Preeclampsia

Practice Essentials

Preeclampsia is a disorder of widespread vascular endothelial malfunction and vasospasm that occurs after 20 weeks' gestation and can present as late as 4-6 weeks post partum. It is clinically defined by hypertension and proteinuria, with or without pathologic edema.

Definitions

Preeclampsia is defined as the presence of (1) a systolic blood pressure (SBP) greater than or equal to 140 mm Hg or a diastolic blood pressure (DBP) greater than or equal to 90 mm Hg or higher, on two occasions at least 4 hours apart in a previously normotensive patient, OR (2) an SBP greater than or equal to 160 mm Hg or a DBP greater than or equal to 110 mm Hg or higher (In this case, hypertension can be confirmed within minutes to facilitate timely antihypertensive therapy.).^[1]

In addition to the blood pressure criteria, proteinuria of greater than or equal to 0.3 grams in a 24-hour urine specimen, a protein (mg/dL)/creatinine (mg/dL) ratio of 0.3 or higher, or a urine dipstick protein of 1+ (if a quantitative measurement is unavailable) is required to diagnose preeclampsia.^[1]

Preeclampsia with severe features is defined as the presence of one of the following symptoms or signs in the presence of preeclampsia^[1] :

• SBP of 160 mm Hg or higher or DBP of 110 mm Hg or higher, on two occasions at least 4 hours apart while the patient is on bed rest (unless antihypertensive therapy has previously been initiated)
• Impaired hepatic function as indicated by abnormally elevated blood concentrations of liver enzymes (to double the normal concentration), severe persistent upper quadrant or epigastric pain that does not respond to pharmacotherapy and is not accounted for by alternative diagnoses, or both.
• Progressive renal insufficiency (serum creatinine concentration >1.1 mg/dL or a doubling of the serum creatinine concentration in the absence of other renal disease)
• New onset cerebral or visual disturbances
• Pulmonary edema
• Thrombocytopenia (platelet count < 100,000/μL)

In a patient with new-onset hypertension without proteinuria, the new onset of any of the following is diagnostic of preeclampsia:

• Platelet count below 100,000/μL
• Serum creatinine level above 1.1 mg/dL or doubling of serum creatinine in the absence of other renal disease
• Liver transaminase levels at least twice the normal concentrations
• Pulmonary edema
• Cerebral or visual symptoms

Eclampsia is defined as seizures that cannot be attributable to other causes in a woman with preeclampsia. HELLP syndrome (hemolysis, elevated liver enzyme, low platelets) may complicate severe preeclampsia.

Risk factors

Risk factors for preeclampsia and their odds ratios are as follows^[2] :

• Nulliparity (3.1)
• Age older than 40 years (3:1)
• Black race (1.5:1)
• Family history (5:1)
• Chronic renal disease (20:1)
• Chronic hypertension (10:1)
• Antiphospholipid syndrome (10:1)
• Diabetes mellitus (2:1)
• Twin gestation (but unaffected by zygosity) (4:1)
• High body mass index (3:1)
• Homozygosity for angiotensinogen gene T235 (20:1)
• Heterozygosity for angiotensinogen gene T235 (4:1)

Signs and symptoms

Because the clinical manifestations of preeclampsia can be heterogeneous, diagnosing preeclampsia may not be straightforward. Preeclampsia without severe features may be asymptomatic. Many cases are detected through routine prenatal screening.

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

• Headache
• Visual disturbances: Blurred, scintillating scotomata
• Altered mental status
• Blindness: May be cortical^[3] or retinal
• Dyspnea
• Edema: Sudden increase in edema or facial edema
• Epigastric or right upper quadrant abdominal pain
• Weakness or malaise: May be evidence of hemolytic anemia
• Clonus: May indicate an increased risk of convulsions

Diagnosis

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

• CBC
• Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels
• Serum creatinine
• Uric acid
• 24-hour urine collection for protein and creatinine (criterion standard) or urine dipstick analysis

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

• Peripheral blood smear
• Serum lactate dehydrogenase (LDH) level
• Indirect bilirubin

Although a coagulation profile (prothrombin time [PT], activated partial thromboplastin time [aPTT], and fibrinogen) should also be evaluated, its clinical value is unclear when the platelet count is 100,000/mm³ or more with no evidence of bleeding.^[4]

• Head CT scanning is used to detect intracranial hemorrhage in selected patients with any of the following:
• Sudden severe headaches
• Focal neurologic deficits
• Seizures with a prolonged postictal state
• Atypical presentation for eclampsia

Other procedures

• Ultrasonography: Transabdominal, to assess the status of the fetus and evaluate for growth restriction; umbilical artery Doppler ultrasonography, to assess blood flow
• Cardiotocography: The standard fetal nonstress test and the mainstay of fetal monitoring

Management

Delivery is the only cure for preeclampsia. Patients with preeclampsia without severe features are often induced after 37 weeks' gestation. Before this, the patient is usually hospitalized and monitored carefully for the development of worsening preeclampsia or complications of preeclampsia, and the immature fetus is treated with expectant management with corticosteroids to accelerate lung maturity in preparation for early delivery.

In patients with preeclampsia with severe features, induction of delivery should be considered after 34 weeks' gestation. In these cases, the severity of disease must be weighed against the risks of infant prematurity. In the emergency setting, control of BP and seizures should be priorities.

Criteria for delivery

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

• Nonreassuring fetal testing including (nonreassuring nonstress test, biophysical profile score, and/or persistent absent or reversed diastolic flow on umbilical artery Doppler velocimetry)
• Ruptured membranes
• Uncontrollable BP (unresponsive to medical therapy)
• Oligohydramnios, with amniotic fluid index (AFI) of less than 5 cm
• Severe intrauterine growth restriction in which the estimated fetal weight is less than 5%
• Oliguria (< 500 mL/24 hr)
• Serum creatinine level of at least 1.5 mg/dL
• Pulmonary edema
• Shortness of breath or chest pain with pulse oximetry of < 94% on room air
• Headache that is persistent and severe
• Right upper quadrant tenderness
• Development of HELLP syndrome
• Eclampsia
• Platelet count less tha 100,000 cells/microL
• Placental abruption
• Unexplained coagulopathy

Seizure treatment and prophylaxis

• The basic principles of airway, breathing, and circulation (ABC) should always be followed
• Magnesium sulfate is the first-line treatment for primary and recurrent eclamptic seizures
• Treat active seizures with IV magnesium sulfate^[5] : A loading dose of 4 g is given by infusion pump over 5-10 minutes, followed by an infusion of 1 g/hr maintained for 24 hours after the last seizure
• Treat recurrent seizures with an additional bolus of 2 g or an increase in the infusion rate to 1.5 or 2 g per hour
• Prophylactic treatment with magnesium sulfate is indicated for all patients with preeclampsia with severe features
• Lorazepam and phenytoin may be used as second-line agents for refractory seizures

Acute treatment of severe hypertension in pregnancy

Antihypertensive treatment is recommended for severe hypertension (SBP >160 mm Hg; DBP >110 mm Hg). The goal of hypertension treatment is to maintain BP around 140/90 mm Hg.

