November 1998 Volume 179 Number 5

Etiology and pathogenesis of preeclampsia: Current concepts

Gustaaf A. Dekker, MD, PhD [MEDLINE LOOKUP]
Baha M. Sibai, MD [MEDLINE LOOKUP]

Amsterdam, The Netherlands, and Memphis,

Tennessee
Sections
Abstract
Uteroplacental circulation
Vascular tone
Pathogenesis of preeclampsia
Etiology of preeclampsia
Preeclampsia as a genetic disease
Underlying disorders associated with
preeclampsia
Unifying hypothesis (Fig 1)
References
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Abstract

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The etiology of preeclampsia is unknown. At present, 4 hypotheses are the subject of extensive
investigation, as follows: (1) Placental ischemiaIncreased trophoblast deportation, as a
consequence of ischemia, may inflict endothelial cell dysfunction. (2) Very low-density lipoprotein
versus toxicity-preventing activityIn compensation for increased energy demand during
pregnancy, nonesterified fatty acids are mobilized. In women with low albumin concentrations,
transporting extra nonesterified fatty acids from adipose tissues to the liver is likely to reduce
albumins antitoxic activity to a point at which very-low density lipoprotein toxicity is expressed. (3)
Immune maladaptationInteraction between decidual leukocytes and invading cytotrophoblast
cells is essential for normal trophoblast invasion and development. Immune maladaptation may
cause shallow invasion of spiral arteries by endovascular cytotrophoblast cells and endothelial
cell dysfunction mediated by an increased decidual release of cytokines, proteolytic enzymes,
and free radical species. (4) Genetic imprintingDevelopment of preeclampsia-eclampsia may
be based on a single recessive gene or a dominant gene with incomplete penetrance.
Penetrance may be dependent on fetal genotype. The possibility of genetic imprinting should be
considered in future genetic investigations of preeclampsia. (Am J Obstet Gynecol
1998;179:1359-75.)
(Click on a term to search this journal for other articles containing that term.)
Key words: Preeclampsia, endothelium, etiology, immune, gene

Shallow endovascular cytotrophoblast invasion in the spiral arteries and endothelial cell
dysfunction are 2 key features in the pathogenesis of preeclampsia, yet the etiology of
preeclampsia is still unknown. Currently, 4 hypotheses are favored: placental ischemia, very lowdensity lipoproteins versus toxicity preventing activity, immune maladaptation, and genetic
imprinting. For the sake of clarity, these 4 hypotheses are described separately; however, it
should be stressed that these 4 hypotheses are not mutually exclusive but probably interactive.
Before discussing the pros and cons of these 4 hypotheses, we will briefly review the literature on
uteroplacental circulation, vascular tone regulation in normal pregnancy, and pathogenesis of the
clinical syndrome.

Uteroplacental circulation

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During the early weeks of gestation, cytotrophoblast cells stream out of the tips of the anchoring
villi and penetrate the trophoblast shell and the overlying syncytiotrophoblast to form
cytotrophoblast columns that develop into the cytotrophoblast shell. Trophoblast cells continue to
migrate into the decidua and eventually colonize the placental beds myometrium. When the
cytotrophoblast shell contacts the spiral arteries openings, trophoblast cells stream into their
lumina, where they form intraluminal plugs. 1-3 Endovascular trophoblast cells replace the
endothelium of spiral arteries and then invade the media, with resulting destruction of the medial
elastic, muscular, and neural tissue. Trophoblast cells become incorporated into the vessel wall,
and in the final stages the endothelial lining is reconstituted. 1-3 Zhou et al4 demonstrated that
endovascular cytotrophoblasts normally transform their adhesion receptor phenotype so as to
resemble the endothelial cells they replace, and they were subsequently successful in
demonstrating that preeclampsia is associated with a failure of cytotrophoblasts to mimic a
vascular adhesion phenotype. Vascular changes may actually precede trophoblast invasion,
suggesting that interstitial trophoblast plays a role in inducing early disruption (probably by
secreting proteolytic enzymes).3 These physiologic changes create a low-resistance arteriolar
system and an absence of maternal vasomotor control, which allows the dramatic increase in
blood supply to the growing fetus. During early stages of implantation, cytotrophoblast plugs may
act as valves regulating blood flow in the intervillous space and protect the embryo from forceful
maternal blood flow. Results of color Doppler studies suggest that the presence of continuous
intervillous space flow in the first trimester is associated with a complicated pregnancy outcome
and that a true intervillous space blood flow is established only by about 12 weeks gestation in
normal pregnancies.4-6
In preeclampsia and some cases of intrauterine growth restriction (IUGR), physiologic changes in
the spiral arteries are confined to the decidual portion of the arteries; about 30% to 50% of the
placental beds spiral arteries escape entirely from endovascular trophoblast invasion. 1,2,7
Myometrial segments remain anatomically intact and undilated, and adrenergic nerve supply to
the spiral arteries remains intact.2,7 Intraluminal cytotrophoblast in spiral arteries is often identified
in preeclampsia and IUGR, unlike in normal pregnancies.2,7 Many vessels are occluded by
atherosis, with an accumulation of lipid-laden macrophages and a perivascular mononuclear cell
infiltrate. Acute atherosis and the associated thrombosis may cause placental infarctions.
Lipoprotein-a deposition is often found in association with atherosis. 8

Vascular endothelial growth factor (VEGF) and the vascular adhesion

phenotype of invading cytotrophoblasts.

VEGF, a growth factor involved in angiogenesis, with a specific action on endothelial cells, is
widely expressed at the fetomaternal interface.9 On implantation, expression is dominant in the
uterine epithelial cells. Subsequently, expression increases in the decidual macrophages, which
remain the principal source of VEGF. First-trimester human intermediate and extravillous
trophoblast has been found to express the flt receptor for VEGF. VEGF is up-regulated by
hypoxia10; neovascularization induced by hypoxia corrects tissue oxygenation, and VEGF release
will be down-regulated. This homeostatic mechanism may have particular relevance in the first
trimester when oxygen tension of trophoblast villi is particularly low.4-6,10-12 VEGF may be involved
in inducing the expression of endothelial markers by invading cytotrophoblasts. VEGF has been
shown to induce the expression of those integrins on endothelial cells that are associated with
angiogenic invasion; these integrins are the same as those described by Zhou et al 4 as being part
of the de novo expression of endothelial characteristics by invading cytotrophoblasts.

Decidual extracellular matrix and cell surface adhesion molecules.

