THE ROLE OF Environmental Hazards in Premature Birth

Workshop Summary

Donald R. Mattison, Samuel Wilson, Christine Coussens, and Dalia Gilbert, Editors

Roundtable on Environmental Health Sciences, Research, and Medicine

Board on Health Sciences Policy

INSTITUTE OF MEDICINE OF THE NATIONAL ACADEMIES

THE NATIONAL ACADEMIES PRESS
Washington, D.C.
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The Role of Environmental Hazards in Premature Birth: Workshop Summary THE ROLE OF Environmental Hazards in Premature Birth Workshop Summary Donald R. Mattison, Samuel Wilson, Christine Coussens, and Dalia Gilbert, Editors Roundtable on Environmental Health Sciences, Research, and Medicine Board on Health Sciences Policy INSTITUTE OF MEDICINE OF THE NATIONAL ACADEMIES THE NATIONAL ACADEMIES PRESS Washington, D.C. www.nap.edu

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The Role of Environmental Hazards in Premature Birth: Workshop Summary THE NATIONAL ACADEMIES PRESS 500 Fifth Street, N.W. Washington, DC 20001 NOTICE: The project that is the subject of this report was approved by the Governing Board of the National Research Council, whose members are drawn from the councils of the National Academy of Sciences, the National Academy of Engineering, and the Institute of Medicine. The members of the committee responsible for the report were chosen for their special competences and with regard for appropriate balance. Support for this project was provided by the National Institute of Environmental Health Sciences, National Institute of Health (Contract No. 282-99-0045, TO#5); National Center for Environmental Health and Agency for Toxic Substances and Disease Registry, Centers for Disease Control and Prevention (Contract No. 200-2000-00629, TO#7); National Institute for Occupational Safety and Health, Centers for Disease Control and Prevention (Contract No. 0000166930); National Health and Environment Effects Research Laboratory and National Center for Environmental Research, Environmental Protection Agency (Contract No. 282-99-0045, TO#5); American Chemistry Council (unnumbered grant); and Exxon-Mobil Corporation (unnumbered grant). The views presented in this book are those of the individual presenters and are not necessarily those of the funding agencies or the Institute of Medicine. Library of Congress Cataloging-in-Publication Data The role of environmental hazards in premature birth / Donald R. Mattison … [et al.], editors. p. ; cm. “Proceedings of a workshop that was sponsored by the Roundtable on Environmental Health Sciences, Research, and Medicine”—T.p. verso. Includes bibliographical references. Support for this project was provided by the National Institute of Environmental Health Sciences, National Institute of Health (contract no. 282-99-0045, TO#5) … [et al.] ISBN 0-309-09065-2 (pbk.); ISBN 0-309-52726-0 (PDF) 1. Infants (Premature)—Congresses. 2. Infants (Premature)—Environmental aspects—Congresses. 3. Environmental health—Congresses. [DNLM: 1. Labor, Premature—etiology—Congresses. 2. Environmental Exposure—adverse effects—Congresses. 3. Hazardous Substances—adverse effects—Congresses. WQ 330 R745 2003] I. Mattison, Donald R. II. Institute of Medicine (U.S.). Roundtable on Environmental Health Sciences, Research, and Medicine. III. National Institute of Environmental Health Sciences. RJ250.R64 2003 618.92’011—dc22 2003018950 This summary is based on the proceedings of a workshop that was sponsored by the Roundtable on Environmental Health Sciences, Research, and Medicine. It is prepared in the form of a workshop summary by and in the names of the editors, with the assistance of staff and consultants, as an individually authored document. Additional copies of this report are available for sale from the National Academies Press, 500 Fifth Street, N.W., Box 285, Washington, DC 20055. Call (800) 624-6242 or (202) 334-3313 (in the Washington metropolitan area), Internet, http://www.nap.edu. For more information about the Institute of Medicine, visit the IOM home page at: www.iom.edu. Copyright 2003 by the National Academy of Sciences. All rights reserved. Printed in the United States of America. The serpent has been a symbol of long life, healing, and knowledge among almost all cultures and religions since the beginning of recorded history. The serpent adopted as a logotype by the Institute of Medicine is a relief carving from ancient Greece, now held by the Staatliche Museen in Berlin.