Medications used for BP control include the following:

• Hydralazine
• Labetalol
• Nifedipine
• Sodium nitroprusside (in severe hypertensive emergency refractory to other medications)

Fluid management

• Diuretics should be avoided
• Aggressive volume resuscitation may lead to pulmonary edema
• Patients should be fluid restricted when possible, at least until the period of postpartum diuresis
• Central venous pressure (CVP) or pulmonary artery pressure monitoring may be indicated in critical cases
• A CVP of 5 mm Hg in women with no heart disease indicates sufficient intravascular volume, and maintenance fluids alone are sufficient
• Total fluids should generally be limited to 80 mL/hr or 1 mL/kg/hr

Postpartum management

• Many patients will have a brief (up to 6 hours) period of oliguria following delivery
• Magnesium sulfate seizure prophylaxis is continued for 24 hours postpartum
• Liver function tests and platelet counts must document decreasing values prior to hospital discharge
• Elevated BP may be controlled with nifedipine or labetalol postpartum
• If a patient is discharged with BP medication, reassessment and a BP check should be performed, at the latest, 1 week after discharge
• Unless a woman has undiagnosed chronic hypertension, in most cases of preeclampsia, the BP returns to baseline by 12 weeks’ postpartum
• Patients should be carefully monitored for recurrent preeclampsia, which may develop up to 4 weeks postpartum, and for eclampsia that has occurred up to 6 weeks after delivery

• References

Overview

Preeclampsia is a disorder of widespread vascular endothelial malfunction and vasospasm that occurs after 20 weeks' gestation and can present as late as 4-6 weeks postpartum. It is clinically defined by hypertension and proteinuria, with or without pathologic edema.^[6]

The incidence of preeclampsia in the United States is estimated to range from 2% to 6% in healthy, nulliparous women.^{[7, 8, 9]} Among all cases of the preeclampsia, 10% occur in pregnancies of less than 34 weeks' gestation. The global incidence of preeclampsia has been estimated at 5-14% of all pregnancies.

In developing nations, the incidence of the disease is reported to be 4-18%,^{[10, 11]} with hypertensive disorders being the second most common obstetric cause of stillbirths and early neonatal deaths in these countries.^[12]

Medical consensus is lacking regarding the values that define preeclampsia, but reasonable criteria in a woman who was normotensive before 20 weeks' gestation include a systolic blood pressure (SBP) greater than 140 mm Hg and a diastolic BP (DBP) greater than 90 mm Hg on two successive measurements, 4 hours apart. 

Preeclampsia and preeclampsia with severe features

Severe preeclampsia accounts for approximately 25% of all cases of preeclampsia.^[5] In its extreme, the disease may lead to liver and renal failure, disseminated intravascular coagulopathy (DIC), and central nervous system (CNS) abnormalities. If preeclampsia-associated seizures develop, the disorder has developed into the condition called eclampsia.

Preeclampsia is defined as the presence of (1) a systolic blood pressure (SBP) greater than or equal to 140 mm Hg or a diastolic blood pressure (DBP) greater than or equal to 90 mm Hg or higher, on two occasions at least 4 hours apart in a previously normotensive patient, OR (2) an SBP greater than or equal to 160 mm Hg or a DBP greater than or equal to 110 mm Hg or higher (In this case, hypertension can be confirmed within minutes to facilitate timely antihypertensive therapy.).^[1]

In addition to the blood pressure criteria, proteinuria of greater than or equal to 0.3 grams in a 24-hour urine specimen, a protein (mg/dL)/creatinine (mg/dL) ratio of 0.3 or higher, or a urine dipstick protein of 1+ (if a quantitative measurement is unavailable) is required to diagnose preeclampsia.^[1]

Preeclampsia with severe features is defined as the presence of one of the following symptoms or signs in the presence of preeclampsia^[1] :

• SBP of 160 mm Hg or higher or DBP of 110 mm Hg or higher, on two occasions at least 4 hours apart while the patient is on bed rest (unless antihypertensive therapy has previously been initiated)
• Impaired hepatic function as indicated by abnormally elevated blood concentrations of liver enzymes (to double the normal concentration), severe persistent upper quadrant or epigastric pain that does not respond to pharmacotherapy and is not accounted for by alternative diagnoses, or both.
• Progressive renal insufficiency (serum creatinine concentration >1.1 mg/dL or a doubling of the serum creatinine concentration in the absence of other renal disease)
• New onset cerebral or visual disturances
• Pulmonary edema
• Thrombocytopenia (platelet count < 100,000/μL)

Also, a patient with new-onset hypertension without proteinuria can be diagnosed if any of the following is present^[1] :

• Platelet count below 100,000/μL
• Serum creatinine level above 1.1 mg/dL or doubling of serum creatinine in the absence of other renal disease
• Liver transaminase levels at least twice the normal concentrations
• Pulmonary edema
• Cerebral or visual symptoms

Classification and characteristics of hypertensive disorders

Preeclampsia is part of a spectrum of hypertensive disorders that complicate pregnancy. As specified by the National High Blood Pressure Education Program (NHBPEP) Working Group, the classification is as follows^[13] :

• Gestational hypertension
• Chronic hypertension
• Preeclampsia/eclampsia
• Superimposed preeclampsia (on chronic hypertension)

Although each of these disorders can appear in isolation, they are thought of as progressive manifestations of a single process and are believed to share a common etiology.

Gestational hypertension

The characteristics of gestational hypertension are as follows:

• BP of 140/90 mm Hg or greater for the first time during pregnancy
• No proteinuria
• BP returns to normal less than 12 weeks' postpartum
• Final diagnosis made only postpartum

Chronic hypertension

Chronic hypertension is characterized by either (1) a BP 140/90 mm Hg or greater before pregnancy or diagnosed before 20 weeks' gestation; not attributable to gestational trophoblastic disease or (2) hypertension first diagnosed after 20 weeks' gestation and persistent after 12 weeks postpartum.

Preexisting chronic hypertension may present with superimposed preeclampsia presenting as new-onset proteinuria after 20 weeks' gestation.

Preeclampsia/eclampsia

Preeclampsia/eclampsia is characterized by a BP of 140/90 mm Hg or greater after 20 weeks' gestation in a women with previously normal BP and who have proteinuria (≥0.3 g protein in 24-h urine specimen).

Eclampsia is defined as seizures that cannot be attributable to other causes, in a woman with preeclampsia

Superimposed preeclampsia

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

HELLP syndrome

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

Proteinuria

Proteinuria is defined as the presence of at least 300 mg of protein in a 24-hour urine collection, a protein (mg/dL)/creatinine (mg/dL) ratio greater than or equal to 0.3, or a urine dipstick protein of 1+ (if a quantitative measurement is unavailable).^[14] Serial confirmations 6 hours apart increase the predictive value. Although more convenient, a urine dipstick value of 1+ or more (30 mg/dL) is not reliable in the diagnosis of proteinuria.

• References

Pathophysiology

An estimated 2-8% of pregnancies are complicated by preeclampsia, with associated maternofetal morbidity and mortality.^[15] In the fetus, preeclampsia can lead to ischemic encephalopathy, growth retardation, and the various sequelae of premature birth.

Eclampsia is estimated to occur in 1 in 200 cases of preeclampsia when magnesium prophylaxis in not administered. (See Seizure Prophylaxis.)^{[16, 17]}

Cardiovascular disease

As previously mentioned, preeclampsia is characterized by endothelial dysfunction in pregnant women. Therefore, the possibility exists that preeclampsia may be a contributor to future cardiovascular disease. In a meta-analysis, several associations were observed between an increased risk of cardiovascular disease and a pregnancy complicated by preeclampsia. These associations included an approximately 4-fold increase in the risk of subsequent development of hypertension and an approximately 2-fold increase in the risk of ischemic heart disease, venous thromboembolism, and stroke.^[18] Moreover, women who had recurrent preeclampsia were more likely to suffer from hypertension later in life.^[18]

In a review of population-based studies, Harskamp and Zeeman noted a relationship between preeclampsia and an increased risk of later chronic hypertension and cardiovascular morbidity/mortality, compared with normotensive pregnancy. Moreover, women who develop preeclampsia before 36 weeks' gestation or who have multiple hypertensive pregnancies were at highest risk.^[19]

A prospective observational study by Vaught that included 63 women with pre-eclampsia with severe features reported higher systolic pressure, higher rates of abnormal diastolic function, decreased global right ventricular longitudinal systolic strain, increased left-sided chamber remodeling, and higher rates of peripartum pulmonary edema in these women when compared with healthy pregnant women.^[112]

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

• References

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.

