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(Hypertension. 2005;46:1243.)
© 2005 American Heart Association, Inc.

Brief Reviews

Preeclampsia

Recent Insights

From the Magee-Womens Research Institute (J.M.R.) and the Departments of Obstetrics, Gynecology, and Reproductive Sciences (J.M.R., H.S.G.), and Epidemiology (J.M.R.) University of Pittsburgh, Pennsylvania.

Correspondence to James M. Roberts, MD, Magee-Womens Research Institute, 204 Craft Ave, Pittsburgh, PA 15213. E-mail RSIJMR{at}mwri.magee.edu

	Abstract

Top Abstract Introduction Preeclampsia: A Two-Stage... Stage 1 of Preeclampsia:... Stage 2 of Preeclampsia:... Maternal Fetal/Placental... The Linkage of Stages... Clinical Implications References

 
Preeclampsia is a pregnancy complication with serious consequences for mother and infant. The disorder is diagnosed by gestational hypertension and proteinuria but is far more than pregnancy induced hypertension. Preeclampsia is proposed to occur in 2 stages. Stage 1 reduced placental perfusion is postulated as the root cause and to lead to the maternal syndrome, Stage 2. Why perfusion is reduced, how this translates to a maternal disease in some but not all women and what is the linkage of the 2 stages are topics of intense study. In the last decade such studies have provided valuable insights into pathophysiology that now guide ongoing clinical trials.

Key Words: preeclampsia • hypertension, pregnancy • oxidative stress • endothelium

	Introduction

Top Abstract Introduction Preeclampsia: A Two-Stage... Stage 1 of Preeclampsia:... Stage 2 of Preeclampsia:... Maternal Fetal/Placental... The Linkage of Stages... Clinical Implications References

 
Preeclampsia is a pregnancy complication recognized by new-onset gestational hypertension and proteinuria (see definitions below). The disorder affects both mothers and their infants. Once the disease is evident clinically, it can be cured only by delivery. In developed countries, surveillance for preeclampsia through prenatal care allows for early identification and intervention via delivery. This management has changed little in the last 100 years, and it is very effective at reducing maternal mortality. However, maternal morbidity remains great with preeclampsia, which continues to be one of the leading causes for the admission of pregnant women to intensive care units in the developed world.¹ Furthermore, fetal mortality and morbidity is considerable, related to the effects of the disease on the fetus as well as prematurity. The indicated delivery of women to prevent the progression of preeclampsia is responsible for 15% of all preterm births.² In developing countries, where inadequate prenatal care limits preeclampsia surveillance, maternal mortality is common, accounting for 50 000 deaths yearly.³

The hypertensive disorders of pregnancy include hypertension that antedates pregnancy, chronic hypertension, and gestational hypertension occurring uniquely during pregnancy. When the gestational hypertension is accompanied by new-onset proteinuria, the disorder is termed preeclampsia, and when not associated with proteinuria, transient hypertension of pregnancy. If the woman with chronic hypertension also manifests evidence of preeclampsia, this is classified chronic hypertension with superimposed preeclampsia. Eclampsia is the occurrence of seizures in women with preeclampsia.⁴

These criteria have been extraordinarily useful to aid in recognizing pregnant women at risk. Greatest risk for mother and baby is present with preeclampsia, and the risk for chronic hypertensive pregnancy is primarily with superimposed preeclampsia. However, the attention to hypertension has, for many years, limited research attention to primarily mechanisms of hypertension. This has not been helpful. In the last 2 decades, appreciation that preeclampsia is a multisystemic syndrome characterized by vasoconstriction, metabolic changes, endothelial dysfunction, activation of the coagulation cascade, and increased inflammatory response, to mention only some of the organ systems involved, has redirected research.⁵ As a result, progress in understanding the disorder has accelerated greatly, with attendant optimism for potentially effective treatments.⁵ In this article, we consider this recent progress and its clinical implications.

