All topics are updated as new evidence becomes available and our peer review process is complete.Literature review current through: Jun 2014. | This topic last updated: Apr 02, 2014.
INTRODUCTION — Preeclampsia is a multi-system disorder characterized by the new onset of hypertension and either proteinuria or end-organ dysfunction in the last half of
pregnancy (table 1). Although most affected pregnancies deliver at term or near term with good maternal and fetal outcomes, these pregnancies are at increased risk for maternal
and/or fetal mortality or serious morbidity [1,2].
DEFINITIONS OF PREGNANCY-RELATED HYPERTENSIVE DISORDERS — There are four major hypertensive disorders related to pregnancy [3,4]:
PREVALENCE — Preeclampsia occurs in up to 7.5 percent of pregnancies worldwide [5,6]. Variations in prevalence reflect, at least in part, differences in the maternal age
distribution and proportion of primiparous women among populations [2]. The prevalence of preeclampsia in the United States is about 3.4 percent, but 1.5-fold to 2-fold higher in
first pregnancies [7]. Late onset disease (≥34 weeks) is more prevalent than early onset disease (<34 weeks) (in one population-based study: 2.72 versus 0.38 percent,
respectively [8]).
BURDEN OF DISEASE — Women with preeclampsia are at an increased risk for life-threatening events, including placental abruption, acute renal failure, cerebral hemorrhage,
hepatic failure or rupture, pulmonary edema, disseminated intravascular coagulation, and progression to eclampsia. Worldwide, 10 to 15 percent of direct maternal deaths (ie,
resulting from obstetric complications of pregnancy) are associated with preeclampsia/eclampsia [9]. In the United States, preeclampsia/eclampsia is one of four leading causes
of maternal death, along with hemorrhage, cardiovascular conditions, and thromboembolism [10-12]. There is approximately one maternal death due to preeclampsia-eclampsia
per 100,000 live births, with a case-fatality rate of 6.4 deaths per 10,000 cases [13,14]. In the Netherlands between 1993 and 2005, preeclampsia was the most common cause of
maternal death, with 3.5 maternal deaths per 100,000 live births [15]. (See "Overview of maternal mortality".)
Morbidity and mortality are also increased for the fetus/neonate because of the greater risk of restricted fetal growth and preterm birth in affected pregnancies.
RISK FACTORS — Risk factors for preeclampsia are listed in the table (table 4). The magnitude of risk depends upon the specific factor and is described below for selected risk
factors evaluated in a systematic review of controlled studies [16].
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Preeclampsia — Preeclampsia refers to the new onset of hypertension and either proteinuria or end-organ dysfunction after 20 weeks of gestation in a previously
normotensive woman (table 1). Severe hypertension and signs/symptoms of end-organ injury are considered the severe spectrum of the disease (table 2) [4]. In 2013, the
American College of Obstetricians and Gynecologists removed proteinuria as an essential criterion for diagnosis of preeclampsia. They also removed massive proteinuria (5
grams/24 hours) and fetal growth restriction as possible features of severe disease because massive proteinuria has a poor correlation with outcome and fetal growth
restriction is managed similarly whether or not preeclampsia is diagnosed [4]. Oliguria was also removed as a characteristic of severe disease.
Eclampsia refers to the development of grand mal seizures in a woman with preeclampsia, in the absence of other neurologic conditions that could account for the seizure.
(See "Eclampsia".)
HELLP syndrome (Hemolysis, Elevated Liver enzymes, Low Platelets) probably represents a severe form of preeclampsia, but this relationship remains controversial; HELLP
may be an independent disorder. As many as 15 to 20 percent of affected patients do not have concurrent hypertension or proteinuria, leading some experts to believe that
HELLP syndrome is a separate disorder from preeclampsia. (See "HELLP syndrome".)
●
Chronic/preexisting hypertension — Chronic/preexisting hypertension is defined as systolic pressure ≥140 mmHg and/or diastolic pressure ≥90 mmHg that antedates
pregnancy or is present before the 20th week of pregnancy (on at least two occasions) or persists longer than 12 weeks postpartum. It can be primary (primary hypertension,
formerly called “essential hypertension”) or secondary to a variety of medical disorders. (See "Overview of hypertension in adults".)
●
Preeclampsia superimposed upon chronic/preexisting hypertension — Superimposed preeclampsia is defined by the new onset of either proteinuria or end-organ
dysfunction after 20 weeks of gestation in a woman with chronic/preexisting hypertension. For women with chronic/preexisting hypertension who have proteinuria prior to or in
early pregnancy, superimposed preeclampsia is defined by worsening or resistant hypertension (especially acutely) in the last half of pregnancy or development of
signs/symptoms of the severe spectrum of the disease (table 2).
●
Gestational hypertension — During pregnancy, gestational hypertension refers to hypertension without proteinuria or other signs/symptoms of preeclampsia that develops
after 20 weeks of gestation (table 3). It should resolve by 12 weeks postpartum. If hypertension persists beyond 12 weeks postpartum, the diagnosis is revised to
chronic/preexisting hypertension that was masked by the physiologic decrease in blood pressure that occurs in early pregnancy. If hypertension resolves postpartum, the
diagnosis is revised to transient hypertension of pregnancy. (See "Gestational hypertension".)
●
A past history of preeclampsia increases the risk of developing preeclampsia in a subsequent pregnancy seven-fold compared to women without this history (RR 7.19,
95% CI 5.85-8.83) [16].
The severity of preeclampsia strongly impacts this risk. Women with severe features of preeclampsia in the second trimester are at greatest risk of developing preeclampsia
in a subsequent pregnancy: rates of 25 to 65 percent have been reported [17-20]. By comparison, women without severe features of preeclampsia in their first pregnancy
develop preeclampsia in 5 to 7 percent of second pregnancies [21,22]. Women who had a normotensive first delivery develop preeclampsia in less than 1 percent of second
pregnancies.