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The Role of Environmental Hazards in Premature Birth: Workshop Summary “Knowing is not enough; we must apply. Willing is not enough; we must do.” —Goethe INSTITUTE OF MEDICINE OF THE NATIONAL ACADEMIES Shaping the Future for Health

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The Role of Environmental Hazards in Premature Birth: Workshop Summary THE NATIONAL ACADEMIES Advisers to the Nation on Science, Engineering, and Medicine The National Academy of Sciences is a private, nonprofit, self-perpetuating society of distinguished scholars engaged in scientific and engineering research, dedicated to the furtherance of science and technology and to their use for the general welfare. Upon the authority of the charter granted to it by the Congress in 1863, the Academy has a mandate that requires it to advise the federal government on scientific and technical matters. Dr. Bruce M. Alberts is president of the National Academy of Sciences. The National Academy of Engineering was established in 1964, under the charter of the National Academy of Sciences, as a parallel organization of outstanding engineers. It is autonomous in its administration and in the selection of its members, sharing with the National Academy of Sciences the responsibility for advising the federal government. The National Academy of Engineering also sponsors engineering programs aimed at meeting national needs, encourages education and research, and recognizes the superior achievements of engineers. Dr. Wm. A. Wulf is president of the National Academy of Engineering. The Institute of Medicine was established in 1970 by the National Academy of Sciences to secure the services of eminent members of appropriate professions in the examination of policy matters pertaining to the health of the public. The Institute acts under the responsibility given to the National Academy of Sciences by its congressional charter to be an adviser to the federal government and, upon its own initiative, to identify issues of medical care, research, and education. Dr. Harvey V. Fineberg is president of the Institute of Medicine. The National Research Council was organized by the National Academy of Sciences in 1916 to associate the broad community of science and technology with the Academy’s purposes of furthering knowledge and advising the federal government. Functioning in accordance with general policies determined by the Academy, the Council has become the principal operating agency of both the National Academy of Sciences and the National Academy of Engineering in providing services to the government, the public, and the scientific and engineering communities. The Council is administered jointly by both Academies and the Institute of Medicine. Dr. Bruce M. Alberts and Dr. Wm. A. Wulf are chair and vice chair, respectively, of the National Research Council. www.national-academies.org

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The Role of Environmental Hazards in Premature Birth: Workshop Summary ROUNDTABLE ON ENVIRONMENTAL HEALTH SCIENCES, RESEARCH, AND MEDICINE (until March 31, 2002) Paul Grant Rogers (Chair), Partner, Hogan & Hartson, Washington, DC Lynn Goldman (Vice-Chair), Professor, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD Pauline Abernathy, Program Officer, The Pew Charitable Trusts, Philadelphia, PA M. Brownell Anderson, Associate Vice President for Medical Education, Association of American Medical Colleges, Washington, DC Roger Bulger, President and Chief Executive Officer, Association of Academic Health Centers, Washington, DC Mark Cullen, Professor of Medicine and Public Health, Yale Occupational and Environmental Medicine Program, Yale University School of Medicine, New Haven, CT Ruth Etzel, Editor of the American Academy of Pediatrics Handbook of Pediatric Environmental Health, Adjunct Professor in the Department of Environmental and Occupational Health at the George Washington University School of Public Health and Health Services, Washington, DC Henry Falk, Assistant Administrator, Agency for Toxic Substance and Disease Registry, Centers for Disease Control and Prevention, Atlanta, GA Baruch Fischhoff, Professor of Social and Decision Sciences, Professor of Engineering & Public Policy, Department of Social and Decision Sciences, Carnegie Mellon University, Pittsburgh, PA Howard Frumkin, Professor and Chair of the Department of Environmental and Occupational Health at Emory University’s Rollins School of Public Health, Director of the Southeast Pediatric Environmental Health Specialty Unit, Atlanta, GA Bernard D. Goldstein, Dean, University of Pittsburgh Graduate School of Public Health, Pittsburgh, PA Robert Graham, Director, Center for Practice and Technology Assessment, Agency for Healthcare Research and Quality, Bethesda, MD John T. Grupenhoff, President, Science and Health Communications Group, Inc., Bethesda, MD Carol Henry, Vice President for Science and Research, American Chemistry Council, Arlington, VA Richard J. Jackson, Director, National Center for Environmental Health, Centers for Disease Control and Prevention, Atlanta, GA Lovell Jones, Professor, Gynecologic Oncology, University of Texas, Houston, TX Patricia G. Kenworthy, Vice-President for Policy and Research and Senior Staff Attorney, National Environmental Trust, Washington, DC

