History

• Medical history
  • Patients may have a history of hypertension and/or preeclampsia during previous pregnancies ^c1c2c3c4c5
  • Patients may have coexisting medical conditions that increase risk (eg, diabetes mellitus, lupus, antiphospholipid antibody syndrome)
• Severity of symptoms ranges from mild to severe ^c6c7c8
  • Some patients may be asymptomatic at the time they are found to have hypertension and proteinuria, whereas others may present with symptoms of severe preeclampsia ^r10c9c10
  • Up to 25% of patients who develop eclampsia are asymptomatic before onset of seizures ^r11
• Timing of symptoms ^{r10c11c12c13c14c15}
  • Onset is gradual in some cases, whereas others proceed to life-threatening complications within hours
  • Preeclampsia and eclampsia may develop before, during, or after delivery
  • Approximately 40% of eclamptic seizures occur before delivery and approximately 16% occur more than 48 hours after delivery
• Evolving symptoms that develop as preeclampsia progresses include: ^r12
  • Epigastric pain accompanied by nausea and vomiting (reflects significant liver damage) ^c16c17
  • Fatigue and malaise ^c18c19
  • Severe headache with pounding or throbbing quality ^c20c21
  • Visual disturbances (eg, blurred vision, photophobia, diplopia) ^c22c23c24
    • May be related to hypertension or cerebral or retinal edema
  • Sudden-onset edema, pronounced in the face ^c25
  • Chest pain, cough, and dyspnea (with pulmonary edema) ^c26c27c28
  • Prolonged oliguria (urine output less than 500 mL/24 hours) ^c29
    • Suggests renal injury outside of pregnancy
• Symptoms that occur before an eclamptic episode include: ^r1
  • Persistent headache ^c30
  • Blurred vision ^c31
  • Right upper quadrant abdominal pain ^c32
  • Photophobia ^c33
  • Altered mental status ^c34

Physical examination

• Prenatal blood pressure measurements ^r10
  • Elevations range from mild to severe (equal to or greater than 160 mm Hg/90 mm Hg) ^c35
• Rapid weight gain and facial edema due to fluid retention ^r10c36c37
  • Signs are not unique to preeclampsia/eclampsia, but presence prompts assessment for proteinuria and hypertension
• Measured fundal height may be low for gestational age owing to intrauterine growth retardation ^r10c38
  • Typically occurs before diagnostic criteria of preeclampsia are met
• Tachypnea and crackles/rales if pulmonary edema develops ^r13c39c40
• Eclamptic seizures are noted by tonic-clonic seizures lasting for approximately 1 minute, followed by postictal coma of short duration ^r14c41c42

Causes

• Exact cause of preeclampsia/eclampsia is unknown, but its pathophysiology is linked to immunologic and angiogenic abnormalities in the placenta ^r2
  • Abnormal trophoblast invasion of decidual spiral arteries and myometrium ^r15c43c44
  • Diminished uteroplacental circulation, leading to ischemia and oxidative stress in the placenta ^r15c45c46
  • Poor development of the fetoplacental vasculature ^r15c47
  • Secretion of angiogenic factors into the maternal circulation, resulting in hypertension and proteinuria ^r16c48c49

