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Review Current thoughts on thepathogenesis of pre-eclampsiaAuthors Rebekah A Smith / Louise C Kenny

Pre-eclampsia remains a leading cause of maternal and perinatal

morbidity and mortality. In this review we examine the leading

hypotheses of the pathogenesis of this disorder and discuss recent

research in this area that has led to the exciting prospect of new

treatments for this devastating condition.

Keywords maternal mortality / pathogenesis / pre-eclampsia

Please cite this article as: Smith RA, Kenny LC. Current thoughts on the pathogenesis of pre-eclampsia. The Obstetrician & Gynaecologist 2006;8:7–13.

Author details

Rebekah A Smith MRCOG

Clinical Research Fellow

Maternal and Fetal Health Research Centre,

St Mary’s Hospital, Whitworth Park, Manchester

M13 0JH, UK

E-mail: [email protected] (corresponding

author)

Louise C Kenny PhD MRCOG

Senior Lecturer and Consultant Obstetrician

St Mary’s Hospital, Manchester, UK

The Obstetrician & Gynaecologist 10.1576/toag.8.1.007.27202 www.rcog.org.uk/togonline 2006;8:7–13 Review

’ 2006 Royal College of Obstetricians and Gynaecologists 7

IntroductionPre-eclampsia occurs in approximately 2% of

pregnancies and is associated with significant

maternal and perinatal mortality and morbidity.

Worldwide, 40 000 women die each year with pre-

eclampsia and eclampsia. In the 2004 report of the

Confidential Enquiries into Maternal Deaths in

the UK,1 hypertensive disorders of pregnancy were

second only to thromboembolism, accounting for

14 deaths. The Confidential Enquiry into

Stillbirths and Deaths in Infancy (CESDI) report

cites one in six stillbirths as occurring in

pregnancies complicated by maternal

hypertension.2 The condition is also responsible

for the occupancy of approximately 20% of special

care baby unit cots. Furthermore, pre-eclampsia

carries significant healthcare implications in adult

life, with offspring of affected pregnancies having

an increased risk of hypertension, heart disease

and diabetes.

Treatment of pre-eclampsia is now, as it has been

for the last 100 years, delivery of the fetus and

placenta. Consequently, part of the increased

perinatal mortality is due to iatrogenic

prematurity. It is estimated that 15% of preterm

births are secondary to delivery for pre-eclampsia.

The aetiology of this condition has remained

elusive for many centuries. However, there is now

a growing body of research in this area and in

recent years new insights into the pathogenesis of

this condition have provided the tantalising

prospect of the development of novel therapeutic

strategies.

Predisposing factors for pre-eclampsiaThere are many risk factors that increase a

woman’s chance of developing pre-eclampsia

(Box 1). A significant factor underlying the

condition is a genetic predisposition. The risk of

pre-eclampsia for women whose mother or sister

has had pre-eclampsia is increased 2–3 fold.

Further substantial risk factors for developing pre-

eclampsia are chronic medical conditions, such as

chronic hypertension, diabetes and collagen

vascular diseases. These conditions have an

underlying microvascular component that can be

associated with a reduction in placental blood

flow, which may precipitate pre-eclampsia.

Theories of pathogenesisThere is now a general consensus regarding the

individual stages in the pathogenesis of pre-

eclampsia. However, debate continues about the

primary precipitating factor. In recent years two

different theories have emerged.

(1) The two-stage process

In this theory it is suggested that the trigger in the

disease process is relative reduction in placental

blood flow secondary to either abnormal

placentation or maternal microvascular disease.

The poorly perfused placenta is thought to release

circulating factor(s) that target the maternal

vascular endothelium and lead to the clinical

syndrome (Figure 1).3 In this model, maternal

factors that antedate pregnancy lead to an

increased susceptibility to the disease and part of

the response to reduced placental perfusion is

thought to be a fetal adaptive response to attempt

to overcome the reduced delivery of nutrients.

This theory is supported by the observation that

not all babies born to mothers with pre-eclampsia

have intrauterine growth restriction and that there

is evidence of abnormal placentation in women

who do not have pre-eclampsia.

