Journal of Obstetrics and Gynaecology, October 2009; 29(7): 576–582

REVIEW

The pathophysiology of pre-eclampsia: Current clinical concepts

D. CUDIHY1 & R. V. LEE1,2

1
Department of Obstetrics and Gynecology State University of New York at Buffalo and Sisters Hospital of Buffalo and
2
Department of Pediatrics, State University of New York at Buffalo, USA
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Summary
Despite decades of intense research on the problem, pre-eclampsia remains one of the great mysteries of medical science. This
paper is an overview of the existing knowledge on the disease that unifies the essential and validated findings of past and current
scientific investigation. A key focus has been an attempt to distinguish foundationally pathogenic mechanisms from multiple
epiphenomena that continue to be elucidated. The hypothesis was developed after taking into consideration the various known
risk factors for pre-eclampsia, epidemiologic trends, and the most available research to date regarding the pathogenesis of the
disease. In summary, it may be stated that pre-eclampsia is a systemic disease of maternal endothelial cell dysfunction, resulting
from a deficient endovascular invasion of fetal extravillous cytotrophoblasts into the maternal spiral arterioles – a process
facilitated by cytokine and angiogenic factor producing uterine/decidual CD56bright Natural Killer (NK) cells and impeded by the
more cytotoxic peripheral CD56dim NK cells of the innate immune system. Therefore, the disease process appears to be
fundamentally one of a unique variant of immune maladaptation at the level of the maternal–fetal interface in the setting of more
For personal use only.

or less susceptible persons caused by a mixture of both insufficient maternal tolerance induction to the paternal antigens and
unfavourable combinations of genetically determined maternal leukocyte receptors and fetal antigens.

Keywords
Pre-eclampsia, endothelial cell dysfunction, spinal arteries, angiogenesis, cytokines, natural killer cells

without HELLP syndrome may also be complicated by

Background
Pre-eclampsia is commonly understood as a hypertensive
disorder of pregnancy characterised by the presence of new
onset hypertension and new onset proteinuria – both
usually occurring after 20 weeks’ gestation. The disease is so-
named as the precursor to eclampsia, wherein the woman
experiences new-onset generalised grand mal seizures as the
prototypical severe manifestation. The diagnostic criteria
includes the following: systolic blood pressure 4140 mmHg
or diastolic blood pressure 490 mmHg and proteinuria
defined as urinary excretion of 0.3 g in 24-h collection,
which will usually correlate with 30 mg/dl (1þ reading
on dipstick) in a random urine determination, with no
evidence of urinary tract infection (Report of the National
High Blood Pressure Education Program Working Group on
High Blood Pressure in Pregnancy 2000). Associated signs
and symptoms of the disease include oedema, headache,
visual changes and epigastric pain. Furthermore, in addition
to specific blood pressure and proteinuria levels, the
following findings suggest the diagnosis of severe pre-
eclampsia: oliguria (5500 ml in 24 h), cerebral or visual
disturbances, pulmonary oedema, epigastric or right upper-
quadrant pain, impaired liver function, thrombocytopaenia
and fetal growth restriction.
Of particular concern are laboratory studies demonstrat-
ing haemolysis, elevated liver enzymes and low platelets
(HELLP syndrome); a finding in about 20% of women
with severe pre-eclampsia. Severe pre-eclampsia with or
placental abruption, renal failure, subcapsular hepatic
haematoma, pre-term delivery and even fetal or maternal
death (ACOG 2002).
This as yet incompletely understood disease affects
approximately 3–14% of all pregnancies worldwide and
about 5–8% in the USA. Furthermore, pre-eclampsia
remains one of the leading causes of maternal and neonatal
mortality and morbidity worldwide (ACOG 2002; Sibai
et al. 1995; Saftlas et al. 1990; MMWR 1998; Cunningham
and Lindheimer 1992). Advances in treatment for the
clinical manifestations of the disease, such as magnesium
sulphate seizure prophylaxis and effective antihyperten-
sives, have effected a steady reduction in maternal mortality
from the disorder in more developed countries. However,
there continue to be unacceptably high maternal and fetal
morbidity and mortality rates attributable to pre-eclampsia,
especially among developing nations (Walker 2000; South
Africa Every Death Counts Writing Group 2008). In order
to develop more effective treatments and actual preventa-
tive measures against this ever-burdensome disease, a
comprehensive and fundamental understanding of its
aetiology is necessary.
