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Preeclampsia: Clinical features and diagnosis

Authors: Phyllis August, MD, MPH, Baha M Sibai, MD


Section Editor: Charles J Lockwood, MD, MHCM
Deputy Editor: Vanessa A Barss, MD, FACOG

All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Dec 2017. | This topic last updated: Dec 05, 2017.

INTRODUCTION — Preeclampsia is a multi-system progressive disorder characterized by the new onset of


hypertension and proteinuria, or hypertension and end-organ dysfunction with or without proteinuria, in the last
half of pregnancy or postpartum (table 1). The disorder is caused by placental and maternal vascular dysfunction
and always resolves after delivery. 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. In addition, women with preeclampsia are at increased risk for future cardiovascular disease.

This topic will discuss the clinical features, diagnosis, and differential diagnosis of preeclampsia. Other
important issues related to this disease are reviewed separately.

● (See "Preeclampsia: Pathogenesis".)

● (See "Preeclampsia: Management and prognosis".)

● (See "Early pregnancy prediction of preeclampsia".)

● (See "Preeclampsia: Prevention".)

DEFINITIONS OF PREGNANCY-RELATED HYPERTENSIVE DISORDERS — There are four major hypertensive


disorders related to pregnancy [1,2]:

● Preeclampsia – Preeclampsia refers to the new onset of hypertension and proteinuria or hypertension and
end-organ dysfunction with or without proteinuria after 20 weeks of gestation in a previously normotensive
woman (table 1). It may also develop postpartum. Severe hypertension or signs/symptoms of end-organ
injury, as listed in the table, represent the severe end of the disease spectrum (table 2) [2].

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 g/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
[2]. 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
authorities to opine that HELLP syndrome is a separate disorder from preeclampsia. (See "HELLP
syndrome".)

● Chronic/pre-existing hypertension – Chronic/pre-existing hypertension is defined as hypertension that


antecedes pregnancy or is present on at least two occasions before the 20th week of gestation 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",
section on 'Definitions'.)

● Preeclampsia superimposed upon chronic/pre-existing hypertension – Superimposed preeclampsia is


defined by the new onset of proteinuria, end-organ dysfunction, or both after 20 weeks of gestation in a
woman with chronic/pre-existing hypertension. For women with chronic/pre-existing 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 end of the disease spectrum (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). Some women (10 to
25 percent) with gestational hypertension may ultimately develop signs and symptoms of preeclampsia. It
should resolve by 12 weeks postpartum. If hypertension persists beyond 12 weeks postpartum, the
diagnosis is "revised" to chronic/pre-existing hypertension that was masked by the physiologic decrease in
blood pressure that occurs in early pregnancy. If hypertension resolves postpartum, and if signs and
symptoms of preeclampsia have not developed, the diagnosis can be "revised" to transient hypertension of
pregnancy. (See "Gestational hypertension".)

PREVALENCE — In a systematic review, 4.6 percent (95% CI 2.7-8.2) of pregnancies worldwide were complicated
by preeclampsia [3]. Variations in prevalence reflect, at least in part, differences in the maternal age distribution
and proportion of nulliparous pregnant women among populations [4]. The prevalence of preeclampsia in the
United States is approximately 3.4 percent, but 1.5-fold to 2-fold higher in first pregnancies [5].

Prevalence also varies by gestational age. Preeclampsia is less prevalent before 34 weeks of gestation. In one
population-based study, the prevalence before and after 34 weeks was 0.3 and 2.7 percent, respectively [6].

BURDEN OF DISEASE — Women with preeclampsia are at an increased risk for life-threatening obstetric or
medical complications. Worldwide, 10 to 15 percent of direct maternal deaths (ie, resulting from obstetric
complications of pregnancy) are associated with preeclampsia/eclampsia [7]. In the United States,
preeclampsia/eclampsia is one of the four leading causes of maternal death, along with hemorrhage,
cardiovascular conditions, and thromboembolism [8-10]. 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 [11,12].
For the fetus, preeclampsia can lead to intrauterine growth restriction and oligohydramnios, as well as medically
or obstetrically indicated preterm birth. As a result, perinatal morbidity and mortality are increased.

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 systematic reviews [13,14]:

● A past history of preeclampsia increases the risk of developing preeclampsia in a subsequent pregnancy
eightfold compared with women without this history (relative risk [RR] 8.4, 95% CI 7.1-9.9) [14].

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 [15-18]. By comparison, women without severe features of preeclampsia in
their first pregnancy develop preeclampsia in 5 to 7 percent of second pregnancies [19,20]. Women who had
a normotensive first pregnancy develop preeclampsia in less than 1 percent of second pregnancies.

● First pregnancy (nulliparity) (RR 2.1, 95% CI 1.9-2.4) [14]. It is unclear why the nulliparous state is
consistently found to be a significant predisposing factor for preeclampsia. One theory is that the immune
system of nulliparous women has had limited exposure to paternal antigens, and this lack of desensitization
may play a role in the pathogenesis of the disease. Epidemiologic data support this theory: Protection from
preeclampsia in subsequent pregnancies is either reduced or eliminated if there is a change in paternity,
women using barrier methods of contraception are at increased risk, and risk is reduced with increased
duration of sexual activity before pregnancy [21]. However, the notion that the risk of preeclampsia is
increased in a second pregnancy with a new partner has been challenged by data suggesting that a longer
interval between pregnancies may be the reason for the increased risk with a new partner [22].

● A family history of preeclampsia in a first-degree relative (RR 2.90, 95% CI 1.70-4.93) [13], suggesting a
heritable mechanism in some cases [23,24]. The occurrence and severity of the disease appears to be
influenced primarily by maternal factors, but the paternal contribution to fetal genes may have a role in
defective placentation and subsequent preeclampsia. (See "Preeclampsia: Pathogenesis", section on
'Genetic factors'.)

● Prior pregnancy complications – fetal growth restriction (RR 1.4, 95% CI 0.6-3.0), abruption (RR 2.0, 95% CI
1.4-2.7), or stillbirth (RR 2.4, 95% CI 1.7-3.4) [14].

