[PREECLAMPSIA] 1

Preeclampsia is a disorder of widespread vascular endothelial malfunction and Cerebral or visual symptoms
vasospasm that occurs after 20 weeks' gestation and can present as late as 4-6 Eclampsia is defined as seizures that cannot be attributable to other causes in a
weeks post partum. It is clinically defined by hypertension and proteinuria, with or woman with preeclampsia. HELLP syndrome (hemolysis, elevated liver enzyme, low
without pathologic edema. platelets) may complicate severe preeclampsia.

Definitions Risk factors

Preeclampsia is defined as the presence of (1) a systolic blood pressure (SBP) Risk factors for preeclampsia and their odds ratios are as follows[2] :
greater than or equal to 140 mm Hg or a diastolic blood pressure (DBP) greater than Nulliparity (3.1)
or equal to 90 mm Hg or higher, on two occasions at least 4 hours apart in a Age older than 40 years (3:1)
previously normotensive patient, OR (2) an SBP greater than or equal to 160 mm Hg Black race (1.5:1)
or a DBP greater than or equal to 110 mm Hg or higher (In this case, hypertension Family history (5:1)
can be confirmed within minutes to facilitate timely antihypertensive therapy.).[1] Chronic renal disease (20:1)
In addition to the blood pressure criteria, proteinuria of greater than or equal to 0.3 Chronic hypertension (10:1)
grams in a 24-hour urine specimen, a protein (mg/dL)/creatinine (mg/dL) ratio of Antiphospholipid syndrome (10:1)
0.3 or higher, or a urine dipstick protein of 1+ (if a quantitative measurement is Diabetes mellitus (2:1)
unavailable) is required to diagnose preeclampsia. Twin gestation (but unaffected by zygosity) (4:1)
High body mass index (3:1)
Preeclampsia with severe features is defined as the presence of one of the following Homozygosity for angiotensinogen gene T235 (20:1)
symptoms or signs in the presence of preeclampsia[1] : Heterozygosity for angiotensinogen gene T235 (4:1)
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 Signs and symptoms
therapy has previously been initiated) Because the clinical manifestations of preeclampsia can be heterogeneous,
Impaired hepatic function as indicated by abnormally elevated blood diagnosing preeclampsia may not be straightforward. Preeclampsia without severe
concentrations of liver enzymes (to double the normal concentration), severe features may be asymptomatic. Many cases are detected through routine prenatal
persistent upper quadrant or epigastric pain that does not respond to screening.
pharmacotherapy and is not accounted for by alternative diagnoses, or both.
Progressive renal insufficiency (serum creatinine concentration >1.1 mg/dL or a Patients with preeclampsia with severe features display end-organ effects and may
doubling of the serum creatinine concentration in the absence of other renal complain of the following:
disease) Headache
New onset cerebral or visual disturances Visual disturbances: Blurred, scintillating scotomata
Pulmonary edema Altered mental status
Thrombocytopenia (platelet count <100,000/L) Blindness: May be cortical [3] or retinal
Dyspnea
In a patient with new-onset hypertension without proteinuria, the new onset of any Edema: Sudden increase in edema or facial edema
of the following is diagnostic of preeclampsia: Epigastric or right upper quadrant abdominal pain
Platelet count below 100,000/L Weakness or malaise: May be evidence of hemolytic anemia
Serum creatinine level above 1.1 mg/dL or doubling of serum creatinine in the Clonus: May indicate an increased risk of convulsions
absence of other renal disease
Liver transaminase levels at least twice the normal concentrations
Pulmonary edema
 [PREECLAMPSIA] 2

