Preeclampsia: Clinical features and diagnosis

INTRODUCTION — Preeclampsia is a multisystem progressive disorder characterized by the new onset of hypertension and proteinuria or the new onset of hypertension plus significant end-organ dysfunction with or without proteinuria, typically presenting after 20 weeks of gestation or postpartum (table 1). The pathogenesis involves both abnormal placentation and maternal systemic vascular dysfunction. Approximately 90 percent of cases present in the late preterm (≥34 to <37 weeks), term, or postpartum period and have good maternal, fetal, and newborn outcomes; however, serious maternal and/or perinatal morbidity or mortality can occur. The remaining 10 percent of cases have an early presentation (<34 weeks) and are associated with higher risks of serious perinatal morbidity or mortality due to risks associated with moderately preterm, very preterm, or extremely preterm birth. Although the disorder always resolves in the days or weeks after birth, individuals with a history of preeclampsia are at increased lifetime risk for cardiovascular-related morbidity and mortality.

This topic will discuss the clinical features, diagnosis, and differential diagnosis of preeclampsia. Other important issues related to this disease are reviewed separately:

●(See "Preeclampsia: Pathogenesis".)

●(See "Preeclampsia: Antepartum management and timing of delivery".)

●(See "Early pregnancy prediction of preeclampsia".)

●(See "Preeclampsia: Prevention".)

DEFINITIONS/DIAGNOSTIC CRITERIA — The major hypertensive disorders that occur in pregnant patients are described below [1,2]. During pregnancy, hypertension is defined as systolic blood pressure ≥140 mmHg and/or diastolic blood pressure ≥90 mmHg. Severe hypertension is defined as systolic blood pressure ≥160 mmHg and/or diastolic blood pressure ≥110 mmHg. The American College of Cardiology and the American Heart Association have endorsed a lower threshold for diagnosing hypertension in nonpregnant patients (systolic blood pressure ≥130 mmHg or diastolic blood pressure ≥80 mmHg). Some have suggested that this definition may also be appropriate for pregnant patients [3]. However, use of the lower threshold has not been widely studied, would increase the incidence of hypertension in pregnancy by about 10 percent, and would increase potentially unnecessary testing, hospitalization, and intervention in the absence of a proven benefit. A meta-analysis found that lowering the blood pressure threshold for abnormal blood pressure at >20 weeks would not assist clinicians in identifying patients at heightened maternal or perinatal risk [4].

United States — The following definitions/diagnostic criteria are commonly used in the United States:

●Preeclampsia refers to the new onset of hypertension and proteinuria or the new onset of hypertension plus significant end-organ dysfunction with or without proteinuria in a previously normotensive patient, typically after 20 weeks of gestation or postpartum (table 1) [2,5-7]. Most patients have proteinuria, but it is important to emphasize that the diagnosis can be made in a pregnant patient with hypertension but no proteinuria if the new-onset hypertension is accompanied by specific signs or symptoms of significant end-organ dysfunction, as listed in the table.

Several subtypes of preeclampsia may exist, with a variety of pathophysiological pathways leading to maternal and fetal mortality and morbidity [8]. The most commonly described subtypes are early onset (<34 weeks of gestation) and late onset (≥34 weeks of gestation). The clinical features overlap, but the spectrum of disease and outcomes differ: Early-onset disease has been associated with more severe placental and maternal/fetal clinical findings and, in turn, poorer maternal/fetal outcomes [9,10]. For this reason, it has been hypothesized that the two phenotypes have different origins and pathophysiologies [9,11,12]. Other possible subtypes include "HELLP syndrome," "gestational hypertension," and "preeclampsia with versus without fetal growth restriction." However, these differences can also be explained by biological variation in the disease process.

●Preeclampsia with severe features (formerly severe preeclampsia) is the subset of patients with preeclampsia who have severe hypertension and/or specific signs or symptoms of significant end-organ dysfunction that signify the severe end of the preeclampsia spectrum. The specific criteria for diagnosis are listed in the table (table 2).

●Preeclampsia superimposed upon chronic hypertension is diagnosed when preeclampsia occurs in a patient with preexisting chronic hypertension (hypertension that precedes pregnancy or is present on at least two occasions before the 20^th week of gestation or persists longer than 12 weeks postpartum). It is characterized by worsening or resistant hypertension (especially acutely), the new onset of proteinuria or a sudden increase in proteinuria, and/or significant new end-organ dysfunction after 20 weeks of gestation or postpartum in a patient with chronic hypertension.

●HELLP syndrome (Hemolysis, Elevated Liver enzymes, Low Platelets) appears to be a subtype of preeclampsia with severe features in which hemolysis, elevated liver enzymes, and thrombocytopenia are the predominant features. Hypertension, central nervous system dysfunction, and/or renal dysfunction may also be present. The majority of patients, but not all, have hypertension (82 to 88 percent, although in some cases the increase in blood pressure may be subtle initially) and/or proteinuria (86 to 100 percent) [13]. Rare patients have neither; other diagnoses associated with similar laboratory abnormalities should be excluded before making the diagnosis of HELLP in these atypical patients. (See "HELLP syndrome (hemolysis, elevated liver enzymes, and low platelets)" and "Hypertensive disorders in pregnancy: Approach to differential diagnosis".)

●Eclampsia refers to the occurrence of a tonic-clonic seizure in a patient with preeclampsia in the absence of other neurologic conditions that could account for the seizure. (See "Eclampsia".)

●Gestational hypertension refers to hypertension without proteinuria or other signs/symptoms of preeclampsia-related end-organ dysfunction that develops after 20 weeks of gestation in a patient with a previously normal blood pressure. Up to 50 percent of these patients may ultimately develop signs and symptoms of preeclampsia. Development of proteinuria upgrades the diagnosis to preeclampsia. Even without proteinuria, patients who develop severe hypertension or other features of severe disease (table 2) are managed in the same way as those with preeclampsia with severe features.

True gestational hypertension should resolve by 12 weeks postpartum. (See "Gestational hypertension".)

International Society for the Study of Hypertension in Pregnancy — The International Society for the Study of Hypertension in Pregnancy (ISSHP) classification system for hypertensive disorders of pregnancy is slightly different [14]:

●Prepregnancy or <20 weeks of gestation

•White-coat hypertension: Systolic pressure ≥140 and/or diastolic pressure ≥90 mmHg when measured in the office or clinic, and blood pressure <135/85 mmHg using home or ambulatory 24-hour blood pressure monitoring readings.

•Masked hypertension: Blood pressure <140/90 mmHg at a clinic/office visit, but

≥135/85 mmHg at other times outside the clinic/office.

•Chronic hypertension: Hypertension detected prepregnancy or before 20 weeks of gestation. Chronic hypertension may be essential hypertension (ie, without a known secondary cause) or Secondary hypertension (ie, with a known secondary cause, eg, kidney disease).

●Pregnancy ≥20 weeks of gestation

•Gestational hypertension: Hypertension de novo ≥20 weeks of gestation without proteinuria or other features suggestive of preeclampsia

•Preeclampsia: Gestational hypertension plus one or more of the following:

-Proteinuria

-Neurological complications (eg, eclampsia, altered mental status, blindness, stroke, clonus, severe headaches, or persistent visual scotomata)

-Pulmonary edema

-Hematological complications (eg, platelet count <150 000/microL, disseminated intravascular coagulation, hemolysis)

-Acute kidney injury (such as creatinine ≥90 mmol/L or 1 mg/dL)

-Liver involvement (eg, elevated transaminases such as ALT or AST >40 IU/L) with or without right upper quadrant or epigastric abdominal pain)

-Uteroplacental dysfunction (eg, placental abruption, angiogenic imbalance, fetal growth restriction, abnormal umbilical artery Doppler waveform analysis, or fetal death)

INCIDENCE — In a systematic review, 4.6 percent (95% CI 2.7-8.2) of pregnancies worldwide were complicated by preeclampsia [15]. The incidence in the United States is approximately 5 percent [16]. Variations in incidence reflect, at least in part, differences in the maternal age distribution and proportion of nulliparous pregnant patients in the population [17]. The incidence is increasing, likely related to population-level increases in risk factors for the disease [18]. (See 'Risk factors' below.)

Late-onset preeclampsia (≥34 weeks of gestation) is more common than early onset preeclampsia (<34 weeks of gestation): incidence 2.7 versus 0.3 percent, respectively, in a population-based study [19]. (See 'Typical presentation' below.)

