Ethical debate over Preimplantation Genetic Diagnosis in Japan

- Yasuko Shirai,
National Institute of Mental Health, NCNP
1-7-3 Kohnodai, Ichikawa, Chiba 272-0827, Japan
Email: shirai@ncnp-k.go.jp
Eubios Journal of Asian and International Bioethics 11 (2001), 132-136.


1. Introduction

Dramatic advances in medical genetics and reproductive medicine have occurred in the last two decades. Especially with respect to human procreation, the technological combination of in vitro fertilization (IVF) and human genome research opened the door to genetic testing and selection of non-affected human embryos. A procedure derived from a combination of IVF and prenatal diagnosis techniques is known as pre-implantation genetic diagnosis (PGD). PGD requires removal of eggs from a woman's ovaries and fertilizing them outside of her womb. When fertilized eggs have divided into four to eight cells, one or two cells can be removed for testing for genetic disorders. After the testing, non-affected embryos are selected for transfer. Having PGD, a couple may avoid a decision whether or not to terminate a pregnancy in the event of an unfavorable test result. But judging form another point of view, a very nature of PGD selecting of embryos for transfer may raise ethical dilemma.

2. The Present Status of Pre-implantation Genetic Diagnosis in Japan

In July 1993, gynecologists' group from Kagoshima University Medical School started to prepare providing PGD for a couple whom already had a boy with Duchenne muscular dystrophy (DMD). They submitted a petition to the Ethics Committee of Kagoshima University Medical School. At the beginning of reviewing process of the petition, the Ethics committee appeared to be heading towards approving it. However, they abstained from decision until December 1995 due to movements by some disabled persons' groups and women's liberation groups against this petition. During this period, the Ethics Committee of Kagoshima University Medical School asked for a formal judgment on an implementation of PGD from the Ethics Committee of the Japan Society of Obstetrics and Gynecology (hereinafter referred to as the Committee). In September 1995, the Committee sent the request back to Kagoshima without any judgment, suggesting that the Ethics Committee of Kagoshima University Medical School will make the final judgment. On 10th February 1997, however, the Committee decided to approve the clinical research of PGD for certain genetic disorders such as DMD and fragile-X syndrome. The Committee submitted their decision to the Board of Directors of JSOBGY on 22nd February 1997. However, the Board of Directors abstained from deciding, due to the movements by some patients' association, disabled persons' groups and women's liberation groups against their decision.

Later on 27th June 1998, the Board of Directors of JSOBGY approved the clinical research of PGD and issued "A Guidelines on Pre-implantation Genetic Diagnosis" (see Appendix 1). It was five years later when the Ethics Committee of Kagoshima University Medical School asked them for their judgment concerning the implementation of PGD. As shown, they announced strict conditions on implementation of PGD and reviewing procedure of a petition. According to the Guidelines, PGD can be offered within the scope of prenatal diagnosis. PGD can be permitted only for a couple who may elevate a chance of having a child with severe genetic disorders, and the implementation of PDG is judged by case-by-case basis. In May 1999, the Kagoshima University gynecologists' group resubmitted the petition of implementation of PGD for the couple with DMD child to the Committee. The Committee rejected it once again because of a method of genetic test for the implementation of PGD. The Kagoshima University gynecologists' group intended not to use DNA testing of DMD but a sex selection of embryos for transfer. At this point of time, another gynecologist of an infertility clinic in Fukuoka City submitted another petition to the Committee. In this case a target of PGD was an infertile couple undergoing IVF treatments and experienced repeated miscarriages. The Committee rejected this proposal, for they judged this case did not confirm to the indications of the PGD guideline. Until now, the Committee accepted no petition for implementation of PGD.

