DEFINITION

Gestational hypertension
Preeclampsia-eclampsia
Chronic hypertension
Preeclampsia superimposed
upon chronic hypertension

 Elevated BP first detected

after 20 weeks of gestation
without proteinuria
= transient hypertension

BP N

Proteinuria
()

Gestational
Hypertension
BP

20th week
of pregnancy

BP N

Proteinuria 12 weeks
()
postpartum

 Gestational hypertension
Preeclampsia-eclampsia
Chronic hypertension
Preeclampsia superimposed
upon chronic hypertension

 The syndrome of new onset of

hypertension & proteinuria after
20 weeks of gestation in a
previously normotensive woman
Preeclampsia Eclampsia

BP N

Proteinuria
()

BP

20th week
of pregnancy

BP N/

Proteinuria 12 weeks
(+)
postpartum

 Gestational hypertension
Preeclampsia-eclampsia
Chronic hypertension
Preeclampsia superimposed
upon chronic hypertension

 SBP > 140 mmHg and / or DBP > 90

mmHg that antedates pregnancy,
is present before the 20th week of
pregnancy, and persists longer
than 12 weeks postpartum
Chronic Hypertension
BP

BP

Proteinur 20th week Proteinur

ia
ia
of pregnancy
()
()

BP

delivery

BP

12 weeks
postpartum

 Gestational hypertension
Preeclampsia-eclampsia
Chronic hypertension
Superimposed preeclampsia
upon chronic hypertension

 Worsening HT w/ new onset

proteinuria in a woman w/
chronic HT
Superimposed preeclampsia upon
Underlying HT
BP
Proteinuria
()

BP

20th week Proteinuria

(+)
of pregnancy

BP
12 weeks Proteinuria
postpartum ( - )/(+)

Functions of the endothelium

Regulate vascular permeability
Regulate vascular cell growth
Mediate inflammatory and
immune mechanism
Modulate lipid oxidation
( metabolic activity )

Endothelial dysfunction
An imbalance between relaxing and
contracting factors between
anti -and pro-coagulant mediators
or growth-inhibiting and growth
promoting factors.

Endothelial cell dysfunction

appears to be the central
pathomechanism in the
pathogenesis of preeclampsia

FIGURE 1. Abnormal placentation in preeclampsia

In normal placental development, invasive cytotrophoblasts of fetal origin invade the maternal spiral arteries,
transforming them from small-caliber resistance vessels to high-caliber capacitance vessels capable of providing
placental perfusion adequate to sustain the growing fetus. During the process of vascular invasion, the
cytotrophoblasts differentiate from an epithelial phenotype to an endothelial phenotype, a process referred to as
pseudovasculogenesis or vascular mimicry (left). In preeclampsia, cytotrophoblasts fail to adopt an invasive
endothelial phenotype. Instead, invasion of the spiral arteries is shallow, and they remain small caliber, resistance
vessels (right).
Maynard S,,Annu. Rev. Med. 2008. 59:6178

1. Placental ischemia
2. Very low-density lipoprotein
versus toxicity-preventing activity
3. Immune maladaptation
4. Genetic imprinting
5. Deficiency of catechol-Omethyltransferase / 2methoxyestradiol
6. The role of RAS

Decreased
uterine
placental blood
flow
Placenta
ischemia
Placental release of factors

Endothelial dysfunction
ET-1

TBX

NO

Renal
pressure
natriuresi
s

PG2

ANG II Sensitivity

Total
periphera
l
resistanc
e

HYPERTENSI
ON

Am J Physiol Heart Circ Physiol 294: H541H550,2008

Lipid peroxides
Cytokines

Placental
ischemia

Platelet aggregation

Endothelial cell damage

PGI2
NO
Endothelin
Mitogenic factors
(eg, PDGF)

Systemic
vasoplasm

Thromboxane A2
Serotonin, PDGF
Thrombin

Organ flow
Intravascular
coagulation

oxLDL ANG II

TNF-

ICAM 1
LOX-1

AT1R

TNFR

NAD(P)H oxidase
O2

eNOS

NO

iNOS

Big ET-1

NF - B

MMP-2

ONOO
PGI2
synthase

ET-1 (132 )

Endothelial cell

Role of oxidative stress in the mediation of endothelial cell dysfunction

in preeclampsia

Expert Reviews in Molecular Medicine 2006

The place of oxidative stress in the

three-stage model of the disease

HUM ONTOGENET 2(1), 2008, 2938

1. Placental ischemia
2. Very low-density lipoprotein
versus toxicity-preventing activity
3. Immune maladaptation
4. Genetic imprinting
5. Deficiency of catechol-Omethyltransferase / 2methoxyestradiol
6. The role of RAS

 FFA 15 - 20 weeks before

the onset of clinical
disease
Sera from preeclampsia
women have both a higher
ratio of FFA to albumin

FFA levels
endothelial cell
triglyceride
accumulation

lipolitic activity resulting

in enhanced endothelial
cell uptake of FFA

cytokinemediated
oxidative stress
ischemia-reperfusion mechanisms
or / and
activated leukocytes

1. Placental ischemia
2. Very low-density lipoprotein
versus toxicity-preventing activity
3. Immune maladaptation
4. Genetic imprinting
5. Deficiency of catechol-Omethyltransferase / 2methoxyestradiol
6. The role of RAS

Normal : Interaction between decidual leukocytes and

invading cytotrophoblast cells is essential for normal
trophoblast invasion and development.
Immun
maladaptation
Shallow invasion of spiral arteries by endovascular cytotrophoblast cells and
endothelial cell dysfunction mediated by an increased decidual release of
cytokines, proteolytic enzymes, and free radical species
NK cells Th1 predominant inflammatory response profile increased
interferon- and TNF- endothelial damage and inflammation systemically

Further investigation !!!!

