Preeclampsia is a disorder of widespread vascular endothelial malfunction and vasospasm

that occurs after 20 weeks' gestation and can present as late as 4-6 weeks postpartum. It is
clinically defined by hypertension and proteinuria, with or without pathologic edema.
The incidence of preeclampsia in the United States is estimated to range from 2% to 6% in
healthy, nulliparous women.[1, 2, 3] Among all cases of the preeclampsia, 10% occur in
pregnancies of less than 34 weeks' gestation. The global incidence of preeclampsia has been
estimated at 5-14% of all pregnancies.
In developing nations, the incidence of the disease is reported to be 4-18%, [4, 5]with
hypertensive disorders being the second most common obstetric cause of stillbirths and early
neonatal deaths in these countries.[6]
Medical consensus is lacking regarding the values that define preeclampsia, but reasonable
criteria in a woman who was normotensive before 20 weeks' gestation include a systolic blood
pressure (SBP) greater than 140 mm Hg and a diastolic BP (DBP) greater than 90 mm Hg on
2 successive measurements, 4-6 hours apart. Preeclampsia in a patient with preexisting
essential hypertension is diagnosed if SBP has increased by 30 mm Hg or if DBP has
increased by 15 mm Hg.

Mild and severe preeclampsia

Preeclampsia is mild in 75% of cases and severe in 25% of them. [7] In its extreme, the disease
may lead to liver and renal failure, disseminated intravascular coagulopathy (DIC), and central
nervous system (CNS) abnormalities. If preeclampsia-associated seizures develop, the
disorder has developed into the condition called eclampsia.
Mild preeclampsia is defined as the presence of hypertension (BP 140/90 mm Hg) on 2
occasions, at least 6 hours apart, but without evidence of end-organ damage in the patient.
Severe preeclampsia is defined as the presence of 1 of the following symptoms or signs in
the presence of preeclampsia:

SBP of 160 mm Hg or higher or DBP of 110 mm Hg or higher on 2 occasions at least

6 hours apart
Proteinuria of more than 5 g in a 24-hour collection or more than 3+ on 2 random
urine samples collected at least 4 hours apart
Pulmonary edema or cyanosis
Oliguria (< 400 mL in 24 h)
Persistent headaches
Epigastric pain and/or impaired liver function
Thrombocytopenia
Oligohydramnios, decreased fetal growth, or placental abruption

Classification and Characteristics of Hypertensive Disorders

Preeclampsia is part of a spectrum of hypertensive disorders that complicate pregnancy. As
specified by the National High Blood Pressure Education Program (NHBPEP) Working Group,
the classification is as follows[8] :

Gestational hypertension
Chronic hypertension
Preeclampsia/eclampsia
Superimposed preeclampsia (on chronic hypertension)
Although each of these disorders can appear in isolation, they are thought of as progressive
manifestations of a single process and are believed to share a common etiology.

Gestational hypertension
The characteristics of gestational hypertension are as follows:

BP of 140/90 mm Hg or greater for the first time during pregnancy

No proteinuria

BP returns to normal less than 12 weeks' postpartum

Final diagnosis made only postpartum

Chronic hypertension
Chronic hypertension is characterized by either (1) a BP 140/90 mm Hg or greater before
pregnancy or diagnosed before 20 weeks' gestation; not attributable to gestational
trophoblastic disease or (2) hypertension first diagnosed after 20 weeks' gestation and
persistent after 12 weeks postpartum.
Preexisting chronic hypertension may present with superimposed preeclampsia presenting as
new-onset proteinuria after 20 weeks' gestation.

Preeclampsia/eclampsia
Preeclampsia/eclampsia is characterized by a BP of 140/90 mm Hg or greater after 20 weeks'
gestation in a women with previously normal BP and who have proteinuria ( 0.3 g protein in
24-h urine specimen).
Eclampsia is defined as seizures that cannot be attributable to other causes, in a woman with
preeclampsia

Superimposed preeclampsia
Superimposed preeclampsia (on chronic hypertension) is characterized by (1) new onset
proteinuria ( 300 mg/24 h) in a woman with hypertension but no proteinuria before 20 weeks'
gestation and (2) a sudden increase in proteinuria or BP, or a platelet count of less than
100,000/mm3, in a woman with hypertension and proteinuria before 20 weeks' gestation.

HELLP syndrome
HELLP syndrome (hemolysis, elevated liver enzyme, low platelets) may be an outcome of
severe preeclampsia, although some authors believe it to have an unrelated etiology. The
syndrome has been associated with particularly high maternal and perinatal morbidity and
mortality rates and may be present without hypertension or, in some cases, without
proteinuria.

Proteinuria
Proteinuria is defined as the presence of at least 300 mg of protein in a 24-hour urine
collection. Some investigators and clinicians have accepted a urine protein-creatinine ratio of
at least 0.3 as a criterion for proteinuria, but the American College of Obstetricians and
Gynecologists (ACOG) has not yet incorporated this into their definition. [9] In the emergency
department, a urine protein-to-creatinine ratio of 0.19 or greater is somewhat predictive of
significant proteinuria (negative predictive value [NPV], 87%). [10] Serial confirmations 6 hours
apart increase the predictive value. Although more convenient, a urine dipstick value of 1+ or
more (30 mg/dL) is not reliable in the diagnosis of proteinuria.

Pathophysiology
In the fetus, preeclampsia can lead to ischemic encephalopathy, growth retardation, and the
various sequelae of premature birth.
Eclampsia is estimated to occur in 1 in 200 cases of preeclampsia when magnesium
prophylaxis in not administered. (See Seizure Prophylaxis.)[11, 12]

Cardiovascular disease
As previously mentioned, preeclampsia is characterized by endothelial dysfunction in
pregnant women. Therefore, the possibility exists that preeclampsia may be a contributor to
future cardiovascular disease. In a meta-analysis, several associations were observed
between an increased risk of cardiovascular disease and a pregnancy complicated by
preeclampsia. These associations included an approximately 4-fold increase in the risk of

subsequent development of hypertension and an approximately 2-fold increase in the risk of

ischemic heart disease, venous thromboembolism, and stroke. [13] Moreover, women who had
recurrent preeclampsia were more likely to suffer from hypertension later in life. [13]
In a review of population-based studies, Harskamp and Zeeman noted a relationship between
preeclampsia and an increased risk of later chronic hypertension and cardiovascular
morbidity/mortality, compared with normotensive pregnancy. Moreover, women who develop
preeclampsia before 36 weeks' gestation or who have multiple hypertensive pregnancies
were at highest risk.[14]
Harskamp and Zeeman also found that the underlying mechanism for the remote effects of
preeclampsia is complex and probably multifactorial. The risk factors that are shared by
cardiovascular disease and preeclampsia are as follows:

Endothelial dysfunction
Obesity
Hypertension
Hyperglycemia
Insulin resistance
Dyslipidemia

Metabolic syndrome, the investigators noted, may be a possible underlying mechanism

common to cardiovascular disease and preeclampsia.

