The Etiology of The Etiology of PreeclampsiaPreeclampsia

9 June 20099 June 2009

Presented by Damon T. Cudihy, MDPresented by Damon T. Cudihy, MD

Mentor: Richard Lee, M.D.Mentor: Richard Lee, M.D.

Goals of ProjectGoals of Project

1.1. To survey and review recent literature To survey and review recent literature proposing evidence for theories of proposing evidence for theories of pathogenesis of preeclampsiapathogenesis of preeclampsia

2.2. To distinguish true causes of To distinguish true causes of preeclampsia as opposed to mere bio-preeclampsia as opposed to mere bio-indices and epiphenomenaindices and epiphenomena

3.3. Regarding the etiology of preeclampsia, Regarding the etiology of preeclampsia, to provide a biologically plausible to provide a biologically plausible theory that unifies the essential and theory that unifies the essential and validated findings of past and validated findings of past and current scientific investigation.current scientific investigation.

Questions to answerQuestions to answer

1.1. What do we know about the burden What do we know about the burden of pre-eclampsia so far?of pre-eclampsia so far?

2.2. Do we know enough to understand Do we know enough to understand the cause of pre-eclampsia?the cause of pre-eclampsia?

3.3. With a better understanding of the With a better understanding of the cause of pre-eclampsia could we cause of pre-eclampsia could we begin to prevent the disease and begin to prevent the disease and develop better treatments that will develop better treatments that will minimize the associated morbidity minimize the associated morbidity and mortality ?and mortality ?

BackgroundBackground

DiagnosisDiagnosis– Hypertension: SBPHypertension: SBP≥140 or DBP≥90≥140 or DBP≥90– Proteinuria: Proteinuria: ≥≥0.1g/L (0.1g/L (2+)2+) in in ≥2 random urine ≥2 random urine

samples ≥4hrs apart; or ≥0.3g in 24hrssamples ≥4hrs apart; or ≥0.3g in 24hrs Disease burdenDisease burden

– Affects 3-14% of all pregnancies worldwide Affects 3-14% of all pregnancies worldwide

(5-8% of pregnancies in the U.S.)(5-8% of pregnancies in the U.S.) Effect on mother and childEffect on mother and child

– Leading cause of worldwide pregnancy-related Leading cause of worldwide pregnancy-related maternal and neonatal mortality and morbiditymaternal and neonatal mortality and morbidity

Spectrum of PreeclampsiaSpectrum of Preeclampsia

Conception

Failed implantationEarly Placental

Vascular dificiencyLate Placental

Dysfunction

Spontaneous abortionEarly onset

PreeclampsiaPreeclampsia

Risk Factors for Risk Factors for PreeclampsiaPreeclampsia

NulliparityNulliparity PrimipaternityPrimipaternity Personal or family Personal or family

history (37% in sisters)history (37% in sisters) Twin gestation (20, Twin gestation (20,

70%)70%) Molar pregnancy Molar pregnancy

(70%)(70%) Maternal infectionMaternal infection Chronic HypertensionChronic Hypertension Renal DiseaseRenal Disease Diabetes (50%)Diabetes (50%)

Androgen excessAndrogen excess Obesity/Insulin Obesity/Insulin

ResistanceResistance DyslipidemiaDyslipidemia Thrombophilias Thrombophilias

((Antiphospholipid, Protein Antiphospholipid, Protein C/S C/S deficiency,AntithromMbin deficiency,AntithromMbin deficiency, Factor V deficiency, Factor V Leiden, MTHFR)Leiden, MTHFR)

Condom useCondom use Donor sperm fertilizationDonor sperm fertilization Non-smokingNon-smoking

Pre-eclampsia as a risk Pre-eclampsia as a risk factor:factor:

Cardiovascular diseaseCardiovascular disease Renal diseaseRenal disease Insulin resistanceInsulin resistance

Current Theories Associated Current Theories Associated with Etiology of Preeclampsiawith Etiology of Preeclampsia

Immunologic phenomenaImmunologic phenomena Abnormal trophoblastic invasionAbnormal trophoblastic invasion Vascular endothelial damageVascular endothelial damage Cardiovascular maladaptationCardiovascular maladaptation Inflammation and oxidative stress Inflammation and oxidative stress Genetic predispositionGenetic predisposition Coagulation abnormalitiesCoagulation abnormalities Dietary deficiencies or excessesDietary deficiencies or excesses

Model of Contributing Model of Contributing FactorsFactors

Preeclampsia

Maternal factors Paternal factors Gestational factors

Genetic Acquired Genetic Acquired

Key PrinciplesKey Principles

““Disease of first pregnancy” Disease of first pregnancy” – 3-7% in nulliparas, 1-5% in multiparas3-7% in nulliparas, 1-5% in multiparas– Primipaternity modelPrimipaternity model

