Medically Assisted Conception: An Agenda for Research : Report of a Study (1989)

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.

CHAPTER 3 BARRIERS TO PROGRESS IN IN VITRO FtXTlLIZATICN AND EMEKTO TRANSFER Since the birth of Louise Brown in England in 1978, in vitro fertilization with enbryo T^fl w_*me**' has borr^pa an <*M -*ft>1 1 «h«»H method of treatment for certain types of infertility that do not respond to alternative methods of treatment. In 1988, 169 centers that offered TVFET were identified in the United States. Appreciable demand for IVFET exists despite some disadvantages, such as a higher rate of ectopic pregnancy than occurs with normal conception, high costs ($6,700 at one of the nation's oldest programs (Jones, 1989) that are often not reimbursed by third-party payers, prolonged treatment time, and uncertain results. Data from 41 clinics that reported to the American Fertility Society indicate the success rate is improving. In 1985, 14.1 percent of stimulation cycles resulted in clinical pregnancies. In 1986 this figure rose to 16.9 percent (Fertility and Sterility, 1988a) . However, the proportion of women entering treatment who attain a live birth is far lower — only 8.9 percent of oocyte retrievals ended in live birth (Journal of the American Medical Association, 1988a) . Moreover, some women start treatment, but for a variety of reasons fail to reach the stage of egg retrieval. Improvements in the success rate of IVFET are probably not the result of significant changes in the methods of ovarian stimulation or laboratory procedures. Rather, improvement may be attributed to a decline in the average age of women undergoing IVFET, increasing experience of clinician and laboratory personnel, and more rigorous criteria for selection of patients (Van Blerkcm, 1989) . Why are the <vHg for successful human IVFET so low? The answer lies in part in the state of knowledge of reproductive and developmental processes. There are a large number of unanswered questions whose resolution would have major impacts on the success of IVFET. Some of the most basic questions include; How does one identify a viable embryo? What are the effects of cxyopreservation of gametes and embryos? How many embryos should be transferred? Why do some embroys fail to continue to develop after apparently normal development? What are the physiological effects of hormonal treatments? What are the factors that control oocyte maturation? What regulates dominance of ovarian follicles and what are the mechanisms of implantation? One of the most important factors that limits the success of medically assisted conception procedures is the natural frequency of egg and embryo wastage. The most reliable and reproducible estimates of inherent developmental failure in indicate that about 20 to 25 percent of meiotically mature human eggs obtained after hyperstimulation have genetic abnormalities, about 7 percent of spermatozoa are genetically abnormal, and about 10 to 15 percent of unfertilized oocytes contain cytoplasmic aberrations or pathologies. In addition, the vast majority of human embryos derived -66-

from fertilization in vivo or in vitro will not develop to a blastocyst. Developmental failure during cleavage is fairly typical. Even enbryos that do develop to the blastocyst stage can contain abnormalities in cell structure or nuntoer that are not consistent with postimplantation development (blighted ovum, for example) . Collectively, developmental failure in the early stages of embryonic development appears to be the normal situation for the human species. The state of clinical practice of IVFET today is limited by lack of knowledge of some of the basic reproductive biology involved. The reason for this is, at least in part, due to 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. This chapter first reviews the y^ial and ethical barriers to in research, and then focuses on the scientific barriers. Brief note is made some of the ethical issues that are raised by the practice of in vitro fertilization, and the history of federal involvement in considerations of human fetal research is described. Some nations have examined the ethical questions and have issued guidelines or regulations. These will be described. Finally, the major science barriers that have slowed progress in human and animal practice of IVFET will be noted. Ethical and Social Issues Some 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; decisions on the fate of concept! , embryos, and fetuses; the moral status of human potential; the ownership of cryopreserved embryos whose parents have divorced or died; the confidentiality of sperm donors; and questions of the right of a child born of medically assisted conception to know his or her complete parentage. Other fundamental questions revolve around concepts of the right of an individual to reproduce, the sale of gametes and embryos, and whether infertility should be defined as a difwtse. Some 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. Die implications for what may be done with an embryo differ according to when human life is thought to begin, whether any biological material containing the potential for human life is considered to be sacrosanct, and other such questions. The determination of the moral status of the embryo drives such decisions as what level of risk to the embryo is acceptable in the practice of IVFET and research; whether it is possible to "discard" -67-