●
First pregnancy (nulliparity) (RR 2.91, 95% CI 1.28-6.61) [16]. It is unclear why the primigravid state is a significant predisposing factor. One theory is that these women
may have had limited recent exposure to paternal antigens, which may play a role in the pathogenesis of the disease.
●
A family history of preeclampsia in a first degree relative (RR 2.90, 95% CI 1.70-4.93) [16], suggesting a heritable mechanism in some cases [23,24]. The father of the
baby may contribute to the increased risk, as the paternal contribution to fetal genes may have a role in defective placentation and subsequent preeclampsia. (See
"Pathogenesis of preeclampsia", section on 'Genetic factors'.)
●
Preexisting medical conditions:●
Pregestational diabetes (RR 3.56, 95% CI 2.54-4.99) [16], an effect that is probably related to a variety of factors, such as underlying renal or vascular disease, high
plasma insulin levels/insulin resistance, and abnormal lipid metabolism [25]. (See "Pregnancy risks in women with type 1 and type 2 diabetes mellitus" and
"Prepregnancy evaluation and management of women with type 1 or type 2 diabetes mellitus".)
•
Blood pressure ≥130/80 mm Hg at the first prenatal visit (RR 1.38-2.37) [16]. The risk of superimposed preeclampsia is highest in women with diastolic blood
pressure ≥110 mm Hg (RR 5.2) and ≥100 mm Hg (RR 3.2) before 20 weeks of gestation.
•
Antiphospholipid antibodies (RR 9.72, 95% CI 4.34-21.75) [16]. (See "Pregnancy in women with antiphospholipid syndrome".)•
Body mass index ≥26.1 (RR 2.47, 95% CI 1.66-3.67) [16]. (See "The impact of obesity on female fertility and pregnancy", section on 'Pregnancy associated
hypertension'.)
•
Chronic kidney disease (CKD) (relative risk varies depending on the degree of reduction of glomerular filtration rate [GFR] and the presence or absence of
hypertension). In women with advanced CKD (stages 3, 4, 5), as many as 40 to 60 percent may be diagnosed with preeclampsia [26,27].
Of note, women who smoke cigarettes have a lower risk of preeclampsia than nonsmokers. (See "Smoking and pregnancy", section on 'Preeclampsia'.)
OVERVIEW OF PATHOPHYSIOLOGY — The pathophysiology of preeclampsia likely involves both maternal and fetal/placental factors. Abnormalities in the development of the
placental vasculature early in pregnancy, weeks to months before development of clinical manifestations of the disease, are well-documented [29,30]. These abnormalities can
result in placental underperfusion, and possibly hypoxia and ischemia. Observational data support the hypothesis that placental underperfusion, hypoxia, and/or ischemia may
lead to release of circulating antiangiogenic factors (soluble fms–like tyrosine kinase [sFlt-1], soluble endoglin [sEng]) and other substances that can cause widespread maternal
systemic endothelial dysfunction (increased vascular permeability, vasoconstriction, activation of coagulation system, microangiopathic hemolysis), resulting in hypertension,
proteinuria, and the other clinical manifestations of preeclampsia [31]. The severity of the disease is influenced primarily by maternal and pregnancy-specific factors, but paternal
and environmental factors may also play a role [32]. (See "Pathogenesis of preeclampsia".)
CLINICAL MANIFESTATIONS
Clinical presentation — The new development of hypertension and either proteinuria or end-organ dysfunction after 20 weeks of gestation is usually due to preeclampsia,
particularly in a nulliparous woman. In most women, these findings first become apparent after 34 weeks of gestation, including when the woman is in labor (ie, “late onset
preeclampsia”) [33,34]. In about 10 percent of women, preeclampsia develops before 34 weeks of gestation (ie, “early onset preeclampsia”) [33], and in about 5 percent,
preeclampsia is first recognized postpartum (ie, “postpartum preeclampsia”), usually within 48 hours of delivery [35-37].
The degree of maternal hypertension and proteinuria, and the presence/absence of other clinical manifestations of the disease are highly variable [38]. Most patients have blood
pressures between 140/90 and 160/110 mm Hg and proteinuria usually accompanied by peripheral edema. About 25 percent develop one or more of the following nonspecific
findings, which indicate the presence of severe disease and the need to consider urgent delivery:
Signs and symptoms:
Laboratory abnormalities:
Atypical presentation — Atypical presentations include any of the following [37,39]:
Onset <20 weeks — Preeclampsia prior to 20 weeks of gestation is usually associated with a complete or partial molar pregnancy. (See "Gestational trophoblastic
disease: Epidemiology, clinical manifestations and diagnosis".) Rarely, characteristic signs and symptoms before 20 weeks have been attributed to severe preeclampsia after
other disorders with similar findings (eg, lupus nephritis, thrombotic thrombocytopenic purpura, hemolytic-uremic syndrome, antiphospholipid syndrome, acute fatty liver of
pregnancy) were excluded. (See 'Differential diagnosis' below.)
Hypertension or proteinuria (not both) — Hypertension or proteinuria (but not both) with characteristic signs and symptoms of severe preeclampsia is uncommon, but
may be observed in 15 percent of patients with HELLP syndrome and in some patients with eclampsia. (See "Eclampsia", section on 'Can eclampsia be predicted?' and "HELLP
syndrome".)
Women with hypertension or proteinuria (but not both) may go on to develop full diagnostic criteria for preeclampsia. No prospective studies have been performed in pregnant
women with isolated gestational proteinuria to determine their risk of developing preeclampsia later in pregnancy, and there are few retrospective studies. Between 15 and 25
percent of women with gestational hypertension subsequently develop preeclampsia. (See "Gestational hypertension", section on 'Risk of progression to preeclampsia'.)
