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Preeclampsia
Author: Kee-Hak Lim, MD, Associate Professor, Department of Obstetrics and Gynecology, Harvard
Medical School; Consulting Staff, Harvard Medical Faculty Physicians and Beth Israel Deaconess
Medical Center
Coauthor(s): Guy Steinberg, MD, MPH, MSc, Fellow in Maternal-Fetal Medicine, Beth Israel Deaconess
Medical Center/Harvard Medical School
Contributor Information and Disclosures
Updated: Sep 4, 2008Print ThisEmail This
Background
Preeclampsia is a pregnancy-specific syndrome characterized by new-onset hypertension and proteinuria,
occurring usually after 20 weeks' gestation. Although the etiology remains unknown, placental
hypoperfusion and diffuse endothelial cell injury are considered be the central pathologic events.
Preeclampsia is classified into mild and severe types and, in its extreme, may lead to liver and renal
failure, disseminated intravascular coagulopathy, and central nervous system abnormalities, including
seizures. Because the only cure is delivery, preeclampsia is associated with high maternal and neonatal
mortality and morbidity. In the United States, preeclampsia is believed to be responsible for 15% of
premature deliveries1 and 17.6% of maternal deaths.2, 3 Worldwide, preeclampsia and eclampsia are
estimated to be responsible for approximately 14% of maternal deaths per year (50,000-75,000).4 Despite
its impact on maternal and child health, efforts to predict and prevent the disease have been disappointing.
Numerous strategies (low-dose aspirin, calcium, and vitamin C and E supplementation) have been shown
to be of little benefit. Because our understanding of the pathogenesis of this disease is incomplete, these
preventive strategies were proposed based on pathogenetic hypotheses that did not withstand the test of
time. Recently, a number of investigators demonstrated and confirmed that an imbalance in angiogenic
molecules play a major role in the pathogenesis of preeclampsia, raising the possibility that these
molecules may be targeted for preventive measures and possible palliative therapy.
See Medscape's Pregnancy and Hypertension Resource Centers.
Pathophysiology
The general consensus is that preeclampsia is an endothelial cell disorder resulting in mild-to-severe
microangiopathy of target organs such as brain, liver, kidney, and placenta.5 While hypertension may be
the most common presenting symptom, it should not be viewed as the initial pathogenetic process.
Evidence of other organ involvement before hypertension becomes fulminant is not uncommon. 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,
plasminogen activator inhibitor-1, and altered prostacyclin/thromboxane profile.6 Evidence to date
suggests that oxidative stress; circulatory maladaptation; inflammation; and humoral, mineral, and
metabolic abnormalities may all contribute to endothelial dysfunction and pathogenesis of preeclampsia.
Many investigators believe that the placenta is the trigger for endothelial cell injury.7 Evidence suggests
that hypoperfused placentas produce various factors that are capable of injuring endothelial cells. Recent
data suggest that circulating factors that interfere with the action of vascular endothelial growth factor
(VEGF) and placental growth factor (PlGF) play a major role in maternal manifestation of the disorder
(see Angiogenic Factors in Preeclampsia).
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.
Placentation in Preeclampsia
The shallow placentation noted in preeclampsia is a result of the inability of trophoblasts to invade the
decidual vessels. 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.8 As a result of these changes, these
vessels 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.
In preeclampsia, this invasion of the decidual arterioles is incomplete. The invasive cytotrophoblasts fail
to replace tunica media, resulting in mostly intact arterioles that are capable of vasoconstriction.
Histologic evaluation of the placental bed demonstrates few cytotrophoblasts beyond the decidual layer.
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 molecule, HLA-G.9, 10
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).
The invasive cytotrophoblasts in preeclampsia fail to make this transition; they do not upregulate matrix
metalloproteinase-9 (MMP-9) and HLA-G, 2 molecules noted in normally invading cytotrophoblasts.
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. In addition, early hypoxic insult to differentiating cytotrophoblasts has been proposed as a
contributing factor. However, these hypotheses need to be tested further.
