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A Personal View of the Etiology of Preeclampsia

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					   The Etiology of
    Preeclampsia
           9 June 2009
Presented by Damon T. Cudihy, MD
    Mentor: Richard Lee, M.D.
             Goals of Project
1. To survey and review recent literature
   proposing evidence for theories of
   pathogenesis of preeclampsia
2. To distinguish true causes of preeclampsia as
   opposed to mere bio-indices and
   epiphenomena
3. Regarding the etiology of preeclampsia, to
     provide a biologically plausible theory
     that unifies the essential and validated
     findings of past and current scientific
     investigation.
         Questions to answer
1.   What do we know about the burden of
     pre-eclampsia so far?
2.   Do we know enough to understand the
     cause of pre-eclampsia?
3.   With a better understanding of the cause
     of pre-eclampsia could we begin to
     prevent the disease and develop better
     treatments that will minimize the
     associated morbidity and mortality ?
                   Background
   Diagnosis
    – Hypertension: SBP≥140 or DBP≥90
    – Proteinuria: ≥0.1g/L (2+) in ≥2 random urine
      samples ≥4hrs apart; or ≥0.3g in 24hrs
   Disease burden
    – Affects 3-14% of all pregnancies worldwide
    (5-8% of pregnancies in the U.S.)
   Effect on mother and child
    – Leading cause of worldwide pregnancy-related
      maternal and neonatal mortality and morbidity
       Spectrum of Preeclampsia

                          Conception




                        Early Placental      Late Placental
 Failed implantation
                       Vascular dificiency    Dysfunction




                         Early onset
Spontaneous abortion                         Preeclampsia
                         Preeclampsia
    Risk Factors for Preeclampsia
   Nulliparity                     Androgen excess
   Primipaternity                  Obesity/Insulin
   Personal or family history       Resistance
    (37% in sisters)                Dyslipidemia
   Twin gestation (20, 70%)        Thrombophilias
   Molar pregnancy (70%)            (Antiphospholipid, Protein C/S
                                     deficiency,AntithromMbin
   Maternal infection               deficiency, Factor V Leiden,
   Chronic Hypertension             MTHFR)
   Renal Disease                   Condom use
                                    Donor sperm fertilization
   Diabetes (50%)
                                    Non-smoking
    Pre-eclampsia as a risk factor:
 Cardiovascular disease
 Renal disease
 Insulin resistance
    Current Theories Associated with
        Etiology of Preeclampsia
 Immunologic phenomena
 Abnormal trophoblastic invasion
 Vascular endothelial damage
 Cardiovascular maladaptation
 Inflammation and oxidative stress
 Genetic predisposition
 Coagulation abnormalities
 Dietary deficiencies or excesses
Model of Contributing Factors

                               Preeclampsia




      Maternal factors            Paternal factors   Gestational factors




Genetic             Acquired          Genetic             Acquired
                Key Principles
   ―Disease of first pregnancy‖
    – 3-7% in nulliparas, 1-5% in multiparas
    – Primipaternity model
   Placental load association
    – Increased incidence and severity in multiple
      gestations and molar gestation
   Global Endothelial dysfunction
    Biomarkers for prediciton and
      detection of Preeclampsia

 the focus of most U.S. studies in past 2
  years
 demonstrate preeclampsia as an
  antiangiogenic state resulting from over-
  production of antiangiogenic factors
       Soluble fms-like tyrosine kinase 1
         (sFlt-1) and Soluble Endoglin
       Circulating placental proteins
         – Inhibit angiogenesis and arteriolar
           vasodilation
    Excessive amounts may lead to systemic
     endothelial dysfunction causing
     preeclampsia
    screening test for preeclampsia?