Risk factors and/or associations

Primary diagnostic tools ^c69

• Diagnosis is typically pursued and further investigated when elevated blood pressures are found at prenatal obstetric appointments in pregnant patients after 20 weeks of gestation ^r5
• Diagnosis requires measurements of blood pressure and proteinuria along with clinical and laboratory assessments to determine presence of end-organ involvement
  • Note: all pregnant patients with new-onset high blood pressure or worsening of preexisting high blood pressure after 20 weeks of gestation should undergo laboratory evaluation ^r5
  • Blood pressure ^r21
    • Systolic blood pressure above 140 mm Hg, diastolic blood pressure above 90 mm Hg, or both, meet blood pressure criteria for preeclampsia ^r2
    • Blood pressure readings above 160/110 mm Hg meet blood pressure criteria for severe preeclampsia ^r2
    • Manage a pregnant patient who presents with hypertension after 20 weeks of gestation whose prepregnancy or earlier blood pressures are unknown as if they have gestational hypertension or preeclampsia
    • Blood pressure technique ^c70
      • Must document at least 2 measurements of high blood pressure taken at least 4 hours apart ^r21
      • Patient must be sitting and should rest for 5 minutes before measurement; cuff must fit properly and be placed on bare upper arm ^r21
      • Blood pressure can be measured using auscultatory devices or automated methods ^r21
  • Proteinuria ^r5c71
    • Assess quantitatively by measuring urine protein after either a 12- or 24-hour urine collection, or by using a spot measurement of protein to creatinine ratio ^c72c73
      • Urine protein dipstick test may be administered if other methods of measurement are not available (reading of 2+ meets diagnostic parameter of proteinuria) ^r2c74
  • Other maternal end-organ dysfunction ^r5
    • CBC with peripheral smear ^c75c76
    • Comprehensive metabolic panel, including renal and liver function tests (include serum creatinine clearance and uric acid level) ^c77
• Formal diagnosis of preeclampsia is made when the following criteria are met: ^r2
  • Hypertension (greater than 140 mm Hg systolic or 90 mm Hg diastolic) and 1 of the following: ^c78
    • Proteinuria (greater than 300 mg of protein in a 24-hour urine collection, or spot protein to creatinine ratio of 0.3) ^c79c80c81
    • 1 or more of the following markers of maternal end-organ dysfunction:
      • Thrombocytopenia (platelet count under 100 × 10⁹ cells/L) ^c82
      • Impaired liver function (transaminases twice the upper reference limit) ^c83c84
      • New renal insufficiency (over 1.1 mg/dL or doubling of serum creatinine clearance) ^c85
      • Pulmonary edema ^c86
      • New-onset cerebral or visual disturbances ^c87c88c89c90
• In a pregnant patient with chronic hypertension, do not diagnose preeclampsia with a rise in blood pressure alone. When there is underlying essential hypertension, diagnose preeclampsia by the presence of proteinuria or by documenting the presence of end-organ dysfunction
• Formal diagnosis of eclampsia
  • Eclampsia is diagnosed if new-onset seizures occur in setting of hypertensive disorders of pregnancy ^c91
• Assess fetal well-being with nonstress test and ultrasonographic evaluation to estimate fetal weight and amniotic fluid index; biophysical profile is indicated if nonstress test findings are nonreactive ^r22c92
  • In potentially unstable situations, fetal monitoring is always performed first using bedside ultrasonography
• Determine if patient is in labor and evaluate cervix with Bishop score ^r7

Laboratory

• Urine protein measurement ^c93
  • Preeclampsia proteinuria criterion met with 1 of the following: ^r2
    • Quantitative urine protein greater than 300 mg over a 24-hour period
      • Accuracy of a 12-hour urine collection is similar to that of 24-hour collection and can be substituted as it is less burdensome ^r23
      • 12-hour results are doubled
    • Protein urine dipstick reading of 2+ (only if quantitative measurement is not available) ^c94
    • Spot urine protein to creatinine ratio of at least 0.3
• Serum chemistry
  • Renal function panel ^c95
    • Serum creatinine measurement (greater than 1.1 mg/dL or doubling of serum creatinine level^r2) is a diagnostic parameter for maternal organ dysfunction ^r12c96
    • Uric acid level ^c97c98
      • Not required, but an increase is associated with renal failure and adverse maternal and perinatal outcomes ^r12
  • Liver function tests ^c99
    • ALT or AST level that is twice the upper reference limit is a diagnostic parameter for maternal organ dysfunction ^r2c100c101
    • Lactate dehydrogenase level ^c102c103
      • Not required, but elevated levels can be a marker of hemolysis ^r12
    • Bilirubin level ^c104c105c106
      • Not required, but increased levels may reflect hemolysis or liver dysfunction ^r12
    • Albumin level ^c107c108
      • Not required, but may be decreased in association with liver failure ^r12
• CBC panel ^c109
  • Thrombocytopenia indicated by a platelet count of less than 100 × 10⁹ cells/L is a diagnostic parameter for maternal organ dysfunction ^r2
  • Hemoglobin level may be increased owing to intravascular volume depletion or decreased owing to microangiopathic process ^r12
    • Microangiopathic hemolytic anemia on review of peripheral blood smear showing RBC fragmentation is a finding in HELLP syndrome

Imaging

• Fetal ultrasonography ^r24c110
  • All patients diagnosed with preeclampsia should have fetal ultrasonography to assess for suboptimal fetal growth ^r25
  • Measurements of biparietal diameter, head circumference, abdominal circumference, and femur length are commonly used to identify intrauterine growth restriction that may be associated with preeclampsia ^r24
    • An abnormal (increased) ratio of head circumference to abdominal circumference is common
  • Other findings include decreased volume of amniotic fluid (index obtained by summing the largest cord-free vertical pocket in each of the 4 quadrants of an equally divided uterus) ^r24

