Pre Eclampsia

9/14/2018 https://emedicine.medscape.
com/article/1476919-print
emedicine.medscape.com
Preeclampsia
Updated: Feb 16, 2018
Author: Kee-Hak Lim, MD; Chief Editor: Ronald M Ramus, MD
Practice Essentials
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 post partum. It is clinically defined by hypertension and proteinuria, with or
without pathologic edema.
Definitions
Preeclampsia is defined as the presence of (1) a systolic blood pressure (SBP) greater than or equal to 140 mm Hg or a
diastolic blood pressure (DBP) greater than or equal to 90 mm Hg or higher, on two occasions at least 4 hours apart in a
previously normotensive patient, OR (2) an SBP greater than or equal to 160 mm Hg or a DBP greater than or equal to 110
mm Hg or higher (In this case, hypertension can be confirmed within minutes to facilitate timely antihypertensive therapy.).
[1]
In addition to the blood pressure criteria, proteinuria of greater than or equal to 0.3 grams in a 24-hour urine specimen, a
protein (mg/dL)/creatinine (mg/dL) ratio of 0.3 or higher, or a urine dipstick protein of 1+ (if a quantitative measurement is
unavailable) is required to diagnose preeclampsia.[1]
Preeclampsia with severe features is defined as the presence of one of the following symptoms or signs in the presence of
preeclampsia[1] :
SBP of 160 mm Hg or higher or DBP of 110 mm Hg or higher, on two occasions at least 4 hours apart while the
patient is on bed rest (unless antihypertensive therapy has previously been initiated)
Impaired hepatic function as indicated by abnormally elevated blood concentrations of liver enzymes (to double the
normal concentration), severe persistent upper quadrant or epigastric pain that does not respond to
pharmacotherapy and is not accounted for by alternative diagnoses, or both.
Progressive renal insufficiency (serum creatinine concentration >1.1 mg/dL or a doubling of the serum creatinine
concentration in the absence of other renal disease)
New onset cerebral or visual disturbances
Pulmonary edema
Thrombocytopenia (platelet count <100,000/μL)
In a patient with new-onset hypertension without proteinuria, the new onset of any of the following is diagnostic of
preeclampsia:
Platelet count below 100,000/μL
Serum creatinine level above 1.1 mg/dL or doubling of serum creatinine in the absence of other renal disease
Liver transaminase levels at least twice the normal concentrations
Pulmonary edema
Cerebral or visual symptoms
Eclampsia is defined as seizures that cannot be attributable to other causes in a woman with preeclampsia. HELLP
syndrome (hemolysis, elevated liver enzyme, low platelets) may complicate severe preeclampsia.
Risk factors
Risk factors for preeclampsia and their odds ratios are as follows[2] :
Nulliparity (3.1)
https://emedicine.medscape.com/article/1476919-print 1/27
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Age older than 40 years (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)
Homozygosity for angiotensinogen gene T235 (20:1)
Heterozygosity for angiotensinogen gene T235 (4:1)
Signs and symptoms
Because the clinical manifestations of preeclampsia can be heterogeneous, diagnosing preeclampsia may not be
straightforward. Preeclampsia without severe features may be asymptomatic. Many cases are detected through routine
prenatal screening.
Patients with preeclampsia with severe features display end-organ effects and may complain of the following:
Headache
Visual disturbances: Blurred, scintillating scotomata
Altered mental status
Blindness: May be cortical[3] or retinal
Dyspnea
Edema: Sudden increase in edema or facial edema
Epigastric or right upper quadrant abdominal pain
Weakness or malaise: May be evidence of hemolytic anemia
Clonus: May indicate an increased risk of convulsions
Diagnosis
All women who present with new-onset hypertension should have the following tests:
CBC
Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels
Serum creatinine
Uric acid
24-hour urine collection for protein and creatinine (criterion standard) or urine dipstick analysis
Additional studies to perform if HELLP syndrome is suspected are as follows:
Peripheral blood smear
Serum lactate dehydrogenase (LDH) level
Indirect bilirubin
Although a coagulation profile (prothrombin time [PT], activated partial thromboplastin time [aPTT], and fibrinogen) should
also be evaluated, its clinical value is unclear when the platelet count is 100,000/mm3 or more with no evidence of bleeding.
[4]
Head CT scanning is used to detect intracranial hemorrhage in selected patients with any of the following:
Sudden severe headaches
Focal neurologic deficits
Seizures with a prolonged postictal state
Atypical presentation for eclampsia
Other procedures
Ultrasonography: Transabdominal, to assess the status of the fetus and evaluate for growth restriction; umbilical
artery Doppler ultrasonography, to assess blood flow
Cardiotocography: The standard fetal nonstress test and the mainstay of fetal monitoring
Management
Delivery is the only cure for preeclampsia. Patients with preeclampsia without severe features are often induced after 37
weeks' gestation. Before this, the patient is usually hospitalized and monitored carefully for the development of worsening
preeclampsia or complications of preeclampsia, and the immature fetus is treated with expectant management with
corticosteroids to accelerate lung maturity in preparation for early delivery.
In patients with preeclampsia with severe features, 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.
Criteria for delivery
Women with preeclampsia with severe features who are managed expectantly must be delivered under the following
circumstances:
Nonreassuring fetal testing including (nonreassuring nonstress test, biophysical profile score, and/or persistent
absent or reversed diastolic flow on umbilical artery Doppler velocimetry)
Ruptured membranes
Uncontrollable BP (unresponsive to medical therapy)
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 hr)