enbryos, even when placement in a uterus diminishes the probability of other embryos surviving; whether it is permissible to create enbryos for research purposes, and up to what stage of development of the embryo should research be allowed, and with what risk to its normal development. At one end of this spectrum of thought is the position taken by the Roman Catholic Church, which holds that life begins with the union of two haploid qametes to form a diploid zygote. 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 accorded to post-natal human life begins with the zygote. This concept makes it impossible to discard spare embryos or use them for research purposes. At the other end of the ±rum is the position that an embryo is merely biological material like any other group of living cells. The fipprial value that might be attached to that material results from the expectations or aspirations of others. Those who hold this view also note that a large number of naturally conceived embryos fail to develop after implantation, thus discarding excess embryos created by IVFET can be viewed as a parallel process (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). This is the position taken in 1979 by the Ethics Advisory Board established in the Department of Health Education and Welfare (DHEW) to advise the Secretary on matters concerning embryo research, and to review specific research proposals. Holding this position, the board concluded that research involving IVFET was acceptable on embryos up to 14 days after fertilization. Other constraints on such research included that it should be designed to improve the safety and efficacy of IVFET, and that the information could not be obtained by other means. The Federal Government and Embryo Research (Unless otherwise noted, this discussion is derived from a summary of fetal research i«-«ai*>g by the Association of American Hftrtifs^l Poling0** (1988)). As mentioned earlier, the Ethics Advisory Board was chartered in 1977 to review applications for federal support of research. This resulted fiuii growing concern about fetal or embryo research, which in turn stemmed from a concern about federal funding of research involving human subjects. Policy concerning research on human subjects had 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 Halter Mondale in 1968 to examine developments in medical research. This commission was not established, -68-

but the impetus from the effort helped put in place the later National Gcnmissicn for the Protection of Human Subjects. Following reports of the infamous Tuskegee syphilis experiments, DHEW IH »miiHnried that Congress establish a permanent body to regulate federally funded research using human subjects. In the 1970s the abortion issue became linked to the issue of embryo research. After the Roe v. Hade decision made legal abortion under certain specific conditions, concern developed that women would be pressured into having abortions and the sale of aborted embryos and fetuses might occur. Many states that had constrained embryo research through abortion statutes proposed separate legislation to ban such research. In 1974, the federal government created the National Commission for the Protection of Human Subjects (P.L. 93-348). Until this commission reported to Congress, research on the living fetus was prohibited unless it was used to help that fetus survive. This Commission did not consider the topic of research on the embryo or TVFET. The Commission however IB> x.iniiended establishing an Ethics Advisory Board (EAB) to review requests for conduct of embryo and IVFET research. Without such review, requests could not be processed. In 1975, CHEW issued regulations based on the findings of the commission. These regulations prohibited federally funded research unless the risk to the embryo was no greater than "those ordinarily encountered in daily life or during the performance of routine physical or psychological examinations or tests," or for therapeutic purposes (cited in Association of American Medical Colleges, 1988). The EAB met for the first time in 1978. In 1980, the Secretary of Health and Human Services allowed the EAB charter to expire and, without explanation, failed to renew it. Thus, federal funding of embryo and IVFET research was, in effect, prohibited. As a result, embryo research has relied on private funding from patient care revenues, pharmaceutical companies, and university budgets. It is estimated that, were the EAB active today, it would receive more than 100 grant applications (Office of Technology Assessment, 1988). In addition, the federal government has lacked a means for controlling the direction of, or practices used in, such research. As was noted in 1979, "Departmental involvement might help to resolve questions of risk and avoid abuse by encouraging well-designed research by qualified scientists. Such involvement might also help to shape the use of the procedures through regulation and by example." (Department of Health Education and Welfare, 1979). This opportunity has been lost for a number of years. In 1985, two events occurred in relation to the future of embryo research. Congress created a Biomedical Ethics Board. This board, ocByoced of members of Congress, six senators and six representatives, is to examine the protection of human subjects in biomedical research.

Included in its brief are studies of the ethical duplications of cnbryo research. By 1987, the 12 congressional members of the board had been appointed. The Board ««t-*Kl i chad a 14 "*•"!•*"•• pi/anft^ingi Ethics Advisory Gcnmittee cnTprfipri of scientists, physicians, clergy, and others. After months of deadlock over disagreements that mainly focused on appointees views on abortion and other ethical issues to do with definitions of human life, the advisory ocnmittee was named (American Mndical News, 1987). The first meeting did not take place until September 1988, and the date for faihmlssim of a report on fetal research had passed (Capron, 1989). Appointing the leaders and members of this Biomedical Ethics Board and the Biomedical Ethics Advisory Ccnmittee has been fraught with delays, as has the initiation of the activities of these bodies. Adequate funding is not assured. Alexander Capron, Chairman of the Bicnedical Ethics Advisory Ccnmittee notes that "one can be hopeful, but not certain that [these groups] will be able to fulfill their statutory purposes." (Capron, 1989) Whether progress in enabling embryo research to proceed will be made is open to doubt in today's political environment. In addition to these congressional groups there has been activity in the executive arm of government. The Department of Health and Human Services intends to reactivate the EAB that expired in 1980. In September 1988, notice of a draft charter was published in the Congressional Record. The 60-day content period has elapsed and a final revised charter is pending. The EAB, if reactivated, will develop specific guidelines to review NIH research proposals. It seems likely that the guidelines will be influenced by the broader policy formed by the congressional groups. Domestic and Foreign Decisions on Embryo Research The two professional societies in the United States that represent the physicians most involved in human IVFET have considered ethical questions about the practice of IVFET and embryo research. The American College of Obstetricians and Gynecologists (AGOG) issued an opinion that IVFET is a clinically applicable procedure that can be practiced if certain standards are assured and the ethical issues are considered (American College of Obstetricians and Gynecologists, 1984). Two years later the ACOG Committee on Ethics (American College of Obstetricians and Gynecologists, 1986) issued a statement that acknowledged the ethical issues that were posed by the creation of embryos outside a uterus, -70-