Delayed postpartum onset or exacerbation of disease — Delayed postpartum preeclampsia can be defined as signs and symptoms of the disease leading to
readmission more than two days but less than six weeks after delivery [37], although various other definitions have been used. Signs and symptoms can be atypical; for example,
the patient may have thunderclap headaches alternating with mild headaches or intermittent hypertension. Risk factors for delayed postpartum preeclampsia appear to be similar
to those for preeclampsia during pregnancy [37,40,41], but some patients have no risk factors.
In a retrospective cohort study including 152 patients with delayed postpartum preeclampsia, 63.2 percent had no antecedent diagnosis of hypertensive disease in the current
pregnancy, whereas 18.4 percent had preeclampsia, 9.2 percent had chronic hypertension, 4.6 percent had gestational hypertension, and 4.6 percent had preeclampsia
superimposed on chronic hypertension during the peripartum period [37]. Of these patients, 14.5 percent developed postpartum eclampsia.
Course — Preeclampsia is a progressive disease. Although most women develop signs of the disease in late pregnancy with gradual worsening until delivery, in about 25 percent
of women, especially those with early onset preeclampsia, hypertension becomes severe and/or signs and symptoms of end-organ damage become apparent over a period of
days to weeks (table 2) [42]. Two percent of these women develop eclampsia.
Preeclampsia can be associated with serious maternal and/or fetal sequelae (eg, abruptio placentae; liver hematoma or rupture; disseminated intravascular coagulation; stroke;
need for mechanical ventilation, invasive hemodynamic monitoring, transfusion, or dialysis) [43,44]. It is important to note that severe sequelae can occur in women without severe
hypertension who have clinical evidence of significant end-organ dysfunction. Chest pain, dyspnea, and low platelet count appear to be particularly predictive of adverse outcome
[45].
Delivery of the placenta always results in complete resolution of signs and symptoms of the disease, with some symptoms disappearing in a matter of hours (eg, headache), while
others may take months (eg, proteinuria). Typically, mobilization of third-space fluid and diuresis begin within 48 hours of delivery. Hypertension may worsen during the first, and
occasionally the second, postpartum week, but normalizes in most women within four weeks postpartum [46]. Rarely, hypertension persists beyond three months. Proteinuria
usually begins to improve within a few days, however, in women with several grams of protein excretion, complete resolution may take weeks to months; a prolonged time to
complete resolution is more likely with severe disease [47]. Delayed postpartum onset or exacerbation of disease is atypical (see 'Delayed postpartum onset or exacerbation of
disease' above).
Clinical features and pathophysiology by organ system
Cardiopulmonary
Twin pregnancies (RR 2.93, 95% 2.04-4.21) [16]. The risk increases with increasing number of fetuses in multiple gestations: triplet pregnancy triples the risk of
preeclampsia compared with twin pregnancy.
●
Advanced maternal age (maternal age ≥40 RR 1.96, 95% CI 1.34-2.87 for multiparas and RR 1.68, 95% CI 1.23-2.29 for primiparas) [16]. Older women tend to have
additional risk factors, such as diabetes mellitus and chronic hypertension. Whether adolescents are at higher risk of preeclampsia is more controversial [28]; a systematic
review did not find an association [16]. (See "Effect of advanced age on fertility and pregnancy in women".)
●
Severe hypertension (systolic blood pressure ≥160 mm Hg or diastolic ≥110 mm Hg on two occasions at least four hours apart or only once if treated)●
Persistent and/or severe headache●
Visual abnormalities (scotomata, photophobia, blurred vision, or temporary blindness [rare])●
Hypertension — Hypertension is generally the earliest clinical finding of preeclampsia and is the most common clinical clue to the presence of the disease. The blood
pressure usually rises gradually, reaching the hypertensive range (≥140/90 mmHg) sometime in the third trimester, often after the 37th week of gestation [33]. However, in some
women, hypertension develops rapidly or before 34 weeks of gestation or postpartum. A systolic blood pressure of ≥160 mm Hg or diastolic blood pressure of ≥110 mm Hg on two
occasions at least four hours apart is a feature of severe disease [4].
Intravascular volume and edema — Intravascular volume may be reduced in preeclampsia with severe features. There is no evidence of underfilling of the arterial
circulation; rather, the reduced volume appears to be a consequence of vasoconstriction from enhanced responses to vasoactive substances. This issue has not been conclusively
resolved.
Edema in preeclampsia may be due to capillary leaking or represent "overfill" edema. Many pregnant women have edema, whether or not they have preeclampsia. However,
sudden and rapid weight gain (eg, >5 pounds/week) and facial edema are more common in women who develop preeclampsia, thus, these findings warrant evaluation for other
clinical manifestations of disease.
Cardiac function — Preeclampsia does not affect the myocardium directly, but the heart responds to physiological changes induced by preeclampsia. Left ventricular
ejection fraction usually remains within normal limits [48], but reductions in longitudinal, circumferential, and radial systolic strain have been observed [49]. The decrement in left
ventricular performance in women with preeclampsia has been attributed to a physiologic response to increased afterload [48-50], but other factors may play a role since systolic
strain was depressed in preeclamptic patients compared to pregnant women with nonproteinuric hypertension with similar resting blood pressure [49]. The high afterload in
preeclampsia is associated with elevated cardiac filling pressures, reflected by four-fold higher concentrations of natriuretic peptides in women with preeclampsia compared to
pregnant women who are normotensive or have chronic hypertension [51].
