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Latest Advances in

Understanding Preeclampsia

Yoav Yinon, MD

Department of Obstetrics and Gynecology

Sheba Medical Center

Preeclampsia

• Worldwide prevalence: 5-8%

• Leading cause of maternal mortality in

developing countries:

>60,000 maternal deaths/yr

• Major cause of perinatal morbidity and

mortality

Preeclampsia-Complications

• Acute renal failure

• Placental abruption

• Pulmonary edema

• Acute liver injury

• Hemolysis

• Thrombocytopenia

• Seizures

Maternal Fetal

• IUGR

• Oligohydramnios

• Prematurity

• Perinatal death

Criteria for Diagnosis

• SBP ≥ 140 mmHg or DBP ≥ 90 mmHg that

occurs after 20 weeks of gestation in a

woman with previously normal BP

• Proteinuria defined as ≥ 0.3 g in a 24h

urine specimen or ≥ 1+ proteinuria

detected by dipstick

Criteria for Diagnosis

• In the absence of proteinuria, new onset

hypertension with new onset of any one of

the following:

– Thrombocytopenia

– Renal insufficiency

– Impaired liver function

– Pulmonary edema

– Cerebral or visual problems

Preeclampsia

Disease of Theories

Two-stage theory:

Preeclampsia is a systemic syndrome that originates

in the placenta and is characterized by maternal

endothelial dysfunction

Risk Factors

• Chronic hypertension/renal disease

• Diabetes

• Connective tissue disease

• Thrombophilia

• Advanced maternal age

• Obesity

• Multifetal gestation

• Chromosomal abnormality (triploidy, trisomy 13)

• Smoking- reduced risk

Risk Factors

• Nulliparity

• Multiparous women pregnant with a new partner

• Increased interpregnancy interval

• Preeclampsia in a previous pregnancy

• Family history of preeclampsia

• Partner who fathered preeclamptic pregnancy with another

woman

Role of Placenta

• Preeclampsia only occurs in the presence of placenta and almost always remits after delivery

• Severe preeclampsia is associated with pathological evidence of placental hypoperfusion and ischemia

• Abnormal uterine artery Doppler is observed before the clinical onset of preeclampsia

Normal Pregnancy

Preeclampsia- Abnormal Placentation

anchoring villus

endovasculartroph.-cells

BP

Dec.

Myo.

endothelialcells

interstitialtroph.-cells

non invadedmedia

topofspiral-artery

topofspiral-artery

border between prolif. and invas. troph.-cells

Healthy Pregnant Patients Preeclampsia

Courtesy of Dr. F. Reister

Preeclampsia- Abnormal Placentation

• Trophoblastic invasion

• Arteries are poorly remodeled

• Capacity of uteroplacental circulation

Adapted from Pre-eclampsia, by Baker & Kingdom

Placental blood flow and vascular impedance

Uterine artery Doppler

Non-

pregnant

At 25 wks

Failure of uterine artery transformation

Normal: Non-pregnant

Abnormal: Pregnant at 25 weeks

Maternal endothelial damage

• Although preeclampsia appears to begin in the placenta, the target organ is maternal endothelium

• Serum markers of endothelial activation are deranged in women with PE

• Circulating factors originating from the placenta lead to endothelial dysfunction

Maternal endothelial dysfunction

• Hemodynamic changes:

vasoconstriction, increased vascular resistance, decreased cardiac output

• Renal pathology:

Glomerular endotheliosis

• Cerebral edema:

Vasogenic cerebral edema and infarctions in the subcortical white matter (PRES)

Pathogenesis: The role of

Angiogenic Factors

• Imbalance of endogenous angiogenic factors play a key role

• Increased expression of soluble fms-like tyrosine kinase-1 (sFlt1) associated with decreased placental growth factor (PLGF)and VEGF signaling

• VEGF deficiency is responsible for proteinuria and glomerular changes

Pathogenesis: The role of

Angiogenic Factors

• Soluble endoglin (sEng), which binds and antagonizes TGF-b, is upregulated in preeclampsia

• Endoglin is expressed at high levels in the syncytiotrophoblast cells

• Levels of endoglin are increased in preeclamptic placentas

Normal Preeclampsia

sFlt-1

PLGF

VEGF

Maynard et al, JCI 2003

The antiangiogenic properties of serum from preeclamptic

patients are due to blockade of VEGF and PLGF by

endogenous sFlt-1


sFlt-1 inhibits VEGF and PLGF-induced

vasodilatation of renal microvessel

sFlt-1 in preeclamptic patients might

oppose physiologic vasorelaxation


sFlt-1 induces glomerular endotheliosis


VEGF and Preeclampsia

• VEGF is highly expressed by glomerular podocytes

• VEGF receptors are present on glomerular endothelial cells

• Podocyte-specific VEGF knockout mouse resulted in renal disease characterized by proteinuria and glomerular endotheliosis (Eremina et al, JCI 2003)