Functional testing

• Pulse oximetry ^r12c111
  • Not required to make a diagnosis, but a measurement of oxygen saturation at the time of diagnostic investigation can indicate likelihood of complications developing owing to preeclampsia
  • Oxygen saturation less than 97% is associated with a risk of severe maternal complications (eg, pulmonary hypertension, peripartum cardiomyopathy, pulmonary embolism)

Other diagnostic tools

• Additional laboratory studies and imaging may be needed to determine disease severity and to identify associated components of multisystemic disease ^r5
  • If oxygen saturation (measured via pulse oximetry) is reduced, or if there are abnormal pulmonary or cardiac findings, order a chest radiograph and ECG and/or echocardiogram ^c112c113c114
  • MRI or CT scan of the brain is indicated if intracranial hemorrhage, cerebral thrombosis, or posterior reversible encephalopathy syndrome is suspected ^c115c116
    • Presence of focal neurologic deficits ^r7c117c118
    • Repeated seizures despite adequate magnesium levels ^r7c119c120
    • Presence of blindness ^r7c121c122
    • Onset of eclamptic seizures before 20 weeks of gestation or after 48 hours postpartum ^r7c123c124
  • If abdominal pain is present and liver function test results are abnormal, order abdominal imaging (ultrasonogram or CT) to evaluate for liver hematoma ^c125c126

Most common

• Gestational hypertension ^r20c127
  • De novo development of high blood pressure after 20 weeks of gestation without proteinuria or other features of preeclampsia, which also resolves by 12 weeks postpartum
  • Similar to preeclampsia in that elevated blood pressure develops in the second half of pregnancy
  • Differentiated from preeclampsia by absence of proteinuria and absence of end-organ dysfunction (ie, no renal or liver dysfunction, thrombocytopenia, pulmonary edema, or cerebral or visual abnormalities)
• Prepregnancy-onset (chronic) hypertension ^r20c128d2
  • Elevations in blood pressure (greater than 140 mm Hg systolic and/or 90 mm Hg diastolic) that develop before pregnancy, or before the 20th week of gestation, or that persist beyond 12 weeks postpartum
  • Similar to preeclampsia by virtue of elevated blood pressures
  • Formally differentiated from preeclampsia by time course
    • Identify date of onset or document persistence of hypertension postpartum
  • Note: preeclampsia can occur superimposed on chronic or preexisting hypertension
• HELLP syndrome ^c129c130d1
  • A combination of hemolysis, elevated liver enzymes, and thrombocytopenia that occurs in the third trimester of pregnancy or postpartum
  • The relationship between preeclampsia and HELLP syndrome is debated; HELLP syndrome may represent a severe form of preeclampsia and there is significant overlap in clinical and biochemical features
  • Similarly to preeclampsia, HELLP syndrome symptoms can include headache, epigastric abdominal pain, and visual disturbances; however, neither hypertension nor proteinuria are required for a diagnosis of HELLP syndrome
  • HELLP syndrome is distinguished from preeclampsia by evidence of a microangiopathic hemolytic anemia (schistocytes) on peripheral blood smear
    • Additional criteria for HELLP syndrome include thrombocytopenia (platelet count of 100 × 10⁹ cells/L or higher), total bilirubin level of 1.2 mg/dL or higher, and serum AST and/or ALT level twice the upper reference limit
• Systemic lupus erythematosus (exacerbation) ^r26c131d3
  • Type 3 hypersensitivity reaction in which the body produces autoantibodies, most commonly antinuclear autoantibodies; a high percentage of patients will experience lupus nephritis
  • Similarly to preeclampsia, systemic lupus erythematosus with lupus nephritis presents with proteinuria
  • Unlike preeclampsia, systemic lupus erythematosus with lupus nephritis presents with a characteristic rash, joint pain, and fever, whereas blood pressure is often within reference range
  • Systemic lupus erythematosus is distinguished from preeclampsia by blood pressure measurements and laboratory testing for autoantibodies
• Antiphospholipid antibody disease ^r27c132
  • Autoimmune condition complicated by multiple episodes of arterial and venous thromboses, which may lead to morbidity in pregnancy (ie, recurrent miscarriages, fetal deaths)
  • Antiphospholipid antibody disease can mimic preeclampsia by virtue of fetal intrauterine growth restriction, which may occur in both
  • Antiphospholipid antibody disease also serves as a risk factor for preeclampsia, or
  • Antiphospholipid antibody disease alone (without meeting criteria for preeclampsia) can cause premature delivery of a fetus owing to placental insufficiency
  • The following laboratory criteria for antiphospholipid antibody disease must be met to make a diagnosis:
    • Presence of antiphospholipid antibodies on 2 or more occasions at least 12 weeks apart and no more than 5 years before clinical manifestations with 1 or more of the following present: ^r28
      • Lupus anticoagulant
      • Medium- to high-titer (40 or more IgG phospholipid units or IgM antiphospholipid units, or over 99th percentile) anticardiolipin IgG or IgM
      • Anti-β2 glycoprotein-I IgG or IgM over 99th percentile
  • Negative test results for antiphospholipid antibodies exclude this disorder
• Mirror syndrome ^r29c133
  • Rare condition characterized by maternal edema in conjunction with fetal hydrops
  • Similarly to preeclampsia, mirror syndrome presents with hypertension and proteinuria
  • Mirror syndrome usually occurs during the first 2 trimesters of pregnancy and is identified by fetal ultrasonography ^r5
  • Distinguishing between preeclampsia and mirror syndrome in the presence of hypertension and proteinuria requires ruling out fetal hydrops or twin-to-twin transfusion syndrome