RISK FACTORS — Risk factors for preeclampsia are listed in the table (table 3) and apply to both early-onset and late-onset disease. The magnitude of risk depends on the specific factor and is described below for selected risk factors evaluated in systematic reviews [20,21]. A past history of preeclampsia, preexisting hypertension, pregestational (preexisting) diabetes, multifetal gestation, chronic kidney disease, and some autoimmune diseases (antiphospholipid syndrome, systemic lupus erythematosus) carry the highest relative risk (RR).

●A past history of preeclampsia increases the risk of developing preeclampsia in a subsequent pregnancy eightfold compared with patients without this history (RR 8.4, 95% CI 7.1-9.9) [21].

The severity of preeclampsia strongly impacts this risk. Patients with severe features of preeclampsia in the second trimester are at greatest risk of developing preeclampsia in a subsequent pregnancy: Recurrence rates of 25 to 65 percent have been reported [22-25]. By comparison, patients with preeclampsia without severe features in their first pregnancy develop preeclampsia in 5 to 7 percent of second pregnancies [26,27]. Patients who had a normotensive first pregnancy develop preeclampsia in less than 1 percent of second pregnancies.

●Preexisting medical conditions:

•Pregestational diabetes (RR 3.7, 95% CI 3.1-4.3) [21] – This increase has been related to a variety of factors, such as underlying kidney or vascular disease, obesity, high plasma insulin levels/insulin resistance, and abnormal lipid metabolism [28].

•Chronic hypertension (RR 5.1, 95% CI 4.0-6.5) [21] – Although chronic hypertension (when defined as blood pressure ≥140/90 mmHg) increases the risk of preeclampsia fivefold compared with patients without this risk factor, chronic hypertension is uncommon in reproductive-age females and thus accounts for only 5 to 10 percent of preeclampsia cases [29].

Increasing data suggest that patients with contemporary definitions of hypertension are also at increased risk for preeclampsia [20,30-33]. There appears to be a dose-response relationship between blood pressure and preeclampsia that becomes clinically significant when blood pressure reaches the elevated level (systolic blood pressure 120 to 129 mmHg and diastolic blood pressure <80 mmHg), increases with stage 1 hypertension (systolic blood pressure 130 to 139 mmHg and/or diastolic blood pressure 80 to 89 mmHg), and increases further with stage 2 hypertension (systolic blood pressure ≥140 mmHg or diastolic blood pressure ≥90 mmHg) [32,33].

•Some autoimmune disorders, such as systemic lupus erythematosus (RR 1.8, 95% CI 1.5-2.1) and antiphospholipid syndrome (RR 2.8, 95% CI 1.8-4.3), increase the risk for developing preeclampsia [21]. The reasons for this relationship are not clear but may include multiple mechanisms involving inflammation, microangiopathy, increased platelet turnover, and kidney dysfunction.

•Prepregnancy overweight or obesity (body mass index >25 kg/m² [RR 2.1, 95% CI 2.0-2.2] and >30 kg/m² [RR 2.8, 95% CI 2.6-3.1]) [21] – The risk of preeclampsia appears to double with each 5 to 7 kg/m² increase in prepregnancy body mass index [34]. This relationship persisted in studies that excluded patients with chronic hypertension, diabetes mellitus, multiple gestations, or after adjustment for other confounders. Although overweight and obesity increase the risk of preeclampsia only two- to threefold, overweight and obesity are highly prevalent worldwide and thus cumulatively are associated with over 40 percent of preeclampsia cases [29].

•Chronic kidney disease (RR 1.8, 95% CI 1.5-2.1) [21] – The risk varies depending on the degree of reduction of glomerular filtration rate and the presence or absence of hypertension. In some studies, as many as 40 to 60 percent of patients with advanced chronic kidney disease (stages 3, 4, 5) were diagnosed with preeclampsia in the latter half of pregnancy [35,36].

●Multifetal pregnancy (RR 2.9, 95% CI 2.6-3.1) [21] – In three large series, preeclampsia occurred in 5 percent of singleton, 8 to 13 percent of twin, and 11 percent of triplet gestations [37-40], although rates over 20 percent in multiple gestations are commonly reported in small series [41].

●Nulliparity (RR 2.1, 95% CI 1.9-2.4) [21] – It is unclear why the nulliparous state is consistently found to be the most prevalent predisposing factor for preeclampsia [21]. One theory is that the immune system of nulliparous individuals has had limited exposure to paternal antigens, and this lack of desensitization may play a role in the pathogenesis of the disease. Epidemiologic data support this theory: preeclampsia risk is increased in subsequent pregnancies if there is a change in paternity, patients using barrier methods of contraception are at increased risk, and risk is reduced with increased duration of sexual activity before pregnancy [42]. However, the notion that the risk of preeclampsia is increased in a subsequent pregnancy with a new partner has been challenged by data suggesting that a longer interval between pregnancies may be the reason for the increased risk with a new partner [43].

●A family history of preeclampsia in a first-degree relative increases the risk for preeclampsia (RR 2.90, 95% CI 1.70-4.93) [20], suggesting a heritable mechanism in some cases [44,45]. The occurrence and severity of the disease appear to be influenced primarily by maternal factors, but the paternal contribution to fetal genes may play a role in defective placentation and subsequent preeclampsia.

A patient who was born preterm, low birth weight, or small for gestational age also appears to be at increased risk of developing gestational hypertension or preeclampsia when they become pregnant [46]. Preeclampsia, preterm birth, low birth weight, and small for gestational age can be different manifestations of a heritable tendency for abnormal placental development. (See "Preeclampsia: Pathogenesis", section on 'Genetic factors'.)

●Prior pregnancy complications associated with placental insufficiency – Fetal growth restriction (RR 1.4, 95% CI 0.6-3.0), abruption (RR 2.0, 95% CI 1.4-2.7), and stillbirth (RR 2.4, 95% CI 1.7-3.4) can be different manifestations of placental insufficiency [21]. They are risk factors for preeclampsia, and preeclampsia is a risk factor for developing these disorders.

●Advanced maternal age (maternal age ≥35: RR 1.2, 95% CI 1.1-1.3; maternal age ≥40: RR 1.5, 95% CI 1.2-2.0) [21] – Older patients tend to have additional risk factors, such as obesity, diabetes mellitus, and chronic hypertension, that predispose them to developing preeclampsia.

Whether adolescents are at higher risk of preeclampsia is more controversial. One systematic review estimated that the prevalence of preeclampsia/eclampsia in adolescent pregnancies was 6.7 percent [47] and another did not find an association between adolescence and risk for preeclampsia [20], but the results are not conclusive given the heterogeneity of the included studies. (See "Effects of advanced maternal age on pregnancy".)

●Use of assisted reproductive technology is a risk factor in large cohort studies (pooled rate 6.2 percent, 95% CI 4.7-7.9; RR 1.8, 95% CI 1.6-2.1) [21]. However, multivariate logistic regression analysis attenuates this association, and propensity analysis further weakens it [48]. In addition, one study reported the risk for hypertensive disorders of pregnancy was increased with both autologous or donor oocyte frozen embryo transfer and fresh donor oocyte embryo transfer, but not with autologous oocyte-fresh embryo transfer [49].

Of note, patients who smoke cigarettes have a lower risk of preeclampsia than nonsmokers. (See "Cigarette and tobacco products in pregnancy: Impact on pregnancy and the neonate", section on 'Preeclampsia'.)

PATHOGENESIS — The pathogenesis of preeclampsia likely involves both placental and maternal factors. Abnormal development of the placental vasculature early in pregnancy (failure of normal spiral artery remodeling) is a key event that results in relative placental underperfusion, hypoxia, ischemia, and oxidative stress, leading to release of antiangiogenic factors into the maternal circulation. These factors can cause widespread maternal systemic endothelial dysfunction, eventually resulting in the clinical manifestations of the disease. (See 'Spectrum of disease' below.)

The pathogenesis of preeclampsia is reviewed in detail separately. (See "Preeclampsia: Pathogenesis".)

SCREENING AND RISK REDUCTION — At the first prenatal visit, screening for traditional risk factors for preeclampsia (table 3) is routinely performed because identifying patients at high risk of developing the disease and treating them with low-dose aspirin throughout pregnancy can reduce their risk. Candidates for low-dose aspirin therapy and the effectiveness of this therapy are reviewed separately. (See "Early pregnancy prediction of preeclampsia", section on 'Routine regular prenatal blood pressure measurement' and "Preeclampsia: Prevention", section on 'Candidates'.)