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
Eclampsia
Platelet count less tha 100,000 cells/microL
Placental abruption
Unexplained coagulopathy
Seizure treatment and prophylaxis
The basic principles of airway, breathing, and circulation (ABC) should always be followed
Magnesium sulfate is the first-line treatment for primary and recurrent eclamptic seizures
Treat active seizures with IV magnesium sulfate[5] : A loading dose of 4 g is given by infusion pump over 5-10
minutes, followed by an infusion of 1 g/hr maintained for 24 hours after the last seizure
Treat recurrent seizures with an additional bolus of 2 g or an increase in the infusion rate to 1.5 or 2 g per hour
Prophylactic treatment with magnesium sulfate is indicated for all patients with preeclampsia with severe features
Lorazepam and phenytoin may be used as second-line agents for refractory seizures
Acute treatment of severe hypertension in pregnancy
Antihypertensive treatment is recommended for severe hypertension (SBP >160 mm Hg; DBP >110 mm Hg). The goal of
hypertension treatment is to maintain BP around 140/90 mm Hg.
Medications used for BP control include the following:
Hydralazine
Labetalol
Nifedipine
Sodium nitroprusside (in severe hypertensive emergency refractory to other medications)
Fluid management
Diuretics should be avoided
Aggressive volume resuscitation may lead to pulmonary edema
Patients should be fluid restricted when possible, at least until the period of postpartum diuresis
Central venous pressure (CVP) or pulmonary artery pressure monitoring may be indicated in critical cases
A 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/hr or 1 mL/kg/hr
Postpartum management
Many patients will have a brief (up to 6 hours) period of oliguria following delivery
Magnesium sulfate seizure prophylaxis is continued for 24 hours postpartum
Liver function tests and platelet counts must document decreasing values prior to hospital discharge
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
Patients should be carefully monitored for recurrent preeclampsia, which may develop up to 4 weeks postpartum,
and for eclampsia that has occurred up to 6 weeks after delivery
Overview
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.[6]
The incidence of preeclampsia in the United States is estimated to range from 2% to 6% in healthy, nulliparous women.[7, 8,
9] 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%,[10, 11] with hypertensive disorders being the
second most common obstetric cause of stillbirths and early neonatal deaths in these countries.[12]
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 two successive measurements, 4 hours apart.
Preeclampsia and preeclampsia with severe features
Severe preeclampsia accounts for approximately 25% of all cases of preeclampsia.[5] 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.
Preeclampsia is defined as the presence of (1) a systolic blood pressure (SBP) greater than or equal to 140 mm Hg or a
diastolic blood pressure (DBP) greater than or equal to 90 mm Hg or higher, on two occasions at least 4 hours apart in a
previously normotensive patient, OR (2) an SBP greater than or equal to 160 mm Hg or a DBP greater than or equal to 110
mm Hg or higher (In this case, hypertension can be confirmed within minutes to facilitate timely antihypertensive therapy.).
[1]
In addition to the blood pressure criteria, proteinuria of greater than or equal to 0.3 grams in a 24-hour urine specimen, a
protein (mg/dL)/creatinine (mg/dL) ratio of 0.3 or higher, or a urine dipstick protein of 1+ (if a quantitative measurement is
unavailable) is required to diagnose preeclampsia.[1]
Preeclampsia with severe features is defined as the presence of one of the following symptoms or signs in the presence of
preeclampsia[1] :
SBP of 160 mm Hg or higher or DBP of 110 mm Hg or higher, on two occasions at least 4 hours apart while the
patient is on bed rest (unless antihypertensive therapy has previously been initiated)
Impaired hepatic function as indicated by abnormally elevated blood concentrations of liver enzymes (to double the
normal concentration), severe persistent upper quadrant or epigastric pain that does not respond to
pharmacotherapy and is not accounted for by alternative diagnoses, or both.
Progressive renal insufficiency (serum creatinine concentration >1.1 mg/dL or a doubling of the serum creatinine
concentration in the absence of other renal disease)
New onset cerebral or visual disturances
Pulmonary edema
Thrombocytopenia (platelet count <100,000/μL)
Also, a patient with new-onset hypertension without proteinuria can be diagnosed if any of the following is present[1] :
Platelet count below 100,000/μL
Serum creatinine level above 1.1 mg/dL or doubling of serum creatinine in the absence of other renal disease
Liver transaminase levels at least twice the normal concentrations
Pulmonary edema
Cerebral or visual symptoms
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[13] :
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.
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, a protein (mg/dL)/creatinine
(mg/dL) ratio greater than or equal to 0.3, or a urine dipstick protein of 1+ (if a quantitative measurement is unavailable).[14]
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
An estimated 2-8% of pregnancies are complicated by preeclampsia, with associated maternofetal morbidity and mortality.
[15] 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.)[16, 17]
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.[18] Moreover, women who had recurrent preeclampsia were more likely to suffer from hypertension later in life.[18]
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.[19]
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[20] :
Maternal immunologic intolerance
Abnormal placental implantation
Genetic, nutritional, and environmental factors
Cardiovascular and inflammatory changes
Immunologic Factors in Preeclampsia