Admission criteria

All patients should be assessed in hospital initially; some may be managed as outpatients providing their condition is stable and the patient can reliably monitor their blood pressure and report problems ^r9

Admit patients with severe manifestations (eg, severely elevated blood pressure, unstable neurologic findings) or those who are unable to be monitored adequately as an outpatient ^r2

Recommendations for specialist referral

• Patients diagnosed with preeclampsia should have an integrative care plan managed by obstetricians and perinatologists
• Refer to specialists in maternal fetal medicine, hypertension, anesthesiology, or critical care if blood pressure is resistant to first line pharmacotherapy ^r26r31
• Refer to anesthesiologist to plan neuraxial analgesia or anesthesia during labor for patients undergoing cesarean delivery ^r1

Drug therapy

• First line antihypertensive agents for severe hypertension ^r5c134
  • Most labor units have standard protocols in place for labetalol, hydralazine, or nitroprusside drip, if needed
  • Labetalol (immediate or emergent therapy for acute-onset hypertension) ^c135
    • Labetalol Hydrochloride Solution for injection; Adults: 10 to 20 mg IV, then 20 to 80 mg IV every 10 to 30 minutes until goal blood pressure is attained. Max cumulative dose: 300 mg.
    • Labetalol Hydrochloride Solution for injection; Adults: 10 to 20 mg IV, then 0.5 to 2 mg/minute continuous IV infusion initially. Titrate every 15 minutes until goal blood pressure is attained. May repeat or double bolus dose after 10 minutes before starting infusion. Max: 10 mg/minute. Max cumulative dose: 300 mg.
  • Hydralazine (immediate or emergent therapy for acute-onset hypertension) ^c136
    • Hydralazine Hydrochloride Solution for injection; Adult females: 5 to 10 mg IV over 2 minutes for SBP of 160 or more or DBP of 110 or more mmHg. Check BP in 20 minutes and if either BP threshold is exceeded, give 10 mg IV over 2 minutes. Check BP in 20 minutes and if either threshold is exceeded, switch to labetalol 20 mg IV over 2 minutes and check BP in 10 minutes. If either BP threshold is exceeded, give labetalol 40 mg IV over 2 minutes, obtain emergency consultation, and give additional antihypertensive medication per specific order. Once SBP is less than 160 and DBP is less than 110, check BP every 10 minutes for 1 hour, then every 15 minutes for 1 hour, then every 30 minutes for 1 hour, and then every hour for 4 hours.
  • Nifedipine ^c137
    • Immediate-release oral nifedipine may be considered as a first line therapy when IV access is not available. ^r2r41
      • Initiate fetal heart rate monitoring before first dose.
      • Nifedipine Oral capsule; Pregnant females: 10 to 20 mg PO every 20 minutes as needed for 2 doses; then 10 to 20 mg PO every 2 to 6 hours as needed. Maximum: 180 mg/day. ^r2r41
    • Used with caution (if at all) if patient is concurrently receiving magnesium sulfate owing to risk of hypotension and neuromuscular blockade when combined. ^r5
  • Sodium nitroprusside ^c138
    • Reserve for extreme emergencies (last resort), and use for the shortest time possible owing to risk of maternal/fetal cyanide toxicity and other possible adverse effects. ^r6
    • Sodium Nitroprusside Solution for injection; Adults: 0.3 to 0.5 mcg/kg/minute continuous IV infusion, initially. Titrate by 0.5 mcg/kg/minute every 5 minutes until desired effect or blood pressure cannot be further reduced without compromising organ perfusion. Max: 10 mcg/kg/minute for 10 minutes.
• Second line agents for severe hypertension
  • Esmolol ^c139
    • Esmolol Hydrochloride Solution for injection; Adults: 500 to 1,000 mcg/kg IV over 1 minute, then 50 mcg/kg/minute continuous IV infusion, initially. Repeat bolus and titrate by 50 mcg/kg/minute until goal blood pressure is attained. Max: 200 mcg/kg/minute.
  • Nicardipine ^c140
    • Nicardipine Hydrochloride Solution for injection; Adults: 5 mg/hour continuous IV infusion, initially. Titrate by 2.5 mg/hour every 5 to 15 minutes until goal blood pressure is attained. Max: 15 mg/hour.
• First line agents for long-term control of blood pressure
  • Labetalol ^c141