focusing particularly on the dilenma posed by surplus enbryos and the acceptability of research using early human embryos. The AGOG ocnmittee reocBBnended standards to guide such research, including that human embryos could be used only if ncnhuman embryos would not provide the needed knowledge. It also reccmnended halting research on embryos that had reached the age of 14 days. One American Fertility Society (AFS) also issued a report in 1986. This document notes eight technologies that the AFS Ethics Ocnmittee found ethically acceptable, including basic IVFET, the use of donor eggs, and the use of frozen sperm. Six procedures were found suitable for clinical experimentation, including the use of frozen eggs, and 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 condition is to be improved (Fertility and Sterility, 1988b). Despite public debate of the issues, statements issued by religious and professional groups, and other evidence of public interest, the government of the United States, since 1979, has not followed the lead of a number of nations that have systematically examined issues related to human IVFET. However, state statutes relevant to embryo research exist. Twenty-five states restrict embryo research, and 19 of those have language that could be interpreted as prohibiting some "pre-embryo" research (Office of Technology Assessment, 1988). Internationally, some governments have issued rules or regulations to control either the clinical practice, level of research, or both. LeRoy Walters, Director of Bicethics at the Kennedy Institute of Ethics, Georgetown University, has reviewed statements on the new reproductive technologies made by committees in other countries (Walters, 1987). He notes that, since 1979, at least 85 statements have been prepared by committees representing at least 25 countries. Walters focused his analysis on the reports listed in Figure 1. His analysis of issues in human embryo research notes that four Australian committees found research on early (preimplantation) embryos to be ethically unacceptable. Eleven committees approved at least some kinds of early embryo research. Six of these accept such research only on embryos left over from clinical activities. Five committee statements (including the 1979 CHEW Ethics Advisory Board) would allow the creation of enbryos for research purposes. Although the majority of committees favor limiting research on embryos to up to fourteen days, one committee allowed it only to seven days, and one only through the first cleavage (for details see Figure 1). An additional, important, position statement was issued by the Vatican in 1987. The Vatican found unacceptable IVFET, artificial insemination, and embryo research if it is not for the direct benefit of the embryo on which the procedure is performed. -71-

In sum, numerous groups have wrestled with questions related to the ethical problems of human embryo or fetal reseai-ch. Some have based their conclusions on religious tenets, some on an interpretation of scientific knowledge, some on a mixture of both. It should not be surprising that there are substantial differences in the conclusions drawn by these groups. However, to the extent that each has laid out the foundations of its arguments, the debate about the acceptability of embryo research has been advanced. -72-