At subsequent provider visits, the body of evidence supports continuing to screen for preeclampsia by measuring blood pressure at every encounter [50,51]. Although preeclampsia is not typically diagnosed before 20 weeks, measuring blood pressure a few times before 20 weeks establishes a baseline for comparison later in pregnancy. (See 'Accurate assessment of blood pressure' below.)

The value of any laboratory or imaging test for screening and subsequent intervention has not been established. Although it is customary to test for proteinuria at each prenatal visit, this practice has not been rigorously evaluated and proven to improve outcomes [51]. We suggest performing a urinalysis to test for proteinuria at the first prenatal visit to establish a baseline and, given the possibility for false-positive and false-negative results, repeating the test only in patients who develop hypertension. By contrast, testing for proteinuria should be performed at each visit in patients with hypertension as proteinuria changes the diagnosis to preeclampsia. Once a diagnosis of preeclampsia is established, testing for proteinuria is no longer diagnostically or prognostically useful. (See "Proteinuria in pregnancy: Diagnosis, differential diagnosis, and management of nephrotic syndrome" and "Proteinuria in pregnancy: Diagnosis, differential diagnosis, and management of nephrotic syndrome", section on 'Semiquantitative (screening)' and "Proteinuria in pregnancy: Diagnosis, differential diagnosis, and management of nephrotic syndrome", section on 'Quantitative (diagnostic)'.)

A calculator that combines maternal characteristics with mean arterial blood pressure, mean uterine artery resistance, and serum PlGF and PAPP-A was developed by the Fetal Medicine Foundation for screening patients in early pregnancy to stratify risk of developing preeclampsia later in pregnancy [52]. It is not used in the United States. (See "Early pregnancy prediction of preeclampsia", section on 'Risk prediction models'.)

CLINICAL PRESENTATION

Typical presentation — One-third of patients are nulliparous, and most of the remainder are at high risk for the disease because of overweight/obesity, prior preeclampsia, chronic hypertension, multifetal pregnancy, chronic kidney disease, or pregestational diabetes [21]. Approximately 85 percent of patients present with new-onset hypertension and proteinuria at ≥34 weeks of gestation, sometimes during labor [53,54]. Approximately 10 percent develop these signs and symptoms at <34 weeks of gestation (ie, early-onset preeclampsia) [53] and rarely as early as 20 to 22 weeks. In approximately 5 percent of cases, the signs and symptoms are first recognized postpartum (ie, postpartum preeclampsia), usually within 48 hours of birth [55-57].

The degree of maternal hypertension and proteinuria, as well as the presence/absence of other clinical manifestations of the disease that represent the severe end of the disease spectrum (alarm findings), are highly variable and described in detail below [58]. (See 'Spectrum of disease' below.)

Alarm blood pressure and symptoms — Approximately 25 percent of patients with preeclampsia develop severe hypertension (systolic pressure ≥160 mmHg and/or diastolic pressure ≥110 mmHg) and/or one or more of the following nonspecific symptoms, which characterize the severe end of the disease spectrum. Severe hypertension and/or alarm symptoms signify the need for urgent evaluation, prompt treatment to reduce blood pressure below the severe level, and possibly delivery by induction or cesarean birth (see 'Patient evaluation' below):

●Persistent and/or severe headache

●Visual abnormalities (scotomata, photophobia, blurred vision, or temporary blindness [rare])

●Upper abdominal, retrosternal, or epigastric pain

●Altered mental status (confusion, altered behavior [agitation])

●New dyspnea, orthopnea

Upper abdominal, retrosternal, or epigastric pain may be the presenting symptom of preeclampsia and reflux is common in pregnant individuals, especially at night; therefore, a high index of suspicion is important to make a timely diagnosis of preeclampsia with severe features rather than reflexively ascribing these symptoms to gastroesophageal reflux. (See "Hypertensive disorders in pregnancy: Approach to differential diagnosis", section on 'Differential diagnosis of other signs/symptoms of preeclampsia with severe features'.)

Rare and atypical presentations

Onset <20 weeks — Most of the rare cases of preeclampsia presenting before 20 weeks of gestation are associated with a complete or partial molar pregnancy or antiphospholipid syndrome (APS). Other disorders with similar signs and symptoms include lupus nephritis, thrombotic thrombocytopenic purpura (which may be hereditary), and hemolytic-uremic syndrome. (See "Hydatidiform mole: Epidemiology, clinical features, and diagnosis", section on 'Preeclampsia <20 weeks of gestation' and "Antiphospholipid syndrome: Obstetric implications and management in pregnancy" and "Diagnostic approach to suspected TTP, HUS, or other thrombotic microangiopathy (TMA)" and "Lupus nephritis: Diagnosis and classification".)

Differential diagnosis can be challenging (table 4). (See "Hypertensive disorders in pregnancy: Approach to differential diagnosis".)

Hydrops-related Mirror syndrome is most common between 22 and 28 weeks, but rare cases have presented before 20 weeks [59,60]. (See "Nonimmune hydrops fetalis", section on 'Mirror syndrome'.)

Onset or exacerbation of symptoms >2 days postpartum — Delayed-onset or late postpartum preeclampsia can be defined as signs and symptoms of the disease leading to readmission more than two days but less than six weeks after birth [57], although various other definitions have been used. Headache is the most common reason for presentation to a health care provider in patients subsequently diagnosed with late postpartum preeclampsia, and was present in nearly 70 percent of such patients in two large studies [57,61]. Shortness of breath was also relatively common, affecting 20 to 30 percent of patients.

Signs and symptoms can be atypical; for example, the patient may have thunderclap headaches alternating with mild headaches or intermittent rather than persistent hypertension. Other etiologies for the signs and symptoms should be considered, such as reversible cerebral vasoconstriction syndrome or impending stroke [62-65]. (See "Overview of thunderclap headache" and "Reversible cerebral vasoconstriction syndrome".)

Risk factors for delayed postpartum preeclampsia appear to be similar to those for the typical cases of preeclampsia (table 3), and some patients have no risk factors [57,66,67].

In a retrospective cohort study including 152 patients with delayed postpartum preeclampsia, 63.2 percent had no antecedent diagnosis of hypertensive disease in the current pregnancy whereas 18.4 percent had preeclampsia, 9.2 percent had chronic hypertension, 4.6 percent had gestational hypertension, and 4.6 percent had preeclampsia superimposed upon chronic hypertension during the peripartum period [57]. Of these patients, 14.5 percent developed postpartum eclampsia and their most common presenting symptom was headache, which occurred in 70 percent of patients.

Severe features of preeclampsia without hypertension — It is uncommon for patients to exhibit the severe features of preeclampsia without hypertension, but this may be observed in 15 percent of patients with HELLP syndrome (which some consider a variant of preeclampsia and others consider a separate disorder) and in some patients with eclampsia (a possible sequelae of preeclampsia). It is possible that in such patients, blood pressure is increased above baseline but does not meet diagnostic criteria for hypertension, similar to what has been described in the syndrome of posterior reversible encephalopathy [68]. (See "Eclampsia", section on 'Can eclampsia be predicted and prevented?' and "HELLP syndrome (hemolysis, elevated liver enzymes, and low platelets)".)

Isolated hypertension — Patients with new onset of mild hypertension but no other criteria for preeclampsia or an underlying disease associated with hypertension are given the diagnosis of gestational hypertension. These patients should be followed closely since up to 50 percent will subsequently develop the full diagnostic criteria for preeclampsia. (See "Gestational hypertension", section on 'Risk of progression to preeclampsia'.)

Isolated proteinuria — Isolated gestational proteinuria may occur before the diagnostic criteria for preeclampsia have manifested [69]. We are unaware of prospective studies describing this finding, but in a retrospective study of 95 pregnant patients with new-onset isolated proteinuria who were followed to term, preeclampsia developed in 22 percent: antepartum or intrapartum in 13 patients and postpartum in 8 patients [70].

PATIENT EVALUATION

Candidates — All pregnant patients with new-onset hypertension or worsening hypertension after 20 weeks of gestation or other potential clinical manifestations of preeclampsia should be promptly evaluated for the disease.

Site — Patients with severe hypertension (systolic pressure ≥160 mmHg and/or diastolic pressure ≥110 mmHg) and/or symptoms suggestive of severe disease, such as cerebral or visual symptoms, epigastric pain, or dyspnea, require hospitalization for initial maternal and fetal evaluation and management. Patients with nonsevere hypertension who are asymptomatic may be followed closely as outpatients provided they are seen frequently and the maternal and fetal status is stable. The decision to monitor patients in the hospital versus in an outpatient setting should be made on a case-by-case basis, taking into consideration both medical and social issues. (See "Preeclampsia: Antepartum management and timing of delivery".)