Diagnosis In patients with preeclampsia with severe features, induction of delivery should be
All women who present with new-onset hypertension should have the following considered after 34 weeks' gestation. In these cases, the severity of disease must be
tests: weighed against the risks of infant prematurity. In the emergency setting, control of
CBC BP and seizures should be priorities.
Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST)
levels Criteria for delivery
Serum creatinine Women with preeclampsia with severe features who are managed expectantly must
Uric acid be delivered under the following circumstances:
24-hour urine collection for protein and creatinine (criterion standard) or urine Nonreassuring fetal testing including (nonreassuring nonstress test, biophysical
dipstick analysis profile score, and/or persistent absent or reversed diastolic flow on umbilical
Additional studies to perform if HELLP syndrome is suspected are as follows: artery Doppler velocimetry)
Peripheral blood smear Ruptured membranes
Serum lactate dehydrogenase (LDH) level Uncontrollable BP (unresponsive to medical therapy)
Indirect bilirubin Oligohydramnios, with amniotic fluid index (AFI) of less than 5 cm
Although a coagulation profile (prothrombin time [PT], activated partial Severe intrauterine growth restriction in which the estimated fetal weight is less
thromboplastin time [aPTT], and fibrinogen) should also be evaluated, its clinical than 5%
value is unclear when the platelet count is 100,000/mm3 or more with no evidence Oliguria (< 500 mL/24 hr)
of bleeding.[4] Serum creatinine level of at least 1.5 mg/dL
Head CT scanning is used to detect intracranial hemorrhage in selected patients Pulmonary edema
with any of the following: Shortness of breath or chest pain with pulse oximetry of < 94% on room air
Sudden severe headaches Headache that is persistent and severe
Focal neurologic deficits Right upper quadrant tenderness
Seizures with a prolonged postictal state Development of HELLP syndrome
Atypical presentation for eclampsia Eclampsia
Platelet count less tha 100,000 cells/microL
Other procedures Placental abruption
Ultrasonography: Transabdominal, to assess the status of the fetus and evaluate for Unexplained coagulopathy
growth restriction; umbilical artery Doppler ultrasonography, to assess blood flow
Cardiotocography: The standard fetal nonstress test and the mainstay of fetal Seizure treatment and prophylaxis
monitoring The basic principles of airway, breathing, and circulation (ABC) should always be
followed
Management Magnesium sulfate is the first-line treatment for primary and recurrent eclamptic
Delivery is the only cure for preeclampsia. Patients with preeclampsia without seizures
severe features are often induced after 37 weeks' gestation. Before this, the patient is Treat active seizures with IV magnesium sulfate [5] : A loading dose of 4 g is given
usually hospitalized and monitored carefully for the development of worsening by infusion pump over 5-10 minutes, followed by an infusion of 1 g/hr
preeclampsia or complications of preeclampsia, and the immature fetus is treated maintained for 24 hours after the last seizure
with expectant management with corticosteroids to accelerate lung maturity in Treat recurrent seizures with an additional bolus of 2 g or an increase in the
preparation for early delivery. 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
[PREECLAMPSIA] 3
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
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.)
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.
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.
[PREECLAMPSIA] 4
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.
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]
[PREECLAMPSIA] 5
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.
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.
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]
1. 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.
[PREECLAMPSIA] 6
2. Maternal age
Women aged 35 years and older have a markedly increased risk of preeclampsia.
3. Race
In the United States, the incidence of preeclampsia is 1.8% among white women and
3% in black women.
4. 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 outcomeseven 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.
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/m 2 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.
An analysis of 456,668 singleton births found that early-onset (<34 weeks'
gestation) and late-onset (34 weeks' gestation) preeclampsia shared some etiologic
 [PREECLAMPSIA] 7

features, but their risk factors and outcomes differed. Shared risk factors for early- preeclampsia. In addition, if a woman has underlying renal or cardiovascular
and late-onset preeclampsia included older maternal age, Hispanic race, Native disease, the diagnosis of preeclampsia may not become clear until the disease
American race, smoking, unmarried status, and male fetus. Risk factors more becomes severe.
strongly associated with early-onset preeclampsia than late-onset disease included Mild to moderate preeclampsia may be asymptomatic. Many cases are detected
black race, chronic hypertension, and congenital anomalies, while younger maternal through routine prenatal screening.
age, nulliparity, and diabetes mellitus were more strongly associated with late-onset Preeclampsia in a previous pregnancy is strongly associated with recurrence in
preeclampsia than with early-onset disease.[41, 42] subsequent pregnancies. A history of gestational hypertension or preeclampsia
should strongly raise clinical suspicion.
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). Physical findings
However, the AOR for perinatal death/severe neonatal morbidity was significant for Patients with preeclampsia with severe features display end-organ effects and may
both early-onset (16.4) and late-onset (2.0) preeclampsia.[41, 42] complain of the following:
In addition, the incidence of preeclampsia increased sharply as gestation progressed: Headache
the rate for early-onset preeclampsia was 0.38% compared with 2.72% for late- Visual disturbances: Blurred, scintillating scotomata
onset preeclampsia.[41, 42] Altered mental status
Blindness: May be cortical [3] or retinal
Table 1. Risk Factors for Preeclampsia* (Open Table in a new window) Dyspnea
Nulliparity 3:1 Edema
Age >40 y 3:1 Epigastric or right upper quadrant abdominal pain
Black race 1.5:1 Weakness or malaise - May be evidence of hemolytic anemia
Family history 5:1
Edema exists in many pregnant women, but a sudden increase in edema or facial
Chronic renal disease 20:1
edema is suggestive of preeclampsia. The edema of preeclampsia occurs by a distinct
Chronic hypertension 10:1
mechanism that is similar to that of angioneurotic edema.
Antiphospholipid syndrome 10:1 Hepatic involvement occurs in 10% of women with severe preeclampsia. The
Diabetes mellitus 2:1 resulting pain (epigastric or right upper quadrant abdominal pain) is frequently
Twin gestation (but unaffected by zygosity) 4:1 accompanied by elevated serum hepatic transaminase levels.
High body mass index 3:1 The presence of clonus may indicate an increased risk of convulsions.
Angiotensinogen gene T235 A study by Cooray et al found that the most common symptoms that immediately
Homozygous 20:1 precede eclamptic seizures are neurologic symptoms (ie, headache, with or without
Heterozygous 4:1 visual disturbance), regardless of degree of hypertension. This suggests that closely
*Adapted from ACOG Technical Bulletin 219, monitoring patients with these symptoms may provide an early warning for
Washington, DC 1996.[1] eclampsia.[43]

