Preeclampsia

Recent Insights
James M. Roberts, Hilary S. Gammill
AbstractPreeclampsia 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. (Hypertension. 2005;
46:1243-1249.)
Key Words: preeclampsia hypertension, pregnancy oxidative stress endothelium

reeclampsia 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

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?

Stage 1 of Preeclampsia: Reduced

Placental Perfusion
Clinical Evidence
More than 60 years ago, Ernest Page formalized the concept
that placental perfusion was reduced in preeclampsia.6 Evi-

Received June 14, 2005; first decision July 1, 2005; revision accepted September 21, 2005.
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@
mwri.magee.edu
2005 American Heart Association, Inc.
Hypertension is available at http://www.hypertensionaha.org

DOI: 10.1161/01.HYP.0000188408.49896.c5

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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).

dence 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.

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-916also 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

Mechanisms

Pathological and Pathophysiological Changes

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

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 endo-

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Roberts and Gammill

thelial 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 feedforward 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 endothelialmediated 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 resistance33,34 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

Preeclampsia: Recent Insights

1245

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.

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
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.
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 5 higher than in mothers-in-law,

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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 functionperturbing 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 placen-

tal 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

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

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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
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 understand-

Preeclampsia: Recent Insights

1247

ing 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 preeclampsia87,88 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.

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Preeclampsia: Recent Insights

James M. Roberts and Hilary S. Gammill
Hypertension. 2005;46:1243-1249; originally published online October 17, 2005;
doi: 10.1161/01.HYP.0000188408.49896.c5
Hypertension is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
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