(2) Continuum theory

This theory proposes that pre-eclampsia is an

exaggerated form of the inflammatory response

characteristic of normal pregnancy. It is suggested

that this occurs in response to a relative increase in

trophoblastic debris, which is released from a

poorly perfused placenta or from a larger placental

mass; for example, in multiple pregnancies. The

exaggerated inflammatory reaction can also be

triggered by a normal amount of trophoblastic

debris in susceptible women (Figure 2).4

Reduced placental perfusionThe pivotal role of the placenta in the

pathogenesis of pre-eclampsia has been established

by several clinical observations. Firstly, it has long

been recognised that removal of the placenta leads

to resolution of the disease and indeed this

remains the mainstay of current clinical

management. Secondly, pre-eclampsia can occur

Box 1Risk factors for developingpre-eclampsia

Risk Factors Examples

Socio-demographicfactors

Extremes of reproductiveage, e.g. age .40 years

Socio-economic statusEthnic group: African–

AmericanGenetic factors Sister had pre-eclampsia

Mother had pre-eclampsiaPartner previously fathered

pregnancy complicatedby pre-eclampsia

Pregnancy factors Multiple pregnanciesPrimigravidaePrevious pre-eclampsia

Personal medical history ObesityChronic renal diseaseChronic hypertensionDiabetes mellitusThrombophilia

Review 2006;8:7–13 The Obstetrician & Gynaecologist

8 ’ 2006 Royal College of Obstetricians and Gynaecologists

in the absence of a fetus. Indeed hydatidiform

moles are associated with an increased incidence

of pre-eclampsia. Finally, the incidence of pre-

eclampsia is increased in pregnancies associated

with hyperplacentosis, such as multiple pregnancy

and diabetes.

Thirty years ago, morphological examination of

placental bed biopsies and caesarean hysterectomy

specimens from women with pre-eclampsia

demonstrated shallow invasion of trophoblasts

and failure of vascular remodelling.5 Applications

of contemporary bioscientific approaches have

provided detailed insight into deficient

mechanisms in this process.

Within the placenta in early gestation,

trophoblasts differentiate and give rise to

subpopulations of cells. One subpopulation, the

extravillous trophoblast, invades the uterine wall

(interstitial invasion) and its blood vessels

(endovascular invasion). During normal

pregnancy, the trophoblasts destined to be

endovascular adopt a more endothelial, cell-like

phenotype and invade the uterine spiral arteries

progressing back as far as the myometrial

segments. Immunohistochemical studies of

placental bed biopsies suggest that trophoblast

cells and endothelial cells transiently coexist on

walls of partially modified spiral arteries.6

Trophoblast cells migrate along the luminal

surfaces of vessels, invading them and partially

replacing the endothelial cells and most of the

musculoelastic tissue in the vessel walls (Figure 3).7

The vessels are subsequently restructured such that

they have little smooth muscle and become larger

in diameter. This creates a high flow, low

resistance circulation that maximises maternal

blood flow to the placental villi at the maternal–

fetal interface. There is contrasting evidence as to

whether trophoblasts themselves are important in

arterial remodelling. Although it has been

suggested that some changes in the decidual

vessels occur independently, as part of the

maternal response to pregnancy, there is also

strong evidence that invasive interstitial

trophoblasts prepare the decidual spiral arteries

for endovascular trophoblast migration.8 The

invasive trophoblast may play an important role in

inducing further changes either by interactions or

factors produced by the interstitial trophoblast or

by direct cellular interactions of the endovascular

trophoblast with the cells of the vessel that they

subsequently replace.

The pathogenesis of pre-eclampsia and

intrauterine growth restriction is associated with

trophoblasts failing to adopt an endothelial cell-

like phenotype and endovascular invasion failing

to proceed beyond the superficial portions of the

spiral arteries in early pregnancy.

The cause of this impaired placentation is not fully

understood but may in part be due to poor

invasive properties of the trophoblastic cells or

changes in the maternal decidual tissues, which

regulate trophoblast behaviour, perhaps mediated

via multifunctional cytokine pathways. The

cytotrophoblastic expression of adhesion

molecules, which influences invasion, is altered in

women with pre-eclampsia. In vitro studies have

shown that trophoblasts from placentas of women

with pre-eclampsia have lower attachment on

fibronectin and vitronectin compared with

normotensive controls, which may reflect

differences in expression of matrix receptors.9

Maternal factors leading to inhibition of

trophoblast invasion include reduced expression

of the histocompatibility antigen HLA-G, local

inflammatory cell behaviour and cytokine

regulation of integrin expression.