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.[21] 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.[22, 23] 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.[6]
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.[24] 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, HLA-G.[25, 26]
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.[3, 27]
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.[28] 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.[29] 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.[30, 31]
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 VEGF165 b may be involved in the increased vascular permeability of
preeclampsia.[32]
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.[29]
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.[30]
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.[33]
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.[34] 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.[21] 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.[35]
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.[36]
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.[36]
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.[2]
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 mellitus: Women with pregnancy-related hypertensive conditions, including preeclampsia, plus preexisting
diabetes or early gestational diabetes appear to remain at increased risk for poor pregnancy outcomes—even when
the gestational diabetes was identified early and treated.[37]
Collagen vascular disease
Periodontal disease[38]
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.[39]
Studies have suggested that smoking during pregnancy is associated with a reduced risk of gestational hypertension and
preeclampsia; however, this is controversial.[26] 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) below 20 kg/m2 to 13.3% in those with a BMI over 35 kg/m2. A United Kingdom study on obesity showed
that 9% of extremely obese women were preeclamptic, compared with 2% of matched controls.[40]
An analysis of 456,668 singleton births found that early-onset (<34 weeks' gestation) and late-onset (≥34 weeks' gestation)
preeclampsia shared some etiologic features, but their risk factors and outcomes differed. Shared risk factors for early- and
late-onset preeclampsia included older maternal age, Hispanic race, Native American race, smoking, unmarried status, and
male fetus. Risk factors more strongly associated with early-onset preeclampsia than late-onset disease included black
race, chronic hypertension, and congenital anomalies, while younger maternal age, nulliparity, and diabetes mellitus were
more strongly associated with late-onset preeclampsia than with early-onset disease.[41, 42]
Early-onset preeclampsia was significantly associated with a high risk for fetal death (adjusted odds ratio [AOR], 5.8), but
late-onset preeclampsia was not (AOR, 1.3). However, the AOR for perinatal death/severe neonatal morbidity was
significant for both early-onset (16.4) and late-onset (2.0) preeclampsia.[41, 42]
In addition, the incidence of preeclampsia increased sharply as gestation progressed: the rate for early-onset preeclampsia
was 0.38% compared with 2.72% for late-onset preeclampsia.[41, 42]
Table 1 lists the risk factors and their odds ratios for preeclampsia.[2]
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.[1]
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 preeclampsia with severe features display end-organ effects and may complain of the following:
Headache
Visual disturbances: Blurred, scintillating scotomata
Blindness: May be cortical[3] 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.[43]
Recurrence of preeclampsia
Uncommonly, patients have antepartum preeclampsia that is treated with delivery but that recurs in the postpartum period.
[44] 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):
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 two BP readings of 140/90 mm Hg or greater are noted 4 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
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 (hemolysis, elevated liver enzyme, low platelets) 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.[4]
Laboratory values for preeclampsia and HELLP syndrome[13, 45]
Renal values are as follows:
Proteinuria level above 300 mg/24 hours
Urine dipstick over 1+
Protein/creatinine ratio greater than 0.3*
Serum uric acid level above 5.6 mg/dL*
Serum creatinine level over 1.1 mg/dL
Platelet/coagulopathy-related results are as follows:
Platelet count below 100,000/mm3
Elevated PT or aPTT*
Decreased fibrinogen*
Increased d-dimer level*
Hemolysis-related results are as follows:
Abnormal peripheral smear*
Indirect bilirubin level over 1.2 mg/dL*
LDH level greater than 600 U/L*
In addition, elevated liver enzymes (serum AST >70 U/L) are found in preeclampsia and HELLP syndrome.[24]
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.[46] 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.[47] 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.[48, 49] (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%.[50] 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.[51]
