Pre-eclampsia
Pre-eclampsia
is a unique disorder found only in human pregnancies. Historically,
pre-eclampsia has been defined as the triad of hypertension, proteinuria and
edema in a pregnant woman. Eclampsia is the occurrence of seizures
that cannot be attributed to another cause in a patient with pre-eclampsia.
Pre-eclampsia typically occurs in the third trimester of pregnancy, although
some cases manifest earlier. Although many patients with pre-eclampsia
demonstrate the classic triad, it is now clear that the disorder is really a
spectrum of clinical signs and symptoms that accompany microvascular changes in
multiple organ systems (Fig. 38.1). The disorder has so many presentations that
it has been called the “great imitator.” Central nervous system involvement can
result in severe headaches, visual changes, seizures, stroke and blindness.
Renal involvement is almost always present and can manifest as proteinuria,
oliguria or renal failure. Edema can accumulate in many sites, including the
feet, hands, face and lungs. Hemoconcentration, thrombocytopenia and
intravascular hemolysis are common signs of hematologic involvement. Hepatic
dysfunction often accompanies hematologic changes and produces a group of
clinical findings known as HELLP syndrome (hemolysis, elevated
liver function tests, low platelets). Patients with HELLP
will often develop vague epigastric pain resulting from liver involvement which
may be mistaken for heartburn, gallbladder disease or the flu by an
unsuspecting health care provider.
The overall
incidence of pre-eclampsia in the obstetric population is 5–8%; the absolute
number depends on the proportion of patients at increased risk. Risk factors
for developing pre-eclampsia include the primigravid state (first pregnancy),
multiple gestation, diabetes, pre-existing hypertension, a long interval
between pregnancies, pre-eclampsia in a previous pregnancy, a family history of
pre-eclampsia, hydatidiform mole, and inherited and acquired clotting disorders
(e.g., protein S and protein C deficiencies and antiphospholipid antibodies).
There is considerable overlap between the risk factors for pre-eclampsia and
those for fetal growth restriction (FGR). Indeed, the presence of FGR may be
the first sign of impending pre-eclampsia and women with pre-eclampsia are at
risk for delivering a growth-restricted baby.
Left
untreated, pre-eclampsia can be a highly morbid and even fatal disease. The
ultimate treatment for the condition is delivery of the pregnancy. This is so
effective a therapy that all deranged physiology will revert to normal after
delivery provided that no permanent tissue damage has occurred. If the mother
is medically supported through a timely delivery and postpartum recovery, her
kidneys will begin to make urine again, blood will clot and seizures will stop.
In spite of its potential for a 100% cure with proper diagnosis and treatment,
pre-eclampsia remains one of the leading causes of maternal death in both
developed and developing countries.
Potential mechanisms in
pre-eclampsia pathogenesis
It is clear
that placental abnormalities are central to the pathogenesis of pre-eclampsia.
Delivery cures pre-eclampsia and hydatidiform mole, a form of gestational
trophoblast disease characterized by pla- cental overgrowth but no fetal
development (Chapter 45), predisposes to the disease. It was originally thought
that the placenta secreted a toxin that caused pre-eclampsia and the disorder
was appropriately called “toxemia.” While no unique toxins have been
identified in the circulation of patients with pre-eclampsia, abnormal
concentrations of specific metabolites are found in many of these patients.
Circulating thromboxane, a vasoconstricting prostaglandin, is elevated while
nitric oxide production is subnormal. A number of other factors, including a
soluble form of a vascular endothelial growth factor (VEGF) receptor (sVEGFR-1
or sFlt-1), placental growth factor (PLGF) and soluble endoglin (sENG), a
circulating receptor for transforming growth factor β (TGF-β), have been shown
to be markedly different in the serum of pregnant women weeks or months before
the symptoms of pre-eclampsia manifest. Unfortunately, the test accuracies of
these markers are inadequate to predict pre-eclampsia in clinical practice.
There are
many unproven but enticing theories about the etiology and pathogenesis of
pre-eclampsia. It is likely that there are several initiators of the disease
that ultimately converge in a final common pathway. Examination of the small
blood vessels in the uteri of women with pre-eclampsia often reveals a failure
of the invading trophoblast to remodel the spiral arteries (Fig. 38.2). There
are several explanations for why the cytotrophoblast might fail to invade these
vessels including abnormal immune activation or genetic predisposition.
Cytotrophoblast differentiation into an invasive phenotype is accompanied by
increased production of VEGF and PLGF, both proangiogenic factors. Placentas
from pre-eclamptic pregnancies secrete increased amounts of sFlt-1, the soluble
antagonist to VEGF, and sENG; both are
antiangiogenic factors.
Abnormal
immune activation that inhibits trophoblast invasion of maternal blood vessels
could explain why pre-eclampsia is most common when a woman is exposed to
paternal antigens for the first time: a first pregnancy or, in a multigravid
woman, the initial pregnancy with a new partner. Loss of immune tolerance over
time would also explain why a long interval between pregnancies is a risk
factor for developing pre-eclampsia. Abnormal activation of the immune system
underlies other autoimmune diseases, such as systemic lupus erythematosus, that
carry an increased risk for pre-eclampsia. Some women with pre-eclampsia have
activating autoantibodies to the angiotensin II receptor that inhibit
trophoblast invasiveness in vitro.
Specific
genetic abnormalities may be involved in the pathophysiology of pre-eclampsia.
Women who carry a mutation in the complement receptor CR-1 have an increased
risk for pre-eclampsia as do women carrying a specific polymorphism for
plasminogen activator inhibitor type 1. Pre-existing insulin resistance confers
an increased risk. The fact that a family history of pre-eclampsia increases a
woman’s risk for the disease indicates that there may be many additional
genetic predispositions to the disease.
A mismatch
between fetal and placental demands and the maternal ability to meet them may
also cause pre-eclampsia and would explain risk factors such as multiple
gestation, maternal vascular disease and hypercoagulable states. Proponents of
this theory propose that the undernourished fetus sends signals to the mother
to increase perfusion of the placenta. If the mother cannot compensate in
response to these initial signals, the fetus sends more urgent signals.
Pre-eclampsia would theoretically result from the effects of excessive signals.
As an example, hypoxia has been shown to increase the production of sFlt-1 by
tro- phoblast cells. Increased sFlt-1 may be part of the pathogenesis of
pre-eclampsia.
While the
initiating placental abnormality is unclear, the final common pathway for
pre-eclampsia is known to be endothelial dysfunction and injury. The
vascular endothelium normally functions to prevent microcoagulation and to
modulate vascular tone. Vascular injury results in coagulation and alters the
response of the underlying vascular smooth muscle to vasoactive substances.
Often, substances that act as vasodilators on an intact endothelium will cause
vasoconstriction of damaged endothelium. In preeclampsia, endothelial
dysfunction can solely explain the basic triad: hypertension (vasospasm), edema
(capillary leak) and proteinuria (renal cell damage secondary to
hypoperfusion). Experiments in animal models indicate that excess sFlt-1 can
directly produce some of the organ dysfunction seen in pre-eclampsia. What
remains inexplicable is why only a few, but not all, of the signs and symptoms
of pre-eclampsia will appear in any given patient.
