Heterogeneous causes constituting the single syndrome of preeclampsia: A hypothesis and its implications

doi:10.1016/S0002-9378(96)70056-X

American Journal of Obstetrics and Gynecology

Volume 175, Issue 5, November 1996, Pages 1365-1370

https://doi.org/10.1016/S0002-9378(96)70056-X Get rights and content

Abstract

The cause of preeclampsia remains elusive in spite of many attempts to understand its biologic characteristics and to characterize its predictors. We suggest that there are distinct origins of preeclampsia, each with its own pathologic characteristics and natural history. One genesis is the result of reduced placental perfusion, which we will call placental, and another results from maternal disorders preexisting (but sometimes not evident before) pregnancy. These preexisting maternal disorders comprise predisposing factors for cardiovascular disease such as hypertension, renal disease, overweight, and diabetes. A critical review of the epidemiologic and pathologic literature is presented, which supports the hypothesis that preeclampsia is the result of heterogeneous causes. The implications of this hypothesis are discussed, particularly its impact on the development of rules to predict the occurrence of preeclampsia. (Am J Obstet Gynecol 1996;175:1365-70.)

Section snippets

THE PLACENTAL GENESIS OF PREECLAMPSIA

Preeclampsia only occurs during pregnancy and appears to require a placenta for its initiation. Preeclampsia can occur in abdominal pregnancies, indicating that uterine distention is not required.⁶ Additionally, pregnancies without a fetus, hydatidiform moles, are associated with an increased risk of preeclampsia.⁷ It has long been proposed that the placental component of preeclampsia is mediated by reduced placental perfusion.⁷ Reduced placental perfusion may be due to abnormal placentation

LIMITATIONS OF THE HYPOTHESIS THAT REDUCED PLACENTAL PERFUSION IS THE SOLE GENESIS OF PREECLAMPSIA

Reduced placental perfusion has been proposed as the point of convergence of maternal and immunologically dictated disorders within preeclampsia.¹⁴ The recognized maternal contributors to preeclampsia (hypertension, collagen vascular disease, diabetes) may alter placental perfusion by their known effects on the microvasculature. However, this notion is not consistent with the fact that 70% of infants of preeclamptic women are normally grown according to birth weight for age criteria.15, 16

EVIDENCE FOR A DISTINCT MATERNAL GENESIS WITHIN THE SYNDROME OF PREECLAMPSIA

The evidence for a specific maternal contribution to preeclampsia other than immunologic includes (1) a distinct natural history among women with prepregnancy maternal morbidity and (2) a distinct set of pathologic findings consistent with unsuspected underlying maternal disease among women with this distinct natural history.

THE INTERACTION OF MATERNAL AND PLACENTAL FACTORS

The interaction of underlying maternal disease and preeclampsia results in particularly high perinatal morbidity and mortality. Hypertension detected before 20 weeks' gestation without superimposed preeclampsia has been shown to increase the rate of perinatal mortality in most but not all studies.34, 35 Chronic hypertension with superimposed preeclampsia has been associated with high perinatal morbidity and mortality rates in all reports. Page and Christianson⁴⁰ prospectively studied 10,074

CRITIQUE OF STUDIES

Methodologic issues that cloud the interpretation of results regarding the maternal component of preeclampsia include misclassification of diseased versus nondiseased individuals, biased patient selection, differential loss to follow-up, lack of control for potential confounders, and difficulties in selecting controls. Classification of women into those with preeclampsia, those with transient hypertension of pregnancy, and controls has been inconsistent and difficult. Some of the differences in

UNDERSTANDING RISK FACTORS FOR PREECLAMPSIA ON THE BASIS OF THE MODEL

We argue that identifying an accurate group of clinical predictors for preeclampsia is hampered by heterogeneous causes. Risk factors consistently shown to be associated with an increased rate of preeclampsia include elevated blood pressure, prepregnancy adiposity, black race, and primiparity. The first three of these factors can be understood in relation to a maternal genesis within preeclampsia. First, higher blood pressure before 20 to 27 weeks' gestation has been shown to be associated with

IMPLICATIONS

Putting the prevalence of the risk markers for maternal disease in context, recurrent preeclampsia accounts for 20% to 40% of the disease,22, 29, 51 and preeclampsia before 37 weeks' gestation accounts for about 10% of primiparous preeclampsia (Gilmour C. Personal communication, single hospital record review). These statistics suggest that the markers consistent with underlying maternal disease may account for 20% to 40% of preeclampsia.

