Below is the uncorrected machine-read text of this chapter, intended to provide our own search engines and external engines with highly rich, chapter-representative searchable text of each book. Because it is UNCORRECTED material, please consider the following text as a useful but insufficient proxy for the authoritative book pages.
sutapy This study was prompted by a concern that, because of a policy that in effect prohibits the vise of federal funds for research involving human embryos, the clinical practice of in vitro fertilization and enbryo transfer (IVFET) was pushing to the limit of its scientific foundations. In addition, there was a perception that animal science had made substantial progress in the development of IVFET but, because of a lack of ocranunication among those working to further human clinical IVFET and those working in the animal science area, the knowledge developed in one sector was not being conveyed to the other. As a result progress in each sector was seen as being slowed. An Institute of Medicine committee was appointed to examine the basic science foundations of medically assisted conception, to develop an agenda for basic science research that would contribute to advances in the clinical and agricultural practice of IVFET, to suggest animal systems that provide useful models for specific research areas, to identify ways of diminishing barriers to progress, and to recommend ways of bringing together the veterinary and human reproductive research workers. The centerpiece of the study was a workshop at which clinicians and investigators reviewed the status of assisted conception and the related basic research in humans and animals, and suggested productive areas for future research. This workshop brought together representatives from the human and animal research worlds to enable them to exchange ideas, enhance their understanding of ways in which they can contribute to each other's work, and participate in a joint activity that could establish continuing ties. Social Concerns That Can be Addressed By IVFET Research directed at pushing forward the frontiers of medically assisted conception has the potential to provide benefits beyond the limited number of couples whose infertility may be solved by IVFET. There are expectations that such research would enable practitioners to identify genetic defects in embryos without damaging them, and to determine the sex of embryos without damaging them, so that those with sex-linked genetic diseases can be identified at a very early stage. Major areas to which advances in basic reproductive biology would make large contributions include; - 1 -
o Infertility. The magnitude of the problem of human infertility is reflected by the number of women with "iirpaired fecundity" â 4.4 million or 8.2 percent of women of childbearing age in 1982 (National Center for Health Statistics, 1985). By one estimate, more than half of the 4.2 million women who have been surgically sterilized for non-contraceptive reasons, and half of the 4.4 million subfecund women would lite to become pregnant. Furthermore, one million women between the ages of 15 and 44 who were or had been married reported at least one medical visit for infertility in 1982 (Puchs and Berrault, 1986). Although data cannot describe the emotional toll of infertility, the communications media are beginning to portray some of the distress. Ihe lengths to which couples will go in attempting to conceive and the formation of nationwide support groups for childless people are indicators of the pain of childlessness. Although IVFET is a solution for only limited numbers of infertile couples, research that advances the practice of IVFET also has the potential of advancing other forms of infertility treatment. Numerous infertility treatments exist, including education to give couples sufficient knowledge of reproductive biology, surgical repair, artificial insemination, and the use of drugs to induce ovulation. Two major new technologies are IVFET and gamete intrafallopian transfer (GIFT). These are complicated technologies. The simple description that follows will facilitate understanding of the research agenda developed by the committee. For IVFET, eggs are removed from the woman either during a natural cycle or after growth and maturation of oocytes has been stimulated by such drugs as human menopausal gonadotrophin. This latter method has the advantage of allowing more than one oocyte to be harvested. The egg is placed in a petri dish together with washed sperm that have been treated to ensure capacitation. If fertilization is achieved, the process of cleavage starts, and somewhere between the 2- and 16-oell stage, the embryo is transferred to the uterus. Pregnancy is established when the developing embryo implants itself into the wall of the uterus. More than one embryo may be transferred to the uterus. For GIFT, growth and retrieval of eggs are performed in a manner similar to that used for IVFET. Semen is collected and placed in a catheter with the eggs, and they are then transferred to the fallopian tube. Fertilization takes place in vivo. Sometimes donated sperm, eggs, or fertilized zygotes are used in assisted conception. For example, excess zygotes collected from a patient undergoing IVFET can be fertilized and implanted in a recipient uterus that has been synchronized with the donor's cycle. o Contraception. Advances in the basic science that would improve the clinical practice of assisted conception would, at the same time, help in the search for better contraceptive technologies. Despite widespread use of such contraceptive methods as sponges, surgical sterilization, intrauterine devices, and birth control pills, there remain unresolved - 2 -
