Safety of Silicone Breast Implants

Stuart Bondurant,
Virginia Ernster,
and Roger Herdman, Editors

Committee on the Safety of Silicone Breast Implants

Division of Health Promotion and Disease Prevention

INSTITUTE OF MEDICINE

NATIONAL ACADEMY PRESS
Washington, D.C.



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Safety of Silicone Breast Implants Stuart Bondurant, Virginia Ernster, and Roger Herdman, Editors Committee on the Safety of Silicone Breast Implants Division of Health Promotion and Disease Prevention INSTITUTE OF MEDICINE NATIONAL ACADEMY PRESS Washington, D.C.

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Page ii NATIONAL ACADEMY PRESS • 2101 Constitution Avenue, N.W. • Washington, D.C. 20418 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 study was provided by the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health under Task Order No. 36, Contract No. N01-OD-4-2139. Library of Congress Cataloging-in-Publication Data Safety of silicone breast implants / Stuart Bondurant, Virginia Ernster, and Roger Herdman, editors; Committee on the Safety of Silicone Breast Implants, Division of Health Promotion and Disease Prevention, Institute of Medicine. p. cm. Includes bibliographical references and index. ISBN 0-309-06532-1 (hardcover) 1. Breast implants—Complications. 2. Silicones—Toxicology. 3. Mammaplasty. I. Bondurant, Stuart. II. Ernster, Virginia L. III. Herdman, Roger. IV. Institute of Medicine (U.S.). Committee on the Safety of Silicone Breast Implants. [DNLM: 1. Breast Implants—adverse effects. 2. Safety. 3. Silicones—adverse effects. WP 910 S128 1999] RD539.8 .S24 1999 618.1'90592—dc21                                                                                           99-040812 Safety of Silicone Breast Implants is available for sale from the National Academy Press, 2101 Constitution Avenue, N.W., Box 285, Washington, DC 20055. Call 800-624-6242 or 202-334-3313 (in the Washington Metropolitan Area). The full text of this publication is available on-line at www.nap.edu. For more information about the Institute of Medicine, visit the IOM home page at www.nas.edu/iom. Copyright 2000 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 image adopted as a logotype by the Institute of Medicine is based on a relief carving from ancient Greece, now held by the Staatliche Museen in Berlin.

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Page iii THE NATIONAL ACADEMIES National Academy of Sciences National Academy of Engineering Institute of Medicine National Research Council 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. William 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. Kenneth I. Shine 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. William A. Wulf are chairman and vice chairman, respectively, of the National Research Council.

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Staff Consultants WESTLEY REEVES, Associate Professor, Department of Medicine, University of North Carolina at Chapel Hill HANSPETER WITSCHI, Professor of Toxicology, Department of Molecular Biosciences, School of Veterinary Medicine, University of California at Davis 1V

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Page v COMMITTEE ON THE SAFETY OF SILICONE BREAST IMPLANTS STUART BONDURANT, M.D. (Chair), Professor of Medicine, University of North Carolina at Chapel Hill VIRGINIA L. ERNSTER, Ph.D. (Vice Chair), Professor and Vice Chair, Department of Epidemiology and Biostatistics, School of Medicine, University of California at San Francisco MARGIT L. BLEECKER, M.D., Ph.D., Director, Center for Occupational and Environmental Neurology, Baltimore, Maryland DIANE V. DADO, M.D., Associate Professor of Surgery and Pediatrics, Loyola University Medical Center CARL J. D'ORSI, M.D., Professor and Vice Chairman, Department of Radiology, University of Massachusetts Medical Center, Worchester JOANN G. ELMORE, M.D., M.P.H., Associate Professor of Medicine and Adjunct Professor of Epidemiology, Division of General Internal Medicine, University of Washington THOMAS J. FAHEY, Jr., M.D., Senior Vice President for Clinical Program Development, Memorial Sloan-Kettering Cancer Center, New York City BRIAN E. HENDERSON, M.D., Professor of Medicine, Department of Preventive Medicine, Norris Comprehensive Cancer Center, University of Southern California ARTHUR C. MARTELLOCK, Ph.D., Consultant, Pittsford, New York CHRIS D. PLATSOUCAS, M.D., Chairman, Department of Microbiology and Immunology, and Laura H. Carnell Professor of Medicine, Temple University School of Medicine NAOMI F. ROTHFIELD, M.D., Professor of Medicine, Chief, Division of Rheumatic Diseases, University of Connecticut School of Medicine DIANA TAYLOR, R.N., N.P., Ph.D., FAAN, Associate Professor, Department of Family Health Care Nursing, CoDirector, University of California at San Francisco, and Center for Collaborative Innovation in Primary Care, San Francisco RALPH C. WILLIAMS, Jr., M.D., Professor Emeritus, Department of Medicine, University of Florida IOM Staff ROGER HERDMAN, Study Director ANNICE HIRT, Research Associate STACEY PATMORE, Research Associate PATRICIA J. SPAULDING, Project Assistant