	Preeclampsia: A Two-Stage Disorder

Top Abstract Introduction Preeclampsia: A Two-Stage... Stage 1 of Preeclampsia:... Stage 2 of Preeclampsia:... Maternal Fetal/Placental... The Linkage of Stages... Clinical Implications References

 
A 2-stage model of preeclampsia (Figure 1) has been proposed as useful conceptually to address its pathophysiology. Stage 1 of preeclampsia, reduced placental perfusion, is considered the "root cause." This then somehow translates, in some but not all women, into stage 2: the multisystemic maternal syndrome of preeclampsia. Although much still remains unknown in both of these areas, the major questions are: (1) why does reduced placental perfusion result in preeclampsia in only some women, and (2) what links stages 1 and 2?

View larger version (14K): [in this window] [in a new window]   Figure 1. Two-stage model of the pathophysiology of preeclampsia. The model indicates preeclampsia as occurring in 2 stages. The initiating abnormality (stage 1) is failed vascular remodeling of the vessels that supply the placental bed. This is linked to the maternal syndrome of preeclampsia (stage 2).

	Stage 1 of Preeclampsia: Reduced Placental Perfusion

Top Abstract Introduction Preeclampsia: A Two-Stage... Stage 1 of Preeclampsia:... Stage 2 of Preeclampsia:... Maternal Fetal/Placental... The Linkage of Stages... Clinical Implications References

 
Clinical Evidence
More than 60 years ago, Ernest Page formalized the concept that placental perfusion was reduced in preeclampsia.⁶ Evidence for this came originally from clinical findings. Preeclampsia is more common in obstetric conditions with very large placentas, including multiple gestations and molar pregnancies. The concept was advanced that the excess of placental tissue could not be perfused adequately. Further support was provided by the increased frequency of preeclampsia in women with preexisting medical conditions that were characterized by microvascular disease, including diabetes, hypertension, and collagen vascular diseases. Direct measurement of intervillous blood flow with radioactive washout studies demonstrated reduced placental perfusion in preeclampsia.⁷ More recently, Doppler velocimetry of uterine vessels has demonstrated increased resistance in the vessels that supply the intervillous space of women with preeclampsia, and in early gestation, in women destined to develop preeclampsia.⁸ Experimental perturbations to reduce placental perfusion in several animal species have resulted in a pregnancy-specific, preeclampsia-like syndrome.⁹

The most compelling observation supporting reduced placental perfusion in preeclampsia is the failure of the maternal uterine spiral arteries that supply the intervillous space to undergo the vascular remodeling characteristic of normal pregnancy. In normal pregnancy, these vessels undergo striking modification.¹⁰ The vascular luminal diameter is increased 4-fold, and the vessel wall modified by the loss of smooth muscle and the inner elastic lamina. This results in flaccid tubes, which provide a low resistance circuit to the intervillous space. Furthermore, the loss of vascular wall components renders the altered vessels unresponsive to vasoactive stimuli. This remodeling does not occur normally in preeclampsia. It is either not present, or, if it does occur, is limited to the superficial portion of the vessel located in the decidua, whereas in normal pregnancy, the modification extends to vessels in the inner third of the myometrium.

Mechanisms
The failed placental site vascular remodeling of preeclampsia has been the target of intense scrutiny. It appears that the remodeling of these vessels is largely a result of trophoblast invasion, in particular, endovascular invasion. Cellular control of cytotrophoblast invasion depends on interactions between maternal decidua and fetal trophoblast. Local oxygen tension and immune-mediated interactions are primary determinants of the process, and their common mechanism may be through apoptosis.¹¹