Placental load associationPlacental load association– Increased incidence and severity in Increased incidence and severity in

multiple gestations and molar gestationmultiple gestations and molar gestation Global Endothelial dysfunctionGlobal Endothelial dysfunction

Biomarkers for prediciton Biomarkers for prediciton and detection of and detection of

PreeclampsiaPreeclampsia

the focus of most U.S. studies in past the focus of most U.S. studies in past 2 years2 years

demonstrate preeclampsia as an demonstrate preeclampsia as an antiangiogenic state resulting from antiangiogenic state resulting from over-production of antiangiogenic over-production of antiangiogenic factorsfactors

Soluble fms-like tyrosine Soluble fms-like tyrosine kinase 1 (sFlt-1) and Soluble kinase 1 (sFlt-1) and Soluble

EndoglinEndoglin Circulating placental proteinsCirculating placental proteins

– Inhibit angiogenesis and arteriolar Inhibit angiogenesis and arteriolar vasodilationvasodilation

Excessive amounts may lead to Excessive amounts may lead to systemic endothelial dysfunction systemic endothelial dysfunction causing preeclampsiacausing preeclampsia

screening test for 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 Clinical manifestations of pre-eclampsiapre-eclampsia

All result from endothelial dysfunction All result from endothelial dysfunction at the various end organs in the body:at the various end organs in the body:– Systemic Arterial vasculatureSystemic Arterial vasculature HTN, HTN,

edemaedema– Central Nervous SystemCentral Nervous System headache, visual headache, visual

changes, seizurechanges, seizure– Hepatic systemHepatic system RUQ pain, HELLP RUQ pain, HELLP– Renal systemRenal system proteinuria, renal failure proteinuria, renal failure– Placental systemPlacental system IUGR, oligohyrdramnios, IUGR, oligohyrdramnios,

abruptionabruption

Risk factors for pre-eclampsiaRisk factors for pre-eclampsiaA loosely defined groupingA loosely defined grouping

1.1. Genetically inherited susceptibilities Genetically inherited susceptibilities (maternal and paternal side)(maternal and paternal side)

2.2. Conditions with known associations Conditions with known associations with endothelial dysfunctionwith endothelial dysfunction

3.3. States affecting the immune-States affecting the immune-modulated placental modulated placental cytotrophoblastic cell invasion of cytotrophoblastic cell invasion of maternal spiral artery endotheliummaternal spiral artery endothelium

1. Genetically Inherited Factors1. Genetically Inherited Factors

Both men and women who themselves Both men and women who themselves were the born of a pregnancy complicated were the born of a pregnancy complicated by pre-eclampsia are significantly more by pre-eclampsia are significantly more likely to be parents of a child with pre-likely to be parents of a child with pre-eclampsiaeclampsia

Baseline “fitness” of maternal endothelial Baseline “fitness” of maternal endothelial functionfunction

Maternal immune system functionMaternal immune system function Particular genotype combinations between Particular genotype combinations between

mother and child (or mother and father) mother and child (or mother and father) associated with preeclampsiaassociated with preeclampsia

2. Endothelial Dysfunction2. Endothelial Dysfunction

All clinical manifestations can be explained All clinical manifestations can be explained by endothelial dysfunctionby endothelial dysfunction

Most risk factors associated with Most risk factors associated with endothelial dysfunctionendothelial dysfunction– all chronic disease risk before and after all chronic disease risk before and after

preeclampsiapreeclampsia– role of infection, diet, exercise, and oxidative role of infection, diet, exercise, and oxidative

stress stress Pregnancy and preeclampsia as a Pregnancy and preeclampsia as a

physiologic endothelial stress testphysiologic endothelial stress test

3. Immune-mediated invasion 3. Immune-mediated invasion and angiogenesisand angiogenesis

Accounts for remaining risk factors: Accounts for remaining risk factors: nulliparity, primipaternity, condom use, nulliparity, primipaternity, condom use, IVF, twins, moles, and non-smokingIVF, twins, moles, and non-smoking

Maternal immune system facilitates Maternal immune system facilitates invasion of fetal extravillous invasion of fetal extravillous cytophoblastic cells into the cytophoblastic cells into the myometrium and arteriolar endotheliummyometrium and arteriolar endothelium

Accounts latest findings of anti-Accounts latest findings of anti-angiogenic factors associated with angiogenic factors associated with preeclampsiapreeclampsia

Grouping of Risk Factors Grouping of Risk Factors for Preeclampsiafor Preeclampsia

1.1. Genetic Genetic – Personal or family Personal or family

history (37% in sisters)history (37% in sisters)

2.2. Endothelial Endothelial dysfunctiondysfunction

– Maternal infectionMaternal infection– Chronic HypertensionChronic Hypertension– Renal DiseaseRenal Disease– Diabetes (50%)Diabetes (50%)– Androgen excessAndrogen excess– Obesity/Insulin Obesity/Insulin

