RBMOnline - Vol 10. No 3. 2005 320-324 Reproductive BioMedicine Online; www.rbmonline.com/Article/1615 on web 5 January 2005
Ethics, legal, social, counselling Ethical consideration of intentioned preimplantation genetic diagnosis to enable future tissue transplantation
Dr Alex Simon
Dr Joseph G Schenker
Dr Alex Simon graduated to the rank of Medical Doctor at the Medical School of the Hebrew University, Jerusalem in 1982. He accomplished his residency in the Department of Obstetrics and Gynecology at Hadassah University Hospital, Jerusalem where he is now a senior faculty and a staff member with tenure. Following his residency he spent different periods of time both in Europe and USA to practice micromanipulation of gametes, laparoscopic surgery and reconstructive pelvic surgery for gynaecologic oncology patients. Since 1987 he has been working in the IVF Unit of Hadassah Hospital. He currently serves as director of the IVF centre at Hadassah and holds an academic appointment of Associated Professor in Obstetrics and Gynecology at the Hebrew University of Jerusalem. He is an author on more than 70 papers in the field of assisted reproduction.
Dr Joseph G Schenker is a Professor of Obstetrics and Gynecology, Hebrew University, Jerusalem and served as Chairman in the Department of Obstetrics and Gynecology, Hadassah University Hospital in Jerusalem 1977–1999. Previously he was Chairman of the IFFS and FIGO ethical committee; currently he is Chairman of the Ethical Committees of both the World Association of Perinatal Medicine and the Asia Oceana Federation of Obstetrics and Gynecology. He is also a Member of FIGO Committee for the Study of Ethical Aspects of Human Reproduction. His main interests are experimental and clinical studies in the field of endocrinology of human reproduction, development of methods for contraception, development of technologies in practice of assisted reproduction, pathological conditions in pregnancy, and related ethical aspects. Dr Schenker is the author of more than 550 publications in medical journals, chapters and several books.
Alex Simon1, Joseph G Schenker Department of Obstetrics and Gynecology, Hadassah University Hospital, Ein Kerem, PO Box 12000, Jerusalem 91120, Israel 1Correspondence: Tel: +972 2 6776424; Fax: +972 2 6433337; e-mail:
[email protected]
Abstract Recently, a case was presented where a couple with one normal child requested preimplantation genetic diagnosis (PGD) with human leukocyte antigen (HLA) typing in order to conceive children who could serve as mutual donors for future transplantations if needed. While PGD for medical reasons is well defined and accepted, application for non-medical conditions is less obvious and still in debate. The present case calls to further extend the indications for PGD and raises a moral question as to whether to allow such intentioned treatment. Although it seems that all siblings might benefit from the procedure, when weighing the risks benefits and the ethical issues included in performing intentioned PGD, it seems that the procedure harbours risks and ethical issues that outweigh the benefit it offers. Therefore, it is time to constrain the slippery slope and state that intentioned PGD for conceiving children who might serve as siblings for mutual tissue donations should be declined. Keywords: ethics, HLA typing, PGD, transplantation
Introduction
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Recently, Johnson (2004) presented a case where a couple with one normal child who planned to have four children requested preimplantation genetic diagnosis (PGD) with human leukocyte antigen (HLA) typing in order to conceive children
who could serve as mutual donors for future transplantations if needed. The couple was presented as intelligent and familiar with the risks and benefit of the procedure. They were wealthy and ready to cover the costs of the procedure, so it would not be a burden on health care resources. According to the couple, everyone would seem to benefit
Ethics - Intentioned PGD- A Simon & JG Schenker
from this preventive treatment. The children would have mutual transplant tissue if the need arose, and future medical resources might not be wasted. The article raises a moral question as to whether to allow this preventive treatment. While new technologies are able to offer new medical treatments, should they be applied without any constraints? The article calls for ethical considerations of the couple’s request. PGD has been available since 1990 for testing chromosomal structural abnormalities, sexing for X-linked diseases and for the detection of single gene mutation diseases. It is estimated that currently, more than 6000 PGD cycles have been performed worldwide with more than 1000 live births. The main purpose of the procedure is to prevent the conception of an abnormal fetus. However, PGD could be extended to other medical and non-medical indications. Therefore, from the very beginning, the PGD procedure has raised both moral and ethical issues warranting public discussion. The procedure involves IVF and the production of embryos. Using sophisticated molecular biology diagnostic methods, the embryos are screened and appropriate embryos are selected while the rest are