hemoconcentration observed in preeclampsia. The plasma volume abnormality involves a redistribution of extracellular fluid, such that interstitial fluid volume is increased while the plasma volume is decreased. The hematocrit increases as the severity of preeclampsia increases. Circulating blood volume is maintained by the increased vascular tone. Whether the vasospasm is the cause or effect of the vascular endothelial injury is not known. Regardless, this injury likely results in the microangiopathic hemolysis and disseminated intravascular coagulation that accompanies severe preeclampsia.
The increased circulating blood volume and cardiac output of normal pregnancy results in increased renal blood flow and glomerular filtration rates (GFRs). Women with preeclampsia have markedly decreased renal blood flow and GFRs.9 Renal biopsies of these women show a constellation of lesions, termed glomerular capillary endotheliosis. Some consider glomerular capillary endothelial swelling that is accompanied by deposits of fibrinogen degradation products within and under the endothelial cells as pathognomonic of the disease. The presence of proteinuria differentiates preeclampsia from gestational hypertension. The degree of proteinuria widely varies. Protein excretion in excess of 300 mg in a 24-h urine collection or 1+ protein or greater on 2 random urine samples (collected at least 4 h apart) is required to meet this criterion.{Ref1}3,17,18 These lesions resolve within a month of delivery.
Frequency
United States
Hypertensive disorders affect 12-22% of pregnancies; 70% of these pregnancies are hypertensive secondary to preeclampsia or the preeclampsia-eclampsia syndrome. Preeclampsia is primarily a disease of primigravidas.1,3 The disease is mild in 75% of cases. HELLP syndrome develops in as many as 10% of pregnancies with severe preeclampsia. Eclampsia, which manifests as seizures in conjunction with headache and visual disturbances, occurs in approximately 5 per 10,000 live births.
The recurrence rate of preeclampsia in future pregnancies varies based on the prior obstetric history. Women who were normotensive in their first pregnancy are at lowest risk. Among women who experienced uncomplicated hypertension during their first pregnancy, the risk of preeclampsia during the second pregnancy is reported to be 5-7%. Pregnancy complicated by early severe preeclampsia increases the recurrence risk to 60-80%.12,19,20
The frequency of preeclampsia complicating pregnancy is further influenced by genetic factors, with studies reporting higher rates of preeclampsia among primiparous siblings.5,7,20,21 Paternal genes may also have a role in abnormal placentation and the genesis of preeclampsia.
International
Hypertensive disorders of pregnancy are a major contributor to maternal mortality and morbidity worldwide. Prevalence rates vary based on the country's developmental status and geographic location. Among developed countries, hypertensive disorders of pregnancy are responsible for 16% of maternal deaths.
A World Health Organization (WHO) analysis reveals that hypertensive disorders complicate 15% of pregnancies and are the leading cause of maternal death in Latin America and the Caribbean (25.7%), as well as a major contributor to maternal death in Africa (9.1%) and Asia (9.1%).22 Although the exact prevalence is unknown, approximately 2-4% of pregnancies (4 million women) are estimated to be complicated by preeclampsia annually; 2% of these women develop eclampsia.
Among nulliparous women, the incidence of preeclampsia is reported to be 5-7%. In the United Kingdom, 15% of maternal deaths are related to preeclampsia-eclampsia syndrome. Approximately 80% of the world's cases preeclampsia are late onset. High rates of neonatal mortality are reported in the remaining pregnancies complicated by early-onset preeclampsia (11.5%) and eclampsia (30%).
Mortality/Morbidity
Maternal morbidity
Maternal morbidity includes severe bleeding from placental abruption, coagulopathy, pulmonary edema, acute renal failure, cerebral hemorrhage, liver rupture, and retinal detachment.1,2,4,23
Eclampsia represents one of several clinical manifestations of severe preeclampsia and may manifest as early as the second trimester. The reported incidence is 4-5 per 10,000 live births. The risk of occurrence is 4-fold higher in women with severe preeclampsia than in women with mild preeclamptic disease. Eclampsia is more common among nonwhite primiparous women with low socioeconomic status. Peak incidences occur among young women in their teens and early third decade of life and in women with advanced maternal age (>35 y). The reported maternal mortality rate is 2-4% in eclampsia or when HELLP syndrome complicates preeclampsia. It rises to 10% in patients with pulmonary edema. Whether HELLP syndrome is solely a manifestation of severe preeclampsia or if it actually represents a separate microangiopathic disorder remains controversial.
Fetal and infant mortality and morbidity
The fetal morbidity and mortality rates are increased in the presence of preeclampsia, which is the result of prolonged uteroplacental insufficiency, the risk of placental abruption, declining maternal health, and the frequent need for premature delivery. Worsening maternal condition or the inability of the fetus to tolerate the in utero environment may necessitate preterm delivery.