• References

Placentation in Preeclampsia

Placental implantation with abnormal trophoblastic invasion of uterine vessels is a major cause of hypertension associated with preeclampsia syndrome.^{[22, 23]} In fact, studies have shown that the degree of incomplete trophoblastic invasion of the spiral arteries is directly correlated with the severity of subsequent maternal hypertension. This is because the placental hypoperfusion resulting from the incomplete invasion leads by an unclear pathway to the release of systemic vasoactive compounds that cause an exaggerated inflammatory response, vasoconstriction, endothelial damage, capillary leak, hypercoagulability, and platelet dysfunction, all of which contribute to organ dysfunction and the various clinical features of the disease.^[6]

Normal placentation and pseudovascularization

In normal pregnancies, a subset of cytotrophoblasts called invasive cytotrophoblasts migrate through the implantation site and invade decidua tunica media of maternal spiral arteries and replace its endothelium in a process called pseudovascularization.^[24] The trophoblast differentiation along the invasive pathway involves alteration in the expression of a number of different classes of molecules, including cytokines, adhesion molecules, extracellular matrix, metalloproteinases, and the class Ib major histocompatibility complex (MHC) molecule, HLA-G.^{[25, 26]}

For example, during normal differentiation, invading trophoblasts alter their adhesion molecule expression from those that are characteristic of epithelial cells (integrins alpha 6/beta 1, alpha V/beta 5, and E-cadherin) to those of endothelial cells (integrins alpha 1/beta 1, alpha V/beta 3, and VE-cadherin).

As a result of these changes, the maternal spiral arteries undergo transformation from small, muscular arterioles to large capacitance, low-resistance vessels. This allows increased blood flow to the maternal-fetal interface. Remodeling of these arterioles probably begins in the first trimester and ends by 18-20 weeks' gestation. However, the exact gestational age at which the invasion stops is unknown.

Failure of pseudovascularization in preeclampsia

The shallow placentation noted in preeclampsia results from the fact that the invasion of the decidual arterioles by cytotrophoblasts is incomplete. This is due to a failure in the alterations in molecular expression necessary for the differentiation of the cytotrophoblasts, as required for pseudovascularization. For example, the upregulation of matrix metalloproteinase-9 (MMP-9) and HLA-G, 2 molecules noted in normally invading cytotrophoblasts, does not occur.

The invasive cytotrophoblasts therefore fail to replace tunica media, which means that mostly intact arterioles, which are capable of vasoconstriction, remain. Histologic evaluation of the placental bed demonstrates few cytotrophoblasts beyond the decidual layer.

The primary cause for the failure of these invasive cytotrophoblasts to undergo pseudovascularization and invade maternal blood vessels is not clear. However, immunologic and genetic factors have been proposed. Early hypoxic insult to differentiating cytotrophoblasts has also been proposed as a contributing factor.

• References

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.

• References

Angiogenic Factors in Preeclampsia

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

VEGF and PlGF

VEGF and PlGF promote angiogenesis by interacting with the VEGF receptor family. Although both growth factors are produced by placenta, the serum level of PlGF rises much more significantly in pregnancy. In a study, Taylor et al demonstrated that the serum level of PlGF decreased in women who later developed preeclampsia.^[28] The fall in serum level was notable as early as the second trimester in women who developed preeclampsia and intrauterine growth restriction.

In another investigation, Maynard et al observed that the serum levels of VEGF and PlGF were decreased in women with preeclampsia.^[29] However, the magnitude of decrease was less pronounced for VEGF, as its serum level was not as high as that of PlGF, even in normal pregnancy. Other investigators have confirmed this finding and have shown that the serum level of PlGF decreased in women before they developed preeclampsia.^{[30, 31]}

Bills et al suggest that circulating VEGF-A levels in preeclampsia are biologically active because of a loss of repression of VEGF-receptor 1 signaling by PlGF-1, and VEGF₁₆₅ b may be involved in the increased vascular permeability of preeclampsia.^[32]

Soluble fms-like tyrosine kinase 1 receptor

The receptor sFlt-1 is a soluble isoform of Flt-1, which is a transmembrane receptor for VEGF. Although sFlt-1 lacks the transmembrane domain, it contains the ligand-binding region and is capable of binding circulating VEGF and PlGF, preventing these growth factors from binding to transmembrane receptors. Thus, sFlt-1 has an antiangiogenic effect.

In addition to angiogenesis, VEGF and PlGF are important in maintaining endothelial homeostasis. Selective knockout of the glomerular VEGF gene has been shown to be lethal in rats, whereas the heterozygotes were born with glomerular endotheliosis (the renal lesion characteristic of preeclampsia) and eventually renal failure. Furthermore, sFlt-1, when injected into pregnant rats, produced hypertension and proteinuria along with glomerular endotheliosis.^[29]

In addition to animal studies, multiple studies in humans have demonstrated that excess production of sFlt-1 is associated with an increased risk of preeclampsia. In a case-control study that measured levels of sFlt-1, VEGF, and PlGF, investigators found an earlier and greater increase in the serum level of sFlt-1 in women who developed preeclampsia (21-24 wk) than in women who did not develop preeclampsia (33-36 wk), whereas the serum levels of VEGF and PlGF deceased. Furthermore, the serum level of sFlt-1 was higher in women who developed severe preeclampsia or early preeclampsia (< 34 wk) than it was in women who developed mild preeclampsia at term.^[30]

Soluble endoglin

sEng is a soluble isoform of co-receptor for transforming growth factor beta (TGF-beta). Endoglin binds to TGF-beta in association with the TGF-beta receptor. Because the soluble isoform contains the TGF-beta binding domain, it can bind to circulating TGF-beta and decrease circulating levels. In addition, TGF-beta is a proangiogenic molecule, so the net effect of high levels of sEng is anti-angiogenic.

Several observations support the role of sEng in the pathogenesis of preeclampsia. It is found in the blood of women with preeclampsia up to 3 months before the clinical signs of the condition, its level in maternal blood correlates with disease severity, and the level of sEng in the blood drops after delivery.^[33]

In studies on pregnant rats, administration of sEng results in vascular permeability and causes hypertension. There is also evidence that it has a synergistic relationship with sFlt-1, because it increases the effects of sFlt-1 in pregnant rats; this results in HELLP syndrome, as evidenced by hepatic necrosis, hemolysis, and placental infarction.^[34] Moreover, sEng inhibits TGF-beta in endothelial cells and also inhibits TGF-beta-1 activation of nitric oxide mediated vasodilatation.

• References

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.

• References

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]

• References

Risk Factors for Preeclampsia

The incidence of preeclampsia is higher in women with a history of preeclampsia, multiple gestations, and chronic hypertension or underlying renal disease. In addition, Lykke et al found that preeclampsia, spontaneous preterm delivery, or fetal growth deviation in a first singleton pregnancy predisposes women to those complications in their second pregnancy, especially if the complications were severe.^[36]

Gestational age

In a registry-based cohort study of 536,419 Danish women, delivery between 32 and 36 weeks’ gestation increased the risk of preterm delivery in the second pregnancy from 2.7% to 14.7% and increased the risk of preeclampsia from 1.1% to 1.8%. A first delivery before 28 weeks increased the risk of a second preterm delivery to 26% and increased the risk of preeclampsia to 3.2%.

Preeclampsia in a first pregnancy, with delivery between 32 and 36 weeks' gestation, increased the risk of preeclampsia in a second pregnancy from 14.1% to 25.3%. Fetal growth 2-3 standard deviations below the mean in a first pregnancy increased the risk of preeclampsia from 1.1% to 1.8% in the second pregnancy.^[36]

Primigravid patients in particular seem to be predisposed to preeclampsia.