discarded. Producing embryos solely for selection, with the subsequent destruction of some of them, raises an ethical argument (Persson, 1999; Schenker, 2003). Those who believe in the right to life will totally oppose the use of PGD, as it involves the creation and destruction of embryos, violating their rights to life. Others, who consider the early embryo to be too rudimentary to have any rights, will probably raise no objection to the main principle of PGD. Since the mainstream of ethicists, scientists and religious authorities consider the early embryo as a cluster of cells having only the potential of creating a human being, but with no defined identity or rights, it appears that PGD as a procedure is ethically acceptable (Fasouliotis and Schenker, 1998). Nevertheless, it may be argued that increased use of PGD may interfere with genetic selection and alter the balance created by nature. Contrary to this argument, however, it could be claimed that there is no difference between PGD and abortions performed after prenatal diagnosis if one addresses the possible interference with genetic selection. PGD, however, might even be advantageous from an ethical, religious and moral point of view when compared with therapeutic abortions (Cameron and Williamson, 2003). In addition, couples might avoid using the procedure because it offers a pregnancy rate of only 25–30% while harbouring the risks associated with an IVF attempt. Couples might also avoid the procedure due to the financial burden. Even if the number of PGD procedures increased substantially, it would contribute only a small proportion of the total treatment cycles and total deliveries associated with IVF. In the near future, it is unlikely that the procedure will have a real impact on genetic selection in the population. There is a consensus about using PGD for medical indications in order to prevent the conception of a sick child. However, this type of selection leads to the fear of a ‘slippery slope’.
With the new technology advances in molecular biology and the anticipated revolution in genetic diagnostic methods, PGD might be suggested for indications that are ethically unacceptable. It is the duty of society, using the combined assistance of ethicists, scientists and jurists, to determine what technologies are ethical and therefore should be permitted and what are considered unethical and should not be performed. While currently reproductive authorities discuss the ethical issues of PGD and recommend what guidelines should be instituted (Robertson, 2003a,b; Shenfield et al., 2003), in the future, governmental regulations or laws may be instituted that will clearly define what is acceptable or unacceptable for PGD. The use of PGD for medical purposes such as testing for aneuploidy, for normal chromosome structure and for Mendelian disorders, is ethically and legally acceptable. The ethical debate revolves around whether it is appropriate to extend these indications to other medical and non-medical conditions.
HLA typing for future need of transplantations PGD has been discussed and ethically accepted for use in late onset medical conditions such as carriers of the P53 mutation (Simpson, 2001; Verlinsky et al., 2001), Alzheimer’s (Verlinsky et al., 2002) and Huntington’s disease traits (Sermon et al., 2002). Moreover, it was successfully applied to obtain a healthy newborn whose cord blood served for bone marrow transplantation of his affected sibling (Kuliev and Verlinsky, 2004). This was feasible by using PGD for diagnosing and transferring healthy embryos that were also HLA matched to the sick child in the family. This procedure has been successfully used mainly for thalassaemia, Fanconi anaemia and leukaemia (Kuliev and Verlinsky, 2004). Although initially this issue raised a heated debate, the goal of saving a life was considered to be of such a high moral value that it overcame the other arguments and the procedure was carried out. This was much easier to be accepted when the HLA typing was performed in conjunction with IVF that was mandatory in order to conceive a newborn free of a hereditary disease. Applying IVF and PGD solely for cord blood transplantation from a matched pre-selected embryo is still in debate. While the UK Human Fertilization and Embryology Authority (HFEA) denied such treatment (Dobson, 2003), others (Kuliev and Verlinsky, 2004) found it acceptable, as saving life should be considered of supreme value. As has been previously mentioned, one can extend the use of PGD for non-imminent but life threatening medical conditions. While carriers of the P53 mutation, BRCA mutations, Alzheimer’s and Huntington’s disease harbour a considerable risk of being affected by the disease, other rare life threatening medical conditions might be resolved in the future by intentioned PGD. The case presented by Johnson (2004) is an example of a dilemma that exists in performing ‘PGD upon request’ as a preventive method for future need of tissue transplantation. Now, a new debate is opened: should technical capabilities be extended to apply intentioned PGD in order to overcome rare but life threatening medical conditions such as non-heritable malignancies and the need for tissue or organ transplantation in the future?
