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
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)

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 (<17 and > 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. 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:

11. 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:

12. SPTB must involve precocious Δ in myo, cx, and/or membranes
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

13. 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.

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. PTB pPROM Cervical Change Uterine Contractions Chorion Decidua + +
Activation of Maternal/Fetal HPA Axis
Inflammation
Decidual
Hemorrhage
Abruption
Pathological
Uterine
Distention
• Infection:
- Chorion-Decidual
- Systemic
Maternal-Fetal Stress
Premature Onset of Physiologic Initiators
• Multifetal Preg
• Polyhydramnios
• Uterine abnormalities
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
CYP1A1
GSTT1 +
CRH
Susceptibility to Environmental toxins +
MMPs
proteases
uterotonins
pPROM
Cervical Change
Uterine Contractions
PTB
Adapted from: Lockwood CJ, Paediatr Perinat Epidemiol 2001;15:78 and Wang X, et al. Paediatr Perinat Epidemiol 2001; 15: 63

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. 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

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 www.prebic.org

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. 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

25. PREGENIA: Preterm Birth and Genetic International Alliance -- www
PREGENIA: Preterm Birth and Genetic International Alliance --

26. PREGENIA

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

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

29. 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

30. 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

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
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. 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
Systematic Reviews
Meta-analyses
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

37. Challenges in MCH
Thank you