3. Ethical Dilemma on PGD in Japanese Society

According to the aforementioned two denied cases, the Committee raised specific ethical questions concerning PGD; in particular the aim of PGD, the method for genetic testing, criteria of selection for transferring embryos after PGD. At the beginning of developing a technique of PGD, it seemed to become a new alternative for prenatal diagnoses. An advantage of PGD was considered to avoid the abortion issue based on fetal abnormalities. The Committee indicated that PGD could be provided for normal fertile couples who have increased possibility of having a child with severe genetic disorders, especially caused by single gene mutation. The prenatal diagnosis can lead to being confronted with the abortion issue. On the contrary, implementation of PGD has to be faced a selection of genetically healthy fertilized eggs. Some critics asserted that on what ground selective birth of non-affected baby using PGD might be appreciated ethically acceptable, comparing to the selective abortion following ordinary prenatal diagnosis such as amniocentesis. Some said that the moral status of fertilized eggs and human embryos may be endangered by such an idea. The second case from Fukuoka infertility clinic indicated that the Committee did not approve of using PGD in the context of artificial reproduction.

Some gynecologists practicing infertility treatments insist that PGD for pre-implantation genetic screening in this context may have two aims (1). In the first place, it enables the couple to be informed about any chromosomal abnormalities in the embryos available for transferring healthy ones. Another aim is improving the success rate of IVF and reducing the number of multiple pregnancies. It envisages a field of application to the couples who qualify for IVF or ICSI treatments because of fertility problems. The use of PGD may be widened in scale to include the routine testing for couples with an infertility problem. Other critics raised two questions concerning the selection of embryos through PGD in the process of infertility treatment: one question is whether it is acceptable to decide not to transfer embryos carrying recessive genetic disorder. Another question is whether it is justified when would-be parents wish to use PGD for sex selection of the future child for non-medical reasons. They warned that the expansion of implementation of PGD used in conjunction with IVF might accelerate the danger of a slippery slope toward the selection of embryos by eugenic reasons. In addition to the above-mentioned situation, there is a grave attitudinal gap between so-called experts and ordinary people concerning PGD. As indicated in Appendix 2, ordinary people, especially women, had more cautious attitudes toward PGD than the experts had (2-3). There is no consensus of opinion concerning PGD in Japanese society.

4. Opinion Survey on Prenatal Diagnosis

4.1. Methods

Two opinion surveys were conducted to compare attitudes between the so-called experts and ordinary people with some particular interest in medical genetics, concerning prenatal diagnoses. A survey of experts was carried out in July 1994 (Shirai 1997) with the cooperation of the Japanese Society of Human Genetics (whose total current membership is 1,321) and the Japanese Society of Inherited Metabolic Disease (whose total current membership is 615). Through a random sampling method, 600 members from the first group and 100 members from the second group were selected as respondents. Seven hundred questionnaires were distributed by mail, and a total of 358 responses were received (a response rate of 51%).

A survey of concerned lay persons was carried out from October through November 1996, with the cooperation of the Sentensei Shishi-syogaiji Fubo-no-kai (the Parents' Association of Children with Malformations in Extremities), two groups of parents with children of Down syndrome, and Kyoto Iryo Hiroba (a medical consumers' self-help group in Kyoto). 330 couples from the three parents groups and 150 members from Kyoto Iryo Hiroba composed the group of laypersons. 810 questionnaires were distributed by mail, and a total of 350 responses were received (a response rate of 43.2%). The main issues of the two opinion surveys were PGD, amniocentesis, abortion and some other relevant topics.

4.2. Sample Characteristics

Table 1 lists the characteristics of the respondents of the two groups. Among the expert group, the age of the respondents ranged from 23 to 87 years old; the average age was 43.2 years old (SD=11.7). More than 80% of the respondents were male medical doctors. The valid answers of a total of 356 respondents were used in the following analysis. Among the group of parents and lay persons, the age of the respondents ranged from 19 to 72 years old, and the average age was 40.5 years old (SD=9.8). About 39% of the total respondents were male, and residual 61% were female respondents. Nearly 60% of the female respondents in this group were housewives, and more than half of the male respondents were businessmen.