Systemic Endothelial Dysfunction
Endothelium regulates vascular permeability, vassal tone, and coagulation cascade. While not all the
factors produced by the placenta responsible for endothelial dysfunction have been characterized, recent
data show that an imbalance of pro- and anti-angiogenic factors produced by the placenta may play a
major role in mediating endothelial dysfunction. The circulating proangiogenic factors secreted by the
placenta include VEGF and 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). Other
substances that have been proposed, but not proven, to contribute to this process include tumor necrosis
factor, interleukins, various lipid molecules, and syncytial knots.11, 12
[#Angiogenic]
Angiogenic Factors in Preeclampsia
VEGF and PlGF
Angiogenesis is critical for successful placentation. Both VEGF and PlGF promote angiogenesis by
interacting with the VEGF receptor family. While both growth factors are produced by placenta, the
serum level of PlGF rises much more significantly in pregnancy. Taylor et al demonstrated that the serum
level of PlGF decreased in women who later developed preeclampsia.13 The fall in serum level was
notable as early as the second trimester in women who developed preeclampsia and intrauterine growth
restriction. In 2003, Maynard et al observed that the serum levels of both VEGF and PlGF were decreased
in women with preeclampsia.14 However, the magnitude of decrease was less pronounced for VEGF
since its serum level was not as high as PlGF, even in normal pregnancy. Others have confirmed this
finding and showed that the serum level of PlGF decreased in women before they developed
preeclampsia.15, 16
Soluble fms-like tyrosine kinase 1 receptor (sFlt-1)
sFlt-1 is a soluble isoform of Flt-1, which is a transmembrane receptor for VEGF. While 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, while 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.14
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, the investigators showed that the serum level of sFlt-1 increased earlier and
higher in women who developed preeclampsia (21-24 wk) in comparison with women who did not
develop preeclampsia (21-24 wk vs 33-36 wk), while 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 those in women who developed mild preeclampsia at term.15
Soluble endoglin (sEng)
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 TGFbeta binding domain, it can bind to circulating TGF-beta and decrease circulating levels. Since TGF-beta
is a proangiogenic molecule, 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 prior to the clinical signs of preeclampsia, its level in
maternal blood correlates with disease severity, and the levels of sEng in the blood drops after delivery.17
In studies on pregnant rats, administration of sEng results in vascular permeability and causes
hypertension. It also has a synergistic relationship with sFlt-1, as it increases the effects of sFlt-1 in
pregnant rats, resulting in HELLP syndrome, as evidenced by hepatic necrosis, hemolysis, and placental
infarction.18 Moreover, sEng inhibits TGF-beta in endothelial cells and inhibits TGF-beta-1 activation of
nitric oxide mediated vasodilatation.
Epidemiology and Risk Factors
The incidence of preeclampsia in the United States is estimated to range from 2-6% in healthy nulliparous
women.19, 20, 21 In the developing world, the incidence is reported to be 4-18%.22, 23 The disease is
mild in 75% of cases and severe in 25%.24 Of all cases of preeclampsia, 10% occur in pregnancies of less
than 34 weeks' gestation. Eclampsia is estimated to occur in 1 in 200 cases of preeclampsia when
magnesium prophylaxis in not administered.25, 26
The incidence is higher in women with a history of preeclampsia, multiple gestations, chronic
hypertension, and underlying renal disease. (For related information, see Medscape's CME Activity
Preeclampsia May Increase Risk for End-Stage Renal Disease.) In addition, obesity, diabetes,
thrombophilia, and age older than 40 years are risk factors that put a woman at an increased risk of
developing preeclampsia. Table 1 lists the risk factors and their odds ratio for preeclampsia.27 Some risk
factors contribute to poor placentation while others contribute to increased placental mass and poor
placental perfusion secondary to vascular abnormalities.