Oxygen tension in the intervillous space is low until 10 to 12 weeks after conception, when maternal vessels begin to perfuse the intervillous space.¹² With this, the oxygen tension increases dramatically, as does the concentration of reactive oxygen species. Maternal antioxidant capacity determines the ability of the decidual/trophoblast interface to accommodate. It is proposed that if the capacity is not sufficient, impaired invasion, poor placental perfusion, and perhaps preeclampsia can result.¹³ There are many consequences to this increase in oxygen delivery. Data obtained in vitro suggest that increased oxygen tension triggers a change in trophoblast behavior and phenotypic expression from primarily proliferative to invasive.¹⁴ Additionally, at higher oxygen tension, cytotrophoblast cells that line maternal vessels further develop a phenotype similar to vascular endothelial cells, expressing cadherins, integrins, and other cellular adhesion molecules. Expression of these molecules is impaired in trophoblastic cells in preeclampsia,¹⁵ which may be because of an inherent inability of these cells to transform, or to a lower antioxidant capacity in preeclamptics. Other cellular factors such as matrix metalloproteinase-9¹⁶ also influence the success of decidual invasion.

In addition to oxygen tension as a major regulator of trophoblast differentiation and invasion, immune mechanisms play an important role. The immune cells that predominate in the decidua are a specific population of uterine natural killer (uNK) cells. Killer immunoglobulin receptors (KIRs) on these maternal uNK cells interact with specific fetal trophoblast cell markers, influencing trophoblast invasion. Trophoblastic human leukocyte antigen C (HLA-C) (a major histocompatibility complex class I molecule) is central in the trophoblast/decidual interaction.^17,18 Specific genotypic combinations of KIR and HLA-C result in an increased risk of preeclampsia. This combination consists of trophoblast HLA-C molecules that interact with an inhibitory KIR, leading to excessive inhibition of uNK cell activity and therefore decreased invasion of trophoblasts.¹⁹ It is increasingly apparent that normal placentation requires a balance of inhibition and activation of uNK cells that is mediated by maternal and fetal factors.

Placental apoptosis may be the final common pathway for these mechanisms. Placentas of preeclamptic patients show more overall apoptosis than controls.²⁰ Apoptosis also leads to the release of syncitiotrophoblast microfragments into the maternal circulation, which is accelerated in preeclampsia.²¹

	Stage 2 of Preeclampsia: More Than Pregnancy-Induced Hypertension

Top Abstract Introduction Preeclampsia: A Two-Stage... Stage 1 of Preeclampsia:... Stage 2 of Preeclampsia:... Maternal Fetal/Placental... The Linkage of Stages... Clinical Implications References

 
Pathological and Pathophysiological Changes
Pathological changes in women dying with eclampsia present a common theme: they are all consistent with profoundly reduced perfusion.²² In the liver and adrenal, reduced perfusion is indicated by infarction, necrosis, and intraparenchymal hemorrhage. Endocardial necrosis is present in the heart, similar to that present with hypovolemic shock, the prototypic-reduced perfusion disorder. The pathological changes in the kidney are termed glomerular endotheliosis and consist largely of marked swelling of glomerular endothelial cells sufficient to occlude the capillary lumen.²³ This is accompanied by minimal changes in the renal podocytes. This change is important because it is present in no other form of hypertension, indicating preeclampsia is not merely an unmasking of prepregnancy hypertension. Additionally, the involvement of primarily endothelium points toward this tissue as an important target in the disorder.

Pathophysiological changes support the reduced perfusion concept. Perfusion is reduced to virtually any organ examined, including the uterus.²² Reduced uterine blood flow further reduces placental perfusion, resulting in a feed-forward loop consistent with the clinical course of preeclampsia. This is a disease that never gets better, only worse, and when it begins to worsen, it worsens rapidly.

Perfusion decreases secondary to vasospasm, activation of the coagulation cascade with the formation of occlusive microthrombae, and loss of fluid from the intravascular space.²² Vasospasm is not secondary to unique pressors or to an increase in usual pressors. Rather, women with preeclampsia are uniquely sensitive to any pressor agent.²⁴ Quite importantly, the increased pressor sensitivity,²⁵ activation of the coagulation cascade,²⁶ and loss of vascular integrity are evident in groups of women before the clinical manifestations of the disorder. This has led to the concept that endothelial dysfunction, which could explain all of the changes described, is a central pathophysiological feature of the disorder.²²