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Intentioned PGD – for whose benefit? Intentioned PGD refers to the use of the procedure in order to achieve a pregnancy of a HLA-matched newborn that might potentially serve as a tissue donor for their sibling when needed. One of the main moral arguments against the use of PGD for HLA-matched embryos in order to treat a sibling who is affected by a disease was that it is an act of designing a baby to serve as a tissue donor. In that case, the chosen embryos were primarily produced to serve someone else’s benefit. This argument is less convincing when intentioned PGD is discussed. With intentioned PGD, as argued by Johnson’s couple, both individuals will benefit from the outcome of the procedure. Cord blood from the ‘designed’ and matched newborn can be frozen and used as needed either for the child or for their siblings. Moreover, if other tissue transplantation is needed, than each one of the siblings can serve as a donor for the benefit of the other. Thus, the act of intentioned PGD becomes a kind of mutual insurance certificate. Thus, as argued by Johnson, if all seem to benefit from intentioned PGD, is it really unacceptable to apply it, or are there other ignored issues that yet have to be considered? Does the risk of developing a disease that might call for tissue transplantation justify the use of intentioned PGD? To answer this question accurately, one needs to estimate the chance that a healthy individual without a family history or risk factors will need tissue transplantation such as bone marrow, liver, kidney, lung or skin. According to the national registry in Israel, the prevalence of leukaemias, Hodgkin’s and nonHodgkin’s lymphomas, and soft tissue malignancies is 2, 4, 7 and 0.5 cases per 1000 population respectively (Israel Ministry of Health, 2001). Using the registry data of the United Network for Organ Sharing (UNOS) in the USA (UNOS, 2004), much lower rates were obtained for renal, liver and lung transplants. The data were extrapolated to show that the need for renal transplant is 0.2 per 1000 habitants, and for liver and lung transplants 0.06 and 0.013 per 1000 habitants respectively. These relatively low risk rates should be weighed against other arguments, including human and embryos’ rights, cost-effectiveness, and the inherent risks of IVF and PGD procedures.
IVF and PGD risk Assuming intentioned PGD is acceptable, it should be stressed that IVF treatment per se is not totally free of medical complications. The couple discussed by Johnson were informed that the risks involved with the treatment were minor, especially when compared with the risk of pregnancy. It is doubtful whether such an estimation should be presented to the couple. Although rare, IVF is associated with increased risk of ovarian hyperstimulation syndrome (OHSS), intraabdominal haemorrhage and infection (Schenker and Ezra, 1994). These conditions sometimes, necessitate hospitalization and seldom call for surgical intervention. Thus, one should raise the question of risk benefit of the procedure, particularly when the immediate benefit is nil.