Table 1. Risk factors for preeclampsia*
Open table in new windowNulliparity 3:1
Age >40 y
3:1
African-American race 1.5:1
Family history 5:1
Chronic renal disease 20:1
Chronic hypertension 10:1
Antiphospholipid syndrome
Diabetes mellitus
2:1
Twin gestation 4:1
High body mass index 3:1
Angiotensinogen gene T235
Homozygous 20:1
Heterozygous 4:1
10:1
*Adapted from ACOG Technical Bulletin 219, Washington, DC 199628
Classifications
The National High Blood Pressure Education Program (NHBPEP) Working Group classifies hypertensive
diseases in pregnancy into 4 groups: chronic hypertension, preeclampsia, preeclampsia superimposed on
chronic hypertension, and gestational hypertension.29
The classification of hypertensive diseases in pregnancy according to the NHBPEP Working Group is as
follows:29
Gestational hypertension
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
BP 140/90 mm Hg or greater before pregnancy or diagnosed before 20 weeks' gestation not attributable to
gestational trophoblastic disease
or
Hypertension first diagnosed after 20 weeks' gestation and persistent after 12 weeks' postpartum.
Preeclampsia/eclampsia
BP of 140/90 mm Hg or greater after 20 weeks' gestation in a women with previously normal blood
pressure and with 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 (on chronic hypertension)
New onset proteinuria (>300 mg/24 h) in a woman with hypertension but no proteinuria before 20 weeks'
gestation
A sudden increase in proteinuria or blood pressure, or platelet count less than 100,000 in women with
hypertension and proteinuria before 20 weeks' gestation
Mild preeclampsia is defined as the presence of hypertension (BP >140/90 mm Hg) on 2 occasions, at
least 6 hours apart. Proteinuria is defined as the presence of greater than or equal to 1+ protein on random
dipstick or 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 in their definition.28
Edema and hyperreflexia are no longer considered to be diagnostic criteria. In addition, the relative rise of
systolic pressure by 30 mm Hg and/or diastolic by 15 mm Hg has been dropped from the criteria for
hypertension.
Severe preeclampsia is defined as the presence of one of the following symptoms or signs in the presence
of preeclampsia:
Systolic BP of 160 mm Hg or higher or diastolic BP of 110 mm Hg or higher on 2 occasions at least 6
hours apart
Proteinuria of more than 5 g in 24-hour period
Pulmonary edema
Oliguria (<400 mL in 24 h)
Persistent headaches
Epigastric pain and/or impaired liver function
Thrombocytopenia
Intrauterine growth restriction
HELLP syndrome (hemolysis, elevated liver enzyme, low platelets) is a form of severe preeclampsia that
has been associated with particularly high maternal and perinatal morbidity and mortality and may be
present without hypertension or, in some occasions, without proteinuria.
Diagnosis of Preeclampsia
Preeclampsia is diagnosed when new-onset hypertension and proteinuria are present in a pregnant woman
according to the criteria described in Classifications. However, because the clinical manifestation of
preeclampsia can be heterogeneous, diagnosing preeclampsia may not be straightforward. In particular,
since 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 she has 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.
Hypertension is diagnosed when 2 blood pressure readings of 140/90 mm Hg or greater are noted 6 hours
apart within a one-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 prior to the BP measurement. She should not be lying down in a lateral decubitus
position, since 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 where the Korotkoff V sound is
not present, the Korotkoff IV sound may be used, but should be noted as such. The difference between the
Korotkoff IV and V sound may be as much as 10 mm Hg. When using an automated cuff, 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.
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.30 Thus, 24-hour urine
protein analysis remains the criterion standard. 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.31 However, the best threshold for identifying pregnant women
with significant proteinuria has not been agreed upon. Up to 10% of patients with preeclampsia and 20%
of patients with eclampsia may not have proteinuria.32, 33 Furthermore, HELLP syndrome has been
known to occur without hypertension or proteinuria. Because the underlying pathophysiology of
preeclampsia is a diffuse endothelial cell disorder influencing multiple organs, hypertension does not
need to necessarily precede other symptoms or laboratory abnormalities (see Pathophysiology).
Presenting symptoms other than hypertension may include edema, visual disturbances, headache, and
epigastric or right upper quadrant tenderness.
