In normal pregnancy, blood pressure declines in the ﬁrst trimester because of a drop in peripheral vascular resistance, despite a marked increase in blood volume and cardiac output. Hypertension during pregnancy, deﬁned as systolic blood pressure ≥140 mm Hg or diastolic pressure ≥90 mm Hg, is a major complication associated with a mortality rate of nearly 20% world-wide. It may be due to:
· Chronic, preexisting hypertension
· Gestational hypertension, which occurs after 20 weeks of pregnancy in a previously normotensive woman
· Preeclampsia or eclampsia
· Preeclampsia superimposed on chronic hypertension
Preeclampsia, a severe complication that occurs in 5% of pregnancies, is deﬁned as the development of proteinuria (< 300 mg/24 hr) and hypertension after 20 weeks of gestation in a previously normotensive woman.
Preeclampsia superimposed on chronic hypertension is deﬁned as the appearance of proteinuria after 20 weeks of gestation. If both hypertension and proteinuria exist before 20 weeks of gestation, preeclampsia is deﬁned as a worsening of the hypertension to systolic blood pressure ≥160 mm Hg or diastolic blood pressure ≥110 mm Hg or more after 20 weeks of gestation.
In most cases, preeclampsia occurs in the third tri-mester, although it may occur earlier in a patient with underlying renal disease. It is classiﬁed as either “mild” or “severe”; criteria for upstaging to severe preeclampsia are listed in the ﬁgure.
Despite intense research, the pathogenesis of preeclampsia remains poorly understood. Current evidence, however, suggests there is abnormal remodeling of the uterine spiral arteries, and that the resulting placental ischemia triggers release of antiangiogenic substances that increase blood pressure and cause diffuse endothelial dysfunction. In the glomerulus, endothelial dysfunction leads to proteinuria.
One of the factors that may mediate the connection between placental ischemia and preeclampsia is the soluble fms-like tyrosine kinase-1 receptor (sFlt1). Flt-1 is a membrane-bound receptor for VEGF and placental growth factor (PlGF). In response to ischemia, however, the placenta releases increased quantities of the soluble, unbound splice-variant sFlt-1, which scavenges circulating VEGF and PlGF without completing their normal signal cascades. The effective reduction in VEGF levels is associated with endothelial cell dysfunction and hypertension, since this factor normally induces endothelial nitric oxide. The dysfunctional endothelial cells may also contribute to the elevation in blood pressure by producing a smaller amount of vasodilatory prostaglandins.
Endothelial dysfunction is most prominent in the brain, liver, and kidney. In the kidney, the pathognomonic ﬁnding is glomerular endotheliosis, which consists of swollen glomerular endothelial cells and occluded, bloodless capillary lumina. It appears that the dysfunctional endothelial cells permit the passage of protein into the urine, since in contrast to many other proteinuric conditions, the podocytes and their foot processes often appear intact. Protein frequently accumulates in the sube dothelial space, producing denseappearing deposits.
The importance of sFlt-1 in the pathogenesis of preeclampsia is underscored by the fact that administration of this factor to mice produces hypertension, proteinuria, and glomerular endotheliosis. Not all women with elevated sFlt-1 levels, however, develop preeclampsia, and not all women with preeclampsia have elevated sFlt-1 levels. Thus other factors involved in precipitating preeclampsia continue to be investigated.
The renin-angiotensin-aldosterone system, for example, may also play a role in the pathogenesis of preeclampsia. In normal pregnancy, this axis is stimulated to maintain blood pressure. In preeclampsia, however, there is an exaggerated response to angiotensin II. There are several possible explanations for this difference. First, placental ischemia leads to increased expression of bradykinin B2 receptors, which form heterodimers with the AT1 angiotensin II receptor. These heterodimers are more sensitive to angiotensin II than normal AT1 receptors. In addition, preeclampsia is associated with increased levels of agonistic anti-AT1 antibodies for unknown reasons.
The events leading to abnormal remodeling of the placental vasculature are also unclear. Recent work, however, has focused attention on the enzyme catechol-O-methyltransferase (COMT), which produces 2-methoxyestradiol (2-ME), a natural metabolite of estradiol that is elevated in the third trimester. Both COMT and 2-ME have been shown to be deﬁcient in patients with severe preeclampsia. Pregnant mice that lack COMT are deﬁcient in 2-ME and develop placental hypoxia, high sFlt1 levels, and symptoms of pre- eclampsia that improve when 2-ME is replenished.
Genetic and environmental factors increase the risk for preeclampsia. A positive family history has been shown to increase the risk; indeed, the mouse model of COMT and 2-ME deﬁciency further emphasizes the role of genetics. Other factors associated with increased risk include prior preeclampsia, advanced maternal age, nulliparity, and twin gestation.
In addition, pregnant women with preexisting hypertension, chronic kidney disease, diabetes mellitus, and obesity are at greater risk. It is possible that these conditions sensitize the endothelium to the antiangiogenic effects of factors such as s-Flt1.
PRESENTATION AND DIAGNOSIS
In most cases, preeclampsia is detected during routine blood pressure screening and urine dipstick. Because of primary renal retention of salt and water, patients may have edema and rapid weight gain. A 24-hour urine collection or spot urine protein : creatinine ratio should be performed to monitor the degree of proteinuria. Serum creatinine concentration is normally low in pregnancy due to hemodilution and may begin to rise with preeclampsia. Serum uric acid may be elevated because of diminished renal clearance. Finally, there may be abnormal liver function tests and evidence of hemolysis on the complete blood count, which suggests HELLP syndrome. The presence of headache and/or visual changes should alert the physician of possible progression to eclampsia.