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The Role of Environmental Hazards in Premature Birth: Workshop Summary Donald R. Mattison, Professor, Mailman School of Public Health, Columbia University, New York, NY Roger McClellan, President Emeritus, Chemical Industry Institute of Toxicology, Albuquerque, NM Sanford Miller, Senior Fellow and Adjunct Professor, Georgetown University, Washington, DC Frank Mirer, Director, Health and Safety, International Union, United Auto Workers, Detroit, MI Alan R. Nelson, Special Advisor to the CEO, American College of Physicians–American Society of Internal Medicine, Fairfax, VA Kenneth Olden, Director, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC Peter Preuss, Director, National Center for Environmental Research, U.S. Environmental Protection Agency, Washington, DC Lawrence Reiter, Director, National Health and Environmental Effects Research Laboratory, U.S. Environmental Protection Agency, Research Triangle Park, NC Kathleen Rest, Acting Director, National Institute of Occupational Safety and Health, Washington, DC Samuel H. Wilson, Deputy Director, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC ROUNDTABLE ON ENVIRONMENTAL HEALTH SCIENCES, RESEARCH, AND MEDICINE (Membership April 1, 2002 to present) Paul Grant Rogers (Chair), Partner, Hogan & Hartson, Washington, DC Lynn Goldman (Vice-Chair), Professor, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD Jacquelyne Agnew, Professor, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD Jack Azar, Vice President, Environment, Health and Safety, Xerox Corporation, Webster, NY Sophie Balk, Chairperson, Committee on Environmental Health, American Academy of Pediatrics, Bronx, NY Roger Bulger, President and CEO, Association of Academic Health Centers, Washington, DC Henry Falk, Assistant Administrator, Agency for Toxic Substance and Disease Registry, Centers for Disease Control and Prevention, Atlanta, GA Baruch Fischhoff, Professor, Department of Engineering & Public Policy and Department of Social and Decision Sciences, Carnegie Mellon University, Pittsburgh, PA