● Pre-existing medical conditions:

• Pregestational diabetes (RR 3.7, 95% CI 3.1-4.3) [14]. This increase has been related to a variety of
factors, such as underlying renal or vascular disease, high plasma insulin levels/insulin resistance, and
abnormal lipid metabolism [25].

• Chronic hypertension (RR 5.1, 95% CI 4.0-6.5) [14]. Blood pressure ≥130/80 mmHg at the first prenatal
visit has also been reported to increase risk (RR 1.38 to 2.37) [13]. Although chronic hypertension
(defined as blood pressure ≥140/90 mmHg) increases the risk of preeclampsia fivefold compared with
women without this risk factor, chronic hypertension is uncommon and thus accounts for only five to 10
percent of preeclampsia cases [26].

• Systemic lupus erythematosus (RR 1.8, 95% CI 1.5-2.1) [14].

• Antiphospholipid syndrome (RR 2.8, 95% CI 1.8-4.3) [14].

• Body mass index >25 (RR 2.1, 95% CI 2.0-2.2) and body mass index (BMI) >30 (RR 2.8, 95% CI 2.6-3.1)
[14]. The risk of preeclampsia doubles with each 5 to 7 kg/m2 increase in prepregnancy BMI [27]. This
relationship persisted in studies that excluded women with chronic hypertension, diabetes mellitus, or
multiple gestations, or after adjustment for other confounders. Although overweight and obesity
increase the risk of preeclampsia only two to three-fold, overweight and obesity are highly prevalent
worldwide and thus cumulatively account for over 40 percent of preeclampsia cases [26].

• Chronic kidney disease (CKD) (RR 1.8, 95% CI 1.5-2.1) [14]. The risk varies depending on the degree of
reduction of glomerular filtration rate and the presence or absence of hypertension. In some studies, as
many as 40 to 60 percent of women with advanced CKD (stages 3, 4, 5) were diagnosed with
preeclampsia in the latter half of pregnancy [28,29].

● Multifetal pregnancy (RR 2.9, RR 2.6-3.1) [14]. The risk increases with increasing numbers of fetuses [30].
● Advanced maternal age (maternal age ≥35 RR 1.2, 95% CI 1.2-2.0 and ≥40 RR 1.5, 95% CI 1.2-2.0) [14]. Older
women tend to have additional risk factors, such as diabetes mellitus and chronic hypertension, that
predispose them to developing preeclampsia.

Whether adolescents are at higher risk of preeclampsia is more controversial [31]; a systematic review did
not find an association [13]. (See "Effects of advanced maternal age on pregnancy".)

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. Abnormal trophoblast invasion of the spiral arteries of the decidua and myometrium early
in pregnancy, weeks to months before development of clinical manifestations of the disease, has been well
documented [32,33]. Failure to establish an adequate uteroplacental blood flow can result in relatively hypoxic
trophoblast tissue, which may promote an exaggerated state of oxidative stress in the placenta [34]. This may
further attenuate trophoblast invasion and appears to alter placental villous angiogenesis, leading to poor
development of the fetoplacental vasculature and abnormal vascular reactivity. Placental secretion of angiogenic
factors (soluble flt1 and endoglin) that bind vascular endothelial growth factor and placental growth factor in the
maternal circulation appears to result in widespread maternal vascular dysfunction, leading to hypertension,
proteinuria, and the other clinical manifestations of preeclampsia [35,36]. (See "Preeclampsia: Pathogenesis".)

Some authorities have characterized preeclampsia as early-onset (<34 weeks of gestation) and late-onset (≥34
weeks of gestation). The clinical features overlap, but the spectrum of disease and outcomes differ: Early-onset
disease has been associated with more severe placental and maternal/fetal clinical findings and, in turn, poorer
maternal/fetal outcomes [37,38]. For this reason, it has been hypothesized that the two phenotypes have
different origins and pathophysiologies [37,39,40]. However, these differences can also be explained by biological
variation in the disease process.

SCREENING — Screening for traditional risk factors for preeclampsia is of value at the first prenatal visit to
identify women at high risk of developing the disease, as these women are offered low-dose aspirin therapy to
reduce their risk of developing the disease. (See "Early pregnancy prediction of preeclampsia", section on
'Universal screening' and "Preeclampsia: Prevention", section on 'Candidates'.)

All pregnant women are at risk for preeclampsia, and evidence supports routinely screening for the disorder by
measuring blood pressure at all provider visits throughout pregnancy [2,41,42]. The value of any laboratory or
imaging test for screening has not been established (see "Early pregnancy prediction of preeclampsia").

It is customary to test for proteinuria at each prenatal visit; however, this practice has not been rigorously
evaluated and proven to improve outcomes [42]. We suggest performing a urinalysis to test for proteinuria at the
first prenatal visit to establish a baseline and, given the possibility for false-positives and false-negatives,
repeating the test in asymptomatic normotensive patients on at least one subsequent prenatal visit. In contrast,
testing for proteinuria should be performed in women with hypertension as proteinuria changes the diagnosis to
preeclampsia. Once a diagnosis of preeclampsia is established, testing for proteinuria is no longer diagnostically
or prognostically useful. (See 'Proteinuria' below and 'Definitions of pregnancy-related hypertensive disorders'
above.)

CLINICAL PRESENTATION — Most patients are nulliparous and present with new-onset hypertension and
proteinuria at ≥34 weeks of gestation, sometimes during labor [43,44]. Approximately 10 percent of affected
women develop these signs and symptoms at <34 weeks of gestation (ie, early-onset preeclampsia) [43] and
rarely as early as 20 to 22 weeks. In approximately 5 percent, the signs and symptoms are first recognized
postpartum (ie, postpartum preeclampsia), usually within 48 hours of delivery [45-47].
The degree of maternal hypertension and proteinuria, and the presence/absence of other clinical manifestations
of the disease (described below) are highly variable [48]. Approximately 25 percent of affected women develop
one or more of the following nonspecific symptoms, which characterize the severe spectrum of the disease and
signify the need for urgent evaluation and possible delivery:

● Persistent and/or severe headache

● Visual abnormalities (scotomata, photophobia, blurred vision, or temporary blindness [rare])

● Upper abdominal or epigastric pain

● Altered mental status

● Dyspnea, retrosternal chest pain

Epigastric pain may be the presenting symptom of preeclampsia; 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.