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Page vi MICAH MILTON, Intern KATHLEEN R. STRATTON, Director, Division of Health Promotion and Disease Prevention DONNA D. THOMPSON, Division Assistant SHARON GALLOWAY, Financial Associate Staff Consultants WESTLEY REEVES, Associate Professor, Department of Medicine, University of North Carolina at Chapel Hill HANSPETER WITSCHI, Professor of Toxicology, Department of Molecular Biosciences, School of Veterinary Medicine, University of California at Davis

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Page vii 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 Institute of Medicine in making the 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. The committee wishes to thank the following individuals for their participation in the review of this report: GRACIELLA ALARCON, M.D., M.P.H., School of Medicine, University of Alabama, Birmingham; J. CLAUDE BENNETT, M.D., BioCryst Pharmaceuticals, Inc., Birmingham, Alabama; DONALD H. BERRY, Ph.D., Department of Chemistry, University of Pennsylvania; JOHN DOULL, M.D., Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas; HAROLD J. FALLON, M.D., School of Medicine, University of Alabama, Birmingham; SUZANNE W. FLETCHER, M.D., Department of Ambulatory Care and Prevention, Harvard Medical School;

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Page viii RUTH T. GROSS, M.D., Stanford Univerity; WALTER PETERS, M.D., Wellesley Central Hospital, Toronto, Ontario, Canada; EDWARD A. SICKLES, M.D., Department of Radiology, University of California at San Francisco; ROBERT WEST, Ph.D., University of Wisconsin; and NANCY FUGATE WOODS, Ph.D., R.N., School of Nursing, University of Washington. While the individuals listed above have provided constructive comments and suggestions, it must be emphasized that responsibility for the final content of this report rests entirely with the authoring committee and the Institute of Medicine.

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Page ix Preface To begin, we reflect that the need for this report and the oft-cited deficiencies of the research relevant to silicone breast implants both derive from the fact that silicone breast implants were widely used before there was any requirement for premarket assessment of toxicity and complications or any form of prior approval or licensing for all medical devices. For many years there were no requirements to document the composition of implants or the specific model that was implanted in a particular individual. Further, there was no systematic, comprehensive, postmarketing surveillance of the long-term positive and negative consequences of silicone breast implantation. In the absence of structured requirements for risk assessment before 1992, much of the literature on aspects of silicone breast implants is anecdotal, lacking in appropriate controls, or otherwise of little value in establishing risk. This report stands as strong evidence of the need for thorough and systematic assessment of medical devices prior to their utilization and for continuing assessment after widespread utilization to discover any rare complications that pre-marketing studies of feasible size might not demonstrate. In the judgment of the committee, however, there have now been sufficient studies of quality to reach a number of well-based conclusions. Several important events have occurred since this study was initiated. A major class action litigation, brought on behalf of women with silicone breast implants, was settled with a substantial award to the plaintiffs. Meanwhile, a court turned to a panel of experts for advice on specific issues before the court concerning health consequences of silicone breast