Table 1: Sample characteristics

Expert Group 1994 Concerned Lay persons 1996

Gender

Male 292 (81.6%) 135 (38.6%)

Female 65 (18.2%) 215 (61.4%)

Age

Under 35 116 (32.4%) 111 (31.7%)

36_ 49 144 (40.0%) 171 (48.9%)

50_ 59 55 (15.4%) 49 (14.0%)

60{ 41 (11.4%) 17 (4.9%)

Uncertain 2 (0.6%) 2 (0.6%)

Specialty Occupation

Medicine 302 (84.4%) Business 81 (23%)

Natural Science 49 (13.7%) Self-employed 16 (5%)

Uncertain 7 (12.0%) Civil Service 28 (9%)

House wife 128 (37%)

Other 97 (28%)

4.3. Attitude toward Pre-implantation Genetic Diagnoses

Figure1 presents the respondents' attitudes toward PGD. Among the expert group, more than 60% of the total respondents were in favor of PGD. About 18% were opposed, and 19% abstained. There was no significant attitudinal difference between the male and female experts. Among the group of laypersons, 35% of the male respondents agreed with PGD. 38% were opposed, and 27% abstained. Whereas among the female laypersons, only 15% were in favor of PGD, 54% were opposed, and 31% abstained. There was a significant attitudinal difference between the male and female laypersons in this case (p0.001 by chi-square test). It was also revealed a large opinion discrepantly between the expert group and the group of lay persons(p0.001 by chi-square test).

4.4. Attitude toward Amniocentesis

Figure 2 indicates the respondents' attitudes toward amniocenteses test. Among the expert group, more than 85% of the total respondents agreed with amniocenteses test. Only 5% were opposed, and 9% abstained. There was no significant attitudinal difference between the male and female experts. Among the group of laypersons, 43% of male respondents favored amniocenteses test. 38% were opposed, and 19%abstained. Among the female laypersons, 32% were in favor, 37% sere opposed, and 32% abstained, indicating a significant attitudinal difference between the male and female laypersons (p0.02 by chi-square test). A large opinion discrepancy between the expert group and the concerned lay group was revealed(p0.001 by chi-square test).

4.5. Attitude toward Women's Right to have an Abortion within the First Three Months of Pregnancy

Among the expert group, 67% of the total respondents agreed with women's right to have an abortion. 15% were opposed, and 18% abstained. Among the group of laypersons, 52% of the male respondents favored women's right to have an abortion. 18% were opposed, and 30% abstained. Among the female laypersons, 44% approved, 26% were opposed, and 30% abstained. There was no significant attitudinal difference between the male and female respondents in each group, however, a significant opinion discrepancy was indicated between the expert group and the group of laypersons (p0.001 by chi-square test).

5. Discussion and Conclusion

Based on the results of the present survey, the following points are suggested:

(1) There were significant attitudinal differences between the experts and the laypersons concerning PGD, amniocentesis and women's right to have an abortion.

(2) Among the group of layperson, female respondents held different attitudes with male respondents toward PGD and amniocenteses.

(3) The attitudinal differences between experts and laypersons were a result of the opinion discrepancy between male experts and female laypersons.

Since 1991, Macer et al. have conducted public opinion surveys concerning applications of biotechnology into agriculture and medicine. The issue of preimplantation diagnosis was taken up in their surveys in 1997 and 2000 (6, 7). A significant changes in public knowledge of preimplantation diagnosis (PD) occurred in 2000 where 58.4% answered to hear about PD compared to 35.8%in 1997. At the same, a decrease of the affirmative responses of public occurred in 2000 where only 37.7% agreed to encourage PD compared to 59.4% in 1997. Comparing these results to a result of Shirai's survey in 1996 (2), the respondents of the former two surveys had more favorable attitudes toward PD than the latter respondents had. As a whole, it is noteworthy that people showed more cautious attitudes toward PD after they got some information concerning the matter.

These findings suggest that a wider open forum is indispensable to consider a fruitful future of prenatal diagnosis including PGD. When forums and/or working group on this matter are organized, it is also necessary to give consideration to the attitudinal differences caused by the factors of gender and expertness.

