Preeclampsia

Preeclampsia and preeclampsia with severe features

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]

Severe preeclampsia accounts for approximately 25% of all cases of preeclampsia. ^[4] In its extreme, the disease may lead to liver and renal failure, disseminated intravascular coagulopathy (DIC), and central nervous system (CNS) abnormalities such as generalized tonic, clonic seizures in cases of eclampsia.

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 ^[5] :

• 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. ^[6]

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 woman with previously normal BP and who has 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). ^[7]  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.

Cardiovascular disease

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. ^[8] Moreover, women who had recurrent preeclampsia were more likely to have hypertension later in life. ^[8]

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. In addition, women who develop preeclampsia before 36 weeks' gestation or who have multiple hypertensive pregnancies were at highest risk. ^[9]

A prospective observational study by Vaught that included 63 women with preeclampsia 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. ^[10]

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 considered to be the most important include the following:

• 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. 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. 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. ^[11]

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. ^[12]  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. ^[13]

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.

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. ^{[2, 14]}

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. ^[15]  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. ^[16]  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. ^{[17, 18]}

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. ^[19]

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. ^[16]

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. ^[17]

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. ^[20]

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. ^[21]  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. ^[22]  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. ^[23]

Risk factors for preeclampsia

Risk factors for preeclampsia include the following ^[1] :

• Nulliparity

• Multifetal gestations

• Preeclampsia in a previous pregnancy

• Chronic hypertension

• Pregestational diabetes

• Gestational diabetes

• Thrombophilia

• Systemic lupus erythematosus

• Prepregnancy body mass index greater than 30

• Antiphospholipid antibody syndrome

• Maternal age 35 years or older

• Kidney disease

• Assisted reproductive technology

• Obstructive sleep apnea

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. ^[24]

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 30 kg/m². A United Kingdom study on obesity showed that 9% of extremely obese women were preeclamptic, compared with 2% of matched controls. ^{[25, 26]}

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, whereas younger maternal age, nulliparity, and diabetes mellitus were more strongly associated with late-onset preeclampsia than with early-onset disease. ^[27]

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. 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. ^[27]

The incidence of preeclampsia in the United States is estimated to range from 2% to 8% in healthy, nulliparous women. ^{[28, 29]}  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%, ^[30]  with hypertensive disorders being the second most common obstetric cause of stillbirths and early neonatal deaths in these countries. ^[31]

Eclampsia is estimated to occur in 1 in 200 cases of preeclampsia when magnesium prophylaxis is not administered. ^[32]

Morbidity/mortality

Worldwide, preeclampsia and eclampsia are estimated to be responsible for approximately 14% of maternal deaths per year (50,000-75,000). ^[22] 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 fetus, preeclampsia can lead to ischemic encephalopathy, growth restriction, and the various sequelae of premature birth.

Fetal exposure to preeclampsia may be linked to autism and developmental delay. In a population-based study of 1061 children from singleton pregnancies — including 517 with autism spectrum disorder (ASD), 194 with developmental delay, and 350 who were typically developing — 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 developmental delay. ^[33]

Complications

The risk of cardiovascular disease is increased later in life in women with a history of preeclampsia. ^[34] Rates of acute myocardial infarction and stroke are four- and threefold higher, respectively, among women with preeclampsia than among those without preeclampsia 10 years after delivery. ^[35]

Recurrence

In general, the recurrence risk of preeclampsia in a woman whose previous pregnancy was complicated by preeclampsia near term is approximately 10%. If a woman has previously had 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 during a subsequent pregnancy. ^{[36, 37]}

If a woman has had HELLP syndrome or eclampsia, the recurrence risk of HELLP syndrome is 5% ^[36] and that of eclampsia is 2%. ^[38] The earlier the disease manifests during the index pregnancy, the higher the likelihood of recurrence rises. If preeclampsia presented clinically before 30 weeks' gestation, the chance of recurrence may be as high as 40%. ^[39]

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. ^[39]