COMPLICATIONS: HELLP SYNDROME AND ECLAMPSIA
The complications of preeclampsia can be severe. HELLP syndrome affects up to 20% of patients with severe preeclampsia, and it is characterized by HEmolysis, abnormally elevated Liver function tests, and Low Platelets. This complication appears to reﬂect severe endothelial dysfunction in the liver, which leads to platelet aggregation and thrombotic occlusion of the hepatic sinusoids, resulting in transaminitis. Red cells are sheared while passing through the narrowed vessels, resulting in microangiopathic hemolytic anemia. Stretching of the Glisson capsule often leads to right upper quadrant pain, nausea, and vomiting, which are the major clinical symptoms. Less frequently, jaundice may occur. Major complications include subcapsular hepatic hematoma formation, placental abruption, retinal detachment, acute kidney injury, pulmonary edema, and disseminated intravascular coagulation.
Eclampsia affects 2% of patients with severe preeclampsia, and it is deﬁned as the occurrence of seizures in the setting of preeclampsia. This complication appears to reﬂect severe endothelial dysfunction in the brain, which leads to cerebral edema and formation of microthrombi. Early warning signs include headaches and visual changes; indeed, the Greek word eklampsis means “sudden ﬂashing” and refers to these visual signs. Cerebral hemorrhage is a potentially fatal complication.
Both HELLP syndrome and eclampsia are associated with a dramatic increase in morbidity and mortality for both mother and fetus.
Delivery is the deﬁnitive treatment for preeclampsia and should be promptly undertaken in women past 37 weeks of gestation. If the fetus is not yet at term, however, patients with mild preeclampsia may undergo careful monitoring to ensure rapid diagnosis of fetal distress and/or maternal complications. Reliable patients can be managed with frequent checks on an outpatient basis; however, patients often need to be hospitalized for careful monitoring, especially if there is any evidence of disease progression.
Intravenous magnesium sulfate is used to treat eclamptic seizures and should be given to all patients with preeclampsia and HELLP syndrome as prophylaxis. Although there is no widely accepted regimen, it is typically given ntrapartum and continued for 1 to 2 days postpartum.
In all pregnant women, whether there is evidence of preeclampsia or not, antihypertensive medications are indicated if systolic blood pressure is ≥150- 160 mm Hg, diastolic pressure is ≥100-110 mm Hg, or if there is evidence of end-organ damage. The thresh-olds are higher than in nonpregnant women because the goal is to prevent severe complications in the mother during the pregnancy without harming the fetus, rather than preventing long-term cardiovascular complications as in nonpregnant patients. Moreover, if there is a sustained decline in blood pressure, the fetus may experience distress or growth retardation.
Most antihypertensive agents are safe for use during pregnancy, with the signiﬁcant exception of those that block the renin-angiotensin system. Angiotensin II plays an important role in nephrogenesis, and the use of ACE inhibitors or angiotensin receptor blockers (ARBs) may cause profound abnormalities in fetal renal development.
Alpha-methyldopa is the drug of choice for chronic hypertension in pregnancy because it has the best long-term safety proﬁle. Labetalol and other β-blockers have been used successfully during pregnancy, and intravenous labetalol is considered the drug of choice for severe hypertension in pregnancy. Although hydralazine has been used for many years, recent data suggest that its safety proﬁle is inferior to that of labetalol.
Calcium channel blockers are effective, although blood pressure may fall precipitously if these agents are administered along with magnesium sulfate. Diuretics are generally not used because they restrict the normal volume expansion associated with pregnancy and may reduce uteroplacental blood ﬂow.
If there is progression to severe preeclampsia, immediate delivery is often required, although some patients who are not yet at term may be candidates for cautious expectant management. Further progression to HELLP syndrome or eclampsia, however, mandates delivery. For pregnancies at less than 34 weeks of gestation, glucocorticoids may be given in advance to promote fetal lung maturation.
Preeclampsia typically resolves within several days post-partum, but symptoms can sometimes persist for weeks or more. Patients should be carefully monitored for the duration of their postpartum hospitalization and may require continued antihypertensive therapy for several weeks after discharge.
Women who experience preeclampsia are at increased risk for recurrence in subsequent pregnancies. In general, women with more severe disease are at greater risk for recurrence. These women are also at elevated risk for developing metabolic syndrome and cardiovascular disease later in life, which may reﬂect either underlying endothelial dysfunction or permanent cardiovascular sequelae associated with preeclampsia. There is a slight increase in the risk of end-stage renal disease compared to the rest of the population, although the absolute risk is still low.
A number of therapies have been used in attempts to prevent or slow the progression of preeclampsia, so far with little success. The drug with the most data is aspirin, which may exert its beneﬁt by altering the abnormal prostaglandin-thromboxane ratios associated with endothelial dysfunction. Although many trials have shown no beneﬁt of aspirin, a recent meta-analysis suggested that if started before 16 weeks of gestation, it may diminish the incidence and/or severity of preeclampsia in high-risk patients. Agents such as vitamin D, antioxidants, and sildenaﬁl have been examined but have so far failed to show any protective effect.
Several tests to identify the patients at highest risk for preeclampsia have been investigated, including uterine artery Doppler ultrasound and measurement of VEGF, sFlt-1, and other angiogenic factors in blood and urine. Although these tests show some promise, at present they have limited usefulness because there is no way to prevent the emergence or progression of preeclampsia. Thus early detection through frequent screening of blood pressure and urine protein is of utmost importance, especially in high-risk patients. Educating patients about symptoms that may be potential warning signs is also valuable.