e§ -u -H O 0-^ rH ~~J A-A Mk ft ** • Li 0 « in • JB • i -rH X 0 «-H 00 « 4> 0 M M « 4> •P g 0* >, > 3fHMCO| • 0) C > IH 0> 0 O 0 1 OJ >• S5COSMH Lu o 0 o Jo c a % o « •" • •H CO rH 0 «*» 0 CO rH 03 <0 IA t. C H 1 <u §M ••» t CO O C O** OH 1 C O O -H -r< C H ^ P j • HO* •H/3 g 0 1 CO 4>$ g MHO. 4J 0 «H P 0H Oh <H c tp 2 U , 1 c o 0 o •* -H 4J O 4> TJ CO 0 JC-* CO - u Q) >, •' £I4J OH 1 o z Li C C iH f 1 - -• f* LJ «+ W *™T| M lT^ ^T 0 > s E 2 *> 0 3 1 CO 3«%0 O H O> 0 0 r-l fiaso H 5"* *- 10 3 ^^ Q) *M i 4J Li O 0 0 0 C-"< «> >l rH C -H O O • •* Ll HI CO rH ja o 0 O U C OK« CO 0 0 H 1 >, 0 P V» rH 0 -r4 I H C O 0 CO • 0> 1 3 "M-H D H a « 4J w 4J 0 0 C -H : o OTJ O « M 0< >i -H 0 > TJ rH Ll 4J 0 COC o a 0 •HE a TJ OO •0 ^j Ll -rl 3 0 CO i ^ |Q c* 0 to 4J O\ S/ ^4 C*> >i 1*) 00 CU -P C rH O IB ^ o H] 0 u> a TJ c jc 0 : a * c co O J-H-H-H CO C Lt P O CT> 0 rH ** (0 ~ | 0 0 H Es O O* 0 H OH >i 3 TJ O C Li 0) rH i 0 3 E 0 (0 X! 0 0 O, CX •2 fa M TJ 0 C Ll (1) \ 0 rH 3 0 XI 1 C a o 1 0 0 4J • 0 T) <M 4J 4J-H C 0 X) 10 4J 1 -H 1 rH cam 0,0 1 JC 0 * -H -*-< CO «£> n — i o > = 0 TJ O P Li 0> 3 4J 0> O CO r-l o x: « o — i CD 0 E 0 C • >, Ef»O M O XI C O >i • 03 >. XI 0 0 • x: 0 CO 3 C D. 0 E O co a E H co o CO CP « o tt 0 Ll 0 rH O CP a) « e 0 -P XI Q) 41 rH 0 ox: 0 > -H 3 O i-4 0 **• - C 0-H rH *» 4J 1 O E a O, Li — H oo •H 0> Ll 1 8 tO rH M O CM «-l 1 P 00 n 0 0 MrH m a o 0 0 LI E S 0 - C « rj *o e 0 ja c» 0 c c js LI a o >• x: a** a au •H 0 M O O> >, C Li T3 3 CT> 0 0 0 an O s = 0 n 10 0 O (v, 0 WWW • (0 CL ^ « EH 0 O T) C Li U 0 4-> 1 TJ >i0 O O-^ 4J < C » - * O 3 Ll rH -r* -H X! t-H JJ o >, -3 M 0 " m -r« E « aau n> - •H iJ rH m >, x: OTJ m 0 >,o H i rH -H 00 rH <J O Ll rH *) 0) O 0 4j .p in M cr> 01 H Ll rH C H ^ >, 4J -H 3 1 CO o 00x:«x»<a >, 0) ~t < u -r< 0 r- C C 4J O 0 P C O -n -H > O CTx n E o H o> O >»-H >1 «M O o: u ~4 :£ TJ 00 rH 0) O 5 g* 3 M O H •»< *J 5 Ll «H <0 --H J W 2 0 C >, E >• <0 < bu *j -H ja o -P r 2 3 r-i 0) >.rH 2 .. ^ E C <0 C 0 80EO>^?oa) O rH J= o ... 4J U *J Ll >,4J *J 3 ^ D 3 « 03 D o ^ *— I <N r^ rr lO CD 00 U » to - 73 -

Eg O-H O *-5S §o> o^ 0 a 0 0 « m •H CO CM I B Vcoj m M o\ 0 I I I I I I t M z 1 AITI B O 0 O O-PTJ-* fc. C-H tree Li c c a 0 0 0 0 0 a 0 D-H rH u. 1 I >x: M U ^^ fa 41 rH 10 0 0 0 rH O-H ^^ U 10 •H 0 0 "f a u •H 0 0 Li C 0 M oo 0 0 C fa u c o o co • o> •H 3 <H-H D rH **— •* rH Ll 0 OTJ O O u co c II 0 O >• M c <0 ^tTrH CO •"*"* O 0 * i i o u a « c co i i >l 0 e o en i i jj O* 0 0 rH X) v> 0 3 E 0 a n Ll O 0 •H oj} J= 0-« i i 1 E 43 fa CC i i 4J Q) O 3 4J O> i i <M O W r-l 0 cn CO 3 rH C < c a 0 « •H 0 Ll «-H 00 U Li 0 > Ll 1 a 3 o CO rH M O (N 0 O rH 1 4J CO $*~i c •M *M « M O <T> 0 0 ^ -H rH 10 ^ 0 >,>, >,4J P 0) LJ-H -»H 0 >. X) rH rH E-H-H x: OTJ 0 XI XI p • fa* M n 10 >O < W-H a r- 0 0 «-l 4J 4J > O o> -^"» «H o a a 3 TJ CO rH 0 (U U < 10 U O z 0 U U u < < kl 3 o • • • • tO 13 X) •o X) 0 0 4» 0 CO C U -U O M I O O-H-H C M «• -HJC § 0 I CO «J W O fcM 2 U rH \O JC-H CO JC4J OM I O rH C M-v 2 *> 0 3 I co 3 O O M Q I O C-H Ll rH CD O 0 M I 4J Ll M •* S 0*> I CO o a M cm >, 0-H4J O rH 0 V 0 O a 0 o >. c > o o> O Ll O E O U < th O -rH-H c 0 a -H -H n <O ; « O-H co ao § o> M a E •- coo rH O - C 0-H « 0 Ll rH tf) TJ e 0 xi eo c n TJ 000 CQ o u. 0 (C o o >• c a to o 0 9 Oi 0 «o -H rJ rH IT1 rH -H CO 10 >t O M I Ll rH C M V +I-H 9 1 CO u e o M o> D 10 O < u. n 0 o >, c u 0 O «M o c o C -H 5 i: a o e a •H 3 u 4J o o 5 •o 0 0 TJ O C rH 3 •o 0 o c >, • JQ 0 0 0 fa rH 4J 0 0 ** 4* 0 I I I I I I <0 -Q O E _ D. O iJ ao S 0 W • CO O C fa U >, O O -H fa-H-H £ O JJ lj Aj E aaw 0 0 O LlrH x: x 0 « 4J 0 4J C --< «M O 3 4-1 10 -H O P >, >. <0 rH >,rH Z C « C O 3 O 0 JJ >,4J P D 02 D ta = m s •a ^ e P 0 9. G 0 4J -P • 0 CD CD "O CTN 0 rH 4) C - 0 rH CO rH 0 (X 0 A H O O 4J a u 0 o •o • o n C. -H U CP •H U rH O X) 0 3 O a 3 « 41 • C m 10 Ll <-H 0 4J -P < rH <0 - 4J >i 0 O -n a u 0 o j w 0 o u