Mechanisms behind preeclampsia

Although hypertension may be the most common presenting symptom of preeclampsia, it
should not be viewed as the initial pathogenic process.
The mechanisms by which preeclampsia occurs is not certain, and numerous maternal,
paternal, and fetal factors have been implicated in its development. The factors currently
considered to be the most important include the following[15] :

Maternal immunologic intolerance

Abnormal placental implantation
Genetic, nutritional, and environmental factors
Cardiovascular and inflammatory changes

Immunologic factors have long been considered to be key players in preeclampsia.

One important component is a poorly understood dysregulation of maternal tolerance
to paternally derived placental and fetal antigens. [16] This maternal-fetal immune
maladaptation is characterized by defective cooperation between uterine natural
killer(NK) cells and fetal human leukocyte antigen (HLA)-C, and results in histologic
changes similar to those seen in acute graft rejection.
The endothelial cell dysfunction that is characteristic of preeclampsia may be partially
due to an extreme activation of leukocytes in the maternal circulation, as evidenced
by an upregulation of type 1 helper T cells.

Placentation in Preeclampsia
Placental implantation with abnormal trophoblastic invasion of uterine vessels is a major
cause of hypertension associated with preeclampsia syndrome. [17, 18] In fact, studies have
shown that the degree of incomplete trophoblastic invasion of the spiral arteries is directly
correlated with the severity of subsequent maternal hypertension. This is because the

placental hypoperfusion resulting from the incomplete invasion leads by an unclear pathway
to the release of systemic vasoactive compounds that cause an exaggerated inflammatory
response, vasoconstriction, endothelial damage, capillary leak, hypercoagulability, and
platelet dysfunction, all of which contribute to organ dysfunction and the various clinical
features of the disease.

Normal placentation and pseudovascularization

In normal pregnancies, a subset of cytotrophoblasts called invasive cytotrophoblasts migrate
through the implantation site and invade decidua tunica media of maternal spiral arteries and
replace its endothelium in a process called pseudovascularization. [19] The trophoblast
differentiation along the invasive pathway involves alteration in the expression of a number of
different classes of molecules, including cytokines, adhesion molecules, extracellular matrix,
metalloproteinases, and the class Ib major histocompatibility complex (MHC) molecule, HLAG.[20, 21]
For example, during normal differentiation, invading trophoblasts alter their adhesion
molecule expression from those that are characteristic of epithelial cells (integrins alpha
6/beta 1, alpha V/beta 5, and E-cadherin) to those of endothelial cells (integrins alpha 1/beta
1, alpha V/beta 3, and VE-cadherin).
As a result of these changes, the maternal spiral arteries undergo transformation from small,
muscular arterioles to large capacitance, low-resistance vessels. This allows increased blood
flow to the maternal-fetal interface. Remodeling of these arterioles probably begins in the first
trimester and ends by 18-20 weeks' gestation. However, the exact gestational age at which
the invasion stops is unknown.

Failure of pseudovascularization in preeclampsia

The shallow placentation noted in preeclampsia results from the fact that the invasion of the
decidual arterioles by cytotrophoblasts is incomplete. This is due to a failure in the alterations
in molecular expression necessary for the differentiation of the cytotrophoblasts, as required
for pseudovascularization. For example, the upregulation of matrix metalloproteinase-9
(MMP-9) and HLA-G, 2 molecules noted in normally invading cytotrophoblasts, does not
occur.
The invasive cytotrophoblasts therefore fail to replace tunica media, which means that mostly
intact arterioles, which are capable of vasoconstriction, remain. Histologic evaluation of the
placental bed demonstrates few cytotrophoblasts beyond the decidual layer.
The primary cause for the failure of these invasive cytotrophoblasts to undergo
pseudovascularization and invade maternal blood vessels is not clear. However, immunologic
and genetic factors have been proposed. Early hypoxic insult to differentiating
cytotrophoblasts has also been proposed as a contributing factor.

Endothelial Dysfunction
Data show that an imbalance of proangiogenic and antiangiogenic factors produced by the
placenta may play a major role in mediating endothelial dysfunction. Angiogenesis is critical
for successful placentation and the normal interaction between trophoblasts and endothelium.
(See Angiogenic Factors in Preeclampsia, below.)
Several circulating markers of endothelial cell injury have been shown to be elevated in
women who develop preeclampsia before they became symptomatic. These include
endothelin, cellular fibronectin, and plasminogen activator inhibitor-1, with an altered
prostacyclin/thromboxane profile also present.[22, 23]

Evidence also suggests that oxidative stress, circulatory maladaptation, inflammation, and
humoral, mineral, and metabolic abnormalities contribute to the endothelial dysfunction and
pathogenesis of preeclampsia.

Angiogenic Factors in Preeclampsia

The circulating proangiogenic factors secreted by the placenta include vascular endothelial
growth factor (VEGF) and placental growth factor (PlGF). The antiangiogenic factors include
soluble fms-like tyrosine kinase I receptor (sFlt-1) (otherwise known as soluble VEGF
receptor type I) and soluble endoglin (sEng).