Maternal age

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

Race

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

Additional risk factors

Some risk factors contribute to poor placentation, whereas others contribute to increased placental mass and poor placental perfusion secondary to vascular abnormalities.^[2]

In addition to those discussed above, preeclampsia risk factors also include the following:

• Hydatidiform mole
• Obesity
• Thrombophilia
• Oocyte donation or donor insemination
• Urinary tract infection
• Diabetes mellitus: Women with pregnancy-related hypertensive conditions, including preeclampsia, plus preexisting diabetes or early gestational diabetes appear to remain at increased risk for poor pregnancy outcomes—even when the gestational diabetes was identified early and treated.^[37]
• Collagen vascular disease
• Periodontal disease^[38]

One literature review suggests that maternal vitamin D deficiency may increase the risk of preeclampsia and fetal growth restriction. Another study determined that vitamin D deficiency/insufficiency was common in a group of women at high risk for preeclampsia. However, it was not associated with the subsequent risk of an adverse pregnancy outcome.^[39]

Studies have suggested that smoking during pregnancy is associated with a reduced risk of gestational hypertension and preeclampsia; however, this is controversial.^[26] Placenta previa has also been correlated with a reduced risk of preeclampsia.

Body weight is strongly correlated with progressively increased preeclampsia risk, ranging from 4.3% for women with a body mass index (BMI) below 20 kg/m² to 13.3% in those with a BMI over 35 kg/m². A United Kingdom study on obesity showed that 9% of extremely obese women were preeclamptic, compared with 2% of matched controls.^[40]

An analysis of 456,668 singleton births found that early-onset (< 34 weeks' gestation) and late-onset (≥34 weeks' gestation) preeclampsia shared some etiologic features, but their risk factors and outcomes differed. Shared risk factors for early- and late-onset preeclampsia included older maternal age, Hispanic race, Native American race, smoking, unmarried status, and male fetus. Risk factors more strongly associated with early-onset preeclampsia than late-onset disease included black race, chronic hypertension, and congenital anomalies, while younger maternal age, nulliparity, and diabetes mellitus were more strongly associated with late-onset preeclampsia than with early-onset disease.^{[41, 42]}

Early-onset preeclampsia was significantly associated with a high risk for fetal death (adjusted odds ratio [AOR], 5.8), but late-onset preeclampsia was not (AOR, 1.3). However, the AOR for perinatal death/severe neonatal morbidity was significant for both early-onset (16.4) and late-onset (2.0) preeclampsia.^{[41, 42]}

In addition, the incidence of preeclampsia increased sharply as gestation progressed: the rate for early-onset preeclampsia was 0.38% compared with 2.72% for late-onset preeclampsia.^{[41, 42]}

Table 1 lists the risk factors and their odds ratios for preeclampsia.^[2]

Table 1. Risk Factors for Preeclampsia*

View Table

See Table

• References

Evaluation of Preeclampsia

Because the clinical manifestations of preeclampsia can be heterogeneous, diagnosing preeclampsia may not be straightforward. In particular, because the final diagnosis of gestational hypertension can only be made in retrospect, a clinician may be forced to treat some women with gestational hypertension as if they have preeclampsia. In addition, if a woman has underlying renal or cardiovascular disease, the diagnosis of preeclampsia may not become clear until the disease becomes severe.

Mild to moderate preeclampsia may be asymptomatic. Many cases are detected through routine prenatal screening.

Preeclampsia in a previous pregnancy is strongly associated with recurrence in subsequent pregnancies. A history of gestational hypertension or preeclampsia should strongly raise clinical suspicion.

Physical findings

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

• Headache
• Visual disturbances: Blurred, scintillating scotomata
• Altered mental status
• Blindness: May be cortical^[3] or retinal
• Dyspnea
• Edema
• Epigastric or right upper quadrant abdominal pain
• Weakness or malaise - May be evidence of hemolytic anemia

Edema exists in many pregnant women, but a sudden increase in edema or facial edema is suggestive of preeclampsia. The edema of preeclampsia occurs by a distinct mechanism that is similar to that of angioneurotic edema.

Hepatic involvement occurs in 10% of women with severe preeclampsia. The resulting pain (epigastric or right upper quadrant abdominal pain) is frequently accompanied by elevated serum hepatic transaminase levels.

The presence of clonus may indicate an increased risk of convulsions.

A study by Cooray et al found that the most common symptoms that immediately precede eclamptic seizures are neurologic symptoms (ie, headache, with or without visual disturbance), regardless of degree of hypertension. This suggests that closely monitoring patients with these symptoms may provide an early warning for eclampsia.^[43]

Recurrence of preeclampsia

Uncommonly, patients have antepartum preeclampsia that is treated with delivery but that recurs in the postpartum period.^[44] Recurrent preeclampsia should be considered in postpartum patients who present with hypertension and proteinuria. (See Prognosis.)

In patients who are suffering a recurrence of preeclampsia, findings on physical examination may include the following (see Prognosis):

• 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

• References

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.

• References

Diagnostic Considerations

Gestational hypertension

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

Placental hypoperfusion

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

Differential diagnosis

Abdominal Trauma, Blunt

Abruptio Placentae

Aneurysm, Abdominal

Appendicitis, Acute

Cholecystitis and Biliary Colic

Cholelithiasis

Congestive Heart Failure and Pulmonary Edema

Domestic Violence

Early Pregnancy Loss

Encephalitis

Headache, Tension

Hypertensive Emergencies

Hyperthyroidism, Thyroid Storm, and Graves Disease

Migraine Headache

Ovarian Torsion

Pregnancy, Eclampsia

Status Epilepticus

Stroke, Hemorrhagic

Stroke, Ischemic

Subarachnoid Hemorrhage

Subdural Hematoma

Thrombotic Thrombocytopenic Purpura

Toxicity, Amphetamine

Toxicity, Sympathomimetic

Toxicity, Thyroid Hormone

Transient Ischemic Attack

Urinary Tract Infection, Female

Withdrawal Syndromes

Cerebrovascular accidents

Seizure disorders

Brain tumors

Metabolic diseases

Metastatic gestational trophoblastic disease

Thrombotic thrombocytopenic purpura

• References

Routine Studies

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

• Complete blood cell (CBC) count
• Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels
• Serum creatinine
• Uric acid

In addition, a peripheral smear should be performed, serum lactate dehydrogenase (LDH) levels should be measured, and an indirect bilirubin should be carried out if HELLP (hemolysis, elevated liver enzyme, low platelets) syndrome is suspected. Although a coagulation profile (prothrombin time [PT], activated partial [aPTT], and fibrinogen) should also be evaluated, the clinical use of routine evaluation is unclear when the platelet count is 100,000/mm³ or more with no evidence of bleeding.^[4]

Laboratory values for preeclampsia and HELLP syndrome ^{[13, 45]}

Renal values are as follows:

• Proteinuria level above 300 mg/24 hours
• Urine dipstick over 1+
• Protein/creatinine ratio greater than 0.3*
• Serum uric acid level above 5.6 mg/dL*
• Serum creatinine level over 1.1 mg/dL

Platelet/coagulopathy-related results are as follows:

• Platelet count below 100,000/mm³
• Elevated PT or aPTT*
• Decreased fibrinogen*
• Increased d-dimer level*

Hemolysis-related results are as follows:

• Abnormal peripheral smear*
• Indirect bilirubin level over 1.2 mg/dL*
• LDH level greater than 600 U/L*

In addition, elevated liver enzymes (serum AST >70 U/L) are found in preeclampsia and HELLP syndrome.^[24]

Urine tests

To diagnose proteinuria, a 24-hour urine collection for protein and creatinine should be obtained whenever possible. Up to 30% of women with gestational hypertension who have trace protein noted on random urine samples may have 300 mg of protein in a 24-hour urine collection.^[46] Thus, a 24-hour urine protein analysis remains the criterion standard for proteinuria diagnosis. Alternatively, greater than 1+ protein on a dipstick analysis on a random sample is sufficient to make the diagnosis of proteinuria.

