Romanian Journal of Bioethics, Vol. 7, No. 2, April – June 2009

PREIMPLANTATION GENETIC DIAGNOSIS. LEGAL, ETHICAL AND MEDICAL IMPLICATIONS IN ROMANIA Emil Anton *, Bogdan Doroftei **, Ivona Anghelache Lupaşcu ***, Demetra Socolov ****, Nicolae Ioanid ***** Abstract Ever since the early 1990s, preimplantation genetic diagnosis (PGD) has been expanding its application area. PGD is used to select genetic normal embryos and replace the embryos with chromosome abnormalities in order to increase pregnancy rates in groups of women with poor IVF success rates. More recent application of PGD to areas such as HLA typing and social sex selection have led to public controversy and concern as far as ethics is concerned, meanwhile keeping PGD firmly among the public opinion. We will describe the predominant lines of argumentation in this debate and the legal and ethical implications of this issue in Romania. Key words: preimplantation genetic diagnosis, sex social selection.

clinics. Information dissemination is mainly carried out through the home pages of these clinics. The infertile couples addressing to these centers are made up of persons with a high level of education, generally 32 year old who, either had postponed the child conception either have exhausted all the

Introduction The emergence and increased addressability of human assisted reproduction techniques is a fact of the reproductive medicine in Romania. In order to have a child, increasingly numerous infertile couples resort to health services provided by specialized *

Lecturer, UMF ”Gr.T. Popa”, Iaşi, Romania Clinical Instructor, UMF ”Gr.T. Popa”, Iaşi, Romania, e-mail: [email protected] *** Prof., UMF ”Gr.T. Popa”, Iaşi, Romania **** Assist. Prof., UMF ”Gr.T. Popa”, Iaşi, Romania ***** MD, “Cuza Vodă” Hospital, Iaşi, Romania **

113

responsible for shortening of life expectancy of patient (Robertson, 2003). The genetic medicine’s developments aim at to help the couples to fulfill their procreative role, in default of accepting the inevitable, genetically speaking. The unanimously accepted identification methods used at the moment for the human genetic diseases include chronic vili biopsy or amniocentesis. When using these methods, an eventual pathological result is offered to the couples after 12 weeks of gestation. If the conception product is carrying a disease with a reserved prognosis after birth, the doctor, with the approval of a medical ethic commission can decide the abortion. Is not the interruption of pregnancy after 12 weeks a trauma for the couple? PGD implies the analysis of a blastomer obtained from an embryo that is its cariotype in order to detect the various mutations of a gene and chromosome abnormalities (Pickering, 2003). During the last years PGD applicability area comprises not only medical implications, but also nonmedical indications. Some of the human assisted reproduction centers diversified the medical offer, including also the possibility of choosing the child's sex by means of preimplantantion genetic diagnosis. Though, given the absence of a European regulatory framework, some of the countries are more permissive and others more restrictive in this respect. Another direction which has been and continues to be a subject of remain a debate within the medical community from an ethical point of view is the identification possibility of the p53, BRCA1, BRCA2 chromosome bearer embryos. Thus, the birth of a child with an increased risk of developing during his lifetime a neoplasic disease is prevented, disease that would imply a

“conventional” methods of infertility treatment. Sex selection of the embryos was a futuristic concept until a few years ago. Nowadays, it has become a fact. In order to prevent a misunderstanding of this concept, some explanations on medical directions admitted by the specialists in the field are necessary. This survey is an attempt to raise awareness of specialists in medical ethics, lawyers, and patients and not last, the medical specialized community on the ethical implications of PGD taking into account the spreading of the assisted human reproduction techniques in Romania and given the lack of a legal frame. 1. Applicability of the Pre-implant Genetic Diagnosis The Preimplantation Genetic Diagnosis (PGD) offers alternatives to a couple affected by genetic diseases in order to have a disease-free child. The genetic diagnosis has been used for the first time in 1990, in order to test aneuploidies in case of couples with lower prognosis for FIV. Later, the method has been also applied to couples with increased transmission risk of xlinked genetic diseases (hemophilia, Duchene muscular dystrophy). The PGD technique is the method by which the chromosomes of a 3 day-old embryo resulting from assisted human reproduction techniques are checked in order to detect severe genetic diseases, incompatible with life or with further lethal potential. One or two cells are extracted out of the embryo and are studied in order to detect chromosome abnormalities. (HFEA 2005) PGD use was also extended to neurological diseases with late outbreak (Alzheimer disease or Huntington disease),