VEGF and PlGF

VEGF and PlGF promote angiogenesis by interacting with the VEGF receptor family. Although
both growth factors are produced by placenta, the serum level of PlGF rises much more
significantly in pregnancy. In a study, Taylor et al demonstrated that the serum level of PlGF
decreased in women who later developed preeclampsia. [24] The fall in serum level was notable
as early as the second trimester in women who developed preeclampsia and intrauterine
growth restriction.
In another investigation, Maynard et al observed that the serum levels of VEGF and PlGF
were decreased in women with preeclampsia.[25] However, the magnitude of decrease was
less pronounced for VEGF, as its serum level was not as high as that of PlGF, even in normal
pregnancy. Other investigators have confirmed this finding and have shown that the serum
level of PlGF decreased in women before they developed preeclampsia. [26, 27]
Bills et al suggest that circulating VEGF-A levels in preeclampsia are biologically active
because of a loss of repression of VEGF-receptor 1 signaling by PlGF-1, and VEGF 165 b may
be involved in the increased vascular permeability of preeclampsia. [28]

Soluble fms-like tyrosine kinase 1 receptor

The receptor sFlt-1 is a soluble isoform of Flt-1, which is a transmembrane receptor for VEGF.
Although sFlt-1 lacks the transmembrane domain, it contains the ligand-binding region and is
capable of binding circulating VEGF and PlGF, preventing these growth factors from binding
to transmembrane receptors. Thus, sFlt-1 has an antiangiogenic effect.
In addition to angiogenesis, VEGF and PlGF are important in maintaining endothelial
homeostasis. Selective knockout of the glomerular VEGF gene has been shown to be lethal
in rats, whereas the heterozygotes were born with glomerular endotheliosis (the renal lesion
characteristic of preeclampsia) and eventually renal failure. Furthermore, sFlt-1, when
injected into pregnant rats, produced hypertension and proteinuria along with glomerular
endotheliosis.[25]
In addition to animal studies, multiple studies in humans have demonstrated that excess
production of sFlt-1 is associated with an increased risk of preeclampsia. In a case-control
study that measured levels of sFlt-1, VEGF, and PlGF, investigators found an earlier and
greater increase in the serum level of sFlt-1 in women who developed preeclampsia (21-24
wk) than in women who did not develop preeclampsia (33-36 wk), whereas the serum levels
of VEGF and PlGF deceased. Furthermore, the serum level of sFlt-1 was higher in women
who developed severe preeclampsia or early preeclampsia (< 34 wk) than it was in women
who developed mild preeclampsia at term.[26]

Soluble endoglin
sEng is a soluble isoform of co-receptor for transforming growth factor beta (TGF-beta).
Endoglin binds to TGF-beta in association with the TGF-beta receptor. Because the soluble

isoform contains the TGF-beta binding domain, it can bind to circulating TGF-beta and
decrease circulating levels. In addition, TGF-beta is a proangiogenic molecule, so the net
effect of high levels of sEng is anti-angiogenic.
Several observations support the role of sEng in the pathogenesis of preeclampsia. It is found
in the blood of women with preeclampsia up to 3 months before the clinical signs of the
condition, its level in maternal blood correlates with disease severity, and the level of sEng in
the blood drops after delivery.[29]
In studies on pregnant rats, administration of sEng results in vascular permeability and
causes hypertension. There is also evidence that it has a synergistic relationship with sFlt-1,
because it increases the effects of sFlt-1 in pregnant rats; this results in HELLP syndrome, as
evidenced by hepatic necrosis, hemolysis, and placental infarction. [30] Moreover, sEng inhibits
TGF-beta in endothelial cells and also inhibits TGF-beta-1 activation of nitric oxide mediated
vasodilatation.

Genetic Factors in Preeclampsia

Preeclampsia has been shown to involve multiple genes. Over 100 maternal and paternal
genes have been studied for their association with preeclampsia, including those known to
play a role in vascular diseases, BP regulation, diabetes, and immunologic functions.
Importantly, the risk of preeclampsia is positively correlated between close relatives; a study
showed that 20-40% of daughters and 11-37% of sisters of women with preeclampsia also
developed the disease.[16] Twin studies have shown a high correlation as well, approaching
40%.
Because preeclampsia is a genetically and phenotypically complex disease, it is unlikely that
any single gene will be shown to play a dominant role in its development.

Additional Factors in Preeclampsia

Other substances that have been proposed, but not proven, to contribute to preeclampsia
include tumor necrosis factor, interleukins, various lipid molecules, and syncytial knots. [31]

Risk Factors for Preeclampsia

The incidence of preeclampsia is higher in women with a history of preeclampsia, multiple
gestations, and chronic hypertension or underlying renal disease. In addition, Lykke et al
found that preeclampsia, spontaneous preterm delivery, or fetal growth deviation in a first
singleton pregnancy predisposes women to those complications in their second pregnancy,
especially if the complications were severe.[32]

Gestational age
In a registry-based cohort study of 536,419 Danish women, delivery between 32 and 36
weeks gestation increased the risk of preterm delivery in the second pregnancy from 2.7% to
14.7% and increased the risk of preeclampsia from 1.1% to 1.8%. A first delivery before 28
weeks increased the risk of a second preterm delivery to 26% and increased the risk of
preeclampsia to 3.2%.
Preeclampsia in a first pregnancy, with delivery between 32 and 36 weeks' gestation,
increased the risk of preeclampsia in a second pregnancy from 14.1% to 25.3%. Fetal growth
2-3 standard deviations below the mean in a first pregnancy increased the risk of
preeclampsia from 1.1% to 1.8% in the second pregnancy.[32]

Primigravid patients in particular seem to be predisposed to preeclampsia.

Maternal age
Women aged 35 years and older have a markedly increased risk of preeclampsia.

Race
In the United States, the incidence of preeclampsia is 1.8% among white women and 3% in
black women.

