ASSESSING THE MEDICAL RISKS OF HUMAN OOCYTE DONATION FOR STEM CELL RESEARCH

Workshop Report

Committee on Assessing the Medical Risks of Human Oocyte Donation for Stem Cell Research

Board on Health Sciences Policy

Institute of Medicine

Board on Life Sciences

Division on Earth and Life Studies

Linda Giudice, Eileen Santa, and Robert Pool, Editors

INSTITUTE OF MEDICINE AND NATIONAL RESEARCH COUNCIL OF THE NATIONAL ACADEMIES

THE NATIONAL ACADEMIES PRESS

Washington, D.C. www.nap.edu



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Assessing the Medical Risks of Human Oocyte Donation for Stem Cell Research: Workshop Report ASSESSING THE MEDICAL RISKS OF HUMAN OOCYTE DONATION FOR STEM CELL RESEARCH Workshop Report Committee on Assessing the Medical Risks of Human Oocyte Donation for Stem Cell Research Board on Health Sciences Policy Institute of Medicine Board on Life Sciences Division on Earth and Life Studies Linda Giudice, Eileen Santa, and Robert Pool, Editors INSTITUTE OF MEDICINE AND NATIONAL RESEARCH COUNCIL OF THE NATIONAL ACADEMIES THE NATIONAL ACADEMIES PRESS Washington, D.C. www.nap.edu

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Assessing the Medical Risks of Human Oocyte Donation for Stem Cell Research: Workshop Report 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. This study was supported by Award No. CIRM-2039 between the National Academy of Sciences and the California Institute for Regenerative Medicine. Any opinions, findings, or conclusions expressed in this publication are those of the author(s) and do not necessarily reflect the view of the organizations or agencies that provided support for this project. International Standard Book Number 10: 0-309-10355-X International Standard Book Number 13: 978-0-309-10355-8 Additional copies of this report are available from the National Academies Press, 500 Fifth Street, N.W., Lockbox 285, Washington, DC 20055; (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 2007 by the National Academy of Sciences. All rights reserved. Printed in the United States of America. Suggested citation: Institute of Medicine (IOM) and National Research Council (NRC). 2007. Assessing the medical risks of human oocyte donation for stem cell research: Workshop Report. Washington, DC: The National Academies Press.

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Assessing the Medical Risks of Human Oocyte Donation for Stem Cell Research: Workshop Report 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. Ralph J. Cicerone 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. Ralph J. Cicerone and Dr. Wm. A. Wulf are chair and vice chair, respectively, of the National Research Council. www.national-academies.org

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Assessing the Medical Risks of Human Oocyte Donation for Stem Cell Research: Workshop Report COMMITTEE ON ASSESSING THE MEDICAL RISKS OF HUMAN OOCYTE DONATION FOR STEM CELL RESEARCH LINDA C. GIUDICE (Chair), University of California, San Francisco EZRA C. DAVIDSON, JR., University of California, Los Angeles NAIHUA DUAN, University of California, Los Angeles BERNARD L. HARLOW, University of Minnesota, Minneapolis SUSAN C. KLOCK, Northwestern University, Chicago, Illinois JUDITH H. LAROSA, State University of New York, Brooklyn CATHERINE RACOWSKY, Harvard Medical School, Boston, Massachusetts ZEV ROSENWAKS, Cornell University, New York JOE LEIGH SIMPSON, Baylor College of Medicine, Houston, Texas Staff EILEEN SANTA, Responsible Staff Officer AMY HAAS, Administrative Assistant ANDREW M. POPE, Director, Board on Health Sciences Policy FRANCES E. SHARPLES, Director, Board on Life Sciences

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Assessing the Medical Risks of Human Oocyte Donation for Stem Cell Research: Workshop Report BOARD ON HEALTH SCIENCES POLICY FRED H. GAGE (Chair), The Salk Institute for Biological Studies, La Jolla, California GAIL H. CASSELL, Eli Lilly and Company, Indianapolis, Indiana JAMES F. CHILDRESS, University of Virginia, Charlottesville ELLEN WRIGHT CLAYTON, Vanderbilt University Medical School, Nashville, Tennessee DAVID R. COX, Perlegen Sciences, Mountain View, California LYNN R. GOLDMAN, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland BERNARD D. GOLDSTEIN, University of Pittsburgh, Pittsburgh, Pennsylvania MARTHA N. HILL, Johns Hopkins University School of Nursing, Baltimore, Maryland ALAN LESHNER, American Association for the Advancement of Science, Washington, D.C. DANIEL MASYS, Vanderbilt University Medical Center, Nashville, Tennessee JONATHAN D. MORENO, University of Virginia, Charlottesville E. ALBERT REECE, University of Arkansas, Little Rock MYRL WEINBERG, National Health Council, Washington, D.C. MICHAEL J. WELCH, Washington University School of Medicine, St. Louis, Missouri OWEN N. WITTE, University of California, Los Angeles MARY WOOLLEY, Research!America, Alexandria, Virginia IOM Staff ANDREW M. POPE, Director AMY HAAS, Board Assistant DAVID CODREA, Financial Associate