114

HLA type embryo matching an individual can be extremely rare and the medical goal in these cases must be well grounded. The premises of accepting the solution of a PGD used in order to obtain a donor rely on these grounds. Any argument can disappear when speaking about the right to life with the risk of diminishing the inheritance of an incurable disease. In our opinion, the medical services must be accessible to any individual. The concept of “social sexing”, that is the possibility offered to the couple to select the sex of the future child is, ethically speaking, even a more sensitive issue. It is unanimously accepted as a non-medical direction. Sex choice has been practiced out of various reasons and in various means since the earliest times (Vicol, 2007). The new sex choice technologies limited the abortion practice and the selective abandon, but did not limit the loss of potential lives. The resulting ethical conflicts regarding the right to life versus self-determination, tradition versus morality, good versus less good must be carefully observed, in order to prevent the sliding trend to life technologizing from the very conception moment and in order to promote the “perfect child”, according to the parents' inconsistent and selfish preferences (Vicol, 2007). The Ethical Board of American Society for Reproduction Medicine (ASRM) has faced these problems in a series of recent approvals. Initially, they did not approve the sex selection in general, without a medical purpose and discouraged the couples resorting to these medical maneuvers. Later, they mentioned that the preconceived idea of selecting the embryo sex can be acceptable in order to diversify the children sex, but not in the case of the first child (ASRM, 2001).

careful screening of the individual's health during his entire lifetime or invasive and mutilating prophylactic surgery. Maybe the most important application of the method which will surely have supporters is connected to the unique possibility to offer curative treatment, proved in case of auto-immune or malignant diseases originated in hematopoetic cells. At present, placental blood is sampled in order to select multipotent cells in hematopoetic line, which could be later used even by the donor. What are the possibilities for a child developing a hematological disorder in which the only accepted medical solution is the multi-potent hematopoetic cell transplant, but in the moment of its birth, there is no option to sample and to stock the own cells or the possibility was denied by the parents? One of the solutions making possible the identification of the stem cells 100% compatible to those needed by the ill child should be to give birth to another child to generate them and from which to sample HLA hematopoetic stem cells from the umbilical cord on delivery, (Human Leukocyte Antigen), compatible to those needed by the ill child. By applying PGD technique on embryos obtained by FIV, a genetic identical HLA embryo that may be hematopoetic stem cells donor can be selected (Reichenbach, 2008). The ethical considerations could become a medical and bioethical controversy subject matter, as far as the applicability of this method is concerned Could such a solution be accepted in a well grounded case or it will be considered that the way to the baby design concept is free? Will the medical interest prevail over the conservationism, morality and public disapproval? Due to the fact that the necessity of obtaining a 115

some debates between lawyers and practitioners specialized in reproductive medicine. In Romania, at this moment, there is no group of legal norms clearly regulating the status of reproductive medicine, although the number of specialized clinics is increasing. The preimplantation genetic diagnosis is not widely spread in Romania. Who can decide when the PGD is recommended and under which conditions? The European member states have various regulations for this matter. Some states totally forbid these procedures, other states partially agree on observing medical directions, and some states are more permissive (Soini, 2007). The most permissive legislations are to be found in the United Kingdom, Sweden, Denmark, France and Norway. The more restrictive states are those with a Catholic majority, such as Austria, Germany and Switzerland, where a PGD for nonmedical purposes is sanctioned by the Criminal Code. In Germany, since early 1990 there is a normative act, “Embryo Protection Act” regulating the genetic diagnosis. Countries in which the PGD is not regulated and it is permitted are: Belgium, Cyprus, Finland, Greece, Netherlands, and Portugal, Spain (The Genetics and Public Policy Center, German National Ethics Council, 2003). However, there is certainly an increasing demand for such kind of medical services. The solution adopted by couples is that of carrying out the PGD procedures in countries where the legislation allows it. Thus, “medical tourism” emerges, a concept applied also in other medical branches. That is the reason for which it is absolutely necessary that in Romania the legislator should present the legal framework under which these medical procedures can be carried out. An act of health reproduction allowing preimplantational genetic