Atypical presentations are described separately. (See 'Atypical presentations' below.)

SPECTRUM OF DISEASE

Clinical findings

Hypertension — All patients with preeclampsia have hypertension (in patients with HELLP, elevations in blood
pressure may be minimal or even absent). It is generally the earliest clinical finding of preeclampsia and the most
common clinical clue to the presence of the disease. The blood pressure usually rises gradually, reaching the
hypertensive range (defined as ≥140/90 mmHg) sometime in the third trimester, often after the 37th week of
gestation [43]. Blood pressures are often around 135/85 mmHg in the one to two weeks before reaching the
hypertensive range. However, in some women, hypertension develops rapidly or before 34 weeks of gestation or
postpartum.

Epigastric pain — Epigastric pain, when present, is a cardinal symptom of the severe end of the disease
spectrum. It is characterized by severe constant pain that often begins at night, usually maximal in the low
retrosternum or epigastrium, but may radiate to the right hypochondrium or back [49]. Nausea and vomiting
sometimes also occur. On examination, the liver may be tender to palpation due to stretching of Glisson's
capsule from hepatic swelling or bleeding.

Liver rupture or hemorrhage is rare, but should be suspected when there is sudden onset of right upper quadrant
pain associated with a decrease in blood pressure. (See "HELLP syndrome", section on 'Management of hepatic
complications'.)

Acute pancreatitis is a rare complication of preeclampsia [50] and can mimic the epigastric pain of preeclampsia
[51].

Headache — Headache, when present, is a cardinal symptom of the severe end of the disease spectrum. It
may be temporal, frontal, occipital, or diffuse [52,53]. The pain usually has a throbbing or pounding quality, but
may be piercing. 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"). However, resolution of the headache with
analgesics does not exclude the possibility of preeclampsia.
The mechanism for headache, as well as other cerebrovascular symptoms of preeclampsia, is 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 [54,55]. These findings may result from generalized endothelial cell dysfunction, leading to vasospasm
of the cerebral vasculature in response to severe hypertension, or they may result from loss of cerebrovascular
autoregulation, leading to areas of both vasoconstriction and forced vasodilation. Thus, they could represent a
form of posterior reversible leukoencephalopathy syndrome (PRES) [56-58]. PRES is typically associated with
severe hypertension but can occur with rapid increases in blood pressure in patients with endothelial damage
[59]. (See "Reversible posterior leukoencephalopathy syndrome" and "Eclampsia", section on 'Clinical
presentation and findings'.)

Visual symptoms — Visual symptoms, when present, are cardinal symptoms of the severe end of the disease
spectrum. They are caused, at least in part, by retinal arteriolar spasm [60]. Symptoms include blurred vision,
flashing lights or sparks (photopsia), and scotomata (dark areas or gaps in the visual field) [61-63]. Diplopia or
amaurosis fugax (blindness in one eye) may also occur. Visual disturbances in preeclampsia may also be
manifestations of PRES [58].

Cortical blindness is rare and typically transient [64]. 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 [65].

Generalized hyperreflexia — Hyperreflexia is a common finding. Sustained ankle clonus may be present.

Peripheral edema — Many pregnant women have edema, whether or not they have preeclampsia. However,
sudden and rapid weight gain (eg, >5 lb/week [2.3 kg]) and facial edema are more common in women who
develop preeclampsia; thus, these findings warrant diagnostic evaluation for the disease. Peripheral edema in
preeclampsia may be due to capillary leaking or represent "overfill" edema.

Pulmonary edema — Pulmonary edema is a feature of the severe end of the disease spectrum. The symptom
complex of dyspnea, chest pain, and/or decreased (≤93 percent) oxygen saturation by pulse oximetry is
predictive of adverse maternal outcome (maternal death and hepatic, central nervous system, renal,
cardiorespiratory, and hematological morbidities) [66].

The etiology of pulmonary edema in preeclampsia is multifactorial [67-70]. Excessive elevation in pulmonary
vascular hydrostatic pressure compared with decreased 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.

Oliguria — Urine output may decrease to <500 mL/24 hours in women at the severe end of the disease
spectrum. (See "Acute kidney injury (acute renal failure) in pregnancy", section on 'Preeclampsia with or without
HELLP'.)

Rarely, women with preeclamptic hepatic disease have developed polyuria due to transient diabetes insipidus of
pregnancy. The mechanism in these cases is decreased degradation of vasopressinase due to hepatic
dysfunction. (See "Polyuria and diabetes insipidus of pregnancy".)

Stroke — Stroke leading to death or disability is the most serious complication of preeclampsia/eclampsia,


which is responsible for approximately 36 percent of pregnancy-associated stroke [71]. 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 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. (See
"Cerebrovascular disorders complicating pregnancy", section on 'Preeclampsia, eclampsia, and HELLP'.)

Abruptio placentae — Abruption occurs in less than 1 percent of pregnancies with preeclampsia without
severe features but 3 percent of those with severe features [72]. (See "Placental abruption: Clinical features and
diagnosis" and "Placental abruption: Management".)

Seizure — Seizure in a preeclamptic woman upstages the diagnosis to eclampsia. Eclamptic seizures develop
in 1 in 400 women with preeclampsia without severe features and 1 in 50 women with preeclampsia with severe
features. Histopathologic correlates include brain hemorrhage, petechiae, edema, vasculopathy, ischemic
damage, microinfarcts, and fibrinoid necrosis [73,74]. Neuroimaging consistent with posterior reversible
encephalopathy syndrome may be seen [75]. (See "Eclampsia".)

Laboratory findings

Proteinuria — Proteinuria in preeclampsia can be defined as any of the following [2]:

● ≥0.3 g protein in a 24-hour urine specimen

● Random protein:creatinine ratio ≥0.3 mg protein/mg creatinine (some clinicians opt to confirm presence of
≥0.3 g protein with a 24-hour collection)

● Protein ≥1+ (30 mg/dL) on a paper test strip dipped into a fresh, clean voided midstream urine specimen
(only if one of the above quantitative methods is not available)

Proteinuria generally increases as preeclampsia progresses, but increased urinary protein excretion may be a late
finding [76,77]. It usually remains <5 g/day, but levels >10 g/day may be seen. Preeclampsia is the most common
cause of severe proteinuria in pregnant women.

