The Etiology of Preeclampsia 9 June 2009Presentation Transcript
The Etiology of Preeclampsia 9 June 2009 Presented by Damon T. Cudihy, MD Mentor: Richard Lee, M.D.
Goals of Project
To survey and review recent literature proposing evidence for theories of pathogenesis of preeclampsia
To distinguish true causes of preeclampsia as opposed to mere bio-indices and epiphenomena
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
What do we know about the burden of pre-eclampsia so far?
Do we know enough to understand the cause of pre-eclampsia?
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 ?
Hypertension: SBP ≥140 or DBP≥90
Proteinuria: ≥ 0.1g/L ( 2+) in ≥2 random urine samples ≥4hrs apart; or ≥0.3g in 24hrs
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 Failed implantation Early Placental Vascular dificiency Late Placental Dysfunction Spontaneous abortion Early onset Preeclampsia Preeclampsia
Risk Factors for Preeclampsia
Personal or family history (37% in sisters)
Twin gestation (20, 70%)
Molar pregnancy (70%)
Thrombophilias ( Antiphospholipid, Protein C/S deficiency,AntithromMbin deficiency, Factor V Leiden, MTHFR)
Donor sperm fertilization
Pre-eclampsia as a risk factor:
Current Theories Associated with Etiology of Preeclampsia
Abnormal trophoblastic invasion
Vascular endothelial damage
Inflammation and oxidative stress
Dietary deficiencies or excesses
Model of Contributing Factors Preeclampsia Maternal factors Paternal factors Gestational factors Genetic Acquired Genetic Acquired
“ Disease of first pregnancy”
3-7% in nulliparas, 1-5% in multiparas
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
Genetically inherited susceptibilities (maternal and paternal side)
Conditions with known associations with endothelial dysfunction
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
Personal or family history (37% in sisters)
Immune-mediated invasion and angiogenesis
Twin gestation (20, 70%)
Molar pregnancy (70%)
Donor sperm fertilization
Pathophysiology of Preeclampsia
2 Stage process
Preclinical ( ≤20 weeks):
inadequate invasion of maternal spiral arterioles by fetal cytotrophoblasts insufficient maternal vascular remodeling and angiogenesis
Clinical (normally >20 weeks):
Oxidatively stressed/hypoxic placenta
generalized systemic inflammatory response with release of anti-angiogenic factors, inflammatory cytokines, and trophoblast debris
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:
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
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?
Early maternal-fetal interface involving decidual/uterine NK cells and extravillous trophoblasts
Healthy pregnancy requires NK cell stimulation of vascular invasion by fetal trophoblasts
(an immune-mediated process)
Inadequate vascular invasion by fetal cells leads to placental hypoxia oxidative stress maternal endothelial dysfunction clinical signs and symptoms of pre-eclampsia
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