Preeclampsia: Clinical features and diagnosis

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Literature review current through: Apr 2016. | This topic last updated: Jan 18, 2016.
INTRODUCTION Preeclampsia is a multi-system disorder characterized by the new
onset of hypertension and proteinuria or end-organ dysfunction or both 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]:
Preeclampsia Preeclampsia refers to the new onset of hypertension and either
proteinuria or end-organ dysfunction or both 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 with severe features. 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 endorgan 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 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".)
PREVALENCE Preeclampsia is estimated to occur in 4.6 percent (95% CI 2.7-8.2)
of pregnancies worldwide [5]. 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 [6]. Late onset disease (34
weeks) is more prevalent than early onset disease (<34 weeks) (in one population-based
study: 2.7 versus 0.3 percent, respectively [7]).
BURDEN OF DISEASE Women with preeclampsia are at an increased risk for lifethreatening events, including placental abruption, acute kidney injury, 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 [8]. In the United States, preeclampsia/eclampsia is one of
four leading causes of maternal death, along with hemorrhage, cardiovascular
conditions, and thromboembolism [9-11]. 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 [12,13]. 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 [14]. (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 [15].
A past history of preeclampsia increases the risk of developing preeclampsia in a
subsequent pregnancy seven-fold compared to women without this history (relative risk
[RR] 7.19, 95% CI 5.85-8.83) [15].
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 [16-19]. By
comparison, women without severe features of preeclampsia in their first pregnancy
develop preeclampsia in 5 to 7 percent of second pregnancies [20,21]. 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) [15]. 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 1.704.93) [15], suggesting a heritable mechanism in some cases [22,23]. 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
"Preeclampsia: Pathogenesis", section on 'Genetic factors'.)
Preexisting medical conditions:
Pregestational diabetes (RR 3.56, 95% CI 2.54-4.99) [15], 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 [24]. (See
"Pregestational diabetes: Preconception counseling, evaluation, and management".)
Blood pressure 130/80 mm Hg at the first prenatal visit (RR 1.38-2.37) [15]. 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) [15]. (See "Pregnancy in
women with antiphospholipid syndrome".)
Body mass index 26.1 (RR 2.47, 95% CI 1.66-3.67) [15]. (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 in the latter half of pregnancy [25,26].
Twin pregnancies (RR 2.93, 95% 2.04-4.21) [15]. Preeclampsia is even more
frequent with multi-order gestations (triplets, quadruplets) [27].
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) [15]. 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 [15]. (See "Effect of advanced age on fertility and
pregnancy in women".)
Of note, women who smoke cigarettes have a lower risk of preeclampsia than
nonsmokers. (See "Cigarette smoking: Impact on pregnancy and the neonate", 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 fmslike 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 "Preeclampsia: Pathogenesis".)
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:
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])
Upper abdominal or epigastric pain
Nausea, vomiting
Dyspnea, retrosternal chest pain
Altered mental status
Laboratory abnormalities:

Microangiopathic hemolytic anemia (abnormal peripheral smear, elevated bilirubin, or