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Any medical treatment should be assessed by its final outcome and profit while the old statement of ‘primum non nocere’
should lead us along the way. Intentioned PGD treatment can be examined under such conditions. It might offer a medical solution for two individuals considering rarely occurring conditions in the future. On the other hand, the patient is placed at risk for a non-medical reason, it wastes money and medical resources, violates the principle of social equality, and might not be totally free of risk to the selected newborn. In a given family, the probability of finding a child who is HLA matched and suitable for tissue transplantation to his sibling is 25%. Therefore, from the statistical point of view, a family with four children might fulfil the criterion and find a suitable candidate for tissue transplantation when needed. However, PGD treatment might be more applicable for this goal. In that case, the risks and efficacy of IVF–PGD treatment should be considered. The pregnancy rate for PGD treatment is somewhat lower than that for conventional IVF treatment and is about 25–30% (ESHRE PGD Consortium, 2002; Kuliev and Verlinsky, 2004). Assuming that only 25% of the generated embryos will be suitable for transfer, it seems that patients would be subjected to repetitive attempts to achieve the goal. Repetitive treatments are associated with increased medical risk and additional consumption of money and medical resources. In addition, when applying polymerase chain reaction diagnostic tools and for accuracy purposes, all PGD cycles for the selection of HLA-matched embryos must use intracytoplasmic sperm injection (ICSI). ICSI was reported to be associated with a slight increase in de-novo chromosomal abnormalities (especially of the sex chromosomes) (Devroey and Van Steirteghem, 2004; Jozwiak et al., 2004). While some reports find no difference in the rate of major congenital malformations between children conceived following IVF or ICSI (Devroey and Van Steirteghem, 2004), others found that children who are born after ICSI have an increased risk of major congenital malformations than those born after spontaneous conception (Katalinic et al., 2004). Although this later finding most probably results from paternal or maternal risk factors that were more prevalent in couples who used ICSI, a technique related risk could not be ruled out (Katalinic et al., 2004). Moreover, recent publications mentioned an association between the ICSI procedure and the birth of a small number of children affected with diseases resulting from imprinting disorders (Devroey and Van Steirteghem, 2004). Thus, although ICSI has been used for 12 years now, there are still questions about its safety and future outcome. Similarly, although recent reports are encouraging and claim that the PGD procedure in humans is safe, it should be stated that this report is based on data gained from approximately 1000 newborns worldwide (Verlinsky et al., 2004a). Thus, currently, the risks acquired by PGD in humans are not completely known, and the safety of the procedure should be estimated cautiously. Moreover, the use of IVF for intentioned PGD might raise legal problems in some countries depending on laws and regulations. At the beginning, IVF was introduced to alleviate a fertility problem. The Israeli regulation for IVF, for example, stated that: ‘Retrieving an oocyte from a woman’s body should be performed only in women who undergo treatment for an infertility problem or if the physician in charge thinks that such an act assists in progressing her treatment’. In such a case, PGD treatment to prevent the delivery of an affected child with
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a hereditary condition might be considered legal. Although raised ethical issues that extensively discussed (Pennings et al., 2002; Edwards, 2004), selecting an HLA-matched embryo to treat a sick sibling might still be considered legal as long as PGD is primarily applied to conceive a healthy non-affected fetus. On the other hand, contradicting such regulations and performing PGD for HLA-matched embryos solely to treat a sick sibling involves both moral and illegal issues until such regulations are updated according to current medical progress. In fact, from the same argument, HFEA allowed PGD treatment using HLA-matched embryos for thalassaemia (Dyer, 2002), but declined such treatment for a sibling with non-hereditary Diamond–Blackfan anaemia (Dobson, 2003). Others, however, consider this treatment legally and ethically acceptable to treat a sick sibling who needs bone marrow stem cells transplantation, or even for other cancer conditions (Verlinsky et al., 2004b,c). Intentioned PGD, however, should be considered illegal, as it does not alleviate a fertility problem, nor can it be be considered as contributing to the patient’s or a sibling’s medical condition. Intentioned PGD aims to suggest a solution to a rarely occurring condition in the future that does not justify the risk or the cost of the treatment. One might argue that it is the patient’s right and autonomy to choose the risk of treatment and that as long as she pays for the treatment it should be allowed. Those who support this treatment will claim that as with other acts in the modern world, it is the right of a person to buy medical insurance for his offspring and pay for it, both in monetary and in health risk terms. The question is, should society agree and accept such a claim, or should it put boundaries to human rights and autonomy? Moreover, if such boundaries are not applied, the principle of equality in medical services is ignored. Patients who can afford the cost might benefit, while other will not be able to acquire such a privilege.