Delivery before 37 weeks' gestation has increased 3-fold in the past 3 decades, leading to a significant decrease in stillbirth and a dramatic increase in late preterm infant births.21,24 Fetal growth restriction imposes an additional risk to the infant. Eclampsia and HELLP syndrome develop prior to 37 weeks' gestation in approximately 50% and 80% of cases, respectively. Perinatal death is commonly due to prematurity, growth restriction, placental abruption, and intrauterine asphyxia.
Intrauterine growth restriction is usually disproportionate or asymmetric because head growth and length are closer to what is expected than weight. In these cases, fetal growth is restricted because of malnutrition rather than decreased growth potential.
The sparing of head growth is thought to result from circulatory changes in the fetus that redistribute blood flow to the brain and heart. Although nutritional constraints on growth are unusual before the 24 weeks' gestation, severe reductions in uteroplacental blood flow may affect head growth. This is observed most commonly in patients with class D diabetes but may occur in severe preeclampsia or when preeclampsia complicates other maternal conditions (eg, systemic lupus erythematosus).
The incidence and severity of fetal growth restriction increases as maternal plasma volume decreases. How this inequity in plasma and interstitial volume correlates with fetal growth is not known.
Preterm, growth restricted infants born to mothers with evidence of placental insufficiency are at increased risk for necrotizing enterocolitis (NEC). Infants experiencing fetal absent or reversed end diastolic blood flow in the umbilical artery exhibit persistent abnormalities in splanchnic blood flow that contribute to feeding intolerance and NEC risk.25,26,27
Risk of later cardiovascular disease
Epidemiological studies indicate differences in recurrence rates and later risks for cardiovascular disease. The earlier the onset of preeclampsia, the greater the risk for cardiovascular death among affected women. Preeclampsia recurs in approximately 60% of women experiencing early onset preeclampsia, whereas preeclampsia is reported to recur in only 10-20% of subsequent pregnancies affected by late-onset preeclampsia.12,20
Intergenerational effects
Studies have linked maternal low birth weight (<5%) with an increased risk of preeclampsia during their own pregnancies.28,29,30 The effect of the mother's own low birth weight was noted during both the first and second pregnancy. Earlier onset preeclampsia before 34 weeks' gestation is also 2-3 times more common among women who were born with weight less than the 5th percentile.11,12,31
Furthermore, approximately 50% of women born of pregnancies complicated by maternal hypertension were likely to develop preeclampsia during their first pregnancy. Whether these effects are attributable solely to a "fetal origin of adult disease" hypothesis or if shared genetic factors contribute to the development of both fetal growth restriction and preeclampsia is unknown. The latter hypothesis is supported by evidence that the occlusive changes in the spiral arteries likely caused by inadequate early fetal trophoblastic invasion occurs in both pregnancies complicated by preeclampsia and normotensive fetal growth restriction. Paternal birth weight has not been shown to influence the risk for preeclampsia in their pregnant partners.32
Race
Relating the frequency of preeclampsia to race is difficult. However, the spectrum of preeclampsia-eclampsia is observed more commonly in black women and is thought to be related to a higher prevalence of hypertensive disorders found in the black population. This is exaggerated by cases of preeclampsia in nulliparous women. Some studies note up to a 3-fold higher risk among black women, while other studies have not found an increased risk in black women.
Individual maternal and paternal genetic factors that appear to increase the risk for development of preeclampsia have been identified. These include conditions under which maternal fetal genotypic concordance changes, such as with differing paternity in multiparous pregnancies and paternal family history of preeclampsia. Genetic variations further influence susceptibility to preeclampsia and the other hypertensive disorders of pregnancy.
Data have shown that rates of preeclampsia are lower among Asians, with both maternity and paternity contributing to a lower rate of disease. Among the Hispanic population, results are more varied, in large part because of the diversity in racial and genetic makeup among women and men of Hispanic origin. Emerging data suggest that Hispanic women may be at an increased risk for preeclampsia (independent of confounding factors such as baseline BP, obesity, diabetes, and multiple gestation), although the risk for gestational hypertension appears to be low among Hispanic women who are not obese or hypertensive.
Sex
By definition, preeclampsia is a disease of pregnant women.
Age
Maternal age of younger 20 years and older than 35-40 years are among the clinical risk factors for the development of preeclampsia. The increased incidence of preeclampsia noted among patients older than 35 years probably reflects undiagnosed chronic hypertension with superimposed PIH.
Clinical
History
The onset of preeclampsia rarely occurs before 20 weeks' gestation. Hypertension is typically the first clinical sign that preeclampsia is developing. Most women typically experience gradual development of hypertension, proteinuria (>0.3 g protein in a 24-h urine specimen), and edema in the latter part of the third trimester. The clinical presentation includes sudden weight gain with the development of edema, particularly of the face and upper extremities.1,2
In women with preexisting chronic hypertension and proteinuria before 20 weeks' gestation, the preeclampsia can be diagnosed when the blood pressure (BP) is exacerbated BP (systolic >160 mm Hg or diastolic >110 mm Hg) during the last half of pregnancy or when proteinuria significantly increases.