Reconciling known risk factors
A natural place to begin in understanding pathogenesis
would be to consider what the patients suffering from the
disease have in common in addition to the disease itself. Of

Correspondence: R. V. Lee, 7664 East Quaker Road, Orchard Park, NY 14127, USA. E-mail: dmdrvl@buffalo.edu
ISSN 0144-3615 print/ISSN 1364-6893 online Ó 2009 Informa Healthcare USA, Inc.
DOI: 10.1080/01443610903061751

the various factors modifying a particular woman’s risk of
pre-eclampsia, there are a few which are uniquely peculiar
and shall be addressed separately. Among these known risk
factors are the following: nulliparity, primipaternity, perso-
nal history, family history, paternal history, twin gestation,
molar gestation, maternal infection, chronic hypertension,
renal disease, diabetes, androgen excess, obesity, insulin
resistance, dyslipidaemia, the various thrombophilias (anti-
phospholipid, protein C or S deficiency, antithrombin
deficiency, factor V Leiden mutation, and MTHFR muta-
tion), history of condom use, fertilisation with donor sperm,
and perhaps one of the most curious of all – being a non-
smoker (ACOG 2002; Barton and Sibai 2008). Similarly, it
has been demonstrated that women who suffer pre-eclampsia
are more apt to develop cardiovascular, renal and other
metabolic diseases, such as diabetes, later in life (Harkskamp
and Zeeman 2007; Thadhani and Solomon 2008; Wolf et al.
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2004; Vikse et al. 2008).
Any thoroughly sound hypothesis would be expected to
have an explanation accounting for each one of the risk
factors, disparate though they may be in some of the
specifics. In other words, what could account for the
unique and somewhat peculiar constellation of risk factors
strongly associated with increased risk of developing pre-
eclampsia? Finally, how does one explain the compelling
association of pre-eclampsia with past, current and future
metabolic/cardiovascular disease?
It seems most plausible that these risk factors can all be
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accounted for by the following proposal: Each one of the
clinical manifestations of pre-eclampsia are the result of
endothelial dysfunction at various key organs in the body.
The various modifying risk factors for the disease fall into
one of three categories, although they cannot be strictly
defined due to significant overlap and interconnectedness.
Among these are the following: (1) characteristics related to
genetic inheritance (both maternal and paternal); (2)
conditions with known associations to endothelial cell
dysfunction; and (3) factors relating to a foundational
theory of immune-modulated cytotrophoblastic cell inva-
sion as the basis of proper placental development.
Genetically inherited factors
The first and simplest in principle are the factors relating to
genetic predisposition. Interestingly, both men and women
who were themselves the product of a pregnancy compli-
cated by pre-eclampsia, were significantly more likely than
control men and women to have a child who was also the
product of a pregnancy complicated by pre-eclampsia. This
increased risk observed among women with a family history
and partners of men whose own gestation was complicated
by pre-eclampsia can be explained by the concept of
genetic predispositions present separately in either the
mother or the father in a given pregnancy (Mogren et al.
1999; Esplin et al. 2001). The inherited susceptibilities in
the woman most likely relate to the ‘fitness’ of her inherited
endothelial function, which connects the couple’s genetic
contribution to the endothelial dysfunction aspect of the
hypothesis. Nearer to the root cause of the disease, the
woman appears to inherit certain traits in her immune
system, more specifically, those related to T-cell-mediated
and innate immune responses which cause her to be more
or less vulnerable to pre-eclampsia. Hiby and colleagues
(2004) have shown that mothers with particular genotypes
of killer cell immunoglobulin receptors (KIRs) pregnant
The pathophysiology of pre-eclampsia 577
with fetuses with specific human leukocyte antigens
(HLAs) are predisposed to pre-eclampsia. More precisely,
mothers with the AA genotype (lacking most of the
activating killer cell immunoglobulin receptors) with
fetuses possessing the HLA-C2 phenotype were at in-
creased risk to develop pre-eclampsia. Their findings in
concert with the finding that different human populations
have a reciprocal relationship between the frequencies of
AA and HLA-C2 phenotypes strongly suggest a selective
pressure against this combination. For example, Australian
Aborigines have a frequency of the AA genotype near 1%,
whereas they express the HLA-C2 genotype at approxi-
mately 60%. Conversely, the Japanese population expresses
the AA genotype at about 50% and the HLA-C2 at around
8% (Hiby et al. 2004). On the paternal side of the equation,
genetic contribution has a role that begins long before the
subject pregnancy, by means of a protective process
described as ‘seminal priming’, wherein previous exposure
to paternal semen plays a protective role against pre-
eclampsia (Saito et al. 2007). After the sperm does result in
successful fertilisation, paternal alloantigens play a pivotal
role in the embryonic cells interaction with the maternal
immune system through precise interaction with decidual
NK cells. Finally, both the mother and father would most
certainly confer genetic attributes to the new conceptus
that allow it to be more or less able to develop the degree of
trophoblastic invasion necessary to sustain a healthy
pregnancy. Of particular interest, is the evidence showing
that defective HLA-G expression and function contributes
to poor trophoblastic invasion and subsequent vascular
deficiencies observed in pre-eclamptic placentas. Immu-
nological factors seem to instigate a series of systemic
events associated with pre-eclampsia (Le Bouteiller et al.