VEGF and Preeclampsia

• In humans, anti-angiogenesis cancer trials with anti-VEGF antibodies have led to proteinuria and hypertension

(Eremina et al, NEJM 2008)

• VEGF may be important in maintaining the health of fenestrated endothelium

• VEGF deficiency is likely responsible for proteinuria and glomerular endotheliosis

PLGF and Preeclampsia

• A potent angiogenic growth factor

• Amplify VEGF signaling

• During pregnancy, inhibition of both

PLGF and VEGF is necessary to

produce preeclampsia-like changes in

pregnant rats

Circulating sFlt-1 levels and the risk of preeclampsia

Levine et al, NEJM 2004

Circulating PLGF levels and the risk of preeclampsia



Circulating angiogenic factors and the risk of

preeclampsia

Summary

• sFlt-1 is upregulated in preeclampsia

• Increased sFlt-1 in preeclamptic patients is associated with decreased circulating levels of VEGF and PLGF, resulting in endothelial dysfunction in vitro

• VEGF and PLGF cause microvascular relaxation of rat renal arterioles in vitro that is blocked by sFlt-1

• Administration of sFlt-1 to pregnant rats induces hypertension, proteinuria and glomerular endotheliosis

• Excess circulating sFlt-1 contributes to the pathogenesis of preeclampsia

Endoglin in Preeclampsia


• sEng levels were three-,

five- and tenfold higher

in women with mild

preeclampsia, severe

preeclampsia and

HELLP syndrome

respectively compared

to preterm controls

Venkatesha et al, Nature Medicine 2006



• VEGF and TGFß1

had additive effects

on vasodilatation

which were blocked

by the combination of

sEng and sFlt1

In vivo effects of sEng and sFlt1


Soluble Endoglin in Preeclampsia

• At 17-20 weeks soluble

endoglin levels were

significantly higher in

women in whom preterm

PET later developed

• At 25-28 weeks levels

were significantly higher in

women in whom term PET

later developed


Soluble Endoglin in Preeclampsia

• An increased level of sEng

was usually accompanied

by an increased ratio of

sFlt1:PLGF

• The risk of preeclampsia

was greatest among women

in the highest quartile for

both biomarkers


Summary

• Endoglin is elevated in the serum of preeclamptic women, correlates with disease severity and falls after delivery

• sEng inhibits formation of capillary tubes in vitro and induces vascular permeability and hypertension in vivo

• Co-administration of sEng and sFlt1 to pregnant rats leads to severe preeclampsia including HELLP syndrome

• sEng leads dysregulated TGF-b signaling

• sEng may act in concert with sFlt1 to induce severe preeclampsia

Pathogenesis

• The molecular basis for placental

dysregulation of these anti-angiogenic

factors remains unknown

• Hypoxia is likely to be an important regulator

Is the shallow cytotrophoblast invasion a consequence or

cause of placental ischemia/ hypoxia?

Effect of Oxygen on Endoglin Expression in

Villous Explants

0

0.5

1

1.5

2

2.5

3

3.5

3% 20%

*P<0.05

*

qRT-PCR Analysis

(oxygen concentration)

En

g t

ran

scrip

t fo

ld c

han

ge

0

1

2

3

4

3% 8% 20%

3% 8% 20%

Eng

sEng

*

*P<0.05

(oxygen concentration)En

g p

rote

in l

evel

s fo

ld c

han

ge

Yinon et al. Am J Path 2008

Pathogenesis: Other pathways

• Renin-angiotensin-aldosterone

• Endothelin-1

• Immunological intolerance

• Oxidative stress

• Genetics

Renin- angiotensin pathway

• In normal pregnancy renin, aldosterone

and angiotensin are increased

• These hormones are suppressed relative

to normal pregnancy in preeclampsia

• Women with preeclampsia have increased

vascular responsiveness to angiotensin II

Renin- angiotensin pathway

• Patients with PE develop agonistic

autoantibodies against the angiotensin II

AT1 receptor (Wallukat et al, JCI 1999)

• AT1 receptor autoantibodies decreases

invasiveness of human trophoblasts(Xia et al, J SGI 2003)

-PE may be a pregnancy-induced autoimmune disease

-Key features of the disease result from

autoantibody-induced angiotensin receptor activation

Endothelin-1 and Preeclampsia

• ET-1 is a potent endothelium-derived

vasoconstrictor:

