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Etiology and PathogenesisTop
Preeclampsia is a pregnancy-specific syndrome characterized by new-onset or worsening hypertension after 20 weeks’ gestation associated with new or increasing proteinuria and/or evidence of end-organ involvement. Fetal manifestations may occur with, precede, or occur in the absence of maternal manifestations.
While the pathophysiology of preeclampsia is still incompletely understood, it is likely related to abnormal placentation occurring in the first trimester. Failure of the spiral arteries in the placental bed to undergo remodeling may cause uteroplacental ischemia and abnormal perfusion, leading to local and systemic inflammation. The fact that the majority of preeclampsia resolves rapidly after delivery is a testament to the role of the placenta; however, evolving evidence suggests that maternal cardiovascular maladaptation may also play a more causal role than it was previously thought.
Risk factors for preeclampsia: Preeclampsia likely involves a genetic predisposition. Individuals with a family history (mother or sister) of preeclampsia are at a heightened risk. Other risk factors include a previous history of preeclampsia, obesity (body mass index >30), age >40 years, multiple pregnancy, autoimmune disease, preexisting kidney disease, chronic hypertension, diabetes mellitus, assisted reproduction, and antiphospholipid antibodies. Some other factors include first pregnancy, Black populations, age >35 years, >10-year pregnancy interval, family history, new partner, and a previous adverse pregnancy outcome. Women felt to be at risk for preeclampsia should be started on acetylsalicylic acid (ASA) (see Eclampsia).
The maternal syndrome of preeclampsia is a systemic syndrome associated with endothelial injury, which can result in vasoconstriction, capillary leak, and activation of the coagulation system. The effect on maternal organ systems can be quite variable (see below).
The fetal syndrome can be characterized by intrauterine growth restriction (IUGR), oligohydramnios, asymmetric growth, or abnormalities in the uterine and umbilical arteries on ultrasonography. All individuals with suspected preeclampsia should have a fetal and placental assessment by an obstetrician.
Clinical Features and DiagnosisTop
A diagnosis of preeclampsia requires the following:
1) Systolic blood pressure (SBP) ≥140 mm Hg or diastolic blood pressure (DBP) ≥90 mm Hg on 2 occasions at least 4 hours apart after 20 weeks’ gestation, or one-time SBP ≥160 mm Hg or DBP ≥110 mm Hg; and
2) At least one of the following:
a) Proteinuria >0.3 g/d in a 24-hour urine collection, protein-to-creatinine ratio >30 mg/mmol in a spot urine sample, or, if not available, urine analysis with >1+ protein.
b) Evidence of end-organ dysfunction (see below).
Note that not all patients with these clinical features have preeclampsia (eg, patients with diabetic nephropathy or other underlying renal disease). In these cases, consultation with a specialist with considerable experience in preeclampsia is often warranted.
In patients without proteinuria, the diagnosis of preeclampsia requires at least one of the following criteria for end-organ dysfunction:
a) Symptoms and signs: Headache and vision changes, marked hyperreflexia.
b) Severe manifestations: Irritability, cortical blindness (rare), altered mental status (Glasgow Coma Scale <13 [see Table 3.3-1]), sustained ankle clonus, stroke, eclampsia.
c) Investigations: Radiologic evidence of intracerebral hemorrhage, posterior reversible encephalopathy syndrome, or reversible cerebral vasoconstriction syndrome (however, imaging is frequently normal).
a) Symptoms and signs: Bleeding or bruising, platelets count <100×109/L.
b) Severe manifestations: Platelet count <50×109/L, transfusion of any blood product.
c) Investigations: Thrombocytopenia, hemolysis (elevated lactate dehydrogenase or indirect bilirubin, decreased haptoglobin).
a) Symptoms and signs: Decreased urine output.
b) Severe manifestations: Acute kidney injury with creatinine >150 micromol/L, decreased urine output or oliguria despite 500 mL trial of fluids, new indication for dialysis.
c) Investigations: Acute kidney injury (serum creatinine levels >100 micromol/L or a 2-fold increase compared with the baseline value indicates severe disease), acutely elevated uric acid levels.
a) Symptoms and signs: Epigastric and/or right upper quadrant pain, nausea or vomiting.
b) Severe manifestations: Hepatic hematoma or rupture.