Moral status of the embryos As previously discussed, the efficacy of PGD to obtain an HLA-matched embryo for a sibling is 25%. Moreover, because the efficacy of IVF–embryo transfer in a PGD programme is about 25–30%, it should be taken into account that repetitive attempts will be performed until pregnancy is achieved. Thus, many surplus, healthy embryos would not be used and most probably would be discarded. Does one have the right to create healthy embryos just to discard them later on? What are the legal and moral rights of such embryos? There are three options with which to consider the moral status of a human embryo: 1. The embryo has no moral status. It is merely a collection of undifferentiated cells lacking individuality. Its status is not different from that of any other human tissue or cluster of cells. In that case, as medical professionals, there is no obligation to consider the embryo as having any rights. Furthermore, because the couple possess the embryo, they have the full right to discard it, donate it or subject it for research if they wish to do so. 2. The embryo has the full status of a human being. A new genotype is established during fertilization and some of the embryos have the potential to become full term fetuses, children, and adults. The embryo has its own rights, and the
gamete donors are only its guardians. The interests of the mother are irrelevant to the future of the embryo. Society is obligated to apply therapeutic measures to the embryo as an individual patient. In that case, the embryo has the rights of a human being, and from the beginning it should not be created if there is an intention first to discriminate against it and then discard it. 3. The embryo is a potential human being. This definition is a relatively new philosophical entity, representing a compromise between the above two approaches. It is this opinion that is currently generally accepted by most scientists, physicians, and ethicists. Inasmuch as the embryo is a potential human being, it should be handled with dignity and its rights should be respected as long as they do not conflict with major social, maternal, or other ethical interests. Yet, it should not be treated as a person, because it has not yet developed the features of personhood, is not yet established as developmentally individual, and may never realize its biological potential. Holding this concept will raise no objection to the principle of PGD as a procedure, but previously mentioned drawbacks that exist in intentioned PGD might raise a debate as to whether the creation of such embryos is justifiable.
Slippery slope argument The slippery slope argument claims that if a given act is allowed, it may end with unacceptable results. PGD was initially developed in order to prevent the birth of an affected child. One cannot, however, ignore the fact that once the technique is available and genetic traits of personality characteristics are established, couples might seek PGD for non-medical indications. These may include intentioned PGD, eye and hair colour, intelligence, height, beauty, sexual orientation and other desired phenotypes. In such a scenario, physicians will be facing the ethical problem of producing a designed baby that would match the couple’s wish. Currently, the discussion on whether to permit PGD for such indications seems to be redundant because the genetic traits of these characteristics are as yet unknown, and unlike Mendelian traits, are most probably determined by multiple unidentified genes. Nevertheless, ethical discussions on this issue should be encouraged. If such embryo’s selection would be permitted, it harbours the risk of interfering with nature by producing ‘designed’ children. Preferring a specific phenotype and creating it raises problems such as intensifying discrimination between subjects, unrealistic expectations of parents from such a child, and the psychosocial effects on the designed child. While most of the non-medical uses of PGD are currently irrelevant, witnessing the rapid developments in the field of genetics and molecular biology should provoke debate. Such debate will help to define the public stance on these issues and assist in crystallizing guidelines for these potential interventions of the future. Unfortunately, it seems that we are already on the curve of the ‘slippery slope’. While PGD was primarily used to conceive a healthy child, the indications were extended to late onset genetic diseases, and then to prevent potentially late onset diseases. In some countries social sexing is acceptable, while in others it is declined. Although debatable at the beginning, HLA typing to cure an
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affected sibling was found to be reasonable, some centres finding it justifiable to apply HLA typing for non-genetic traits in order to cure a sick sibling. Now, Johnson’s article calls upon further extending the indication and it seems that sooner or later someone might find arguments to support its application. What about other non-medical conditions? One can argue positively for the application of PGD for those cases, and subsequently someone else may justify it and perform it. When is enough enough? In summary, if one has to grant the couple presented by Johnson their request, they should be told that although it seems that all siblings might benefit from the procedure, while weighing the risks and benefits and the ethical issues included in their request, it seems that the procedure harbours risks and ethical issues that outweigh the benefit it offers. Sometimes society should apply boundaries and overrule the principle of human rights and freedom to choose. It is time to constrain the slippery slope that was previously described, and decline intentioned PGD. For the sanity and integrity of a normative society, the couple may be advised that their request is unacceptable.
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Received 15 November 2004; refereed 30 November 2004; accepted 10 December 2004.