Our hypothesis, that preeclampsia comprises a group of

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Citation Excerpt :
These and additional mounting controversial clinical and laboratory findings challenged the homogenous etiology regarding PE. Heterogeneous origination of PE was discussed by Ness and Roberts as recent as 1996 [34]. In 2003, while examining clinical features and central hemodynamics, two markedly distinguishable groups with hypo- and hypervolemia emerged among preeclamptic patients [35].
During normal pregnancy, blood volume increases by nearly two liters. Distinctively, the absence coupled with the extreme extent regarding the volume expansion, are likely accompanied with pathological conditions. Undoubtedly, preeclampsia, defined as the appearance of hypertension and organ deficiency, such as proteinuria during the second half of pregnancy, is not a homogenous disease. Clinically speaking, two main types of preeclampsia can be distinguished, in which a marked difference between them is vascular condition, and consequently, the blood volume.
The “classic” preeclampsia, as a two-phase disease, described in the first, latent phase, in which, placenta development is diminished. Agents from this malperfused placenta generate a maternal disease, the second phase, in which endothelial damage leads to hypertension and organ damage due to vasoconstriction and thrombotic microangiopathy. In this hypovolemia-associated condition, decreasing platelet count, signs of hemolysis, renal and liver involvement are characteristic findings; proteinuria is marked and increasing. In the terminal phase, visible edema develops due to increasing capillary transparency, augmenting end-organ damages. “Classic” preeclampsia is a severe and quickly progressing condition with placental insufficiency and consequent fetal growth restriction and oligohydramnios. The outcome of this condition often leads to fetal hypoxia, eclampsia or placental abruption. The management is limited to a diligent prolongation of pregnancy to accomplish improved neonatal pulmonary function, careful diminishing high blood pressure, and delivery induction in due time.
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^☆: From the Department of Epidemiology, Graduate School of Public Health,^aand the Department of Obstetrics, Gynecology, and Reproductive Sciences, University of Pittsburgh^band Magee-Womens Research Institute.^c

^☆☆: Reprint requests: Roberta B. Ness, MD, MPH, University of Pittsburgh, Graduate School of Public Health, 130 DeSoto St., Room 513 Parran Hall, Pittsburgh, PA 15261.

^★: 0002-9378/96 $5.00 + 0 6/1/74923

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Heterogeneous causes constituting the single syndrome of preeclampsia: A hypothesis and its implications☆,☆☆,★

Abstract

Section snippets

THE PLACENTAL GENESIS OF PREECLAMPSIA

LIMITATIONS OF THE HYPOTHESIS THAT REDUCED PLACENTAL PERFUSION IS THE SOLE GENESIS OF PREECLAMPSIA

EVIDENCE FOR A DISTINCT MATERNAL GENESIS WITHIN THE SYNDROME OF PREECLAMPSIA

THE INTERACTION OF MATERNAL AND PLACENTAL FACTORS

CRITIQUE OF STUDIES

UNDERSTANDING RISK FACTORS FOR PREECLAMPSIA ON THE BASIS OF THE MODEL

IMPLICATIONS

Am J Obstet Gynecol

Am J Obstet Gynecol

Am J Kidney Dis

J Reprod Immunol

Lancet

Am J Obstet Gynecol

Am J Obstet Gynecol

Am J Obstet Gynecol

Am J Obstet Gynecol

Am J Obstet Gynecol

Am J Obstet Gynecol

Lancet

Am J Obstet Gynecol

Am J Obstet Gynecol

Am J Obstet Gynecol

Am J Obstet Gynecol

Am J Obstet Gynecol

Am J Obstet Gynecol

Am J Obstet Gynecol

Am J Obstet Gynecol

Am J Obstet Gynecol

Am J Obstet Gynecol

Am J Obstet Gynecol

Am J Obstet Gynecol

Am J Obstet Gynecol