c) Investigations: Liver cell damage (serum aminotransferase levels ≥2 × upper limit of normal).
a) Symptoms and signs: Shortness of breath, cough.
b) Severe manifestations: Oxygen saturation <90%, intubation, pulmonary edema.
c) Investigations: Pulmonary edema on radiologic imaging.
a) Symptoms and signs: Angina-like chest pain, dyspnea.
b) Severe manifestations: Uncontrolled severe hypertension (inability to control after >12 hours or requiring 3 antihypertensive drugs).
c) Investigations: Heart failure (reduced left ventricular ejection fraction, diastolic dysfunction), elevated troponin levels.
a) Fetal manifestations: Intrauterine growth restriction (IUGR), abnormal fetal heart rate, oligohydramnios, stillbirth.
b) Uterine artery manifestations: Absent or reversed end-diastolic flow, uterine artery nicking.
c) Investigations: Fetal ultrasonography and uterine artery ultrasonography.
Biochemical markers in the prediction and diagnosis of preeclampsia: Specific angiogenic factors implicated in the pathogenesis of preeclampsia can be measured but are not yet widely available in North America. These include the antiangiogenic soluble fms-like tyrosine kinase-1 (sFlt-1) and angiogenic placental growth factor (PlGF). Normal levels of circulating PlGF have been found to have a high negative predictive value in excluding suspected preeclampsia between 20 to 35 weeks’ gestation and the role of these assays as an adjunct to usual clinical practice is supported in many countries.
HELLP syndrome: The syndrome of HELLP (hemolysis, elevated liver enzymes, low platelets) is most often seen in preeclampsia but can occur in other situations, for example, in placental abruption, amniotic fluid embolism, or septicemia. The exact pathophysiology of HELLP is unclear, but it is considered a subtype of severe preeclampsia. The majority of individuals have hypertension with proteinuria, but some may have hypertension or proteinuria or, rarely, neither. The management of the HELLP syndrome is the same as in preeclampsia.
Key diagnostic studies to look for evidence of end-organ dysfunction: Table 15.3-10.
Preeclampsia is a progressive disease that will resolve only with delivery of the placenta. However, if this syndrome occurs before term, the risk of continued pregnancy to the mother must be weighed against the risk to the baby from preterm delivery. For this reason, the management of preeclampsia should not be undertaken without close partnership with an obstetrician, as it is the obstetrician who is usually best equipped to weigh the risks and benefits of expediting delivery versus expectant management. Before 37 weeks’ gestation, this is a complex decision that is outside the scope of this chapter. In general, however, those who are likely to deliver prior to 34 weeks’ gestation will receive betamethasone for fetal lung maturation. After 37 weeks’ gestation, treatment is almost always delivery of the baby. The diagnosis of preeclampsia is not an indication for cesarean section if not otherwise required for obstetric indications.
Urgent delivery, regardless of gestational age, is often indicated in the presence of preeclampsia with any of the following severe manifestations: eclampsia, severe fetal compromise (severe IUGR, reversed diastolic umbilical artery flow), cortical blindness, stroke, platelets <50×109/L, acute kidney injury (creatinine >110 micromol/L with no prior disease), inability to control hypertension after >12 hours on >3 antihypertensive agents.
Supportive management is directed towards mitigating the effects of vasoconstriction, capillary leak, and systemic inflammation. The priorities for management are therefore:
1) Vasodilation (vasodilators).
2) Restoration of intravascular volume (if depleted).
3) Clotting factor replacement if depleted (rarely needed).
Increased blood pressure needs to be reduced to safe levels (usually <160 mm Hg SBP and 110 mm Hg DBP). Treatment should be initiated promptly but then titrated to produce a steady rather than precipitous decrease to target levels (see Table 15.3-3). Blood pressure lowering may be augmented by volume expansion (see below), magnesium sulfate, and epidural or spinal anesthesia, so antihypertensive therapy needs to be adjusted with these factors taken into consideration. Subsequent longer-term antihypertensive treatment is usually required (see Table 15.3-2).
The goal of treatment of severe hypertension is to reduce the maternal risk of stroke. Treatment does not alter the course of preeclampsia.
