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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
Maynard et al, JCI 2003
sFlt-1 inhibits VEGF and PLGF-induced
vasodilatation of renal microvessel
sFlt-1 in preeclamptic patients might
oppose physiologic vasorelaxation
Maynard et al, JCI 2003
sFlt-1 induces glomerular endotheliosis
Maynard et al, JCI 2003
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
Levine et al, NEJM 2004
Levine et al, NEJM 2004
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
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
Endoglin in Preeclampsia
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
Venkatesha et al, Nature Medicine 2006
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
Levine et al, NEJM 2006
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
Levine et al, NEJM 2006
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
The dual etiology of late-onset
Preeclampsia
Verlohren et al., UOG 2014
The dual etiology of late-onset
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
Verlohren et al., UOG 2014
The dual etiology of late-onset
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
Verlohren et al., UOG 2014
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
cardiovascular disease
• 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
†
†
††
†
†
Yinon et al, Circulation 2010
sFlt-1
Control Late PE Early PE IUGR0
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
Control Late PE Early PE IUGR0
50
100
150
200
250
300
350
400
450
pg
/ml
PlGF
Control Late PE Early PE IUGR0
1
2
3
4
5
6
7
8
9
pg
/ml
Yinon et al, Circulation 2010
Preeclampsia and future
cardiovascular disease
Preeclampsia
Endothelial dysfunction
Vascular disease
sEngsFlt1
Endothelial dysfunction
Vascular diseasePreeclampsia
Preeclampsia and future
cardiovascular disease
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