Random urine samples can be used to calculate the protein-creatinine ratio. Thresholds of 0.14-0.3 have been proposed for diagnosing proteinuria.^[47] However, there is no agreement yet as to the best threshold for identifying pregnant women with significant proteinuria. Moreover, up to 10% of patients with preeclampsia and 20% of patients with eclampsia may not have proteinuria.^{[48, 49]} (HELLP syndrome has been known to occur without hypertension or proteinuria.)

Hyperuricemia is one of the earliest laboratory manifestations of preeclampsia. It has a low sensitivity, ranging from 0% to 55%, but a relatively high specificity of 77-95%.^[50] Serial levels may be useful to indicate disease progression.

Baweja et al suggest that when measuring urinary albumin using high-performance liquid chromatography in an early and uncomplicated pregnancy, spot urinary albumin:creatinine ratio (ACR) values are higher. If measured early in the second trimester, an ACR of 35.5 mg/mmol or higher may predict preeclampsia before symptoms arise.^[51]

Congo red dye

A study at Yale University showed preliminary results suggesting that Congo red (CR), a dye currently used to locate atypical amyloid aggregates in Alzheimer disease, may also be effective in the early diagnosis of preeclampsia.^[50] It was thought that this finding might lead to a spot urine test that could be used in emergency departments and internationally, especially in resource-poor countries where preeclampsia continues to be underdiagnosed and accounts for a large percentage of maternal and fetal mortality.

In a study of 40 pregnant women with severe preeclampsia and 40 healthy pregnant controls, Buhimschi et al found that the urine and placentas of women with preeclampsia contain aggregates of misfolded proteins.^{[52, 53]} They suggested that urine CR spotting tests (CR binds to misfolded proteins) may be better than currently used current dipstick methods at diagnosing preeclampsia and indicating the need for medically indicated delivery.^{[52, 53]}

In this study, a cutoff value of a 15% measure of redness on the CR spotting test had 100% sensitivity and 100% specificity for distinguishing women with severe preeclampsia from control subjects.^[53] In a separate validation cohort of 563 pregnant women, the test had a sensitivity of 85.9%, a specificity of 85.0%, a positive likelihood ratio of 5.7, and a negative likelihood ratio of 0.17.

Liver enzymes

Although controversy exists over the threshold for elevated liver enzyme, the values proposed by Sibai et al (AST of >70 U/L and LDH of >600 U/L) appear to be the most widely accepted. Alternatively, values that are three standard deviations away from the mean for each laboratory value may be used for AST.^[45]

Histology

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

Additional laboratory tests

Other laboratory values suggestive of preeclampsia include an elevation in hematocrit and a rise in serum creatinine and/or uric acid. A decreased level of placental growth factor (PlGF) in the blood is also suggestive of preeclampsia.^{[54, 55]} Although these laboratory abnormalities increase the suspicion for preeclampsia, none of these laboratory tests should be used to diagnose preeclampsia.

In a study of 540 women with type 1 diabetes, Holmes and colleagues found that those women who developed preeclampsia had abnormal serum levels of angiogenic and antiangiogenic compounds in the second trimester. At 26 weeks’ gestation, women who later developed preeclampsia had significantly lower levels of the angiogenic factor PlGF, significantly higher levels of the antiangiogenic factors soluble fms-like tyrosine kinase-1 (sFlt-1) and soluble endoglin (sEng), as well as alteration in the ratio of PlGF to sEng or the ratio of sFlt-1 to PlGF.^{[56, 57]}

A test that measures the PIGF level in the blood (Triage) accurately identified preeclampsia requiring delivery in a prospective study of 625 pregnant women presenting before 35 weeks' gestation with suspected preeclampsia. Of the 625 subjects, 346 (55%) developed confirmed preeclampsia.^{[54, 55]}

Between 20 and 34 weeks' gestation, the sensitivity of the Triage test in predicting the need for delivery within 14 days was 0.96 (95% confidence interval [CI], 0.89–0.99), and the negative predictive value was 0.98 (95% CI 0.93–0.995).^{[54, 55]} Between 35 and 36 weeks' gestation, the sensitivity was 0.70 (95% CI, 0.58–0.81), and the negative predictive value was 0.69 (95% CI 0.57–0.80). At 37 weeks' gestation or more, the sensitivity was 0.57 (95% CI, 0.46–0.68), and the negative predictive value was 0.70 (95% CI, 0.62–0.78).^{[54, 55]}

A PlGF level below 100 pg/mL was just as good as a PlGF level below the fifth centile for gestational age at predicting preeclampsia requiring delivery within 14 days. PIGF levels lower than 12 pg/mL indicated an average time to delivery of just 9 days. Used alone or in combination , the PlGF test was significantly (P< 0.001) better than other commonly used tests, including systolic and diastolic blood pressure, uric acid, alanine transaminase, and proteinuria, in predicting preeclampsia requiring delivery within 14 days.^{[54, 55]}

A multicenter, prospective observational study of the ratio of sFlt-1 to PlGF in women with a clinical suspicion of preeclampsia or HELLP syndrome, who were between 24 and 37 weeks' gestational age, has demonstrated that an sFlt-1 to PlGF ratio of 38 or lower to have important predictive value^[58] : An sFlt-1:PlGF ratio of 38 or lower had a negative predictive value of 99.3% (95% confidence interval [CI], 97.9 to 99.9), suggesting an extremely unlikely development of preeclampsia or HELLP within 1 week. However, the positive predictive value of an sFlt-1:PlGF ratio above 38 for a diagnosis of preeclampsia within 4 weeks was 36.7% (95% CI, 28.4 to 45.7). The authors concluded that an sFlt-1:PlGF ratio of 38 or lower can be used to predict the short-term absence of preeclampsia in women in whom the syndrome is suspected clinically.^[58]

• References

CT Scanning and MRI

Computed tomography (CT) scanning and magnetic resonance imaging (MRI) scans have revealed numerous abnormalities in patients with eclampsia, such as cerebral edema, focal infarction, intracranial hemorrhage, and posterior leukoencephalopathy.^[59]

Currently, however, there is no pathognomonic CT scan or MRI finding for eclampsia. Furthermore, cerebral imaging is not necessary for the condition’s diagnosis and management. However, head CT scanning is used to detect intracranial hemorrhage in selected patients with sudden severe headaches, focal neurologic deficits, seizures with a prolonged postictal state, or atypical presentation for eclampsia.

• References

Ultrasonography

Ultrasonography is used to assess the status of the fetus as well as to evaluate for growth restriction (typically asymmetrical—use abdominal circumference).^[60] Aside from transabdominal ultrasonography, umbilical artery Doppler ultrasonography should be performed to assess blood flow. The value of Doppler ultrasonography in other fetal vessels has not been demonstrated.

Guidelines on preeclampsia ultrasound were released by the International Society of Ultrasound in Obstetrics and Gynecology on October 15, 2018.^[114]

• The pulsatility index (PI) should be used for examination of uterine artery resistance in the context of preeclampsia (PE) screening.
• Doppler examination of the uterine arteries at 11 + 0 to 13 + 6 weeks can be performed either transabdominally or transvaginally, according to local preferences and resources.
• Because maternal factors can affect uterine artery PI, inclusion of uterine artery PI in a multifactorial screening model should be preferred over its use as a standalone test with absolute cut‐offs, whenever feasible.
• Mean uterine artery PI should be the Doppler index of choice for first-trimester screening.
• Doppler examination of the uterine arteries at the second‐trimester scan can be performed either transabdominally or transvaginally.
• Mean uterine artery PI should be used for prediction of PE. In the case of a unilateral placenta, a unilaterally increased PI does not appear to increase the risk for PE if the mean PI is within normal limits.
• Although uterine artery velocimetry can be assessed transvaginally, the most common method of uterine artery Doppler examination in the third trimester is a transabdominal approach.
• The most efficient screening model for identification of women at risk of PE seems to be a combination of maternal factors, maternal mean arterial blood pressure, uterine artery Doppler, and placental growth factor (PlGF) level at 11-13 weeks.
• There is convincing evidence that low‐dose aspirin can significantly decrease the risk of early PE when begun at first‐trimester screening.