All women who present with new-onset hypertension should have the following laboratory tests:
complete blood count (CBC), serum alanine aminotransferase (ALT) and aspartate aminotransferase
(AST) levels, serum creatinine, and uric acid. In addition, a peripheral smear, serum lactate
dehydrogenase (LDH) levels measured, and indirect bilirubin should be done if HELLP syndrome is
suspected. While a coagulation profile (PT, aPTT, and fibrinogen) should also be evaluated, the clinical
use of routine evaluation is unclear when the platelet count is 100,000 or more with no evidence of
bleeding.34
While 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.35 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.
Other laboratory values suggestive of preeclampsia include elevation in hematocrit and a rise in serum
creatinine and/or uric acid. While these laboratory abnormalities increase the suspicion for preeclampsia,
none of these laboratory tests should be used to diagnose preeclampsia.
Laboratory values for preeclampsia and HELLP syndrome 29, 35
Renal
Proteinuria of >300 mg/24 h
Urine dipstick >1+
Protein/creatinine ratio >0.3*
Serum uric acid >5.6 mg/dL*
Serum creatinine >1.2 mg/dL
Low platelets/coagulopathy
Platelet count <100,000/mm3
Elevated PT or aPTT*
Decreased fibrinogen*
Increased d-dimer*
Hemolysis
Abnormal peripheral smear*
Indirect bilirubin >1.2 mg/dL*
Lactate dehydrogenase >600 U/L*
Elevated liver enzymes
Serum AST >70 U/L8
Eclampsia, defined as new-onset tonic-clonic seizure in an otherwise healthy woman with hypertensive
disorder of pregnancy, is a significant complication of preeclampsia and is associated with high maternal
and neonatal morbidity and mortality. Multiple studies have described various abnormalities noted on
CNS imaging studies. Both CT and MRI scans have revealed numerous abnormalities such as cerebral
edema, focal infarction, intracranial hemorrhage, and posterior leukoencephalopathy.36
Unfortunately, at this time, there is no pathognomonic CT or MRI finding for eclampsia. Furthermore,
cerebral imaging is not necessary for diagnosis and management. Cerebral imaging should be obtained in
women with focal neurologic deficits, prolonged coma, or atypical presentation for eclampsia.
Differential diagnosis for eclampsia includes cerebrovascular accidents, seizure disorders, brain tumors,
metabolic diseases, metastatic gestational trophoblastic disease, and thrombotic thrombocytopenic
purpura, among others.
Management of Preeclampsia
The optimal management of a woman with preeclampsia depends on gestational age and severity of the
disease. Since 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.
Preeclampsia
A pregnancy complicated by mild preeclampsia at or beyond 37 weeks should be delivered. While the
pregnancy outcome is similar in these women as those with a normotensive pregnancy, the risk of
placental abruption and progression to severe disease is slightly increased.37, 38 Thus, regardless of
cervical status, induction of labor should be recommended. Cesarean section may be performed based on
standard obstetric criteria.
Prior to 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. While 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.39 Therefore, the safety of managing a
woman with mild preeclampsia as an outpatient still needs to be investigated. While 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.
Antepartum testing is generally indicated during expectant management of these patients. However, the
types of tests to be used and the frequency of testing have little consensus. 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.27, 28
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.
Severe preeclampsia
When severe preeclampsia is diagnosed after 34 weeks' gestation, delivery is most appropriate. The mode
of delivery should depend on severity of the disease and the likelihood of a successful induction.
However, whenever possible, vaginal delivery should be attempted and cesarean section should be
reserved for routine obstetric indications. In addition, 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 stable and fetal
condition is reassuring, expectant management may be considered provided they meet the strict criteria
set by Sibai et al (see Laboratory values for preeclampsia and HELLP syndrome).40 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 on 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 severegrowthrestriction 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 less than 2 times the normal value)
and hypertension that can be controlled.
Fetal monitoring should include daily nonstress test 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. In addition, 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 LFTs, CBC, uric acid, and LDH. Patients should be instructed
to report any headache, visual changes, epigastric pain, or decreased fetal movement.