This hypothesis is also supported by altered endothelial-mediated vasodilatation, when vessels from several sites of preeclamptic women are examined ex vivo.²⁷ Furthermore, a myriad of markers of endothelial injury or dysfunction are present in women with preeclampsia and, in many cases, precede clinically evident disease supporting a causal role.²⁸ Although most models of endothelial activation or dysfunction in preeclampsia posit that placental products produced in response to reduced perfusion alter endothelial function, it is also likely that deficiency of repair secondary to reduced mobilization of endothelial progenitor cells may also be relevant.²⁹ Endothelial activation is only one component of a generalized activation of inflammatory responses that is characteristic of pregnancy (sometimes showing changes nearly as pronounced as those seen in sepsis) and further accentuated in preeclampsia.³⁰

Striking metabolic changes also characterize preeclampsia. These include a dyslipidemia with elevated triglycerides, free fatty acids, and LDL cholesterol, and reduced HDL cholesterol,³¹ with an increased prevalence of low dense LDL.³² Insulin resistance^33,34 and uric acid, other components of the metabolic syndrome, are also increased in preeclampsia.²² Many of these changes, including elevated free fatty acids³⁵ and uric acid,³⁶ can be demonstrated from very early pregnancy. Whether they antedate pregnancy has not been established. Self-reported history of hypercholesterolemia has been reported in nonpregnant women who later develop preeclampsia.³⁷

Uric acid has received increasing attention as potentially relevant not merely as a marker of cardiovascular disease but as causally important.³⁸ For example, rats in which uric acid is increased experimentally have increased blood pressure.³⁹ Whether hyperuricemia, one of the earliest and most consistent findings in preeclampsia, is causally important is being re-evaluated. A recent study by our group found that in women with gestational hypertension, uric acid was an indicator of increased adverse fetal outcome even in the absence of proteinuria.⁴⁰

	Maternal Fetal/Placental Interactions in Preeclampsia

Top Abstract Introduction Preeclampsia: A Two-Stage... Stage 1 of Preeclampsia:... Stage 2 of Preeclampsia:... Maternal Fetal/Placental... The Linkage of Stages... Clinical Implications References

 
Not all women with reduced placental perfusion develop preeclampsia. Pregnancies complicated by intrauterine growth restriction, the failure of infants to exercise their full growth potential, also have a similar reduction of placental perfusion. The failed remodeling of the uterine vessels supplying the placenta that is characteristic of preeclampsia is also present in intrauterine growth restriction,⁴¹ as well as in about one third of cases of spontaneous preterm birth⁴² without the clinical manifestations of preeclampsia. This has led to the concept that reduced placental perfusion must interact with maternal factors to result in clinical preeclampsia (Figure 2). These factors are proposed to be genetic, behavioral, and environmental. They are modified by the normal physiological changes of pregnancy, of which the increased inflammatory response may be particularly relevant. Conditions recognized to increase the risk of preeclampsia include obesity,⁴³ hypertension,⁴⁴ diabetes,⁴⁴ hyperhomocysteinemia,⁴⁵ increased androgens,⁴⁶ and black race.⁴⁷ Of course, these are all risk factors for cardiovascular disease in later life. The similarities between the pathophysiological features of preeclampsia and cardiovascular risk factors suggest a relationship between these conditions that is supported by epidemiological follow-up studies.

View larger version (30K): [in this window] [in a new window]   Figure 2. Maternal fetal/placental interactions in preeclampsia. The development of the maternal syndrome of preeclampsia (stage 2) requires that reduced placental perfusion interact with maternal factors. These constitutional factors are the maternal characteristics that increase the risk of cardiovascular disease in later life. They are modified by the physiological changes of pregnancy.

