3. Preeclampsia is progressive disorder leads to maternal &
perinatal morbidity and mortality.
The term, preeclampsia, a condition prior to eclampsia (Greek
word “eklampsis” meaning sudden flashing) is a systemic
syndrome.
Pregnancy Induced Hypertension, characterized by New onset
of hypertension (140/90 mmHg) & proteinuria (≥300 mg/24 h)
after 20 weeks of gestation in previously normotensive non-
proteinuric pregnant women.
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4. In low and middle income countries, about 10% of all
maternal deaths.
Approximately, 800 women die from pregnancy and child
birth related complications around the world every day
An estimated >60,000 maternal deaths worldwide per year.
Preeclampsia and eclampsia accounts for 24% of all maternal
deaths in India.
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5. › Genetic risk factors
› Family history of preeclampsia
› First pregnancy
› Previous pregnancy with preeclampsia
› Gestational age < 20 & > 40 years
› Women who are carrying twins, triplets or more
› Prolonged interval between pregnancies
› Women with gestational diabetes
› A hydatidiform mole
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Continued…
6. › Conception by in-vitro fertilization (IVF)
› Nulliparity
› Pre-existing - Diabetes Mellitus, Metabolic syndrome, Insulin
resistance, Uncontrolled Hyperthyroidism, PCOS & Chronic
hypertension
› Thrombophilia
› Systemic lupus erythematosus or antiphospholipid syndrome
› Kidney disease
› Periodontal disease during pregnancy
› Environmental factors such as living at high altitude & stress
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7. From mild to severe due to slow or rapid progress of
disease condition.
They include –
› Persistent headache
› Blurred vision
› Right upper quadrant pain
› Pulmonary edema
› Vomiting and abdominal pain
› Acute renal failure (ARF)
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Continued…
8. › Acute hepatic failure
› Bleeding at the time of delivery & postpartum bleeding
› Maternal mortality & morbidity
Complications:
› Premature delivery
› Intrauterine growth restriction
› Perinatal mortality and morbidity
› HELLP syndrome
› Seizures
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9. Predominantly as consequence of abnormal placentation.
Disease process can involve multiple organ systems &
› Involvement of utero-placental blood flow
› Vascular resistance
› Endothelial integrity & endothelial damage
› Coagulation system
It can occur in early pregnancy termed as “early onset
preeclampsia” at <34 weeks of gestation and “late onset
preeclampsia” after 34 weeks of gestation.
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11. Definition:
Free radical is a molecule or molecular fragment that contains
one or more unpaired electrons in its outer orbital.
Represented by a superscript dot, (R•).
Oxidation reactions ensure that molecular oxygen is
completely reduced to water.
The products of partial reduction of oxygen are highly
reactive, called Reactive Oxygen Species or ROS
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14. Independent existence
Contains an unpaired electrons
Extreme reactivity
Short life span
Generation of new ROS by chain reaction
Damage to biomolecules, cells & various tissues
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15. An imbalance between ROS production & breakdown by
endogenous antioxidants defense.
May lead to tissue injury.
OS may result in damage to macromolecules
› Carbohydrates
› Lipids
› Proteins
› Nucleic acids
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16. Oxygen containing molecules that have a higher reactivity
than the ground state oxygen.
High doses and/or inadequate removal of ROS results in
oxidative stress, which may cause damage to biological
macromolecules.
There are many different sources by which the ROS are
generated.
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17. Exogenous sources include
› Exposure to cigarette smoke
› Emission from automobiles & industries
› Excess alcohol
› Asbestos
› Exposure to ionizing radiation
› Bacterial, fungal or viral infections
Endogenous sources of ROS includes as
By-products of normal & essential metabolic reactions such as
energy generation from mitochondria or the detoxification
reactions involving the liver cytochrome P-450 system.
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19. Sources of superoxide in neutrophils & vascular endothelial
cells, also from neutrophil respiratory burst.
Increased feto-placental vascular shear stress & enhanced
angiotensin II sensitivity, stimulates NADPH oxidase activity
NADPH oxidase, increased in early-onset Preeclampsia
NADPH oxidase mediates superoxide generation.
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20. In Preeclampsia, improper spiral arteries implantation leads to
hypoxicated tropoblastic tissue destruction, produces
hypoxanthine & xanthine, cytokines leads to inflammation.
Hypoxia stimulates Xanthine oxidase activity.
Hypoxanthine , Xanthine is converted to UA & H2O2 by XO
XO & UA levels increased in Preeclampsia
XO, expressed in cytotrophoblast, syncytiotrophoblast &
villous stromal cells.
XO, mediates superoxide radical generation.
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21. NO• is vasodilator
Half-life: 1-30s
Mediates endothelial function by regulating
› Vascular tone, Platelet aggregation, Leukocyte adhesion,
Smooth muscle cell development
Types of NOS:
Neuronal – nitric oxide synthase (nNOS)
Inducible – nitric oxide synthase (iNOS)
Endothelial – nitric oxide synthase (eNOS)
eNOS associated with trophoblast differentiation.
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22. eNOS, a source of superoxide formation & ↓NO production
↓Tetrahydrobiopterin (BH4), cofactor of eNOS & post-
translational changes regulate eNOS function.