During invasion, trophoblast cells are not cytolytic but secrete enzymes that affect the
extracellular matrix. Immunohistochemical studies have localized plasminogen activator, as well
as metalloproteinases, which include collagenases within the extravillous trophoblast. 3,13,14
Metalloproteinase activity is influenced by a variety of mediators. Secretion of metalloproteinases
is plasmin dependent but is inhibited by -human chorionic gonadotropin, which would favor an
autocrine regulatory system. However, interleukin-l (IL-1 ) is stimulatory, and because
trophoblast cells release IL-1 and also express the IL-1 receptor, there may be an autocrine
stimulatory loop.15 Another potential candidate for stimulation of type IV collagenase is tumor
necrosis factor- (TNF- ).3
Cell migration is dependent on adhesion to extracellular matrix proteins for anchorage and
traction. In addition to mediating adhesion, extracellular matrix binding to specific transmembrane
receptors also affects cell growth and differentiation.16,17 Also, trophoblast behavior during
implantation is influenced by decidual extracellular matrix proteins. 18,19 Cells bind to extracellular
matrix proteins by appropriate surface receptors called adhesion molecules. 20 The 4 major
families of adhesion molecules are integrins, cadherins, immunoglobulin superfamily, and
selectins. E-Cadherin is involved in differentiation of cytotrophoblast into syncytiotrophoblast, 21
whereas integrins mediate adhesion to the extracellular matrix. 20 Integrins are transmembrane
glycoproteins consisting of noncovalently associated - and -subunits.22 Integrin ligand
specificity is determined by combination of the various - and -subunits.22-26 Thus onset of
migratory or invasive behavior of trophoblast is associated with a shift in integrin expression,
thereby changing the binding tendency of trophoblast from a basal lamina (laminin) to a stromal
type (fibronectin) of matrix.3,27-31
Integrin switching by invasive cytotrophoblasts is abnormal in preeclampsia. Invading trophoblast
within the placental bed of preeclamptic patients fails to down-regulate 4 and to make the switch
from 6 to 5 and 1 integrin subunits.25,27-30 Pijnenborg et al32 observed lower trophoblast
attachment on the extracellular matrix proteins fibronectin and vitronectin in preeclamptic
pregnancies. This probably reflects differences in trophoblast integrin expression. In contrast,
Divers et al33 failed to find any difference in trophoblast integrin expression between normal and
preeclamptic pregnancies. The abnormal cytotrophoblast differentiation in preeclampsia is not
necessarily a primary feature. An alternative explanation is an abnormal interaction between
trophoblast and decidual lymphoid cells.31 In a monkey model hypoxia was demonstrated to be
associated with increased invasion.34 However, it is uncertain whether this phenomenon is
mediated by a direct effect of hypoxia on cytotrophoblast integrin expression or reflects increased
VEGF action.4

Vascular tone

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In normal pregnancy there is an 8-fold to 10-fold increase in prostacyclin. Thromboxane A2 (TxA2)

biosynthesis is also increased throughout normal pregnancy; the net result, however, is a biologic
dominance of prostacyclin over TxA2.35,36 The dominance of prostacyclin provides an explanation
for vascular refractoriness to angiotensin II in normal pregnancy, although its role as a circulating
hormone is still controversial because of its evanescent nature. 35-37 However, prostaglandins may
not be the major vasodilators of pregnancy.38,39 A number of peptide regulatory factors (cytokines,
binding proteins, growth factors) released in an appropriate cortico-steroid environment play an
integral part in this mediation.40-42 Nitric oxide is probably an important messenger, but certainly
not the only one, in inducing vasodilation in normal pregnancy.42-47 In pregnant animals chronic
inhibition of nitric oxide synthesis reverses refractoriness to angiotensin and vasopressin and
eventually produces a preeclampsia-like syndrome.48 Nitric oxide is probably not the only
explanation for the marked vasodilatation of normal pregnancy. Pascoal and Umans 49 recently
provided strong evidence for the presence of an endothelium-derived hyperpolarizing vasodilatory
factor in causing pregnancy-associated vasorelaxation.
Nitric oxide is more important than prostacyclin in maintaining low vascular tone in fetoplacental
vessels.50-52 Immunohistochemical studies to localize endothelial nitric oxide synthetase in term
placentae found strong staining patterns in syncytiotrophoblast and absence of staining in
endothelial cells of small fetoplacental vessels and the cytotrophoblast. 53 Negligible nitric oxide
production in the placental bed is unlikely to contribute substantially to uteroplacental
vasodilation.54 Additionally, recent studies found significantly higher inducible nitric oxide
synthetase activity in basal plate and villous tissue compared with the activity of endothelial nitric
oxide synthetase.54,55

Pathogenesis of preeclampsia

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In preeclampsia, absence of normal stimulation of the renin-angiotensin system, despite

hypovolemia, and increased vascular sensitivity to angiotensin II and norepinephrine can be
explained by a biologic dominance of TxA2 over prostacyclin.35-37,56,57 A reduction in urinary
excretion of prostacyclin metabolites precedes the development of clinical disease, whereas TxA 2
biosynthesis is increased in preeclampsia.58 Increased TxA2 production in preeclampsia is largely
derived from platelets35 and the placenta.59 Placental prostacyclin production is reduced.60
Although the increased TxA2-to-prostacyclin ratio allows an explanation for vasoconstriction,
platelet destruction, and reduced uteroplacental blood flow, evidence is mounting that
preeclampsia is not simply a state of prostacyclin deficiency.57,61 Increased levels of factor VIII
related antigen, total and cellular fibronectin, thrombomodulin, endothelin, growth factor activity, a
disturbance of the tissue plasminogen activator/plasminogen activator inhibitor balance, and the
prostacyclin/TxA2 balance all support the hypothesis that a more global endothelial cell
dysfunction is intimately involved in the pathogenesis of preeclampsia.62-73 Morphologic evidence
of endothelial cell injury is provided by glomerular endotheliosis and ultrastructural changes in the
placental bed, uterine boundary vessels, and other parts of the circulation. 74-76 In in vitro
experiments preeclamptic sera do not cause actual endothelial cell damage but rather activate
specific endothelial cell metabolic pathways, 77 which may be related to the disturbances in
vascular function encountered in vivo. 78 Results of studies on actual nitric oxide production in
preeclampsia have yielded controversial results: Plasma nitrite and nitrate levels have been found
to be decreased, unchanged, and increased as compared with the levens in normotensive control
subjects.79-84 However, the best indicator (in vivo) of overall nitric oxide production is the steadystate urinary excretion of nitrites, and Davidge et al85 found urinary excretion, but not plasma
levels, of these nitric oxide metabolites to be decreased in preeclampsia. Plasma concentrations
of endogenous nitric oxide synthetase inhibitors are raised in patients with preeclampsia as
compared with the levels in patients with normal pregnancies or patients with gestational
hypertension.86,87 Nitric oxide donors cause a significant decrease in uterine artery resistance in
patients with an elevated uterine artery resistance index. 88