Proteinuria 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 [80,81]. 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 signaling appears to account, at least in part, for these findings. (See
"Preeclampsia: Pathogenesis", section on 'Pathogenesis of systemic endothelial dysfunction'.)

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. This value can be used to estimate the 24-hour protein excretion
(calculator 1) [82-90]. Measurement of proteinuria is discussed in detail separately. (See "Proteinuria in
pregnancy: Evaluation and management".)

Elevated creatinine — The physiologic increase in glomerular filtration rate (GFR) during a normal pregnancy
results in a decrease in serum creatinine concentration, which falls by an average of 0.4 mg/dL (35 micromol/L)
to a range of 0.4 to 0.8 mg/dL (35 to 70 micromol/L). The serum creatinine concentration in women with
preeclampsia generally remains in this range or only slightly elevated. A creatinine level >1.1 mg/dL (97.3
micromol/L) concentration indicates the severe end of the disease spectrum. Some guidelines also include
doubling of the patient's baseline creatinine in the absence of other renal disease as indicative of the severe end
of the disease spectrum [2]. Although creatinine levels remain <1.5 mg/dL (133 micromol/L) in most patients,
preeclampsia is the most common cause of acute kidney injury in pregnancy. (See "Acute kidney injury (acute
renal failure) in pregnancy", section on 'Preeclampsia with or without HELLP'.)
The rise in serum creatinine is due primarily to a fall in GFR; renal plasma flow also decreases, but to a lesser
degree. In severe disease, reduced plasma volume due to capillary leaking and due to systemic vasoconstriction
lead to sodium retention and renal vasoconstriction.

Decreased platelet count — The platelet count is normal, unless the patient is at the severe end of the disease
spectrum, which is characterized by a platelet count less than 100,000/microL.

Thrombocytopenia is the most common coagulation abnormality in preeclampsia. 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 [91].

Hemolysis — Schistocytes and helmet cells on the peripheral blood smear (picture 1A-B) suggest
microangiopathic hemolysis, which is a finding at the severe end of the disease spectrum. Elevation in the serum
indirect bilirubin level also suggest hemolysis, whereas elevations in lactate dehydrogenase are usually related to
liver dysfunction.

Hemoconcentration — Hemoconcentration may result from a reduction of plasma volume due to capillary


leaking. Hematocrit typically increases. When both hemolysis and hemoconcentration occur concurrently, the
effects on hematocrit may negate each other, resulting in a normal value. (See "Thrombocytopenia in pregnancy"
and "Preeclampsia: Pathogenesis" and "Maternal adaptations to pregnancy: Hematologic changes".)

Coagulation studies — The prothrombin time, partial thromboplastin time, and fibrinogen concentration are
not affected by preeclampsia, unless there are additional complications, such as abruptio placentae, severe
bleeding, or severe liver dysfunction [92].

Liver chemistries — Liver function tests are normal, except at the severe end of the disease spectrum, which
is characterized by elevated transaminase levels (twice the upper limit of normal for the local laboratory).

Elevation in the serum indirect bilirubin level suggests hemolysis. (See 'Hemolysis' above.)

Abnormalities in liver chemistries are due to reduced hepatic blood flow, potentially resulting in ischemia and
periportal hemorrhage. Periportal and sinusoidal fibrin deposition and microvesicular fat deposition also occur
and may affect hepatocyte function [93,94].

Hyperuricemia — The association between hyperuricemia and preeclampsia has been known for decades.
The cause is most likely related to a 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 [95]. Although meta-analyses published in 2006 concluded that uric acid levels are not an
accurate predictor of complications associated with preeclampsia [96,97], 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 [98].

Other

● Urine sediment – The urine sediment is typically benign.

● Lipids – Women with preeclampsia appear to have changes in lipid metabolism resulting in higher total
cholesterol and triglyceride levels than normotensive pregnant women [99,100].

● Neutrophilia – The white blood count may be slightly higher in preeclampsia due to neutrophilia.
● Troponin – Preeclampsia is not associated with elevated troponin levels in the absence of cardiac disease
[101]. A small subgroup of women with severe preeclampsia may develop myocardial damage or global
diastolic dysfunction [102]. Therefore, 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 [103,104].

Imaging

Fetal ultrasound — Preeclampsia that develops clinically before term may be associated with suboptimal fetal
growth due to reduced uteroplacental perfusion [105] (see 'Overview of pathophysiology' above). Fetal growth
restriction may be accompanied by oligohydramnios due to redistribution of the fetal circulation away from the
kidneys and toward more vital organs, particularly the brain (see "Oligohydramnios"). In contrast, preeclampsia
that develops clinically at term tends to be associated with fetal growth that is appropriate for gestational age
and normal amniotic fluid volume. In some cases, the fetus may be large for gestational age [106-111].

Fetal anatomy is usually normal. However, three population-based studies have reported a relationship between
fetal congenital cardiac defects and maternal preeclampsia, particularly preterm preeclampsia [112-114]. It has
been hypothesized that characteristics of the maternal cardiovascular system impair adequate adaption to the
vascular load of pregnancy and this may be the primary mechanism leading to the development of preeclampsia
[115]. Shared angiogenic imbalance in the mother and fetus may explain the increased risk of congenital heart
disease in the offspring of these women.

Fetal hydrops of any etiology is an uncommon cause of preeclampsia-like symptoms. (See 'Mirror syndrome'
below.)

Uterine and umbilical artery Doppler — Increased impedance to flow in the uterine arteries due to
uteroplacental maldevelopment is 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 "Early pregnancy prediction of preeclampsia", section on 'Uterine artery Doppler velocimetry'.)

Increased resistance in the placental vasculature is 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".)