Severe preeclampsia can be associated with a highly variable hemodynamic profile [50-54]. A small subgroup of women with severe preeclampsia develops myocardial damage or
global diastolic dysfunction [55]. Troponin I levels should be obtained when clinically indicated, such as when the patient complains of chest pain suggestive of myocardial
ischemia or new electrocardiogram changes are observed [56,57]. Preeclampsia is not associated with elevated troponin levels in the absence of cardiac disease [58].
Pulmonary edema — The presence of pulmonary edema is a feature of the severe spectrum of the disease. The etiology of pulmonary edema in preeclampsia is
multifactorial [59-62]. Excessive elevation in pulmonary vascular hydrostatic pressure compared with plasma oncotic pressure may produce pulmonary edema in some women,
particularly in the postpartum period. However, not all preeclamptic patients with pulmonary edema demonstrate this phenomenon. Other causes of pulmonary edema are capillary
leak, left heart failure, and iatrogenic volume overload.
Renal — The kidney is the organ most likely to manifest endothelial injury related to preeclampsia.
Proteinuria — Proteinuria in preeclampsia is defined as ≥0.3 grams protein in a 24-hour urine specimen or persistent 1+ (30 mg/dL) on dipstick or a random
protein:creatinine ratio >0.3. Although proteinuria in women with preeclampsia is most often <5 g/day, preeclampsia remains the most common cause of severe proteinuria in
pregnant women; levels of proteinuria >10 g/day may be seen. [note: the urine protein concentration in a spot sample is measured in mg/dL and is divided by the urine creatinine
concentration also measured in mg/dL, yielding a dimensionless number that estimates the 24-hour protein excretion in grams per day (calculator 1) [63-71]. If SI units are desired
(mg/mmol), this value is multiplied by 1000 and divided by 8.8] (See "Proteinuria in pregnancy: Evaluation and management".)
Urinary protein excretion may be a late finding [72,73], but generally increases as preeclampsia progresses. It is due, in part, to impaired integrity of the glomerular barrier and
altered tubular handling of filtered proteins (hypofiltration) leading to increased protein excretion [74]. Both size and charge selectivity of the glomerular barrier are affected [75].
Using special studies, podocyturia (urinary excretion of podocytes) has been observed in patients with preeclampsia [76]. Urinary shedding of podocytes may indicate podocyte
loss from the glomerulus, which may lead to a disruption of the glomerular filtration barrier and consequent proteinuria. Deficient vascular endothelial growth factor (VEGF)
signaling appears to account, at least in part, for these effects. (See "Pathogenesis of preeclampsia", section on 'Pathogenesis of systemic endothelial dysfunction'.)
Renal function — Glomerular filtration rate (GFR) decreases by 30 to 40 percent in preeclampsia compared to pregnant normotensive controls; renal plasma flow also
decreases, but to a lesser degree. The plasma creatinine concentration is generally normal or only slightly elevated (1.0 to 1.5 mg/dL [88 to 133 micromol/L]). A creatinine >1.1
mg/dL or doubling of the creatinine concentration indicates severe disease and results from renal vasoconstriction and sodium retention due to reduced plasma volume and
systemic vasoconstriction. Urine output may decrease to <500 mL/24 hours. (See "Acute kidney injury (acute renal failure) in pregnancy", section on 'Preeclampsia'.)
Although hyperuricemia is associated with preeclampsia, serum uric acid level is a poor predictor of development of the disease or maternal and fetal complications in women with
preeclampsia [77,78].
Urine sediment — The urine sediment is typically benign.
Renal histology — The renal histologic changes described in women with preeclampsia who have had kidney biopsies, and in autopsy specimens obtained from women
who died of eclampsia, are termed ‘glomerular endotheliosis.’ Light and electron microscopy of glomerular endotheliosis show the following (picture 1A-C) [79]:
Foot process effacement is not a prominent feature, despite marked proteinuria.
Glomerular endotheliosis shares histologic features with non-preeclamptic thrombotic microangiopathies [79], except thrombi are rare in preeclampsia (although fibrin deposition
may be observed by immunofluorescence microscopy). Rarely, it may be present without proteinuria and in nonpregnant women [80,81].
Hematologic — The most common coagulation abnormality in preeclampsia is thrombocytopenia. Microangiopathic endothelial injury and activation result in formation of
platelet and fibrin thrombi in the microvasculature. Accelerated platelet consumption leads to thrombocytopenia; immune mechanisms may also play a role [82]. A platelet count
less than 100,000/microL upstages preeclampsia from mild to severe.
The prothrombin time, partial thromboplastin time, and fibrinogen concentration are not affected unless there are additional complications, such as abruptio placentae or severe
liver dysfunction [83].
Microangiopathic hemolysis may also occur and is detected by examination of a blood smear for schistocytes and helmet cells (picture 2A-B) or elevation in the serum lactate
dehydrogenase concentration. Hemoconcentration may result from reduction of plasma volume from capillary leaking. Hemolysis is associated with a low hematocrit, while
hemoconcentration is associated with a high hematocrit; when both hemolysis and reduced plasma volume are present, the effects on hematocrit may negate each other,
resulting in a normal value. (See "Thrombocytopenia in pregnancy" and "Pathogenesis of preeclampsia" and "Hematologic changes in pregnancy".)
The white blood cell count may be slightly higher due to neutrophilia [84].
Hepatic — Periportal and sinusoidal fibrin deposition and microvesicular fat deposition are histologic findings observed in the livers of preeclamptic women [85,86]. Reduced
hepatic blood flow can lead to ischemia and periportal hemorrhage. The clinical manifestations of hepatic dysfunction include right upper quadrant or epigastric pain, elevated
transaminase levels, coagulopathy, and, in the most severe cases, subcapsular hemorrhage or hepatic rupture. These hepatic changes upstage the preeclampsia from mild to
severe. Nausea and vomiting may occur.