In preeclampsia, endothelial cell dysfunction and platelet aggregation precede the increase in
thrombin and fibrin formation.89,90 An inadequate production of either antiaggregatory prostacyclin
or nitric oxide, or both, provides an attractive hypothetical explanation for surface-mediated
platelet activation occurring on the inner lining of spiral arteries. Platelets adhere to and release
and dense granule constituents, specifically, TxA2 and serotonin, contributing to platelet
aggregation and inducing fibrin formation. Zeeman and Dekker 61 suggested that if there are still
intact endothelial cells left in the spiral arteries the increased platelet-derived serotonin levels 91
may interact with endothelial S1 receptors, which may induce a partial recovery of endothelial
prostacyclin and nitric oxide release.92 Local prostacyclin may stimulate the uteroplacental reninangiotensin system and thus induce the release of angiotensin II, which may improve
uteroplacental perfusion by increasing maternal blood pressure (perfusion pressure) and by
forming an extra stimulus for prostacyclin and nitric oxide release by the uteroplacental
vessels.61,93
In preeclampsia and IUGR the fetoplacental unit is also characterized by a prostacyclin/TxA 2
imbalance.94 Concerning fetoplacental nitric oxide synthesis, Morris et al 54 found
syncytiotrophoblast nitric oxide release, as judged by nitric oxide synthetase activity, to be
decreased in preeclampsia as compared with normal placentas. Wang et al95 found no
differences in nitric oxide production, as judged by nitrite levels, between normal and
preeclamptic placentas. Ghabour et al96 reported that syncytiotrophoblast endothelial nitric oxide
synthetase immunostains appeared primarily apical in location and diffuse in distribution in
preeclamptic placentas but primarily basal and punctate in normal placentas. In the villous
trophoblast differentiation of cytotrophoblast into syncytiotrophoblast is associated with
endothelial nitric oxide synthetase expression.97 Thus alterations in endothelial nitric oxide
synthetase expression in preeclamptic placentas may be a result of placental damage and repair
processes rather than the primary mediator.

Etiology of preeclampsia

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Endothelial cell activation or dysfunction appears to be the central theme in the pathogenesis of
preeclampsia, but what causes these endothelial changes in preeclampsia? Four hypotheses are
currently the subject of extensive investigation. For the sake of clarity these hypotheses are
described separately; however, it should be stressed that they are not mutually exclusive but
probably interactive.

Placental ischemia.
According to the Oxford group of researchers, preeclampsia is a 2-stage placental disease. The
first stage is the process that affects the spiral arteries and results in a deficient blood supply to
the placenta. The second stage encompasses the effects of the ensuing placental ischemia on
both the fetus and the mother.98-100 Syncytiotrophoblast microvillous membranes from normal and
preeclamptic placentas were found to suppress endothelial cell proliferation to a similar extent
and disrupted endothelial monolayers to form a honeycomb-like pattern. 98 Deportation of
placental tissue, a feature also present in normal pregnancy, is increased in established
preeclampsia. Although deportation of intact trophoblasts could, at least in theory, exert a
systemic effect by impairing the substantial pulmonary nitric oxide production, it is (according to
the Oxford group) the increased microdeportation of syncytiotrophoblast microvillous membrane
particles that is probably more related to the systemic endothelial cell dysfunction in
preeclampsia.99,100 The increased syncytiotrophoblast deportation in preeclampsia is probably
explained by the presence of syncytial sprouts that may be elongated on long pedicles. 99
Cytotrophoblast proliferation and formation of these outgrowth lesions of syncytiotrophoblast may
represent evidence of placental repair mechanisms. Preeclampsia is associated with glycogen
accumulation in syncytiotrophoblast,101 which could be another expression of increased

syncytiotrophoblast deportation and increased cytotrophoblast proliferation. Placental villous

cytotrophoblasts produce TxA2, the amount decreasing as they mature into
syncytiotrophoblasts.102 Tsukimori et al103 found a syncytiotrophoblast factor that was cytotoxic to
endothelial cells to be present in preeclamptic placentas but not in normal ones.
Placental ischemia as the cause of endothelial cell dysfunction in preeclampsia is an attractive
concept, but several concerns are conceivable that may dispute its validity. First, if placental
ischemia is the actual cause of endothelial cell dysfunction, one would expect a closer correlation
between the presence of maternal and fetal components of the disease. However, this is not the
usual finding in clinical practice. Next, the chronology of the maternal components of the
syndrome appear not to fit with the placental ischemia hypothesis. The findings of some recent
studies suggest that endothelial cell involvement is already present in the first trimester, 104,105
which is difficult to reconcile with the first conceivable stages of placental ischemia. The normal
environment for trophoblast in the first trimester is low in oxygen, 10-12 and this relative hypoxia is
likely to be of physiologic importance because signs of increased intervillous flow are associated
with adverse pregnancy outcome.6 Low oxygen also affects trophoblast function later in
pregnancy, and the fact that hypoxia-induced syncytiotrophoblast and cytotrophoblast changes in
third-trimester placentas resemble the histologic changes in preeclampsia suggests that the
placenta may indeed be relatively hypoxic in the end stage of a preeclamptic pregnancy. 106 The
basic problem with the Oxford hypothesis is the fact that the studies are confined to patients with
established disease. Thus increased syncytiotrophoblast deportation, which is of pivotal
importance in this hypothesis, is likely to be just a feature of end-stage disease. Nevertheless,
this phenomenon might be clinically relevant because it could be involved in causing the extreme
refractory hypertension and vasospasm, which are so common in the terminal stages of severe
preeclampsia-eclampsia.

Very low-density lipoproteins (VLDL) versus toxicity-preventing activity.

In preeclampsia, circulating free fatty acids (FFA) are already increased 15 to 20 weeks before
the onset of clinical disease.107 Sera from preeclamptic women have both a higher ratio of FFA to
albumin and increased lipolytic activity resulting in enhanced endothelial cell uptake of FFA,
which are further esterified into triglycerides.108,109 Among the FFA, oleic, linoleic, and palmitic
acids have been found to be increased by 37%, 25%, and 25%, respectively. Linoleic acid
reduces thrombin-stimulated prostacyclin release by 30% to 60% and oleic acid by 10% to 30%,
whereas palmitic acid has no effect. Incubation with linoleic acid reduces endothelial cyclic
guanosine monophosphate levels by 70% and the ability to inhibit platelet aggregation by 10% to
45%.110 Plasma albumin exists as several isoelectric species, which range from isoelectric point
(pI) 4.8 to pI 5.6. The more FFA are bound to albumin, the lower the pI. Plasma albumin exerts a
toxicity-preventing activity if it is in the pI 5.6 form. Because higher ratios of FFA to albumin cause
a shift from the pI 5.6 to the pI 4.8 form of albumin, patients with preeclampsia will have lower
amounts of protective toxicity-preventing acivity (pI 5.6) than normotensive pregnant women. A
low ratio of toxicity-preventing activity to VLDL would result in cytotoxicity and triglyceride
accumulation in endothelial cells.111 According to Arbogast et al,111 pregnancy increases energy
demands, which are reflected by increasing VLDL concentrations throughout pregnancy. In
women with low albumin concentrations, the burden of transporting extra FFA from adipose tissue
to the liver is likely to reduce the concentration of toxicity-preventing activity to a point at which
VLDL toxicity is expressed, leading to endothelial cell injury.
Similar to the concerns with regard to the placental ischemia hypothesis, it is difficult to reconcile
an exaggerated energy demand occurring so early that it will cause a severe VLDL/toxicitypreventing activity imbalance and subsequently endothelial cell dysfunction in the first trimester.
Thus FFA and endothelial cell triglyceride accumulation are early and probably very relevant
features in preeclampsia, but they are not necessarily caused by an exaggerated energy
demand.111,112 Increased FFA levels and endothelial cell triglyceride accumulation in preeclampsia