Gestational hypertension is the occurrence of hypertension, typically mild, without proteinuria or other signs of preeclampsia, that develops in late pregnancy. It may be transient in nature, resolving by 12 weeks postpartum or may represent underlying chronic hypertension. Among women with the onset of gestational hypertension before 30 weeks' gestation, the risk for development of preeclampsia is increased.
The classic triad of hypertension (systolic BP >140 mm Hg or diastolic BP >90 mm Hg in a women who was previously normotensive prior to 20 weeks' gestation), proteinuria, and edema seems to result from suppression of the normal physiologic responses to pregnancy. Elements of increased BP, increased vascular permeability, disordered intravascular coagulation, and decreased perfusion of certain organs produce the clinical effects. Initiation of the disease requires only a placenta because cases of preeclampsia in women with molar pregnancies have been reported. Definitive treatment is the delivery of the placenta, although disease progression may occur for a time.
Preeclampsia renders kidneys highly susceptible to endothelial injury as a result of decreased renal blood flow and glomerular filtration rate (GFR). Pulmonary edema may also develop; its cause is felt to be multifactorial.
Hematological findings include abnormalities in clotting and platelet function. In severe preeclampsia, thrombocytopenia due to microthrombi formation and a mild consumptive coagulopathy are frequent findings.
Hemolysis, elevated liver enzymes, and low platelets (HELLP) syndrome may accompany severe cases of preeclampsia. In these patients, hepatic subcapsular hematomas may occur and result in life-threatening capsular rupture. Periportal hemorrhagic necrosis in the periphery of the liver lobule probably results in the elevation of liver enzymes and the site of hemorrhage. Once again, the endothelial damage is considered the underlying etiology.
CNS effects of headache, dizziness, tinnitus, altered mental status, visual changes, and seizures are thought to result from the increased vascular resistance and vasospasm of preeclampsia. Although total cerebral blood flow and cerebral oxygen metabolism generally are not altered in preeclampsia, regional changes certainly do occur. One third of patients who died from eclampsia experienced cerebral hemorrhages of varying degrees. The visual changes may result from vasospasm, ischemia, and hemorrhage in the occipital cortex, or from retinal artery spasm, edema, or retinal detachment.
Fetal consequences of preeclampsia vary with the time of onset and severity of maternal disease. Early onset and severe preeclampsia are important contributors to fetal growth restriction and preterm birth. The risk for abruptio placenta triples with the increasing severity of the maternal disease.
Physical
Preeclampsia is a disease of the pregnant woman.
Maternal findings upon examination may include edema, hypertension, retinal-vascular changes, hyperreflexia, and hepatic enlargement and tenderness. Severe preeclampsia may result in anasarca and disseminated intravascular coagulopathy (DIC) with purpura.
Infants who experienced fetal growth restriction exhibit variable effects on growth parameters, weight, length, and head circumference. The time of onset, severity of disease, and genetic, environmental, and behavioral factors, as well as the presence of underlying maternal vascular disease, influence the fetal growth processes. Oligohydramnios and abnormalities in Doppler studies of the umbilical artery and the fetal middle cerebral artery develop in the presence of severe disease.
Neonates born to mothers with preeclampsia may have low birth weight or be premature. Maternal treatment with magnesium sulfate may also confer generalized hypotonia on the newborn, with or without apnea or respiratory compromise.
Causes
The cause of preeclampsia has not been fully elucidated. Current evidence suggests an important role of reduced placental perfusion leading to maternal disease that is characterized in reduced systemic blood flow, endothelial dysfunction, and the potential for multiple organ injury.
A growing body of evidence supports a relationship between intrauterine growth restriction and preeclampsia. In both circumstances, remodeling of maternal myometrial and decidual vessels does not occur as in normal pregnancies. The speculation is that early-onset preeclampsia represents a different disease than preeclampsia at term because reduced placental perfusion may not be a significant component of the later disease.
More on Preeclampsia |
 Overview: Preeclampsia |
| Differential Diagnoses & Workup: Preeclampsia |
| Treatment & Medication: Preeclampsia |
| Follow-up: Preeclampsia |
| References |
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Further Reading
Keywords
preeclampsia, hypertensive disorders of pregnancy, gestational hypertension, hypertension of pregnancy, hypertension in pregnancy, pre-eclampsia, pregnancy-induced hypertension, PIH, hypertension, proteinuria, edema, high-risk pregnancy, complications of pregnancy, HELLP syndrome, stillbirth, intrauterine growth restriction, low birth weight, prematurity, diabetes, hypertension, collagen vascular disease, diabetes mellitus, necrotizing enterocolitis, obesity, diabetes, pulmonary edema, tinnitus, anasarca, disseminated intravascular coagulopathy, DIC, oligohydramnios