Additional risk factors

Some risk factors contribute to poor placentation, whereas others contribute to increased
placental mass and poor placental perfusion secondary to vascular abnormalities. [33]
In addition to those discussed above, preeclampsia risk factors also include the following:

Hydatidiform mole
Obesity
Thrombophilia
Oocyte donation or donor insemination
Urinary tract infection
Diabetes
Collagen vascular disease
Periodontal disease[34]
One literature review suggests that maternal vitamin D deficiency may increase the risk of
preeclampsia and fetal growth restriction. Another study determined that vitamin D
deficiency/insufficiency was common in a group of women at high risk for preeclampsia.
However, it was not associated with the subsequent risk of an adverse pregnancy outcome. [35]
Studies have suggested that smoking during pregnancy is associated with a reduced risk of
gestational hypertension and preeclampsia; however, this is controversial. [21] Placenta previa
has also been correlated with a reduced risk of preeclampsia.
Body weight is strongly correlated with progressively increased preeclampsia risk, ranging
from 4.3% for women with a body mass index (BMI) < 20 kg/m2 to 13.3% in those with a BMI
>35 kg/m2. A United Kingdom study on obesity showed that 9% of extremely obese women
were preeclamptic, compared with 2% of matched controls. [36]
Table 1 lists the risk factors and their odds ratios for preeclampsia. [33]
Table 1. Risk Factors for Preeclampsia* (Open Table in a new window)
Nulliparity

3:1

Age >40 y

3:1

Black race

1.5:1

Family history

5:1

Chronic renal disease

20:1

Chronic hypertension

10:1

Antiphospholipid syndrome

10:1

Diabetes mellitus

2:1

Twin gestation (but unaffected by zygosity)

4:1

High body mass index

3:1

Angiotensinogen gene T235

Homozygous

20:1

Heterozygous

4:1

*Adapted from ACOG Technical Bulletin 219, Washington, DC 1996.[9]

Evaluation of Preeclampsia
Because the clinical manifestations of preeclampsia can be heterogeneous, diagnosing
preeclampsia may not be straightforward. In particular, because the final diagnosis of
gestational hypertension can only be made in retrospect, a clinician may be forced to treat
some women with gestational hypertension as if they have preeclampsia. In addition, if a
woman has underlying renal or cardiovascular disease, the diagnosis of preeclampsia may
not become clear until the disease becomes severe.
Mild to moderate preeclampsia may be asymptomatic. Many cases are detected through
routine prenatal screening.
Preeclampsia in a previous pregnancy is strongly associated with recurrence in subsequent
pregnancies. A history of gestational hypertension or preeclampsia should strongly raise
clinical suspicion.

Physical findings
Patients with severe preeclampsia display end-organ effects and may complain of the
following:

Headache
Visual disturbances - Blurred, scintillating scotomata
Altered mental status
Blindness - May be cortical[22] or retinal
Dyspnea
Edema
Epigastric or right upper quadrant abdominal pain
Weakness or malaise - May be evidence of hemolytic anemia
Edema exists in many pregnant women, but a sudden increase in edema or facial edema is
suggestive of preeclampsia. The edema of preeclampsia occurs by a distinct mechanism that
is similar to that of angioneurotic edema.
Hepatic involvement occurs in 10% of women with severe preeclampsia. The resulting pain
(epigastric or right upper quadrant abdominal pain) is frequently accompanied by elevated
serum hepatic transaminase levels.
The presence of clonus may indicate an increased risk of convulsions.

A study by Cooray et al found that the most common symptoms that immediately precede
eclamptic seizures are neurologic symptoms (ie, headache, with or without visual
disturbance), regardless of degree of hypertension. This suggests that closely monitoring
patients with these symptoms may provide an early warning for eclampsia. [37]

Recurrence of preeclampsia
Uncommonly, patients have antepartum preeclampsia that is treated with delivery but that
recurs in the postpartum period.[38] Recurrent preeclampsia should be considered in
postpartum patients who present with hypertension and proteinuria. (See Prognosis.)
In patients who are suffering a recurrence of preeclampsia, findings on physical examination
may include the following (see Prognosis):

Altered mental status

Decreased vision or scotomas
Papilledema
Epigastric or right upper quadrant abdominal tenderness
Peripheral edema Hyperreflexia or clonus: Although deep tendon
reflexes are more useful in assessing magnesium toxicity, the presence of
clonus may indicate an increased risk of convulsions.
Seizures
Focal neurologic deficit
Measurement of Hypertension
Hypertension is diagnosed when 2 BP readings of 140/90 mm Hg or greater are noted 6
hours apart within a 1-week period. Measuring BP with an appropriate-sized cuff placed on
the right arm at the same level as the heart is important. The patient must be sitting and,
ideally, have had a chance to rest for at least 10 minutes before the BP measurement. She
should not be lying down in a lateral decubitus position, as the arm often used to measure the
pressure in this position will be above the right atrium.
The Korotkoff V sound should be used for the diastolic pressure. In cases in which the
Korotkoff V sound is not present, the Korotkoff IV sound may be used, but it should be noted
as such. The difference between the Korotkoff IV and V sounds may be as much as 10 mm
Hg. When an automated cuff is used, it must be able to record the Korotkoff V sound. When
serial readings are obtained during an observational period, the higher values should be used
to make the diagnosis.

Lack of hypertension on examination

Although hypertension is an important characteristic of preeclampsia, because the underlying
pathophysiology of preeclampsia is a diffuse endothelial cell disorder influencing multiple
organs, hypertension does not necessarily need to precede other preeclamptic symptoms or
laboratory abnormalities. Presenting symptoms other than hypertension may include, as
previously mentioned, edema, visual disturbances, headache, and epigastric or right upper
quadrant tenderness.

Diagnostic Considerations
Gestational hypertension

During diagnosis, preeclampsia must be differentiated from gestational hypertension;

although gestational hypertension is more common and may present with symptoms similar to
those of preeclampsia, including epigastric discomfort or thrombocytopenia, it is which is not
characterized by proteinuria. (See Classification and Characteristics of Hypertensive
Disorders.)

Placental hypoperfusion
Placental hypoperfusion or ischemia in preeclampsia has many causes. Preexisting vascular
disorders, such as hypertension and connective tissue disorders, can result in poor placental
circulation. In cases of multiple gestation or increased placental mass, it is not surprising for
the placenta to become underperfused. However, most women who develop preeclampsia
are healthy and do not have underlying medical conditions. In this group of women,
abnormally shallow placentation has been shown to be responsible for placental
hypoperfusion. (See Placentation in Preeclampsia.)