may reflect cytokine-mediated oxidative stress, caused by either ischemia-reperfusion

mechanisms or activated leukocytes, or both.113

Immune maladaptation.
In humans, organ transplants will be rejected if there are differences between donor and recipient
with respect to major histocompatibility complex (MHC) genes (ie, human leukocyte antigens
[HLA]). It has been found that trophoblast cells in contact with maternal blood are negative for
MHC class I and II alloantigens, whereas those in contact with maternal tissue are often MHC
class I positive. Hence first-trimester syncytiotrophoblast and noninvasive villous cytotrophoblast
do not express MHC class I alloantigens, but rather the extravillous cytotrophoblast at the tips of
the cell columns and in spiral arteries is MHC class I positive. ll4-ll7 The HLA class I gene family
encodes cell-surface glycoproteins that include the highly polymorphic transplantation molecules
HLA-A, HLA-B, and HLA-C, which show widespread tissue expression and function in the
presentation of autologous peptide antigens to T cells. At least 3 additional class I genes (HLA-E,
HLA-F, and HLA-G, known as nonclassical [class Ib] genes) have been identified that are highly
homologous to classical HLA genes. HLA-E and HLA-F are expressed in many fetal and adult
tissues. By contrast, HLA-G is only expressed by the extravillous trophoblast at the maternofetal
interface, where classical class I and II antigens are absent; this restricted expression suggests
that HLA-G plays a role in the immune tolerance of the semiallogenic fetus by the mother.114-117 An
important feature of HLA-G is that its gene locus appears to exhibit a very limited degree of
polymorphism, which is not likely to affect unduly the sequence of expressed proteins. However,
van der Ven and Ober118 presented evidence of many distinctive alleles in the African-American
population and the presence of subtle HLA-G mutations in African-American neonates with IUGR,
which appears to contrast with the finding that HLA-G shows very little polymorphism in
Caucasian persons.
The decidua contains an abundance of cells of bone marrow origin as is demonstrable by their
cell surface antigen expression (CD45). These antigens are designated by their CD number, an
arbitrary number assigned to each Cluster of Differentiation. In the late secretory phase of the
endometrium an unusual population expressing CD56, a marker of peripheral blood large
granular lymphocytes, becomes dominant. These uterine large granular leukocytes resemble
natural killer (NK) cells but do not express such strong NK cell activity as peripheral blood NK
cells. About 75% of decidual cells express CD45, reflecting their bone marrow origin (ie, 45%
uterine large granular leukocytes, 19% macrophages, and 8% T cells). As pregnancy progresses,
the number of macrophages and T cells remains constant but the number of uterine large
granular leukocytes declines dramatically.119-121
Cells of the NK lineage, such as uterine large granular leukocytes, kill target cells that are
deficient in MHC expression rather than recognizing the presence of foreign MHC. This is the
basis of the missing self hypothesis for NK cytolysis. 122-124 Therefore simple lack of classical
class I molecules on trophoectoderm and later on invading cytotrophoblast would seem to be
inadequate to explain their protection from NK(-like) cells. The presence of a nonpolymorphic
nonclassical class I antigen, HLA-G, on the surface of invasive cytotrophoblast cells may be an
explanation for this conundrum.125 HLA-G is indeed capable of inhibiting NK activity of uterine
large granular leukocytes against trophoblast cells at the maternofetal interface. 114,120,123 Thus the
remarkable absence of regular HLA expression and the presence of HLA-G on invasive
cytotrophoblast are likely to be of pivotal significance in protecting trophoblast from effective
maternal immune recognition or cytotoxic attack.115-117 Throughout gestation, extravillous
cytotrophoblast cells retain the ability to up-regulate HLA-G expression. Apparently they must
avoid maternal immune surveillance constantly. In contrast, cytotrophoblast cells only express
invasive characteristics transiently (ie, only in early gestation are they characterized by enhanced
metalloproteinase expression and integrin switching). 126 Colbern et al127 observed a lower level of
messenger ribonucleic acid for HLA-G in chorionic tissue in preeclampsia than in normal
pregnancy. However, normalization to messenger ribonucleic acid for cytokeratin revealed that

this was caused by a smaller number of trophoblast cells present in preeclamptic placentas, thus
showing that these findings were only a reflection of the well-established reduced trophoblast
invasion in preeclampsia. Recent studies suggest that extravillous trophoblast cells also express
HLA-C. It may be that the coordinated expression of both HLA-G and HLA-C is required to
provide a set of trophoblast HLA class I molecules, which act together for optimal NK recognition
and to prevent lysis by these cells. 114,116
An alternative biologic role for uterine large granular lymphocytes and other decidual CD56 cells
has recently been consideredthat trophoblast growth and invasion may be dependent on
appropriate cytokines being produced by these cells in response to HLA-G expressed on
cytotrophoblast cells.128 Hence decidual leukocyte activity could actually be beneficial to
trophoblast growth and function by a phenomenon named immunotrophism. 129 In addition, colonystimulating factors are produced by decidual macrophages and by the developing placenta itself.
The amount increases with implantation.130 Colony-stimulating factors stimulate the endometrial
macrophage population, trophoblast human placental lactogen, and human chorionic
gonadotropin synthesis and thus appear to be intimately involved in decidual trophoblast
interactions during early pregnancy.131 Several cytokines are now known to be integral to early
pregnancy development. Granulocyte-macrophage colony-stimulating factor (GM-CSF), IL-1,
TNF- , interferon- (IFN- ), and colony-stimulating factor-1 (CSF-1) have all been implicated in
blastocyst attachment and in trophoblast implantation, proliferation, and invasion. Because TNF, IFN- , IFN- , IFN- , and transforming growth factor (TGF)-l are produced in the uteroplacental
unit and inhibit trophoblast deoxyribonucleic acid synthesis, they may take part in regulating
trophoblast growth. Conversely, IL-1, GM-CSF, and IL-6 are thought to have trophoblast growthstimulating effects. It should be emphasized that the majority of these cytokine effects occur in a
close and complex interaction with cortico-steroids and prostaglandins. l19, 132-134
In 1986, 2 distinct and mutually inhibitory types of T-helper cells were described. 135 The first type
of cell, termed Th1, secretes IL-2, IFN- , and lymphotoxin. This contrast with Th2 cells, which
secrete IL-4, IL-4, IL-6, and IL-10.136 Th1 cytokines are associated with cell-mediated immunity
and delayed hypersensitivity reactions, whereas Th2 cytokines foster antibody responses and
allergic reactions. Because Th1 cytokines are considered to be harmful to pregnancy and Th2
cytokines (IL-10) can down-regulate production of Th1 cytokines, it has been proposed that
successful pregnancy is a Th2 phenomenon.137 This hypothesis is consistent with the observation
that cell-mediated autoimmune conditions such as rheumatoid arthritis are often improved during
pregnancy, whereas disorders associated with autoantibodies may be worsened by pregnancy.138
Several substances such as prostaglandin E2, TGF- , GM-CSF, and IL-10139-141 play a part in the
immunoendocrine network in pregnancy maintenance. PGE 2 has many immunosuppressive
properties, including the inhibition of all cells of the immune system. 140 IL-10 potentially has 2
mechanisms by which it may inhibit immune function: (1) directly as a cytokine synthesis
inhibitory factor and (2) indirectly as an inducer of adrenocorticotropic hormone. Although these
data are intriguing, they must be considered in light of the successful reproduction of IL-10
knock-out mice.142
In addition to cytokines, fetal and placental growth is at least partially regulated by insulin-like
growth factors (IGF) and insulin-like growth factorbinding proteins (IGFBP-1 or placental protein
12). Trophoblast substances such as human placental lactogen stimulate an increasing
production of IGF-I by the maternal liver, whereas, on the other hand, IGF-I binding to trophoblast
cells changes during trophoblast differentiation.143 Fetal and maternal IGF-I levels are positively
correlated with fetal weight. IGFBP-1, which is produced by decidual stromal cells, impairs
trophoblast growth by inhibiting IGF-I. Another explanation may be that IGFBP-1 also contains an
integrin arginineglycineaspartic acid recognition sequence that can bind to the 4D1 integrin
(fibronectin receptor).144 The presence of elevated maternal levels of IGFBP-1, at 16-24 weeks
gestation, in future preeclampsia and IUGR suggests that decidual overproduction of IGFBP-1
may be at least partially involved in the causation of abnormal placentation. 143-145 In contrast, de
Groot et al146 found midtrimester plasma IGFBP-1 concentrations to be significantly lower in

