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Preterm Birth Network Siobhan Dolan, MD, MPH March of Dimes Birth Defects Foundation Albert Einstein College of Medicine, Bronx, NY Network of Networks.

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Presentation on theme: "Preterm Birth Network Siobhan Dolan, MD, MPH March of Dimes Birth Defects Foundation Albert Einstein College of Medicine, Bronx, NY Network of Networks."— Presentation transcript:

1 Preterm Birth Network Siobhan Dolan, MD, MPH March of Dimes Birth Defects Foundation Albert Einstein College of Medicine, Bronx, NY Network of Networks Meeting October 2005

2 Preterm Birth - Challenges Preterm Birth rates are high and rising

3 Preterm Births United States, 1982, 1992, 2002, 2003 Preterm is less than 37 completed weeks gestation. Source: National Center for Health Statistics, final natality data Prepared by March of Dimes Perinatal Data Center, 2004 (Final PTB rate for 2003 added 9/9/05) Percent Healthy People Objective 30 Percent Increase

4 Preterm Birth - Challenges Preterm Birth rates are high and rising There is a persistent racial disparity in the occurrence of preterm birth

5 Preterm Births by Race/Ethnicity, US, 1990 and 2001 Percent People of Hispanic ethnicity may be any race; all other categories are non-Hispanic Source: National Center for Health Statistics Prepared by March of Dimes Perinatal Data Center, 2004

6 Preterm Birth - Challenges Preterm Birth rates are high and rising There is a persistent racial disparity in the occurrence of preterm birth We know a lot about “risk factors”...

7 Risk Factors for Preterm Labor/Delivery The best predictor of having a preterm birth is multifetal gestation or history of preterm labor/delivery Other risk factors: –multifetal pregnancy –maternal age ( 35 years) –black race –low SES –unmarried –previous fetal or neonatal death –3+ spontaneous losses –uterine abnormalities –incompetent cervix –genetic predisposition –low pre-pregnant weight –obesity –infections –bleeding –anemia –major stress –lack of social supports –tobacco use –illicit drug use –alcohol abuse –folic acid deficiency

8 Preterm Birth - Challenges Preterm Birth rates are high and rising There is a persistent racial disparity in the occurrence of preterm birth We know a lot about “risk factors”... But …. There are few, if any, effective preventive strategies or treatment options

9 Preterm Birth - Challenges In summary, we have had to work hard to get preterm birth on the map of common complex disease and to promote the concept that genetic epidemiology/genomics is an appropriate approach We have done this through manuscript preparation/submission and presentations at national meetings

10 Source: Romero R, Mazor M, Munoz H, Gomez R, Galasso M, Sherer DM. The preterm labor syndrome. Ann N Y Acad Sci 1994;734: The Preterm Labor Syndrome

11 Source: Romero R, Mazor M, Munoz H, Gomez R, Galasso M, Sherer DM. The preterm labor syndrome. Ann N Y Acad Sci 1994;734: Components of the common terminal pathway of human parturition (left) and the clinical manifestations of their premature activation (right)

12 Source: Simhan HN ASSUME: SPTB must involve precocious Δ in myo, cx, and/or membranes Downstream events are redundant & highly conserved Core group of inflammatory initiator & regulator mole  “pathways” or “distinct” etiologies converge very early mechanistically

13 Source: Lockwood CJ, Kuczynski E. Risk stratification and pathological mechanisms in preterm delivery. Paediatr Perinat Epidemiol 2001;15: Pathways of preterm delivery resulting from preterm premature rupture of the membranes and/or preterm labor

14 Common Complex Disorders “The study of genomics will most likely make its greatest contribution to health by revealing mechanisms of common, complex diseases, such as hypertension, diabetes, and asthma.” … and preterm birth. Guttmacher AE, Collins FS. Genomic Medicine – A Primer. N Engl J Med 2002:347(19):

15 proteases Uterine Contractions Cervical Change Infection: - Chorion-Decidual - Systemic Decidual Hemorrhage Abruption CRH E1-E3 Prothrombin G20210A Factor V Leiden Protein C, S, Z Type 1 Plasminogen MTHFR Pathological Uterine Distention Multifetal Preg Polyhydramnios Uterine abnormalities Inflammation Maternal-Fetal Stress Premature Onset of Physiologic Initiators Activation of Maternal/Fetal HPA Axis CRH + + Chorion Decidua Chorion Decidua uterotonins Mechanical stretch Gap jct IL-8 PGE2 Oxytocin recep pPROM Interleukins IL-1, IL-5, IL-8 TNF-  Fas L Adapted from: Lockwood CJ, Paediatr Perinat Epidemiol 2001;15:78 and Wang X, et al. Paediatr Perinat Epidemiol 2001; 15: 63 Susceptibility to Environmental toxins CYP1A1 GSTT1 MMPs PTB

16 Preterm Birth - Challenges Multidisciplinary approaches and international collaboration are required to make progress in preterm birth research March of Dimes has played a leadership role in funding and convening

17 March of Dimes Prematurity Campaign Aims 1. Generate concern and action around the problem of prematurity 2. Educate women of reproductive age about risk reduction and warning signs 3. Provide affected families with information, emotional support, and opportunities to help other families 4. Assist health practitioners to improve prematurity risk detection and address risk-associated factors 5. Invest more public and private research dollars to identify causes of preterm labor and prematurity, and to identify and test promising interventions 6. Expand access to health coverage in order to improve maternity care and infant health outcomes