problems of safety and efficacy. The search for improved forms of contraception is spurred not only by the desire of individuals to gain control over their reproductive lives, but also by the social cost of unwanted pregnancies and the problems caused by fast-growing populations in countries unable to provide an adequate standard of living for the present population. o Agriculture. The application of assisted conception techniques has made rapid inroads in the domestic cattle industry. Artificial insemination is the norm, with 70 percent of dairy cows conceiving in this manner in 1985. In less than two decades, a multimillion dollar TVFET bovine industry has developed. About 25 percent of embryo transfers in 1984 were of frozen embryos. Artificial insemination has resulted in genetic improvements in dairy cattle that have doubled milk production per cow in thirty years (First, Crister, and Robl, 1985). Embryo transfer technology increases the rate of production of valuable cows. The adoption of new reproductive technologies to enhance the production of food-producing animals has the potential for lowering the cost of food and quickening the process by which animals genetically suited to difficult climates can be created. o Biodiversity. Advances in reproductive technologies may sustain biodiversity by improving the reproductive efficiency of endangered species. o Primates for Research. A limited number of primates are in captivity and available for research, and there is a possibility that the capture of more may be halted because of concerns for the future of the species. It will be increasingly important to maximize the reproductive capabilities of the primates available to science. Barriers to Progress in In Vitro Fertilization and Embryo Transfer Since the birth of Louise Brown in England in 1978, in vitro fertilization with embryo replacement has become an established method of treatment for certain types of infertility that do not respond to alternative methods of treatment. However, the chances of success in IVF are relatively low. In 1985, 14.1 percent of stimulation cycles resulted in clinical pregnancies. In 1986 this figure rose to 16.9 percent (Fertility and Sterility, 1988). But, the proportion of women entering treatment who attain a live birth is far lower â only 8.9 percent of oocyte retrievals ended in live birth (Journal of the American Medical Association, 1988). Why are the odds for successful IVFET so low? The state of clinical practice of IVFET today is limited by lack of knowledge of some of the basic reproductive biology involved. This is caused, in part, by the many ethical questions raised by research in pursuit of the needed information. Difficulties in resolving these issues have caused the research to be deprived of federal funding. - 3 -
Ethical and Social Issues Sane of the ethical or social issues that arise from the various forms of assisted conception are unrelated to decisions about the progress of research. Examples of these are questions about the protection of the rights of gamete donors, gestational parents, and social parents; the ownership of cryopresexved embryos; and the sale of fpjr**t'*»g and enbryos. Sane ethical questions have a direct bearing on research, and have had important consequences for the funding of research. The major questions focus on the status of the embryo at each stage of its development. How the embryo is regarded dictates what is morally acceptable to do to it. At one end of this spectrum of thought is the position taken by the Reman Catholic Church. The Vatican's Instruction on Respect for Human Life states that "from the first moment of its existence until birth . . . no moral distinction is considered between zygotes, pre-embryos, embryos or fetuses" (cited in Fertility and Sterility, 1988b). Therefore, the absolute sanctity that is accorded to post-natal human life begins with the zygote. This concept makes it impossible to discard spare embryos or use then for research purposes. At the other end of the spectrum is the position that an embryo is merely biological material like any other group of living cells. The special value that might be attached to that material results from the expectations or aspirations of others (Office of Technology Assessment, 1988). Midway between these two positions is one that holds that "the human embryo is entitled to profound respect; but this respect does not necessarily encompass the full legal and moral rights attributed to a person" (Department of Health, Education, and Welfare, 1979). Holding this position, the Ethics Advisory Board (established by the Department of Health, Education and Welfare (CHEW) in 1979) concluded that research was acceptable on embryos up to 14 days after fertilization. The Federal Government and Embryo Research Policy roncerning research on human subjects has been slowly evolving since the 1960s. A study group was convened at NIH to develop guidelines, and a National Advisory Commission on Health Science and Society was proposed by Senator Walter Mondale in 1968 to examine developments in ipftdical research. Following reports of the infamous Tuskegee syphilis experiments, CHEW recommended that Congress establish a permanent body to regulate federally funded research using human subjects. In the 1970s the abortion issue Ytecsmp. linked to the issue of embryo research. After the Roe v. Wade decision legalized abortion under certain conditions, concern developed that women would be pressured into having abortions and the sale of aborted embryos might occur. In 1974, the federal government created the National Commission for the Protection of - 4 -