The genetic predisposition to preeclampsia has attracted much attention. Preeclampsia is clearly inherited. The frequency of preeclampsia in mothers, daughters, sisters, and granddaughters is 2 to 5x higher than in mothers-in-law, daughters-in-law, or control populations.⁴⁸ Attempts to impute genetic mechanisms are problematic because the syndrome occurs in only half of the population and is not manifest until reproductive years and then only in women who become pregnant. In a summary of inheritance studies, Arngrimmson concluded that within these limitations, data were consistent with a major dominant gene with variable penetrance or multifactorial inheritance.⁴⁹ The major contribution is from the maternal genome; however, fetal (paternal) genes are also contributors.⁵⁰ Attempts to identify preeclampsia gene(s) have used hypothesis-driven searches for candidate genes and genome-wide searches. Several function-perturbing polymorphisms of candidate genes are reported as more common in women with a history of preeclampsia. These include genes relevant to thrombophillias, folate metabolism, lipid metabolism, oxidative stress, and components of the renin-angiotensin system.⁵¹ The interesting feature of all of these candidate genes is the inconsistency with which they are found in different populations. As an example, the function-perturbing polymorphism of the methylenetetrahydrafolate reductase gene C677T has been examined in >27 studies, with widely diverging results in different populations.⁵² This may represent population differences consistent with the heterogeneity of preeclampsia but also reflects differing definitions of preeclampsia and, interestingly, year of publication. Early reports support a relationship, whereas more recent reports do not, suggesting publication bias.⁵² This same inconsistency characterizes reports of all genetic polymorphisms associated with preeclampsia.

Genome-wide searches are in progress. Reports of significant linkages between preeclampsia and loci on several chromosomes have been reported in studies from Iceland,⁵³ Australia,⁵⁴ the Netherlands,⁵⁵ and Finland.⁵⁶ As with candidate genes, the results are inconsistent. Linkage to chromosome 2 was found in 3 studies.^53,54,56 In 2 of these, it could not be excluded that the sites were the same,^53,54 but in the third, the site was clearly different.⁵⁶ In the Finnish study, linkage to chromosome 9 was to a site similar to that associated with type 2 diabetes in studies from China and Finland. A recent study indicates expression of highly polymorphic genes relevant to implantation with missense mutations cosegregating with preeclampsia in a chromosomal site identified as related to preeclampsia in Dutch studies.⁵⁷ Interestingly, most of the preeclampsia gene candidates are not localized to these sites. These studies support the heterogeneity of preeclampsia and its multifactorial inheritance.

The concept that maternal factors interact with reduced placental perfusion to produce the preeclampsia syndrome provides 2 especially important insights. First, it can help explain the diverse fetal manifestations of preeclampsia. Preeclampsia is associated with growth-restricted infants; however, this occurs in only one third of cases.⁵⁸ In preeclamptic pregnancies terminating after 37 weeks of gestation, there is actually an excess of large infants.⁵⁹ The maternal/fetal/placental interaction model proposes that the contribution of maternal and fetal/placental factors may vary in proportion. Thus, in the woman with abundant predisposing factors, even minor reduction in placental perfusion is sufficient for stage 2, whereas profound reductions in placental perfusion will result in the preeclampsia syndrome even in a woman with minimal predisposing factors. Second, the identification of these maternal factors provides specific targets for prevention of preeclampsia that are relevant to a subset of at-risk women.

	The Linkage of Stages 1 and 2

Top Abstract Introduction Preeclampsia: A Two-Stage... Stage 1 of Preeclampsia:... Stage 2 of Preeclampsia:... Maternal Fetal/Placental... The Linkage of Stages... Clinical Implications References