Differential diagnosis
Abdominal Trauma, Blunt
Abruptio Placentae
Aneurysm, Abdominal
Appendicitis, Acute
Cholecystitis and Biliary Colic
Cholelithiasis
Congestive Heart Failure and Pulmonary Edema
Domestic Violence
Early Pregnancy Loss
Encephalitis
Headache, Tension
Hypertensive Emergencies
Hyperthyroidism, Thyroid Storm, and Graves Disease
Migraine Headache
Ovarian Torsion
Pregnancy, Eclampsia
Status Epilepticus
Stroke, Hemorrhagic
Stroke, Ischemic

Subarachnoid Hemorrhage
Subdural Hematoma
Thrombotic Thrombocytopenic Purpura
Toxicity, Amphetamine
Toxicity, Sympathomimetic
Toxicity, Thyroid Hormone
Transient Ischemic Attack
Urinary Tract Infection, Female
Withdrawal Syndromes
Cerebrovascular accidents
Seizure disorders
Brain tumors
Metabolic diseases
Metastatic gestational trophoblastic disease
Thrombotic thrombocytopenic purpura

Routine Studies
All women who present with new-onset hypertension should have the following laboratory
tests:

Complete blood cell (CBC) count

Serum alanine aminotransferase (ALT) and aspartate aminotransferase
(AST) levels
Serum creatinine
Uric acid
In addition, a peripheral smear should be performed, serum lactate dehydrogenase (LDH)
levels should be measured, and an indirect bilirubin should be carried out if HELLP syndrome
is suspected. Although a coagulation profile (prothrombin time [PT], activated partial [aPTT],
and fibrinogen) should also be evaluated, the clinical use of routine evaluation is unclear
when the platelet count is 100,000/mm3 or more with no evidence of bleeding. [39]
Laboratory values for preeclampsia and HELLP syndrome
Renal values are as follows:

Proteinuria of >300 mg/24 h

Urine dipstick >1+
Protein/creatinine ratio >0.3*

[8, 40]

Serum uric acid >5.6 mg/dL*

Serum creatinine >1.2 mg/dL
Platelet/coagulopathy-related results are as follows:

Platelet count < 100,000/mm3

Elevated PT or aPTT*
Decreased fibrinogen*
Increased d-dimer*
Hemolysis-related results are as follows:

Abnormal peripheral smear*

Indirect bilirubin >1.2 mg/dL*
Lactate dehydrogenase >600 U/L*
In addition, elevated liver enzymes (serum AST >70 U/L) are found in preeclampsia and
HELLP syndrome.[19]

Urine tests
To diagnose proteinuria, a 24-hour urine collection for protein and creatinine should be
obtained whenever possible. Up to 30% of women with gestational hypertension who have
trace protein noted on random urine samples may have 300 mg of protein in a 24-hour urine
collection.[41] Thus, a 24-hour urine protein analysis remains the criterion standard for
proteinuria diagnosis. Alternatively, greater than 1+ protein on a dipstick analysis on a random
sample is sufficient to make the diagnosis of proteinuria.
Random urine samples can be used to calculate the protein-creatinine ratio. Thresholds of
0.14-0.3 have been proposed for diagnosing proteinuria. [42]However, there is no agreement yet
as to the best threshold for identifying pregnant women with significant proteinuria. Moreover,
up to 10% of patients with preeclampsia and 20% of patients with eclampsia may not have
proteinuria.[43, 44](HELLP syndrome has been known to occur without hypertension or
proteinuria.)
Hyperuricemia is one of the earliest laboratory manifestations of preeclampsia. It has a low
sensitivity, ranging from 0% to 55%, but a relatively high specificity of 77-95%. [45] Serial levels
may be useful to indicate disease progression.
Baweja et al suggest that when measuring urinary albumin using high-performance liquid
chromatography in an early and uncomplicated pregnancy, spot urinary albumin:creatinine
ratio (ACR) values are higher. If measured early in the second trimester, an ACR of 35.5
mg/mmol or higher may predict preeclampsia before symptoms arise. [46]

Congo red dye

A study at Yale University has shown preliminary results that Congo red, a dye currently used
to locate atypical amyloid aggregates in Alzheimer disease, may also be effective in the early
diagnosis of preeclampsia.[45] This finding may lead to a spot urine test that can be used in
emergency departments and internationally, especially in resource-poor countries where
preeclampsia continues to be underdiagnosed and accounts for a large percentage of
maternal and fetal mortality.

Liver enzymes

Although controversy exists over the threshold for elevated liver enzyme, the values proposed
by Sibai et al (AST of >70 U/L and LDH of >600 U/L) appear to be the most widely accepted.
Alternatively, values that are 3 standard deviations away from the mean for each laboratory
value may be used for AST.[40]

Histology
The presence of schistocytes, burr cells, or echinocytes on peripheral smears, or elevated
indirect bilirubin and low serum heptoglobin levels, may be used as evidence of hemolysis in
diagnosing HELLP syndrome. The differential diagnosis for HELLP syndrome must include
various causes for thrombocytopenia and liver failure such as acute fatty liver of
pregnancy, hemolytic uremic syndrome, acute pancreatitis, fulminant hepatitis, systemic lupus
erythematosus, cholecystitis, and thrombotic thrombocytopenic purpura.

Additional laboratory tests

Other laboratory values suggestive of preeclampsia include an elevation in hematocrit and a
rise in serum creatinine and/or uric acid. Although these laboratory abnormalities increase the
suspicion for preeclampsia, none of these laboratory tests should be used to diagnose
preeclampsia.

CT Scanning and MRI

Computed tomography (CT) scanning and magnetic resonance imaging (MRI) scans have
revealed numerous abnormalities in patients with eclampsia, such as cerebral edema, focal
infarction, intracranial hemorrhage, and posterior leukoencephalopathy.[47]
Currently, however, there is no pathognomonic CT scan or MRI finding for eclampsia.
Furthermore, cerebral imaging is not necessary for the conditions diagnosis and
management. However, head CT scanning is used to detect intracranial hemorrhage in
selected patients with sudden severe headaches, focal neurologic deficits, seizures with a
prolonged postictal state, or atypical presentation for eclampsia.

Ultrasonography
Ultrasonography is used to assess the status of the fetus as well as to evaluate for growth
restriction (typically asymmetricaluse abdominal circumference). Aside from transabdominal
ultrasonography, umbilical artery Doppler ultrasonography should be performed to assess
blood flow. The value of Doppler ultrasonography in other fetal vessels has not been
demonstrated.