Hunan Subjects (P.L. 93-348). Until this ocomissicn reported to Congress, research on the living fetus was prohibited unless it was used to help that fetus survive. In 1975, EHEW issued regulations based on the findings of the ocnraission. These regulations did not cover embryo research. The ocnmission also run imiended establishing an Ethics Advisory Board (EftB) to review requests for research on embryos and in vitro fertilization. However, in 1980, the Secretary of DHHS allowed the EAB charter to expire. Thus, no research could be approved, and federal funding of embryo research was de facto prohibited. As a result, embryo research has relied on private funding from patient care revenues, pharmaceutical companies, and university budgets. Since 1985, efforts have been made that, if successful, might establish some rules under which embryo research could proceed. However, the chances of such an outcome in the near future appears to be slim. A Congressional Biomedical Ethics Board, caifmBPri of six senators and six representatives, has been appointed. This group established a Biomadical Ethics Advisory Committee. In 1988 the Department of Health and Human Services announced its intention to revive the Ethics Advisory Board and publish a proposed charter. A final charter is awaited. Domestic and Foreign Decisions Concerning Embryo Research The two professional societies in the United States that represent the physicians most involved in human TVFET have considered ethical questions about the practice of IVFET and embryo research. In 1986 the Committee on Ethics of the American College of Obstetricians and Gynecologists (AGOG) (1986) issued a statement that acknowledged the ethical issues posed by the creation of embryos outside a uterus, the dilemma of surplus embryos, and the acceptability of research using early human embryos. The AOOG committee reoommended that human embryos should be used only if nonhuman embryos could not provide the needed knowledge. It also reoomrnended banning research on embryos that had reached the age of 14 days. The American Fertility Society (AFS) also issued a report in 1986, approving experiments on embryos up to 14 days (Fertility and Sterility, 1986). A year later, after consideration of the Vatican's Instruction for Human Life in its Origin and on the Dignity of Procreation, issued by the Congregation for the Doctrine of Faith, the AFS issued another report. This report stated that progressive degrees of respect are due with progressive development of embryos, and that experimentation can be justified and is necessary if the human erudition is to be improved (Fertility and Sterility, 1988b). The government of the United States, since 1979, has not followed the lead of nations that have systematically examined issues related to human IVFET. Since 1979, at least 85 statements have been prepared by - 5 -
ocnmittees representing at least 25 countries. Four Australian ocnndttees found research en early (preinplantaticn) embryos to be ethically unacceptable. Eleven ocnmittees approved at least seme kinds of early embryo research. Six of these accept such research only on embryos left over from clinical activities. Five permittee statements (including the 1979 DHEW Ethics Advisory Board) would allow the creation of embryos for research purposes. Although the majority of ocmnittees favor limiting research on embryos to up to fourteen days, one oonmittee allowed it only to seven days, and one only through the first cleavage (Walters, 1987). In sum, numerous groups have wrestled with questions related to the ethical problems of embryo or fetal research. Some have based their conclusions on religious tenets, seme on an interpretation of scientific knowledge, some on a mixture of both. Other Barriers to Scientific Progress Other factors besides ethical considerations are slowing the progress of research in areas of reproductive biology related to assisted conception. Deficiencies in the Science Pas^ Papers presented at the committee's workshop and the research agenda developed from that workshop indicate deficiencies in the scientific underpinnings of reproductive biology, and identify many areas in which further research efforts would make major contributions to improvements in medically assisted conception. The deficiencies are on three levels: basic science knowledge; knowledge needed to irrprove the technologies being used for medically assisted conception, such as cryobiology; and knowledge needed to improve both human and animal clinical practice of IVFET. Research Funding Approximately $155 million annually is spend on research in reproductive processes. Federal agencies are the principal support for research. In 1986 they provided $109 million for research in reproductive processes (National Institutes of Health, undated) . Federal funds for research relating to agricultural animal reproduction are available from the U.S. Department of Agriculture. Funding for basic research in reproductive biology is undoubtedly constrained by the lack of vocal and focused advocacy groups. lacking such a voice a major increase in federal support is unlikely. Iffck of Communication ATTTW R|5jfa*r>;i*'rrt*ftrp Discussion with the scientists and clinicians at the committee's workshop revealed an underuse of available mechanisms for communications among the individuals involved with various aspects of research in reproductive biology â basic, clinical, animal sciences, etc. Also revealed was a desire for greater - 6 -
