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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 hypoxiaoxidative stressmaternal endothelial dysfunctionclinical 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. References 1. Report of the National High Blood Pressure Education Program Working Group on High Blood Pressure in Pregnancy. American Journal of Obstetrics and Gynecology.2000;183:S1-S22 2. ACOG Committee on Practice Bulletins--Obstetrics. ACOG practice bulletin. Diagnosis and management of preeclampsia and eclampsia. Obstetrics and Gynecology 2002; 99:159. 3. 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