Basic Science

Technological Advances

• Improved cryopreservation techniques, including freezing and thawing protocols for eggs and embryos.
• Improved resolution of ultrasonography for localization and noninvasive harvest of occytes, eggs, and embryos—would have particular usefulness for non-human primates and food-producing animals.
• Development of new culture media and methods for in vitro maturation of oocytes.
• 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 improve the quality and success rates of IVFET nationally and, possibly, internationally.

• Evaluation of hormonal stimulation protocols in terms of number of oocytes harvested, quality of oocytes, and rate of fertilization success
• Documentation on the incidence of abnormal implantation rates in IVFET practice and correlation of incidence with particular stimulation protocol used.
• Collection of information regarding the incidence of abnormal egg and embryos, failed fertilization, and developmental arrest of embryos.
• Analysis of data pertaining to synchronization of embryonic stage with endometrial stage and development of methods to improve synchronization.
• Collection of information on sharing of spare occytes and arrested embryos for research purposes.

Developing Research Policy

The 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 is 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 also 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 oonsidered. 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, as well as 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, if the groups currently being formed fail to come to conclusions concerning embryo and fetal research, a non-governmental organization should be established to develop guidelines for embryo and fetal research based on the most advanced knowledge that science can muster, and with serious consideration of the expressed values of society. The group should be composed of individuals with expertise in the relevant scientific disciplines, representatives of the lay public, and experts in the legal, ethical and social issues. The organization should be housed in an institution that would allow it to conduct its deliberations free from undue pressures from political and special interest groups. A model for such activities can be found in the Voluntary Licensing Authority of Great Britain. This group was established after a governmental committee recommended a statutory licensing authority. Recognizing that it would be some time before legislation would be completed, the Medical Research Council and the Royal College of Obstetricians jointly sponsored the voluntary body. Five of its 13 members are lay people. The group has a mandate to undertake five major activities:

• to approve a code of practice on research related to human fertilization and embryology;
• to invite all centers, clinicians and scientists engaged in research on IVF to submit their work for approval and licensing;
• to visit each center before it is granted a license;
• to report to the sponsoring organizations; and
• to make known publicly the details of both approved and unapproved work.

Basic Science Foundations

The number and range of topics included in this chapter's research agenda indicate the exciting potential for productive scientific exploration. Funding that would allow investigation of the areas targeted in the research agenda would allow significant advances to be made in understanding reproductive processes. The committee 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 models, 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.

This report attempts to define not only the state of knowledge in reproductive science relating to IVFET, but to assess and highlight some research opportunities. It is important that aspects of male as well as female reproductive biology be studied. It is also important 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. For example, eggs that have failed to fertilized can become material for studies seeking chromosomal abnormalities. Fertilized eggs that fail to develop may be used to investigate the reasons for developmental failure, and to answer questions about the natural wastage that occurs in pregnancy.

Research of this type would generally be funded by the grant of the National Institutes of Health and by the United States Department of Agriculture. For adequate attention to a research agenda, however, administrators of NIH need mechanisms to insure that studies on a variety of these topics are being funded. For this an RFP or a contract mechanism might be necessary to ins adequate coverage of the various aspects of reproductive biology. Foundations are also encouraged to consider increased support for basic studies in reproduction. A stable funding base for reproductive research will encourage young, well-trained scientists to pursue research in reproductive biology.

The committee recommends that a vigorous program for funding of a basic science agenda in reproductive biology be maintained in a coordinated fashion by an appropriate office in the National Institutes of Health.

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 oocytes to be used for fertilization.

Since these studies would be technology driven, it is unlikely that the research will be funded by a grant mechanism, therefore a contract mechanism should be used.

The committee recommends that applied research into technologies used in medically assisted conception be undertaken to provide a firm foundation for the safe and effective practice of in vitro fertilization and embryo transfer. Such applied research should be coordinated by the appropriate office at the National Institutes of Health.

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 human IVFET. In addition to scientific questions, there are questions to do with the organization of clinics and the outcomes of procedures. The answers to these questions would enable practitioners to work more effectively, and enable policy makers to make decisions on the basis of the best available information. Such questions include: Who provides the quality assurance for facilities and procedures used (including the training of those providing services)? How are protocols developed? How standard are they? What are the outcomes for each protocol? What is the role of Institutional Review Boards in the establishment and maintenance of clinical facilities?

Some specific questions to be answered from data that could be collected from clinics include: What ovarian stimulation protocols are the most successful? Is chromosomal damage associated with any of the procedures used? What indicates whether a zygote will implant successfully? Much data relating to these questions already exist in the centers. Other questions may require a cooperative prospective study to be undertaken.

Clinical IVFET centers can also provide unique opportunities for important studies. For example, human eggs that fail to fertilize in vitro are material that could be used to investigate the phenomenon of failed fertilization. Improved understanding of reasons for failure has implications for reversing infertility and ensuring conception. Another for investigation for which the IVFET centers are particularly suited is arrested zygotic development. In producing embryos by in vitro fertilization, it has been noted that certain zygotes stop dividing. The reasons for such arrested zygotic development are unknown. Have these cells died? Can one tell from studying the newly dividing zygotes which ones will be most likely to initiate a successful pregnancy?

Failed fertilization in the peri-implantation period in both the natural situation and during the procedures of IVFET is an important area to be understood. Developmental failure in the early stages of embryonic development appears to be a normal event for the human species. Whether this loss results from lethal genetic defects, chromosomal anomalies, biochemical or structural abnormalities, or technical difficulties needs further elucidation. Research that seeks to understand the basis of reproductive failure, and its relationship to hyperstimulation should be encouraged. Coordinated studies utilizing the mass of material and experience from IVFET centers could begin to answer these and other questions. In addition, the experience of centers performing IVFET for farm animals could provide valuable information.

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. On the animal side, The American Embryo Transfer Society has started to establish some quality measures for commercial bovine embryo transfer. States in general get involved by licensing physicians, hospitals, and clinics, and as yet have not played a dominant role in assuring quality of care.

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 recommends that a mechanism for multi-centered data collection be established to monitor and evaluate human and veterinary practices of medically assisted conception in order to improve the safety, effectiveness, and quality of clinical practice. A cooperative group composed of the relevant professional societies should be established to fund and initiate data collection under the direction of an inter-society council composed of representatives of each participating organization.

Improving Communications

The IOM 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 recommends that a mechanism (or multiple mechanisms) be found for fostering continued communication between researchers in diverse areas of reproductive science. The initiative should come both from NIH research administrators who could sponsor additional workshop opportunities and from the professional societies, either individually or through an intersociety council.