Congo red dye
A study at Yale University showed preliminary results suggesting that Congo red (CR), a dye currently used to locate
atypical amyloid aggregates in Alzheimer disease, may also be effective in the early diagnosis of preeclampsia.[50] It was
thought that this finding might lead to a spot urine test that could 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.
In a study of 40 pregnant women with severe preeclampsia and 40 healthy pregnant controls, Buhimschi et al found that the
urine and placentas of women with preeclampsia contain aggregates of misfolded proteins.[52, 53] They suggested that
urine CR spotting tests (CR binds to misfolded proteins) may be better than currently used current dipstick methods at
diagnosing preeclampsia and indicating the need for medically indicated delivery.[52, 53]
In this study, a cutoff value of a 15% measure of redness on the CR spotting test had 100% sensitivity and 100% specificity
for distinguishing women with severe preeclampsia from control subjects.[53] In a separate validation cohort of 563
pregnant women, the test had a sensitivity of 85.9%, a specificity of 85.0%, a positive likelihood ratio of 5.7, and a negative
likelihood ratio of 0.17.
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 three standard deviations
away from the mean for each laboratory value may be used for AST.[45]
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. A decreased level of placental growth factor (PlGF) in the blood is also suggestive of preeclampsia.[54, 55]
Although these laboratory abnormalities increase the suspicion for preeclampsia, none of these laboratory tests should be
used to diagnose preeclampsia.
In a study of 540 women with type 1 diabetes, Holmes and colleagues found that those women who developed
preeclampsia had abnormal serum levels of angiogenic and antiangiogenic compounds in the second trimester. At 26
weeks’ gestation, women who later developed preeclampsia had significantly lower levels of the angiogenic factor PlGF,
significantly higher levels of the antiangiogenic factors soluble fms-like tyrosine kinase-1 (sFlt-1) and soluble endoglin
(sEng), as well as alteration in the ratio of PlGF to sEng or the ratio of sFlt-1 to PlGF.[56, 57]
A test that measures the PIGF level in the blood (Triage) accurately identified preeclampsia requiring delivery in a
prospective study of 625 pregnant women presenting before 35 weeks' gestation with suspected preeclampsia. Of the 625
subjects, 346 (55%) developed confirmed preeclampsia.[54, 55]
Between 20 and 34 weeks' gestation, the sensitivity of the Triage test in predicting the need for delivery within 14 days was
0.96 (95% confidence interval [CI], 0.89–0.99), and the negative predictive value was 0.98 (95% CI 0.93–0.995).[54, 55]
Between 35 and 36 weeks' gestation, the sensitivity was 0.70 (95% CI, 0.58–0.81), and the negative predictive value was
0.69 (95% CI 0.57–0.80). At 37 weeks' gestation or more, the sensitivity was 0.57 (95% CI, 0.46–0.68), and the negative
predictive value was 0.70 (95% CI, 0.62–0.78).[54, 55]
A PlGF level below 100 pg/mL was just as good as a PlGF level below the fifth centile for gestational age at predicting
preeclampsia requiring delivery within 14 days. PIGF levels lower than 12 pg/mL indicated an average time to delivery of
just 9 days. Used alone or in combination , the PlGF test was significantly (P < 0.001) better than other commonly used
tests, including systolic and diastolic blood pressure, uric acid, alanine transaminase, and proteinuria, in predicting
preeclampsia requiring delivery within 14 days.[54, 55]
A multicenter, prospective observational study of the ratio of sFlt-1 to PlGF in women with a clinical suspicion of
preeclampsia or HELLP syndrome, who were between 24 and 37 weeks' gestational age, has demonstrated that an sFlt-1
to PlGF ratio of 38 or lower to have important predictive value[58] : An sFlt-1:PlGF ratio of 38 or lower had a negative
predictive value of 99.3% (95% confidence interval [CI], 97.9 to 99.9), suggesting an extremely unlikely development of
preeclampsia or HELLP within 1 week. However, the positive predictive value of an sFlt-1:PlGF ratio above 38 for a
diagnosis of preeclampsia within 4 weeks was 36.7% (95% CI, 28.4 to 45.7). The authors concluded that an sFlt-1:PlGF
ratio of 38 or lower can be used to predict the short-term absence of preeclampsia in women in whom the syndrome is
suspected clinically.[58]
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.[59]
Currently, however, there is no pathognomonic CT scan or MRI finding for eclampsia. Furthermore, cerebral imaging is not
necessary for the condition’s 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 asymmetrical
—use abdominal circumference).[60] 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.[61]
Patients with preeclampsia without severe features 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 preeclampsia with severe features, 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 Preeclampsia Without Severe Features

