PREECLAMPSIA
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.
PATHOPHYSIOLOGY
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.
RISK FACTORS
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.
TREATMENT
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.
PROGNOSIS
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.
PREVENTION
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.