Cardiotocography
Cardiotocography is the standard fetal nonstress test and the mainstay of fetal monitoring.
Although it gives continuing information about fetal well being, it has little predictive value.

Management of Preeclampsia
The optimal management of a woman with preeclampsia depends on gestational age and
disease severity. Because delivery is the only cure for preeclampsia, clinicians must try to
minimize maternal risk while maximizing fetal maturity. The primary objective is the safety of
the mother and then the delivery of a healthy newborn. Obstetric consultation should be
sought early to coordinate transfer to an obstetric floor, as appropriate. [48]

Patients with mild preeclampsia are often induced after 37 weeks' gestation. Before this, the
immature fetus is treated with expectant management with corticosteroids to accelerate lung
maturity in preparation for early delivery.
In patients with severe preeclampsia, induction of delivery should be considered after 34
weeks' gestation. In these cases, the severity of disease must be weighed against the risks of
infant prematurity. In the emergency setting, control of BP and seizures should be priorities. In
general, the further the pregnancy is from term, the greater the impetus to manage the patient
medically.

Prehospital Treatment
Prehospital care for pregnant patients with suspected preeclampsia includes the following:

Oxygen via face mask

Intravenous access
Cardiac monitoring
Transportation of patient in left lateral decubitus position
Seizure precautions
Care in Mild Preeclampsia
Before 37 weeks, expectant management is appropriate. In most cases, patients should be
hospitalized and monitored carefully for the development of worsening preeclampsia or
complications of preeclampsia. Although randomized trials in women with gestational
hypertension and mild preeclampsia demonstrate the safety of outpatient management with
frequent maternal and fetal evaluations, most of the patients in these studies had mild
gestational hypertension.[49]Therefore, the safety of managing a woman with mild
preeclampsia as an outpatient still needs to be investigated.
Although bedrest has been recommended in women with preeclampsia, little evidence
supports its benefit. In fact, prolonged bed rest during pregnancy increases the risk of
thromboembolism.
A pregnancy complicated by mild preeclampsia at or beyond 37 weeks should be delivered.
Although the pregnancy outcome is similar in these women as it is in women with a
normotensive pregnancy, the risk of placental abruption and progression to severe disease is
slightly increased.[50, 51] Thus, regardless of cervical status, induction of labor should be
recommended. Cesarean section may be performed based on standard obstetric criteria.
Antepartum testing is generally indicated during expectant management of patients with mild
preeclampsia. However, there is little consensus regarding the types of tests to be used and
the frequency of testing. Most clinicians offer a nonstress test (NST) and a biophysical profile
(BPP) at the time of the diagnosis and usually twice per week until delivery.[33, 9]
If a patient is at 34 weeks' gestation or more and has ruptured membranes, abnormal fetal
testing, progressive labor, or fetal growth restriction in the setting of mild preeclampsia,
delivery is recommended.

Care in Severe Preeclampsia

When severe preeclampsia is diagnosed after 34 weeks' gestation, delivery is most
appropriate. The mode of delivery should depend on the severity of the disease and the
likelihood of a successful induction. Whenever possible, however, vaginal delivery should be
attempted and cesarean section should be reserved for routine obstetric indications.

Women with severe preeclampsia who have nonreassuring fetal status, ruptured membranes,
labor, or maternal distress should be delivered regardless of gestational age. If a woman with
severe preeclampsia is at 32 weeks' gestation or more and has received a course of steroid,
she should be delivered as well.
Patients presenting with severe, unremitting headache, visual disturbance, and right upper
quadrant tenderness in the presence of hypertension and/or proteinuria should be treated
with utmost caution.

Expectant management of severe preeclampsia

If a patient presents with severe preeclampsia before 34 weeks' gestation but appears to be
stable, and if the fetal condition is reassuring, expectant management may be considered,
provided that the patient meets the strict criteria set by Sibai et al (see Laboratory values for
preeclampsia and HELLP syndrome).[52] This type of management should be considered only
in a tertiary center. In addition, because delivery is always appropriate for the mother, some
authorities consider delivery as the definitive treatment regardless of gestational age.
However, delivery may not be optimal for a fetus that is extremely premature. Therefore, in a
carefully chosen population, expectant management may benefit the fetus without greatly
compromising maternal health.
All of these patients must be evaluated in a labor and delivery unit for 24 hours before a
decision for expectant management can be made. During this period, maternal and fetal
evaluation must show that the fetus does not have severe growth restriction or fetal distress.
In addition, maternal urine output must be adequate. The woman must have essentially
normal laboratory values (with the exclusive exception of mildly elevated liver function test
results that are less than twice the normal value) and hypertension that can be controlled.
Fetal monitoring should include daily nonstress testing and ultrasonography performed to
monitor for the development of oligohydramnios and decreased fetal movement. In addition,
fetal growth determination at 2-week intervals must be performed to document adequate fetal
growth. A 24-hour urine collection for protein may be repeated. Corticosteroids for fetal lung
maturity should be administered prior to 34 weeks.
Daily blood tests should be performed for liver function tests (LFTs), CBC count, uric acid, and
LDH. Patients should be instructed to report any headache, visual changes, epigastric pain,
or decreased fetal movement.