Accurate assessment of blood pressure — A standardized validated technique for blood pressure measurement in pregnancy is critically important both in the office and at home. These techniques are reviewed separately. (See "Treatment of hypertension in pregnant and postpartum patients", section on 'Technique for accurate measurement of blood pressure'.)

Repeated measurements should be performed to confirm hypertension, ideally over several hours or days unless blood pressure is severely elevated thus requiring prompt treatment.

Laboratory tests

Routine — For all patients with suspected preeclampsia, routine laboratory testing includes:

●Complete blood count with platelets

●Serum creatinine level

●Liver chemistries (aspartate aminotransferase [AST], alanine aminotransferase [ALT]) and bilirubin

●Quantitative urinary protein (protein to creatinine ratio in a random urine specimen or 24-hour urine collection for total protein)

Additional testing depends on results of initial laboratory tests and patient presentation:

●Patients with abnormal liver chemistries – lactate dehydrogenase (LDH) level

●Patients with complications, such as placental abruption, severe bleeding, thrombocytopenia, or severe liver dysfunction – coagulation studies (prothrombin time, partial thromboplastin time, fibrinogen)

●Patients with acute upper abdominal or epigastric pain or those found to have severe liver dysfunction – glucose, amylase, lipase, and ammonia levels can help in differential diagnosis (table 4). (See "Hypertensive disorders in pregnancy: Approach to differential diagnosis".)

●Patients with thrombocytopenia (particularly platelet count <50,000/microL), hemolysis with fragmented red blood cells on the blood smear, severe neurologic findings, and a normal clotting screen (prothrombin time, activated partial thromboplastin time, fibrinogen level) – ADAMTS13 activity. Thrombocytopenic purpura (TTP) is rare in pregnancy, but very low ADAMTS13 activity (<10 percent) confirms the diagnosis. (See "Diagnosis of immune TTP".)

Role of measurement of angiogenic markers — Preeclampsia is associated with abnormal angiogenic imbalance. Measurement of urinary or plasma antiangiogenic markers, such as soluble fms-like tyrosine kinase-1 (sFlt-1), and angiogenic markers, such as placental growth factor (PlGF), or their ratios may be useful for:

●Distinguishing preeclampsia from other hypertensive-proteinuric disorders

●Determining whether a patient with some of the manifestations of preeclampsia but not meeting diagnostic criteria requires medical intervention, such as hospitalization or delivery

●Predicting short-term risk of progression to preeclampsia with severe features

The clinical utility of these tests remains somewhat unclear, due to heterogeneity among studies in measurement of markers, study populations, and outcomes of interest. For example, PlGF alone, sFlt-1/PlGF, and combinations of angiogenic markers and clinical features have been studied as predictors of development of any preeclampsia, preterm preeclampsia, preeclampsia with severe features, and other adverse maternal and fetal outcomes [71]. Despite these limitations, prospective studies and trials suggest that angiogenic markers accurately diagnose preeclampsia and have a high negative predictive value, thus they may be useful in ruling out preeclampsia [72-75]. (See "Preeclampsia: Pathogenesis", section on 'sFlt-1, VEGF, PlGF'.)

●ACOG/SMFM – The American College of Obstetricians and Gynecologists (ACOG) and the Society for Maternal-Fetal Medicine (SMFM) have not recommended measurement of angiogenic markers for diagnosis or exclusion of preeclampsia [2]. One angiogenic marker test (sFlt-1/PlGF ratio) is commercially available in the United States.

●NICE – In the United Kingdom, the National Institute for Health and Care Excellence (NICE) suggests offering PlGF-based tests, which should be used with standard clinical assessment, to help rule in or rule out preeclampsia in patients suspected of the disorder between 20+0 and 36+6 weeks of gestation [76]. They suggest use of any of four specific tests (DELFIA Xpress PlGF 1-2-3, DELFIA Xpress sFlt-1/Xpress PlGF1-2-3 ratio, Elecsys immunoassay sFlt-1/PlGF ratio, Triage PlGF test) and not repeating testing if initial testing is negative. They emphasize using the test in conjunction with clinical information for decisions on care (eg, hospitalization or transfer to a specialist unit) and recommend not using PlGF testing to make decisions on timing of delivery in pregnant patients between 20+0 and 36+6 weeks of gestation. Lastly, they suggest that the test may be of greater benefit in patients at greater risk of adverse maternal outcomes.

●ISSHP – The International Society for the Study of Hypertension in Pregnancy (ISSHP) practice guideline states that assessment of angiogenic imbalance could be performed (if available). An imbalance (reduced PlGF <5^th percentile for gestational age or increased sFlt/PlGF ratio [eg, >38 by the Roche assay]) would strengthen the clinical diagnosis of preeclampsia, but should not be used as a sole criterion for diagnosis [14].

Evidence — In a meta-analysis of observational studies examining the performance of sFlt-1, PlGF, or the sFlt-1/PlGF ratio in predicting adverse outcomes in patients with suspected or confirmed preeclampsia, both PlGF and the sFlt-1/PlGF ratio demonstrated pooled area under the summary receiver operating characteristic curve values from 0.68 to 0.87 for predicting composite adverse maternal and perinatal outcomes, preterm birth, and fetal growth restriction, but very high heterogeneity of the population sampled coupled with differences in study methodology, study quality, and the outcomes measured limited conclusions regarding the prognostic value of these biomarkers in clinical practice [77]. The best available evidence is from the following clinical trials and one large prospective observational study testing the potential benefits of PlGF-based testing:

●The PARROT trial was a multicenter, pragmatic, stepped wedge cluster randomized controlled trial of 1023 patients with suspected preeclampsia who were between 20+0 and 36+6 weeks of gestation. It was performed in 11 maternity units in the United Kingdom and used the Triage PlGF test [73]. Maternity units were randomly allocated to a management strategy using PlGF testing that was revealed to the care team or to management without knowledge of PlGF levels (concealed).

•The median time to preeclampsia diagnosis was shorter in the revealed testing group (1.9 versus 4.1 days).

•Maternal severe adverse outcomes were reduced in the revealed testing group (4 versus 5 percent).

•Perinatal outcomes and gestational age at delivery were similar for both groups.  

In contrast, the PARROT Ireland trial, which used a similar design and same test but had a larger sample size (n = 2313), reported opposite results regarding median days to diagnosis (median time to diagnosis: PlGF testing 8 days, no PlGF testing 7 days) [78]. In addition, maternal and neonatal morbidity trended higher in the PlGF testing group.

●The INSPIRE trial was a prospective, interventional, parallel-group, randomized clinical trial of 370 patients with suspected preeclampsia who were between 24+0 and 37+0 weeks of gestation [72]. It was based in a single UK tertiary referral hospital and used the Elecsys immunoassay sFlt-1/PLGF ratio. Patients were allocated to management based on knowledge of sFlt-1/PlGF levels (reveal) or to a nonreveal group. Nearly 400 patients were recruited.  

•The primary outcome (hospitalization within 24 hours of the test) was not different in the two groups

•Adverse maternal-fetal outcomes were also similar for both groups

The test in this study, as in others, had a high sensitivity and negative predictive value for diagnosis of preeclampsia, but this information did not translate into an improvement in pregnancy outcome.

●The PRAECIS study recruited 1014 hospitalized patients with a hypertensive disorder of pregnancy between 23+0 and 34+6 weeks of gestation and obtained baseline levels of sFlt-1:PlGF (results not available to treatment team) to determine whether this test could accurately predict development of preeclampsia with severe features or adverse outcomes within two weeks [79].

•Patients who developed preeclampsia with severe features had significantly higher ratios compared with those who did not (median 200, interquartile range 53-458 versus median 6, interquartile range 3-26).

•Compared with the 289 patients whose ratio was <40, the 267 patients with a ratio ≥40 were at higher risk for composite adverse maternal outcomes (16.1 versus 2.8 percent; RR 5.8, 95% CI 2.8-12.2). Abnormal liver function tests accounted for most of the adverse maternal outcomes in the ratio ≥40 group (26 cases versus 2 cases in the <40 group), followed by abruption (12 versus 5 cases), and thrombocytopenia (9 versus 1 case). The ratio ≥40 group also had more fetal/neonatal deaths (8 versus 1 case) and fetal growth restriction (79 versus 23 cases).

•Sensitivity and specificity for developing preeclampsia with severe features within two weeks were: sensitivity 94 percent, 95% CI 89-96; specificity 75 percent, 95% CI 70-79.