Epigastric pain is one of the cardinal symptoms of severe preeclampsia. A review of this nonspecific symptom revealed that it is typically experienced as a severe constant pain
that begins at night, usually maximal in the low retrosternum or epigastrium, but may radiate to the right hypochondrium or back [87]. The pain is thought to be due to stretching
of Glisson’s capsule due to hepatic swelling or bleeding. It may be the only symptom on presentation, thus a high index of suspicion is important to make the diagnosis of
preeclampsia rather than gastroesophageal reflux, which is common in pregnant women, especially at night. The liver may be tender to palpation.
Rarely, transient diabetes insipidus has been reported in preeclampsia with hepatic dysfunction. (See "Renal and urinary tract physiology in normal pregnancy", section on 'DI
associated with hepatic dysfunction'.)
Acute pancreatitis is an even rarer complication of severe preeclampsia [88].
Central nervous system and eye — Central nervous system manifestations of preeclampsia include headache, visual symptoms, and generalized hyperreflexia; sustained
Headache in preeclampsia may be temporal, frontal, occipital, or diffuse [89,90]. It is usually a throbbing/pounding pain, but may be piercing pain. Although not pathognomonic, a
feature that suggests preeclampsia-related headache rather than another type of headache is that it persists despite administration of over-the-counter analgesics and it may
become severe (ie, incapacitating, "the worst headache of my life").
Visual symptoms are caused, at least in part, by constriction of retinal arteries. Symptoms include blurred vision, flashing lights or sparks (photopsia), and scotomata (dark areas
or gaps in the visual field) [91-93]. Diplopia or amaurosis fugax (blindness in one eye) may also occur. Cortical blindness is rare and typically transient [94]. Blindness related to
retinal pathology, such as retinal artery or venous thrombosis, retinal detachment, optic nerve damage, retinal artery spasm, and retinal ischemia, may be permanent [95].
Seizures in a preeclamptic woman signify a change in diagnosis to eclampsia. One in 400 mildly preeclamptic and 1 in 50 severely preeclamptic women develop eclamptic
seizures.
Histopathologic correlates include hemorrhage, petechiae, cerebral edema, vasculopathy, ischemic brain damage, microinfarcts, and fibrinoid necrosis [96,97].
The cerebrovascular manifestations of severe preeclampsia are poorly understood. Cerebral edema and ischemic/hemorrhagic changes in the posterior hemispheres observed on
computed tomography and magnetic resonance imaging help to explain, but do not fully account for, the clinical findings [98,99]. These findings may result from vasospasm of the
cerebral vasculature in response to severe hypertension or may result from loss of cerebrovascular autoregulation leading to areas of both vasoconstriction and forced vasodilation
and thus represent a form of posterior reversible leukoencephalopathy syndrome (PRES) [100,101]. PRES is typically associated with severe hypertension, but can occur with
rapid increases in blood pressure in patients with endothelial damage [102]. (See "Reversible posterior leukoencephalopathy syndrome" and "Eclampsia", section on 'Clinical
manifestations and diagnosis'.)
Stroke leading to death or disability is the most serious complication of severe preeclampsia/eclampsia, but is rare.
Fetus and placenta — The fetal consequences of chronic placental hypoperfusion are fetal growth restriction and oligohydramnios.
Severe and early onset preeclampsia result in the greatest decrements in birth weight compared to normotensive pregnancies, 12 and 23 percent, respectively [103]. By
comparison, late onset preeclampsia can be associated with higher than average birth weight [104-108], possibly related to greater placental perfusion [109], which may be due to
elevated cardiac output sometimes observed with late onset disease. However, this association may also be the result of confounders associated with both preeclampsia and birth
of large for gestational age infants (eg, obesity, impaired glucose tolerance) [110].
In a large study, early onset preeclampsia increased the risk of fetal death greater than five-fold and increased the risk of perinatal death/severe neonatal morbidity sixteen-fold [8].
In contrast, late onset preeclampsia was not associated with a significant increase in risk of fetal death, and only a two-fold increase in risk of perinatal death/severe neonatal
morbidity.
Indicated preterm delivery is a secondary result of fetal or maternal complications. Preeclampsia does not appear to accelerate fetal maturation, as once believed. The frequency
of neonatal morbidities such as respiratory distress, intraventricular hemorrhage, and necrotizing enterocolitis is similar in infants of preeclamptic women and age-matched
nonhypertensive controls [111].
Abruptio placenta is infrequent (less than 1 percent) in women with preeclampsia without severe features, but has been reported in 3 percent of those with severe features [112].
(See "Placental abruption: Clinical features and diagnosis".)
Impaired placentation can lead to increased impedance to flow in the uterine arteries, manifested by elevation of the pulsatility index accompanied by uterine artery notching on
uterine artery Doppler velocimetry. However, this finding is neither sensitive nor specific for preeclampsia. (See "Prediction of preeclampsia", section on 'Uterine artery Doppler
velocimetry'.)
Increased resistance in the placental vasculature is also reflected by rising Doppler indices of the umbilical artery. Absent and reversed end diastolic flow are the most severe
abnormalities and associated with a poor perinatal outcome. (See "Doppler ultrasound of the umbilical artery for fetal surveillance".)
Placental histology is described separately. (See "The placental pathology report", section on 'Parenchymal infarcts, syncytial knotting, and other lesions associated with
malperfusion'.)
Fetal hydrops (nonimmune or immune) can result in maternal symptoms identical to those seen in typical preeclampsia. This disorder is called mirror or Ballantyne syndrome and
resolves without delivery if hydrops resolves. (See "Nonimmune hydrops fetalis", section on 'Mirror syndrome'.)