<xranunicatian to allow cross-fertilization of ideas and development of ongoing relationships among investigators pursuing similar approaches to problems. Sources of Research Material for Experiments with Humans and Other Kimates The ocnmittee's workshop provided many excellent examples of instances in which information about reproductive physiology derived from animal models has been useful in understanding human physiology. However, animal models cannot suffice for investigating all central questions; progress is some areas requires the use of human tissue. An example of this is investigation of reasons for developmental failure of human embryos. Although specific primates are good TffrKLg for some aspects of human reproductive physiology, there are only a limited number of monkeys of desirable species in captivity and many of them are presently being used for AXES research. Research Agenda A workshop was held August 21-23, 1988 at the Arnold and Mabel Beckman Center in Irvine, California. Overviews of the experience gained by the clinical practice of IVTET and of the practice of assisted conception in food-producing animals directed attention to unanswered questions that will require basic science research for their resolution. These questions reflect important gaps in our knowledge of the biology of all the stages of reproduction from the development of male and female gametes to the process of embryo implantation. The topics listed below are areas in which further research was reoomnended by workshop participants and conrtiittee members. Work in these areas is expected to increase understanding of the biology of reproduction with the hope that increased knowledge will eventually lead to improvements in the practice of IVFET in humans and other animals, or to advances in contraception. Research areas are listed here in summary form and apply both to lower animals and human beings unless specifically noted. The complete summary of the workshop is contained in Chapter Two of the full report. Basic Science Gametoqengsis o Definition of the role of cell adhesion molecules in interactions between Sertoli cells and developing sperm cells. o Understanding the function of differential protein synthesis in different stages of sperm development. - 7 -
o Determination of the role of paracrine factors including fibroblast growth factor, somatomedin C, epidermal growth factor, and interleukin-1 on the development and differentiation of male gametes. o Structural analysis to identify normal and abnormal sperm and the development of markers for abnormal sperm. o Understanding of the biochemistry of sperm capacitation. Female Gametoaenesis o Analysis of the effects of superovulation or hormonal stimulation protocols on oocyte development and maturation. This work should also examine differences between species. o Development of ways to mature oocytes in vitro. o Investigation of ways to naturally stimulate oocyte and follicular development. o Investigation into the biochemistry of meiotic arrest and the factors, such as cyclic AMP, purines, calcium, and maturation-promoting factor, that may mediate this process. o Development of ways to produce or synthesize hormones from non-human primates to be used in ovarian stimulation. o Definition of the role of ovarian estrogen in oocyte maturation and ovulation and the interactions between estrogen and paracrine factors including fibroblast and epidermal growth factors, insulin-like growth factor, transforming growth factor, and inhibin. o Definition of the point at which oocytes beorme sensitive to factors that influence their development. o Elucidation of the processes that underlie oocyte depletion, to determine why oocytes are lost at a predictable rate throughout life. o Investigation into ways to augment natural hormone release. o Investigation into the biochemistry of protein synthesis and modification in ovarian cells. Fertilization o Investigation into the biophysics of cell membranes as it relates to sperm and egg interactions at fertilization. - 8 -
o Continued investigation to identify the genes for zona proteins in various species, especially humans. o Further delineation of the role of zona proteins, especially ZP2 and ZP3, in sperm binding. o Understanding of the biochemistry of the modification of zona proteins in preventing polyspermy. o Elucidation of the molecular determinants of antibody formation to zona proteins and their possible role in contraceptive strategies. o Definition of the biochemical B»<*"fo*n't«ania of the cortical reaction in the egg and the effects of this reaction on zona proteins. o Determination of the physiological significance of germinal vesicle breakdown and the biochemistry of sperm chromatin decondensation. o Definition of the molecular events associated with formation of the male and female pronuclei. o Definition of the molecular events during zygote formation and the first cleavage. Preinplantation Development o Definition of the metabolic requirements of early embryos at different stages. o Determination of embryonic gene expression. o Assessing the potential of individual embryonic cells and defining the point at which embryonic cells are committed to particular fates. o Identification of substances produced by early embryos that signal changes in the uterus prior to implantation. o Improvements in embryo multiplication and embryo splitting, especially for food producing animals. Irl flntation o Definition of the biochemical events that make the uterus permissive to implantation. - 9 -