 
A key question in the 2-stage model of preeclampsia is what is the linkage of the 2 stages? This is the "holy grail" of preeclampsia research because identifying such linkage would provide a target for therapy common to all cases of preeclampsia regardless of predisposing factors. Over the years, numerous candidates have been considered and discarded. The search for unique factors present in the circulation of women with preeclampsia, "Substance X," occupied at least a generation of investigators.⁶⁰ The idea was eventually abandoned after numerous false starts in favor of an excess of usual factors such as cytokines, growth factors, or placental hormones. The concept of unique placental products, nonetheless, remains viable with the hypothesis that microvillus particles, likely the product of syncitiotrophoblast apoptosis, are present in excess in the blood of women with preeclampsia. It is proposed that these products interact with and activate circulating inflammatory cells or perhaps directly affect endothelial function.⁶¹ Several cytokines and other inflammatory markers that could alter endothelial function are increased in the blood of women with preeclampsia.⁶² However, neither increased placental mRNA nor uterine vein concentrations of relevant cytokines support a placental origin for these molecules.⁶³ There is evidence for increased activation of inflammatory cells, which could take place during passage through the intervillous space. These cells could then be the source of increased inflammatory molecules.^64,65 Placental hormones including estrogen,⁶⁶ progesterone,⁶⁷ and human placental lactogen⁶⁸ have been suggested as the linkage, but in general, their role has been inconsistently supported. The role of aberrations of the renin-angiotensin system has been considered for many years. Several reports have identified autoantibodies to the angiotensin subtype 1 receptor (AT₁) angiotensin antibodies in women with preeclampsia. These antibodies can activate the AT₁ receptor in vitro with resultant increases in tissue factor and NADP-H oxidase activity.⁶⁹ The origin of these autoantibodies and the natural history of their appearance and disappearance are not as yet determined. A preeclampsia-like syndrome can be induced in rats genetically modified to increase angiotensin production. Interestingly, these rats evidence an increase in autoantibodies to the AT₁ receptor.⁷⁰

Recent findings of increased concentrations of the soluble receptor for the angiogenic factors vascular endothelial growth factor and placental growth factor (s-Flt) in preeclampsia suggest that this molecule, which can be produced by the placenta in response to hypoxia, may be involved in the linkage. When the growth factors are bound to s-Flt, they are inactive.⁷¹ Animal experiments indicate that administration of s-Flt to pregnant rats results in hypertension and proteinuria.⁷¹ The conclusion that s-Flt is solely responsible for the linkage must be tempered by the finding that s-Flt is not increased in all women with preeclampsia, including some with even severe disease.⁷²

Oxidative stress, the excess of reactive oxygen species beyond the buffering capacity of endogenous antioxidants, is considered a prime candidate for linkage of the 2 stages. Most of the suggested linkages could contribute to or be stimulated by oxidative stress. Cytokines cause the release of free radicals⁷³ as part of their mechanism of action, whereas activated monocytes and neutrophils release free radicals when in contact with activated endothelium. NADP-H activation by angiotensin autoantibodies would result in the generation of free radicals. Oxidative stress triggers placental apoptosis,⁷⁴ causing the release of microvillous particles containing oxidized lipids, which can then act systemically. The growth factor inhibitor s-Flt is increased with hypoxia,⁷⁵ which, when accompanied by reperfusion, can also increase the generation of free radicals.

Oxidative stress is proposed as relevant to many diseases, and a role in preeclampsia has been entertained for &50 years.^76,77 Abundant evidence supports the presence of oxidative stress in preeclampsia.³¹ However, there is controversy regarding lipid markers of oxidative stress that are increased in the disorder.⁷⁸ Lipid peroxides and other oxidatively modified lipids such as isoprostanes have been reported to be increased in blood and tissues of women with preeclampsia for many years.³¹ However, oxidative modifications of these lipids can occur independent of oxidative stress either ex vivo or by enzymatic modification of lipids.⁷⁸ This has raised the question as to the relevance of increases of these materials to oxidative stress in preeclampsia. Nonetheless, there is abundant other evidence for oxidative stress in preeclampsia, including protein products of oxidative stress in maternal⁷⁹ and fetal tissues⁸⁰ as well as antibodies to oxidatively modified LDL.⁸¹ Furthermore, concentrations of the lynchpin antioxidant ascorbate are reduced in women with preeclampsia and women destined to develop preeclampsia.⁸²

The ultimate test of the role of oxidative stress is whether reduction or prevention of oxidative stress can ameliorate or prevent endothelial dysfunction and the maternal preeclampsia syndrome. As with all other interventions, the use of antioxidants after clinical evidence of preeclampsia was unsuccessful.⁸³ However, in a small trial of antioxidant therapy, 1000 mg of vitamin C and 400 IU of vitamin E administered from 20 weeks gestation not only reduced evidence of endothelial activation but also significantly reduced the incidence of preeclampsia.⁸⁴ Although promising, only 79 women actually received therapy in this study. Also, another small study did not demonstrate benefit with 50 treated and control subjects.⁸⁵ Larger international multicenter studies testing the efficacy of therapy and definitively establishing proof of safety in pregnancy are now in progress.