Based on this study, the FDA approved use of sFlt-1:PlGF in patients hospitalized with hypertension to predict progression to preeclampsia with severe features within two weeks. Clinical use for managing such patients is discussed separately. (See "Preeclampsia: Antepartum management and timing of delivery", section on 'Inpatient versus outpatient care'.)

The findings from this study are not generalizable for clinical use in ambulatory patients with hypertension and limited by the observational design.

Assessment of fetal status — Fetal status is assessed concurrently with the maternal evaluation or post-diagnosis, depending on the degree of concern when the mother is evaluated. At a minimum, a nonstress test or biophysical profile is performed, if appropriate for gestational age. Ultrasound is indicated to evaluate amniotic fluid volume and estimate fetal weight given the increased risk for oligohydramnios and fetal growth restriction (FGR). (See "Overview of antepartum fetal assessment".)

When to obtain consultation — The neurology service should be consulted to evaluate patients with neurologic deficits/abnormal neurologic examination, ocular signs and symptoms, or a severe persistent headache that does not respond to repeat doses of acetaminophen and initial routine management of preeclampsia. The symptom of sudden onset of severe headache ("worst headache of my life") is sufficiently characteristic of subarachnoid hemorrhage that it should prompt neurology consultation and consideration of imaging. The headache in subarachnoid hemorrhage is lateralized in 30 percent of patients and may be associated with a brief period of altered consciousness, collapse, nausea or vomiting, preretinal subhyaloid hemorrhages, or meningismus. (See "Aneurysmal subarachnoid hemorrhage: Clinical manifestations and diagnosis".)

Consultation with other services is useful if there is uncertainty about differential diagnosis or management of severe hematologic, renal, hepatic, or cardiopulmonary disease.

SPECTRUM OF DISEASE — The clinical findings of preeclampsia result from the underlying pathophysiology of the disease: placental insufficiency, vasoconstriction, increased capillary permeability, and endothelial dysfunction.

Potential clinical findings

Hypertension — All patients with preeclampsia have hypertension, but a small proportion of those with HELLP and rare patients with eclampsia do not meet diagnostic criteria for hypertension in pregnancy. Hypertension is generally the earliest clinical finding and the most common clinical clue to the presence of the disease. The blood pressure usually rises gradually, reaching the hypertensive range (defined as ≥140/90 mmHg) sometime in the third trimester, often after the 37^th week of gestation [53]. Blood pressures are often around 135/85 mmHg in the one to two weeks before reaching the hypertensive range. However, in some patients, hypertension develops rapidly, before 34 weeks of gestation, or postpartum.

Vasoconstriction, reduced vasodilation, and imbalance between endothelium-derived constrictor and dilatory products in systemic maternal arteries increase vascular tone and peripheral vascular resistance, leading to maternal hypertension [80]. Cardiac output usually is normal for pregnancy, except in a minority of patients in whom preeclampsia is complicated by peripartum cardiomyopathy. Some patients with onset near term have decreased vascular resistance and increased cardiac output.

Pheochromocytoma is a rare cause of hypertension during pregnancy and may be difficult to distinguish from preeclampsia. (See "Hypertensive disorders in pregnancy: Approach to differential diagnosis", section on 'Pheochromocytoma'.)

Epigastric, upper abdominal, or retrosternal pain — Epigastric, upper abdominal, or retrosternal pain, when present, is a cardinal symptom of the severe end of the disease spectrum. Severe constant pain often begins at night and is usually maximal in the low retrosternal area or epigastrium, but may radiate to the right hypochondrium or back [81]. Nausea or vomiting sometimes occurs, but when persistent and associated with loss of appetite, fatty liver of pregnancy should be ruled out. (See "Acute fatty liver of pregnancy".)

On examination, the liver may be tender to palpation due to stretching of Glisson's capsule from hepatic swelling or bleeding. Liver rupture or hemorrhage is rare but should be suspected when there is sudden onset of right upper quadrant pain associated with a decrease in blood pressure. (See "HELLP syndrome (hemolysis, elevated liver enzymes, and low platelets)", section on 'Management of hepatic bleeding'.)

Acute pancreatitis is a rare complication of preeclampsia [82] and can mimic the epigastric pain of preeclampsia [83]. (See "Hypertensive disorders in pregnancy: Approach to differential diagnosis", section on 'Medical and surgical disorders associated with elevated blood pressure, headache, and/or abdominal pain'.)

Rarely, patients develop chest pain caused by cardiac disease (eg, ischemia, acute spontaneous coronary artery dissection).

Neurologic

●Headache – Headache, when present, is a feature of the severe end of the disease spectrum. It may be temporal, frontal, occipital, or diffuse [84,85]. The pain usually has a throbbing or pounding quality but may be piercing. Although not pathognomonic, a feature that suggests preeclampsia-related headache rather than another type of headache is that it persists despite administration of over-the-counter analgesics, and it may become severe (ie, incapacitating, "the worst headache of my life"). However, resolution of the headache with analgesics does not exclude the possibility of preeclampsia. The American College of Obstetricians and Gynecologists' criteria for preeclampsia-related headache are "new-onset headache unresponsive to medication and not accounted for by alternative diagnoses" [2].

The mechanism for headache, as well as other cerebrovascular symptoms of preeclampsia, is poorly understood. Cerebral edema and ischemic/hemorrhagic changes in the posterior hemispheres observed on computed tomography and magnetic resonance imaging help to explain, but do not fully account for, the clinical findings [86,87]. These findings may result from generalized endothelial cell dysfunction, leading to vasospasm of the cerebral vasculature in response to severe hypertension, or they may result from loss of cerebrovascular autoregulation, leading to areas of both vasoconstriction and forced vasodilation. Thus, they could represent a form of posterior reversible leukoencephalopathy syndrome (PRES) [68,88,89]. PRES is typically associated with severe hypertension but can also occur with rapid increases in blood pressure in patients with endothelial damage and in patients with only mildly elevated blood pressure [90]. (See "Reversible posterior leukoencephalopathy syndrome" and "Eclampsia", section on 'Clinical findings'.)

Acetaminophen is commonly used to treat headache. Doses ≤2 g/day can be administered safely to many patients with preeclampsia-related hepatic or renal insufficiency.

●Visual symptoms – Visual symptoms, when present, are also symptoms of the severe end of the disease spectrum. They are caused, at least in part, by retinal arteriolar spasm, impaired cerebrovascular autoregulation, and cerebral edema [68,91]. Symptoms may include blurred vision, photopsia (flashing lights or sparks), scotomata (dark areas or gaps in the visual field) [92-94], diplopia, or amaurosis fugax (blindness in one or both eyes). Visual disturbances in preeclampsia may be manifestations of PRES [89].

Cortical blindness is rare and typically transient [95]. Blindness related to retinal pathology, such as retinal artery or vein occlusion, retinal detachment, optic nerve damage, retinal artery spasm, and retinal ischemia, may be permanent [96].

●Mental status changes – Mental status changes include confusion and altered behavior, such as agitation.

●Stroke – Stroke leading to death or disability is the most serious complication of preeclampsia/eclampsia and is responsible for approximately 36 percent of pregnancy-associated stroke [97]. Most strokes in this setting are hemorrhagic and preceded by severe headache and severe hypertension (especially severe systolic hypertension), but ischemic strokes also occur [98,99]. Eclamptic seizures occur in some, but not all, cases. Lowering blood pressure reduces the risk of stroke. A common approach is to lower systolic blood pressure by no more than 25 percent in the first hour, with a target systolic blood pressure <160 mmHg in the next few hours. (See "Cerebrovascular disorders complicating pregnancy", section on 'Preeclampsia, eclampsia, and HELLP' and "Treatment of hypertension in pregnant and postpartum patients", section on 'Acute therapy of severe hypertension'.)

●Generalized hyperreflexia – Hyperreflexia is a common finding. Sustained ankle clonus may be present.

●Seizure (eclampsia) – In some patients, the combination of hypertension and endothelial activation results in posterior reversible encephalopathy syndrome (PRES), manifested as headaches, scotomata, scintillations, and seizure. Seizure in a preeclamptic patient upstages the diagnosis to eclampsia. Eclamptic seizures develop in 1 in 400 patients with preeclampsia without severe features and in 1 in 50 patients with preeclampsia with severe features. Histopathologic correlates include brain hemorrhage, petechiae, edema, vasculopathy, ischemic damage, microinfarcts, and fibrinoid necrosis [100,101]. Neuroimaging consistent with PRES may be seen [102]. (See "Eclampsia", section on 'Clinical findings'.)

