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
Preterm Birth - Challenges • Preterm Birth rates are high and rising
Preterm BirthsUnited States, 1982, 1992, 2002, 2003 Percent Healthy People Objective 30 Percent Increase 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)
Preterm Birth - Challenges • Preterm Birth rates are high and rising • There is a persistent racial disparity in the occurrence of preterm birth
Preterm Birthsby 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
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” ...
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 (<17 and >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
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
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
The Preterm Labor Syndrome Source: Romero R, Mazor M, Munoz H, Gomez R, Galasso M, Sherer DM. The preterm labor syndrome. Ann N Y Acad Sci 1994;734:414-29.
Components of the common terminal pathway of human parturition (left) and the clinical manifestations of their premature activation (right) Source: Romero R, Mazor M, Munoz H, Gomez R, Galasso M, Sherer DM. The preterm labor syndrome. Ann N Y Acad Sci 1994;734:414-29.
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 Source: Simhan HN
Pathways of preterm delivery resulting from preterm premature rupture of the membranes and/or preterm labor Source: Lockwood CJ, Kuczynski E. Risk stratification and pathological mechanisms in preterm delivery. Paediatr Perinat Epidemiol 2001;15:78-89.
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):1512-1520.
Activation of Maternal/Fetal HPA Axis Inflammation Pathological Uterine Distention Decidual Hemorrhage Abruption • Infection: - Chorion-Decidual - Systemic • Multifetal Preg • Polyhydramnios • Uterine abnormalities • Maternal-Fetal Stress • Premature Onset of Physiologic Initiators Prothrombin G20210A Factor V Leiden Protein C, S, Z Type 1 Plasminogen MTHFR Interleukins IL-1, IL-5, IL-8 TNF-a Fas L Gap jct IL-8 PGE2 Oxytocin recep CRH E1-E3 Mechanical stretch Chorion Decidua + CRH CYP1A1 GSTT1 Susceptibility to Environmental toxins + MMPs proteases uterotonins pPROM Uterine Contractions Cervical Change PTB Adapted from: Lockwood CJ, Paediatr Perinat Epidemiol 2001;15:78 and Wang X, et al. Paediatr Perinat Epidemiol 2001; 15: 63
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
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
1998-2005 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
1998-2005 PERI Grantees • 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
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
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
PREBIC: Preterm Birth International Collaborativewww.prebic.org
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
PREBIC --> PREGENIA • 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
PREGENIA: Preterm Birth and Genetic International Alliance -- www.prebic.org/pregenia
PREGENIA • 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 • SMFM meeting, USA February 2005 0.5 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 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 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
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
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
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
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
Systematic Reviews Meta-analyses Perinatal Genomics: A Knowledge Base for Genetics and Prematurity Preterm Birth Network Implications Perinatal Genomics Knowledge Base Guide research agendas Evidence-Based Products Selected Networks Cardiovascular Disease 1. Registry of investigators 2. Registry of studies or data collection platforms Inform clinical trials BreastCancer 3. Compendium of publications (published & “grey” literature) International Network of Networks HuGENet Influence public policy Multidiscplinary Collaborative Research Parkinson’s Disease Other Diseases Educate consumers Osteoperosis HIV = this application for grant funding
Challenges in MCH Thank you