1. Placental ischemia
2. Very low-density lipoprotein
versus toxicity-preventing activity
3. Immune maladaptation
4. Genetic imprinting
5. Deficiency of catechol-Omethyltransferase / 2methoxyestradiol
6. The role of RAS

Genetic factors
Environment factor
(deficiency in nutritions?)

Endothelial
damage

Placental
deficiency

Clinical signs of
preeclampsia

Increased
demand from
embryo?

Kanasaki K,Kalluri R, Kidney International,2009

1. Placental ischemia
2. Very low-density lipoprotein
versus toxicity-preventing activity
3. Immune maladaptation
4. Genetic imprinting
5. Deficiency of catechol-Omethyltransferase / 2methoxyestradiol
6. The role of RAS

Figure 2. The putative role of COMT/2-methoxyestradiol (2-ME) in pregnancy. In normal

pregnancy, 2-ME may have a role in regulating hypoxia-inducible factor (HIF)-1a in
diverse ways. In preeclampsia, low COMT/2-ME levels may induce accumulation of
HIF-1a, vascular defect, placental hypoxia, and inflammatory responses in the
placenta. Such a response may induce placental defects and result in suppression of
placental-derived estradiol and further reduction in 2-ME levels. COMT, catechol-Omethyltransferase; CYP450, cytochrome 450.

1. Placental ischemia
2. Very low-density lipoprotein
versus toxicity-preventing activity
3. Immune maladaptation
4. Genetic imprinting
5. Deficiency of catechol-Omethyltransferase / 2methoxyestradiol
6. The role of RAS

Deficient uteroplacental perfusion

pressure and blood flow
Progesterone and
other mediators

Reciprocal
renal RAS

Vascular dysfunction:
systemic and multi-organ
effects

Uteroplacental
RAS

Chronic subpressor
angiotensin II
Figure 3. Pathogenesis of preeclampsia
Proximate biochemical-molecular event is the activation of uterine RAS. Uterus is
the clipped kidney with reduced perfusion pressure, and the two kidneys are the
nonclipped kidney with reciprocal suppression of renal RAS, which is manifested in
the systemic circulation. RASrenin-angiotensin system.

HYPERTENSION

Uteroplacental
insufficiency

Vascular
dysfunction

Kidney

Proteinuria

Deficient
vascular
remodeling

Activation
of decidual
RAS

sFLT1
s EnG

Placental hypoxia

Elevated
subpressor
Ang II
Vascular
maladaptation

Figure 4 : Decidual RAS activation and the placental release of antiangiogenic factors may
explain the manifestations of human preeclampsia
Current Opinion in Nephrology and Hypertension 2007, 16:213220

Maternal Outcome

Fetal Compromise

Severe Disease

Mild Disease

Hypovolemia Vasoconstriction Platelet Aggregation

Balance
th
Bad endo

oth
Good end

elium

elium

presence of underlying disorders:

(maternal susceptibility genes)
chronic hypertension
hyperhomocysteinemia
thrombophilic disorders
obesity, syndrome X
diabetes mellitus

EC Dysfunction

Increased STB Deportation

In End-Stage Disease

Placental
Ischemia
Acute
Atherosis

Cytokine-Mediated
Oxidative Stress

Shallow Trophoblast
Invasion in
Spiral Arteries abnormal CTB integrin switching
abnormal decidual CK activity

EC Adhesion
Molecules
(neutrophil
recruitment)

Immune Maladaptation
Genetic Conflict

Risk Factors

Unadjusted relative risk

(95% confidence interval)

Age > 40 years, primiparae

1.68 (1.23 2.29)

Age > 40 years, multiparae

1.96 (1.34 2.87)

Family history

2.90 (1.70 4.93)

Nulliparity

2.91 (1.28 6.61)

Multiple pregnancy

2.93 (2.04 4.21)

Preexisting diabetes

3.56 (2.54 4.99)

Prepregnancy body mass

index > 35

4.29 (3.52 5.49)

Previous preeclampsia

7.19 (5.85 8.83)

Antiphospholipis syndrome

9.72 (4.34 21.75)

SUMMARY THE PATHOMECHANISM OF PREECLAMPSIA

Patofisiologi Preeklampsia
Gangguan Plasentasi
(remodelling arteri spiralis)

Hipoperfusi Plasenta
Pelepasan Faktor-faktor dari Plasenta
(TNF-, stress oksidatif)

Disfungsi Endotel

Gangguan
Pressure Natriuresis Ginjal

Vasokonstriksi Sistemik

Hipertensi