women who later had preeclampsia compared with control subjects with normal pregnancies. At
the moment it is not clear whether these contradictory findings can be explained by assay
differences.
Epidemiologic evidence suggests that immune mechanisms ought to be involved in the etiology
of preeclampsia.147-149 Genuine preeclampsia is primarily a disease of first pregnancies. A
previous normal pregnancy is associated with a markedly lowered incidence of preeclampsia.
Even a previous abortion provides some protection. Multiparitys protective effect, however, is lost
with change of partner; thus preeclampsia may be a problem of primipaternity rather than
primigravidity.148 In a recent article Trupin et al149 studied 5068 nulliparous and 5800 multiparous
women, 573 of whom had new partners. The preeclampsia incidence in nulliparous women
(3.2%) and multiparous women with changed paternity (3%) was found to be similar, as
contrasted with the significantly lower incidence of preeclampsia (1.9%) in multiparous women
with no change in partners. Analogous to altered paternity, artificial donor insemination and
oocyte donation result in an increased incidence of preeclampsia.150 Additionally, the length of
time of unprotected sexual cohabitation before conception appears to be inversely related to the
incidence of pregnancy-induced hypertensive disorders. 151 There are numerous reports of
immunologic phenomena in preeclampsia. Beginning early in the second trimester, women in
whom preeclampsia develops later have a significantly lower proportion of T-helper cells
compared with the proportion in those women who remain normotensive. 152 Antibodies against
endothelial cells have been found in 50% of women with preeclampsia versus 15% of control
women.153 Deposition of immunoglobulins (IgM), complement (C3), and fibrin has been noted in
the walls of preeclamptic spiral arteries, especially in acute atherosis, in which substantial
granular deposits of IgM can often be seen. Immunologic pathogenesis of acute atherosis is
suggested by morphologic similarities to lesions seen in allograft rejection. 154 However, acute
atherosis usually occurs in those arteries that have not undergone physiologic changes mediated
by trophoblast invasion; thus, if a transplantation analogy is pursued, it is necessary to consider
that the fetus is rejecting the mother.154
What is the link between immune maladaptation and endothelial cell activation in preeclampsia?
The decidua contains an abundance of cells of bone marrow origin. These cells, when activated,
can release a host of mediators that may interact with endothelial cells.

Elastase.
Activated neutrophils release elastase and other toxic proteases, which can destroy the integrity
of endothelium. Plasma elastase levels are significantly higher in preeclampsia than in normal
pregnancy and correlate with elevated levels of endothelin and factor VIIIrelated antigen,
supporting their involvement in causing endothelial cell dysfunction in preeclampsia. The number
of elastase-positive decidual neutrophils is significantly greater in preeclampsia than in normal
pregnancies and correlates with plasma uric acid.155,156

Cytokines.
So far, most cytokine research has been concerned with TNF and IL-1 because their endothelial
effects resemble changes described in preeclampsia. TNF and IL-1 enhance the generation of
thrombin, platelet-activating factor, factor VIIIrelated antigen, and plasminogen activator
inhibitor-l, endothelial cell permeability, and expression of intercellular adhesion molecule-1
(ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) and increase inducible nitric oxide
synthetase activity and levels of a variety of prostaglandins, at the same time that endothelial
nitric oxide synthetase activity is down-regulated.157,158 So far, most studies reported found an
increase in TNF- levels in preeclampsia, although it is still controversial whether this increase in
TNF- occurs after the syndrome is detected clinically and whether this increase only occurs in
preeclamptic pregnancies complicated by IUGR.159-161 TNF- detection is problematic as a result

of a short half-life and possible interference of its soluble receptors. It may be deceptive to draw
conclusions from plasma TNF levels. Soluble TNF receptors are more reliable markers for TNF
activity. There are 2 specific receptors for TNF- of 75 and 55 kd molecular weight (p75 and p55,
respectively). Each can be shed as soluble protein that specifically binds TNF . Levels of soluble
TNF receptors are known to increase after an increase in TNF- , bind TNF- , and thus provide a
protective mechanism against excessive TNF- production. Because TNF receptors have a
longer half-life than TNF- , they are footprints of TNF- activity. The p55 and p75 soluble TNF
receptor levels are significantly elevated in preeclampsia as compared with uncomplicated
pregnancy.162,163 Thus the rise in TNF- levels reported in preeclampsia is probably real.164 The
source of this excessive production may be activated (decidual) leukocytes or the placenta itself,
because syncytiotrophoblast contains TNF- messenger ribonucleic acid.165 Preeclampsia shows
some aspects of an acute-phase response, which may be caused by the elevated IL-6 levels. 166
Changes in plasma proteins, which include increases in plasma ceruloplasmin, l-antitrypsin, and
haptoglobin, hypoalbuminemia, and reduced plasma transferrin are characteristic of an acutephase reaction, as are certain alterations in complement activity in preeclamptic sera. Also, Il-6
has definite effects on endothelial cells such as increased permeability, stimulation of plateletderived growth factor synthesis, and impairment of prostacyclin synthesis. Oxygen free radicals
are known to induce endothelial IL-6 synthesis. Il-6 production is thought to be integrally related
to TNF- . Whereas IL-6 has direct negative feedback on TNF- production, its production in
decidua and trophoblast is increased by TNF-a and IL-1.167 IFN- levels are increased in
preeclampsia.168 IFN- up-regulates endothelial cell ICAM-1 expression and IL-6 synthesis, which
may be another explanation for the increased plasma IL-6 levels in preeclampsia. IL-8 and GMCSF levels have been found to be similar in normal and preeclamptic pregnancies. 166
Dysfunctional endothelial cells undergo activation with production of cell surface proteins that
mediate adherence of inflammatory cells. This inductive process is mediated by cytokines
produced by inflammatory cells and activated endothelial cells. A number of so-called leukocyteendothelial adhesion molecules have been identified, including E-selectin, VCAM-1, and ICAM-1.
ICAM-1 and VCAM-1 have a wide tissue distribution, whereas E-selectin is only expressed by
endothelial cells. Preeclampsia is associated with increased maternal serum levels of soluble
VCAM-1, E-selectin, and probably also ICAM-1.168,169 This increase may be an early event.168 The
increased IL-6 and IL-1 receptor antagonist (reflecting increased IL-1 concentrations) levels in
preeclampsia correlate with elevated VCAM-1 concentrations. 166 The increase in these soluble
cell adhesion molecules reflects increased expression of these molecules on endothelial cells and
thereby explains leukocyte activation in preeclampsia.156 Abnormal endothelial cellleukocyte
interaction in preeclampsia is confined to maternal circulation, as is demonstrated by similar
expression of cell adhesion molecules in placental vessels and elastase levels in fetal plasma in
preeclampsia as compared with normal pregnancy.156,170