Many individuals with preeclampsia associated with vasoconstriction have intravascular hypovolemia when they present. This aggravates vasoconstriction, increases hypertension and organ ischemia, and increases the risk of acute kidney injury. Volume expansion can reduce the overall systemic vascular resistance, improving blood pressure control and ischemia, but may result in fluid overload. The optimum management remains controversial. Usually at least 500 mL to 1 L of normal saline or Ringer solution can be given quickly; however, the administration of fluids should be associated with meticulous input/output documentation, so as to avoid inadvertent volume overload. Clinical assessment of the jugular venous pressure and point-of-care lung ultrasound are important guides to intravascular volume when fluids are administered. In severe cases, colloid replacement could be considered, especially if the serum albumin level is very low (<20 g/L). A urine output >30 mL/h usually indicates adequate intravascular volume, but not if the woman is receiving magnesium (osmotic diuretic effect). The volume management of patients with preeclampsia that is associated with pulmonary capillary leak (causing pulmonary edema) can be extremely difficult. In such situations, we would recommend consultation and transfer of the patient to a high acuity care ward (an intensive care or a step-down unit) before the administration of fluids is considered.
Otherwise, supportive management is directed at the affected organ systems:
1) Neurologic: Prevention or treatment of seizures: Anticonvulsant treatment (usually magnesium sulfate) is indicated for seizures and also for signs of cerebral irritability (agitation, visual scotomata, clonus). Treatment: see Eclampsia.
Red flags: Confusion and obtundation (except in the immediate postictal phase) and fixed neurologic deficits are rarely seen; these should be investigated with imaging of the brain.
a) Thrombocytopenia, even severe (platelets <25×109/L), is not usually associated with a major risk of hemorrhage. As platelet transfusion is a consumptive process, the life-span of transfused platelets is very short (minutes), so this measure should be reserved for situations when treatment of active bleeding is required (eg, after the baby is delivered by cesarean section). Red flag: The platelet count will usually begin to rise by 48 hours following delivery of the placenta. If not, thrombotic thrombocytopenic purpura or hemolytic-uremic syndrome (HUS) need to be considered.
b) Hemolysis: This rarely requires transfusion. While hemolysis is microangiopathic, any associated disseminated intravascular coagulation (DIC) is of greater concern.
c) Coagulation: A small decrease in fibrinogen and increase in the international normalized ratio (INR) may be seen in patients with severe preeclampsia and DIC. Close monitoring for progression is vital. Red flag: Fibrinogen <1.5 g/L implies serious defibrination. A prolonged INR (>1.3) is rare in preeclampsia and usually indicates severe liver dysfunction (acute fatty liver of pregnancy needs to be considered). Prompt clotting factor replacement in these situations may be life-saving.
3) Renal: Correcting the intravascular volume deficit is a priority to mitigate acute kidney injury.
Red flag #1: Oliguria (urine output <25 mL/h) should be treated with volume expansion unless or until there are definite signs of left ventricular failure. Furosemide is not appropriate in such cases and may in fact worsen oliguria.
Red flag #2: Serum creatinine may increase up until 48 hours post partum before stabilizing and decreasing. An increase after this period is of serious concern, warranting consideration of an alternative renal diagnosis (eg, complement-mediated HUS).
Red flag #3: Polyuria (>3 L/d) may simply be due to clearance of excess extravascular water as the woman recovers from preeclampsia. However, it may be due to renal tubular dysfunction (acute tubular necrosis) and may precipitate secondary severe hypovolemia a few days after delivery. Monitoring jugular venous pressure and serum creatinine levels is helpful.
4) Hepatic: Serum transaminases may be markedly elevated (10-20 times the upper limit of normal) due to ischemic liver cell injury. This usually begins to resolve promptly as perfusion is improved (vasodilators and volume expansion).
Red flag #1: Jaundice is relatively uncommon and usually associated with the combination of severe hemolysis, DIC, and often liver dysfunction.
Red flag #2: The INR is usually normal or only slightly raised in preeclampsia. An INR >1.3 suggests significant liver dysfunction (such as can occur with acute fatty liver of pregnancy). The coagulation defect is the greatest threat and requires prompt treatment.