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Page x implants. The report of the National Science Panel, described in Appendix C, is a substantial work that sets forth clearly and definitively the strong scientific evidence not always available in the past to courts with jurisdiction over breast implant litigation. The report of the National Science Panel is a model of the provision to the courts of the best available scientific advice in a matter in which balanced and informed scientific information and judgment are essential. The committee considered whether various known disease-related conditions occur more frequently in women with silicone breast implants than in women in the general population and also whether there might be a novel disease syndrome or syndromes in women with silicone breast implants. To date, proposals for the latter possibility have been based on criteria that are inadequate for scientific evaluation or confirmation. The proposed syndromes often involve ill-defined subjective symptoms that occur with substantial frequency in the general population. Absent a marker or set of markers to confer specificity, the existence of such a syndrome cannot be proven or used to exclude or include any individual or group. The committee heard directly and indirectly from many women who suffer severe systemic illnesses that they firmly believe are due to their silicone breast implants. Many of these women are seriously ill, and the committee was moved by their suffering. However, the committee is convinced that in most instances the silicone breast implants are not causally related to these illnesses since such illnesses appear to occur at about the same frequency in women with silicone breast implants and in women without implants. On the other hand, the committee was impressed by what appear to be the relatively high frequencies of local complications (such as rupture and contracture) that are unique to women with silicone breast implants. Although they are not life-threatening, these local complications may re-suit in discomfort, inconvenience, disfigurement, pain, and other morbidity and when further corrective procedures are necessary, in additional expense. Many women with silicone breast implants feel strongly that they were not provided with adequate information as a basis for consenting to have these implants. The committee is aware that recall by patients of the specific conditions and terms of medical consent is imperfect, and it is aware that several medical organizations have worked diligently to improve the quality of informed consent of patients with silicone breast implants. The committee believes, however, that more consistent and higher quality informed consent is possible and, among its recommendations, urges the development and testing of model processes and systems for ensuring fully informed consent for future recipients of silicone breast

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Page xi implants. A successful system may be applicable to other implantable devices in the future. In addition to the acknowledgment in Chapter 1 that many individuals and groups helped in the committee's work, the committee wishes to express especially its respect and appreciation for the extraordinary work of Dr. Roger Herdman in serving as director of this study. Dr. Herdman oversaw the collection of the world's English language literature on silicone breast implants, and he personally mastered most of it. His database and the good and important help of his expert assistants, first Annice Hirt and subsequently Stacey Patmore, made this literature easily available to the committee. Dr. Herdman's reasoned, systematic, and fact-based approach earned him the respect and trust of the committee and of interested parties. Patricia Spaulding did an outstanding job of orchestrating the flow of information and arranging for meetings. The committee thanks Dr. Herdman and his staff for all they have contributed to this report. STUART BONDURANT, M.D. CHAIR VIRGINIA L. ERNSTER, PH.D. VICE CHAIR

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. . X11 8 9 10 11 CONTENTS Induction of Hypergammaglobulinemia by Silicone, ~ 52 Conclusions, 153 ANTINUCLEAR ANTIBODIES AND SILICONE BREAST IMPLANTS 154 Technical Considerations Necessary to Interpret Reported ANA Titers, ~ 54 Antinuclear Antibodies in Normal Individuals, ~ 55 Antinuclear Antibodies in Women with Silicone Breast Implants, 156 A Prospective Study, 161 ANA and Autoantibody Analysis in Epidemiological Cohort Studies, ~ 62 Specific Antinuclear Autoantibodies in Normals and the Predictive Value of a Positive Autoantibody Test, 163 Specific Antinuclear Antibodies and Rheumatoid Factor in Women with Implants, ~ 64 Conclusions, 166 EPIDEMIOLOGICAL STUDIES OF CONNECTIVE TISSUE OR RHEUMATIC DISEASES AND BREAST IMPLANTS........................................... Cross-Sectional Study, 168 Case Control Studies, 169 Cohort Studies, 170 Conclusions, 174 Other Atypical Signs and Symptoms, ~ 75 Conclusions, 179 SILICONE BREAST IMPLANTS AND CANCER...................................... Breast Sarcomas and Other Tumors, ~ 85 Conclusions, 187 .167 181 NEUROLOGICAL DISEASE AND ITS ASSOCIATION WITH SILICONE BREAST IMPLANTS 188 Epidemiological Studies, 188 Case Series and Reports, ~ 89 Conclusions, ~ 9 ~ EFFECTS ON PREGNANCY, LACTATION, AND CHILDREN 193 Effect of Silicone Breast Implants during Pregnancy, 193 Effects of Silicone Breast during Lactation: Effect on Breast Milk, ~ 94 Breast Implants and Problems with Breast Feeding, 196 Breast Feeding in the United States: Prevalence and Advantages, ~ 98 Effects on Children, 199 Connective Tissue or Autoimmune Disease and Esophageal Effects, ~ 99 Immunological Studies, 202 Epidemiological Studies, 203 Conclusions, 204