Women with severe preeclampsia who are managed expectantly, must be delivered under the following
circumstances:
Nonreassuring fetal heart status
Uncontrollable blood pressure
Oligohydramnios with AFI of less than 5 cm
Severe intrauterine growth restriction where 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 prophylaxis
Magnesium sulfate is the drug of choice for seizure prophylaxis in women with preeclampsia. Although
the precise mechanism of its antiseizure activity is unknown, several randomized studies showed that
magnesium sulfate is better than benzodiazepam or phenytoin in preventing the onset of initial eclamptic
seizures and recurring seizures.
Therapy is started at the beginning of labor or prior to cesarean section and continued 24 hours
postpartum in most cases. The duration of postpartum therapy may be modified depending on the severity
of the disease. Treatment is started by administering an intravenous (IV) loading dose of 4-6 g
magnesium sulfate, followed by a maintenance dose of 1-3 g/h. Proposed mechanisms of action of
magnesium sulfate therapy are prevention of calcium ion transport, cerebral blood vessel dilatation, and
prevention of platelet aggregations (28 in up-to-date management of preeclampsia).
Patients receiving magnesium sulfate should be monitored carefully for signs and symptoms of
magnesium toxicity. Magnesium toxicity manifests initially as loss of patellar reflexes and shortness of
breath. Therefore, the patellar reflexes must be checked every 4 hours and oxygen saturation and
respiratory rate must be monitored. As magnesium sulfate is excreted by the kidney, urine output should
be monitored closely and should be at least 30 mL/h. If magnesium toxicity is suspected, a blood test for
magnesium level should be performed. Most practitioners feel comfortable with a level below 9.0 mg/dL.
However, patients have been reported to show signs of toxicity below 6.0 mg/dL. Therefore, clinical
evaluation of the patient should continue even if the serum magnesium level is below 9.0 mg/dL. Side
effects of IV magnesium administration include flushing, chest heaviness, blurred vision, and minor
headache. While these are not symptoms of toxicity, it may be reasonable to consider lowering the
doseorwithholding therapy if they become severe. Rarely, magnesium can be administered
intramuscularly (IM) if a patient does not have an IV access. The standard dose is to inject 5 grams IM in
each buttock for a total of 10 g. The entire amount should not be injected in one site. If IV access is not
established, a 5-g injection can be given every 4 hours until IV administration becomes possible.
Magnesium sulfate therapy is contraindicated in patients with myasthenia gravis.
Magnesium sulfate therapy for seizure prophylaxis should be administered to all women with severe
preeclampsia during induction or labor. However, prophylaxis for mild preeclampsia is controversial.
ACOG recommends magnesium sulfate in severe preeclampsia. However, ACOG has not recommended
magnesium sulfate therapy in all cases of mild preeclampsia. Some practitioners withhold magnesium
sulfate if blood pressure is stable and/or mildly elevated and if the laboratory values for liver function
tests and platelets are mildly abnormal and/or stable. Others feel that even patients with gestational
hypertension should receive magnesium, since a small percentage of these patients may either have or
develop preeclampsia. The ultimate decision should depend on the comfort level of the labor and delivery
staff in administering IV magnesium sulfate. An estimated 100 patients need to be treated with
magnesium sulfate therapy to prevent one case of eclampsia.41, 42, 43
Acute treatment of severe hypertension in pregnancy
Systolic blood pressure of 160 mm Hg or greater and/or diastolic pressure of 110 mm Hg or greater must
be treated right away. The goal is to maintain the blood pressure around 140/90 mm Hg. Hydralazine is a
direct peripheral arteriolar vasodilator and, in the past, was widely used as the first-line treatment for
acute hypertension in pregnancy.44, 45 Hydralazine 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. It 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 may subsequently result in a
nonreassuring fetal heart rate tracing in the fetus.29 In a recent meta-analysis, Magee et al pointed out that
hydralazine was associated with worse maternal andperinataloutcomes than labetalol and nifedipine.