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 preeclampsia demonstrate the safety of outpatient management with frequent
maternal and fetal evaluations, most of the patients in these studies had mild gestational hypertension.[62] Therefore, the
safety of managing a woman with preeclampsia without severe features 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 preeclampsia without severe features 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.[63, 64] 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 preeclampsia without severe
features. 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.[2, 1]
If a patient is at 34 weeks' gestation or more and has ruptured membranes, abnormal fetal testing, or progressive labor in
the setting of preeclampsia, delivery is recommended.
Care Preeclampsia With Severe Features

When preeclampsia with severe features 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 preeclampsia with severe features who have nonreassuring fetal status, ruptured membranes, labor, or
maternal distress should be delivered regardless of gestational age. If a woman with preeclampsia with severe features is at
32 weeks' gestation or more and has received a course of steroids, 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 preeclampsia with severe features
If a patient presents with preeclampsia with severe features 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).[65] 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 testing including nonreassuring nonstress test, biophysical profile score, and/or persistent absent
or reversed diastolic flow on umbilical artery Doppler velocimetry
Ruptured membranes
Uncontrollable BP (unresponsive to medical therapy)
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 hours)
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 (hemolysis, elevated liver enzyme, low platelets) syndrome
Eclampsia
Platelet count less than 100,000/μL
Placental abruption
Unexplained coagulopathy
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.
The American College of Obstetricians and Gynecologists (ACOG) and the Society for Maternal-Fetal Medicine (SMFM)
continue to support the short-term (usually <48 hours) use of magnesium sulfate in obstetric care for conditions and
treatment durations that include the following[66] :
For prevention and treatment of seizures in women with preeclampsia or eclampsia

