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“Preeclampsia”
new concepts in an age-old
disease
Dr. Sujnanendra Mishra
MD (ObGyn)
DIC
CardioRenal
Syndrome
Elevated LFTs
Hypertension Proteinuria
HELLP Syndrome Abdominal pain
Seizure
Stroke
HUS Headaches...
History
• 2200 BC Egypt: pregnant women with
fists
• 400 BC Hippocrates: pregnant women
with convulsions
• Eclampsia: Gree...
2200 BC – Egypt
400 BC -Greece MiddleAges
Third Papyrus
-Tongue biting at birth
_Olive oil treatment
Hippocrates
_Sei...
ICD 10 ( WHO )
Timely And Correctly Diagnosed
Preeclampsia brings Peace of mind
for physicians
• A disease where the clinical picture is ...
Hypertensive Disorder in Pregnancy
Pregnancy induced hypertension
Gestational
hypertension w/o
proteinuria
Preeclampsia
(P...
RISK FACTORS with Odd Ratio.
Nulliparity (3:1) Immunologic factors :
Antiphospholipid syndrome
(10:1)
Previous pregnancy c...
Primipaternity 4: 1 Black Race (2:1) Maternal infection12:1
Duration of relationship prior to
pregnancy & age at delivery ...
Age >40 years (3:1) Chronic renal disease
(20:1)
Chronic hypertension
(10:1)
Diabetes mellitus
(2:1)
In vitro fertilizatio...
PLACENTA,
Origin Of Life and the Disease Too ????
• POOR IMMUNOREGULATIONStage 0
3-8 weeks
• POOR
PLACENTATION
Stage 1
8-18 weeks
• CLINICAL
MANIFESTATION
Stage 2
20 weeks ...
Proposed Pathogenic Factors of the Maternal Syndrome of
Preeclampsia
Oxidative Stress Lipid Hydroperoxides
Placental troph...
Pathophysiology of the Clinical
Manifestations of Preeclampsia
Pathogenesis
of
Preeclampsia
Genetic
factors
Abnormal
troph...
PLACENTATION
Invasive cytotrophoblasts
of fetal origin invade the
maternal spiral arteries
Transforms them from
small-cali...
Normal placentation
 Deep trophoblast invasion
 Remodeling of spiral artery
 Endovascular replacement
 Controlled, seq...
cytotrophoblasts fail to adopt an invasive
endothelial phenotype
invasion of the spiral arteries is shallow and they
remai...
ANGIOGENESIS,
Key to Placental Development
SPIRAL ARTERY
REMODELING
Unmodeled decidual spiral artery
VSMC:- vascular smooth muscle cells
EC:- Endothelial cells
EVT:- Extra-villous trophoblas...
END RESULT SPIRAL ARTERY REMODELING DEFECT
NORMAL Endothelial Function
•Vasorelaxation
• Blood pressure
•Permeability
• Filtering
•Coagulation
• Thrombosis
•Adhesive...
Soluble Flt-1 (sFlt-1) causes endothelial
dysfunction by antagonizing vascular
endothelial growth factor (VEGF) and
placen...
Faulty placentation
Excessive trophoblastsMaternal vascular disease
Reduced Uteroplacental Perfusion
Genetic/Immunologic/I...
Activation of CoagulationCapillary LeakVasospasm
Abruption
Seizures
Hypertension
Liver Ischemia
Oliguria
Proteinuria
Edema...
Maternal Decidual Natural killer cells (dNK) are key
mediators of implantation
 Predominant lymphocyte in decidua
 Highl...
PREDICTION
“Preeclampsia is a
common
and potentially serious
condition
that presents a
continuing
challenge to clinicians
due to the
...
• sFlt-1/PlGF ratio < 38: Rule-out preeclampsia for 1 week.
• sFlt-1/PlGF ratio ≥ 38: Rule-in preeclampsia within 4 weeks....
Novel innovative sFlt-1/PlGF ratio test
Precise, consistent, reliable (Elecsys)
Positive And Negative Predictive Values (P...
Endothelial Control Of Blood Pressure
ANGIOGENIC Blockade by sFlt-1 cause Hypertension
Recent Insights into the
Pathogenesis of Preeclampsia -
The Role of Nrf2 Activators and their Potential
Therapeutic Impact...
• "Activation of the PAR1
receptor by MMP-1
causes changes in the
endothelial cells of
blood vessels that we
speculated co...
Daily measurements
Mon Tue Wed Thu Fri Sat Sun
Blood pressure .
8am
4pm
12pm
Pulse
Weight
Urine protein
Fetal movements
Da...