ResistanceResistance– DyslipidemiaDyslipidemia– ThrombophiliasThrombophilias

3.3. Immune-mediated Immune-mediated invasion invasion and angiogenesisand angiogenesis

– NulliparityNulliparity– PrimipaternityPrimipaternity– Twin gestation (20, Twin gestation (20,

70%)70%)– Molar pregnancy Molar pregnancy

(70%)(70%)– Condom useCondom use– Donor sperm Donor sperm

fertilizationfertilization– Non-smokingNon-smoking

Pathophysiology of Pathophysiology of PreeclampsiaPreeclampsia

2 Stage process2 Stage process1.1. Preclinical (Preclinical (≤20 weeks): ≤20 weeks):

– inadequate invasion of maternal spiral inadequate invasion of maternal spiral arterioles by fetal cytotrophoblastsarterioles by fetal cytotrophoblasts insufficient maternal vascular remodeling and insufficient maternal vascular remodeling and angiogenesisangiogenesis

2.2. Clinical (normally >20 weeks): Clinical (normally >20 weeks): – Oxidatively stressed/hypoxic placentaOxidatively stressed/hypoxic placenta

generalized systemic inflammatory response generalized systemic inflammatory response with release of anti-angiogenic factors, with release of anti-angiogenic factors, inflammatory cytokines, and trophoblast debrisinflammatory cytokines, and trophoblast debris maternal syndromematernal syndrome

Natural Killer Cells:Natural Killer Cells:Friend or Foe?Friend or Foe?

Named for their cytotoxic action against Named for their cytotoxic action against virus-infected and tumor-transformed cellsvirus-infected and tumor-transformed cells

Paradoxically, NK cells play a key role in Paradoxically, NK cells play a key role in facilitating and stimulatingfacilitating and stimulating the invasion the invasion of of tumor-like fetal trophoblastictumor-like fetal trophoblastic cells cells into the maternal vasculature.into the maternal vasculature.

The dysfunction/dysregulation of decidual The dysfunction/dysregulation of decidual NK cells recocile the two leading theories:NK cells recocile the two leading theories:

1.1. Immune maladaptationImmune maladaptation2.2. Insufficient invasion of the maternal spiral Insufficient invasion of the maternal spiral

arteries by fetal trophoblastsarteries by fetal trophoblasts

Diagram of basic maternal and Diagram of basic maternal and placental vasculatureplacental vasculature

Normal vs Abnormal Vascular Normal vs Abnormal Vascular Remodeling of Spiral ArteriesRemodeling of Spiral Arteries

Future DirectionsFuture Directions Further clarification of the physiologic vs. Further clarification of the physiologic vs.

pathologic interactions between maternal pathologic interactions between maternal decidual NK cells and fetal extravillous decidual NK cells and fetal extravillous trophoblaststrophoblasts

Identification of genes involved with immune Identification of genes involved with immune maladaptationmaladaptation

Biomarkers as screening tools to target Biomarkers as screening tools to target interventions to reduce riskinterventions to reduce risk

Tx’s designed to boost extravillous trophoblastic Tx’s designed to boost extravillous trophoblastic invasion targeted to high risk women?invasion targeted to high risk women?

Pharmacologic manipulation of NK cells to direct Pharmacologic manipulation of NK cells to direct them in the pro-angiogenic pathway? them in the pro-angiogenic pathway?

ConclusionConclusion

1.1. Early maternal-fetal interface involving Early maternal-fetal interface involving decidual/uterine NK cells and extravillous decidual/uterine NK cells and extravillous trophoblaststrophoblasts

2.2. Healthy pregnancy requires NK cell stimulation Healthy pregnancy requires NK cell stimulation of vascular invasion by fetal trophoblasts of vascular invasion by fetal trophoblasts

(an immune-mediated process)(an immune-mediated process)

3.3. Inadequate vascular invasion by fetal cells Inadequate vascular invasion by fetal cells leads to placental hypoxialeads to placental hypoxiaoxidative oxidative stressstressmaternal endothelial maternal endothelial dysfunctiondysfunctionclinical signs and symptoms of clinical signs and symptoms of pre-eclampsiapre-eclampsia

““Therefore, one may state at least Therefore, one may state at least tentatively, that future collaboration tentatively, that future collaboration between the obstetrician and between the obstetrician and immunologist should produce the immunologist should produce the needed diagnostic and therapeutic needed diagnostic and therapeutic tools to place preeclampsia together tools to place preeclampsia together with Rh isoimmunization as an with Rh isoimmunization as an interesting, but eminently treatable interesting, but eminently treatable immunologic dysfunction.”immunologic dysfunction.”

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

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