For fetal neuroprotection before anticipated early preterm (<32 weeks of gestation) delivery
For short-term prolongation of pregnancy (≤48 hours) to allow for the administration of antenatal corticosteroids in
pregnant women who are at risk of preterm delivery within 7 days
Active seizures should be treated with intravenous magnesium sulfate as a first-line agent.[5] 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.[5, 67, 68]
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.
A retrospective cohort study by Cleary et al that included 239,454 patients with preeclampsia (126,595 women with mild,
31,628 with superimposed, and 81,231 with severe preeclampsia) reported that the rate of patients with preeclampsia
receiving antihypertensive medication increased from 37.8% in 2006 to 49.4% in 2015. During this time period, the risk for
stroke for severe preeclampsia also decreased from 13.5 per 10,000 deliveries in 2006-2008 (n=27) to 6.0 in 2012-2014
(n=20) (P=.02).[69]
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.[70, 71] 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.[13]
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.[70]
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.
[13, 70]
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.[13, 70]
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.[13]
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.[72] 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 q6-12h for 2 doses) has been
proposed in the postpartum period to restore platelet count to normal range in patients with persistent thrombocytopenia.[73,
74] 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.[75] Patients at risk for eclampsia should be carefully monitored postpartum.[76]
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.[77]
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.[78] Low-dose aspirin in unselected nulliparous women seems to reduce the incidence of preeclampsia
only slightly.[79] 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.[78, 80]
A 2016 ACOG Practice Advisory upheld the recommendation for the possible use of low-dose aspirin (81 mg/day),
introduced between 12 and 28 weeks of gestation, to prevent preeclampsia in women who are high-risk. The U.S.
Preventive Services Task Force defined high-risk for preeclampsia as women with a history of preeclampsia, multifetal
gestation, chronic hypertension, diabetes, renal disease, or an autoimmune disease.[81]
On the basis of limited evidence from a systematic review and meta-analysis, the addition of low–molecular weight heparin
or unfractionated heparin to low-dose aspirin has the potential to reduce the prevalence of preeclampsia and birth of small-
for-gestational-age neonates in women with a history of preeclampsia.[82]
A multicenter, double-blind, placebo-controlled trial by Rolnik et al that included 1620 women at high-risk for preterm
preeclampsia reported that 1.6% of the patients in the low-dose aspirin group had preterm preeclampsia compared to 4.3%
in the placebo group (odds ratio in the aspirin group, 0.38; 95% confidence interval, 0.20 to 0.74; P=0.004).[83]
Heparin
The use of low–molecular 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.[84, 85, 86] 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.[87]
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.[88]
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.[89]
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.[90] (Measurement of urinary kallikrein was shown to
have a high predictive value, but it was not reproducible.[91, 92] )
A prospective study demonstrated that an sFlt-1:PlGF ratio of 38 or lower had a negative predictive value of 99.3% (95%
confidence interval [CI], 97.9 to 99.9), suggesting an extremely unlikely development of preeclampsia or HELLP (hemolysis,
elevated liver enzyme, low platelets) syndrome within 1 week, in women with a clinical suspicion of preeclampsia or HELLP
syndrome.[58] Therefore, an sFlt-1:PlGF ratio of 38 or lower may have a potential role in predicting the short-term absence
of preeclampsia in women in whom the syndrome is suspected clinically.[58] A randomized trial is necessary to determine
the interval of such testing in women suspected on having preeclampsia or HELLP syndrome, as well as the effect of this
screening test on maternal and fetal outcomes.
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.
The USPSTF recommends screening pregnant women for preeclampsia with blood pressure measurements throughout
pregnancy.[93]
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).[21] 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
Central nervous system (CNS) events, such as seizures, strokes, and hemorrhage
Acute tubular necrosis
Coagulopathies
Placental abruption in the mother
Fetal exposure to preeclampsia may be linked to autism and developmental delay (DD).[94, 95] In a population-based
study of 1061 children from singleton pregnancies — including 517 with autism spectrum disorder (ASD), 194 with DD, and
350 who were typically developing (TD) — fetal exposure to preeclampsia was associated with a greater than twofold
increase in the risk of ASD and a greater than fivefold increase in the risk of DD.[94, 95]
Of the children with ASD, 7.7% had been exposed to preeclampsia in utero, compared with 5.1% of those with DD and 3.7%
of those with TD.[95] After adjustment for parity, maternal education, and prepregnancy obesity, the adjusted odds ratio