Maternal hemodynamic imaging studies — Preeclampsia can be associated with a highly variable


hemodynamic profile, including cardiac failure [116-120]. Changes in cardiac function and morphology may be
seen on echocardiography at an asymptomatic early stage and progress with increasing disease severity [121].
Preeclampsia does not affect the myocardium directly, but the heart responds to physiological changes induced
by the disease. Left ventricular ejection fraction usually remains within normal limits [122], but reductions in
longitudinal, circumferential, and radial systolic strain have been observed [123]. The decrement in left ventricular
performance has been attributed to a physiologic response to increased afterload [116,122,123], but other
factors may play a role since systolic strain was depressed in preeclamptic patients compared with pregnant
women with nonproteinuric hypertension and similar resting blood pressure [123].

The high afterload in preeclampsia is associated with elevated cardiac filling pressures, reflected by fourfold
higher concentrations of natriuretic peptides in women with preeclampsia compared with pregnant women who
are normotensive or who have chronic hypertension [117].

Intravascular volume may be reduced in preeclampsia, especially with severe features [124]. 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; however, this issue has not been
conclusively resolved.
Histologic findings

Placenta — Abnormalities in the placenta are believed to be a critical feature of the preeclampsia syndrome;
however, many findings are nonspecific. In blinded studies, the pooled prevalence of villous lesions in
preeclamptic and normal pregnancies was 42 and 19 percent, respectively, and the pooled prevalence of vascular
lesions was 39 and 10 percent, respectively [125].

The parenchymal finding most characteristically associated with preeclampsia is acute atherosis (ie, fibrinoid
necrosis of the vessel wall with an accumulation of lipid-laden "foamy" macrophages and a mononuclear
perivascular infiltrate). Cytotrophoblast invasion of the interstitial uterine compartment is frequently shallow, with
incomplete invasion and remodeling of spiral arteries in many places [126]. This maldevelopment of the
uteroplacental circulation can result in reduced placental perfusion, leading to placental infarcts, villous
hypoplasia, and, in some cases, the clinical sequelae of intrauterine growth restriction.

Placental histology is described in detail separately. (See "The placental pathology report", section on
'Preeclampsia'.)

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 endothelial cell swelling, loss of
fenestrations, and occlusion of capillary lumens (picture 2A-C) [127]. Foot process effacement is not a prominent
feature, despite marked proteinuria.

Glomerular endotheliosis shares histologic features with non-preeclamptic thrombotic microangiopathies [127],
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 [128,129].

NATURAL HISTORY/COURSE OF DISEASE — Preeclampsia can be a progressive disease. Although most women


develop signs of the disease in late pregnancy with gradual worsening until delivery, in approximately 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 [130]. It is important to note
that severe sequelae can occur in women without severe hypertension but who have clinical evidence of
significant end-organ dysfunction. Chest pain, dyspnea, and low platelet count appear to be particularly predictive
of fatal or life-threatening complications [131].

Delivery of the placenta always results in complete resolution of the maternal signs and symptoms of the
disease, with some symptoms disappearing in a matter of hours (eg, headache), while others may take weeks or
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 [132]. 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 [133].

Long-term prognosis is reviewed separately. (See "Preeclampsia: Management and prognosis", section on
'Prognosis'.)

DIAGNOSIS — Professional guidelines generally agree that the diagnosis of preeclampsia should be made in a
previously normotensive woman with new onset of hypertension and proteinuria after 20 weeks of gestation
[2,134-136]. In the absence of proteinuria, the diagnosis can still be made if new-onset hypertension is
accompanied by end-organ dysfunction, as shown in the following table (table 1).
Criteria for the severe end of the disease spectrum (called "preeclampsia with severe features," formerly "severe
preeclampsia") include the presence of any of the following:

● Severe hypertension: defined as systolic blood pressure ≥160 mmHg or diastolic blood pressure ≥110
mmHg; confirmation within 15 to 30 minutes is sufficient.

● New-onset cerebral or visual disturbance, such as:

• Photopsia, scotomata, cortical blindness, or retinal vasospasm.

• Severe headache (ie, incapacitating, "the worst headache I've ever had") or headache that persists and
progresses despite analgesic therapy.

• Altered mental status.

● Severe persistent right upper quadrant or epigastric pain unresponsive to medication and not accounted for
by an alternative diagnosis, or serum transaminase concentration ≥2 times upper limit of normal for a
specific laboratory, or both.

● <100,000 platelets/microL.

● Progressive renal insufficiency (serum creatinine >1.1 mg/dL [97.3 micromol/L]; some guidelines also
include doubling of serum creatinine concentration in the absence of other renal disease [2]).

● Pulmonary edema.

DIAGNOSTIC EVALUATION

Accurate assessment of blood pressure — Blood pressure is obtained after five minutes of rest, with the patient
sitting with feet on the ground and legs uncrossed or in a semi-reclining position with her back supported.
Whether sitting or in semi-Fowler, the arm should be supported and at heart level. The left or right lateral position
should not be used as the reading will not be true. Choose an appropriately sized cuff: width of bladder 40
percent of circumference and encircling 80 percent of the upper arm. Use a large adult cuff in women with an
upper-arm circumference 35 to 44cm, and use a thigh cuff if the upper-arm circumference is 45 to 52 cm. The
first audible sound (Kortokoff I) is the systolic pressure and the disappearance of sound (Kortokoff V) is the
diastolic pressure. Caffeine or nicotine within 30 minutes of measurement can increase readings. Additional
details regarding accurate assessment of blood pressure are reviewed separately. (See "Blood pressure
measurement in the diagnosis and management of hypertension in adults".)

Routine laboratory evaluation — Pregnant women with suspected preeclampsia due to hypertension and
proteinuria or hypertension and signs and symptoms associated with the severe end of the disease spectrum
(eg, headache, visual symptoms, epigastric pain, pulmonary edema) should have a complete blood count,
creatinine level, liver chemistries, and urinary protein determination (protein:creatinine ratio or 24-hour urine
protein).

Assessment of fetal status — Fetal status is assessed concurrent with the maternal diagnostic evaluation or
postdiagnosis, depending on the degree of concern when the mother is evaluated. At a minimum, a nonstress
test or biophysical profile is performed. Ultrasound is indicated to evaluate amniotic fluid volume and estimate
fetal weight, given the increased risk for oligohydramnios and fetal growth restriction.