– ETA receptor: vasoconstrictive response

– ETB receptor : vasodilatory response

• Elevated levels of plasma ET-1 in

preeclamptic women

Endothelin-1 and Preeclampsia

• Plasma ET-1 levels ae increased in women with

a high sFlt1/PLGF ratio

• High antiangiogenic state is associated with

ET-1 activation

• Hypertension in pregnant rats can be completely

attenuated by ETA receptor antagonism

• ETB receptor activity is reduced in pregnant rats

with placental ischemia-induced hypertension

Immunological Intolerance

• Normal placentation requires the

development of immune tolerance

between the fetus and the mother

• Natural killer (NK) cells play an important

role (Hanna et al, Nat Med 2006)

Immunological Intolerance-

Epidemiological evidence

• Preeclampsia is more common :

– First pregnancies

– After a change in paternity

– Long inter-pregnancy interval

– Women using barrier contraceptive methods

PE = abnormal maternal immune response

to novel paternally derived fetal antigens

IVF with

ejaculated

sperm

(n=1075)

ICSI with

ejaculated

sperm

(n=464)

ICSI with

surgically

obtained

sperm (n=82)

Gestational

Hypertension 11% 12% 22%

Pre-eclampsia

4% 4% 11%

Wang et al, Lancet 2002

Oocyte donation and preeclampsia

Oocyte donation is independently associated with a higher

rate of hypertensive diseases of pregnancy

Immunological Intolerance

• Decidua: Trophoblasts meet maternal NK

cells

• NK cells have an unusual phenotype:– High cytokine production

– Receptors that recognize the HLA’s on invasive

cytotrophoblasts (CT)

• The invasive CT and decidual NK cells are

closely apposed to each other

Preeclampsia and Maternal Systemic

Inflammatory Response (MSIR)

• PE is associated

with a systemic

inflammatory

response

• Normal pregnancy

is also associated

with MSIR but to a

lesser extent

Preeclampsia is the extreme end of a continuum

common to all pregnancies

Preeclampsia and Maternal Systemic

Inflammatory Response (MSIR)

• Placenta releases

trophoblast debris into

maternal circulation:

– Syncytiotrophoblast

microparticles

– Cytokeratin fragments

– Fetal DNA

• This debris is

proinflammatory and

increased in PE

Redman, Placenta 2003

Preeclampsia and oxidative stress

• The hypoxic placenta of PE suffers

oxidative stress

• In Preeclampsia:– Enzymatic antioxidants

– Markers of high oxidative stress

Redman, Science 2005

Vitamins C and E during pregnancy has not been shown

to reduce risk of PE

Poston et al, Lancet 2006

Rumbold et al, NEJM 2006

Summary: Pathogenesis of Preeclampsia

Early vs late-onset Preeclampsia

• Incomplete transformation of

the spiral arteries

• Hypoperfusion of the

placenta

• IUGR

• No change/shallow

modification of the spiral

arteries

• No signs of placental

underperfusion

• Most are not IUGR

Early (< 34 wks) Late (> 34 wks)

The dual etiology of late-onset

Preeclampsia

Verlohren et al., UOG 2014


Preeclampsia

• Late-onset PE may have two different

etiologies:

– one shared with early-onset PE

resulting in SGA births

(poor trophoblast development)

–another associated with LGA births



Preeclampsia

• LGA form of late–onset PE:

Maternal cardiac dysfunction and inability to

meet the increased metabolic demands of an

overgrown fetoplacental unit resulting in placental

hypoxemia

• Maternal cardiac dysfunction precedes the

clinical presentation of both early and late PE


Clinical Implications

• Biomarkers for PE:

– sFlt-1 and sEng rise 5-8 weeks before onset of

disease

– PLGF is a better 1st trimester marker

• Differential diagnosis

• Treatment:

– Restoration of normal angiogenic balance (VEGF)

– Statins: Effect on heme oxygenase-1 activity,

lowers sFlt1 production

(Cudmore et al, Circulation 2007)

VEGF treatment in a rat model of

preeclampsia

Li et al, Hypertension 2007

VEGF treatment in a rat model of

preeclampsia

Li et al, Hypertension 2007

control sFlt-1 sFlt-1+ VEGF

Pravastatin and Preeclampsia

Brownfoot et al, Hypertension 2015

Thadhani al, Circulation 2011

Preeclampsia, twins and sFlt-1

• In twin pregnancies with preeclampsia only one

placenta secretes elevated levels of sFlt-1

• Twins with early onset PET, IUFD of one twin

resulted in resolution of PET and reduction in

circulating sFlt-1 levels

Hladunewich et al, Nat Rev Nephrol 2006

Selective reduction in twins with

very early severe PET and IUGR

Preeclampsia and Long Term Outcomes

• Women with a history of preeclampsia

risk for hypertension, stroke, coronary

artery disease and end stage renal disease

8 fold increased risk of cardiovascular death in women with a

history of preeclampsia requiring delivery prior to 37 weeks(Irgens et al, BMJ 2001)