(aOR) for ASD with exposure to preeclampsia was 2.36 (95% confidence interval [CI], 1.18-4.68). In analyses limited to
women who had had severe preeclampsia, the aOR for ASD was 2.29 (95% CI, 0.97-5.43), and the aOR for DD was 5.49
(95% CI, 2.06-14.64).
Recurrence
In general, the recurrence risk of preeclampsia in a woman whose previous pregnancy was complicated by preeclampsia
near term is approximately 10%.[48] If a woman has previously suffered from preeclampsia with severe features (including
HELLP [hemolysis, elevated liver enzyme, low platelets] syndrome and/or eclampsia), she has a 20% risk of developing
preeclampsia some time in her subsequent pregnancy.[96, 97, 98, 99, 100, 101]
If a woman has had HELLP syndrome or eclampsia, the recurrence risk of HELLP syndrome is 5%[97] and of eclampsia it is
2%.[99, 100, 101] 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%.[102]
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.[103]
Contributor Information and Disclosures
Author
Kee-Hak Lim, MD Clinical Associate Professor, Department of Obstetrics and Gynecology, Harvard Medical School;
Physician in Maternal-Fetal Medicine, Beth Israel Deaconess Medical Center
Kee-Hak Lim, MD is a member of the following medical societies: American College of Obstetricians and Gynecologists,
American Institute of Ultrasound in Medicine, Society for Maternal-Fetal Medicine, Johns Hopkins Medical and Surgical
Association
Disclosure: Nothing to disclose.
Coauthor(s)
Guy Steinberg, MD, MPH, MSc Fellow in Maternal-Fetal Medicine, Beth Israel Deaconess Medical Center/Harvard Medical
School
Chief Editor
Ronald M Ramus, MD Professor of Obstetrics and Gynecology, Director, Division of Maternal-Fetal Medicine, Virginia
Commonwealth University School of Medicine
Ronald M Ramus, MD is a member of the following medical societies: American College of Obstetricians and Gynecologists,
American Institute of Ultrasound in Medicine, Medical Society of Virginia, Society for Maternal-Fetal Medicine
Acknowledgements
A David Barnes, MD, PhD, MPH, FACOG Consulting Staff, Department of Obstetrics and Gynecology, Mammoth Hospital
(Mammoth Lakes, California), Pioneer Valley Hospital (Salt Lake City, Utah), Warren General Hospital (Warren,
Pennsylvania), and Mountain West Hospital (Tooele, Utah)
A David Barnes, MD, PhD, MPH, FACOG is a member of the following medical societies: American College of Forensic
Examiners, American College of Obstetricians and Gynecologists, American Medical Association, Association of Military
Surgeons of the US, and Utah Medical Association
Pamela L Dyne, MD Professor of Clinical Medicine/Emergency Medicine, University of California, Los Angeles, David
Geffen School of Medicine; Attending Physician, Department of Emergency Medicine, Olive View-UCLA Medical Center
Pamela L Dyne, MD is a member of the following medical societies: American Academy of Emergency Medicine, American
College of Emergency Physicians, and Society for Academic Emergency Medicine
Mert Erogul, MD Assistant Professor of Emergency Medicine, University Hospital of Brooklyn: Consulting Staff, Department
of Emergency Medicine, Kings County Hospital Center
Mert Erogul, MD is a member of the following medical societies: American College of Emergency Physicians, American
Medical Association, and Society for Academic Emergency Medicine
John J Kavanagh Jr MD, Chief, Professor, Department of Internal Medicine, Section of Gynecological and Medical
Therapeutics, MD Anderson Cancer Center, University of Texas Medical School at Houston
John J Kavanagh Jr is a member of the following medical societies: American Association for Cancer Research, American
Association for the Advancement of Science, American Association for the History of Medicine, American College of
Physicians, American Federation for Medical Research, American Medical Association, Society of Gynecologist
Oncologists, Southern Medical Association, and Texas Medical Association
Assaad J Sayah, MD Chief, Department of Emergency Medicine, Cambridge Health Alliance
Assaad J Sayah, MD is a member of the following medical societies: National Association of EMS Physicians
Zina Semenovskaya, MD Resident Physician, Department of Emergency Medicine, Kings County Hospital, State University
of New York Downstate Medical Center College of Medicine
Aashit K Shah, MD, FAAN, FANA Professor of Neurology, Director, Comprehensive Epilepsy Program, Program Director,
Clinical Neurophysiology Fellowship, Detroit Medical Center, Wayne State University School of Medicine
Aashit K Shah, MD, FAAN, FANA is a member of the following medical societies: American Academy of Neurology,
American Clinical Neurophysiology Society, American Epilepsy Society, and American Neurological Assocation
Disclosure: UCB Pharma, Consulting fee, Speaking and teaching; Cyberonics, Consulting fee, Consulting; UCB Pharma,
Grant/research funds, Other
Guy Steinberg, MD, MPH, MSc Fellow in Maternal-Fetal Medicine, Beth Israel Deaconess Medical Center/Harvard Medical
School
Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of
Pharmacy; Editor-in-Chief, Medscape Drug Reference
Disclosure: Medscape Salary Employment
Mark Zwanger, MD, MBA Assistant Professor, Department of Emergency Medicine, Jefferson Medical College of Thomas
Jefferson University
Mark Zwanger, MD, MBA is a member of the following medical societies: American Academy of Emergency Medicine,
American College of Emergency Physicians, and American Medical Association
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9/14/2018 https://emedicine.medscape.