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The Role of Environmental Hazards in Premature Birth: Workshop Summary John Froines, Professor and Director, Center for Occupational and Environmental Health, Southern California Particle Center and Supersite, University of California, Los Angeles, CA Howard Frumkin, Professor and Chair of the Department of Environmental and Occupational Health at Emory University’s Rollins School of Public Health, Atlanta, GA Michael Gallo, Professor of Environmental and Community Medicine, University of Medicine and Dentistry, New Jersey–Robert Wood Johnson Medical School, Piscataway, NJ Bernard Goldstein, Dean, University of Pittsburgh Graduate School of Public Health, Pittsburgh, PA Robert Graham, Director, Center for Practice and Technology Assessment, Agency for Healthcare Research and Quality, Rockville, MD Charles Groat, Director, U.S. Geological Survey, Reston, VA Myron Harrison, Senior Health Advisor, Exxon-Mobil, Inc., Irving, TX Carol Henry, Vice President for Science and Research, American Chemistry Council, Arlington, VA John Howard, Acting Director, National Institute of Occupational Safety and Health, Centers for Disease Control and Prevention, Washington, DC (from September 30, 2002) Richard Jackson, Director, National Center for Environmental Health, Centers for Disease Control and Prevention, Atlanta, GA Lovell Jones, Director, Center for Research on Minority Health; Professor, Gynecologic Oncology, University of Texas, M.D. Anderson Cancer Center, Houston, TX Alexis Karolides, Senior Research Associate, Rocky Mountain Institute, Snowmass, CO Donald R. Mattison, Professor, Mailman School of Public Health, Columbia University, New York, NY; National Institute of Child Health and Human Development, National Institutes of Health (from July 15, 2002) Michael McGinnis, Senior Vice President and Director of the Health Group, Robert Wood Johnson Foundation, Princeton, NJ James Melius, Director, Division of Occupational Health and Environmental Epidemiology, New York State Department of Health, New York, NY James Merchant, Professor and Dean, College of Public Health, Iowa University, Iowa City, IA Sanford Miller, Senior Fellow, Center for Food and Nutrition Policy, Virginia Polytechnic Institute and State University, Alexandria, VA Alan R. Nelson, Special Advisor to the CEO, American College of Physicians–American Society of Internal Medicine, Fairfax, VA Kenneth Olden, Director, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC

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The Role of Environmental Hazards in Premature Birth: Workshop Summary Peter Preuss, Director National Center for Environmental Research, U.S. Environmental Protection Agency, Washington, DC Lawrence Reiter, Director, National Health and Environmental Effects Research Laboratory, U.S. Environmental Protection Agency, Research Triangle Park, NC Kathleen Rest, Deputy Director, National Institute of Occupational Safety and Health, Centers for Disease Control and Prevention, Washington, DC (until September 30, 2002) Samuel Wilson, Deputy Director, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC IOM Health Sciences Policy Board Liaisons Mark Cullen, Professor of Medicine and Public Health, Yale Occupational and Environmental Medicine Program, Yale University, School of Medicine, New Haven, CT Bernard D. Goldstein, Dean of the University of Pittsburgh Graduate School of Public Health, Pittsburgh, PA Study Staff Christine Coussens, Study Director Dalia Gilbert, Research Assistant Bina Russell, Senior Project Assistant Division Staff Andrew Pope, Division Director Troy Prince, Administrative Assistant Carlos Gabriel, Financial Associate Kathi Hanna, Consultant

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The Role of Environmental Hazards in Premature Birth: Workshop Summary Reviewers This report has been reviewed in draft form by individuals chosen for their diverse perspectives and technical expertise, in accordance with procedures approved by the National Research Council’s Report Review Committee. The purpose of this independent review is to provide candid and critical comments that will assist the institution in making its published report as sound as possible and to ensure that the report meets institutional standards for objectivity, evidence, and responsiveness to the study charge. The review comments and draft manuscript remain confidential to protect the integrity of the deliberative process. We wish to thank the following individuals for their review of this report: Marilee Allen, Associate Professor of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, NJ Laura T. Goldsmith, Professor, Department of Obstetrics, Gynecology and Women’s Health, New Jersey Medical School, Newark, NJ Michael G. Narotsky, U.S. Environmental Protection Agency, Reproductive Toxicology Facility, Durham, NC Gloria Elizabeth Sarto, Professor, University of Wisconsin, Department of Obstetrics and Gynecology, Madison, WI Although the reviewers listed above have provided many constructive comments and suggestions, they were not asked to endorse the final draft of the

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The Role of Environmental Hazards in Premature Birth: Workshop Summary report before its release. The review of this report was overseen by Melvin Worth, Scholar-in-Residence, Institute of Medicine, who was responsible for making certain that an independent examination of this report was carried out in accordance with institutional procedures and that all review comments were carefully considered. Responsibility for the final content of this report rests entirely with the authoring committee and the institution.