low serum haptoglobin levels U/L)
Thrombocytopenia (<100,000/microL)
Elevated serum creatinine concentration (>1.1 mg/dL)
Elevated liver enzymes (twice the upper limit of normal)
Atypical presentation Atypical presentations include any of the following [37,39]:
Onset of signs/symptoms at <20 weeks of gestation
Hypertension or proteinuria (but not both) with or without characteristic signs and
symptoms of severe preeclampsia
Delayed postpartum onset or exacerbation of disease (>2 days postpartum)
Onset <20 weeks Preeclampsia prior to 20 weeks of gestation is usually associated
with a complete or partial molar pregnancy (see "Hydatidiform mole: Epidemiology,
clinical features, 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 prevented?'
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. Other etiologies of the signs and symptoms should be
considered, such as cerebral vasoconstriction syndrome or even impending stroke [4043]. Risk factors for delayed postpartum preeclampsia appear to be similar to those for
preeclampsia during pregnancy [37,44,45], 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) [46]. 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; liver failure; heart failure; disseminated
intravascular coagulation; stroke; need for mechanical ventilation, invasive
hemodynamic monitoring, transfusion, or dialysis) [47,48]. 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 [49].
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 [50]. 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 [51]. 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
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 [52], but reductions in longitudinal,
circumferential, and radial systolic strain have been observed [53]. The decrement in
left ventricular performance in women with preeclampsia has been attributed to a
physiologic response to increased afterload [52-54], 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 [53]. 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 [55].
Severe preeclampsia can be associated with a highly variable hemodynamic profile [5458]. A small subgroup of women with severe preeclampsia develops myocardial
damage or global diastolic dysfunction [59]. 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 [60,61].
Preeclampsia is not associated with elevated troponin levels in the absence of cardiac
disease [62].
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 [63-66]. 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 number that estimates the 24-hour protein excretion
in grams per day (calculator 1) [67-75]. 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".)
Increased urinary protein excretion may be a late finding [76,77], but generally
increases as preeclampsia progresses. It is due, in part, to impaired integrity of the
glomerular filtration barrier and altered tubular handling of filtered proteins
(hypofiltration) leading to increased protein excretion [78]. Both size and charge
selectivity of the glomerular barrier are affected [79]. Using special studies, podocyturia
(urinary excretion of podocytes) has been observed in patients with preeclampsia [80].
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 "Preeclampsia: Pathogenesis", section on
'Pathogenesis of systemic endothelial dysfunction'.)
Renal function Glomerular filtration rate (GFR) decreases by 30 to 40 percent in
preeclampsia compared with 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 with or without HELLP'.)
The association of hyperuricemia with preeclampsia has been known for decades. The
cause is most likely related to the reduction in GFR. However, the increase in serum
uric acid is often greater than expected for mild reductions in GFR, leading to the
hypothesis that decreased tubular secretion or increased reabsorption play a role [81].
Although meta-analyses published in 2006 concluded that uric acid levels are not an
accurate predictor of complications associated with preeclampsia [82,83], this issue
remains controversial. Data from an ongoing international prospective study of women
admitted to the hospital with preeclampsia showed that serum uric acid corrected for
gestational age is clinically useful in predicting adverse perinatal, but not maternal
outcomes [84].
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) [85]:
Endothelial cell swelling
Loss of fenestrations
Occlusion of capillary lumens
Foot process effacement is not a prominent feature, despite marked proteinuria.

Glomerular endotheliosis shares histologic features with non-preeclamptic thrombotic

microangiopathies [85], 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 [86,87].
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
[88]. 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 [89].
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 "Preeclampsia:
Pathogenesis" and "Hematologic changes in pregnancy".)
The white blood cell count may be slightly higher due to neutrophilia.
Hepatic Periportal and sinusoidal fibrin deposition and microvesicular fat deposition
are histologic findings observed in the livers of preeclamptic women [90,91]. 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 [92]. The pain is thought to be due to
stretching of Glissons 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".)
Central nervous system and eye Central nervous system manifestations of
preeclampsia include headache, visual symptoms, and generalized hyperreflexia;
sustained ankle clonus may be present.

Headache in preeclampsia may be temporal, frontal, occipital, or diffuse [93,94]. 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 retinal arteriolar spasm [95]. Symptoms
include blurred vision, flashing lights or sparks (photopsia), and scotomata (dark areas
or gaps in the visual field) [96-98]. Diplopia or amaurosis fugax (blindness in one eye)
may also occur. Cortical blindness is rare and typically transient [99]. Blindness related
to retinal pathology, such as retinal artery or vein occlusion, retinal detachment, optic
nerve damage, retinal artery spasm, and retinal ischemia, may be permanent [100].
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 [101,102].
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 [103,104]. These findings may result
from generalized endothelial cell dysfunction leading to 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) [105,106]. PRES is typically associated with severe hypertension, but
can occur with rapid increases in blood pressure in patients with endothelial damage
[107]. (See "Reversible posterior leukoencephalopathy syndrome" and "Eclampsia",
section on 'Clinical presentation and findings'.)
Stroke leading to death or disability is the most serious complication of severe
preeclampsia/eclampsia, which is responsible for approximately 36 percent of
pregnancy-associated stroke [108]. Most strokes in this setting are hemorrhagic and
preceded by severe headache and severe and fluctuating blood pressure levels.
Eclamptic seizures occur in some, but not all cases. Risk factors for hemorrhagic stroke
in women with preeclampsia include persistent severe hypertension (ie, persistent
systolic blood pressures 160 mmHg and/or diastolic blood pressures 110 mmHg)
associated with significant headache and/or seizures. Lowering blood pressure may
reduce the risk; however, criteria for persistent hypertension and timing of initiation of
acute antihypertensive therapy (after 15 minutes, 30 minutes, or >60 minutes) are
unclear.
Other maternal manifestations Women with preeclampsia appear to have greater
changes in lipid metabolism (eg, elevated total cholesterol and triglyceride levels) than
normotensive pregnant women [109,110]. Acute pancreatitis is a rare complication of
preeclampsia [111] and can mimic preeclampsia [112].