2003; Goldman-Whol et al. 2000).
Endothelial dysfunction
The second grouping of diseases associated with an
increased risk of pre-eclampsia includes a variety of chronic
conditions. Among these are pre-existing hypertension,
renal disease, diabetes, obesity, dyslipidaemia and the
various thrombophilias. These diseases can be convincingly
grouped together based on their common association with
vascular endothelial dysfunction, especially those which have
been included in the proposed metabolic syndrome.
Similarly, each of the clinical manifestations of pre-eclamp-
sia can be attributed to vascular endothelial dysfunction
within the various target organs. Patients suffering from the
chronic conditions listed above would be expected to have
pre-existing endothelial cell dysfunction – correlated to the
severity of the disease. Therefore, it follows logically, that
these women will be more predisposed to suffer the clinical
manifestations of a pregnancy-associated pathology that can
be traced to endothelial cell dysfunction. The observation
that the severity (i.e. lack of adequate control) of one’s
hypertension or diabetes is directly correlated with the risk of
developing pre-eclampsia further supports this theory
(Barton and Sibai 2008). A noteworthy feature of endothelial
dysfunction is that among other insults, it is frequently
caused by infection. Evidence shows that pre-eclampsia is
more frequent among pregnant women with urinary tract
infection and periodontal disease (Conde-Agudelo et al.
2008).
Endothelial cells function to mediate vasomotor
tone, regulate nutrient exchange, modulate inflammatory
 578 D. Cudihy & R. V. Lee
processes, and play a primary role in angiogenesis (Cines
et al. 1998). Numerous predisposing risk factors (chronic
diseases) and clinical manifestations of pre-eclampsia all
seem to be converging on widespread maternal endothelial
dysfunction as the common principle. Similarly, insulin
resistance and dyslipidaemia as noted by increased levels of
both triglyceride-rich lipoproteins and non-esterified fatty
acids are more common in women who proceed to develop
pre-eclampsia. Related data obtained from a placental
ischaemia model suggest that such metabolic derange-
ments are not the consequence of the pre-eclampsia disease
process; rather, these abnormalities seem to contribute to
the cardiovascular dysfunction of pre-eclampsia when it
occurs (LaMarca et al. 2008). Conversely, evidence is now
showing that women suffering from pre-eclampsia are at
increased risk for future development of cardiovascular
disease, renal disease and insulin resistance (type 2
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diabetes) later in life. Indeed, it appears that pre-eclampsia
acts as a sort of physiological stress test, providing
information about a woman’s personal susceptibility to
other diseases sharing the common feature of endothelial
dysfunction (Harkskamp and Zeeman 2007; Thadhani and
Solomon 2008; Wolf et al. 2004; Vikse et al. 2008).
Immune-mediated invasion and angiogenesis
The remaining risk factors to be reconciled with a
consistent unifying theory are the following: nulliparity,
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primipaternity (new fathers), use of condoms, IVF
(especially with donor gametes), twin gestation, molar
pregnancy, and non-smoking status.
Classically, pre-eclampsia has been described principally
as the ‘disease of primiparae’, and in those cases where
women remain monogamous, this concept is still valid.
However, more recent observations, changing social and
demographic trends have revealed that multigravid women
with new partners and with decreased antecedent paternal
semen exposure (condom use, donor insemination, etc.)
have the same risk as primigravidae. Therefore, a more
accurate characterisation of pre-eclampsia would describe
it as the disease of primipaternity or first couples. The
observation that pre-eclampsia is in fact a ‘couple disease’
furthers the case that a paternal–maternal interaction plays
a role in the aetiology (Robillard et al. 2007).