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Page xiii Contents Executive Summary 1 1 Introduction 13 Legislative and Executive Branch History of This Report, 13 Early History of the Institute of Medicine Study, 14 The IOM Committee on the Safety of Silicone Breast Implants, 15 Collection and Evaluation of Evidence, 16 Cosmetic Breast Surgery and the Historical Context of This Report, 19 Silicone Implants, 25 Summary, 37 2 Silicone Chemistry 39 Silica, Silicon, and Silicone, 39 Chemistry of Silicones, 41 Functionality and Nomenclature, 42 Uses of Silicones, 45 Silicone Breast Implants, 49 Barrier-Layer Implants, 51 3 Implant Catalogue 54 General Considerations, 54 Implant Types, 57 Implant Shell Characteristics, 60

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Page xiv Implants from Dow Corning, 69 Heyer-Schulte-Mentor Implants, 71 Polyurethane History and Medical Engineering Corporation (Surgitek) Implants, 72 Inamed-McGhan Medical and CUI Implants, 73 Bioplasty and Other Manufacturers, 76 Conclusion, 77 4 Silicone Toxicology 80 Scope and Criteria for the Toxicology Review, 80 Brief History of Silicone Toxicology, 82 The Current Database, 84 Results of Studies in Four Main Groups, 85 Toxicology of Subcutaneously Implanted or Injected Silicones, 89 General Toxicology of Silicone Compounds, Including Low Molecular Weight Cyclic and Linear Poly(Dimethylsiloxanes), 100 Platinum, 107 Tin, 110 Conclusions, 112 5 Reoperations and Specific Local and Perioperative Complications 114 Introduction, 114 Overall Frequency of Local Complications, 116 Specific Complications, 124 Conclusions, 178 6 Immunology of Silicone 179 Immune Response to Silicone in Experimental Animals, 179 Possible Relationship to Autoimmune Disorders, 181 Studies of the Immune Response, 182 Studies of the Adaptive Immune Response, 185 Effects of Silicone: Granulomatous Inflammatory Reactions, 190 Tissue Response to Silicone, 191 Specific Autoantibodies Involved in Symptomatic Responses to Silicone Breast Implants, 192 Induction of Hypergammaglobulinemia by Silicone, 195 Conclusions, 197

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Page xv 7 Antinuclear Antibodies and Silicone Breast Implants 198 Technical Considerations Necessary to Interpret Reported ANA Titers, 199 Antinuclear Antibodies in Normal Individuals, 199 Antinuclear Antibodies in Women with Silicone Breast Implants, 201 Specific Antinuclear Autoantibodies in Normals and the Predictive Value of a Positive Autoantibody Test, 211 Specific Antinuclear Antibodies and Rheumatoid Factor in Women with Implants, 212 Conclusions, 214 8 Epidemiological Studies of Connective Tissue or Rheumatic Diseases and Breast Implants 215 Cross-Sectional Study, 216 Case Control Studies, 217 Cohort Studies, 219 Other Atypical Signs and Symptoms, 226 Conclusions, 231 9 Silicone Breast Implants and Cancer 233 Breast Sarcomas and Other Tumors, 238 Conclusions, 241 10 Neurological Disease and Its Association with Silicone Breast Implants 242 Epidemiological Studies, 242 Case Series and Reports, 243 Conclusions, 247 11 Effects on Pregnancy, Lactation, and Children 248 Effect of Silicone Breast Implants During Pregnancy, 248 Effects During Lactation, 249 Effects on Children, 256 Conclusions, 263 12 Silicone Implants and Breast Imaging 264 Implant Integrity Assessment, 264 Mammography and Implants, 272 Cancer Detection in a Screening Situation, 278 Conclusions, 284

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Page xvi Reference Lists 285 List of Peer-Reviewed Scientific Reports, 286 Other References, 418 Appendixes   A Brief Description of the Scientific Workshop 483 B Description of the Public Meeting 488 C Review of the Reports of the Independent Review Group and the National Science Panel 505 D Glossary 515 Index 525

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SAFETY OF SILICONE BREAST IMPLANTS

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