placentalperfusion

Small placenta Normal placentaLarge placenta

(eg twins)

trophoblastic debristrophoblastic debris Normal amount of

trophoblastic debris

Maternal susceptibilityMaternal response

Inflammatory reaction

Endothelial cell dysfunction

Maternal syndrome Fetal effects

First stage Second stage

Endothelialcelldamage

Release offactors intomaternalcirculation

Normal

Pre-eclampsia

Maternalsyndrome

Multisystemdisorder

Fetal effects

Reducedplacentalperfusion

Figure 1

Two-stage model of pre-eclampsia. Adapted

from Roberts et al.3

Figure 2

Continuum theory of inflammatory response to

trophoblastic debris. Adapted from Redman

et al.4

The Obstetrician & Gynaecologist 2006;8:7–13 Review


The end result of altered differentiation is

inadequate trophoblast invasion. The incomplete

remodelling of the maternal vasculature results in

inadequate uteroplacental perfusion, particularly

later in pregnancy. The subsequent hypoxia/

ischaemia is presumed to trigger the release of a

circulating factor(s) into the maternal circulation.

Release of circulating factorsThe link between deficient trophoblastic invasion

early in pregnancy and the widespread endothelial

dysfunction manifesting much later has eluded

researchers for many years. The observation that

terminating the pregnancy, and more specifically,

that delivery of the placenta results in resolution of

the disease suggest that the placenta is the focus of

production of the putative factor(s) that

influences the endothelial cell. This hypothesis,

and the nature of the circulating factor(s), has

been investigated in a wide variety of both in vivo

and ex vivo studies. One of the first studies10 to

investigate the potential of circulating factors was

reported over a decade ago and is widely credited

with reviving the concept of toxaemia. This much

cited study demonstrated that serum from women

with pre-eclampsia was cytotoxic to cultured

human umbilical vein endothelial cells (HUVECs)

when compared with control sera from normal

pregnant women. This landmark study has

subsequently been extended by other investigators

in a wide variety of cultured cell types and on

isolated small vessels. Pre-constricted vessels from

women with a normal pregnancy relax well when

exposed to the endothelium-dependent

vasodilator bradykinin. However, in the presence

of plasma from women with pre-eclampsia, the

response of these vessels is markedly impaired.

Under these conditions vessels from normal

pregnant women mimic the behaviour of vessels

isolated from women with pre-eclampsia.11

The nature of this circulating factor or factors has

been much debated. Putative candidates include

vascular endothelial growth factor (VEGF),

tumour necrosis factor, lipid peroxides and

syncytiotrophoblast microfragments.

Vascular endothelial growth factor

Serum levels of VEGF and its soluble receptor-1

(sFlt-1) are elevated in pre-eclampsia, even before

the onset of clinical symptoms.12 The source of

the elevated circulating levels of VEGF in

pregnancies complicated by pre-eclampsia is

unclear. VEGF is expressed in placental tissue and

when trophoblast cells are cultured in hypoxic

conditions, VEGF production is increased.

However, studies of placental tissue are equivocal;

some have demonstrated that the expression of

VEGF mRNA is decreased in pregnancies

complicated by pre-eclampsia, whereas others

using immunohistochemical analysis have

reported that staining for VEGF is increased in

pregnancies complicated by pre-eclampsia. In

addition, several alternative explanations have

been advanced to account for the increase in

circulating levels of VEGF observed in pre-

eclampsia. It has been postulated that VEGF can

increase secondary to impaired renal function and

diminished excretion. Alternatively, VEGF

production can increase in response to vascular

endothelial cell injury as it has recently been

demonstrated that VEGF produced in vascular

smooth muscle can contribute to the initiation of

endothelial repair. As endothelial cell damage is

widespread in pre-eclampsia, this would lead to an

Figure 3

Histology of the placental bed in the early first

trimester, with the enlarged portions

demonstrating a spiral artery undergoing

transformation. In (a) the spiral artery remains

thick walled and muscular. In (b) endovascular

trophoblast is now present and there has been a

complete loss of smooth muscle.7 Reproduced

with permission from John Wiley and Sons Ltd

on behalf of the Pathological Society.



increase in both local and circulating

concentrations of VEGF.

VEGF has been demonstrated to induce a

functional change in the response of myometrial

resistance arteries to the endothelium-dependent

vasodilator bradykinin. Incubation with VEGF

induces a dose and time-dependent diminution in

endothelium-dependent relaxation in these

arteries, which mirrors that found following

incubation with plasma from women with pre-

eclampsia. Intriguingly, pre-treatment of both

VEGF and plasma from women with pre-

eclampsia with an antibody to VEGF protects

against loss of endothelium-dependent

relaxation.13 This suggests that the elevated levels

of VEGF observed in pre-eclampsia may play a

role in the pathogenesis of vascular damage, rather

than merely being an epiphenomenon.