Which could be the position accepted by the Romanian medical community from the point of view of the medical act ethics related to this problem? How could this possibility be justified or it will be denied? As soon as the gene responsible for a certain cognitive particularity was identified, it is possible to make the embryo screening for the allele’s pair transmitting these characteristics. Prevalence of these genes is low, amounting approximately 3% in general population, but it can be higher in certain families of musicians, for example. These couples would like to transmit their skills to their descendants (Robertson, 2003, Blakeslee, 1990. The identification of genes responsible for a certain hair color, eye color, height and intelligence of a certain individual represent non-medical directions of the preimplantation genetic diagnosis (Devolder, 2005, Robertson, 2003). However, PGD can offer therapeutic alternatives in many cases with no treatment possibility available up to some years ago. Recent figures, referring to 39 centers that published results regarding the number of oocytes sampled between January 2005 - October 2006, show that 845 pregnancies have been obtained from 3488 oocytes out of which only 670 were births. Out of the total number of obtained embryos, PGD was carried out on 85 embryos only to select the embryo’s sex. For 108 embryos, PGD was applied for x-linked diseases. On over 2000 obtained embryos, a PGD screening was carried out (Goossens, 2008). 2. Legal, medical and ethical implications of PGD The legal implications of these methods can be the subject matter of 116

“baby design”, but can somebody decide the destiny of a child affected by one of the following disorders: Fanconi anemia, thalassemia, Wiscott-Aldrich syndrome, leukemia, Diamond-Blackfan aplastic anemia, where it was demonstrated that the hematopoetic stem cells transplant with identical HLA compatibility is the only treatment method available? (Steffann, 2005). Unfortunately, in Romania, there is a lack of legislation on this matter. The current Romanian judicial norms refer only to the authorization process of some medical units providing medical services of assisted human reproduction. The sex selection of the first child “social sex selection” has not yet appealed to many couples in Romania. A questionnaire carried out on a lot of young students in Medicine in the final year of study showed that the idea of selecting the sex of the future child was accepted by less than 10% of them.

diagnosis can prevent a wider liberty of the applicability of this medical practice. The medical directions in cases of xlinked genetic diseases are unanimously accepted. The medical ethics of the subject tackled in this article implies several points of view. Is the selection of embryo sex acceptable in the case of xlinked transmissible genetic diseases? Starting from the premise that the medicine and the medical progress are in the benefit of the individual and of the society he belongs to, the selection of a female embryo that certainly should not be affected by Duchenne muscular dystrophy can be accepted. The extension of these directions to the aneuploids’ screening can also be accepted. Embryo screening for mutations on p53 or BRCA1 and BRCA2 genes should be encouraged, due to the fact that, in this way, the emergence of a neoplasic process with unknown outbreak, later affecting the individual health state, would be prevented. In 2001, Verlinsky reported the first PGD combined with HLA patterns in order to obtain a healthy child and an identical HLA with the sister affected by Fanconi anemia. The “baby design” concept has thus been created. The French law that permitted the PGD under the condition of genetic affectation of a parent extends through Law 2131-41/August 2004 Act, the applicability area of the method and to obtain an embryo that later, at birth, will be a donor for hematopoetic stem cells (Kuliev, 2005). The restrictive terms of a judicial norm can largely limit the development and the applicability area of the method. The development of this method is going to be carried out mainly in countries with permissive legislation. Legislation will thus play a key role in developing and improving the human life. The medical act ethics will certainly reject the idea of

3. Conclusions The preimplantational genetic diagnosis is safe and of high accuracy (Vandervors, 2000). But ethical, legal and medical implications are still debatable. The arguments in favor of developing this diagnosis method in Romania have a medical, social-human character and can be accepted by the medical community. It is worth mentioning also the fact that while the regulations in the United States refer to whether financing or not out of the federal budget, the so-called non-ethical research, on an European level the interest is focused on the subject of permitting or not such research, either from public or private founds (Vicoleanu, 2007). The legal implications are extended on more plans that focus on the need of an updated legislation, covering the 117

directions of the PGD, in order to prevent some x-linked genetic disorders. The ethics of the medical act referring to the “HLA matching” concept is under debate and will generate ardent debates between specialists involved in the field and medical community. However, as the only option in treating some genetic disorders, the arguments brought against it should be extremely consistent. For how long and under what terms should the idea of creating a new child in order to save another child in need be accepted? The argument of getting a “savior brother” through medical assisted reproduction methods would be invoked, but could it be accepted by medical ethics, too? The answer could be the beginning of regulating the use of PGD in Romania.

necessary regulations for developing the PGD. Maybe the most important role should be played by the physicians specialized in assisted reproduction medicine, besides the geneticists, community representatives, lawyers, ethicists, theologians, philosophers. At the moment, it is prematurely to initiate legislation on this subject because the PGD is in an early stage in Romania. Given the fact that Romania is an European member state, where the reproductive medicine “benefits” from an increased attention on behalf of the authorities in the field, the need will become more obvious in a couple of years The ethical implications of the PGD are among the most complex. The medical ethics can favor the medical