Oxygen free radicals.

Preeclampsia is associated with oxidative stress, defined as an imbalance between prooxidant
and antioxidant forces in favor of prooxidants, leading to potential cell or tissue damage. 171
Oxygen free radicals can lead to the formation of lipid peroxides. Once lipid peroxidation is
initiated, it becomes self-propagating. According to some investigators, oxidized low-density
lipoproteins may have a half-life of 3 hours in the circulatory system, suggesting the still
controversial possibility that they may function as circulating compounds. 171-173 Because lipid
peroxides, measured as stable lipid peroxide metabolites, 172 are increased above nonpregnant
levels in normal pregnancy, it seems that even normal pregnancy induces a certain degree of
oxidative stress. Lipid peroxide levels are further increased in preeclampsia and correlate with an
increase in blood pressure but not with perinatal outcome. 174-178 Preeclamptic lesions of decidual
vessels resemble atherosclerotic lesions, both showing fibrinoid necrosis of the vessel wall and
accumulation of lipid-laden foam cells, a hallmark of oxidized low-density lipoproteins. 173,174,179
Some,180 but not all,181 investigators found titers of IgG autoantibody to oxidized low-density
lipoproteins to be increased in preeclampsia.

Activated leukocytes may provide one of the major sources of oxygen free radicals in
preeclampsia. Additionally, activated leukocytes may, by producing certain cytokines, irreversibly
convert endothelial cell xanthine dehydrogenase to xanthine oxidase, thus causing endothelial
release of oxygen free radicals.182-184 Oxygen free radicals and elastase may work synergistically
in causing endothelial cell damage.182,185,186 The placenta is another source of free radical species
in preeclampsia; placental lipid peroxide production correlates with the increased placental
production of TxA2.175 Metabolism of arachidonic acid generates oxygen free radicals by both
lipoxygenase and cyclooxygenase pathways, but the cyclooxygenase pathway generates >1000
times more superoxide than the lipoxygenase pathway.187 Walsh175 hypothesized that neutrophils
could be activated as they circulate through the intervillous space by lipid peroxide generated by
trophoblast cells. Increased lipid peroxide has also been observed in platelets and red blood
cells.188
Free radical species cause a type of endothelial cell dysfunction that is similar to changes seen in
preeclampsia.174,175 Lipid peroxides stimulate prostaglandin H synthase but inhibit prostacyclin
synthase; therefore increased lipid peroxide levels in preeclampsia favor production of plateletderived TxA2 above vascular prostacyclin synthesis. Free radical species impair endothelial cell
nitric oxide production and inhibit macrophage inducible nitric oxide synthetase. 189,190 Lipid
peroxides alter capillary permeability to proteins186 and may thus be involved in causing edema
and proteinuria.175 Lipid peroxides trigger thrombosis by increasing thrombin generation and
endothelial plasminogen activator inhibitor-1 release while at the same time decreasing
antithrombin and endothelial tissue plasminogen activator release. 191 Lipid peroxides alter cell
membrane fluidity by increasing incorporation of cholesterol, oxidized fatty acids, and low-density
lipoproteins. In preeclampsia this phenomenon has been described for platelets, erythrocytes,
and trophoblast cells.188,192 This may partially explain why incubation of endothelial cells with sera
from preeclamptic women increases the endothelial cell content of triglycerides, which results in a
disturbance of endothelial cell physiologic characteristics. 77,108,113
Antioxidants are a diverse family of compounds designed to prevent overproduction of and
damage caused by free radical species. The picture in preeclampsia is complex, but it is apparent
that the disease cannot be characterized as a state of global antioxidant deficiency.193 One
apparent paradox of the oxidative stress theory of preeclampsia concerns the antioxidant function
of uric acid.183,194 In preeclampsia the ability of plasma to scavenge aqueous radicals is markedly
augmented, and most of this increase is caused by the increase in uric acid. 193,194 Thus, although
increased xanthine oxidase activity may contribute to oxidative stress in preeclampsia,
hyperuricemia itself may serve a protective role as antioxidant. 194
Vitamin E is the major lipid-soluble antioxidant. According to Wang et al, 36 maternal concentration
ratios of antioxidant vitamin E to lipid peroxides and prostacyclin to TxA 2 favor the antioxidant
activity of vitamin E and the vasodilator effects of prostacyclin with advancing gestation in
normotensive pregnancy, whereas in severe preeclampsia the lipid peroxide levels are increased
and the vitamin E levels are decreased; this imbalance correlates with the imbalance of increased
TxA2 and decreased prostacyclin177 and with the increase in blood pressure.195 Several authors
did not find decreased vitamin E levels in preeclampsia.178,193,196
Generation of highly toxic radicals, such as OH, that initiate lipid peroxidation and reactions
causing propagation of lipid peroxidation require the presence of a low-molecular-weight pool of
iron or other transition metals. Thus a critical group of antioxidants is those designed to bind
metal ions in forms that will not generate free radical species, including transferrin, albumin, and
ceruloplasmin.197,198 When brain tissue is homogenized in a buffer solution, endogenous lipids
undergo rapid peroxidation as a result of transition metals released from cells. The ability of small
amounts of serum to inhibit this peroxidation provides an assay for serum antioxidant activity.
Peroxidation is inhibited by several iron-chelating agents; thus the assay has a predilection for
antioxidants that function by sequestering metals. 197-199 Using this assay, Davidge et al199 found an