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Assessing the Medical Risks of Human Oocyte Donation for Stem Cell Research: Workshop Report BOARD ON LIFE SCIENCES KEITH YAMAMOTO (Chair), University of California, San Francisco ANN M. ARVIN, Stanford University School of Medicine, Stanford, California JEFFREY L. BENNETZEN, University of Georgia, Athens RUTH BERKELMAN, Emory University, Atlanta, Georgia DEBORAH BLUM, University of Wisconsin, Madison R. ALTA CHARO, University of Wisconsin, Madison JEFFREY L. DANGL, University of North Carolina, Chapel Hill PAUL R. EHRLICH, Stanford University, Stanford, California MARK D. FITZSIMMONS, John D. and Catherine T. MacArthur Foundation, Chicago, Illinois JO HANDELSMAN, University of Wisconsin, Madison ED HARLOW, Harvard Medical School, Boston, Massachusetts KENNETH H. KELLER, University of Minnesota, Minneapolis RANDALL MURCH, Virginia Polytechnic Institute and State University, Alexandria GREGORY A. PETSKO, Brandeis University, Waltham, Massachusetts MURIEL E. POSTON, Skidmore College, Saratoga Springs, New York JAMES REICHMAN, University of California, Santa Barbara MARC T. TESSIER-LAVIGNE, Genentech, Inc., South San Francisco, California JAMES TIEDJE, Michigan State University, East Lansing TERRY L. YATES, University of New Mexico, Albuquerque NRC Staff FRANCES E. SHARPLES, Director KERRY A. BRENNER, Senior Program Officer MARILEE K. SHELTON-DAVENPORT, Senior Program Officer EVONNE P.Y. TANG, Senior Program Officer ROBERT T. YUAN, Senior Program Officer ADAM P. FAGEN, Program Officer ANN H. REID, Senior Program Officer ANNA FARRAR, Financial Associate ANNE F. JURKOWSKI, Senior Program Assistant TOVA G. JACOBOVITS, Senior Program Assistant

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Assessing the Medical Risks of Human Oocyte Donation for Stem Cell Research: Workshop Report Independent Report 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 NRC’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: Linda D. Applegarth, The Center for Reproductive Medicine & Infertility, Weill Medical College of Cornell University Louise A. Brinton, Hormonal and Reproductive Epidemiology Branch, National Cancer Institute Susan Berke Fogel, Pro-Choice Alliance for Responsible Research Joel Howell, School of Public Health and Medical School, University of Michigan Richard S. Legro, Department of Obstetrics and Gynecology, Pennsylvania State University College of Medicine Richard Paulson, Division of Reproductive Endocrinology and Infertility, Keck School of Medicine, University of Southern California Although the reviewers listed above have provided many constructive comments and suggestions, they were not asked to endorse the final draft of the report before its release. The review of this report was over-

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Assessing the Medical Risks of Human Oocyte Donation for Stem Cell Research: Workshop Report seen by Dr. Mary Jane Osborn, University of Connecticut Health Center. Appointed by the National Research Council and the Institute of Medicine, she 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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Assessing the Medical Risks of Human Oocyte Donation for Stem Cell Research: Workshop Report Preface Stem cells have the potential to cure common, as well as rare, chronic diseases. They also are the focus of intense basic research to elucidate fundamental biological processes as well as the subject of applied research efforts, such as in testing the efficacy and mechanisms of specific drugs and chemicals. Because of the far-reaching opportunities offered by stem cells, the voters in California, in November 2004, approved Proposition 71, a 10-year, $3 billion program to fund stem cell research under the auspices of the newly formed California Institute for Regenerative Medicine. This bold program has articulated a strategic plan that includes building facilities in which stem cell research will be conducted, training scientists in the conduct of stem cell research, and developing therapies of stem cell transplantation into people with the goal of improving human health. To accomplish these goals, stem cells from a variety of sources—adult tissues, fetal tissues, gametes, amniotic fluid, human embryos—will be of value in this major program, and a large supply of these is anticipated for eventual, large-scale therapeutic trials and eventually therapies for relief of human suffering from chronic diseases. Human eggs (oocytes) and embryos that may serve as a resource in stem cell research will come from human donors. The task of the Committee on Assessing the Medical Risks of Human Oocyte Donation for Stem Cell Research was to organize a workshop and prepare a summary of the current state of knowledge of the medical risks of human oocyte donation for stem cell research.