Complaints
Mon Tue Wed Thu Fri Sat Sun
Swelling (face, feet, hands)
Nausea-vomiting
Headache
Agitation
Visual disturbances...
pathogenesis of Pre eclampsia
pathogenesis of Pre eclampsia
pathogenesis of Pre eclampsia
pathogenesis of Pre eclampsia
pathogenesis of Pre eclampsia
pathogenesis of Pre eclampsia
pathogenesis of Pre eclampsia
pathogenesis of Pre eclampsia
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pathogenesis of Pre eclampsia Slide 1 pathogenesis of Pre eclampsia Slide 2 pathogenesis of Pre eclampsia Slide 3 pathogenesis of Pre eclampsia Slide 4 pathogenesis of Pre eclampsia Slide 5 pathogenesis of Pre eclampsia Slide 6 pathogenesis of Pre eclampsia Slide 7 pathogenesis of Pre eclampsia Slide 8 pathogenesis of Pre eclampsia Slide 9 pathogenesis of Pre eclampsia Slide 10 pathogenesis of Pre eclampsia Slide 11 pathogenesis of Pre eclampsia Slide 12 pathogenesis of Pre eclampsia Slide 13 pathogenesis of Pre eclampsia Slide 14 pathogenesis of Pre eclampsia Slide 15 pathogenesis of Pre eclampsia Slide 16 pathogenesis of Pre eclampsia Slide 17 pathogenesis of Pre eclampsia Slide 18 pathogenesis of Pre eclampsia Slide 19 pathogenesis of Pre eclampsia Slide 20 pathogenesis of Pre eclampsia Slide 21 pathogenesis of Pre eclampsia Slide 22 pathogenesis of Pre eclampsia Slide 23 pathogenesis of Pre eclampsia Slide 24 pathogenesis of Pre eclampsia Slide 25 pathogenesis of Pre eclampsia Slide 26 pathogenesis of Pre eclampsia Slide 27 pathogenesis of Pre eclampsia Slide 28 pathogenesis of Pre eclampsia Slide 29 pathogenesis of Pre eclampsia Slide 30 pathogenesis of Pre eclampsia Slide 31 pathogenesis of Pre eclampsia Slide 32 pathogenesis of Pre eclampsia Slide 33 pathogenesis of Pre eclampsia Slide 34 pathogenesis of Pre eclampsia Slide 35 pathogenesis of Pre eclampsia Slide 36 pathogenesis of Pre eclampsia Slide 37 pathogenesis of Pre eclampsia Slide 38 pathogenesis of Pre eclampsia Slide 39 pathogenesis of Pre eclampsia Slide 40 pathogenesis of Pre eclampsia Slide 41 pathogenesis of Pre eclampsia Slide 42 pathogenesis of Pre eclampsia Slide 43 pathogenesis of Pre eclampsia Slide 44

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pathogenesis of Pre eclampsia

Preeclampsia is a disorder that is unique to human pregnancy, and the only known cure for this complication is delivery. Preeclampsia affects approximately 4% to 5% of pregnancies . The Preeclampsia Foundation states that: “Globally, preeclampsia and other hypertensive disorders of pregnancy are a leading cause of maternal and infant illness and death. By conservative estimates, these disorders are responsible for 76,000 maternal and 500,000 infant deaths each year.” As is evident from the statement that, preeclampsia is a major contributor to maternal and fetal morbidity and mortality worldwide. In India, the incidence of preeclampsia is reported to be 8-10% among the pregnant women. According to a study, the prevalence of hypertensive disorders of pregnancy was 7.8% with preeclampsia in 5.4% of the study population in India

pathogenesis of Pre eclampsia

  1. 1. “Preeclampsia” new concepts in an age-old disease Dr. Sujnanendra Mishra MD (ObGyn)
  2. 2. DIC CardioRenal Syndrome Elevated LFTs Hypertension Proteinuria HELLP Syndrome Abdominal pain Seizure Stroke HUS Headaches Thrombocytopenia OliguriaScotomataFatty LiverTTP PRES Hemoconcentration Hyperuricemia Edema Mirror Syndrome Pulmonary edema Hemolysis IUGR
  3. 3. History • 2200 BC Egypt: pregnant women with fists • 400 BC Hippocrates: pregnant women with convulsions • Eclampsia: Greek word: suddenly, flash • 1619: Varardus: first use of word eclampsia • 1843: Lever. Proteinuria. Swelling and convulsions: Nephritic toxemia • 1897: Vaquez. Hypertension • 1899: Strogonov: treatment, sedation • 1900s: prenatal care, preeclampsia • New concept in the 20th century • 1902: Ballantyne. Pro-maternity clinic. • 1910: USA. Nursing visits at home. • 1920: Prenatal visits: check for hypertension, swelling, proteinuria to detect : Preeclampsia • Maternal mortality reduced in UK from 319/100,000 in 1936 to 15/100,000 in 1985 Eclampsia - Preeclampsia Prenatal Care Lytic cocktail :- Artificial hibernation Magnesium Sulfate Treatment of eclampsia