Criteria for delivery

Women with severe preeclampsia who are managed expectantly must be delivered under the
following circumstances:

Nonreassuring fetal heart status

Uncontrollable BP
Oligohydramnios, with amniotic fluid index (AFI) of less than 5 cm
Severe intrauterine growth restriction in which the estimated fetal
weight is less than 5%
Oliguria (< 500 mL/24 h)
Serum creatinine level of at least 1.5 mg/dL
Pulmonary edema
Shortness of breath or chest pain with pulse oximetry of < 94% on
room air
Headache that is persistent and severe
Right upper quadrant tenderness

Development of HELLP syndrome

Seizure Treatment and Prophylaxis With Magnesium Sulfate
The basic principles of airway, breathing, and circulation (ABC) should always be followed as
a general principle of seizure management.
Magnesium sulfate is the first-line treatment for the prevention of primary and recurrent
eclamptic seizures. For eclamptic seizures that are refractory to magnesium sulfate,
lorazepam and phenytoin may be used as second-line agents.
Active seizures should be treated with intravenous magnesium sulfate as a first-line agent. [7] A
loading dose of 4 g should be given by an infusion pump over 5-10 minutes, followed by an
infusion of 1 g/h maintained for 24 hours after the last seizure. Recurrent seizures should be
treated with an additional bolus of 2 g or an increase in the infusion rate to 1.5 g or 2 g per
hour.
Prophylactic treatment with magnesium sulfate is indicated for all patients with severe
preeclampsia. However, no consensus exists as to whether patients with mild preeclampsia
need magnesium seizure prophylaxis. Although ACOG recommends magnesium sulfate in
severe preeclampsia, it has not recommended this therapy in all cases of mild preeclampsia.
Some practitioners withhold magnesium sulfate if BP is stable and/or mildly elevated and if
the laboratory values for LFTs and platelets are mildly abnormal and/or stable. Other
physicians feel that even patients with gestational hypertension should receive magnesium,
as a small percentage of these patients may either have preeclampsia or may develop it. The
ultimate decision should depend on the comfort level of the labor and delivery staff in
administering intravenous (IV) magnesium sulfate. An estimated 100 patients need to be
treated with magnesium sulfate therapy to prevent 1 case of eclampsia. [53, 7, 54]

Acute Treatment of Severe Hypertension in Pregnancy

In the setting of severe hypertension (SBP >160 mm Hg; DBP >110 mm Hg), antihypertensive
treatment is recommended. The goal of hypertension treatment is to lower BP to prevent
cerebrovascular and cardiac complications while maintaining uteroplacental blood flow (ie,
maintain BP around 140/90 mm Hg). However, although antihypertensive treatment
decreases the incidence of cerebrovascular problems, it does not alter the progression of
preeclampsia. Control of mildly increased BP does not appear to improve perinatal morbidity
or mortality, and it may, in fact, reduce birth weight.

Hydralazine
Hydralazine is a direct peripheral arteriolar vasodilator and, in the past, was widely used as
the first-line treatment for acute hypertension in pregnancy.[55, 56] This agent has a slow onset of
action (10-20 min) and peaks approximately 20 minutes after administration. Hydralazine
should be given as an IV bolus at a dose of 5-10 mg, depending on the severity of
hypertension, and may be administered every 20 minutes up to a maximum dose of 30 mg.
The side effects of hydralazine are headache, nausea, and vomiting. Importantly, hydralazine
may result in maternal hypotension, which can subsequently result in a nonreassuring fetal
heart rate tracing in the fetus.[8]
In a meta-analysis, Magee et al pointed out that hydralazine was associated with worse
maternal and perinatal outcomes than were labetalol and nifedipine. Furthermore, hydralazine
was associated with more maternal side effects than were labetalol and nifedipine. [55]

Labetalol

Labetalol is a selective alpha blocker and a nonselective beta blocker that produces
vasodilatation and results in a decrease in systemic vascular resistance. The dosage for
labetalol is 20 mg IV with repeat doses (40, 80, 80, and 80 mg) every 10 minutes up to a
maximum dose of 300 mg. Decreases in BP are observed after 5 minutes (in contrast to the
slower onset of action of hydralazine), and the drug results in less overshoot hypertension
than does hydralazine.
Labetalol decreases supraventricular rhythm and slows the heart rate, reducing myocardial
oxygen consumption. No change in afterload is observed after treatment with labetalol. The
side effects of labetalol are dizziness, nausea, and headaches. After satisfactory control with
IV administration has been achieved, an oral maintenance dose can be started. [8, 55]

Nifedipine
Calcium channel blockers act on arteriolar smooth muscle and induce vasodilatation by
blocking calcium entry into the cells. Nifedipine is the oral calcium channel blocker that is
used in the management of hypertension in pregnancy. The dosage of nifedipine is 10 mg PO
every 15-30 minutes, with a maximum of 3 doses. The side effects of calcium channel
blockers include tachycardia, palpitations, and headaches. Concomitant use of calcium
channel blockers and magnesium sulfate is to be avoided. Nifedipine is commonly used
postpartum in patients with preeclampsia, for BP control. [8, 55]

Sodium nitroprusside
In a severe hypertensive emergency, when the above-mentioned medications have failed to
lower BP, sodium nitroprusside may be given. Nitroprusside results in the release of nitric
oxide, which in turn causes significant vasodilation. Preload and afterload are then greatly
decreased. The onset of action is rapid, and severe rebound hypertension may result.
Cyanide poisoning may occur subsequent to its use in the fetus. Therefore, sodium
nitroprusside should be reserved for use in postpartum care or for administration just before
the delivery of the fetus.[8]

Fluid Management
Little clinical evidence exists in the published literature on which to base decisions regarding
the management of fluids during preeclampsia. Currently, no prospective studies on this topic
are available, and guidelines are largely based on consensus and retrospective review.
Despite the presence of peripheral edema, patients with preeclampsia are intravascularly
volume depleted, with high peripheral vascular resistance. Diuretics should be avoided.
Aggressive volume resuscitation may lead to pulmonary edema, which is a common cause of
maternal morbidity and mortality. Pulmonary edema occurs most frequently 48-72 hours
postpartum, probably due to mobilization of extravascular fluid. Because volume expansion
has no demonstrated benefit, patients should be fluid restricted when possible, at least until
the period of postpartum diuresis.
Volume expansion has not been shown to reduce the incidence of fetal distress and should
be used judiciously.
Central venous or pulmonary artery pressure monitoring may be indicated in critical cases. A
central venous pressure (CVP) of 5 mm Hg in women with no heart disease indicates
sufficient intravascular volume, and maintenance fluids alone are sufficient. Total fluids should
generally be limited to 80 mL/h or 1 mL/kg/h.

Careful measurement of fluid input and output is advisable, particularly in the immediate
postpartum period. Many patients will have a brief (up to 6 h) period of oliguria following
delivery; this should be anticipated and not overcorrected.