Indications for neurology consultation — The neurology service should be consulted to evaluate women with
neurological deficits/abnormal neurological examination, ocular signs and symptoms, or a severe persistent
headache that does not respond to acetaminophen and initial routine management of preeclampsia.
The complaint of the sudden onset of severe headache ("worst headache of my life") is sufficiently characteristic
of subarachnoid hemorrhage that this diagnosis should prompt neurology consultation. The headache is
lateralized in 30 percent of patients and may or may not be associated with a brief period of altered
consciousness, nausea or vomiting, and meningismus. (See "Clinical manifestations and diagnosis of
aneurysmal subarachnoid hemorrhage".)

Measurement of angiogenic factors — In the future, measurement of urinary or plasma angiogenic factors
(soluble fms-like tyrosine kinase-1 [sFlt-1], placental growth factor [PlGF]) may be useful for distinguishing
preeclampsia from other hypertensive-proteinuric disorders; this test is commercially available in some countries
but still considered investigational and should be limited to patients in research studies [137-139].

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, PlGF'). It has also been
demonstrated that the ratio of sFlt-1/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
[140]. The study included 500 women with singleton pregnancies at 24 to 366/7ths 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. The latter can only be answered with a randomized
trial.

DIFFERENTIAL DIAGNOSIS — 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.

Pre-existing hypertension versus preeclampsia — In a prospective study, maternal blood pressure gradually fell
after 6 weeks of gestation, reached a nadir between weeks 16 and 20, and then gradually increased to
prepregnancy levels by term [141]. Because of the reduction in blood pressure that typically occurs early in
pregnancy, a woman with pre-existent 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 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 pre-existing hypertension rather than to
preeclampsia.

● Proteinuria is usually 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 [19]. (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 pre-existing hypertension, as are older multiparous women. (See 'Risk factors' above.)

Superimposed preeclampsia — Reproductive age women with primary (essential) hypertension typically have no
or mild proteinuria so severe proteinuria suggests development of superimposed preeclampsia. In women with
chronic/pre-existing 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 end of the disease spectrum.

Exacerbation of pre-existing renal disease — Superimposed preeclampsia frequently develops in women with


pre-existing primary or secondary renal disease [142,143]. However, worsening hypertension and proteinuria in a
woman with pre-existing 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) [144]. 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 antiphospholipid syndrome" and "Diagnosis
of antiphospholipid syndrome" and "Management of antiphospholipid syndrome in pregnant and postpartum
women".)

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, elevations in serum ammonia, and disseminated intravascular
coagulation are common features, while unusual in preeclampsia/HELLP. AFLP is also usually associated
with more significant renal dysfunction compared with preeclampsia/HELLP. (See "Acute fatty liver of
pregnancy".)

● Thrombotic thrombocytopenic purpura (TTP) or hemolytic uremic syndrome (HUS) – Although neurologic
abnormalities and acute renal failure are often seen in TTP and HUS, respectively, distinguishing among
related thrombotic microangiopathy syndromes may be challenging. An approach to the patient suspected
of having 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 preeclampsia. This disorder is called mirror or Ballantyne syndrome and resolves
without delivery if hydrops resolves. (See "Nonimmune hydrops fetalis", section on 'Mirror syndrome'.)

ATYPICAL PRESENTATIONS

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 preeclampsia with severe features 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'
above.)

Severe features of preeclampsia without hypertension — It is uncommon for women to exhibit the severe
features of preeclampsia without hypertension, but this may be observed in 15 percent of patients with HELLP
syndrome (which some consider a variant of preeclampsia and others consider a separate disorder) and in some
patients with eclampsia (a possible sequelae of preeclampsia). It is possible that in such patients, blood
pressure is increased above a lower baseline but does not meet diagnostic criteria for hypertension. (See
"Eclampsia", section on 'Can eclampsia be predicted and prevented?' and "HELLP syndrome".)

Isolated hypertension — Women with new onset of hypertension but no other criteria for preeclampsia or an
underlying disease associated with hypertension are given the diagnosis of gestational hypertension. These
women should be followed closely, since 15 to 25 percent will subsequently develop the full diagnostic criteria
for preeclampsia. (See "Gestational hypertension", section on 'Risk of progression to preeclampsia'.)

Isolated proteinuria — Isolated gestational proteinuria may be an early manifestation of preeclampsia [145],


although this is not well described and we are unaware of prospective studies describing this finding. In a
retrospective study of 95 pregnant women with new-onset isolated proteinuria who were followed to term, 13
developed preeclampsia during pregnancy and 8 developed preeclampsia postpartum [146].

Onset or exacerbation of symptoms >2 days postpartum — 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 [47], 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 for the signs and symptoms should be considered, such as cerebral
vasoconstriction syndrome or impending stroke [147-150]. Risk factors for delayed postpartum preeclampsia
appear to be similar to those for preeclampsia during pregnancy [47,151,152], 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 [47]. Of these patients,
14.5 percent developed postpartum eclampsia.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries
and regions around the world are provided separately. (See "Society guideline links: Hypertensive disorders of
pregnancy".)

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 10th 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 education: Preeclampsia (The Basics)" and "Patient education: High blood
pressure and pregnancy (The Basics)" and "Patient education: HELLP syndrome (The Basics)")

● Beyond the Basics topics (see "Patient education: 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. (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
(table 4). (See 'Risk factors' above.)

● The diagnosis of preeclampsia is based on the new onset of hypertension and proteinuria or end-organ
dysfunction with or without proteinuria after 20 weeks of gestation in a previously normotensive woman
(table 1). Severe hypertension or signs of end-organ dysfunction characterize the severe end of the disease
spectrum (table 2). (See 'Diagnosis' above.)

● At the first prenatal visit, we evaluate pregnant women for traditional risk factors for preeclampsia to identify
those at high risk for developing the disease. These women are offered low-dose aspirin therapy in the
second and third trimesters to reduce their risk of developing preeclampsia. (See "Early pregnancy prediction
of preeclampsia", section on 'Universal screening' and "Preeclampsia: Prevention", section on 'Candidates'.)

