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Mapping the Theories of Preeclampsia

Dr. Luciano E. Mignini
Research Training Fellow, UNDP/UNFPA/WHO/World Bank Special Program of Research
Department of Obstetrics and Gynecology
Birmingham Women’s Health Care NHS Trust,
Birmingham, U.K.
In association with Women’s Health & Education Center (WHEC)

Preeclampsia is a major cause of maternal and perinatal mortality and morbidity worldwide. It affects 2-3% of all pregnancies. Its etiology is elusive and theories abound regarding its pathogenesis. Preeclampsia can cause changes in virtually all organ systems. Several organ systems are consistently and characteristically involved. The pathologic findings indicate that the pathogenetic factor of primary importance is not blood pressure elevation, but rather poor tissue perfusion. The histologic data support the clinical impression that the poor perfusion is secondary to profound vasospasm, which also increases total peripheral resistance and blood pressure. Preeclampsia is not merely an alternate form of malignant hypertension.

The purpose of this document is to understand various theories of preeclampsia. Recently homocysteine, a metabolite of the essential amino acid methionine has been postulated to produce oxidative stress and endothelial cell dysfunction, alterations associated with preeclampsia. The studies examining the relationship between serum homocysteine concentrations and preeclampsia are also discussed.

Clinical Presentation:

Women with preeclampsia might present with spectrum of cardiovascular findings dependent upon both severity and duration. Chronic underlying disease may modify the clinical presentation. Therapeutic interventions may significantly alter these findings. Severe disturbances of normal cardiovascular function are common with preeclampsia and eclampsia. These basically are related to increase in cardiac after-load caused by hypertension, cardiac preload that is substantively affected by pathologically diminished hypervolemia of pregnancy or iatrogenically increased by intravenous crystalloid or oncotic solutions, and endothelial activation with extravasation into extracellular space, especially lung.

For details please review the articles:

Theories of Preeclampsia (Pathophysiology)

Any satisfactory theory on the pathophysiology of preeclampsia must account for the observation that hypertensive disorders due to pregnancy are very much more likely to develop in the woman who is exposed the chorionic villi for the first time; is exposed to a superabundance of chorionic villi as with twins or hydatidiform mole; has preexisting vascular disease and is genetically predisposed to hypertension developing during pregnancy. Vasospasm is basic to the pathophysiology of preeclampsia and eclampsia.

Increased Pressor Responses:

Normally pregnant women develop refractoriness to infused vasopressors. Increased vascular reactivity to pressors in women with early preeclampsia has been identified by Raab and co-workers (1956) and Talledo and associates (1968) using either norepinephrine or angiotensin II, and by Dieckmann and Michel (1937) and Browne (1946) using vasopressin. Grant and co-workers in 1973 demonstrated that increased sensitivity to angiotensin II clearly preceded the onset of pregnancy-induced hypertension. Nulliparas who remained normotensive were refractory to the pressor effect of infused angiotensin II, while women who subsequently became hypertensive lost this refractoriness weeks before the onset of hypertension. Women with underlying chronic hypertension have almost identical responses.


The exact mechanism by which prostaglandins or related substances mediate vascular reactivity during pregnancy is unknown. From a number of observations, there is evidence that compared with normal pregnancy, prostacyclin production is decreased significantly and thromboxane A2 significantly increased in preeclampsia. Thus in preeclamptic women, thromboxane is increased and prostacyclin and prostaglandin E2 are decreased, resulting in vasoconstriction and sensitivity to infused angiotensin II. Spitz and colleagues (1988) reported that 81 mg of aspirin given daily to future hypertensive women restored angiotensin II refractoriness by suppressing synthesis of thromboxane A2 by about 75%; however prostacyclin synthesis was decreased by only 20% and prostaglandin E2 by 30%. These observations indicate that vessel reactivity may be mediated through a delicate balance of production and metabolism of these vasoactive prostaglandins. In this scheme, preeclampsia may follow inappropriately increased production or destruction of one prostaglandin, diminished synthesis or release of the other, or perhaps both.

Vascular Endothelial Growth Factor (VEGF):

VEGF is important in vasculogenesis and control of microvascular permeability and has been identified in the human placenta. Serum levels of VEGF increase in the first half of pregnancy concurrent with trophoblast and uterine vascular events characteristic of pregnancy. VEGF has been reported to be increased in serum from women with preeclampsia. Simmons and co-workers (2000) found an increase in VEGF parallel to increased uteroplacental vessel resistance in women with preeclampsia. VEGF may represent a compensatory mechanism attempting to restore uteroplacental blood flow toward normal.

Genetic and Immunological Factors:

Chesley and Cooper (1986) studied the tendency for preeclampsia and eclampsia in the family members with the possibility that it is inherited. A multifactorial inheritance was also considered possible. An association between the histocompatibility antigen HLA-DR4 and proteinuric hypertension is also a possibility. Certain HLA types are more common in the mother and the fetus from preeclamptic pregnancies. Certain medical disorders, which have genetic predisposition like diabetes and hypertension, also predispose to preeclampsia. The risk of hypertensive disorders due to pregnancy is appreciably enhanced in circumstances where formation of blocking antibodies to antigenic sites on the placental might be impaired. This may arise where effective immunization by a previous pregnancy is lacking, as in first pregnancies; or where the number of antigenic sites provided by the placenta is unusually great compared with the amount of antibody, as with multiple fetuses.