Bibliography [1]. American Society of Reproductive Medicine, Ethics Committee, Preconception sex selection for nonmedical reasons, Fertility Steriityl, 75:861-4, 2001 [2]. Blakeslee S., Perfect pitch: the key may lie in the genes, The New York Times, Nov. 30:1. 1990 [3]. Devolder K., Preimplantation HLA typing, Having children to save our loved ones. Journal Medical Ethics, October 1, 31(10): 582 - 586. 2005 [4]. Donoso P., Staessen C., Fauser BC., Devroey P., Current value of preimplantation genetic aneuploidy screening in IVF, Human Reproduction Update, Jan-Feb, 13(1):1525, 2007 [5]. German National Ethics Council (Nationaler Ethikrat), Genetic Diagnosis Before and During Pregnancy, 2003 [6]. Goossens V., Harton G., Moutou C., ESHRE PGD Consortium data collection VIII: cycles from January to December 2005 with pregnancy follow-up to October 2006, Human Reproduction, Dec, 23(12):2629-45, 2008 [7]. Human Fertilisation Embryology Authority, Guide to Infertility and Directory of Clinics 2005/06, London, HFEA/Dr Foster, 2005 [8]. Kuliev A., Rechitsky S., Tur-Kaspa I., Verlinsky Y., Preimplantation genetics: Improving access to stem cell therapy, Annals of the New York Academy of Sciences, 1054:223-7, 2005 [9]. Munne S., Magli C., Bahce M. şi colab., Preimplantation diagnosis of the aneuploidies most commonly found in spontaneous abortions and live births: XY, 13, 14, 15, 16, 18, 21, 22, Prenatal Diagnosis, 18:1459–1466, 1998 [10]. Pickering S., Polidoropoulos N., Caller J. şi colab., Strategies and outcomes of the first 100 cycles of preimplantation genetic diagnosis at the Guy's and St. Thomas' Center, Fertility Sterility, 79:81–90, 2003 [11]. Reichenbach J., Van de Velde H., De Rycke M., First successful bone marrow transplantation for X-linked chronic granulomatous disease by using preimplantation

118

female sex typing and HLA matching, Pediatrics, Sep, 122(3):e778-82, 2008 [12]. Robertson J.A., Extending preimplantation genetic diagnosis: medical and non-medical uses, Journal Medical Ethics, 29:213-216, 2003 [13]. Robertson J.A., Extending preimplantation genetic diagnosis: the ethical debate. Ethical issues in new uses of preimplantation genetic diagnosis, Human Reproduction, 18:465–471, 2003 [14]. Soini S., Preimplantation genetic diagnosis (PGD) in Europe: diversity of legislation a challenge to the community and its citizens, Med Law., Jun., 26(2):309-23, 2007 [15]. Steffann J., Frydman N., Burlet P. şi colab., Extending preimplantation genetic diagnosis to HLA typing: the Paris experience, Gynecology Obstetrics Fertility, Oct., 33(10):824-7, 2005 [16]. The Genetics and Public Policy Center - Johns Hopkins University, INTERNATIONAL LAW SEARCH, http://www.dnapolicy.org/policy.international.php?action=detail&laws_ id=52 [17]. Vandervors M., Staessen C., Sermon K. şi colab., The Brussels' experience of more than 5 years of clinical preimplantation genetic diagnosis, Human Reproduction Update, JulAug., 6(4):364-73, 2000 [18]. Verlinsky Y., Rechitsky Svetlana, Schoolcraft W. şi colab.,  Preimplantation Diagnosis for Fanconi Anemia Combined With HLA Matching, JAMA., 285:3130-3133, 2001 [19]. Vicol M.C., Stînga O.C., Selecţia sexului între motivaţie şi etică, Revista Română de Bioetică, Vol. 5, nr. 1, 2007 [20]. Vicoleanu S. A., Carasevici B., Aspecte etice ale cercetării pe embrioni umani, Revista Română de Bioetică., Vol. 5, nr. 2, 2007 [21]. Voullaire L., Wilton L., Slater H. şi colab., Detection of aneuploidy in single cells using comparative genomic hybridization, Prenatal Diagnosis, 19:846–851, 1999 [22]. Wells D., Delhanty J.D., Comprehensive chromosomal analysis of human preimplantation embryos using whole genome amplification and single cell comparative genomic hybridization, Molecular Human Reproduction, 6:1055–1062, 2000.

119