● At all provider visits throughout pregnancy, we recommend routinely measuring blood pressure to screen for
preeclampsia (Grade 1B). The value of any laboratory or imaging test as a screening tool, including routine
assessment of proteinuria at each visit, has not been established. (See 'Screening' 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. Delivery of the placenta always results in complete resolution of the maternal signs and
symptoms of the disease. (See 'Clinical presentation' above and 'Natural history/course of disease' above.)

● Pregnant women with suspected preeclampsia should have a complete blood count, creatinine level, liver
chemistries, and determination of urinary protein excretion. Fetal status is assessed concurrently or
postdiagnosis, depending on the degree of concern when the mother is evaluated. At a minimum, a
nonstress test or biophysical profile is performed. Ultrasound is indicated to evaluate amniotic fluid volume
and estimate fetal weight, given the increased risk for oligohydramnios and fetal growth restriction. (See
'Diagnostic evaluation' above.)

● Differential diagnosis includes exacerbation of underlying renal disease, acute fatty liver of pregnancy,
thrombotic thrombocytopenic purpura or hemolytic uremic syndrome, and exacerbation of systemic lupus
erythematosus. (See 'Differential diagnosis' above.)

● Atypical presentations of preeclampsia include onset before 20 weeks of gestation or after the second
postpartum day. Some patients initially present with gestational hypertension or proteinuria alone. Others
present with end-organ dysfunction, and minimal or even absent hypertension or proteinuria; these patients
are typically classified as HELLP syndrome (Hemolysis, Elevated Liver enzymes, Low Platelets). (See
'Atypical presentations' above.)

● Women with preeclampsia are at increased risk for life-threatening events, including placental abruption,
acute kidney injury, cerebral hemorrhage, hepatic failure or rupture, pulmonary edema, stroke, cardiac failure,
and progression to eclampsia. The fetus is at increased risk for growth restriction and medically or
obstetrically indicated preterm birth. (See 'Spectrum of disease' above and 'Burden of disease' above.)

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Topic 6814 Version 91.0


GRAPHICS

Criteria for the diagnosis of preeclampsia

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 g in a 24-hour urine specimen or protein/creatinine ratio ≥0.3 (mg/mg)(30 mg/mmol)

Dipstick ≥1+ if a quantitative measurement is unavailable

                                                                     OR

New-onset hypertension with the new onset of any of the following (with or without proteinuria):

Platelet count <100,000/microL

Serum creatinine >1.1 mg/dL (97.2 micromol/L) or doubling of the creatinine concentration in the absence of other renal disease

Liver transaminases at least twice the upper limit of the normal concentrations for the local laboratory

Pulmonary edema

Cerebral or visual symptoms (eg, new-onset and persistent headaches not responding to usual doses of analgesics*; blurred vision,
flashing lights or sparks, scotomata)

* Response to analgesia does not exclude the possibility of preeclampsia.

Adapted from: American College of Obstetricians and Gynecologists, Task Force on Hypertension in Pregnancy. 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 25.0


In a patient with preeclampsia, the presence of one or more of the following indicates a diagnosis of
"preeclampsia with severe features"

Symptoms of central nervous system dysfunction:


New-onset cerebral or visual disturbance, such as:
Photopsia, scotomata, cortical blindness, retinal vasospasm
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 ≥2 times the upper limit of the normal range, 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
(antihypertensive therapy may be initiated upon confirmation of severe hypertension, in which case criteria for severe blood pressure elevation can be
satisfied without waiting until four hours have elapsed)

Thrombocytopenia:
<100,000 platelets/microL

Renal abnormality:
Progressive renal insufficiency (serum creatinine >1.1 mg/dL [97.2 micromol/L] or a doubling of the 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 g/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 18.0


Criteria for gestational hypertension

New onset of systolic blood pressure ≥140 mmHg

OR

Diastolic blood pressure ≥90 mmHg

AND no proteinuria or signs of end-organ damage

Developing AFTER the 20 th week of gestation in women known to be normotensive before pregnancy. Blood pressure should be elevated
on at least two occasions at least six hours apart.

Graphic 56709 Version 3.0


Clinical factors that have been associated with an increased risk of developing preeclampsia

Nulliparity

Preeclampsia in a previous pregnancy

Age >40 years or <18 years

Family history of preeclampsia

Chronic hypertension

Chronic renal disease

Autoimmune disease (eg, antiphospholipid syndrome, systemic lupus erythematosus) 

Vascular disease

Diabetes mellitus (pregestational and gestational)

Multifetal gestation

Obesity

Black race

Hydrops fetalis

Woman herself was small for gestational age

Fetal growth restriction, abruptio placentae, or fetal demise in a previous pregnancy

Prolonged interpregnancy interval if the previous pregnancy was normotensive. If the previous pregnancy was preeclamptic, a short
interpregnancy interval increases the risk of recurrence.

Partner-related factors (new partner, limited sperm exposure [eg, previous use of barrier contraception])
In vitro fertilization

By comparison, smoking decreases the risk of preeclampsia, and Asian and Hispanic women have a lower risk of preeclampsia than
white women and a much lower risk than black women.

Graphic 61266 Version 6.0


Peripheral smear in microangiopathic hemolytic anemia showing
presence of schistocytes

Peripheral blood smear from a patient with a microangiopathic hemolytic anemia with
marked red cell fragmentation. The smear shows multiple helmet cells (arrows) and other
fragmented red cells (small arrowhead); microspherocytes are also seen (large
arrowheads). The platelet number is reduced; the large platelet in the center (dashed arrow)
suggests that the thrombocytopenia is due to enhanced destruction.

Courtesy of Carola von Kapff, SH (ASCP).

Graphic 70851 Version 8.0

Normal peripheral blood smear

High-power view of a normal peripheral blood smear. Several platelets (arrows) and a
normal lymphocyte (arrowhead) can also be seen. The red cells are of relatively uniform
size and shape. The diameter of the normal red cell should approximate that of the
nucleus of the small lymphocyte; central pallor (dashed arrow) should equal one-third of
its diameter.