    • Avoid in asthma, heart disease, congestive heart failure, or if maternal heart rate is less than 60 beats per minute. ^r5
    • Labetalol Hydrochloride Oral tablet; Adults: 100 mg PO twice daily, initially. Titrate dosage by 100 to 200 mg twice daily every 2 to 3 days until goal blood pressure is attained. Usual dose: 200 to 400 mg twice daily. Max: 2,400 mg/day.
  • Nifedipine ^c142c143
    • Nifedipine Oral tablet, extended-release; Adults: Initially, 30 to 60 mg PO once daily. Max: 90 mg/day for most extended-release products; 120 mg/day for Procardia XL.
  • Methyldopa ^r5c144
    • May be less effective in controlling higher blood pressures than other commonly used medications.
    • Methyldopa Oral tablet; Adults and Adolescents: Initially, 250 mg PO given 2—3x/day. The usual dosage is 500—2000 mg/day PO, given in 2—4 divided doses. Max 3 g/day PO.
• Second line agent for long-term control of blood pressure
  • Thiazide diuretics ^r5c145
    • Use with caution owing to potential for intravascular volume depletion and hypokalemia.
    • Hydrochlorothiazide Oral tablet; Adults: Initially, 12.5 to 25 mg PO once daily. Increase up to 50 mg/day PO given in 1 to 2 divided doses.
• Corticosteroids ^c146c147
  • Betamethasone ^c148
    • Antenatally, to induce fetal lung maturation in preparation for premature delivery.
    • Betamethasone is the most well-studied and preferred corticosteroid for fetal lung maturation.
      • Betamethasone Acetate, Betamethasone Sodium Phosphate Suspension for injection; Pregnant females: 12 mg IM every 24 hours for 2 doses in all pregnant women between 24 and 34 weeks gestation who are at risk for preterm delivery within 7 days; administer first dose even if ability to administer second dose is unlikely. Consider therapy starting at 23 weeks gestation for pregnant women who are at risk of preterm delivery within 7 days. Consider a repeat or rescue course in women who are less than 34 weeks gestation, at risk of preterm delivery within the next 7 days, and prior course of antenatal corticosteroids was administered more than 14 days previously. Rescue course could be provided as early as 7 days from the prior dose if indicated by clinical situation.
  • Dexamethasone ^c149c150
    • For HELLP syndrome:
      • Dexamethasone Sodium Phosphate Solution for injection; Adults: 10 mg IV every 12 hours for 48 hours has been reported. ^r37
    • For preeclampsia:
      • Antenatally, to promote fetal pulmonary maturity when delivery is anticipated within the next 7 days and gestational age is less than 34 weeks. ^r37
      • Acceptable alternative to betamethasone for fetal lung maturation.
• Anticonvulsant (for both treatment and prophylaxis) ^c151
  • Magnesium sulfate ^r42c152
    • Dosage schedule for severe preeclampsia is the same as for eclampsia. ^r40
    • Continue magnesium sulfate for at least 24 hours after delivery, after the last seizure, or both. ^r7
    • Has been associated with an increased risk of postpartum hemorrhage and uterine atony in observational studies; however, this has not been confirmed in randomized trials. ^r43
    • Magnesium Sulfate Solution for injection; Adults: 4 to 6 g IV loading dose followed by a maintenance dose of 1 to 2 g/hour IV for at least 24 hours. Max: 30 to 40 g/day.
• Low-dose aspirin prophylaxis for prevention of preeclampsia ^r44
  • Indicated in patients at high risk and should be initiated between 12 and 28 weeks gestation (optimally before 16 weeks).
    • High-risk status includes any of the following: history of preeclampsia, multifetal gestation, chronic hypertension, type 1 or 2 diabetes, renal disease, or autoimmune disease (systemic lupus erythematosus, the antiphospholipid syndrome).
  • Can be considered in patients at moderate risk if more than 1 of the following risk factors is present:
    • Nulliparity, BMI greater than 30, family history of preeclampsia (mother or sister), sociodemographic characteristics (African American race, low socioeconomic status), age 35 years or older, or personal history factors (eg, low birth weight or small for gestational age, previous adverse pregnancy outcome, more than 10-year pregnancy interval)
  • Aspirin Oral tablet; Adult Females: 81 mg PO once daily starting at 12 weeks of gestation.