Pulmonary edema — Pulmonary edema is a feature of the severe end of the disease spectrum and was observed in approximately 10 percent of 63 cases of preeclampsia with severe features in a prospective study [103]. Symptoms may include shortness of breath, cough, wheezing, anxiety/restlessness, chest pain, palpitations, or excessive perspiration. The symptom complex of dyspnea, chest pain, and/or decreased (≤93 percent) oxygen saturation by pulse oximetry is predictive of adverse maternal outcome (maternal death and hepatic, central nervous system, renal, cardiorespiratory, and hematologic morbidities) [104].

The etiology of pulmonary edema in preeclampsia is multifactorial [105-108]. Excessive elevation in pulmonary vascular hydrostatic pressure combined with decreased plasma oncotic pressure may produce pulmonary edema in some patients, particularly in the postpartum period. However, not all preeclamptic patients with pulmonary edema demonstrate this phenomenon. Other causes of pulmonary edema are capillary leak from endothelial activation, left heart failure, acute severe hypertension, and iatrogenic volume overload. There may be some overlap between preeclampsia and peripartum cardiomyopathy as the two disorders may coexist [109,110]. (See "Peripartum cardiomyopathy: Etiology, clinical manifestations, and diagnosis".)

Oliguria — Patients with preeclampsia commonly have transient oliguria (less than 100 mL over 4 hours) in labor or the first 24 hours postpartum. Those at the severe end of the disease spectrum may have urine output <500 mL/24 hours. Oliguria in preeclampsia is due to contraction of the intravascular space secondary to vasospasm, leading to increased renal sodium and water retention, as well as intrarenal vasospasm [111]. The glomerular filtration rate (GFR) may fall by over 25 percent. (See "Acute kidney injury in pregnancy", section on 'Preeclampsia with severe features/HELLP'.)

Rarely, patients with preeclamptic liver disease develop polyuria due to transient diabetes insipidus of pregnancy. The mechanism in these cases is decreased degradation of vasopressinase due to hepatic dysfunction. (See "Polyuria and diabetes insipidus of pregnancy".)

Generalized edema — Many pregnant individuals have peripheral edema whether or not they have preeclampsia. However, sudden and rapid weight gain (eg, >5 lb/week [2.3 kg/week]) and facial edema are more common in patients who develop preeclampsia; thus, these findings warrant diagnostic evaluation for the disease. Generalized edema in preeclampsia may be due to capillary leak from endothelial damage and/or increased sodium retention that may be related to glomerular endotheliosis and proteinuria.

Placental abruption — Abruption can be a life-threatening event for the mother and/or fetus. It occurs in less than 1 percent of pregnancies with preeclampsia without severe features but 3 percent of those with severe features [112]. It has been attributed to ischemia-reperfusion injury in maternal uteroplacental vessels. (See "Acute placental abruption: Pathophysiology, clinical features, diagnosis, and consequences" and "Acute placental abruption: Management and long-term prognosis".)

Potential laboratory findings

●Proteinuria – Proteinuria in preeclampsia can be defined as any of the following [2]:

•≥0.3 g protein in a 24-hour urine specimen. The completeness of the 24-hour urine collection can be estimated from creatinine excretion, which should be 15 to 20 mg/kg (133 to 177 micromol/kg) of lean body weight in females. (See "Assessment of urinary protein excretion and evaluation of isolated non-nephrotic proteinuria in adults", section on '24-hour versus spot urine collection'.)

•Random urine protein to creatinine ratio ≥0.3 mg protein/mg creatinine (30 mg/mmol) (some clinicians opt to confirm presence of ≥0.3 g protein with a 24-hour collection).

The urine protein concentration in a spot sample is measured in mg/dL and is divided by the urine creatinine concentration, also measured in mg/dL. This value can be used to estimate the 24-hour protein excretion (calculator 1) [113-121].

•Protein ≥2+ on a paper test strip dipped into a fresh, clean voided midstream urine specimen (only if one of the above quantitative methods is not available. (2+ is equivalent to 100 to 300 mg/dL and performs better than 1+, which does not accurately detect or exclude the protein threshold for preeclampsia [122]).

Measurement of proteinuria is discussed in detail separately. (See "Proteinuria in pregnancy: Diagnosis, differential diagnosis, and management of nephrotic syndrome", section on 'Measurement'.)

Proteinuria generally increases as preeclampsia progresses, but increased urinary protein excretion may be a late finding [123,124]. It usually remains <5 g/day, but levels >10 g/day may be seen. Preeclampsia is the most common cause of severe proteinuria in pregnancy.

Proteinuria is due, in part, to impaired integrity of the glomerular filtration barrier and altered tubular handling of filtered proteins leading to increased nonselective protein excretion [125]. Both size and charge selectivity of the glomerular barrier are affected [122,126]. Using special studies, podocyturia (urinary excretion of podocytes) has been observed in patients with preeclampsia [127,128]. Urinary shedding of podocytes may indicate podocyte loss from the glomerulus, which may lead to a disruption of the glomerular filtration barrier and consequent proteinuria. Deficient vascular endothelial growth factor (VEGF) signaling appears to account, at least in part, for these findings. (See "Preeclampsia: Pathogenesis", section on 'Role of systemic endothelial dysfunction in clinical findings'.)

Kidney histology is reviewed below. (See 'Potential histologic findings' below.)

●Elevated creatinine level – The physiologic increase in GFR during a normal pregnancy results in a decrease in serum creatinine concentration, which falls by an average of 0.4 mg/dL (35 micromol/L) to a range of 0.4 to 0.8 mg/dL (35 to 70 micromol/L). The serum creatinine concentration in patients with preeclampsia generally remains in this range or only slightly elevated. A creatinine level >1.1 mg/dL (97.3 micromol/L) concentration indicates the severe end of the disease spectrum. Some guidelines also include doubling of the patient's baseline creatinine in the absence of other kidney disease as indicative of the severe end of the disease spectrum. Although creatinine levels remain <1.5 mg/dL (133 micromol/L) in most patients, preeclampsia is the most common cause of acute kidney injury in pregnancy. (See "Acute kidney injury in pregnancy", section on 'Preeclampsia with severe features/HELLP'.)

The rise in serum creatinine is due primarily to a fall in GFR; renal plasma flow also decreases but to a lesser degree.

●Thrombocytopenia – A platelet count less than 150,000/microL occurs in approximately 20 percent of patients with preeclampsia [2]. The severe end of the disease spectrum is characterized by a platelet count less than 100,000/microL.

Thrombocytopenia is the most common coagulation abnormality in preeclampsia. Microangiopathic endothelial injury and activation result in formation of platelet and fibrin thrombi in the microvasculature. Accelerated platelet consumption leads to thrombocytopenia; immune mechanisms may also play a role [129]. (See "Thrombocytopenia in pregnancy", section on 'List of causes'.)

●Hemolysis – Schistocytes and helmet cells on the peripheral blood smear (picture 1A-B) suggest microangiopathic hemolysis, which is a finding in severe disease. Elevation in the serum indirect bilirubin level also suggests hemolysis. Elevations in lactate dehydrogenase (LDH) are usually related to liver dysfunction but can be due to hemolysis or both.

●Hemoconcentration – Hemoconcentration may result from contraction of the intravascular space secondary to vasospasm as well as capillary leaking. Hematocrit typically increases (range 36 to 43 percent in one study [130]). When both hemolysis and hemoconcentration occur concurrently, the effects on hematocrit may negate each other, resulting in a normal value.

●Coagulation studies – The prothrombin time, activated partial thromboplastin time, and fibrinogen concentration are not usually affected by preeclampsia unless there are additional complications, such as severe thrombocytopenia, placental abruption, severe bleeding, or severe liver dysfunction [131,132].

●Elevated liver chemistries – Liver chemistries are increased in patients at the severe end of the disease spectrum, which is characterized by elevated transaminase levels (defined as twice the upper limit of normal for the local laboratory). Abnormalities in liver chemistries are due to reduced hepatic blood flow from periportal and sinusoidal fibrin deposition and microvesicular fat deposition, potentially resulting in ischemia, necrosis, and periportal hemorrhage [133,134]. Infrequently, subcapsular hematoma, hepatic failure, or rupture occurs.

An elevated serum indirect bilirubin level suggests hemolysis.

●Hyperuricemia – The association between hyperuricemia and preeclampsia has been known for decades. The cause is most likely related to a reduction in GFR. However, the increase in serum uric acid is often greater than expected for mild reductions in GFR, leading to the hypothesis that decreased tubular secretion or increased reabsorption in the proximal renal tubules plays a role [135].