Courtesy of Carola von Kapff, SH (ASCP).

Graphic 59683 Version 4.0


Helmet cells in microangiopathic hemolytic anemia

Peripheral smears from two patients with microangiopathic hemolytic anemia, showing a
number of red cell fragments (ie, schistocytes), some of which take the form of combat (arrow),
bicycle (arrowhead), or football (short arrow) "helmets." Microspherocytes are also seen (dashed
arrows), along with a nucleated red cell (thick arrow).

Courtesy of Carola von Kapff, SH (ASCP).

Graphic 50715 Version 4.0


Preeclampsia

Light micrograph in preeclampsia showing glomerular endotheliosis. The primary changes


are swelling of damaged endothelial cells, leading to partial closure of many of the capillary
lumens (arrows). Mitosis within an endothelial cell (short arrow) is a sign of cellular repair.

Courtesy of Helmut Rennke, MD.

Graphic 78879 Version 3.0

Normal glomerulus

Light micrograph of a normal glomerulus. There are only 1 or 2 cells per capillary tuft,
the capillary lumens are open, the thickness of the glomerular capillary wall (long arrow)
is similar to that of the tubular basement membranes (short arrow), and the mesangial
cells and mesangial matrix are located in the central or stalk regions of the tuft (arrows).

Courtesy of Helmut G Rennke, MD.

Graphic 75094 Version 4.0


Preeclampsia

Electron micrograph in preeclampsia showing narrowing of the capillary lumen due to


expansion of the mesangium, swelling of the endothelial (Endo) cell cytoplasm (arrow), and
subendothelial deposition of hyaline (Hy) material which represents large macromolecules
such as immunoglobulin M. The damaged endothelial cell has become partially separated
(*) from the glomerular basement membrane (GBM).

Courtesy of Helmut Rennke, MD.

Graphic 59970 Version 3.0

Electron micrograph of a normal glomerulus

Electron micrograph of a normal glomerular capillary loop showing the fenestrated


endothelial cell (Endo), the glomerular basement membrane (GBM), and the epithelial
cells with its interdigitating foot processes (arrow). The GBM is thin, and no electron-
dense deposits are present. Two normal platelets are seen in the capillary lumen.

Courtesy of Helmut G Rennke, MD.

Graphic 50018 Version 7.0


IgM deposition in preeclampsia

Immunofluorescence microscopy in preeclampsia showing diffuse immunoglobulin M (IgM)


deposition. This represents nonspecific entrapment of larger proteins in the more
permeable glomerular capillary wall, rather than the formation of discrete immune
complexes. There is, for example, generally no deposition of immunoglobulin G (IgG).

Courtesy of Helmut Rennke, MD.

Graphic 68634 Version 3.0


Frequency of various signs and symptoms among imitators of preeclampsia-eclampsia

Signs and HELLP syndrome, AFLP, TTP, HUS, Exacerbation of SLE,


symptoms percent percent percent percent percent

Hypertension 85 50 20 to 75 80 to 90 80 with APA, nephritis

Proteinuria 90 to 95 30 to 50 With 80 to 90 100 with nephritis


hematuria

Fever Absent 25 to 32 20 to 50 NR Common during flare

Jaundice 5 to 10 40 to 90 Rare Rare Absent

Nausea and vomiting 40 50 to 80 Common Common Only with APA

Abdominal pain 60 to 80 35 to 50 Common Common Only with APA

Central nervous 40 to 60 30 to 40 60 to 70 NR 50 with APA


system

HELLP: hemolysis, elevated liver enzymes, low platelets; AFLP: acute fatty liver of pregnancy; TTP: thrombotic thrombocytopenic purpura; HUS:
hemolytic uremic syndrome; SLE: systemic lupus erythematosus; APA: antiphospholipid antibodies with or without catastrophic antiphospholipid
syndrome; NR: values not reported; common: reported as the most common presentation.

Reproduced with permission from: Sibai BM. Imitators of severe preeclampsia. Obstet Gynecol 2007; 109:956. Copyright © 2007 Lippincott
Williams & Wilkins.

Graphic 64296 Version 10.0


Frequency and severity of laboratory findings among imitators of preeclampsia-eclampsia

HELLP Exacerbation of
Laboratory findings AFLP TTP HUS
syndrome SLE

Thrombocytopenia (less than More than 20,000 More than 20,000 or More than More than 20,000
100,000/mm 3) 50,000 less 20,000

Hemolysis (%) 50 to 100 15 to 20 100 100 14 to 23 with APA

Anemia (%) Less than 50 Absent 100 100 14 to 23 with APA

DIC (%) Less than 20 50 to 100 Rare Rare Rare

Hypoglycemia (%) Absent 50 to 100 Absent Absent Absent

VW factor multimers (%) Absent Absent 80 to 90 80 Less than 10

ADAMTS13 less than 5% (%) Absent Absent 33 to 100 Rare Rare

Impaired renal function (%) 50 90 to 100 30 100 40 to 80

LDH (international units/L) 600 or more Variable More than More than With APA
1000 1000

Elevated ammonia (%) Rare 50 Absent Absent Absent

Elevated bilirubin (%) 50 to 60 100 100 NA Less than 10

Elevated transaminases (%) 100 100 Usually mild* Usually mild* With APA

HELLP: hemolysis, elevated liver enzymes, low platelets; AFLP: acute fatty liver of pregnancy; TTP: thrombotic thrombocytopenic purpura; HUS:
hemolytic uremic syndrome; SLE: systemic lupus erythematosus; APA: antiphospholipid antibodies with or without catastrophic antiphospholipid
syndrome; DIC: disseminated intravascular coagulopathy; VW: von Willebrand; ADAMTS13: von Willebrand factor-cleaving metalloprotease; LDH:
lactic dehydrogenase; NR: values not reported.
* Levels less than 100 international units/L.

Reproduced with permission from: Sibai BM. Imitators of severe preeclampsia. Obstet Gynecol 2007; 109:956. Copyright © 2007 Lippincott
Williams & Wilkins.

Graphic 65674 Version 11.0


Contributor 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, FACOG Nothing to disclose

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