Postpartum Management
Preeclampsia resolves after delivery. However, patients may still have an elevated BP
postpartum. Liver function tests and platelet counts must be performed to document
decreasing values prior to hospital discharge. In addition, one third of seizures occur in the
postpartum period, most within 24 hours of delivery, and almost all within 48 hours.
[57]
Therefore, magnesium sulfate seizure prophylaxis is continued for 24 hours postpartum.
(See Seizure Treatment and Prophylaxis With Magnesium Sulfate.)
Rarely, a patient may have elevated liver enzymes, thrombocytopenia, and renal insufficiency
more than 72 hours after delivery. In these cases, the possibility of hemolytic uremic
syndrome (HUS) or thrombotic thrombocytopenic purpura (TTP) must be considered. In such
situations, plasmapheresis, along with corticosteroid therapy, may be of some benefit to such
patients and must be discussed with renal and hematology consultants.
In addition, the use of dexamethasone (10 mg IV q6-12h for 2 doses followed by 5 mg IV q612h for 2 doses) has been proposed in the postpartum period to restore platelet count to
normal range in patients with persistent thrombocytopenia. [58, 59]The effectiveness of this
therapy in preventing severe hemorrhage or ameliorating the disease course needs further
investigation.
Elevated BP may be controlled with nifedipine or labetalol postpartum. If a patient is
discharged with BP medication, reassessment and a BP check should be performed, at the
latest, 1 week after discharge. Unless a woman has undiagnosed chronic hypertension, in
most cases of preeclampsia, the BP returns to baseline by 12 weeks postpartum.
Eclampsia is common after delivery and has occurred up to 6 weeks after delivery. Al-Safi et
al suggest that the first week after discharge is the most critical period for the development of
postpartum eclampsia. Discussing the risks and educating patients about the possibility of
delayed postpartum preeclampsia is important, regardless of whether they develop
hypertensive disease prior to discharge.[60] Patients at risk for eclampsia should be carefully
monitored postpartum.[61] Additionally, patients with preeclampsia who were successfully
treated with delivery may present with recurrent preeclampsia up to 4 weeks postpartum.

Prevention and Prediction of Preeclampsia

Efforts to prevent preeclampsia have been disappointing. [62]

Aspirin
A systematic review of 14 trials using low-dose aspirin (60-150 mg/d) in women with risk
factors for preeclampsia concluded that aspirin reduced the risk of preeclampsia and perinatal
death, although it did not significantly affect birth weight or the risk of abruption. [63] Low-dose
aspirin in unselected nulliparous women seems to reduce the incidence of preeclampsia only
slightly.[64] For women with risk factors for preeclampsia, starting low-dose aspirin (commonly,
1 tablet of baby aspirin per day), beginning at 12-14 weeks' gestation, is reasonable. The
safety of low-dose aspirin use in the second and third trimesters is well established. [63, 65]

Heparin
The use of lowmolecular weight heparin in women with thrombophilia who have a history of
adverse outcome has been investigated. To date, however, no data suggest that the use of
heparin prophylaxis lowers the incidence of preeclampsia.

Calcium and vitamin supplements

Research into the use of calcium and vitamin C and E supplementations in low-risk
populations did not find a reduction in the incidence of preeclampsia. [66, 67, 68]In a multicenter,
randomized, controlled trial, Villar et al found that at the doses used for supplementation,
vitamins C and E were not associated with a reduction of preeclampsia, eclampsia,
gestational hypertension, or any other maternal outcome. Low birthweight, small for
gestational age, and perinatal deaths were also unaffected. [69]
A study by Vadillo-Ortega et al suggests that in a high-risk population, supplementation during
pregnancy with a special food (eg, bars) containing L-arginine and antioxidant vitamins may
reduce the risk of preeclampsia. However, antioxidant vitamins alone do not protect against
preeclampsia. More studies performed on low-risk populations are needed. [70]
Results from the Norwegian Mother and Child Cohort Study suggest that supplementation of
milk-based probiotics may reduce the risk of preeclampsia in primiparous women. A
prospective randomized trial has not yet been done to evaluate this intervention. [71]

Screening Tests
Preeclampsia is an appropriate disease to screen, as it is common, important, and increases
maternal and perinatal mortality. However, although numerous screening tests for
preeclampsia have been proposed over the past few decades, no test has so far been shown
to appropriately screen for the disease.[72](Measurement of urinary kallikrein was shown to
have a high predictive value, but it was not reproducible. [73, 74] )
Although work on sFlt-1, PlGF, and VEGF have been promising, their positive predictive value
in predicting preeclampsia have yet to be evaluated in a prospective fashion.
Currently, the clinical value of an accurate predictive test for preeclampsia is not clear, as
effective prevention is still lacking. Intensive monitoring in women who are at increased risk
for developing preeclampsia, when identified by a predictive test, may lower the incidence of
adverse outcome for the mother and the neonate. However, the effectiveness of such a
strategy must be rigorously investigated.

Prognosis
Morbidity and mortality
Worldwide, preeclampsia and eclampsia are estimated to be responsible for approximately
14% of maternal deaths per year (50,000-75,000). [16] Morbidity and mortality in preeclampsia
and eclampsia are related to the following conditions:

Systemic endothelial dysfunction

Vasospasm and small-vessel thrombosis leading to tissue and organ
ischemia
CNS events, such as seizures, strokes, and hemorrhage
Acute tubular necrosis
Coagulopathies
Placental abruption in the mother
Recurrence

In general, the recurrence risk of preeclampsia in a woman whose previous pregnancy was
complicated by preeclampsia near term is approximately 10%. [43]If a woman has previously
suffered from severe preeclampsia (including HELLP syndrome and/or eclampsia), she has a
20% risk of developing preeclampsia sometime in her subsequent pregnancy.[75, 76, 77, 78, 79, 80]
If a woman has had HELLP syndrome or eclampsia, the recurrence risk of HELLP syndrome
is 5%[76] and of eclampsia it is 2%.[78, 79, 80] The earlier the disease manifests during the index
pregnancy, the higher the chance of recurrence rises. If preeclampsia presented clinically
before 30 weeks' gestation, the chance of recurrence may be as high as 40%. [81]
The fullPIERS model has been validated and was successful in predicting adverse outcomes
in advance; therefore, it is potentially able to influence treatment choices before complications
arise.[82]