New onset cerebral or visual disturbances

Thrombocytopenia (platelet count <100,000/μL)

Platelet count below 100,000/μL

Liver transaminase levels at least twice the normal concentrations

Cerebral or visual symptoms

Age older than 40 years (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)

Homozygosity for angiotensinogen gene T235 (20:1)

Heterozygosity for angiotensinogen gene T235 (4:1)

Signs and symptoms

Visual disturbances: Blurred, scintillating scotomata

Altered mental status

Blindness: May be cortical[3] or retinal

Edema: Sudden increase in edema or facial edema

Epigastric or right upper quadrant abdominal pain

Weakness or malaise: May be evidence of hemolytic anemia

Clonus: May indicate an increased risk of convulsions

Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels

Additional studies to perform if HELLP syndrome is suspected are as follows:

Peripheral blood smear

Serum lactate dehydrogenase (LDH) level

Sudden severe headaches

Focal neurologic deficits

Seizures with a prolonged postictal state

Atypical presentation for eclampsia

Criteria for delivery

Uncontrollable BP (unresponsive to medical therapy)

Oligohydramnios, with amniotic fluid index (AFI) of less than 5 cm

Oliguria (< 500 mL/24 hr)

Serum creatinine level of at least 1.5 mg/dL

Headache that is persistent and severe

Right upper quadrant tenderness

Development of HELLP syndrome

Platelet count less tha 100,000 cells/microL

Seizure treatment and prophylaxis

Acute treatment of severe hypertension in pregnancy

Medications used for BP control include the following:

Sodium nitroprusside (in severe hypertensive emergency refractory to other medications)

Diuretics should be avoided

Aggressive volume resuscitation may lead to pulmonary edema

Total fluids should generally be limited to 80 mL/hr or 1 mL/kg/hr

Magnesium sulfate seizure prophylaxis is continued for 24 hours postpartum

Elevated BP may be controlled with nifedipine or labetalol postpartum

Preeclampsia and preeclampsia with severe features

New onset cerebral or visual disturances

Thrombocytopenia (platelet count <100,000/μL)

Platelet count below 100,000/μL

Liver transaminase levels at least twice the normal concentrations

Cerebral or visual symptoms

Classification and characteristics of hypertensive disorders

Superimposed preeclampsia (on chronic hypertension)