DIAGNOSIS — International guidelines generally agree that the diagnosis of preeclampsia should be made in a previously normotensive woman with new onset of hypertension
and either proteinuria or end-organ dysfunction after 20 weeks of gestation [4,84,113,114]. Criteria for diagnosis are [4]:
Initial assessment for proteinuria is commonly performed by dipping a paper test strip into a fresh clean voided midstream urine specimen. Proteinuria ≥+1 on dipstick should be
confirmed by quantitative assessment (24 urine collection or protein:creatinine ratio). (See "Proteinuria in pregnancy: Evaluation and management".)
Mildly elevated blood pressure should be documented by at least two measurements at least four hours apart; asymptomatic outpatients with mild hypertension can be
reassessed within three to seven days [4]. The technique for blood pressure measurement is described separately. (See "Blood pressure measurement in the diagnosis and
management of hypertension in adults".)
For women with chronic/preexisting hypertension who have proteinuria prior to or in early pregnancy, superimposed preeclampsia is difficult to diagnose definitively, but should be
suspected when there is a significant worsening of hypertension (especially acutely) in the last half of pregnancy or development of signs/symptoms associated with the severe
spectrum of disease (table 2).
Post-diagnostic evaluation — The purpose of the post-diagnostic evaluation is to determine the severity of disease and assess maternal and fetal well-being. These factors, as
well as gestational age, guide management. (See "Preeclampsia: Management and prognosis".)
Preeclampsia is generally classified as having severe features if any of the following are present in a woman with preeclampsia (table 2) [3,4,84,113-115]:
Therefore, the history and physical examination should evaluate the patient for:
The minimum post-diagnostic laboratory/imaging evaluation should include:
Proteinuria ≥0.3 grams in a 24-hour urine specimen or protein:creatinine ratio ≥0.3, or•
Signs of end-organ dysfunction (platelet count <100,000/microliter, serum creatinine >1.1 mg/dL or doubling of the serum creatinine, elevated serum transaminases to
twice normal concentration)
•
Severe hypertension (systolic blood pressure ≥160 mm Hg or diastolic blood pressure ≥110 mm Hg)●
Signs/symptoms of end-organ injury (thrombocytopenia, impaired liver function, progressive renal insufficiency, pulmonary edema, new onset cerebral or visual disturbances)●
Persistent and/or severe headache●
Visual abnormalities (scotomata, photophobia, blurred vision, or temporary blindness)●
Additional tests that can be informative include blood smear and serum lactate dehydrogenase (LDH) and bilirubin concentrations. Microangiopathic hemolysis is suggested by
elevated LDH and indirect bilirubin levels and red cell fragmentation (schistocytes or helmet cells) on peripheral blood smear (picture 2A-B). Hemoconcentration occurs in
preeclampsia, but hemolysis, if present, can decrease the hematocrit to normal or anemic levels.
Coagulation function tests (eg, prothrombin time, activated partial thromboplastin time, fibrinogen concentration) are usually normal if there is no thrombocytopenia or liver
dysfunction; therefore, they are not checked routinely [116].
Differential diagnosis
Preexisting hypertension versus preeclampsia — Because of the reduction in blood pressure that typically occurs early in pregnancy, a woman with preexistent
hypertension may be normotensive when first seen by the obstetrical provider. Later in pregnancy when her blood pressure returns to its prepregnancy baseline, she may appear
to be developing mild preeclampsia if there are no documented prepregnancy blood pressure measurements.
In this setting, a variety of factors can be helpful in establishing the likely diagnosis:
Superimposed preeclampsia — In women with known primary (essential) hypertension and increasing blood pressure and/or proteinuria, the presence of systemic
manifestations of severe features of preeclampsia, such as thrombocytopenia, increased serum levels of aminotransferases, and visual symptoms strongly suggest development of
superimposed preeclampsia (table 2) [117]. Reproductive age women with primary (essential) hypertension typically have no or mild proteinuria so severe proteinuria suggests
development of superimposed preeclampsia.
Exacerbation of preexisting renal disease — Superimposed preeclampsia frequently develops in women with preexisting primary or secondary renal disease [118,119].
However, worsening hypertension and proteinuria in a woman with preexisting renal disease may also represent an exacerbation of the underlying disease or the physiological
effects of pregnancy. The ability to accurately distinguish among these possibilities is important, as management and complications are different.
Significant clues to the diagnosis of preeclampsia with severe features are the presence of systemic manifestations of the disorder, such as thrombocytopenia, increased serum
levels of aminotransferases, and visual symptoms (table 2) [117]. Onset of disease in the first half of pregnancy suggests exacerbation of underlying renal disease, rather than
preeclampsia.
Laboratory evidence suggestive of exacerbation of renal disease includes the presence of findings specific for disease activity (eg, low complement levels in a patient with
systemic lupus erythematosus, urinalysis consistent with a proliferative glomerular disorder [red and white cells and/or cellular casts]). An active urine sediment is not a feature of
preeclampsia. (See "Pregnancy in women with underlying renal disease" and "Pregnancy in women with diabetic kidney disease".)
Antiphospholipid syndrome — Hypertension, proteinuria, and thrombocytopenia, and other signs of end-organ dysfunction can be seen in antiphospholipid syndrome. The
absence of laboratory evidence of antiphospholipid antibodies excludes this diagnosis. (See "Clinical manifestations of the antiphospholipid syndrome" and "Diagnosis of the
antiphospholipid syndrome" and "Pregnancy in women with antiphospholipid syndrome".)
AFLP, TTP, HUS, SLE — Although preeclampsia/HELLP is the most common cause of hypertension, thrombocytopenia, liver abnormalities, and renal abnormalities in
pregnant women, the following conditions should be considered and excluded, if possible. Laboratory findings in these disorders are compared in the tables (table 5A-B).