Furthermore, hydralazine was associated with more maternal side effects than labetalol and nifedipine.44
Labetalol is a selective alpha-blocker and 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 blood
pressure are observed after 5 minutes (in contrast to the slower onset of action of hydralazine) and results
in less overshoot hypertension than 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
achieving satisfactory control with IV administration, an oral maintenance dose can begin.29, 44
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 blood pressure control.29, 44
In a severe hypertensive emergency, when above mentioned medications have failed to lower blood
pressure, sodium nitroprusside may be given. Nitroprusside results in the release of nitric oxide, which
subsequently results in 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, its use should be reserved for postpartum care or just before
the delivery of the fetus.29
Eclampsia
When eclamptic seizures occur, maternal injury must be prevented. The airway must be protected and
oxygenation assured, including placement of a supportive airway, if necessary, to prevent aspiration.
Management may include placement of a padded tongue blade and suctioning of the oral cavity. Pulse
oximetry should be performed to monitor oxygenation and oxygen by facemask should be provided.36
Fetal monitoring may be instituted when the maternal airway and seizures are under control, since
intervention for the fetus should not be considered until the mother’s condition is stabilized.
Magnesium sulfate must be administered to prevent further seizure activity. A loading dose of 4-6 g
followed by a maintenance dose of 2 g/h is given. Of women with eclampsia, 10% will have a second
convulsion after receiving magnesium sulfate.36, 43 Occasionally, convulsions may recur even though a
patient receives adequate doses of magnesium sulfate. In these patients, sodium amobarbital, 250 mg IV
over 3–5 minutes, may be administered.36 Alternatively, benzodiazepine may be administered along with
magnesium sulfate, since patients may have other underlying CNS causes for their seizure.
Blood pressure must be controlled after initiation of magnesium sulfate therapy. This is accomplished by
the administration of parental hydralazine and/or labetalol, as described previously. Hypoxemia, which
may occur during maternal convulsive episodes, may lead to nonreassuring fetal heart rate status.
Emergency cesarean section should be avoided until maternal status has been stabilized. Furthermore,
most cases of nonreassuring fetal heart rate tracing will respond to in-utero resuscitation. Both maternal
and fetal resuscitation can be performed concurrently. However, if bradycardia and/or recurrent late
decelerations persist beyond 10–15 minutes despite all resuscitative efforts, and if the mother is stable,
cesarean delivery may be considered. The utmost priority in managing eclampsia is maternal safety. Only
when the mother is safe enough to undergo surgery may cesarean delivery be considered. If a cesarean
delivery is not indicated, a vaginal delivery should be attempted.
In terms of anesthesia for cesarean section or for pain control during labor, spinal and epidural anesthesia
are contraindicated if the patient has severe thrombocytopenia (platelet count <50,000/mm3). If general
anesthesia is necessary in case of an emergency cesarean or secondary to severe thrombocytopenia, a
significant increase in blood pressure may be encountered during intubation, therefore elevating the risk
of stroke. In this situation, blood pressure must be controlled in close collaboration with the
anesthesiology team. Transfusion of blood products must be anticipated.
Postpartum Management
Preeclampsia resolves after delivery. However, patients may still have elevated blood pressure
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.46 Therefore, magnesium sulfate seizure prophylaxis
is continued for 24 hours postpartum.
Rarely, a patient may have elevated liver enzymes, thrombocytopenia, and renal insufficiency beyond 72
hours after delivery. In these cases, the possibility of hemolytic uremic syndrome (HUS) or thrombotic
thrombocytopenic purpura (TTP) must be considered. In these situations, plasmapheresis along with
corticosteroid therapy may be of some benefit and must be discussed with renal and hematology
consultants.
In addition, 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 those with
persistent thrombocytopenia.47, 48 The effectiveness of this therapy in preventing severe hemorrhage or
ameliorating the disease course needs to be investigated further.
Elevated blood pressure may be controlled with nifedipine or labetalol postpartum. If a patient is
discharged with blood pressure medication, reassessment and a blood pressure check should be performed
at the latest one week after discharge. Unless a woman has undiagnosed chronic hypertension, in most
cases of preeclampsia, the blood pressure returns to baseline by 12 weeks' postpartum.