5) Respiratory: Pulmonary edema is primarily due to capillary leak and possible diastolic dysfunction; it may be aggravated by reduced plasma oncotic pressure due to reduced serum albumin levels. Left ventricular failure or fluid overload is rarely a factor. Management is aimed at maintaining adequate oxygenation, adding positive airway pressure if necessary. Volume restriction and diuretics are usually unhelpful in such situations and indicated only for pulmonary edema not responding to oxygen or positive airway pressure.
6) Cardiac: Myocardial cell injury (increased troponin and cardiac enzymes) is not uncommon as a consequence of preeclampsia-induced ischemia. This usually resolves quickly with improved perfusion/vasodilation. Coronary arteriography is rarely indicated.
Red flag: Heart failure is rare but can occur as a consequence of “stunned myocardium,” diastolic dysfunction, or both. Cardiac ultrasonography is invaluable in identifying left ventricular failure (reduced ejection fraction) and wall motion abnormalities. Diuretics are indicated if heart failure is demonstrated.
Preeclampsia Phenotypes and Targeted Antihypertensive Therapy
Evolving evidence has identified 2 different phenotypes of preeclampsia, with fetal growth restriction being the key distinguishing factor. These 2 phenotypes have opposite underlying cardiovascular hemodynamic profiles with regard to maternal cardiac output and peripheral vascular resistance. While fetal growth restriction can occur at any gestation, it is more commonly seen with early-onset preeclampsia.
In the early-onset preeclampsia phenotype, maladaptive maternal cardiovascular changes can be seen before the development of overt disease. Cardiac output is low with high peripheral vascular resistance. This is the opposite of the second phenotype, which typically has a later onset, with an increased cardiac output and low peripheral vascular resistance.
The emergence of these 2 divergent preeclampsia phenotypes suggests that initial antihypertensive therapy may be targeted towards the underlying maternal hemodynamic profile. In early-onset preeclampsia with fetal growth restriction, the low cardiac output and high peripheral vascular resistance may respond better to long-acting calcium channel blockers given their vasodilatory effect. In late-onset preeclampsia with high cardiac output and low peripheral vascular resistance, the negative chronotropic effects of beta-blockers may be more beneficial to improve maternal hemodynamics.
Tailoring antihypertensive therapy to the underlying maternal hemodynamic profile is an emerging frontier in preeclampsia research. Current first-line therapies include labetalol, nifedipine, and methyldopa, with the most important management principle being to reduce maternal blood pressures to nonsevere levels.
Follow-up is the same as in eclampsia.
Although delivery of the placenta usually results in the resolution of preeclampsia, there is a subset of women who will go on to develop delayed preeclampsia in the postpartum period. Clinical symptoms may be more atypical and, in many cases, without antecedent hypertension. It is for this reason that all patients should be instructed on the signs and symptoms of preeclampsia prior to discharge from the hospital and, ideally, have blood pressure taken between days 3 and 6 post partum. Treatment is similar to that of antepartum preeclampsia, with the exception that delivery has already occurred. Angiotensin-converting enzyme inhibitors may be preferred in the treatment of ongoing hypertension.
Anemia if hemolysis is present, thrombocytopenia
Elevation of transaminases can occur in both preeclampsia and other causes of HELLP syndrome
Creatinine, uric acid
Baseline creatinine values in pregnancy are decreased. Elevations may be reported as “normal”; therefore, it is helpful to have a prepregnancy/early pregnancy value
Elevated if hemolysis is present
Any increase suggests coagulation factor deficit. INR >1.3 suggests serious liver disease (consider acute fatty liver of pregnancy)
Placental growth factor
Not currently available in Canada
Evidence of proteinuria or hematuria
Urine PCR or 24-h urine collection for protein
24-h urine >0.3 g/d or PCR >30 mg/mmol
ECG, chest radiography, troponin
Warranted if chest pain, shortness of breath, or other clinical signs suggestive of ischemia, edema, or ventricular depression are present. Consider in the case of a first presentation of hypertension to investigate for evidence of chronicity or underlying structural heart disease
Fetal and uterine artery ultrasonography
Fetal growth restriction, abnormal heart rate, stillbirth; abnormal uterine artery flow
ALT, alanine aminotransferase; AST, aspartate aminotransferase; CBC, complete blood count; ECG, electrocardiography; HELLP, hemolysis, elevated liver enzymes, low platelets; INR, international normalized ratio; LDH, lactate dehydrogenase; PCR, protein-to-creatinine ratio.
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