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The Role of Environmental Hazards in Premature Birth: Workshop Summary Preface This workshop is the third of a series of workshops sponsored by the Roundtable on Environmental Health Sciences, Research, and Medicine since the Roundtable began meeting in 1998. When choosing workshops and activities, the Roundtable looks for areas of mutual concerns and also areas that need further research to develop a strong environmental science background. The Roundtable delegated the planning of this workshop to a planning group. The group was headed by Donald R. Mattison and Samuel Wilson, who were involved in the editing of this summary. Like many organizations and health agencies, the Roundtable is interested in children and other special populations that may be particularly vulnerable to environmental exposures. Through basic research, the members of the research community and policy makers have begun to address the needs of children and environmental exposures. There is a growing understanding, based on their physiology and metabolism, that the effects of food, drugs, and environmental exposures are vastly different between children and adults. For example, the rate at which a child absorbs lead, a known neurotoxicant, from the gastrointestinal tract is higher than that of adults. These differences in environmental exposure can have a dramatic impact on the child’s health and well-being throughout his/ or her life. In response to the need for healthy starts, the U.S. government has created several agencies that are charged with improving the health of mothers and children. In May 1997, the U.S. Environmental Protection Agency (EPA) established the Office of Children’s Health Protection (OCHP). Its mission is to make protection of children’s health a fundamental goal of public health and environ-

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The Role of Environmental Hazards in Premature Birth: Workshop Summary mental protection in the United States. The Maternal and Child Health Bureau (MCHB) of the Department of Health and Human Services (DHHS) provides leadership, partnership, and resources for advancing the health of all of our nation’s mothers, infants, children, and adolescents. The National Center on Birth Defects and Developmental Disabilities (NCBDDD) at the Centers for Disease Control and Prevention (CDC) seeks to promote fetal, infant, and child development and to prevent birth defects. The National Institute of Child Health and Human Development (NICHD) at the National Institutes of Health (NIH) seeks to ensure that every individual is born healthy and wanted, that women suffer no adverse consequences from the reproductive process, and that all children have the opportunity to fulfill their potential for a healthy and productive life unhampered by disease or disability. These agencies perform an excellent service in focusing on children’s and maternal health issues. As many of the speakers noted during the workshop, the first environment that people are exposed to is the uterus. It is there that the fetus undergoes a profound development from a single cell to an infant in nine months, and there are many opportunities for problems to occur because of gene–environment interactions. The health community is still at the point at which additional research is needed to understand these interactions and their effects on health. During this workshop, numerous individuals highlighted the growing problem of preterm birth and the idea that it has many potential causes. Although some preterm births are medically indicated,* the vast majority are spontaneous—occurring for unknown reasons. The current estimates suggest that preterm birth occurs in approximately one in eight births, accounting for about 75 percent of neonatal deaths and contributing to approximately 50 percent of the long-term neurological damage in children in this country. Babies who survive the odds of preterm birth often spend months, or even years, overcoming illnesses and fighting for survival. To protect children more effectively from the consequences of being born preterm, the health community must examine the role of social and behavioral factors—such as stress, anxiety, depression, drugs use, alcohol use, and tobacco smoking—in placing a woman at risk for delivering a premature baby. The health community also needs to know what types of environmental exposures adversely affect pregnant women and their unborn children and which women are at particular risk. The challenge is difficult, but it can be met. Our past successes can guide us. In the 1970s when lead exposure dominated the headlines, as a member of Congress I held hearings to address the problem. When presented with solid scientific evidence, Congress responded, and changes in the law resulted in decreased blood lead levels. *   Medically indicated refers to the intervention of a clinician because the fetus and/or mother are in danger of dying.

