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

Gestational Hypertension

BP N BP  BP N

Proteinuria 20th week Proteinuria 12 weeks

(–) of pregnancy (–) 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/
BP N BP 

Proteinuria 20th week Proteinuria 12 weeks

(–) of pregnancy (+) 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  BP  BP 

Proteinuria 20th week Proteinuria delivery 12 weeks

(–) of pregnancy (–) 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  BP   BP 

Proteinuria 20th week Proteinuria 12 weeks Proteinuria

(–) of pregnancy (+) 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. 59:61–78
1. Placental ischemia
2. Very low-density lipoprotein versus
toxicity-preventing activity
3. Immune maladaptation
4. Genetic imprinting
5. Deficiency of catechol-O-
methyltransferase / 2-methoxyestradiol
6. The role of RAS
 Decreased
uterine placental
blood flow

Placenta
ischemia

Placental release of factors

Endothelial dysfunction
 ET-1  TBX  NO  PG2  ANG II Sensitivity

 Renal  Total
pressure peripheral
natriuresis resistance

HYPERTENSION
Am J Physiol Heart Circ Physiol 294: H541–H550,2008
 Lipid peroxides Placental
Cytokines ischemia

Endothelial cell damage Platelet aggregation

Thromboxane A2 
PGI2  Systemic Serotonin, PDGF 
NO  vasoplasm
Endothelin 
Thrombin 
Mitogenic factors 
(eg, PDGF)
 Organ flow

Intravascular
coagulation
 oxLDL ANG II TNF-

 ICAM 1
LOX-1 AT1R TNFR

NAD(P)H oxidase eNOS  iNOS Big ET-1

O2–
NO NF - B
MMP-2

ONOO – ET-1 (1–32 )

 PGI2
synthase
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, 29–38

1. Placental ischemia
2. Very low-density lipoprotein versus
toxicity-preventing activity
3. Immune maladaptation
4. Genetic imprinting
5. Deficiency of catechol-O-
methyltransferase / 2-methoxyestradiol
6. The role of RAS
 FFA 15 - 20 weeks before
the onset of clinical
disease
 FFA levels
Sera from preeclampsia
women have both a higher endothelial cell
ratio of FFA to albumin triglyceride
accumulation
 lipolitic activity resulting
in enhanced endothelial
cell uptake of FFA
cytokine-mediated
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-O-
methyltransferase / 2-methoxyestradiol
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-O-
methyltransferase / 2-methoxyestradiol
6. The role of RAS
 Genetic factors
Environment factor
(deficiency in nutritions?)

Increased
Endothelial
demand from
damage Placental embryo?
deficiency ?
Clinical signs of
?
preeclampsia

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-O-
methyltransferase / 2-methoxyestradiol
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-O-
methyltransferase; 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-O-
methyltransferase / 2-methoxyestradiol
6. The role of RAS
 Deficient uteroplacental perfusion
pressure and blood flow

Progesterone and
other mediators
Vascular dysfunction:
systemic and multi-organ
effects
 Reciprocal  Uteroplacental
renal RAS 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. RAS—renin-angiotensin system.
 HYPERTENSION

Proteinuria Kidney  sFLT1

Deficient  s EnG
vascular
remodeling

Activation
Uteroplacental Placental hypoxia
insufficiency
of decidual
RAS

Vascular
dysfunction 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, 16:213–220
Fetal Compromise Maternal Outcome

Severe Disease Mild Disease

Hypovolemia  Vasoconstriction  Platelet Aggregation

Balance

presence of underlying disorders:

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

Placental Increased STB Deportation EC Adhesion

Ischemia In End-Stage Disease Molecules
Cytokine-Mediated (neutrophil
Acute
Oxidative Stress recruitment)
Atherosis

Shallow Trophoblast
Invasion in
Spiral Arteries • abnormal CTB integrin switching
Immune Maladaptation
• abnormal decidual CK activity
Genetic Conflict ?
 Unadjusted relative risk
Risk Factors
(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
4.29 (3.52 – 5.49)
> 35
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 Vasokonstriksi Sistemik

Pressure Natriuresis Ginjal

Hipertensi