It has long been demonstrated that placental tissue is
both sufficient and necessary for the development of pre-
eclampsia. Molar pregnancy without fetal tissue is fre-
quently complicated by pre-eclampsia, and case reports of
pre-eclampsia with an abdominal pregnancies without
uterine attachment suggests that the uterus is not required
for the pre-eclampsia to develop. Furthermore, removal of
the fetus alone provides insufficient treatment as pre-
eclamptic symptoms relent only after delivery of the
placenta (Willems 1977; Shembrey and Noble 1995; Clark
and Niles 1967). Twin gestation and molar pregnancies are
both associated with increased placental load (Barton and
Sibai 2008), a finding which continues to implicate the
placenta as a central point in the aetiology and pathogenesis
of pre-eclampsia. Clinical evidence has continued to
demonstrate that not only is pre-eclampsia a disease of
primipaternity, but also one that is somehow directly linked
to placental tissue.
The explanation for this foundational role of placental
function can be understood in light of the maternal
immune system playing a vitally active role in facilitating
proper invasion of the fetal tumour-like extravillous
cytotrophoblast cells into the maternal myometrium. Saito
and colleagues (2007) have shown that maternal major
histocompatibility complex (MHC) class I tolerance to
paternal-derived MHC I protein occurs after long-term
exposure to paternal seminal fluid. This concept supported
by the finding of abundant paternal soluble MHC class I
antigens within the seminal fluid which are most likely
taken up by vaginal and/or uterine epithelial cells.
Similarly, MHC class II-specific tolerance seems to require
exposure to sperm which express MHC class II structures
on the post-acrosomal membranes. This line of evidence
most clearly explains the increased risk of pre-eclampsia
seen with nulliparity, primipaternity, antecedent condom
use, and fertilisation achieved with donor sperm (Saito
et al. 2007).
That smokers have a decreased risk of pre-eclampsia has
always seemed out of place. This is particularly perplexing
in light of the fact that smoking is actually associated with
endothelial dysfunction, not unlike the various other states
associated with an increased risk of preeclampsia. A clue to
this mystery is related to the decreased expression of the
anti-angiogenic factor, soluble fms-like tyrosine kinase I
(sFlt-1), among smokers (Kopcow and Karumanchi 2007).
Furthermore, nicotine itself has been shown to enhance
angiogenesis. This is likely to occur through nicotinic
acetylcholine receptors on both endothelial and immune
cells. After recognising an epidemiologic trend of smokers
producing much larger placentas, scanning elecronmicro-
scopy of placentas from smokers revealed increased
capillary density and related adaptive responses of the fetal
capillary bed within the placental villi. This appears to be a
response designed to increase the surface area available for
oxygen exchange in order to compensate for impaired
oxygen transport caused by carbon monoxide in cigarette
smoke (Sibai et al. 1995; Pfarrer et al. 1999; Egleton et al.
2009).
Pathophysiology of pre-eclampsia
Recent breakthroughs have provided necessary insight in
proposing the pathogenesis of pre-eclampsia as a two stage
process: the preclinical (the first 20 weeks’ gestation) and
the clinical (normally after 20 weeks’ gestation). The first
stage or preclinical occurs soon after implantation when
there is inadequate invasion by a subtype of trophoblasts
described as extravillous cytotrophoblasts (Redman and
Sargent 2005). These cells display properties similar to
metastatic cancer both in their invasive characteristics and
their ability to induce vascular remodeling and to facilitate
angiogenesis (Soundararajan and Rao 2004). Surprisingly,
of all the maternal cells, natural killer cells (which are
unique in their ability to destroy cancer-transformed cells)
are the very ones apparently responsible for promoting this
tumour like behaviour. These extravillous cytotrophoblasts
then become endovascular trophoblasts partially replacing
the maternal endothelium forming a fascinating hybrid
vessel lined with both maternal and fetal cells. However, in
pre-eclampsia, the deficient invasion of the maternal spiral
arteries results in either absent or incomplete remodeling of
the spiral arteries necessary for adequate placental perfu-
sion later in the second stage of pre-eclampsia (Redman
and Sargent 2005).