	Clinical Implications

Top Abstract Introduction Preeclampsia: A Two-Stage... Stage 1 of Preeclampsia:... Stage 2 of Preeclampsia:... Maternal Fetal/Placental... The Linkage of Stages... Clinical Implications References

 
The fact that stage 1 of preeclampsia, including abnormal placental bed vascular remodeling, is present in settings other than preeclampsia indicates that understanding this phenomenon has importance beyond preeclampsia. It also suggests that a useful target for investigation would be the understanding of what is the same and different in the several conditions associated with abnormal uterine perfusion.

As we learn more about preeclampsia, it is increasingly evident that it is not merely hypertension unmasked by pregnancy. Hypertension seems to be a marker of the disorder rather than a causal factor. Thus, success in treating preeclampsia is not merely reducing blood pressure but rather ameliorating the syndrome itself, including improving perinatal outcome, the major complication of the current management strategy of early delivery. This has led investigators directing the National Institute of Child Health and Human Development (NICHD) Maternal Fetal Medicine Networks study of antioxidant therapy to prevent preeclampsia not to choose the diagnosis of preeclampsia as the primary outcome. Rather, the primary outcome is the frequency of gestational hypertension in combination with markers of maternal organ dysfunction or perinatal morbidity or mortality.

The similarities in risk factors and pathophysiological changes of preeclampsia and later-life cardiovascular disease mandate consideration of their relationship. It is evident that women with preeclampsia have approximately a doubling of risk of death from cardiovascular disease.^86–88 The risk is greater in certain subsets. Women with preeclampsia who deliver preterm⁸⁶ or with recurrent preeclampsia^87,88 appear to be at greater risk. Whether the association of preeclampsia with later-life cardiovascular disease indicates: (1) that preeclampsia and cardiovascular disease have the same antecedents (as conventional wisdom dictates), (2) that preeclampsia causes cardiovascular disease, or (3) that having a normal pregnancy is protective or identifies low-risk status cannot be established without longitudinal studies beginning before pregnancy. Whatever the reason for the relationship, women with preeclampsia and certainly those with recurrent preeclampsia are at increased risk for later-life cardiovascular disease. They should be encouraged to obtain follow-up and to modify lifestyle to reduce cardiovascular risk.

The final point relates to fetal considerations. Preeclampsia is clearly inherited, suggesting some survival value. However, it is difficult to determine what this might be. Certain findings suggest the benefit may be to the fetus. Despite the reduced uterine perfusion of stage 1, only one third of fetuses of preeclamptic pregnancies are growth restricted.⁵⁸ The maternal metabolic changes of preeclampsia would favor increased nutrient availability for the fetus.²² As approaches to management are proposed and evaluated, it is important to consider the possibility that preeclampsia may represent an appropriate fetal response to reduced placental perfusion that some women cannot tolerate. This certainly is consistent with the heterogeneous nature of the disorder.

We have learned a great deal about this fascinating disorder in the last decade, and although we still have much to learn, the rate of progress in our understanding provides reason for optimism.

	Acknowledgments

 
This work was supported by National Institutes of Health grant HD 30367.

Received June 14, 2005; first decision July 1, 2005; accepted September 21, 2005.

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Top Abstract Introduction Preeclampsia: A Two-Stage... Stage 1 of Preeclampsia:... Stage 2 of Preeclampsia:... Maternal Fetal/Placental... The Linkage of Stages... Clinical Implications References

 
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