Nondrug and supportive care

Fluid management ^r1c153

• Resuscitation ^r45
  • Restrict fluid to a maximum of 80 mL/hour when IV is inserted ^r1
  • Titrate to systolic blood pressure above 90 mm Hg ^r45
• Maintenance ^r45
  • NPO status (60-80 mL/hour crystalloid) ^r45
• Preloading ^r45
  • Fluid challenge before vasodilation or regional anesthesia: administer volume expanders (300 mL crystalloid) ^r45

Bed rest is not indicated as a form of management ^r2r8

Special populations

• Patients with preeclampsia superimposed on chronic or prepartum hypertension
  • Preeclampsia can occur superimposed on chronic or preexisting hypertension that is often identified owing to worsening control of blood pressure
  • In these patients, superimposed preeclampsia is identified by de novo proteinuria and/or end-organ dysfunction in the second half of pregnancy
• Patients with HELLP syndrome ^r2
  • If gestational age is before fetal viability, proceed to delivery shortly after maternal stabilization
  • At 34 weeks of gestation and beyond, proceed to delivery soon after maternal stabilization
  • From gestational age of fetal viability up until 34 weeks of gestation, delay delivery for 24 to 48 hours to complete a course of corticosteroids for fetal benefit if possible
• Postpartum preeclampsia ^r49
  • New-onset hypertension developing 48 hours to 6 weeks after delivery; usually within the first 7 to 10 days
  • Most patients present with headache or other neurologic symptoms; other symptoms include shortness of breath, chest pain, and peripheral edema
    • Consider neuroimaging to exclude other causes of postpartum headache such as stroke or posterior reversible cerebral encephalopathy, or subarachnoid hemorrhage
  • Less frequently detected based on routine home or in-office blood pressure monitoring
  • Treatment consists of antihypertensive agents and magnesium as for preeclampsia of antenatal onset; diuresis is indicated for volume overload if present
  • May be associated with a higher risk of maternal morbidity than preeclampsia with antepartum onset

At-risk populations ^r56

• Patients with previous pregnancies complicated by preeclampsia, and especially those who had adverse outcomes
• Patients with:
  • Type 1 or type 2 diabetes
  • Chronic hypertension
  • Chronic kidney disease
  • Multifetal gestation
  • Autoimmune disease

Screening tests

• Screen all pregnant patients with routine measurement of blood pressure and obtain medical history to identify relevant risk factors ^{r2r57c200c201}
• Screening tests to predict development of preeclampsia—including use of biomarkers and Doppler ultrasonographic characteristics—are not currently recommended outside of investigational settings in the United States ^r2r22r58
• In the first trimester, a combination of maternal risk factors, blood pressure, placental growth factor, and uterine artery Doppler findings may be used to identify patients who may benefit from low-dose aspirin to prevent preeclampsia developing before 37 weeks of gestation (but not preeclampsia at term); the International Society for the Study of Hypertension in Pregnancy supports this approach, although cost effectiveness is unclear ^{r9c202c203c204}