• References

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.

• References

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.

• References

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

• References

Care in Preeclampsia Without Severe Features

Before 37 weeks, expectant management is appropriate. In most cases, patients should be hospitalized and monitored carefully for the development of worsening preeclampsia or complications of preeclampsia. Although randomized trials in women with gestational hypertension and preeclampsia demonstrate the safety of outpatient management with frequent maternal and fetal evaluations, most of the patients in these studies had mild gestational hypertension.^[62] Therefore, the safety of managing a woman with preeclampsia without severe features as an outpatient still needs to be investigated.

Although bedrest has been recommended in women with preeclampsia, little evidence supports its benefit. In fact, prolonged bed rest during pregnancy increases the risk of thromboembolism.

A pregnancy complicated by preeclampsia without severe features at or beyond 37 weeks should be delivered. Although the pregnancy outcome is similar in these women as it is in women with a normotensive pregnancy, the risk of placental abruption and progression to severe disease is slightly increased.^{[63, 64]} Thus, regardless of cervical status, induction of labor should be recommended. Cesarean section may be performed based on standard obstetric criteria.

Antepartum testing is generally indicated during expectant management of patients with preeclampsia without severe features. However, there is little consensus regarding the types of tests to be used and the frequency of testing. Most clinicians offer a nonstress test (NST) and a biophysical profile (BPP) at the time of the diagnosis and usually twice per week until delivery.^{[2, 1]}

If a patient is at 34 weeks' gestation or more and has ruptured membranes, abnormal fetal testing, or progressive labor in the setting of preeclampsia, delivery is recommended.

• References

Care Preeclampsia With Severe Features

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

Women with preeclampsia with severe features who have nonreassuring fetal status, ruptured membranes, labor, or maternal distress should be delivered regardless of gestational age. If a woman with preeclampsia with severe features is at 32 weeks' gestation or more and has received a course of steroids, she should be delivered as well.

Patients presenting with severe, unremitting headache, visual disturbance, and right upper quadrant tenderness in the presence of hypertension and/or proteinuria should be treated with utmost caution.

Expectant management of preeclampsia with severe features

If a patient presents with preeclampsia with severe features before 34 weeks' gestation but appears to be stable, and if the fetal condition is reassuring, expectant management may be considered, provided that the patient meets the strict criteria set by Sibai et al (see Laboratory values for preeclampsia and HELLP syndrome).^[65] This type of management should be considered only in a tertiary center. In addition, because delivery is always appropriate for the mother, some authorities consider delivery as the definitive treatment regardless of gestational age. However, delivery may not be optimal for a fetus that is extremely premature. Therefore, in a carefully chosen population, expectant management may benefit the fetus without greatly compromising maternal health.

All of these patients must be evaluated in a labor and delivery unit for 24 hours before a decision for expectant management can be made. During this period, maternal and fetal evaluation must show that the fetus does not have severe growth restriction or fetal distress. In addition, maternal urine output must be adequate. The woman must have essentially normal laboratory values (with the exclusive exception of mildly elevated liver function test results that are less than twice the normal value) and hypertension that can be controlled.

Fetal monitoring should include daily nonstress testing and ultrasonography performed to monitor for the development of oligohydramnios and decreased fetal movement. In addition, fetal growth determination at 2-week intervals must be performed to document adequate fetal growth. A 24-hour urine collection for protein may be repeated. Corticosteroids for fetal lung maturity should be administered prior to 34 weeks.

Daily blood tests should be performed for liver function tests (LFTs), CBC count, uric acid, and LDH. Patients should be instructed to report any headache, visual changes, epigastric pain, or decreased fetal movement.

Criteria for delivery

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

• Nonreassuring fetal testing including nonreassuring nonstress test, biophysical profile score, and/or persistent absent or reversed diastolic flow on umbilical artery Doppler velocimetry
• Ruptured membranes
• Uncontrollable BP (unresponsive to medical therapy)
• Oligohydramnios, with amniotic fluid index (AFI) of less than 5 cm
• Severe intrauterine growth restriction in which the estimated fetal weight is less than 5%
• Oliguria (< 500 mL/24 hours)
• Serum creatinine level of at least 1.5 mg/dL
• Pulmonary edema
• Shortness of breath or chest pain with pulse oximetry of < 94% on room air
• Headache that is persistent and severe
• Right upper quadrant tenderness
• Development of HELLP (hemolysis, elevated liver enzyme, low platelets) syndrome
• Eclampsia
• Platelet count less than 100,000/μL
• Placental abruption
• Unexplained coagulopathy

• References

Seizure Treatment and Prophylaxis With Magnesium Sulfate

The basic principles of airway, breathing, and circulation (ABC) should always be followed as a general principle of seizure management.

Magnesium sulfate is the first-line treatment for the prevention of primary and recurrent eclamptic seizures. For eclamptic seizures that are refractory to magnesium sulfate, lorazepam and phenytoin may be used as second-line agents.

The American College of Obstetricians and Gynecologists (ACOG) and the Society for Maternal-Fetal Medicine (SMFM) continue to support the short-term (usually < 48 hours) use of magnesium sulfate in obstetric care for conditions and treatment durations that include the following^[66] :

• For prevention and treatment of seizures in women with preeclampsia or eclampsia
• For fetal neuroprotection before anticipated early preterm (< 32 weeks of gestation) delivery
• For short-term prolongation of pregnancy (≤48 hours) to allow for the administration of antenatal corticosteroids in pregnant women who are at risk of preterm delivery within 7 days

Active seizures should be treated with intravenous magnesium sulfate as a first-line agent.^[5] A loading dose of 4 g should be given by an infusion pump over 5-10 minutes, followed by an infusion of 1 g/h maintained for 24 hours after the last seizure. Recurrent seizures should be treated with an additional bolus of 2 g or an increase in the infusion rate to 1.5 g or 2 g per hour.

Prophylactic treatment with magnesium sulfate is indicated for all patients with severe preeclampsia. However, no consensus exists as to whether patients with mild preeclampsia need magnesium seizure prophylaxis. Although ACOG recommends magnesium sulfate in severe preeclampsia, it has not recommended this therapy in all cases of mild preeclampsia.

Some practitioners withhold magnesium sulfate if BP is stable and/or mildly elevated and if the laboratory values for LFTs and platelets are mildly abnormal and/or stable. Other physicians feel that even patients with gestational hypertension should receive magnesium, as a small percentage of these patients may either have preeclampsia or may develop it. The ultimate decision should depend on the comfort level of the labor and delivery staff in administering intravenous (IV) magnesium sulfate. An estimated 100 patients need to be treated with magnesium sulfate therapy to prevent 1 case of eclampsia.^{[5, 67, 68]}

• References

Acute Treatment of Severe Hypertension in Pregnancy

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

A retrospective cohort study by Cleary et al that included 239,454 patients with preeclampsia (126,595 women with mild, 31,628 with superimposed, and 81,231 with severe preeclampsia) reported that the rate of patients with preeclampsia receiving antihypertensive medication increased from 37.8% in 2006 to 49.4% in 2015. During this time period, the risk for stroke for severe preeclampsia also decreased from 13.5 per 10,000 deliveries in 2006-2008 (n=27) to 6.0 in 2012-2014 (n=20) (P=.02).^[69]  

Hydralazine

Hydralazine is a direct peripheral arteriolar vasodilator and, in the past, was widely used as the first-line treatment for acute hypertension in pregnancy.^{[70, 71]} This agent has a slow onset of action (10-20 min) and peaks approximately 20 minutes after administration. Hydralazine should be given as an IV bolus at a dose of 5-10 mg, depending on the severity of hypertension, and may be administered every 20 minutes up to a maximum dose of 30 mg.