increased serum antioxidant capacity during uncomplicated pregnancy, whereas the antioxidant
capacity in preeclampsia was found to be reduced by 50%.
Erythrocyte glutathione levels and glutathione peroxidase activity, another lipid peroxide
scavenger system, are increased in preeclampsia in comparison with normal pregnancy; this
increase may represent a compensatory response.176 Tissue glutathione peroxidase levels may
be different from erythrocyte levels. Indeed, Walsh and Wang200 found decreased glutathione
peroxidase levels in placentas from preeclamptic pregnancies as compared with normotensive
pregnancies.
Ascorbic acid, -tocopherol, and -carotene are potent antioxidant nutrients. Ascorbic acid has
been described as the major front-line water-soluble antioxidant. Ascorbic acid levels are
significantly decreased in patients with mild and severe preeclampsia, whereas -tocopherol and
-carotene levels are significantly decreased only in severe preeclampsia.201 Thus, in
preeclampsia, antioxidant nutrients may be used to a greater extent to counteract free radicalmediated cell disturbances, resulting in a reduction in antioxidant plasma levels. Water-soluble
antioxidant nutrients may initially be consumed, followed by lipid-soluble antioxidants. Diminished
serum metal-binding antioxidant capacity and placental antioxidants may be of special
importance in allowing initiation and propagation of lipid peroxidation in preeclampsia.175,194,199
The hypothesis that cytokines, especially TNF- , may contribute to oxidative stress in
preeclampsia was reviewed by Stark.202 Mitochondrial injury is the first detectable effect of TNFin cultured cell lines, whereas some studies found preeclampsia to be associated with a very
similar type of mitochondrial damage.74-76 Oxidative disequilibrium in preeclampsia is probably
closely linked with cytokine activity, particularly TNF- . Antioxidants selectively inhibit TNFrelease because they control the oxidation-reduction status of glutathione peroxidase, which is of
major importance as an endogenous modulator of TNF- production. In mitochondria, TNFsubverts part of the electron flow to release oxygen free radicals with subsequent lipid peroxide
formation. If these are not removed with subsequent efficient reduction of the oxidized glutathione
peroxidase, serious toxic effects ensue.
Immune maladaptation is an attractive hypothesis to explain several of the well-known
epidemiologic features of preeclampsia. It should be emphasized that although there is no doubt
that patients with preeclampsia manifest immunopathologic characteristics, the question remains
as to whether such immunologic abnormality causes or results from preeclampsia.
Immunoglobulin, immune complex, complement, and fibrin deposits in decidual vessels may be
the effect of occluded vessels rather than the cause; analogous results described in chorionic
villous tissue may have resulted from placental ischemia, and the IgM, IgG, and complement
deposits in glomeruli in preeclampsia also are not direct proof for an immunologic pathogenesis
of these lesions. The immune maladaptation hypothesis is, of course, not mutually exclusive with
the placental ischemia hypothesis. Immune maladaptation may be the cause of abnormal
implantation and thus evoke placental ischemia. Moreover, placental ischemia provides an
alternative explanation for the cytokine changes 203 and oxidative stress seen in preeclampsia.
Placental cells express erythropoietin, which is the prototype molecule for transcriptional
regulation by hypoxia in mammals. TNF- and IL-1 have deoxyribonucleic acid sequences that
are homologous or nearly homologous to the hypoxia-responsive enhancer element of the
erythropoietin gene, thus providing a potential but as of yet untested molecular link between
placental hypoxia and stimulation of cytokine production. 203

Preeclampsia as a genetic disease

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Severe preeclampsia and eclampsia have a familial tendency. Chesley et al204 found a 26%
incidence of preeclampsia in daughters of women with preeclampsia but only an 8% incidence in

the daughters-in-law. Published reports are consistent with a relatively common allele acting as a
major gene conferring susceptibility to preeclampsia. The development of preeclampsia may be
based on a single recessive gene or a dominant gene with incomplete penetrance. Multifactorial
inheritance is another possibility.205,206 The principal reason for suspecting the existence of a
maternal gene as the sole explanation for preeclampsia is data showing a lack of concordance for
susceptibility in a small sample (n = 10) of monozygous twins. 207 The increased prevalence of
preeclampsia in daughters born to an eclamptic mother, as opposed to a noneclamptic pregnancy
of the same mother, could indicate an influence of the fetal genotype on susceptibility to
preeclampsia.205,206 An example of the impact of the fetal genotype on preeclampsia is the
association between HELLP (hemolysis, elevated liver enzymes, and low platelets) syndrome
and a rare fetal metabolic disorder208 and the increased incidence of preeclampsia in cases of
fetal chromosomal abnormalities (for example, triploid and trisomy 13). 209
Arngrimsson et al210 provided epidemiologic evidence that the genetic predisposition to
preeclampsia may be related to implantation and placentation.
Conflicting data have been reported regarding the involvement of HLA antigens. Several studies
revealed an increased HLA compatibility between patients and their mates. 205 Kilpatrick et al211
found a significant association between HLA-DR4 and preeclampsia. However, association of
preeclampsia with HLA-DR4 has now been excluded by detailed genetic analysis of restriction
fragment polymorphisms of HLA-DR4 in informative pedigrees; the association probably indicates
an underlying tendency to autoimmune disease with which HLA-DR4 is linked. 212,213 In contrast,
Peterson et al214 observed that mothers with HLA haplotypes A23/29, B44, and DR7 are at a
higher risk for development of preeclampsia and IUGR than mothers without such haplotypes.
Humphrey et al215 studied HLA-G deletion polymorphisms in preeclamptic pedigrees and controls
and concluded that there is no detectable relationship between susceptibility to preeclampsia or
being born of a preeclamptic pregnancy and the HLA genotype. However, as mentioned earlier,
Van der Ven and 0ber118 demonstrated the presence of subtle HLA-G mutations in AfricanAmerican neonates with IUGR.
An amino substitution in the angiotensinogen gene on chromosome 1 (the presence of threonine
rather than methionine at residue 235 [T235] in the protein) has been suggested to correlate with
the risk of preeclampsia but not with the risk of HELLP syndrome.216 Other studies found no
association between the T235 allele and preeclampsia217,218 and suggested that the T235 allele
has more to do with a tendency for high blood pressure to develop rather than with
preeclampsia.219 Genetic alterations in angiotensin II receptors are currently studied because
changes in their expression may be involved in regulating vasodilation in uteroplacental and
fetoplacental vessels.220,221 Involvement of (genetic) TNF- mediated mitochondrial dysfunction in
the etiology of preeclampsia158,203 is supported by the increased incidence of severe preeclampsia
in a family with a failure of the reduced nicotinamide adenine dinucleotide ubiquinone
oxidoreductase step in the mitochondrial electron chain. 222 Furui et al223 observed reduced
expression of mitochondrial genes in placental dysfunction in preeclamptic pregnancies. Chen et
al158 demonstrated the presence of an increased TNF- messenger ribonucleic acid expression in
leukocytes from women with preeclampsia as compared with women with normal pregnancies
and nonpregnant women. This high expression of TNF- may be associated with the TNF-1
allele, whose frequency is markedly increased in preeclampsia.158
Opinion on whether placental antigens or the fetal genetic component is more relevant in the
etiology of preeclampsia may be moving toward genetic (rather than immunologic) interpretation.
According to Haig,224 a genetic conflict can be said to exist between maternal and fetal genes.
Maternal and fetal genomes perform different roles during development. Heritable paternal, rather
than maternal, imprinting of the genome is necessary for normal development of trophoblast and
extraembryonic membranes.224 This is clearly revealed in aberrant development of human
conceptuses with abnormal ratios of maternal-to-paternal genomes (a complete hydatidiform
mole is a good example). Most complete moles are diploid (with both sets of chromosomes