  4. 4. 2200 BC – Egypt 400 BC -Greece MiddleAges Third Papyrus -Tongue biting at birth _Olive oil treatment Hippocrates _Seizure in labor are fatal _Eclampsia = brilliant light Midwifery care Fetus won’t survive fits Toxic humors => phlebotomy, blistering, starvation, purges •Key observations • 1797 – Edema (Demanet) • 1847 – Hypertension (Vaquez and Nobelcourt) • 1842 – Proteinuria (Lever)
  5. 5. ICD 10 ( WHO )
  6. 6. Timely And Correctly Diagnosed Preeclampsia brings Peace of mind for physicians • A disease where the clinical picture is not always clear. • A disease where the onset is unpredictable. • A disease where the assessment of the severity/ prognosis is difficult. • A disease where timely decision can be critical both for mother and fetus. Preeclampsia is a disease………………
  7. 7. Hypertensive Disorder in Pregnancy Pregnancy induced hypertension Gestational hypertension w/o proteinuria Preeclampsia (PIH + proteinuria) Eclampsia (PIH + convulsions) HELLP syndrome Pre-existing hypertension (chronic hypertension) Preeclampsia syndrome superimposed on chronic hypertension Unclassified hypertension
  8. 8. RISK FACTORS with Odd Ratio. Nulliparity (3:1) Immunologic factors : Antiphospholipid syndrome (10:1) Previous pregnancy complicated by Preeclampsia/Eclampsia/HELLP(2:1) Family history of Preeclampsia(5:1) Obesity (3:1) Multifetal gestation (unaffected by zygosity) (4:1)
  9. 9. Primipaternity 4: 1 Black Race (2:1) Maternal infection12:1 Duration of relationship prior to pregnancy & age at delivery of 1st Pregnancy High body mass index (3:1) Smoking Reduces !! (1:3.5) RISK FACTORS
  10. 10. Age >40 years (3:1) Chronic renal disease (20:1) Chronic hypertension (10:1) Diabetes mellitus (2:1) In vitro fertilization (2.5: 1) UA S/D ratio >2.6 (4:1) RISK FACTORS  Homozygosity for angiotensinogen gene T235 (20:1)  Heterozygosity for angiotensinogen gene T235 (4:1)
  11. 11. PLACENTA, Origin Of Life and the Disease Too ????
  12. 12. • POOR IMMUNOREGULATIONStage 0 3-8 weeks • POOR PLACENTATION Stage 1 8-18 weeks • CLINICAL MANIFESTATION Stage 2 20 weeks to birth Deficient trophoblast invasion and spiral artery remodelling Over activation of maternal endothelium and systemic inflammatory network Oxidative Stress Endoplasmic reticulum Stress Inflammatory Stress Inadequate tolerance to feto-paternal antigens during conception and implantation0- LAUNCHING PAD 1- IGNATION 2- TAKEUP COURSE
  13. 13. Proposed Pathogenic Factors of the Maternal Syndrome of Preeclampsia Oxidative Stress Lipid Hydroperoxides Placental trophoblast debris Inflammatory cytokines (TNF-a, IL-6) Activated neutrophils monocytes and platelets Inflammatory prostaglandins (thromboxane) Inhibitors of nitric oxide synthase (ADMA) Agonistic anti-angiotensin receptor autoantibodies Endothelin-1 Anti-angiogenic growth factors (sFlt-1, sEnd)
  14. 14. Pathophysiology of the Clinical Manifestations of Preeclampsia Pathogenesis of Preeclampsia Genetic factors Abnormal trophoblastic invasion Vasospasm Endothelial cell injury
  15. 15. PLACENTATION Invasive cytotrophoblasts of fetal origin invade the maternal spiral arteries Transforms them from small-caliber resistance vessels to high-caliber capacitance vessels Capable of providing placental perfusion adequate to sustain the growing fetus Normal Pregnancy
  16. 16. Normal placentation  Deep trophoblast invasion  Remodeling of spiral artery  Endovascular replacement  Controlled, sequential perfusion Pathological placentation  Shallow trophoblast invasion  Limited arterial remodeling  Failed endovascular invasion  Over, or under-perfusion of placenta PLACENTATION
  17. 17. cytotrophoblasts fail to adopt an invasive endothelial phenotype invasion of the spiral arteries is shallow and they remain small caliber, resistance vessels placental ischemia Preeclampsia PLACENTATION
  18. 18. ANGIOGENESIS, Key to Placental Development
  19. 19. SPIRAL ARTERY REMODELING
  20. 20. Unmodeled decidual spiral artery VSMC:- vascular smooth muscle cells EC:- Endothelial cells EVT:- Extra-villous trophoblast SPIRAL ARTERY REMODELING (CELLULAR)
  21. 21. END RESULT SPIRAL ARTERY REMODELING DEFECT
  22. 22. NORMAL Endothelial Function •Vasorelaxation • Blood pressure •Permeability • Filtering •Coagulation • Thrombosis •Adhesiveness •Platelet and •monocyte •Proliferation • Smooth muscle