In the future, measurement of urinary or plasma angiogenic factors (soluble fms-like tyrosine kinase, placental growth factor) may be useful in distinguishing preeclampsia from
other hypertensive-proteinuric disorders, but this test is investigational and not readily available [120-122]. (See "Pathogenesis of preeclampsia", section on 'sFlt-1, VEGF, PIGF'.)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, “The Basics” and “Beyond the Basics.” The Basics patient education pieces are
written in plain language, at the 5 to 6 grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best
for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more
detailed. These articles are written at the 10 to 12 grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education
articles on a variety of subjects by searching on “patient info” and the keyword(s) of interest.)
SUMMARY AND RECOMMENDATIONS
Serum aspartate aminotransferase (AST) or alanine aminotransferase (ALT)●
Fetal assessment (biophysical profile or nonstress test)●
Hypertension occurring before the 20th week is usually due to preexisting hypertension rather than to preeclampsia.●
Proteinuria is present and increases with time in preeclampsia, occasionally reaching the nephrotic range; by comparison, protein excretion is usually absent or less than 1
g/day in hypertensive nephrosclerosis [21]. (See "Clinical features, diagnosis, and treatment of hypertensive nephrosclerosis".)
●
Preeclampsia is more common in nulliparas than in multiparas.●
Preeclampsia is more common in older (>40 years) nulliparas, although these women are also more likely to have preexisting hypertension, as are older multiparous women
(see 'Risk factors' above).
●
Acute fatty liver of pregnancy (AFLP). Low grade fever can be present in AFLP, but does not occur in preeclampsia/HELLP. AFLP is associated with more serious liver
dysfunction: hypoglycemia and disseminated intravascular coagulation are common features, while unusual in preeclampsia/HELLP. AFLP is also usually associated with
more significant renal dysfunction compared to preeclampsia/HELLP. (See "Acute fatty liver of pregnancy".)
●
Thrombotic thrombocytopenic purpura-hemolytic uremic syndrome (TTP-HUS). Although neurologic abnormalities and acute renal failure are more prominent in TTP-HUS,
this disorder may be indistinguishable from severe preeclampsia/HELLP syndrome. Fever and thrombocytopenia <20,000/microL support a diagnosis of TTP.
Preeclampsia/HELLP begins to resolve within 48 hours after delivery, while HUS has a more protracted postpartum course, and patients develop severe renal failure in the
postpartum period. (See "Diagnosis of thrombotic thrombocytopenic purpura-hemolytic uremic syndrome in adults".)
●
Exacerbation of systemic lupus erythematosus (SLE). Flares of SLE are likely to be associated with hypocomplementemia and increased titers of anti-DNA antibodies; by
comparison, complement levels are usually, but not always, normal or increased in preeclampsia. (See "Pregnancy in women with systemic lupus erythematosus".)
●
th th
th th
Basics topics (see "Patient information: Preeclampsia (The Basics)" and "Patient information: High blood pressure and pregnancy (The Basics)" and "Patient information:
HELLP syndrome (The Basics)")
●
Beyond the Basics topics (see "Patient information: Preeclampsia (Beyond the Basics)")●
The four major hypertensive disorders related to pregnancy are preeclampsia, chronic hypertension, preeclampsia superimposed upon chronic hypertension, and gestational
hypertension (table 3). (See 'Definitions of pregnancy-related hypertensive disorders' above.)
●
Major risk factors for development of preeclampsia include past history of preeclampsia, nulliparity, pregestational diabetes, chronic hypertension, obesity, family history of
preeclampsia, and multiple gestation. (See 'Risk factors' above.)
●
The gradual development of hypertension and proteinuria in the last half of pregnancy is usually due to preeclampsia, particularly in a nullipara. These findings typically
become apparent after 34 weeks of gestation and progress until delivery, but some women develop symptoms earlier in gestation, intrapartum, or postpartum. (See 'Clinical
presentation' above.)
●
The diagnosis of preeclampsia is based on the new onset of hypertension and either proteinuria or end-organ dysfunction after 20 weeks of gestation in a previously
normotensive woman (table 1) (see 'Diagnosis' above):
●
Systolic blood pressure ≥140 mmHg or diastolic blood pressure ≥90 mmHg, and
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Proteinuria ≥0.3 grams in a 24-hour urine specimen or protein:creatinine ratio ≥0.3, or•
Signs of end-organ dysfunction (platelet count <100,000/microliter, serum creatinine >1/1 mg/dL or doubling of the serum creatinine, elevated serum transaminases to
twice normal concentration)
•
The goal of the post-diagnostic evaluation is to determine the severity of disease and assess maternal and fetal well-being. Findings indicative of severe disease are listed in
the table (table 2). Post-diagnostic laboratory/imaging evaluation should include (see 'Post-diagnostic evaluation' above):
●
Platelet count•
Serum creatinine•
Serum aspartate aminotransferase (AST) or alanine aminotransferase (ALT)•
Fetal assessment (biophysical profile or nonstress test)•
Differential diagnosis includes exacerbation of underlying renal disease, acute fatty liver of pregnancy, thrombotic thrombocytopenic purpura-hemolytic uremic syndrome, and
exacerbation of systemic lupus erythematosus. (See 'Differential diagnosis' above.)
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50. Hankins GD, Wendel GD Jr, Cunningham FG, Leveno KJ. Longitudinal evaluation of hemodynamic changes in eclampsia. Am J Obstet Gynecol 1984; 150:506.
51. Cotton DB, Lee W, Huhta JC, Dorman KF. Hemodynamic profile of severe pregnancy-induced hypertension. Am J Obstet Gynecol 1988; 158:523.