E m 0 0 CO ill Jo 0 m •H CO CM I O 0H* 6 I ec • M O> & H x-o e o 0 o •* O 4* "O 00 I •a C C >H in >. « •o CO JS41 OH O«-l C H •« ; *» 0 3 I 3 0 O H o OSCO 4> 0 . 8 0 U -U rH O 14 i 0 —< O O • •* O fc C O X eo U C O 0 to • 3 «M-H 3 O OTJ O CO C O 0) a ic c 00 e a 0 0 r-l O 3 a 4J >4 00 3 -P o> o u CO 3 »-l --H 00 0 > i-i I X M ll •-! COl 0 0 H I *> fc H ^» B) 4J I 00 0 O H O * 3 , M O 0 0 14 tH m ON T3 E 41 XI c CTJ 3 000 nob «4iJiH in •H -^ CO 0 >iO M I Vl r-l C M •* 4J -H 3 I CD (A E O M oy 3 « O < b -M M 0 c «3 o 0 •O 0 TJ 0 0 TS 0 0 £ CP *J 4J « • g 9 0 4J -M • 0 CO CO •O en OJ .-( 4> C » *) 0 «H C « •-! ffl 0 Vi 0 0 o c 0- n 6 C O 4> 0 h 0 4> O 0 OK 0 XI M O 0) -U a u « o OK ^ O XI 01 3 O a c - 133 <0 41 ~ C V) <0 U t-H OJ -U 2 >> 4J >, 01 O -H IX U Q) O •J to 0 u u 3 tw O O •H 4> 0 9 •o • T-! A •H W 0 Q. 03 r-4 M O ( r-l I 4J CO « M o a> W OT3 U Vl — ( 10 r- > O T3 03 «-H < • >, W > 3 U <0 Vl-H 0 £ <M ^4 H O 9 (A o U) - 75 -

Figure 1 (continued) THE SIXTEEN EXTENDED COMMITTEE STATEMENTS ON THE NEW REPRODUCTIVE TECHNOLOGIES: 1979-1987 A. U.S. , Department of Health, Education, and Welfare (HEW) , Ethics Fertilization and Entoyo Transfer (May 4, 1979) B. Victoria, Australia, Ccnmittee to Consider the Social, Ethical and Legal Issues Arising from In Vitro Fertilization 1. Interim Report (= Waller I) (September 1982) 2. Issues Paper on Donor Gametes (• Waller H) (April 1983) 3. Report on Donor Gamete's and In Vitro (= Waller ni) (August 1983) 4. Report on the Disposition of Embryo Produced by In Vitro Fertilization (= Waller 3V) (August 1984) C. South Australia, Report of the working Party on In Vitro Fertilization and Artificial Insemination by Donor (January 1984 D. Queensland, Australia, Report of the Special Committee Appointed bv the Queensland Gov^Tntnsnt to EP<y''re into the Ii*™? Relatincf to Artificial Insemination. In Vitro Fertilization and Other Related Matters (= Demack Queensland, report) (March 1, 1984) E. Council for Science and Society (United Kingdom) , Working Party, Human Procreation; Ethical Aspects of the New Techniques (May 1984) F. United Kingdom, Department of Health and Social Security, Report of the Committee of Inquiry into Human Fertilization and Embryology (= Warnock, United Kingdom) (July 1984) G. Tasmania, Australia, Committee to Investigate Artificial Conception and Related Matters 1. Interim Report («= Tasmania I) (December 1984) 2. firpfll Report (m Tasmania H) (June 1985) H. Ontario, law Reform Commission, Report on Human Artif jcja.1 Reproduction and Related Matters (tabled June 13, 1985) . I. Australia, Family Law Council 1. Interim Report (= Family Law Council I) (July 1984) 2. Creating children; A Uniform Approach to the If*w and jim3uctive Technology in (= Family Law Council II) (July 1985) - 76 -