  23. 23. Soluble Flt-1 (sFlt-1) causes endothelial dysfunction by antagonizing vascular endothelial growth factor (VEGF) and placental growth factor (PlGF) In normal pregnancy, the placenta produces modest concentrations of VEGF, PlGF, and soluble Flt-1 In preeclampsia, excess placental soluble Flt-1 binds circulating VEGF and PlGF and prevents their interaction with endothelial cell-surface receptors decreased prostacyclin nitric oxide production release of pro-coagulant proteins ENDOTHELIAL DYSFUNCTION ENDOTHELIAL DYSFUNCTION
  24. 24. Faulty placentation Excessive trophoblastsMaternal vascular disease Reduced Uteroplacental Perfusion Genetic/Immunologic/Inflammatory factors Activation of CoagulationCapillary Leak Endothelial Activation Vasospasm Vasoactive Agents:  Prostaglandin  Nitric oxide  Endothelins Noxious Agents:  Cytokines  Lipid Peroxidases  Multiple gestation  Hydrops fetalis SUMMARY
  25. 25. Activation of CoagulationCapillary LeakVasospasm Abruption Seizures Hypertension Liver Ischemia Oliguria Proteinuria Edema Hemoconcentration Endothelial Activation Thrombocytopenia SUMMARY
  26. 26. Maternal Decidual Natural killer cells (dNK) are key mediators of implantation  Predominant lymphocyte in decidua  Highly active ▪ Chemokines, angiogenic growth factors, proteinases  Induce spiral arteriole remodeling  Enhance trophoblast invasion and differentiation  Suppress immune rejection  dNK cells reduced (8-fold) in preeclampsia* RobsonA, et al. FASEB J, 2012. *Lockwood C, et al. Am J Path, 2013
  27. 27. PREDICTION
  28. 28. “Preeclampsia is a common and potentially serious condition that presents a continuing challenge to clinicians due to the variable features and lack of diagnostic tests.” “Our understanding of the pathophysiology of preeclampsia, including the role of the placental factors sFlt-1 and PlGF, has improved. With this better understanding comes the opportunity to improve the way we diagnose this common and sometimes serious condition.”
  29. 29. • sFlt-1/PlGF ratio < 38: Rule-out preeclampsia for 1 week. • sFlt-1/PlGF ratio ≥ 38: Rule-in preeclampsia within 4 weeks. Elecsys
  30. 30. Novel innovative sFlt-1/PlGF ratio test Precise, consistent, reliable (Elecsys) Positive And Negative Predictive Values (PPV And NPV Respectively
  31. 31. Endothelial Control Of Blood Pressure
  32. 32. ANGIOGENIC Blockade by sFlt-1 cause Hypertension
  33. 33. Recent Insights into the Pathogenesis of Preeclampsia - The Role of Nrf2 Activators and their Potential Therapeutic Impact. • It provides an overview of the possible beneficial effects of Nrf2 inducers in PE. • Potent Nrf2 activator sulforaphane increase Nrf2 protein levels and led to the upregulation of phase II antioxidant enzymes.
  34. 34. • "Activation of the PAR1 receptor by MMP-1 causes changes in the endothelial cells of blood vessels that we speculated could result in contraction of blood vessels. This new information provides a rationale for the use of PAR1 inhibitors to treat preeclampsia,"
  35. 35. Daily measurements Mon Tue Wed Thu Fri Sat Sun Blood pressure . 8am 4pm 12pm Pulse Weight Urine protein Fetal movements Daily evaluation at home for non severe Preeclampsia cases
  36. 36. Complaints Mon Tue Wed Thu Fri Sat Sun Swelling (face, feet, hands) Nausea-vomiting Headache Agitation Visual disturbances (scotoma, blurred vision) Abdominal pain Reduced urine output
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Preeclampsia is a disorder that is unique to human pregnancy, and the only known cure for this complication is delivery. Preeclampsia affects approximately 4% to 5% of pregnancies . The Preeclampsia Foundation states that: “Globally, preeclampsia and other hypertensive disorders of pregnancy are a leading cause of maternal and infant illness and death. By conservative estimates, these disorders are responsible for 76,000 maternal and 500,000 infant deaths each year.” As is evident from the statement that, preeclampsia is a major contributor to maternal and fetal morbidity and mortality worldwide. In India, the incidence of preeclampsia is reported to be 8-10% among the pregnant women. According to a study, the prevalence of hypertensive disorders of pregnancy was 7.8% with preeclampsia in 5.4% of the study population in India

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