In Japan, genetic disorders are always a serious family problem. In the traditional Japanese way of thinking, genetic disorders were regarded as a shameful occurrence to be hidden from society. The traditional religious teaching in our society contributed to as idea that genetic disorders were the result of misconduct in a previous generation of the family (5). Although such ideas have rapidly diminished in its impact, there is still implicit discrimination and prejudice against those who have genetic disorders and/or those who have a family history related to it. A person and his/her family with genetic problems are almost always faced with not only medical problems but also psychosocial and ethical dilemmas.

Another cause of ethical dilemma was embedded in the abortion law. In Japan, the Eugenic Protection Law of 1948 authorized the abortion for eugenic reasons until 1996. In September 1996, however, the Law was amended, and finally revised into a new law, the Mother's Body Protection Law. Words and phrases regarding eugenics were completely deleted from the new law. The Law authorized only two types of abortion. One was an abortion for so-called "economic" reasons and the other was a termination of pregnancy as a result of rape. Based on the new law, selective abortion following prenatal diagnosis cannot be strictly justified, and is performed under "economic reasons".

Reconsidering the guidelines on PGD, the author would like to present some critical points on assessing ethical and social implications of PGD after the suggestions of the Committee on Assessing Genetic Risks in USA (4). First, PGD may strengthen the notion of "selective birth" based on genetic predisposition of embryos. Second, it will open another door to gene manipulation of germ-line cells. Third, it may accelerate a tendency to fix a stigma upon a person due to his/her genetic predisposition. These three issues should be examined and discussed openly and in depth. It is indispensable to discuss whether PGD should be allowed as an extraordinary test for couples who have elevated chances of having a child with serious genetic disorders or a standard test for all the diagnosable genetic disorders and routinely provide for couples with an infertility problem form the ethical point of view. Open public discussion considered in the light of culture, religion, and jurisprudence is also essential.

6. References

  1. Health Council of the Netherlands: Committee on in vitro fertilization: IVF-related research.1998.
  2. Shirai, Y: Health professionals' attitudes toward preimplantation diagnosis in Japan. EJAIB 7(1997); 49-52.
  3. Shirai, Y & Saito Y: Ethical and psychosocial implications of preimplantation genetic diagnoses. In Ishihara, T. (ed.): A final report on genetic counseling and epidemiology of muscular dystrophy. Saitama, Japan, 1999. pp.162-164 (Japanese).
  4. Andrews LB, Fullarton JE, Holtzman NA & Motulsky G (eds.): Assessing Genetic Risks: Implications for health and social policy. National Academy Press, Washington, D.C., 1994.
5. Ohkura, K. & Kimura, R.: Ethics and medical genetics in Japan. In Wertz, D.C. & Fletcher, J.C (Eds.): Ethics and Human Genetics: A cross-cultural perspectives. Springer-Verlag. Berlin, Heidelberg, New York, 1989. pp. 294-316.

6. Macer, D.R.J., H. Bezar, N. Harman, H. Kamada, and N. Macer 'Attitudes to Biotechnology in Japan and New Zealand in 1997, with International Comparisons', EJAIB 7 (1997), 137-151.

7. Chen Ng, M.A., Takeda, C., Watanabe, T. & Macer, D. 2000. " Attitudes of the Public and Scientists to Biotechnology in Japan at the start of 2000", EJAIB 106.4: 106-13.


Appendix 1:
Guidelines on preimplantation genetic diagnosis issued by the Japan Society of Obstetrics & Gynecology (October 1998)

Recommendation To Members of the Society

Kazuo Sato,

President of the Japan Society of Obstetrics & Gynecology

The Ethics Committee set up within the Board of Councilors to advise on ethical issues in treatment and research conducted its deliberations regarding the limits of clinical applications of human in vitro fertilization-embryo transfer and pre-implantation genetic diagnosis. In its discussion the Committee paid careful attention to the various opinions of the communities concerned. As a result, the Committee made its recommendation to the Board. The Board approved these proposals (at the second meeting on June 27, 1998), and here gives notice of its approval to Society members in the form of a Recommendation.