paternally derived) and are associated with a relatively high incidence of severe early-onset
preeclampsia. Principally, parental imprinting refers to a parent-of-origin dependent expression of
a subset of autosomal loci, independent of the sex of the offspring. McCowan and Becroft 225
reported on the association of Beckwith-Wiedemann syndrome and preeclampsia.
Overexpression of the IGF-2 gene during development may be the cause of excessive growth
associated with the Beckwith-Wiedemann syndrome. It is interesting that the IGF-2 gene is
subject to parental imprinting in humans.226 Animal experiments suggest that gene imprinting is
also involved in placental HLA expression.227
According to the genetic conflict theory, fetal genes will be selected to increase nutrient transfer to
the fetus, and maternal genes will be selected to limit transfers in excess of some maternal
optimum. The phenomenon of genomic imprinting means that a similar conflict exists within fetal
cells between genes that are maternally derived and genes that are paternally derived. Haig 224
stresses the fact that endovascular trophoblast invasion has 3 consequences: (1) The fetus gains
direct access to its mothers arterial blood. Therefore a mother cannot reduce the nutrient content
of blood reaching the placenta without reducing the nutrient supply to her own tissues. (2) The
volume of blood reaching the placenta becomes largely independent of control by the local
maternal vasculature. (3) The placenta is able to release hormones and other substances directly
into the maternal circulation. The conflict hypothesis predicts that placental factors (fetal genes)
will act to increase maternal blood pressure, whereas maternal factors will act to reduce blood
pressure. It also suggests that the mother reduces vascular resistance early in pregnancy to
ration fetal nutrients and that subsequent physiologic increase in vascular resistance represents
the changing balance of power as the fetus grows larger. A corollary is that placental factors
contribute to an increase in maternal cardiac output. Placental factors have an opportunity to
preferentially increase nonplacental resistance because uteroplacental arteries are highly
modified and unresponsive to vasoconstrictors.224 Intrinsic effects of a high maternal systemic
blood pressure are ultimately beneficial to the fetus. Thus Haigs conflict hypothesis 224 predicts
that fetal genes will enhance maternal blood flow through the intervillous space by increasing
maternal blood pressure (perfusion pressure). Maternal blood pressures form a continuum so that
the dividing line between normotensive and hypertensive pregnancies is arbitrary. The conflict
hypothesis predicts that a mothers position on this continuum is determined by the balance
between fetal factors increasing blood pressure and maternal factors decreasing blood pressure.
This mechanism may be operative in gestational hypertension, in which fetal prognosis is known
to be good.224 In contrast, in preeclampsia the hypertension results from vasoconstriction rather
than increased cardiac output. A hypoxic placenta may release cytotoxic factors that damage
maternal endothelial cells98-102 and thus cause vasoconstriction and an increase in maternal blood
pressure. In this situation small increments in the birth weight of semistarved fetuses may often
have caused major increases in subsequent survival despite substantial costs to the mother.
Thus endothelial cell dysfunction may have evolved as a high-risk fetal strategy to increase
nonplacental resistance when the uteroplacental blood supply of a fetus is inadequate.

Underlying disorders associated with preeclampsia

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Chronic hypertension, diabetes, and obesity predispose women to the development of

preeclampsia.228-230 The link between obesity and preeclampsia is complex; many mechanisms
may be involved. Obesity is characterized by expanded blood volume, increased cardiac output,
and hypertension. Elevated cardiac output with compensatory vasodilatation may expose
capillary beds to systemic pressures and increased flow, eventually leading to endothelial cell
dysfunction characteristic of preeclampsia.231 Obesity is also associated with increased lipid
availability, increased delivery of FFA to tissues, higher cholesterol and triglyceride levels, insulin
resistance, and hyperinsulinemia.232,233 Women with preeclampsia are relatively insulin resistant
and hyperinsulinemic during pregnancy, as well as months after delivery.234 These metabolic
changes may, at least theoretically, cause a derangement of the VLDL/toxicity-preventing activity
balance. High insulin levels may also directly cause hypertension, by increased sympathetic

activity or increased tubular sodium resorption.235,236 High insulin levels in obesity may also
aggravate cytokine-mediated oxidative stress.237 The combination of insulin resistance and
compensatory hyperinsulinemia may be part of a cluster of abnormalities, the so-called syndrome
X, including some degree of glucose intolerance, increased triglyceride levels, decreased highdensity lipoprotein cholesterol levels, hypertension, hyperuricemia, smaller, denser low-density
lipoprotein particles, and higher circulating levels of plasminogen activator inhibitor-1, which is
more frequent in adults who themselves had growth restruction at birth. 233,236
Severe early-onset preeclampsia is also associated with a high incidence of underlying disorders
such as protein S deficiency, activated protein C resistance [factor V mutation],
hyperhomocysteinemia, and anticardiolipin antibodies, which may cause a more aggressive
accelerated course of the disease by inducing an abnormal interaction between endothelial cells,
platelets, leukocytes, and plasmatic coagulation and fibrinolytic factors. 228

Unifying hypothesis (Fig 1)

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Fig. 1. Hypothesis on genesis of preeclampsia, in which most

previously discussed concepts are integrated. EC, Endothelial cell;
CTB, cytotrophoblast; STB, syncytiotrophoblast; CK, cytokine.

Click on Image to view full size

Endothelial cell dysfunction appears to be the final common pathway in the pathogenesis of
preeclampsia, yet the etiology of the disease remains obscure. Genetic factors are involved;
however, it is likely that there is not 1 major preeclampsia gene but several genetic factors that
are associated with maternal susceptibility. Placental ischemia and increased syncytiotrophoblast
deportation probably represent an end-stage disease phenomenon, actually very similar to that
predicted by the conflict hypothesis, in which it is stated that endothelial cell damage may have
evolved as a high-risk fetal strategy to increase nonplacental resistance when the uteroplacental
blood supply to a fetus is inadequate.224 Immune maladaptation and the genetic conflict
hypothesis are the hypotheses that are congruous with data on the effects of changing partners
and the protective effect of sperm exposure. Presence of an abundance of decidual leukocytes
and the complex cytokine network underlines the pivotal impact of a correct fetal (paternal)maternal interaction. Cytokine-mediated oxidative stress, caused by immune maladaptation or a
genetic conflict, fits with data on cytokines, oxidative stress, lipid changes, and the type and
chronologic sequence of endothelial cell dysfunction in preeclampsia.

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Publishing and Reprint Information

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From the Division of Maternal-Fetal Medicine, Department of Obstetrics and

Gynaecology, Free University Hospital, Amsterdam, and the Division of Maternal-Fetal
Medicine, Department of Obstetrics and Gynecology, University of Tennessee, Memphis.
Reprint requests: Baha M. Sibai, MD, Department of Obstetrics and Gynecology, 853
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Copyright 1998 by Mosby, Inc.
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