Fetus 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 with normotensive pregnancies, 12 and 23 percent lower than expected for
gestational age, respectively [113]. By comparison, late onset preeclampsia can be
associated with higher than average birth weight [114-118], possibly related to greater
placental perfusion [119], 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) [120].
In large studies, early onset preeclampsia substantially increased the risks for both fetal
death [121,122] and perinatal death/severe neonatal morbidity [121]. In contrast, late
onset preeclampsia was associated with much lower risks for fetal death [121,122] and
perinatal death/severe neonatal morbidity [121].
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 [123].
In a population-based study, preeclampsia was associated with a small but statistical
increase in noncritical heart defects in offspring; women with onset of preeclampsia
before 34 weeks also had an increased risk of critical heart defects in offspring [124].
Further study is required to confirm this observation and, if confirmed, to determine the
nature of the relationship.
Placenta 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 [125]. (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'.)
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

[4,126-128]. Criteria for diagnosis are [4]:
Systolic blood pressure 140 mmHg or diastolic blood pressure 90 mmHg, and
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 and signs/symptoms of end-organ injury are considered the severe
spectrum of the disease (table 2).
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]. If systolic blood pressure is 160 mmHg or
diastolic blood pressure is 110 mmHg, confirmation within minutes is sufficient. 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.
When evaluating women for possible preeclampsia, it is generally safer to assume that
new onset hypertension in pregnancy is due to preeclampsia, even if all the diagnostic
criteria are not fulfilled and the blood pressure is only mildly elevated, since
preeclampsia may progress to eclampsia or other severe forms of the disease in a short
period of time. Women with mild elevations of blood pressure who do not meet criteria
for preeclampsia have gestational hypertension and should be followed closely and
monitored, since 25 percent will develop preeclampsia later in pregnancy.
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) [3,4,126-129]:
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)
Therefore, the history and physical examination should evaluate the patient for:
Persistent and/or severe headache
Visual abnormalities (scotomata, photophobia, blurred vision, or temporary blindness)
Upper abdominal or epigastric pain
Nausea, vomiting
Dyspnea
Altered mental status
The minimum post-diagnostic laboratory/imaging evaluation should include:
Platelet count
Serum creatinine
Serum aspartate aminotransferase (AST) or alanine aminotransferase (ALT)
Obstetrical ultrasound (fetal weight, amniotic fluid volume)
Fetal assessment (biophysical profile or nonstress test)
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 in patients without thrombocytopenia or
liver dysfunction; therefore, they are not checked routinely [130].
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:
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 [20]. (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).
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) [131]. 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 [132,133].
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) [131]. 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).
Acute fatty liver of pregnancy (AFLP). Anorexia, nausea, and vomiting are common
clinical features of 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 (TTP) or hemolytic uremic syndrome (HUS).
Although neurologic abnormalities and acute renal failure often are seen in TTP and
HUS, respectively, they are not always seen, and these disorders may be
indistinguishable from severe preeclampsia/HELLP syndrome. Preeclampsia/HELLP
begins to resolve within 48 hours after delivery, while TTP and HUS do not resolve
with delivery. Distinguishing among TTP, HUS, and related thrombotic
microangiopathy syndromes may be challenging. An approach to the patient suspected
to have TTP or HUS, including urgent interventions before the diagnosis is established,
is presented separately. (See "Approach to the patient with suspected TTP, HUS, or
other thrombotic microangiopathy (TMA)".)
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. Acute onset, accelerated hypertension is more likely to be due to
preeclampsia than a lupus flare. (See "Pregnancy in women with systemic lupus
erythematosus".)
Mirror syndrome Fetal hydrops from any cause (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'.)
Measurement of angiogenic factors In the future, measurement of urinary or plasma
angiogenic factors (soluble fms-like tyrosine kinase, placental growth factor) may be
useful for distinguishing preeclampsia from other hypertensive-proteinuric disorders;
this test is commercially available but investigational and should be limited to patients
in research studies [134-136].
Multiple studies have demonstrated that angiogenic factors (sFLT-1 and PlGF) are
altered in women with clinical features of preeclampsia (see "Preeclampsia:
Pathogenesis", section on 'sFlt-1, VEGF, PIGF'). It has also been demonstrated that the
ratio of sFLT1/PlGF is particularly sensitive in making a clinical diagnosis. What
remains to be determined is whether, and in what circumstances, measurement of
angiogenic factors could be clinically useful and improve patient outcomes. One
particular scenario that is clinically challenging is determining whether a woman with
signs of preeclampsia, such as an increase in blood pressure or a slightly elevated level

