preterm birth network

Preterm Birth Network

Siobhan Dolan, MD, MPHMarch of Dimes Birth Defects Foundation

Albert Einstein College of Medicine, Bronx, NY

Network of Networks MeetingOctober 2005

Preterm Birth - Challenges

• Preterm Birth rates are high and rising

9.510.7

12.1 12.3

7.6

0

2

4

6

8

10

12

14

1982 1992 2002 2003 2010

Preterm BirthsPreterm BirthsUnited States, 1982, 1992, 2002, 2003United 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



• There is a persistent racial disparity in the occurrence of preterm birth

Preterm Birthsby Race/Ethnicity, US, 1990 and 2001

8.5

18.9

12

10.111 10.610.8

17.6

13.2

10.311.4 11.9

0

5

10

15

20

White Black NativeAmerican

Asian orPacific

Islander

Hispanic All Races/Ethnicities

1990 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




• 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




• 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

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.

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: 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

Source: Lockwood CJ, Kuczynski E. Risk stratification and pathological mechanisms in preterm delivery. Paediatr Perinat Epidemiol 2001;15:78-89.

Pathways of preterm delivery resulting from preterm premature rupture of the membranes and/or preterm labor

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.

proteases

Uterine Contractions

Cervical Change

• Infection: - Chorion-Decidual - Systemic

DecidualHemorrhageAbruption

CRHE1-E3

Prothrombin G20210AFactor V LeidenProtein C, S, ZType 1 PlasminogenMTHFR

PathologicalUterine

Distention

• Multifetal Preg• Polyhydramnios• Uterine

abnormalities

Inflammation

• Maternal-Fetal Stress

• Premature Onset of Physiologic Initiators

Activation of Maternal/Fetal

HPA Axis

CRH

+

+ChorionDeciduaChorionDecidua

uterotonins

Mechanical stretchGap jct

IL-8 PGE2

Oxytocin recep

pPROM

InterleukinsIL-1, IL-5, IL-8TNF- 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

CYP1A1GSTT1

MMPs

PTB


• 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

• 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

1998-2005 PERI Grantees

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


• 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

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

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

PREGENIA1. Candidate gene approach - review article

2. Pilot study for SNP prevalence has been designedA 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 collectionNeed substantial funding -- currently applying for grants

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WHO Centers

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 published2. Two manuscripts submitted:

Preterm Birth as a Common Complex DisorderGenetic 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 DimesCenters for Disease Control and Prevention/ Office of Genomics and Disease PreventionWorld Health OrganizationAmerican College of Obstetricians and GynecologistsSociety for Maternal-Fetal Medicine

5. Multiple grants submitted - to MOD, NIH, private foundations6. Participation in the Network of Networks7. PREBIC is solid -- next meeting in April 2006 in Geneva

PREGENIA - Challenges1. Sustainable research funding2. Sustainable research funding3. 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

International Network of Networks

HuGENet

Perinatal Genomics: A Knowledge Base for Genetics and Prematurity

BreastCancer

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

Informclinical 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

MultidiscplinaryCollaborativeResearch

Challenges in MCH

Thank you

preterm birth network

Documents

occurrence of preterm

pathways of preterm

preterm labor syndromesource

preterm premature rupture

risk factors

national center

risk stratification

gomez r