The second or clinical stage of pre-eclampsia, the mater-
nal syndrome, is heralded by the effects of a generalised

inflammatory response originating from an oxidatively
stressed or hypoxic placenta. Placental hypoxia results
from incomplete remodeling of the maternal spiral arteries
into low resistance dilated vessels. The oxidative stress
within the placenta causes the release of such factors as
sFlt-1, soluble endoglin, pro-inflammatory cytokines, and
even trophoblast debris: all of which lead to a systemic
inflammatory response in the mother. This inflammatory
milieu causes generalised endothelial dysfunction which
manifests in various key organs of the mother causing the
classic syndrome of pre-eclampsia. For example, decreased
vasodilatory capacity in the vascular beds leads to
hypertension; increased endothelial permeability causes
numerous injurious effects in the various target organs:
proteinuria in the kidney; headache and visual disturbances
in the brain; abdominal pain associated with hepatic
congestion, shortness of breath accompanying pulmonary
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oedema; and, finally, eclamptic seizures due to focal
ischaemia caused by vasospasm within the brain (Redman
and Sargent 2005; Sargent et al. 2006; Wiessgerber et al.
2004).
A substantial contribution has been made in recent years
to elucidate the roles of various factors associated with pre-
eclampsia, such as sFlt-1 and soluble endoglin. This work
has helped to clarify a key dimension of pre-eclampsia as an
antiangiogenic state resulting from over-production of
antiangiogenic factors. In searching for the elusive ‘pre-
eclampsia factor’, gene expression profiling of placental
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tissue identified the antiangiogenic protein, sFlt-1, to be
increased in pre-eclampsia. Furthermore, elevated circulat-
ing levels of sFlt-1 coincided with decreased levels of
vascular endothelial growth factor (VEGF) and placental
growth factor (PlGF) in pre-eclamptic women. sFlt-1
antagonises VEGF and PlGF thereby preventing their
normal interaction with endothelial receptors. Interest-
ingly, VEGF antagonists developed as chemotherapy
agents caused proteinuria and hypertension in humans –
essentially reproducing the diagnostic criteria for pre-
eclampsia (Maynard et al. 2005).
Soluble endoglin appears to have similar effects as sFlt-1
and even functions synergistically with it in causing a
generalised endothelial dysfunction. So far, however, the
measurable differences in both sFlt-1 and soluble endoglin
are only seen after 17 weeks’ gestation. Since the invasion
and remodelling process of maternal spiral arteries occurs
from 6 to 18 weeks’ gestation (Levin et al. 2007; Rana et al.
2007), these markers would appear to be in the realm of
epiphenomena that occur as a consequence rather than a
cause of the disease. Nonetheless, they may very well play a
valuable role in early diagnosis of pre-eclampsia which
could facilitate secondary prevention and related treat-
ments during the duration of the pregnancy.
A discussion of the pathophysiology of pre-eclampsia
would not be complete without acknowledging the
contribution of diet and its association with oxidative
stress. An imbalance in pro-oxidants and antioxidants
with resultant oxidative stress also seems to contribute to
the disease process of pre-eclampsia. Increased urinary
secretion of isoprostane prior to the clinical symptoms of
pre-eclampsia supports this concept. It seems that, at least
in part, the clinical syndrome of pre-eclampsia involves
excess generation of free radicals that causes oxidative
damage to lipids, protein and DNA. There is persuasive
evidence to suggest that certain dietary habits such as
excessive intakes of polyunsaturated fats increase the
The pathophysiology of pre-eclampsia 579
likelihood of developing pre-eclampsia (Scholl et al.
2005).
Natural killer cells: Friend or foe
One of the more interesting directions in contemporary
research on pre-eclampsia pertains to the rather unex-
pected beneficial role that the so-called ‘natural killer cells’
of the innate immune system play in the healthy progres-
sion of a normal pregnancy. As is often the case in
biological science or in the human experience generally,
newly discovered entities are frequently named based on
first impressions of their function. While this unique
population of leukocytes known as natural killer cells is
known for its cytotoxic potential against virus-infected and
tumour-transformed cells, increasing evidence is demon-
strating a fundamental dependence on sufficient NK cell
activation in order for adequate placentation to occur
(Sargent et al. 2006, 2007; Moffet and Hiby 2007). Clearly
the physiological purpose of NK cells is more complex than
that of mere ‘killers’ on the prowl for pathogens or infected
cells. In other words, a successful and healthy pregnancy
does not require a state of relative immunosuppression;
rather a specific type of cytokine activation of and by the
NK cells of the innate immune system is required. Rather
than the NK cells acting as armed guards against foreign
invaders, in placentation at least, they act rather as gracious
hosts hoping their guests feel at home as they invite them
inside. In fact, some authors have similarly proposed a
‘peaceful’ model for reproductive immunology, whereby
decidual NK cells behave constructively in human preg-
nancy (Hanna et al. 2006).