Page 2 (Figure 1 continued) J. Federal Republic of Germany, Minister for Research and Technology and Justice Minister, Working Group, In Vitro PertJI'JT'-fl'tion. Genome Analysis, and Gene Therapy (» Benda, flyman Federal Republic) (November 1985) K. Spain, Congress of Deputies, General Secretariat, Special Commission for the Study of Human In Vitro Fertilization and Artificial Insemination, Report (April 10, 1986) L. American Fertility Society, Ethics Committee, Ethirq*l QTrtpiderations of the New Reproductive Technologies (September 1986) M. Western Australia, Committee to Enquire into the Social, Legal and Ethical Issues Relating to In Vitro Fertilization and Its Supervision 1. Interim Report (= Western Australia I) (August 1984) 2. Report (= Western Australia II) (October 1986) N. Netherlands, Health Council, Committee on In Vitro Fertilization and Artificial Insemination by Donor 1. Interim Report on In Vitro Fertilization («= Dutch Health Council I) (October 10, 1984) 2. Report on Artificial Reproduction, with Spec^T Reference to Sperm, and Surrogate Motherhood (* Dutch Health Council II) (October 16, 1986) O. France, National Consultative Committee on Ethics 1. Report on Ethical Problems Related to Techniques of Artificial Reproduction (= National Ethics Committee I) (October 23, 1984) 2. Report on Research Involving Human Embryos In Vitro and Ethics Committee II) (December 15, 1986) P. New South Wales, Australia, law Reform Commission 1. Surrogate Motherhood: Australian Public Opinion (« New South Wales I) (May 1987) 2. Artificj?] fprnoeption. Dip"»v«ion Paper 2; In Vitro (= New South Wales II) (July 1987) - 77 -

Other Barriers to Scientific Progress The research agenda developed by the Institute of Hedicine, Board on Agriculture permittee (see Chapter 4) identifies many areas in which further research would make major contributions to improvements in medically assisted conception in humans and animals. As noted in Chapter 1, improving the application of medically assisted conception would benefit society in several ways, including making possible the preservation of some endangered species, as well as providing some relief from infertility and making production of meat and milk more economical. Progress, however, has been delayed by a number of factors, most of which stem from the generally controversial nature of concepts surrounding issues in reproduction, and specific controversies related to elements important to reproductive research — zygotes and embryos. As a prerequisite to developing recommendations to advance the science base of medically assisted conception, the committee first examined the impediments. In addition to the ethical considerations referred to earlier, the following barriers deserve particular emphasis: 1) deficiencies in the scientific base of this area of reproductive biology; 2) the resources available for research in this area of science; 3) lack of mechanisms for communication within the reproductive research community among basic scientists, clinicians, and animal husbandry scientists; 4) fear of abuses of reproductive technologies; 5) a relative lack of sympathy and understanding of the problems being experienced by infertile couples; 6) lack of a cohesive public interest group favoring such research, in contrast to well organized opposition; 7) limited health insurance coverage of IVFET services; 8) limited sources of research materials for experiments relating to human beings and to animals; and 9) the present dilemma of our society concerning how to handle our ethical disagreements. Almost none of these factors is independent of the others; rather a causal relationship is often found. Some of the barriers identified may be amenable to policy intervention. The following sections briefly review the impact of the major barriers to progress and how they have come to be in existence. Deficiencies in the Science Base The papers presented at the committee's workshop and the research agenda developed from that workshop (see Chapters 2 and 4) 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 improve the technologies being used for medically assisted conception, such as cryobiology; and knowledge needed to improve both human and animal clinical practice of IVFET. As explained in detail in -78-

Chapter 2, deficiencies in all three levels limit both the quality and efficiency of the practice of IVFET. ncaearch. directed toward improving the reproduction of food-producing animals such as cattle is often ahead of research in the area of human reproduction. As a result, the use of in vitro sperm capacitation, artificial insemination with frozen semen, transfer of frozen embryos, oocyte harvesting from dead animals (the Lazarus effect), and the splitting of the dividing cells of the early embryo into more than one individual animal, are routinely used in animal husbandry. A number of factors have allowed medically assisted conception to proceed at a faster pace in animals than in humans: research using food-producing animals has been stimulated by an expected economic return on the research investment, a larger volume of materials is available for study, and research has not been subject to as many ethical constraints. The latter two factors noted — greater volume of material available for study and fewer ethical constraints — derive from a difference in the esteem accorded to animals and humans by many members of society. The economic value of IVFET, which acts as a spur to progress in the animal area, is to some, although lesser extent, paralleled in human IVFET. That there is an economic value to IVFET for humans is indicated by the fact that clinicians can charge, and people are willing to pay, quite substantial fees for the procedure. This has enabled a small amount of research to be conducted in the absence of federal help. Research Funding Approximately $115 million annually is spent on research in human reproductive processes. The major sources of private funding (the Ford, Rockefeller, and A.W. Mellon foundations, and the Population Council) in 1985 together contributed $2.8 million to research related to reproductive processes. This includes grants to investigate male and female infertility, fertilization, zygote transport, preimplantation development and implantation, and reproductive endocrinology (National Institutes of Health, 1988). Federal agencies are the principal support for research. In 1986 they provided $109 million for research in reproductive processes (National Institutes of Health, undated). The National Institute of Child Health and Human Development (NICHD) of the National Institutes of Health provides the major portion of federal support of human reproductive iceearch. Approximately $100 million per year, one third of the budget of NICHD, is spent in the reproductive sciences branch of NICHD on contracts and grants to academic centers and to the NIH centers for reproductive biology. In addition, the Contraceptive Development Branch, which uses mainly contract mechanisms to support contraceptive technologies, contributes to basic reproductive research. Federal funds for reeicarch relating to agricultural animal reproduction are available from the U.S. Department of Agriculture. -79-