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
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):
Altered mental status
Decreased vision or scotomas
Papilledema
Epigastric or right upper quadrant abdominal tenderness
Peripheral edema Hyperreflexia or clonus: Although deep tendon reflexes are
more useful in assessing magnesium toxicity, the presence of clonus may
indicate an increased risk of convulsions.
Seizures
Focal neurologic deficit
Measurement of Hypertension
Hypertension is diagnosed when 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
Gestational hypertension
During diagnosis, preeclampsia must be differentiated from gestational
hypertension; although gestational hypertension is more common and may present
with symptoms similar to those of preeclampsia, including epigastric discomfort or
thrombocytopenia, it is which is not characterized by proteinuria. (See Classification
[PREECLAMPSIA] 8
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/mm 3
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.
[PREECLAMPSIA] 9
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 0.930.995).[54, 55] Between
35 and 36 weeks' gestation, the sensitivity was 0.70 (95% CI, 0.580.81), and the
negative predictive value was 0.69 (95% CI 0.570.80). At 37 weeks' gestation or
more, the sensitivity was 0.57 (95% CI, 0.460.68), and the negative predictive value
was 0.70 (95% CI, 0.620.78).[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
[PREECLAMPSIA] 10
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 conditions diagnosis and
management. However, head CT scanning is used to detect intracranial hemorrhage
in selected patients with sudden severe headaches, focal neurologic deficits, seizures
with a prolonged postictal state, or atypical presentation for eclampsia.
Ultrasonography
Ultrasonography is used to assess the status of the fetus as well as to evaluate for
growth restriction (typically asymmetricaluse abdominal circumference).[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
[PREECLAMPSIA] 11
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/L
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
[PREECLAMPSIA] 12
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.
Acute Treatment of Severe Hypertension in Pregnancy
In the setting of severe hypertension (SBP >160 mm Hg; DBP >110 mm Hg),
antihypertensive treatment is recommended. The goal of hypertension treatment is
to lower BP to prevent cerebrovascular and cardiac complications while maintaining
uteroplacental blood flow (ie, maintain BP around 140/90 mm Hg). However,
although antihypertensive treatment decreases the incidence of cerebrovascular
problems, it does not alter the progression of preeclampsia. Control of mildly

increased BP does not appear to improve perinatal morbidity or mortality, and it
may, in fact, reduce birth weight.
Hydralazine
Hydralazine is a direct peripheral arteriolar vasodilator and, in the past, was widely
used as the first-line treatment for acute hypertension in pregnancy.[69, 70] 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.[69]
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.
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, 69]
[PREECLAMPSIA] 13
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.[71] 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. [72, 73]
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.[74]
Patients at risk for eclampsia should be carefully monitored postpartum.[75]
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.[76]
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.[77] Low-dose aspirin in unselected nulliparous women seems
to reduce the incidence of preeclampsia only slightly.[78] 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.[77, 79]
On the basis of limited evidence from a systematic review and meta-analysis, the
[PREECLAMPSIA] 14
addition of lowmolecular 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.[80]
Heparin
The use of lowmolecular weight heparin in women with thrombophilia who have a
history of adverse outcome has been investigated. To date, however, no data suggest
that the use of heparin prophylaxis lowers the incidence of preeclampsia.
Calcium and vitamin supplements
Research into the use of calcium and vitamin C and E supplementations in low-risk
populations did not find a reduction in the incidence of preeclampsia.[81, 82, 83] 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.[84]
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.[85]
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.[86]
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.[87] (Measurement of urinary
kallikrein was shown to have a high predictive value, but it was not reproducible. [88,
89] )
More recently, 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
 [PREECLAMPSIA] 15

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.
Currently, the clinical value of an accurate predictive test for preeclampsia is not
clear, as effective prevention is still lacking. Intensive monitoring in women who are
at increased risk for developing preeclampsia, when identified by a predictive test,
may lower the incidence of adverse outcome for the mother and the neonate.
However, the effectiveness of such a strategy must be rigorously investigated.
Prognosis
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.[92, 93, 94, 95, 96, 97]
If a woman has had HELLP syndrome or eclampsia, the recurrence risk of HELLP
syndrome is 5%[93] and of eclampsia it is 2%.[95, 96, 97] 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%.[98]
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.[99]

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).[90, 91] 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.[90, 91]
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.[91] 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