The uterine stroma and mucosa contain an abundance of
decidual NK cells. Murine models with the peri-implanta-
tion stroma made of up to 80% decidual NK cells, to the
point that the ‘embryo implants as if in the core of a
(transient) NK-filled lymph node’ (Chaouat et al. 2006).
Similarly, human investigation has shown that 440% of
the cells in the maternal uterine mucosa are of a unique
subset of NK cells (Hanna et al., 2006). Of all the decidual
leukocytes, NK cells comprise 70% (Moffet and Hiby
2007). It proceeds with all logic that this unique population
of cells, surrounding the new embryo, plays such an
essential role in facilitating the proper invasion by
trophoblastic cells. The answer to the apparent dilemma
of reconciling the theory of (1) inadequate invasion of the
maternal spiral arteries by extravillous trophoblasts and (2)
that of an immune maladaptation seems to be found in the
dysfunction and/or dysregulation of the decidual NK cells.
Two distinct subsets of human NK cells have been
described based on their cell surface density of CD56.
Most endometrial NK cells are CD56bright, also described
as uterine natural killer cells (uNKs) or decidual natural
killer cells (dNKs) by various authors around the world.
These CD56bright cells are unique in that they are less
cytotoxic than their CD56dim, i.e. peripheral/circulating
natural killer (pNK) cell counterparts. Instead of the
prototypical cytotoxic role carried out by the pNK cells,
the uNK/dNK cells have principally inflammatory and
regulatory roles. These uNK cells act by means of secreting
trophoblast invasion-promoting cytokines (IL-8 and IP-10)
in addition to angiogenic factors such as VEGF and PlGF.
This combination of cytokines and angiogenic factors
serves to induce and support the invasion of the tumour-
like extravillous trophoblasts into the maternal spiral
 580 D. Cudihy & R. V. Lee
arteries in order to cause the remodelling of the spiral
arterioles required for adequate placental perfusion later in
the pregnancy. The disease of pre-eclampsia results from
insufficient activation of the uNK cells which prematurely
halts the process of placental development and maternal
decidual spiral artery remodeling by the extravillous
cytotrophoblasts. The pre-eclamptic state also seems to
entail a dominance of activity among the peripheral
(CD56dim dominant) NK cells whose increased activity
has been associated not only with pre-eclampsia, but also
recurrent spontaneous abortions and infertility (Kopcow
and Karumanchi 2007; Kwak-Kim and Gilman-Sachs
2008; Hiby et al. 2008). Miko and colleagues (2008) have
described invariant NKT (iNKT) cells, a minor subset of
peripheral leukocytes, as a group of immune cells also
increasingly activated in pre-eclampsia, apparently as a
result of an imbalance in the NK cell activating and
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inhibitory receptors. Others have seen a similar association
with implantation failure among NKT cells with this
altered expression of activating versus inhibitory NK cell
receptors. It appears all the more likely that at least one
cause of spontaneous abortion and infertility may in fact be
essentially the same disease process that leads to clinical
pre-eclampsia in those pregnancies that survive beyond 20
weeks. In summary, it seems that NK cells may act toward
the developing fetus as either friend or foe depending on
which population (peripheral or uterine/decidual) predo-
minates.
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The final problem to unravel begs an explanation of why
peripheral NK cells predominate in some pregnancies and
initiate the chain of events ultimately leading to the
maternal syndrome of pre-eclampsia. Perhaps the answer
lies in the variable expression of particular HLAs on
extravillous trophoblasts. HLA-G, HLA-E, and HLA-C
are the only HLA class I molecules displayed by this group
of trophoblasts and the NK cells have receptors for each of
them. Of the three, only HLA-C is highly polymorphic.