TNF-α & CRP ↑ in Preeclampsia
TNF-α downregulates eNOS & mitochondrial dysfunction
(MD) and elevates ROS production
BH4, eNOS & NO• still not well understood in Preeclampsia.
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23. Superoxide radical (O2
-•) used by immune system to kill
invading pathogens
Main quencher of superoxide radical (O2
-•) is SOD,
converts it to H2O2 & water.
H2O2 is neutralized by catalase.
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24. Peroxynitrite (ONOO-), primary product of the reaction of
superoxide & nitric oxide.
It is a new member of the nitroxidative array of reactive
metabolites.
Half-life: 10-20 ms
ONOO- reacts with protein tyrosine residues to produce 3-
nitrotyrosine (3-NT)
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25. ONOO- can also cause DNA damage & lipid structural
alteration
Mechanism of nitration:
Peroxynitrite & heme-peroxidase pathways, lead to
concomitant formation of tyrosyl radicals & •NO2 , which
combine at diffusion-controlled rates to form 3-nitrotyrosine.
Nitroxidative stress in Preeclampsia:
3-NT levels in Preeclampsia are controversial.
MAPK significantly nitrated in Preeclampsia
MAPK involved in connective tissue remodeling.
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26. Placental trophoblasts and endothelial cells constitute the
placental barrier which effectively separates the fetal and
maternal circulation.
Elevated oxidative stress causes tissue damage and
inflammation which alters the barrier and causes leakage of
fetal and placental derived factors in to the maternal
circulation
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27. Thus oxidative stress disturbs the normal redox state of the
cell and brings toxic effects on the cellular components which
results in apoptosis.
Due to high reactive nature of reactive species and its
influence on endoplasmic reticulum triggers unfolded protein
response pathway in placental cell.
This results in accumulation of abnormally folded proteins
with high turnover accounts to cell death and the basis of
pathogenesis of preeclampsia
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28. The effect of oxidative stress at systemic level occurs by
inflammation process, which is mediated through the
localization of leukocytes, pro-inflammatory cytokines,
adhesion molecules, chemokines.
↑ superoxide production in oxidative stress binds NO & limits
its availability which results in an altered endothelial function
and also inflammatory process.
This elevated systemic oxidative stress responsible for the
release of substances from placenta into maternal circulation
in preeclampsia
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30. Preeclampsia is characterized by inflammatory response after
hypoxia / reperfusion insult.
In Preeclampsia, placental reperfusion injury converges into a
damaging inflammatory response, responsible for
inflammation & oxidative damage orchestrated by OS
Immediately after placental reperfusion injury, reestablished
blood flow releases cytokines & inflammatory factors like
TNF-α, IL-6, IL-10 & CRP and damaging levels of ROS like
superoxide, in response to these events.
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32. Increased ROS may eventually trigger a redox signaling
process to induce cell apoptosis.
Evidences suggest that reduced perfusion due to aberrant
placentation & swallow trophoblast invasion, triggers
placental oxidative stress, leading to intravascular
inflammatory response and endothelial dysfunction, leading
to elevated blood pressure.
These situations are probably involved in the pathogenesis of
preeclampsia.
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33. Lipid peroxidation (MDA)
F2 – isoprostanes (8 – epi-prostaglandin F2α)
Nitrotyrosine
Protein carbonyls
Advanced oxidation protein products (AOPP)
DNA damage – 8-hydroxy – 2-deoxyguanosine
MDA/total antioxidant capacity ratio etc, increased in
Preeclampsia
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34. Oxidative stress index (OSI)
Total antioxidant status (TAS)
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35. Definition:
Substance (present in low concentrations compared to an
oxidizable substrate) that significantly delays or inhibits
oxidation of a substrate.
Antioxidants may be considered as the scavengers of free
radicals.
Enzymatic antioxidants:
Superoxide dismutase
Catalase
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39. Isoforms of SOD:
1. Copper-zinc-SOD: Cytosol
2. Mn-SOD: Mitochondria
3. Extracellular SOD: Vascular cell
Normal conditions, •O2
- is low & SOD is high, catalyses
dismutation of •O2
- as H2O2 & O2
Catalase:
Catalase converts H2O2 to H2O and O2
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40. SOD-1 & GPx-1/3/4 deficiencies are key antioxidants in
pathogenesis of Preeclampsia.
↓SOD-1 level will cause an increase in superoxide anion,
which then reacts with NO to form peroxinitrite.
This reduce the bioavailability of NO
Glutathione peroxidase (GPx) deficiency second key player in
etiology of Preeclampsia
↓activity of GPx associated with synthesis of vasoconstrictive
eicosanoids, e.g., F2-isoprostanes & thromboxanes (↑ in PE)
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41. It detoxifies H2O2 to H2O, while reduced glutathione (G-SH)
is converted to oxidized glutathione (GS-SG).
Contains selenium.
The reduced glutathione can be regenerated by the enzyme
glutathione reductase utilizing NADPH .
The HMP hunt is the major source of NADPH.
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42. Catalyzes the conjugation of the reduced form
of glutathione (GSH) to xenobiotic substrates (detoxification)
The GST family consists of three superfamilies:
cytosolic, mitochondrial and microsomal.
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