These guidelines have also been approved by the Japan Society of Fertility and Sterility, the Japanese Urological Association, the Japan Society of Andrology, the Japan Society of Terinatology, the Japan Society of Human Genetics, and the Japan Society of Mass Screening.

The Guidelines on " the Limits of the Clinical Use of Human In Vitro Fertilization-Embryo Transfer"

Approval has been granted for the application of human in vitro fertilization-embryo transfer in clinical use other than infertility treatment. However, the limits of its application are to be discussed and determined on a case-by-case basis when a petition for approval of clinical use is made to the Japan Society of Obstetrics and Gynecology. The petition procedure including the forms is to be provided separately.

Comment on the Guideline on "the Limit of the Clinical Use of Human In Vitro Fertilization-Embryo Transfer"

Human in vitro fertilization-embryo transfer ("IVF-ET") has already been applied and implemented in infertility treatment according to the Recommendation of the Japan Society of Obstetrics and Gynecology (hereafter referred to as "this Society") of October 1983. But knowledge of reproductive physiology, which is the basis of IVF-ET, has increased strikingly since then and it has brought about a remarkable advance in the technology dealing with human ova and fertilized eggs. With such progress in reproductive medical technology, IVF-ET, which has been regarded only as an infertility therapy, is facing a possibility of its new clinical use and this is likely to expand hereafter.

In such a situation, this Society, with deliberate consideration and discussion based on the outcome of clinical as well as basic research both at home and abroad, has come to the conclusion that the application of IVF-ET needs to be expanded; and that our technology has advanced to the satisfactory level.

However, lest the application of IVF-ET be expanded without adequate control, in case of its implementation, it should be performed within proper limits, and at facilities provided with sufficient technology and experience in reproductive medicine. Therefore, facilities and permissible cases of application are to be assessed and determined on an individual basis by the Society.

The Guidelines on "Preimplantation Genetic Diagnosis"

1) Approval has been granted for the application of the technology of human in vitro fertilization-embryo transfer in the pre-implantation genetic diagnosis of fertilized eggs (embryo) (hereafter referred to as this Procedure).

2) In case of application of the Procedure, the following conditions are to be observed.

(1) This Procedure is a medical performance requiring a high level of technology and is to be conducted as clinical research.

(2) It is required that this Procedure be conducted by a physician with a high level of knowledge and skill in reproductive medicine. At the same time he/she should have sufficient knowledge of genetic diseases and extensive experience in prenatal diagnosis.

(3) The hospitals or clinics where this Procedure is implemented should have experience of delivery by means of in vitro fertilization-embryo transfer and also have an acknowledged record of achievements in the use of the technique of gene diagnosis.

(4) This Procedure should only be used for serious genetic diseases. Whether or not it is appropriate to apply this Procedure to a particular disease is to be judged by the Japan Society of Obstetrics and Gynecology (hereafter referred to as this Society) on a case-by-case basis, when a petition is made. This Procedure must not be used except for the purpose of the diagnosis of serious genetic diseases.

(5) Prior to any implementation of this Procedure, the Society must be petitioned according to the prescribed formalities in order to obtain its authorization. Furthermore practitioners are obliged to report on the situation and results of implementation yearly at regular intervals. Before any petition can be made to the Society, authorization must first be granted by the ethics committee of the hospital or clinic concerned where a member of this Society staffs.

(6) Implementation of this Procedure is to be permitted only in the case of couples who are in agreement and have expressed a strong desire that this Procedure be carried out. Before implementation, the couple in question should be offered an explanation in writing of how this Procedure will be performed, the likely results, risks, and differences with respect to current prenatal diagnosis; their autonomy in the decision-making process should be respected; and after that their informed consent is to be given in a written document and be stored in registry. The privacy of the couple and their newborn should be strictly protected.


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