Accordingly, as stated previously, it has been shown that
the KR/HLA-C2 combination predisposes a woman to pre-
eclampsia. The HLA-C2 gene expressed on the fetal
trophoblasts may come from either the mother or father,
and increases the risk of pre-eclampsia even when it is her
own HLA-C2 gene being expressed by the fetal cells
(Moffet and Hiby 2007; Hiby et al. 2008). However, HLA-
G expression on extravillous trophoblast seems to play a
critical role in allowing proper invasion. The degree of
invasion of the trophoblasts corresponds to the degree of
HLA-G expression, where HLA-G expression was absent
or significantly reduced in pre-eclampsia. Amazingly,
HLA-G expression was absent or reduced in 9 out of 10
pre-eclamptic placentas, whereas all the controls displayed
normal levels of HLA-G. It appears that trophoblasts
lacking HLA-G expression may be vulnerable to attack by
the maternal NK cells and their invasion is not facilitated
by the maternal NK cells (Le Bouteiller et al. 2003;
Goldman-Whol et al. 2000).
Future directions
Within the realm of molecular biology, more work is clearly
needed to further clarify various interactions, both physio-
logical and pathological, between the maternal decidual
NK cells and the fetal extravillous trophoblasts. Additional
genetic analysis of parents experiencing pregnancies
complicated by pre-eclampsia in comparison to those that
have non-pre-eclamptic pregnancies will likely identify new
genes both maternal and fetal that contribute to this
apparent disease process attributable in part to immune
maladaptation.
As for clinical applications, it is hoped that one or more
of the various markers associated with pre-eclampsia will
prove useful as a potential screening tool to identify those
women destined to develop pre-eclampsia earlier in the
pregnancy. As with virtually all diseases, early diagnosis
tends to optimise the opportunity and effectiveness of
treatments as they become available. Since these markers
for early detection of pre-eclampsia may only be helpful
after physiological establishment that the disease has
already occurred, their primary use would be targeted as
secondary prevention or early treatment of actual disease.
Already, we have evidence that such intervention as
introducing regular prenatal exercise and medications such
as aspirin and heparin for select persons decreases the risk
of pre-eclampsia (Barton and Sibai 2008). Furthermore,
there has been some promising research showing that
aerobic conditioning is not only protective against the
development of pre-eclampsia, but that it may even reverse
the vascular endothelial dysfunction that women experi-
ence after a diagnosis of pre-eclampsia (Wiessgerber et al.
2004).
The ultimate goal, of course, would be to find a cure for
pre-eclampsia itself. Such a cure might come in the form of
treatments aimed at boosting the extravillous cytotropho-
blast invasion during early pregnancy in women known to
be at high-risk for developing pre-eclampsia. This may
entail pharmacological manipulation of the decidual/
uterine NK cells to direct them in the pro-angiogenic
pathway. These women could potentially be identified
prior to pregnancy based on various familial genetic
linkages or even based on their known health in regard to
other diseases of endothelial dysfunction.
Conclusion
The root cause of pre-eclampsia appears to lie within the
maternal–fetal interface of early pregnancy. The disease is
initiated by a multifactorial immune-mediated process
leading to a biochemical signaling milieu inhibiting
invasion of the uterine wall by fetal extravillous tropho-
blastic cell. At the centre of this immune process are the
uterine NK cells which play a vital role in promoting the
establishment of adequate placental invasion. Healthy
pregnancy is far from being simply a state of relative
immunosuppression as once thought. On the contrary,
successful implantation and placental development is
dependent on the active assistance of the maternal immune
system to stimulate adequate invasion (by means of various
cytokines) of the maternal uterine wall by the trophoblastic
tissue of the fetus. When this process of invasion of the
maternal spiral arterioles within the myometrium by the
extravillous cytotrophoblasts does not occur, vascular
remodelling of the spiral arterioles does not occur. This
sets up the conditions for placental hypoxia and oxidative
stress that eventually triggers widespread maternal en-
dothelial dysfunction – leading to the various clinical
manifestations of pre-eclampsia.
Our intention is that the hypothesis outlined above will
contribute to the growing body of literature on this topic in
order that we may soon reach Dr Willems optimistic
statement of 33 years ago: ‘future collaboration between

the obstetrician and immunologist should produce the
diagnostic and therapeutic tools to place pre-eclampsia
together with Rh isoimmunisation as an interesting, but
eminently treatable dysfunction’ (Willems 1977).
Declaration of interest: The authors report no conflicts
of interest. The authors alone are responsible for the
content and writing of the paper.
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