o Definition of the factors released by embryos that cause endometrial changes at the site of inplantaticn. o Identification of the role of embryo-released factors in suppressing the innune responses of the mother. o Isolation and analysis of substances released by endonetrlal cells and their effects on embryos. o Continued work with in vitro models of human implantation to study the biochemistry and mechanisms of embryo-endometrial interactions, especially the role of extracellular matrix proteins and the biochemistry of trophoblast invasion of the endometrium. Technological Advances o Improved cryopreservation techniques, including freezing and thawing protocols for eggs and embryos. o Improved resolution of ultrasonography for localization and noninvasive harvest of occytes, eggs, embryosâwould have particular usefulness for non-human primates and food producing animals. o Development of new culture media and methods for in vitro maturation of oocytes. o Development of safe methods of biopsy of early embryos for preimplantation diagnosis of genetic diseases. Clinical Research Opportunities The following areas are those in which a coordinated data collection effort across IVFET clinical centers would help improve the quality and success rates of IVFET nationally and, possibly, internationally. o Evaluation of hormonal stimulation protocols in terms of number of oocytes harvested, quality of oocytes, and rate of fertilization o Documentation on the incidence of abnormal implantation rates in IVFET practice and correlation of incidence with particular stimulation protocol used. o Collection of information regarding the incidence of abnormal zygotes and embryos, failed fertilization, and developmental arrest of embryos. o Analysis of data pertaining to synchronization of embryonic stage with endometrial stage and development of methods to improve synchronization. o Collection of information on sharing of spare eggs and arrested embryos for research purposes. - 10 -
Conclusions and Recommendations Developing Research Policy Lack of a mechanism for dealing with ethical disagreement over the use of embryos in research has slowed the rate of progress in research by, in effect, placing a moratorium on the use of federal funds for eight years. This has had undesirable results: the human clinical practice of IVFET is less effective than it might have been had research progressed at a faster pace; other socially desirable goals such as improved contraception, better techniques to preserve endangered species, and more cost-effective methods of producing food have developed at a pace slower than optimal. The recent appointment of the Biomedical Advisory Committee by the Biomedical Ethics Board, to report to Congress by November 1990 on embryo research issues, could be a step toward a solution. The committee applauds the intention to revive the Ethics Advisory Board of the Department of Health and Human Services to rule on the ethical acceptability of research relating to human embryos, which is required before federal funding of such a research grant can be considered. However, until these groups become fully functional and show evidence of progress, their impact must remain in question. If these groups can assume leadership roles in resolving the difficult issues of reproductive research, and develop guidelines for research that are based on information provided by science, and on concepts that are ethically acceptable to society, research in reproduction will be able to move forward. But if these groups become paralyzed because of political considerations or an inability to develop a framework for the resolution of differences of opinion, another organization should take over the role. The committee recommends that, jf establish*^ to develop cf^^^jji^s for embryo and fer^i r**gftaTT'f'> ffifflt- flT? based on the most advanced knowledge that science can muster, and with consideration of the exressed values of society. The group should be cciiixmed of individuals with expyrti1^ in the relevant scientif j,g disciplines. representatives of the lay public, and experts in model for such activities can be found in the Voluntary Licensing Authority of Great Britain. - 11 -
Basic Sci Foundations The number and range of topics included in the research agenda indicate the exciting potential for productive scientific exploration. The occmittee believes that fundamental research to enhance the basic science foundations of reproductive biology should be stimulated and supported. This includes studies of human beings, laboratory animal mnrtelB, and food-producing animals. The knowledge that would be generated is fundamental to an understanding of how to reverse infertility, to new approaches in the area of contraception, and to increasing the world's food supply. It is important that male as well as female reproductive biology be studied and that investigators make use of some opportunities that are largely ignored today. These opportunities occur as a result of clinical activities as well as research activities. The conuittee reuum|<itnf^i that a of furtiina far a scence fashion bv an a in reproductive biology be maintained in a Health. EEESES Late office in the