FMnding fear basic research in human reproductive biology is undoubtedly constrained by the lack of vocal and focused advocate groups that have beon fanned for sane ftinnnnrn such as cancer and heart Lacking such a constituency, a major increase in federal support is unlikely. Yet, as the research agenda in Chapter 4 suggests, additional investment in research in reproductive biology can expect to be repaid in improvements in the reproductive health of the nation. Lack of Communication Among Researchers Discussion with the scientists and clinicians at the committee's workshop revealed an underage of available mechanisms for oomnunications among the individuals involved with various aspects of research in reproductive biology — basic, clinical, animal sciences, etc. Also revealed was a desire for greater communication to allow cross-fertilization of ideas and development of ongoing relationships among investigators pursuing similar approaches to problems. Difficulty in establishing oomnunications is sometimes caused by the locale of investigators and the way science is organized. Basic scientists are frequently Fh.D.s in basic science departments such as anatomy or physiology. They often use animal models for their studies and have little or no contact with patients. Clinicians have an M.D. degree with subsequent residency training and are generally housed in clinical departments such as obstetrics and gyneoology. They are frequently heavily involved with patient care. S2me researchers working in animal sciences have veterinarian degrees, others have basic science degrees, and frequently work in departments related to animal sciences or agricultural practices and deal with animals of economic importance. The excitement and stimulation experienced by the individuals attending this ICM workshop, which encouraged interaction with individuals from differing backgrounds, underscored how infrequently meaningful interactions among these communities occur, and how useful this interaction could be. Societal den Ihe fear of abuses of reproductive technologies, the seeming lack of societal sympathy and understanding of the problems experienced by infertile couples, and the lack of a cohesive public interest support group are to some extent related phenomena. -80-

Fears of abuses of the new reproductive technologies are legitimate srns in a society that has not consistently shown an ability to monitor the ethical implications of scientific progress. Nor has this society established deliberative bodies that might reassure the public that applications of reproductive science will be controlled in ways sensitive to the delicate balance between preserving ethical standards and improving the human condition. This is not to imply that concerns about the uses of new reproductive technologies can be easily quieted by the creation of deliberative or regulatory bodies. Rather, that to date the U.S. has not grappled with the issues as some other nations have done. However, if renewed efforts to put in place the needed mechanisms are successful in dispelling some of the worst fears about research abuses and the new technologies, scientific progress may be furthered. It is clear that concerns are deeply felt. The strength of opposition to legal abortion demonstrates concerns that result from religious conviction and concerns about social values. The strength of support for legal abortions demonstrates concern for the freedom of individuals and the social impact of restrictive reproductive policies. Advances in science are making available technologies that open up new opportunities. Some view these technologies as opportunities to enhance the human condition. Others view them as potentially damaging to the social fabric. Indeed, there already exist technologies that are used in animal husbandry that members of society will not wish to have applied to human beings. Animals can presently be cloned, and genetic alterations have been made to animal germ cell lines. These are some of the issues that deserve careful scrutiny and public input. It is therefore important that society has mechanisms to consider and to debate the application of new technological capabilities and to ultimately provide safeguards against their Tnigng**- Reinforcing a sense of discomfort with some of the possible uses and abuses of new reproductive technologies, and also constraining efforts to advance in this area, may be a sense that infertility is a less vital concern than, for example, life threatening illness, disability, or more generally accepted signs of ill health. Although private third-party payers reimbursed roughly 70 percent of total non-IVEET infertility expenditures in 1980, the services are usually covered only if "they are with medical conditions or diseases requiring diagnosis and/or treatment and not solely related to infertility and fertilization" (Office of Technology Assessment, 1988). Insurance coverage for IVFBT is still limited, in part because the procedure is considered experimental. However, coverage is available for many parts of the IVFET workup (Office of Technology Assessment, 1988). If concerns about the allocation of trained health care resources continue to be high on the nation's agenda, it seems likely that less "acute" conditions such as infertility will lose out to more generally accepted forms of medical care, and will be available only to those who can pay the price. Also, a high cost -81-