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Assessing the Medical Risks of Human Oocyte Donation for Stem Cell Research: Workshop Report Human embryonic stem cells are currently derived primarily from unwanted or “surplus” (donated) human embryos from patients who have undergone treatments for infertility. Human embryonic stem cells may also be derived by a process called somatic cell nuclear transfer, in which the nucleus of a somatic cell (i.e., a cell that is neither an egg nor a sperm) is transferred into a human egg as its nucleus. Thus, for human embryonic stem cells, the human egg is a vital component of the process, and these eggs come from the ovaries of women who would choose to donate their eggs (or embryos) for this research effort. Because it is not known with certainty how many unwanted and donated embryos from fertility clinics are available nationally for stem cell research, it is likely that the majority of eggs will come from human donors. The donation process involves stimulation of the ovaries with fertility medications (gonadotropins) and subsequent retrieval of the eggs from a woman’s ovaries, usually in an operative procedure requiring light anesthesia. The California Institute for Regenerative Medicine approached the Institute of Medicine and the National Research Council about convening a committee of experts to ascertain the medical risks of oocyte donation for stem cell research. The committee members are leaders in the fields of human embryology, reproductive medicine, reproductive psychology, women’s health, and biostatistics. The group prioritized the issues and recommended a group of experts in the field to attend a workshop to discuss what is known about the medical risks, what needs to be known, and what can be done to reduce the potential risks over time. This workshop was convened on September 28, 2006, in San Francisco. The workshop focused on potential acute and chronic risks of oocyte donation for stem cell research. The acute risks discussed were ovarian hyperstimulation syndrome and surgical, infectious, and anesthetic risks; and potential chronic risks, including breast, ovarian, and endometrial cancer; future fertility; and psychological risks. The workshop included attendees with expertise and interest in the field, and a dialogue ensued among the speakers, the committee members, and the attendees in the audience. The event was also webcast so that interested members of the public could participate in the proceedings. This report describes scientific and clinical studies and the data derived from them, on which the risks were assessed as well as the methodological and study limitations that have made definitive risk assessment, for some risks, difficult to ascertain. The report contains neither speculation nor information outside what was discussed at the work-

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Assessing the Medical Risks of Human Oocyte Donation for Stem Cell Research: Workshop Report shop, and it does not contain recommendations. We hope that the report will serve as a resource on the state of the knowledge of acute, chronic, and potential risks associated with oocyte donation for stem cell research for the California Institute for Regenerative Medicine and others wanting more information about this interface between science and medicine. Linda C. Giudice, Chair Committee on Assessing the Medical Risks of Human Oocyte Donation for Stem Cell Research

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Assessing the Medical Risks of Human Oocyte Donation for Stem Cell Research: Workshop Report Contents     SUMMARY   1 1   INTRODUCTION   7      Sources of Stem Cells,   8      Egg Donation,   10      Potential Risks,   11 2   POTENTIAL RISKS ASSOCIATED WITH HORMONE TREATMENT   13      Oocyte Production,   14      Ovarian Stimulation,   16      Potential Risk of Ovarian Hyperstimulation Syndrome,   17      Potential Risk of Cancer,   22      Potential Long-Term Fertility Effects,   26      Summary: What We Know About the Risks of Ovarian Stimulation for Oocyte Production,   28 3   POTENTIAL RISKS ASSOCIATED WITH EGG RETRIEVAL   31      Potential Surgical Risks,   32      Potential Risks of Anesthesia,   34      Potential Long-Term Effects on Fertility,   37      Summary: What We Know About the Risks of Egg Retrieval,   38

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Assessing the Medical Risks of Human Oocyte Donation for Stem Cell Research: Workshop Report 4   POTENTIAL PSYCHOLOGICAL RISKS   41      Potential Psychological Risks in the Screening Process,   41      Potential Psychological Risks of the Donation Procedure,   44      Potential Psychological Risks of Post-Donation Adjustment,   45      Summary: What We Know About the Psychological Risks of Oocyte Donation,   48 5   DIRECTIONS FOR THE FUTURE   51      The Need for More and Better Data,   51      Minimizing Potential Risks,   54      Preventing Ovarian Hyperstimulation Syndrome,   57      Alternative Sources for Oocytes,   59     APPENDIXES     A   References   61 B   Public Workshop on Assessing the Medical Risks of Human Oocyte Donation for Stem Cell Research   67 C   Workshop Attendees   73 D   Glossary   77 E   Biographical Sketches of Committee Members, Invited Speakers, and Staff   85