Tumour necrosis factor

The plasma levels of tumour necrosis factor a

(TNF-a) are high in pre-eclampsia, and in vitro

placental production of TNF-a is greater in

placentas from women with pre-eclampsia.14

Microvascular filtration capacity can be measured

in vivo as a measure of microvascular permeability.

The microvascular filtration capacity is

significantly increased in pre-eclampsia and this is

correlated with plasma levels of TNF-a. TNF-a

increases endothelial cell activation and increases

microvascular protein leakage.15

Syncytiotrophoblast microfragments

Syncytiotrophoblast microfragments (STBMs) are

debris from syncytial apoptosis. Apoptosis is

programmed cell death and occurs in the normal

placenta. The rates of apoptosis are increased in

pre-eclampsia, and levels of STBMs are increased

in the plasma of women with pre-eclampsia.16 If

STBMs are cultured in vitro with endothelial cells

there is disruption of the endothelial cell

monolayer. When cultured with neutrophils,

STBMs isolated from the placentas of women with

pre-eclampsia cause activation of neutrophils and

an increased superoxide production.17 In contrast,

when STBMs were incubated with myometrial

vessels at the increased levels seen in women with

pre-eclampsia, there was no change in the

endothelial dependent relaxation of these

vessels.18 This would suggest that it is unlikely that

STBMs themselves induce the endothelial cell

dysfunction seen in pre-eclampsia, but STBMs

may interact with other factors such as leucocytes.

There are, therefore, several candidate circulating

factors in pre-eclampsia. The complex clinical

manifestations of the disease seem unlikely to be

related to one single factor and it seems much

more likely that these factors act in combination

to trigger the disease process.

Oxidative stressEvidence has emerged to support a role for

oxidative stress in linking reduced placental

perfusion with systemic maternal

pathophysiology.19

Oxidative stress is a pathological state, implicated

in the aetiology of many disorders, including

atherosclerosis, in which pro-oxidants dominate

over antioxidants. The resultant increase in the

formation of reactive oxygen species can damage

cell membranes, proteins and DNA.

Epidemiological studies have revealed that many

of the risk factors associated with the development

of pre-eclampsia such as obesity, black race, lipid

abnormalities, insulin resistance and raised serum

homocysteine are also associated with the risk of

developing atherosclerosis in later life. These

observations have led to the emerging hypothesis

that suggests reduced placental perfusion generates

oxidative stress and leads to widespread

endothelial dysfunction in pre-eclampsia.

One such factor involved in oxidative stress is

nitric oxide (NO). Within the circulation,

superoxide is formed by the reduction of oxygen.

Superoxide is normally broken down by

superoxide dismutase. However, NO competes

with superoxide dismutase and combines with

superoxide to form peroxynitrite. Therefore, high

concentrations of NO and superoxide, or a

reduction in superoxide dismutase, will lead to

increased peroxynitrite and its resulting toxic

effects.

Levels of superoxide dismutase in subcutaneous

fat vessels are lower in women with pre-eclampsia

compared with those from normotensive pregnant

women.20 Immunostaining of endothelial cells

from subcutaneous fat vessels showed

nitrotyrosine (as a marker of peroxynitrite and

therefore oxidative stress) to be present in 3% of

vessels in normal women, but present in 73% of

vessels in women with pre-eclampsia.20 Therefore,

in pre-eclampsia there is an increase in oxidative

stress in which NO plays a major role. The levels of

NO, cGMP and NO synthase may be increased in

pre-eclampsia; it is not known whether this is a

compensatory mechanism to produce more vessel

relaxation or a pathophysiological condition with

NO involved in oxidative stress. It may be for this

reason that efforts simply to increase total NO

production by the use of NO donors in pre-

eclampsia have not been shown to be clinically

beneficial, but that an increase in NO could

increase peryoxynitrite production and cause

endothelial dysfunction.

Further evidence supporting the role of oxidative

stress in pre-eclampsia has come from a

randomised placebo-controlled trial in which the



antioxidants vitamins C and E were given from

18–22 weeks of gestation to women who were

known to be at high risk of pre-eclampsia from

previous history or abnormal uterine artery

Doppler waveforms.21 The trial demonstrated a

significant reduction in the incidence of pre-

eclampsia in those taking vitamin

supplementation compared with those on a

placebo, and a significant fall in the biochemical

markers of endothelial cell activation. The possible

use of vitamin supplementation as prophylactic

agents in women at high risk of developing pre-

eclampsia is extremely encouraging. However, it is

important that vitamin supplementation is not

brought into routine clinical practice until the

results of larger multicentre vitamins in pregnancy

trials (currently continuing) are known.