Pre-eclampsia and future

cardiovascular disease

Births 1967-

1992

GA at

birth

All

Deaths

Cardio.

death

Death from

stroke

NO PET >37 1 1 1

NO PET 16-361.56

(1.38-1.76)

2.95 (2.12-4.11)

1.91

(1.26-2.91)

PET >371.04

(0.88-1.23)

1.65

(1.01-2.7)

0.98

(0.50-1.91)

PET 16-362.71

(1.99-3.68)

8.12

(4.3-15.3)

5.08 (2.09-12.35)

Irgens et al, BMJ 2001

Pre-eclampsia and future


• 8-fold higher risk of

cardiovascular

death in women with

pre-eclampsia that

required preterm

delivery

Irgens et al, BMJ 2001

Pre-eclampsia and risk of cardiovascular

disease: Meta-analysis

• After pre-eclampsia women have an

increased risk of vascular disease:

– Hypertension: 3.7 (2.7-5.05)

– Ischemic heart disease: 2.16 (1.86-2.52)

– Stroke: 1.81 (1.45-2.27)

– Overall mortality: 1.49 (1.05-2.14)

Bellamy et al, BMJ 2007

Pre-eclampsia and the risk of ESRD

• Preeclampsia during the first pregnancy-RR of 4.7 (3.6-6.1) for ESRD

• Preeclampsia during 2 or 3 pregnancies was associated with a RR of 15.5 (7.8-30.8)

• Having a low birth weight infant or preterm infant increased the relative risk of ESRD

Vikse et al, NEJM 2008

Smith et al, AJOG 2009

What is the link between

preeclampsia and future

cardiovascular disease?

Endothelial Dysfunction

Endothelial Dysfunction

Chambers et al, JAMA 2001

Controls

(25)

Previous PET

(38)

P value

FMD 4.6 2.5 0.03

GTN induced 21.1 21.2 0.97

BMI 21.9 22.3 0.37

SBP 106 109 0.28

DBP 66 69 0.17

T. Cholesterol 182 182 0.98

Endothelial-Dependent Vasodilatation

Control Late PE Early PE IUGR0

1

2

3

4

5

6

7

8

9

10

11F

low

-med

iate

d v

aso

dilata

tio

n (

%)

*

*

* p<0.05 versus control, † p<0.05 versus late PE

NS

†

†

Yinon et al, Circulation 2010

Control

(n=16)

Late PE

(n=9)

Early PE

(n=15)

IUGR

(n=9)

FMD (%) 9.1±0.9 7.9±1.3 3.3±0.7 2.1±0.4

FMD/flow (units) 0.25±0.04 0.29±0.08 0.08±0.02 0.07±0.02

GTN-mediated

dilatation (%)18±1.1 20±1.5 16±0.9 16±1.3

Endothelial

Dysfunction, n (%)2 (13) 2 (22) 14 (93) 8 (89)

Vascular Function

*

**

**

*

* p<0.05 versus control, † p<0.05 versus late PE

†

†

††

†

†


sFlt-1


50

100

150

200

250

ng

/ml

sEng

Control Late PE Early PE IUGR0.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5

4.0

4.5

ng

/ml

VEGF


50

100

150

200

250

300

350

400

450

pg

/ml

PlGF


1

2

3

4

5

6

7

8

9

pg

/ml


Preeclampsia and future


Preeclampsia

Endothelial dysfunction

Vascular disease

sEngsFlt1

Endothelial dysfunction

Vascular diseasePreeclampsia

Preeclampsia and future


Powe and Karumanchi, Circulation 2011

Summary

• The antiangiogenic factors sFlt-1 and soluble endoglin produce systemic endothelial dysfunction resulting in hypertension, proteinuria and other systemic manifestations of PE

• The molecular basis for placental dysregulation of these pathogenic factors remains unknown

Summary

• The renin-aldosterone-angiotensin II axis, excessive oxidative stress, syncytiotrophoblast debris, immune maladaptation and genetic susceptibility may all have roles in the pathogenesis of PE

• Middle-aged women with previous preeclampsia, especially if early and severe, have the highest risk of future cardiovascular disease and may benefit from prophylaxis

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