--MAYNARD, SHARON E.; et al. Soluble Fms-like Tyrosine Kinase 1 and Endothelial Dysfunction in the
Pathogenesis of Preeclampsia. Pediatric Research. Review Issue. 57(5 Part 2):1R-7R, May 2005.
--Levine, Richard J.;et al. for the CPEP Study Group Soluble Endoglin and Other Circulating Antiangiogenic
Factors in Preeclampsia. Obstetrical & Gynecological Survey. 62(2):82-83, February 2007.
Pathophysiology of preeclampsia and resulting symptoms; EDFMD,
endothelium-dependent flow-mediated vasodilation.
From: WEISSGERBER: Med Sci Sports Exerc, Volume 36(12).December 2004.2024-2031
         Clinical manifestations of
               pre-eclampsia
   All result from endothelial dysfunction at
    the various end organs in the body:
    – Systemic Arterial vasculature HTN, edema
    – Central Nervous System headache, visual
      changes, seizure
    – Hepatic system RUQ pain, HELLP
    – Renal system proteinuria, renal failure
    – Placental system IUGR, oligohyrdramnios,
      abruption
     Risk factors for pre-eclampsia
          A loosely defined grouping
1.   Genetically inherited susceptibilities
     (maternal and paternal side)
2.   Conditions with known associations with
     endothelial dysfunction
3.   States affecting the immune-modulated
     placental cytotrophoblastic cell invasion
     of maternal spiral artery endothelium
    1. Genetically Inherited Factors
 Both men and women who themselves were the
  born of a pregnancy complicated by pre-
  eclampsia are significantly more likely to be
  parents of a child with pre-eclampsia
 Baseline ―fitness‖ of maternal endothelial
  function
 Maternal immune system function
 Particular genotype combinations between
  mother and child (or mother and father)
  associated with preeclampsia
        2. Endothelial Dysfunction
 All clinical manifestations can be explained by
  endothelial dysfunction
 Most risk factors associated with endothelial
  dysfunction
    – all chronic disease risk before and after preeclampsia
    – role of infection, diet, exercise, and oxidative stress
   Pregnancy and preeclampsia as a physiologic
    endothelial stress test
    3. Immune-mediated invasion
         and angiogenesis
 Accounts for remaining risk factors:
  nulliparity, primipaternity, condom use,
  IVF, twins, moles, and non-smoking
 Maternal immune system facilitates
  invasion of fetal extravillous cytophoblastic
  cells into the myometrium and arteriolar
  endothelium
 Accounts latest findings of anti-angiogenic
  factors associated with preeclampsia
            Grouping of Risk Factors
               for Preeclampsia
1.   Genetic                          3.   Immune-mediated
     –   Personal or family history        invasion
         (37% in sisters)                  and angiogenesis
2.   Endothelial dysfunction               –   Nulliparity
     –   Maternal infection                –   Primipaternity
     –   Chronic Hypertension              –   Twin gestation (20, 70%)
     –   Renal Disease                     –   Molar pregnancy (70%)
     –   Diabetes (50%)                    –   Condom use
     –   Androgen excess                   –   Donor sperm fertilization
     –   Obesity/Insulin                   –   Non-smoking
         Resistance
     –   Dyslipidemia
     –   Thrombophilias
    Pathophysiology of Preeclampsia
    2 Stage process
    1. Preclinical (≤20 weeks):
      – inadequate invasion of maternal spiral arterioles
        by fetal cytotrophoblasts insufficient maternal
        vascular remodeling and angiogenesis
    2. Clinical (normally >20 weeks):
      – Oxidatively stressed/hypoxic placenta
         generalized systemic inflammatory response
        with release of anti-angiogenic factors,
        inflammatory cytokines, and trophoblast debris
         maternal syndrome
               Natural Killer Cells:
                 Friend or Foe?
    Named for their cytotoxic action against virus-
     infected and tumor-transformed cells
    Paradoxically, NK cells play a key role in
     facilitating and stimulating the invasion of
     tumor-like fetal trophoblastic cells into the
     maternal vasculature.
    The dysfunction/dysregulation of decidual NK
     cells recocile the two leading theories:
    1. Immune maladaptation
    2. Insufficient invasion of the maternal spiral arteries
       by fetal trophoblasts
Diagram of basic maternal and
    placental vasculature
Normal vs Abnormal Vascular
Remodeling of Spiral Arteries
               Future Directions
   Further clarification of the physiologic vs. pathologic
    interactions between maternal decidual NK cells and
    fetal extravillous trophoblasts
   Identification of genes involved with immune
    maladaptation
   Biomarkers as screening tools to target interventions to
    reduce risk
   Tx‘s designed to boost extravillous trophoblastic invasion
    targeted to high risk women?
   Pharmacologic manipulation of NK cells to direct them in
    the pro-angiogenic pathway?
                   Conclusion
1.   Early maternal-fetal interface involving
     decidual/uterine NK cells and extravillous
     trophoblasts
2.   Healthy pregnancy requires NK cell stimulation of
     vascular invasion by fetal trophoblasts
     (an immune-mediated process)
3.   Inadequate vascular invasion by fetal cells leads to
     placental hypoxiaoxidative stressmaternal
     endothelial dysfunctionclinical signs and
     symptoms of pre-eclampsia
―Therefore, one may state at least
  tentatively, that future collaboration
  between the obstetrician and
  immunologist should produce the needed
  diagnostic and therapeutic tools to place
  preeclampsia together with Rh
  isoimmunization as an interesting, but
  eminently treatable immunologic
  dysfunction.‖

--John Willems. The Etiology of Preeclampsia: A Hypothesis. Obstetrics
   and Gynecology, 50 (4), Oct 1977.
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