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The Role of Environmental Hazards in Premature Birth: Workshop Summary This workshop provided the Roundtable members, speakers, and participants the opportunity to take a critical look at the issue of preterm birth as an environmental health problem. There are still a number of gaps in the knowledge of basic mechanisms of labor and delivery, as well as the interactions that might contribute to preterm birth. During the formal and informal discussions, many individuals commented on the need to have places where researchers across the scientific disciplines can gather to find areas of commonality and opportunities for future collaborations. I was struck by the end of the workshop that the researchers had made significant progress in this area and there is solid science that is beginning to unravel the mysteries of preterm birth. It was clear that researchers and policy makers has to continue to support policy that is based on solid science grounding. Finally, the public need to remember that children do not have the capacity to make informed decisions on their own. They rely on us—researchers, scientists, policy makers, and community groups—to be their voice and to protect them. Paul G. Rogers, J.D. Chair

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The Role of Environmental Hazards in Premature Birth: Workshop Summary Contents     SUMMARY   1      Preterm Birth,   1     CHARGE TO PARTICIPANTS AND WORKSHOP SCOPE   6     PROBLEM STATEMENT   9 1   PRETERM BIRTH AND ITS CONSEQUENCES   13      Preterm Birth,   13      What Is Preterm Birth?,   14      Incidence,   15      Long-Term Outcomes of Premature Infants,   17      Measuring Predictors of Preterm Birth,   20      Interventions in Preterm Birth,   21      Purpose and Timing of this Workshop,   26 2   LABOR AND DELIVERY   27      Understanding the Switch from Pregnancy to Labor and Delivery,   28 3   PRETERM BIRTH—BRIEF SUMMARY OF BIOLOGICAL PATHWAYS   42      Biological Causes and Mechanisms of Preterm Labor,   42

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The Role of Environmental Hazards in Premature Birth: Workshop Summary 4   PRETERM BIRTH—GENE–ENVIRONMENT INTERACTIONS   46      Environmental Factors Associated with Preterm Birth,   47      Convergence of Cellular Pathways,   51      Gene–Environment Interactions and Preterm Birth,   52      Immune-Deficient Knockout Mice as a Model to Elucidate Environmental Toxicants,   54      Federal Government Toxicology Programs,   56 5   PRETERM BIRTH—SOCIAL IMPLICATIONS   62      Stress,   63      Social Support,   66      Social Position,   66      Coping Strategies,   67 6   FUTURE DIRECTIONS   68      Overview,   68      Research Opportunities,   69     ABSTRACTS   77      Evaluating Chemical Agents for Potential Hazards to Reproduction,   77      Models That Study the Actions of Uterine Lymphocytes During Pregnancy,   78      Regulation and Assessment of Uterine Contractility and Cervical Ripening During Pregnancy,   81      Function of Steroids in Parturition and Preterm Labor,   83      Clinical and Public Health Interventions—Why Nothing Has Worked,   84      Adverse Child Outcomes Associated with Preterm Birth,   86      A Framework for Social and Cultural Determinants of Prematurity,   87      Current Approaches to Reproductive and Developmental Toxicity Testing and Risk Assessment,   89      Assessment and Relevance of Environmental Chemical Effects on Uterine Muscle,   90      Exposures to Environmental Agents and Preterm Delivery,   92      Fetal Size and Preterm Birth,   93      Species Differentiation and Animal Models of Parturition,   95      Toxic Social Environment: A Factor in Preterm Birth?,   98      Causes and Mechanisms of Premature Labor,   99      Molecular Mechanisms and Cellular Signaling Pathways Associated with Parturition,   101

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The Role of Environmental Hazards in Premature Birth: Workshop Summary      Behavior, Nutrition, Infection, and Stress: Epidemiologic Clues to the Study of the Environment and Preterm Birth,   102      Gene–Environment Interactions and Preterm Delivery,   104      Role of Nitric Oxide in Uterine Activity and Premature Parturition,   105     REFERENCES   107     APPENDIXES     A   WORKSHOP AGENDA   113 B   SPEAKERS AND PANELISTS   120 C   WORKSHOP PARTICIPANTS   123

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