of urinary protein, requires medical intervention, such as hospitalization or even

delivery. A biomarker test that improved our ability to predict patients who require or
do not require a higher degree of medical intervention would be helpful.
A prospective, multicenter, international observational study (PROGNOSIS) attempted
to derive and validate a serum sFlt-1:PlGF ratio that would predict the absence or
presence of preeclampsia in the short-term in women who already had signs suggestive
of preeclampsia, such as an increase in blood pressure and/or proteinuria [137]. The
study included 500 women with singleton pregnancies at 24 to 36 6/7ths weeks of
gestation with suspected preeclampsia based on one or more of the following: new
increase in blood pressure but less than 140/90 mmHg, new proteinuria but less than 2+
dipstick, preeclampsia-related laboratory findings but not meeting criteria for HELLP
syndrome, preeclampsia-related symptoms (edema, headache, visual changes, sudden
weight gain). Although the authors concluded that an sFlt-1:PlGF ratio cutoff of 38
using a specific automated commercial assay had a negative predictive value (no
preeclampsia in the next seven days) of 99.3 percent (95% CI 97.9-99.9), with
sensitivity of 80 percent (95% CI 51.9-95.7) and specificity of 78.3 percent (95% CI
74.6-81.7), we question the clinical usefulness of this conclusion since the women
enrolled in the study appeared to have a clinical profile of mild disease and the
prevalence of preeclampsia was quite low in this group. The positive predictive value
for preeclampsia was only 36.7 percent in the next four weeks (95% CI 28.4-45.7).
Whether this ratio will be helpful in reducing iatrogenic morbidity due to overdiagnosis
in women with suggestive signs of preeclampsia is unclear. Further exploration of this
test is warranted, including determining whether the cut-off varies among laboratories
and patient populations, the best interval for repeat testing, and how this information
affects clinical outcomes and costs.
PREDICTING WOMEN WHO WILL DEVELOP PREECLAMPSIA No test
performed in early pregnancy performs well for selecting women who are likely to
develop preeclampsia. (See "Prediction of preeclampsia".)
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 5th to 6th 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 th to 12th 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.)
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)")
SUMMARY AND RECOMMENDATIONS
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
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)
Obstetrical ultrasound (fetal weight, amniotic fluid volume)
Fetal assessment (biophysical profile or nonstress test)
Differential diagnosis includes exacerbation of underlying renal disease, acute fatty
liver of pregnancy, thrombotic thrombocytopenic purpura (TTP) or hemolytic uremic

syndrome (HUS), and exacerbation of systemic lupus erythematosus. (See 'Differential

diagnosis' above.)