National Institutes of Applied Research Research needs to be stimulated concerning technologies used in medically assisted conception in food producing animals and in human beings. lack of support in these areas is leading to inadequate scientific underpinnings for safe and effective clinical practice. An example of a technique used, but not carefully evaluated for possible detrimental effects, is freezing eggs or zygotes. Further experiments should be conducted to assess the effects on safety and viability of this technology which is standard practice in many IVFET clinics. Other areas of technology that need to be developed include less invasive ways to retrieve oocytes, ways to mature oocytes in vitro, and ways to assess the quality of spermatozoa or eggs to be used for fertilization. Lttee recommends that app in medieallvâ assisted oonaeution be i-**^-1 ive oractice of in vitro appropriate office Clinical Research Opportunities Perhaps the most obvious missed opportunity is the failure to learn from the diverse experiences of the approximately 160 clinical programs that provide IVFET. In addition to scientific questions, there are - 12 -
questions to do with the organization of clinics and the outcomes of procedures, the answers to which would enable practitioners to work more effectively, and policy makers to make decisions on the basis of the best available information. Clinical IVFET centers can provide unique opportunities for important studies. For example, human oocytes that fail to fertilize in vitro could be used to investigate the phenomenon of failed fertilization. Research that seeks to understand the basis of reproductive failure, and its relationship to hyperstimulation should be encouraged. Coordinated studies utilizing the mass of n»*wj^i and experience from IVFET centers could begin to answer these and other questions. The committee applauds the activities of the various professional societies that have issued non-binding statements about the quality of practice of IVF. The American Fertility Society has also provided a voluntary registry for centers. The committee believes that a mechanism is needed to monitor and evaluate clinical practice so that existing information that is relatively easy and inexpensive to collect can be disseminated. This would enable clinicians to build on the broadly based experience of the community and help ensure that patients have access to information about developments in IVFET and to well-informed physicians. The committee reccmends that a m for BP-^j^Tji^^?^nt'6iFscl c*?^^^i ooHecj^iot^ t?^ ^^t^tf^l isheci T*O m?nitor ^UTC* evaluate human and veterinar ractices of sssed tion pi'dd-ice. A cooperative groin ooHixjsed of the relevant professional societies should be estabi "» *&*** fo fund and initiate data collection under Direction of an interâ society council ouiuxised of representatives of narticinatina oraanizatian . Improving Communications The KM Workshop on Medically Assisted Conception brought together researchers from basic science, clinical practice, and animal sciences. The resulting interaction was viewed as extremely helpful by investigators from each of these communities. The committee reccmnerrig that a 1B?ctKtfUS!rc> between researchers in Diverse areas of reproductive science. The initiv vi^ come both from NIH r**s**f*Th fyrators who suunsor additional professional societi18*1. council. irri''vi<friallv or throuh an from the - 13 -
REFERENCES American College of Obstetricians and Gynecologists. 1986. Ethical Issues in Human In Vitro Fertilization and Embryo Placement. Ccnmittee on Ethics AOOG Committee Opinion Number 47. Washington, D.C. Department of Health, Education and Welfare. 1979. HEW Support of Involving Human In Vitro Fertilization and Embryo Transfer. Report and Conclusions. May 4. Washington, D.C. , U.S. Government Printing Office. Fertility and Sterility. 1988a. Invitro Fertilization/Eobryo Transfer in the United States: 1985 and 1986 Results from the National IVF/ET Registry. 49(2) : 212-215. Fertility and Sterility. 1988b. Ethical considerations of the new reproductive technologies. By the Ethics Comnittee (1986-7) of the American Fertility Society in light of Instruction on the Respect for Human Life in its Origin and on the Dignity of Procreation issued by the Congregation for the Doctrine of the Faith. Feb;49(2 Suppl 1):I-7S Fertility and Sterility. 1986. Ethical Considerations of the New Reproductive Technologies. The Ethics Committee of The American Fertility Society. Sep;46(3 Suppl 1) :IS-94S. First, N.L. , Critser, E.S., and Robl, J.M. 1985. Bcving Embryo: Development, Cloning, Sexing and Transfer of Genes for Immunology of Reproduction and Contraception, P. Talwas, ed. Elsevier, 1985. Fuchs, V.R. and Perreault, L. 1986. Expenditures for Reproduction-Related Health Care. Journal of the American Medical Association. Vol. 225, No.l. January 3:76-81. Journal of the American Medical Association. 1988. IYF Registry Notes More Centers, More Births, slightly Improved Odds. 259 (13): 1920-1921. National Institutes of Health. Undated. Inventory and Analysis of Federal Population Research. Fiscal Year 1986. U.S. Department of Health and Human Services, Public Health Service, National Institutes of Health. Office of Technology Assessment. 1988. Infertility: Medical and Social Choices. OTA BA HP 48. August. Washington, D.C. Walters, LeRoy. 1987. Ethics and New Reproductive Technologies: An International Review of Ocnmittee Statements. Hastings Center Report. June: 3-9. - 14 -