18 PERI Grantees Stress as factor in PTD physiologic responses and stress- related hormones -cortisol, catecholamines and CRH –Claudia Holzman, DVM, MPH, PhD –Michigan State U. Link of low socioeconomic status and PTD –Michael S. Kramer, MD –McGill University, Montreal Women’s Exposure to racism and violence --chronic strain of racism/violence linked to CRH levels –Janet Rich-Edwards, ScD –Harvard Medical School

19 Infections of the reproductive track -cytokine markers –Poul Thorsen, MD, PhD –Denmark and CDC, Atlanta Identifying genetic traits linked to PTD –Xiaobin Wang, MD, MPH, ScD –China and Boston Univ. Pathogenesis and Pathways of Preterm Labor –Charles J. Lockwood, MD –Yale University PERI Grantees

20 The 2005 PRI Grantees Genetic Analysis of Human Preterm Birth –Louis J. Muglia, MD, PhD, –Washington University, St. Louis, MO Identification of Loci Associated with Spontaneous Preterm Birth in Africian-Americans by Admixture Linkage Disequilibrium Mapping –Jerome F. Strauss, III, MD, PhD –University of Pennsylvania, Philadelphia, PA Molecular Mechanisms of Cervical Ripening –Mala Mahendroo, PhD –Univ. of Texas Southwestern Medical Center

21 The 2005 PRI Grantees Cellular Mechanisms in the Initiation of Labor –Carole R. Mendelson, PhD –Univ. of Texas Southwestern Medical Center, Dallas, TX Mechanisms Underlying Myometrial Smooth Muscle Relaxation During Pregnancy –Sarah K. England, PhD –University of Iowa, College of Medicine The Diagnosis of True Pre-Term Labor –Stephen J. Lye, PhD –Mount Sinai Hospital –University of Toronto, Canada

22 PREBIC: Preterm Birth International Collaborative

23 Preterm Birth - Challenges Multidisciplinary approaches and international collaboration are required to make progress in preterm birth research PREBIC has played a key leadership role in promoting international collaboration and convening

24 1.2nd PREBIC meeting, Denmark June 2004, 2 days Protocol development, funding Telephone conferences Organizational structure - steering committee, funding Geneva meeting, WHO September 2004, 2.5 days Extended the group with a geneticist Changed name from genetic group to PREGENIA Protocol development Grant writing & submission PREBIC --> PREGENIA

25 PREGENIA: Preterm Birth and Genetic International Alliance --

26 PREGENIA

27 Telephone conferences - Skype Organizational structure Grant writing & submission Review article Atlanta meeting CDC, December 2004, 2.5 days Review article Organizational structure Publication rules PREGENIA

28 SMFM meeting, USA February days Review article Telephone/Skype conferences Grant identification Review article 3rd PREBIC meeting Los Angeles, USA March 2005, 0.5 days Review articles Project modification for different grants Organizational structure PREGENIA

29 Study the association between spontaneous preterm birth and gene- gene, gene-environment interaction in populations in different parts of the world/different ethnic population World wide - not the same genetic markers Insights into mechanisms and interactions between pathways PREGENIA

30 1. Candidate gene approach - review article 2. Pilot study for SNP prevalence has been designed A large prospective international study collecting samples from: 3 developed countries (USA, Denmark and Sweden) 10 established WHO centers in the third world Standardized protocol for data collection Need substantial funding -- currently applying for grants

31 WHO Centers

32 Preterm Birth - Challenges Multidisciplinary approaches and international collaboration are required to make progress in preterm birth research CDC’s Office of Genomics and Disease Prevention has played a key leadership role in providing technical assistance, methodologic support, and perspective on how the preterm birth network fits into the network of networks

33 Preterm Birth Network - Successes 1. March of Dimes Research Agenda published 2. Two manuscripts submitted: Preterm Birth as a Common Complex Disorder Genetic Epidemiologic Standards in Preterm Birth Research 3. Systematic Review of the Literature on Genetics and Prematurity is in preparation

34 Preterm Birth Network - Successes 4. Strong international collaboration including multiple committed organizations: March of Dimes Centers for Disease Control and Prevention/ Office of Genomics and Disease Prevention World Health Organization American College of Obstetricians and Gynecologists Society for Maternal-Fetal Medicine 5. Multiple grants submitted - to MOD, NIH, private foundations 6. Participation in the Network of Networks 7. PREBIC is solid -- next meeting in April 2006 in Geneva

35 PREGENIA - Challenges 1. Sustainable research funding 2. Sustainable research funding 3. Sustainable research funding 4. Money for Infrastructure and Support -- many grants submitted 5. Most recent grant submitted to develop a perinatal genomics knowledge base with a focus on preterm birth

36 International Network of Networks HuGENet Perinatal Genomics: A Knowledge Base for Genetics and Prematurity BreastCa ncer Parkinson’s Disease Osteoperosis 1. Registry of investigators 3. Compendium of publications (published & “grey” literature) 2. Registry of studies or data collection platforms Systematic Reviews Meta-analyses Guide research agendas Inform clinical trials Influence public policy Educate consumers Evidence-Based Products Implications HIV Perinatal Genomics Knowledge Base Other Diseases Cardiovascular Disease Selected Networks = this application for grant funding Preterm Birth Network Multidiscplinary Collaborative Research

37 Challenges in MCH Thank you


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