Hypoxia–reoxygenationUntil recently the primary problem in pre-

eclampsia was thought to be a poorly perfused

placenta. Failure of the spiral arteries to remodel

in pre-eclampsia results in them retaining their

vasoreactivity. Therefore, it is now suggested that,

instead of a chronically hypoxic placental blood

supply, there is intermittent perfusion of the

intervillous space. This results in a fluctuating level

of oxygenation to the placenta and has been

termed a hypoxia–reoxygenation or ischaemia–

reperfusion injury. In vitro studies have

demonstrated an increase in oxidative stress in

placentas exposed to hypoxia–reoxygenation. In

contrast, placentas exposed to chronic hypoxia did

not show an increase in oxidative stress.22 The

effect of hypoxia–reoxygenation on the amount of

apoptosis has also been studied, with hypoxia–

reoxygenation being associated with an increase in

apoptosis.23

Endothelial cell activation andinjuryThe underlying pathophysiology in pre-eclampsia

is a loss of normal endothelial function with

leakage of protein and fluid from the intravascular

space. This is evident by the clinical signs of

proteinuria and oedema. The increased capillary

permeability in pre-eclampsia has also been

demonstrated using Evans blue dye.24

There are biochemical markers evident in the

blood of women with pre-eclampsia suggestive of

endothelial cell injury or activation. Levels of

cellular fibronectin (cFN, a marker of significant

endothelial cell injury), von Willebrand’s factor

(vWF, an activator of platelet adhesion), tissue

plasminogen activator (tPA, a fibrinolysis

promoter) and plasminogen activator inhibitor-1

(PAI-1, a fibrinolysis inhibitor) are higher in sera

of women with pre-eclampsia compared with

normotensive women.25

Further evidence of endothelial dysfunction in

pre-eclampsia can be seen in the relaxation of

myometrial vessels. The contractility and

relaxation of small myometrial vessels dissected

from myometrial biopsies taken at caesarean

sections can be measured in vitro. The relaxation

of myometrial vessels from women with pre-

eclampsia is reduced compared with normotensive

pregnant women (Figure 4).26 This relaxation was

shown to be endothelium dependent as the

difference in relaxation of vessels from women

with pre-eclampsia and normotensive pregnant

women is abolished when the endothelium is

removed. Endothelial dependent relaxation of

myometrial vessels in normal pregnancy is

through endothelium-derived hyperpolarising

factor (EDHF) and NO. However, in pre-

eclampsia endothelial dependent relaxation is

entirely through the NO pathway, and the activity

of this system is reduced.27 Any mechanism to

improve endothelial dependent relaxation of

myometrial vessels in women with pre-eclampsia

could have significant effects on the oxygenation

of the placenta and also the release of circulating

factors. One suggested avenue may be

phosphodiesterase inhibitors. Phosphodiesterase is

present within endothelial cells and degrades cyclic

GMP (the second messenger in the NO pathway).

Phosphodiesterase inhibitors will limit this step

and promote vasodilatation. This relaxant effect

has been demonstrated in myometrial vessels from

women with pre-eclampsia in vitro, so that the

response of these vessels is approaching that of

normal pregnancies.26

100

80

60

40

% A

VPm

ax

20

0P=0.0035 (ANOVA)

_11 _10 _9 _8

[Bradykinin]

Normal pregnant (N=12)Pre-eclampsia (N=18)

_7 _6

Figure 4

Bradykinin induced (mol/L) endothelium-

dependent relaxation of myometrial vessels in

normal pregnancy and pre-eclampsia. The y axis

demonstrates the relaxation as a percentage of

the maximal constriction to arginine vasopressin

(AVP).26 Reproduced with permission from

Elsevier.



SummaryThere has been extensive research into the

pathogenesis of pre-eclampsia in recent years and

while a unifying hypothesis has not yet been

reached, there is general consensus regarding

many of the key steps in the disease process.

Deficient remodelling of the spiral arteries in early

pregnancy results in a reduced absolute placental

blood flow and fluctuations in oxygen

concentration. There is an increase in oxidative

stress within the placenta and throughout the

maternal circulation. This increase in placental

oxidative stress is likely to be related to the

increase in apoptosis seen in pre-eclampsia. The

placenta releases circulating factors that target the

maternal vascular endothelium and this in turn

causes the fetal and maternal effects seen in this

serious condition. Most importantly, a greater

understanding of this complex disease pathway

has led to new avenues for therapeutic strategies.

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