procedure such as IVFET, likely to benefit a very limited number of people, will be further f*«nir»m-t«aart in a cost-conscious health services environment. That there is no single cohesive public interest group pressing for heightened research in the area of reproductive biology might be partially explained by the complex religious and ethical icnuec involved with certain types of research, by the lack of a cohesive research community, by fear of abuses in the area of reproductive technology, by a low public awareness of the size of the nation's infertility problem and the complex effect of infertility on individuals and couples, or a combination of these and other factors. Sources of Research Material The committee'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. Instances, however, were also presented in which the human processes have marked differences fmn those elucidated by animal T"nr*c>1ig, and to move forward in understanding the human physiology requires the use of human tissue. An example of this is investigation of reasons for the developmental failure of human embryos, and cryopreservation of human eggs and zygotes. Preservation of human tissue by freezing allows excess zygotes to be thawed for use at a later time. At present, we do not know all the possible negative consequences of freezing and thawing of the human tissue, nor do we know the optimum conditions under which these procedures should be done. However, cryopreservation has crept into clinical practice despite these uncertainties. This has happened in part because of the dilemma caused by excess embryos. Discarding them is unacceptable to some. Therefore cryopreservation has become an acceptable option. In addition, although specific primates are good models 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 AIDS research. To optimize the use of each primate, it would be helpful to develop noninvasive procedures for steps such as oocyte harvesting. Such a procedure would also be of great importance to patients. The committee believes that restrictions on the amount of material available for research use is slowing the rate of progress in developing a scientific base for IVFET and the technological advances that would make it more efficient. These limitations are the result of a concern that human material be used with proper respect, and that the use of animals for research purposes be controlled to ensure that they are not abused. -82-

There exist ways, however, of enlarging the amount of available research Material while preserving a proper consideration for these issues. Making available material from organs that have been surgically removed would increase the supply of human tissue. For instance, when an organ such as the ovary is removed for medical reasons, it might be made available for harvesting oocytes and eggs. In sum, as discussed in many places in this report, ethical, and social concerns underlie many of the barriers to ptogress in reproductive research and the clinical application of new technologies. lack of mechanisms for resolving such disagreements has inhibited progress in the necessary debate that must precede the development of policies. It is raging that Congress has established the Bionedical Ethics Boards, and that the executive branch of government is taking steps to reactivate the Ethics Advisory Board. If these bodies become functional the nation will have taken steps to establish entities to handle difficult issues in reproductive biology. -83-

KErZKBICEB American College of Obstetricians and Gynecologists. 1986. Ethical IsBiien in Human In Vitro Fertilization and Embryo Placement. Ccranittee on Ethics. AGOG Committee Opinion Nunber 47. Washington, D.C. American College of Obstetricians and Gynecologists. 1984. Hunan In Vitro Fertilization and Embryo Placement. Ocnmittee on Gynecologic Practice. Ocnmittee Statement. Washington, D.C. American Medical News. 1987. Ethics Panel Members Are Named. Aug 14. Association of American Medical Colleges. 1988. Fetal Research and Fetal Tissue Itoeeaixh. Washington, D.C. : Association of American Mp^i**8*"! Colleges. June. Capron, Alexander Morgan. 1989. Bioethics on the Congressional Agenda. Hastings Center Report. March/April pp. 22-23 Department of Health, Education and Welfare. 1979. HEW Support of Research Involving Human In Vitro Fertilization and Embryo Transfer. Report and Conclusions. May 4. Washington, D.C. : U.S. Government Printing Office. Fertility and sterility. 1986. Ethical Considerations of the New Reproductive Technologies. The Ethics Committee of The American Fertility Society. 46(3 Suppl 1): IS-94S Fertility and Sterility. 1988a. In vitro fertilization/embryo 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 Committee (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):IS-7S Jones, Howard W. Jr. 1989. Eastern Virginia Medical School. Personal Communication, January 23. Journal of the American Medical Association. 1988. IVF Registry Notes More Centers, More Births, Slightly Improved Odds. 259 (13): 1920-1921. National Institutes of Health. 1988. Inventory and Analysis of Private Agency Population Research. 1984 and 1985. U.S. Department of Health and Human Services, Public Health Services, National Institutes of Health. June. -84-

National Institutes of Health. Undated. Inventory and Analysis of Federal Population Research. Fiscal year 1986. U.S. Department of Health and Hunan Services, Public Health Service, national Institutes of Health. Office of Technology Assessment. 1988. Infertility: Medical and fiorinl Choices. OTA BA BP 48. August. Washington, D.C.: Office of Technology Assessment. Van Blerkon, Jonthan. 1989. Professor of Molecular, Cellular, and Developmental Biology, University of Colorado at Boulder. Personal Qoflnunication, January. Walters, LeRoy. 1987. Ethics and New Reproductive Technologies: An International Review of Oomoittee Statements. Hastings Center Report. June:3-9 -85-