Prevention and Prediction of Preeclampsia
Efforts to prevent preeclampsia have been disappointing.49 To date, 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 (OR 0.86, 95% CI, 0.76-0.96) along with perinatal death, but did not
significantly affect birth weight or the risk of abruption.50 Low-dose aspirin in unselected nulliparous
women seems to reduce the incidence only slightly (RR 0.7, 95% CI 0.6-1.0).51 For women with risk
factors for preeclampsia, starting low-dose aspirin (commonly, one 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.50, 52
The use of calcium and vitamin C and E supplementations in low-risk populations did not reduce the
incidence of preeclampsia.53, 54, 55 Use of low molecular weight heparin in women with thrombophilia
who have a history of adverse outcome has been investigated. However, to date, no data suggest that the
use of heparin prophylaxis lowers the incidence of preeclampsia.
Numerous screening tests for preeclampsia have been proposed over the past few decades. A screening
test should be safe, valid, reliable, acceptable to the population, reproducible, appropriate for the
population, and economical. Preeclampsia is an appropriate disease to screen, as it is common, important,
and increases both maternal mortality and perinatal mortality. However, to date, no test has been shown to
appropriately screen for preeclampsia.56 Although measurement of urinary kallikrein has been shown to
have high predictive value, it was not reproducible.57, 58
While recent works on sFlt-1, PlGF, and VEGF are promising, their positive predictive values in
predicting preeclampsia are yet to be evaluated in a prospective fashion.
Currently, the clinical value of an accurate predictive test for preeclampsia is not clear since we lack
effective prevention. Intensive monitoring in women who are at increased risk of developing
preeclampsia, when identified by a predictive test, may lower the incidence of adverse outcome for both
mother and the neonate. However, the effectiveness of such a strategy must be rigorously investigated.
Recurrence
In general, the recurrence risk of preeclampsia in a woman whose previous pregnancy was complicated
by preeclampsia near term is approximately 10%.59 If a woman had severe preeclampsia (including
HELLP syndrome and/or eclampsia), she has 20% risk of developing preeclampsia sometime in her
subsequent pregnancy.60, 61, 62, 63, 64, 65
If a woman had HELLP syndrome or eclampsia, the recurrence risk of HELLP syndrome and eclampsia
are 5%61 and 2%,63, 64, 65 respectively. The recurrence rate rises the earlier the disease manifested
during the index pregnancy. If preeclampsia presents clinically before 30 weeks' gestation, the recurrence
rate may be as high as 40%.66
Future cardiovascular disease
Preeclampsia is a syndrome characterized by endothelial dysfunction in the mother. Therefore, the
possibility exists that preeclampsia may be a contributor to future cardiovascular disease. In a recent
metaanalysis, several associations were observed between an increased risk of cardiovascular disease and
a pregnancy complicated by preeclampsia. These associations included an approximate fourfold increase
in risk of subsequent development of hypertension and an approximate 2 times risk of ischemic heart
disease, venous thromboembolism, and stroke.67 Moreover, women who had recurrent preeclampsia
were more likely to suffer from hypertension later in life.67
In another review, Harskamp and Zeeman noted that population-based studies relate preeclampsia to an
increased risk of later chronic hypertension (RR, 2.00-8.00) and cardiovascular morbidity/mortality (RR,
1.3-3.07), compared with normotensive pregnancy. Moreover, women who develop preeclampsia before
36 weeks' gestation or have multiple hypertensive pregnancies are at highest risk (RR, 3.4-8.12).68
Harskamp and Zeeman note 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 endothelial dysfunction, obesity, hypertension, hyperglycemia, insulin resistance, and
dyslipidemia. Metabolic syndrome, they note, may be a possible underlying mechanism common to
cardiovascular disease and preeclampsia.
Keywords
preeclampsia, eclampsia, hypertension, proteinuria, placental hypoperfusion, diffuse endothelial cell
injury, liver failure, renal failure, disseminated intravascular coagulopathy, seizures, chronic
hypertension, preeclampsia superimposed on chronic hypertension, gestational hypertension, HELLP
syndrome, thrombocytopenia, intrauterine growth restriction, Korotkoff sound, new-onset tonic-clonic
seizure
References
Acknowledgments
The authors and editors of eMedicine greatly acknowledge the contributions of previous authors
MatthewWarden, MD and Brian Euerle, MD, FACEP to the development and writing of this article