The side effects of hydralazine are headache, nausea, and vomiting. Importantly, hydralazine may result in maternal hypotension, which can subsequently result in a nonreassuring fetal heart rate tracing in the fetus.^[13]

In a meta-analysis, Magee et al pointed out that hydralazine was associated with worse maternal and perinatal outcomes than were labetalol and nifedipine. Furthermore, hydralazine was associated with more maternal side effects than were labetalol and nifedipine.^[70]

Labetalol

Labetalol is a selective alpha blocker and a nonselective beta blocker that produces vasodilatation and results in a decrease in systemic vascular resistance. The dosage for labetalol is 20 mg IV with repeat doses (40, 80, 80, and 80 mg) every 10 minutes up to a maximum dose of 300 mg. Decreases in BP are observed after 5 minutes (in contrast to the slower onset of action of hydralazine), and the drug results in less overshoot hypertension than does hydralazine.

Labetalol decreases supraventricular rhythm and slows the heart rate, reducing myocardial oxygen consumption. No change in afterload is observed after treatment with labetalol. The side effects of labetalol are dizziness, nausea, and headaches. After satisfactory control with IV administration has been achieved, an oral maintenance dose can be started.^{[13, 70]}

Nifedipine

Calcium channel blockers act on arteriolar smooth muscle and induce vasodilatation by blocking calcium entry into the cells. Nifedipine is the oral calcium channel blocker that is used in the management of hypertension in pregnancy. The dosage of nifedipine is 10 mg PO every 15-30 minutes, with a maximum of 3 doses. The side effects of calcium channel blockers include tachycardia, palpitations, and headaches. Concomitant use of calcium channel blockers and magnesium sulfate is to be avoided. Nifedipine is commonly used postpartum in patients with preeclampsia, for BP control.^{[13, 70]}

Sodium nitroprusside

In a severe hypertensive emergency, when the above-mentioned medications have failed to lower BP, sodium nitroprusside may be given. Nitroprusside results in the release of nitric oxide, which in turn causes significant vasodilation. Preload and afterload are then greatly decreased. The onset of action is rapid, and severe rebound hypertension may result. Cyanide poisoning may occur subsequent to its use in the fetus. Therefore, sodium nitroprusside should be reserved for use in postpartum care or for administration just before the delivery of the fetus.^[13]

• References

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.

• References

Postpartum Management

Preeclampsia resolves after delivery. However, patients may still have an elevated BP postpartum. Liver function tests and platelet counts must be performed to document decreasing values prior to hospital discharge. In addition, one third of seizures occur in the postpartum period, most within 24 hours of delivery, and almost all within 48 hours.^[72] Therefore, magnesium sulfate seizure prophylaxis is continued for 24 hours postpartum. (See Seizure Treatment and Prophylaxis With Magnesium Sulfate.)

Rarely, a patient may have elevated liver enzymes, thrombocytopenia, and renal insufficiency more than 72 hours after delivery. In these cases, the possibility of hemolytic uremic syndrome (HUS) or thrombotic thrombocytopenic purpura (TTP) must be considered. In such situations, plasmapheresis, along with corticosteroid therapy, may be of some benefit to such patients and must be discussed with renal and hematology consultants.

In addition, the use of dexamethasone (10 mg IV q6-12h for 2 doses followed by 5 mg IV q6-12h for 2 doses) has been proposed in the postpartum period to restore platelet count to normal range in patients with persistent thrombocytopenia.^{[73, 74]} The effectiveness of this therapy in preventing severe hemorrhage or ameliorating the disease course needs further investigation.

Elevated BP may be controlled with nifedipine or labetalol postpartum. If a patient is discharged with BP medication, reassessment and a BP check should be performed, at the latest, 1 week after discharge. Unless a woman has undiagnosed chronic hypertension, in most cases of preeclampsia, the BP returns to baseline by 12 weeks postpartum.

Eclampsia is common after delivery and has occurred up to 6 weeks after delivery. Al-Safi et al suggest that the first week after discharge is the most critical period for the development of postpartum eclampsia. Discussing the risks and educating patients about the possibility of delayed postpartum preeclampsia is important, regardless of whether they develop hypertensive disease prior to discharge.^[75] Patients at risk for eclampsia should be carefully monitored postpartum.^[76] Additionally, patients with preeclampsia who were successfully treated with delivery may present with recurrent preeclampsia up to 4 weeks postpartum.

• References

Prevention and Prediction of Preeclampsia

Efforts to prevent preeclampsia have been disappointing.^[77]

Aspirin

A systematic review of 14 trials using low-dose aspirin (60-150 mg/d) in women with risk factors for preeclampsia concluded that aspirin reduced the risk of preeclampsia and perinatal death, although it did not significantly affect birth weight or the risk of abruption.^[78] Low-dose aspirin in unselected nulliparous women seems to reduce the incidence of preeclampsia only slightly.^[79] For women with risk factors for preeclampsia, starting low-dose aspirin (commonly, 1 tablet of baby aspirin per day), beginning at 12-14 weeks' gestation, is reasonable. The safety of low-dose aspirin use in the second and third trimesters is well established.^{[78, 80]}

A 2016 ACOG Practice Advisory upheld the recommendation for the possible use of low-dose aspirin (81 mg/day), introduced between 12 and 28 weeks of gestation, to prevent preeclampsia in women who are high-risk. The U.S. Preventive Services Task Force defined high-risk for preeclampsia as women with a history of preeclampsia, multifetal gestation, chronic hypertension, diabetes, renal disease, or an autoimmune disease.^[81]

On the basis of limited evidence from a systematic review and meta-analysis, the addition of low–molecular weight heparin or unfractionated heparin to low-dose aspirin has the potential to reduce the prevalence of preeclampsia and birth of small-for-gestational-age neonates in women with a history of preeclampsia.^[82]

A multicenter, double-blind, placebo-controlled trial by Rolnik et al that included 1620 women at high-risk for preterm preeclampsia reported that 1.6% of the patients in the low-dose aspirin group had preterm preeclampsia compared to 4.3% in the placebo group (odds ratio in the aspirin group, 0.38; 95% confidence interval, 0.20 to 0.74; P=0.004).^[83]

A secondary analysis of data from the Aspirin for Evidence-Based Preeclampsia Prevention trial reported that in high risk of preeclampsia pregnancies, administration of aspirin reduces the length of stay in the neonatal intensive care unit by about 70%.^[113]

Heparin

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

Calcium and vitamin supplements

Research into the use of calcium and vitamin C and E supplementations in low-risk populations did not find a reduction in the incidence of preeclampsia.^{[84, 85, 86]} In a multicenter, randomized, controlled trial, Villar et al found that at the doses used for supplementation, vitamins C and E were not associated with a reduction of preeclampsia, eclampsia, gestational hypertension, or any other maternal outcome. Low birthweight, small for gestational age, and perinatal deaths were also unaffected.^[87]

A study by Vadillo-Ortega et al suggests that in a high-risk population, supplementation during pregnancy with a special food (eg, bars) containing L-arginine and antioxidant vitamins may reduce the risk of preeclampsia. However, antioxidant vitamins alone do not protect against preeclampsia. More studies performed on low-risk populations are needed.^[88]

Results from the Norwegian Mother and Child Cohort Study suggest that supplementation of milk-based probiotics may reduce the risk of preeclampsia in primiparous women. A prospective randomized trial has not yet been done to evaluate this intervention.^[89]

Screening Tests

Preeclampsia is an appropriate disease to screen, as it is common, important, and increases maternal and perinatal mortality. However, although numerous screening tests for preeclampsia have been proposed over the past few decades, no test has so far been shown to appropriately screen for the disease.^[90] (Measurement of urinary kallikrein was shown to have a high predictive value, but it was not reproducible.^{[91, 92]} )

 A prospective study demonstrated that an sFlt-1:PlGF ratio of 38 or lower had a negative predictive value of 99.3% (95% confidence interval [CI], 97.9 to 99.9), suggesting an extremely unlikely development of preeclampsia or HELLP (hemolysis, elevated liver enzyme, low platelets) syndrome within 1 week, in women with a clinical suspicion of preeclampsia or HELLP syndrome.^[58] Therefore, an sFlt-1:PlGF ratio of 38 or lower may have a potential role in predicting the short-term absence of preeclampsia in women in whom the syndrome is suspected clinically.^[58] A randomized trial is necessary to determine the interval of such testing in women suspected on having preeclampsia or HELLP syndrome, as well as the effect of this screening test on maternal and fetal outcomes.