52. Phelan JP, Yurth DA. Severe preeclampsia. I. Peripartum hemodynamic observations. Am J Obstet Gynecol 1982; 144:17.
53. Clark SL, Greenspoon JS, Aldahl D, Phelan JP. Severe preeclampsia with persistent oliguria: management of hemodynamic subsets. Am J Obstet Gynecol 1986; 154:490.
54. Mabie WC, Ratts TE, Sibai BM. The central hemodynamics of severe preeclampsia. Am J Obstet Gynecol 1989; 161:1443.
55. Melchiorre K, Sutherland GR, Baltabaeva A, et al. Maternal cardiac dysfunction and remodeling in women with preeclampsia at term. Hypertension 2011; 57:85.
56. Nabatian S, Quinn P, Brookfield L, Lakier J. Acute coronary syndrome and preeclampsia. Obstet Gynecol 2005; 106:1204.
57. Fleming SM, O'Gorman T, Finn J, et al. Cardiac troponin I in pre-eclampsia and gestational hypertension. BJOG 2000; 107:1417.
58. Joyal D, Leya F, Koh M, et al. Troponin I levels in patients with preeclampsia. Am J Med 2007; 120:819.e13.
59. Benedetti TJ, Kates R, Williams V. Hemodynamic observations in severe preeclampsia complicated by pulmonary edema. Am J Obstet Gynecol 1985; 152:330.
61. Desai DK, Moodley J, Naidoo DP, Bhorat I. Cardiac abnormalities in pulmonary oedema associated with hypertensive crises in pregnancy. Br J Obstet Gynaecol 1996;103:523.
62. Thornton CE, von Dadelszen P, Makris A, et al. Acute pulmonary oedema as a complication of hypertension during pregnancy. Hypertens Pregnancy 2011; 30:169.
63. Ginsberg JM, Chang BS, Matarese RA, Garella S. Use of single voided urine samples to estimate quantitative proteinuria. N Engl J Med 1983; 309:1543.
64. Schwab SJ, Christensen RL, Dougherty K, Klahr S. Quantitation of proteinuria by the use of protein-to-creatinine ratios in single urine samples. Arch Intern Med 1987;147:943.
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66. Steinhäuslin F, Wauters JP. Quantitation of proteinuria in kidney transplant patients: accuracy of the urinary protein/creatinine ratio. Clin Nephrol 1995; 43:110.
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85. Minakami H, Oka N, Sato T, et al. Preeclampsia: a microvesicular fat disease of the liver? Am J Obstet Gynecol 1988; 159:1043.
86. Dani R, Mendes GS, Medeiros Jde L, et al. Study of the liver changes occurring in preeclampsia and their possible pathogenetic connection with acute fatty liver ofpregnancy. Am J Gastroenterol 1996; 91:292.
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Systolic blood pressure ≥140 mmHg or diastolic blood pressure ≥90 mmHg on two occasions at least four hours apart after 20 weeks of gestation in a
previously normotensive patient
If systolic blood pressure is ≥160 mmHg or diastolic blood pressure is ≥110 mmHg, confirmation within minutes is sufficient
and
Proteinuria ≥0.3 grams in a 24-hour urine specimen or protein (mg/dL)/creatinine (mg/dL) ratio ≥0.3
Dipstick 1+ if a quantitative measurement is unavailable
In patients with new-onset hypertension without proteinuria, the new onset of any of the following is diagnostic of preeclampsia:
Platelet count <100,000/microliter
Serum creatinine >1.1 mg/dL or doubling of serum creatinine in the absence of other renal disease
Liver transaminases at least twice the normal concentrations
Pulmonary edema
Cerebral or visual symptoms
Adapted from: Hypertension in pregnancy: Report of the American College of Obstetricians and Gynecologists' Task Force on Hypertension in Pregnancy. Obstet
Gynecol 2013; 122:1122.
Graphic 79977 Version 9.0
20/7/2014 Preeclampsia: Clinical features and diagnosis
Severe headache (ie, incapacitating, "the worst headache I've ever had") or headache that persists and progresses despite analgesic therapy
Altered mental status
Hepatic abnormality:
Severe persistent right upper quadrant or epigastric pain unresponsive to medication and not accounted for by an alternative diagnosis or serum transaminase
concentration ≥ twice normal, or both
Severe blood pressure elevation:
Systolic blood pressure ≥160 mmHg or diastolic blood pressure ≥110 mmHg on two occasions at least four hours apart while the patient is on bedrest (unless the
patient is on antihypertensive therapy)
Thrombocytopenia:
<100,000 platelets/microL
Renal abnormality:
Progressive renal insufficiency (serum creatinine >1.1 mg/dL or doubling of serum creatinine concentration in the absence of other renal disease)
Pulmonary edema
In contrast to older criteria, the 2013 criteria do not include proteinuria >5 grams/24 hours and fetal growth restriction as features of severe
disease.
Adapted from: Hypertension in pregnancy: Report of the American College of Obstetricians and Gynecologists' Task Force on Hypertension in Pregnancy. Obstet
Gynecol 2013; 122:1122.
Graphic 76975 Version 8.0
20/7/2014 Preeclampsia: Clinical features and diagnosis
Disclosures: Phyllis August, MD, MPH Nothing to disclose. Baha M Sibai, MD Nothing to disclose. Charles J Lockwood, MD,MHCM Nothing to disclose. Vanessa A Barss, MD Employee of UpToDate, Inc. Equity Ow nership/Stock Options: Merck; Pfizer;Abbvie.
Contributor disclosures are review ed for conflicts of interest by the editorial group. When found, these are addressed by vettingthrough a multi-level review process, and through requirements for references to be provided to support the content. Appropriatelyreferenced content is required of all authors and must conform to UpToDate standards of evidence.