Although meta-analyses have concluded that uric acid levels are not an accurate predictor of complications associated with preeclampsia [136-138], this issue remains controversial because of inconsistency among studies. For example, data from a prospective international study of patients admitted to the hospital with preeclampsia showed that serum uric acid corrected for gestational age is clinically useful in predicting adverse perinatal, but not maternal, outcomes [139].

●Other

•Urine sediment – The urine sediment is typically benign.

•Lipids – Total cholesterol and triglyceride levels are higher than in normotensive pregnant patients [140,141].

•Neutrophilia – The white blood count may be slightly higher due to neutrophilia.

•Hypocalciuria – Hypocalciuria has been attributed to increased tubular reabsorption of calcium [142-144]. Lower levels of parathyroid hormone, compared with normal pregnancy, have also been reported [145].

•Troponin – Several studies have reported that cardiac troponin I can be elevated above the normal threshold [146]. A very small subgroup of patients with severe preeclampsia may develop myocardial damage or global diastolic dysfunction [147]. Therefore, troponin I levels should be obtained when clinically indicated, such as when the patient complains of chest pain suggestive of myocardial ischemia or new electrocardiogram changes are observed [148,149].

Potential sonographic findings

●Fetal ultrasound – Preeclampsia that develops clinically before term is often associated with suboptimal fetal growth due to reduced uteroplacental perfusion [150]. Fetal growth restriction (FGR) may be accompanied by oligohydramnios due to redistribution of the fetal circulation away from the kidneys and toward more vital organs, particularly the brain. By contrast, preeclampsia that develops clinically at term tends to be associated with appropriate growth for gestational age and normal amniotic fluid volume; in some cases, the fetus may be large for gestational age [151-156].

Fetal hydrops is rarely observed and is the cause rather than the result of preeclampsia. Hydrops of any etiology can be associated with preeclampsia-like symptoms and is called Mirror syndrome. (See "Nonimmune hydrops fetalis", section on 'Mirror syndrome'.)

●Uterine and umbilical artery Doppler – Increased impedance to flow in the uterine arteries due to uteroplacental maldevelopment is manifested by an increase in the uterine artery pulsatility index and uterine artery notching on Doppler velocimetry. However, this finding is neither sensitive nor specific for preeclampsia. (See "Early pregnancy prediction of preeclampsia", section on 'Uterine artery Doppler velocimetry'.)

Increased resistance in placental blood vessels is reflected by rising Doppler indices of the umbilical artery. Absent and reversed end diastolic flow are the most severe abnormalities and are associated with a poor perinatal outcome. (See "Doppler ultrasound of the umbilical artery for fetal surveillance in singleton pregnancies".)

●Maternal hemodynamic imaging studies – Preeclampsia can be associated with a highly variable hemodynamic profile, including heart failure [157-161]. Changes in cardiac function and morphology may be seen on echocardiography at an asymptomatic early stage and progress with increasing disease severity [162]. Preeclampsia does not affect the myocardium directly, but the heart responds to physiologic changes induced by the disease. Left ventricular ejection fraction usually remains within normal limits [163], but reductions in longitudinal, circumferential, and radial systolic strain have been observed [164]. The decrement in left ventricular performance has been attributed to a physiologic response to increased afterload [157,163,164], but other factors may play a role since systolic strain was depressed in preeclamptic patients compared with pregnant patients with nonproteinuric hypertension and similar resting blood pressure [164].

The high afterload in preeclampsia is associated with elevated cardiac filling pressures, reflected by fourfold higher concentrations of natriuretic peptides in patients with preeclampsia compared with pregnant patients who are normotensive or who have chronic hypertension [158].

Intravascular volume may be reduced in preeclampsia (especially with severe features) compared with a normal pregnancy [165]. There is no evidence of underfilling of the arterial circulation; rather, the reduced volume appears to be a consequence of vasoconstriction from enhanced responses to vasoactive substances. Activation of the renin angiotensin aldosterone system (RAAS) increases vascular tone and renal reabsorption of sodium and water. In normal pregnancy, despite lower blood pressure compared with the nonpregnant state, the RAAS is upregulated, an appropriate physiologic response to vasodilation. Sensitivity to angiotensin II is reduced [166]. In contrast, in multiple studies of patients with preeclampsia, levels of renin and angiotensin I and II were reduced compared with normal pregnancy and sensitivity to angiotensin II was increased, consistent with vasoconstriction, reduced sodium excretion, and possibly some overfilling of the circulation, similar to what is observed in acute glomerulonephritis [167,168].

Potential histologic findings

●Placenta – Abnormalities in the placenta are believed to be a critical feature of the preeclampsia syndrome; however, many findings are nonspecific. In blinded studies, the pooled prevalence of villous lesions in preeclamptic and normal pregnancies was 42 and 19 percent, respectively, and the pooled prevalence of vascular lesions was 39 and 10 percent, respectively [169].

The parenchymal finding most characteristically associated with preeclampsia on routine hematoxylin and eosin staining is acute atherosis (ie, fibrinoid necrosis of the vessel wall with an accumulation of lipid-laden "foamy" macrophages and a mononuclear perivascular infiltrate). Cytotrophoblast invasion of the interstitial uterine compartment is frequently shallow, with incomplete invasion and remodeling of spiral arteries in many places [170]. This maldevelopment of the uteroplacental circulation can result in reduced placental perfusion, leading to placental infarcts, villous hypoplasia, and, in some cases, the clinical sequelae of FGR. Research studies using more advanced techniques (eg, special stains) have described additional findings (eg, reduced uterine natural killer cells in the decidua).

Placental histology is described in detail separately. (See "The placental pathology report", section on 'Preeclampsia'.)

●Kidney – The renal histologic changes described in patients with preeclampsia who have had kidney biopsies, and in autopsy specimens obtained from patients who died of eclampsia, are termed "glomerular endotheliosis." Light and electron microscopy of glomerular endotheliosis show endothelial cell swelling, loss of fenestrations, and occlusion of capillary lumens (picture 2A-B) [171]. Podocyte foot process effacement is not a prominent feature, despite marked proteinuria.

Glomerular endotheliosis shares some histologic features with nonpreeclamptic thrombotic microangiopathies [171], except thrombi are rare in preeclampsia (although fibrin deposition may be observed by immunofluorescence microscopy). Patients treated with anti-VEGF chemotherapy have also been found to have glomerular endotheliosis, along with hypertension and proteinuria [172]. Rarely, it may be present without proteinuria and in nonpregnant females [173,174].

DIFFERENTIAL DIAGNOSIS — When evaluating patients for possible preeclampsia, it is generally safer to assume that new-onset hypertension in pregnancy is due to preeclampsia, even if all the diagnostic criteria are not fulfilled and the blood pressure is only mildly elevated, since preeclampsia may progress to eclampsia or other severe forms of the disease in a short period of time. However, several other disorders can manifest some or many of the signs and symptoms of preeclampsia.

Causes of hypertension in pregnancy that are unrelated to the pregnant state include chronic hypertension, chronic kidney disease, acute kidney injury, other medical disorders (eg, pheochromocytoma, some neurologic disorders, some endocrine disorders [eg, hyperthyroidism]), and use/withdrawal of some drugs. Most pregnant patients with hypertension and thrombocytopenia and/or elevated transaminases have preeclampsia with severe features; alternative diagnoses to consider include HELLP syndrome, acute fatty liver of pregnancy (AFLP), thrombotic microangiopathy (eg, thrombotic thrombocytopenic purpura [TTP], hemolytic-uremic syndrome [HUS]), systemic lupus erythematosus (SLE), and antiphospholipid syndrome (APS). Differential diagnosis is reviewed separately. (See "Hypertensive disorders in pregnancy: Approach to differential diagnosis".)

NATURAL HISTORY/COURSE OF DISEASE

Overview — Preeclampsia can be a progressive disease. Although most patients develop signs of the disease in late pregnancy with gradual worsening until giving birth, in approximately 25 percent of patients, especially those with early-onset preeclampsia, hypertension becomes severe and/or signs and symptoms of significant end-organ damage become apparent over a period of days to weeks. It is important to note that severe sequelae (significant end-organ dysfunction, death) can occur in patients without severe hypertension. Chest pain, dyspnea, and low platelet count appear to be particularly predictive of fatal or life-threatening complications [175].