Intensive monitoring in women who are at increased risk for developing preeclampsia, when identified by a predictive test, may lower the incidence of adverse outcome for the mother and the neonate. 

The USPSTF recommends screening pregnant women for preeclampsia with blood pressure measurements throughout pregnancy.^[93]

• References

Prognosis

Morbidity and mortality

Worldwide, preeclampsia and eclampsia are estimated to be responsible for approximately 14% of maternal deaths per year (50,000-75,000).^[21] Morbidity and mortality in preeclampsia and eclampsia are related to the following conditions:

• Systemic endothelial dysfunction
• Vasospasm and small-vessel thrombosis leading to tissue and organ ischemia
• Central nervous system (CNS) events, such as seizures, strokes, and hemorrhage
• Acute tubular necrosis
• Coagulopathies
• Placental abruption in the mother

Fetal exposure to preeclampsia may be linked to autism and developmental delay (DD).^{[94, 95]}  In a population-based study of 1061 children from singleton pregnancies — including 517 with autism spectrum disorder (ASD), 194 with DD, and 350 who were typically developing (TD) — fetal exposure to preeclampsia was associated with a greater than twofold increase in the risk of ASD and a greater than fivefold increase in the risk of DD.^{[94, 95]}

Of the children with ASD, 7.7% had been exposed to preeclampsia in utero, compared with 5.1% of those with DD and 3.7% of those with TD.^[95]  After adjustment for parity, maternal education, and prepregnancy obesity, the adjusted odds ratio (aOR) for ASD with exposure to preeclampsia was 2.36 (95% confidence interval [CI], 1.18-4.68). In analyses limited to women who had had severe preeclampsia, the aOR for ASD was 2.29 (95% CI, 0.97-5.43), and the aOR for DD was 5.49 (95% CI, 2.06-14.64).

Recurrence

In general, the recurrence risk of preeclampsia in a woman whose previous pregnancy was complicated by preeclampsia near term is approximately 10%.^[48] If a woman has previously suffered from preeclampsia with severe features (including HELLP [hemolysis, elevated liver enzyme, low platelets] syndrome and/or eclampsia), she has a 20% risk of developing preeclampsia some time in her subsequent pregnancy.^{[96, 97, 98, 99, 100, 101]}

If a woman has had HELLP syndrome or eclampsia, the recurrence risk of HELLP syndrome is 5%^[97] and of eclampsia it is 2%.^{[99, 100, 101]} The earlier the disease manifests during the index pregnancy, the higher the chance of recurrence rises. If preeclampsia presented clinically before 30 weeks' gestation, the chance of recurrence may be as high as 40%.^[102]

The fullPIERS model has been validated and was successful in predicting adverse outcomes in advance; therefore, it is potentially able to influence treatment choices before complications arise.^[103]

• References

Author

Kee-Hak Lim, MD, Clinical Associate Professor, Department of Obstetrics and Gynecology, Harvard Medical School; Physician in Maternal-Fetal Medicine, Beth Israel Deaconess Medical Center

Disclosure: Nothing to disclose.

Coauthor(s)

Guy Steinberg, MD, MPH, MSc, Fellow in Maternal-Fetal Medicine, Beth Israel Deaconess Medical Center/Harvard Medical School

Disclosure: Nothing to disclose.

Chief Editor

Ronald M Ramus, MD, Professor of Obstetrics and Gynecology, Director, Division of Maternal-Fetal Medicine, Virginia Commonwealth University School of Medicine

Disclosure: Nothing to disclose.

Acknowledgements

A David Barnes, MD, PhD, MPH, FACOG Consulting Staff, Department of Obstetrics and Gynecology, Mammoth Hospital (Mammoth Lakes, California), Pioneer Valley Hospital (Salt Lake City, Utah), Warren General Hospital (Warren, Pennsylvania), and Mountain West Hospital (Tooele, Utah)

A David Barnes, MD, PhD, MPH, FACOG is a member of the following medical societies: American College of Forensic Examiners, American College of Obstetricians and Gynecologists, American Medical Association, Association of Military Surgeons of the US, and Utah Medical Association

Disclosure: Nothing to disclose.

Pamela L Dyne, MD Professor of Clinical Medicine/Emergency Medicine, University of California, Los Angeles, David Geffen School of Medicine; Attending Physician, Department of Emergency Medicine, Olive View-UCLA Medical Center

Pamela L Dyne, MD is a member of the following medical societies: American Academy of Emergency Medicine, American College of Emergency Physicians, and Society for Academic Emergency Medicine

Disclosure: Nothing to disclose.

Mert Erogul, MD Assistant Professor of Emergency Medicine, University Hospital of Brooklyn: Consulting Staff, Department of Emergency Medicine, Kings County Hospital Center

Mert Erogul, MD is a member of the following medical societies: American College of Emergency Physicians, American Medical Association, and Society for Academic Emergency Medicine

Disclosure: Nothing to disclose.

John J Kavanagh Jr MD, Chief, Professor, Department of Internal Medicine, Section of Gynecological and Medical Therapeutics, MD Anderson Cancer Center, University of Texas Medical School at Houston

John J Kavanagh Jr is a member of the following medical societies: American Association for Cancer Research, American Association for the Advancement of Science, American Association for the History of Medicine, American College of Physicians, American Federation for Medical Research, American Medical Association, Society of Gynecologist Oncologists, Southern Medical Association, and Texas Medical Association

Disclosure: Nothing to disclose.

Assaad J Sayah, MD Chief, Department of Emergency Medicine, Cambridge Health Alliance

Assaad J Sayah, MD is a member of the following medical societies: National Association of EMS Physicians

Disclosure: Nothing to disclose.

Zina Semenovskaya, MD Resident Physician, Department of Emergency Medicine, Kings County Hospital, State University of New York Downstate Medical Center College of Medicine

Disclosure: Nothing to disclose.

Aashit K Shah, MD, FAAN, FANA Professor of Neurology, Director, Comprehensive Epilepsy Program, Program Director, Clinical Neurophysiology Fellowship, Detroit Medical Center, Wayne State University School of Medicine

Aashit K Shah, MD, FAAN, FANA is a member of the following medical societies: American Academy of Neurology, American Clinical Neurophysiology Society, American Epilepsy Society, and American Neurological Assocation

Disclosure: UCB Pharma, Consulting fee, Speaking and teaching; Cyberonics, Consulting fee, Consulting; UCB Pharma, Grant/research funds, Other

Guy Steinberg, MD, MPH, MSc Fellow in Maternal-Fetal Medicine, Beth Israel Deaconess Medical Center/Harvard Medical School

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

Mark Zwanger, MD, MBA Assistant Professor, Department of Emergency Medicine, Jefferson Medical College of Thomas Jefferson University

Mark Zwanger, MD, MBA is a member of the following medical societies: American Academy of Emergency Medicine, American College of Emergency Physicians, and American Medical Association

Disclosure: Nothing to disclose.

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