The immunization concept is supported by the observation that preeclampsia develops more frequently in multiparous women impregnated by a new consort. Dekker and Sibai (1998) have reviewed the possible role of immune maladaptation in the pathophysiology of preeclampsia. Beginning in the early second trimester, women destined to develop preeclampsia have a significantly lower proportion of T-helper cells compared with women who remain normotensive. Antibodies against endothelial cells have been found in 50% of women with preeclampsia versus 15% of normotensive controls.

Inflammatory Factors:

Redman and colleagues (1999) have proposed that the endothelial cell dysfunction associated with preeclampsia can result from a generalized perturbation of the normal, generalized maternal intravascular inflammatory adaptation to pregnancy. In this hypothesis preeclampsia is considered a disease due to an extreme state of activated leukocytes in the maternal circulation. Briefly, cytokines, to include tumor necrosis factor-alpha (TNF-alpha) and the interleukins, may contribute to the oxidative stress associated with preeclampsia. In this scheme, oxygen-free radicals lead to the formation of self-propagating lipid peroxides that in turn injure endothelial cells. Such injury modifies endothelial cell production of nitric oxide, as well as interfering with prostaglandin balance. Other consequences of oxidative stress include production of the lipid-laden macrophage foam cells characteristics of atherosis, activation of microvascular coagulation (thrombocytopenia), and increased capillary permeability (edema and proteinuria). These observations on the effects of oxidative stress in preeclampsia have given rise to increased interest in the potential benefit of antioxidant therapy given for the prevention of hypertensive disorders due to pregnancy. Antioxidants are a diverse family of components that function to prevent overproduction of and damage caused by noxious free radicals. Examples of antioxidants include vitamins E and C and beta-carotene.

Nitric Oxide and Endothelins:

Previously termed endothelium-derived relaxing factor (EDRF), nitric oxide is synthesized by endothelial cells from L-arginine. It is a potent vasodilator whose absence or decreased concentration might play a role in the etiology of hypertensive disorders due to pregnancy. Benedetto and associates (2000) studies showed its production appears to be increased in severe preeclampsia. Inhibition of nitric oxide has been shown to increase mean arterial pressure, decrease heart rate, and pressors in some animals. Equally important, it appears characteristic of fetoplacental perfusion in the humans. The changes in nitric oxide concentrations in women with hypertensive disorders due to pregnancy may be the consequence of hypertension and not the inciting event.

Endothelins are the polypeptides and potent vasoconstrictors. Endothelins –1 is the only species produced by human endothelium it has been shown by Mastrogiennis and co-workers (1991) that it is increased in normotensive laboring and non-laboring women. Higher levels have been reported in preeclamptic women.

The Role of Homocysteine:

Prevailing evidence is that endothelial cell activation is the centerpiece in the contemporary understanding of the pathogenesis of preeclampsia. Homocysteine concentrations are slightly increased in normotensive pregnancies that later develop preeclampsia and are considerably increased once preeclampsia is established. It is currently unclear whether high concentrations of circulating homocysteine cause preeclampsia or whether this is merely a secondary phenomena reflecting, perhaps metabolic alterations that result from the disorder. If causally linked, the concentrations would be elevated earlier in gestation and they might be useful for early detection. Moreover, the potential to control hyper-homocysteinemia pharmacologically (eg, by vitamin supplementation) might lead to strategies for preventing preeclampsia.

Most studies qualitatively showed a positive association between hyper-homocysteinemia in pregnancy and preeclampsia. It was unclear how hyper-homocysteinemia developed because none of the purported factors (folate, vitamin B12, and genetic polymorphisms) showed an association. However, we observed a biologically plausible role for oxidative stress and endothelial dysfunction, factors through which hyper-homocysteinemia may lead to preeclampsia. Efforts in preeclampsia prevention have been disappointing to date. Our review raises questions about the way in which the role of homocysteine in the etiology and/or pathophysiology of preeclampsia has been evaluated and disseminated. It is clear that, in the process of developing clinical trials, existing research regarding basic science and theory of etiopathogenesis should be rigorously assessed.

Suggested Reading: Luciano E. Mignini, Pallavi M. Latthe, Jose Villar et al. Mapping the theories of preeclampsia: The role of homocysteine. Obstetrics and Gynecology. Vol. 105, No. 2 February 2005 pp 411-425.

Editor’s Note:

We are grateful to Dr. Luciano E. Mignini for sharing his research and work with Women’s Health & Education Center (WHEC). His insights and efforts are complimentary to our educational efforts in women’s healthcare. We look forward to work with him and Birmingham Women’s Hospital/ University of Birmingham (UK)/ CREP (Argentina) to improve health & status of women worldwide. Thanks again Dr. Mignini.

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