In most patients, resolution of the maternal signs and symptoms of the disease occurs variably in the postpartum period, with some symptoms disappearing in a matter of hours (eg, headache), while others may take weeks or months (eg, proteinuria). Typically, mobilization of third-space fluid and diuresis begin within 48 hours postpartum. Hypertension may worsen during the first, and occasionally the second, postpartum week but normalizes in most patients within four weeks after giving birth [176]. Rarely, hypertension persists beyond three months. Proteinuria usually begins to improve within a few days; however, in patients with several grams of protein excretion, complete resolution may take weeks to months [177].

In some patients, signs and symptoms of preeclampsia are first recognized postpartum (ie, postpartum preeclampsia), usually within 48 hours of birth. Even though it is not clear why signs and symptoms of preeclampsia may be first recognized or worsen after birth, postpartum preeclampsia is not caused by large fragments of retained placenta. Postpartum preeclampsia may represent a subgroup of patients who had subclinical preeclampsia before birth, delayed clearance of antiangiogenic factors, activation of the complement system after birth, and/or mobilization of extracellular fluid into the intravascular system leading to volume overload, hypertension, and cerebral vasoconstriction [62,178,179].

Curettage may slightly accelerate the fall of the soluble fms-like tyrosine kinase-1 (sFlt-1) concentration by removing residual cytotrophoblast in the decidua basalis. Randomized trials have reported conflicting data about the value of curettage for hastening recovery from preeclampsia and eclampsia [180-183] and progression of prepartum preeclampsia to postpartum eclampsia has been reported after cesarean hysterectomy, suggesting fragments of retained placenta are not a causal factor [184]. Therefore, we recommend not performing postpartum curettage as an adjunctive treatment of the disorder.

Risk of maternal death — Patients with preeclampsia are at an increased risk for life-threatening obstetric or medical complications (cerebrovascular hemorrhage, pulmonary edema, acute kidney injury, liver rupture, abruption, eclampsia). Worldwide, 10 to 15 percent of direct maternal deaths (ie, resulting from obstetric complications of pregnancy) are associated with preeclampsia/eclampsia [185].

In the United States, preeclampsia/eclampsia is one of the four leading causes of maternal death, along with hemorrhage, cardiovascular conditions, and thromboembolism [186-188]. Among maternal deaths in the US that occurred during delivery hospitalization (2017 to 2019), approximately one-quarter had documented pregnancy-associated hypertension (gestational hypertension, preeclampsia, eclampsia, chronic hypertension with superimposed preeclampsia) and one-third had documented hypertension (chronic, pregnancy-associated, or unspecified) [189]. In previous US studies, there was approximately one maternal death due to preeclampsia/eclampsia per 100,000 live births, with a case-fatality rate of 6.4 deaths per 10,000 cases [190,191]. In low- and middle-income countries, the maternal mortality rate from preeclampsia is higher, approximately 40 per 100,000 live births in one study [192].

Maternal mortality is particularly high in patients with both preeclampsia and heart disease. In a worldwide prospective registry of nearly 6000 pregnancies in patients with heart disease, 172 developed preeclampsia and six of these patients died (3.5 percent); three of the deaths were from heart failure [193]. Maternal mortality was much less (0.6 percent) in those with no hypertensive disorder of pregnancy.

Fetal complications — For the fetus, preeclampsia can lead to growth restriction and oligohydramnios as well as medically or obstetrically indicated preterm birth. Fetal growth restriction results from inadequate placentation, usually associated with early-onset preeclampsia. As a result, perinatal morbidity and mortality are increased, with the highest risk in pregnancies with onset of preeclampsia before 34 weeks of gestation. Late-onset preeclampsia may not affect fetal growth. (See 'Potential sonographic findings' above.)

Long-term outcomes — Long-term maternal prognosis (recurrence risk, increased risk for related obstetric complications in future pregnancies, increased risk for cardiovascular and renal disease in later life) and long-term prognosis for offspring are reviewed separately. (See "Preeclampsia: Intrapartum and postpartum management and long-term prognosis", section on 'Prognosis'.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Hypertensive disorders of pregnancy".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topics (see "Patient education: Preeclampsia (The Basics)" and "Patient education: High blood pressure and pregnancy (The Basics)" and "Patient education: HELLP syndrome (The Basics)")

●Beyond the Basics topics (see "Patient education: Preeclampsia (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●Definitions/diagnosis

•Major hypertensive disorders of pregnancy – Definitions of the four major hypertensive disorders related to pregnancy (preeclampsia, chronic hypertension, preeclampsia superimposed upon chronic hypertension, and gestational hypertension) are summarized in the table (table 5). The approach to diagnosis of these disorders is shown in the algorithm (algorithm 1). (See 'Definitions/diagnostic criteria' above.)

•Diagnostic criteria for preeclampsia – The diagnostic criteria for preeclampsia are summarized in the table (table 1). Preeclamptic patients with severe hypertension or signs of significant end-organ dysfunction meet criteria for the severe end of the disease spectrum (table 2). (See 'Definitions/diagnostic criteria' above.)

•Differential diagnosis – Several other disorders can manifest some or many of the signs and symptoms of preeclampsia. Causes of hypertension include chronic hypertension, chronic kidney disease, pheochromocytoma, and use/withdrawal of some drugs. Hypertension with thrombocytopenia and/or elevated transaminases may be caused by acute fatty liver of pregnancy, thrombotic microangiopathy, systemic lupus erythematosus (SLE), or antiphospholipid syndrome (APS) (table 6). (See "Hypertensive disorders in pregnancy: Approach to differential diagnosis".)

●Risk factors – At the first prenatal visit, patients should be evaluated for traditional risk factors for preeclampsia (table 3) to identify those at high risk for developing the disease. High-risk factors include a past history of preeclampsia, multiple gestation, type 1 or type 2 diabetes, chronic hypertension, chronic kidney disease, or autoimmune disease with potential vascular complications (APS, SLE). Moderate risk factors include nulliparity, obesity, and family history of preeclampsia in a mother or sister. (See 'Risk factors' above.)

•Low-dose aspirin prophylaxis for high-risk patients – Patients at high risk are offered low-dose aspirin therapy beginning in the second trimester and continuing until birth to reduce their risk of developing preeclampsia. (See "Preeclampsia: Prevention", section on 'Candidates'.)

●Screening – At all provider visits throughout pregnancy, routine measurement of blood pressure to identify patients with preeclampsia is required. The value of any laboratory or imaging test as a screening tool, including routine assessment of proteinuria at each visit, has not been established. (See 'Screening and risk reduction' above.)

●Typical presentation and course of disease – The gradual development of hypertension and proteinuria in the last half of pregnancy is usually due to preeclampsia, particularly in a nulliparous patient. These findings typically become apparent after 34 weeks of gestation and progress until birth, but some patients develop symptoms earlier in gestation, intrapartum, or postpartum.

Patients with preeclampsia are at increased risk for life-threatening events, including placental abruption, acute kidney injury, cerebral hemorrhage, hepatic failure or rupture, pulmonary edema, stroke, cardiac failure, and progression to eclampsia. (See 'Spectrum of disease' above and 'Overview' above and 'Risk of maternal death' above.)

The fetus is at increased risk for growth restriction and medically or obstetrically indicated preterm birth. (See 'Fetal complications' above.)

Placental delivery always results in complete resolution of the maternal signs and symptoms of the disease over a variable period of time. (See 'Clinical presentation' above and 'Natural history/course of disease' above.)

•Atypical presentations – Atypical presentations include onset before 20 weeks or after the second postpartum day. Some patients initially present with gestational hypertension or proteinuria alone. Others present with significant end-organ dysfunction and minimal or even absent hypertension or proteinuria; these patients are classified as HELLP syndrome (hemolysis, elevated liver enzymes, low platelets). (See 'Rare and atypical presentations' above.)

●Diagnostic evaluation

•Laboratory – Patients with suspected preeclampsia should have a complete blood count with platelets, creatinine level, liver chemistries, and determination of urinary protein excretion. (See 'Laboratory tests' above and 'Potential laboratory findings' above.)

•Fetal status – Fetal status is assessed concurrently or postdiagnosis, depending on the degree of concern during maternal evaluation. At a minimum, a nonstress test or biophysical profile is performed if appropriate for gestational age. Ultrasound is used to evaluate amniotic fluid volume and estimate fetal weight, given the increased risk for oligohydramnios and growth restriction. (See 'Assessment of fetal status' above and 'Potential sonographic findings' above.)

•Consultation with the neurology service is generally indicated in patients with neurologic deficits/abnormal neurologic examination, which may include ocular symptoms or a severe persistent headache that does not respond to initial routine management of preeclampsia. (See 'When to obtain consultation' above.)