Genetic Disorders and the Fetus. Группа авторов
with the development of the technique and its implementation into clinical practice. In other countries, such as the Netherlands, PGT is governed by the law on medical experiments, which contains a section on embryo research. It prohibits “cloning,” but probably will not ban PGT research because it provides an alternative to prenatal diagnosis and abortion of genetically affected fetuses. In the United Kingdom, PGT, as well as the practice of IVF and research involving human embryos, is regulated through a statutory body, the Human Fertilisation and Embryology Authority, and the Fertilisation and Embryology Act (1990), allowing research on human embryos up to 14 days of development under an appropriate license. In Spain, although a 1988 law regulating human embryo research forbade the fertilization of human oocytes for any purpose other than human procreation, it permitted research on embryos within 14 days of preimplantation development under the supervision of the national health and scientific authorities.179 Therefore, this law did not conflict with the development of research in preimplantation genetics and its application to assisted reproduction practices. In fact, according to a survey on PGT availability in Europe, the number of PGT centers presently available in the country is more than in most of the other European countries.
In the United States and Australia, the legal status of PGT and community attitudes differ in different states. For example, in the six states of Australia, only three have laws governing IVF and embryo research. In Victoria, embryo research is prohibited, except for approved experiments, although this law does not actually affect PGT because IVF is allowed for infertile couples, and PGT also can be justified as the procedure for avoiding the risk of transmitting genetic disease to affected children. In Western Australia, PGT cannot be done because of the Experimentation Law, whereas in South Australia it is possible unless destructive to an implantable human embryo.
In the United States, the issue of embryo research is closely associated with the debates on abortion and cloning, and there has been no government system for regulating reproductive research projects. Because there is no ethical advisory board (EAB) that is legally given responsibility for reviewing such research proposals, federal funding for human embryo research has not been available. In addition, a wide variation of policy positions exists among different states, mainly being compromised over consideration of the question of when human life begins. However, despite existing differences in current legal restrictions in this field, selection of pre‐embryos on genetic grounds may be ethically acceptable based on the premise that the goal of avoiding the birth of offspring with severe genetic handicaps is part of the constitutional rights of procreative liberty.180, 181 Although the National Institutes of Health Revitalization Act of 1993 lifted the requirement (45 CFR 46.204.d) for a federal‐level EAB review for IVF research, leaving consideration for clinical research relating to IVF to individual institutional review boards, none of the federal funds may be used for research in which a human embryo or embryos are destroyed, discarded, or knowingly subjected to risk of injury or death greater than allowed for research on fetuses in utero.
In Canada, recent legislation to regulate assisted human reproduction technologies has been introduced, entitled an “Act Respecting Assisted Human Reproduction,” which allows PGT for medical reasons but excludes identifying the sex of an embryo for social purposes.182, 183 The Society of Obstetricians and Gynaecologists of Canada have provided valuable guidelines that optimize obstetrical management and counseling for prospective parents undergoing IVF, integral to PGT. Emphasis is given to the increasing evidence that both infertility and subfertility remain as independent risk factors for subsequent complications and adverse perinatal outcomes, even without IVF. Their report also draws attention to the very low but actual risk of imprinting disorders, such as Beckwith–Wiedemann syndrome or Angelman syndrome, estimated to occur in fewer than one in 5,000 patients.
Important ethical issues have recently been raised with increasing use of PGT for gender determination for social reasons,184, 185 late‐onset disorders with genetic predisposition,6, 7, 186, 187 and PGT‐HLA to produce an HLA‐compatible donor to treat a family member with fatal bone marrow disease or cancer requiring a stem cell transplantation.5, 188, 189 Although there is no actual difference in the application of PGT for the latter conditions, the controversy can be explained by the fact that in traditional prenatal diagnosis, if the fetus was found to carry the gene predisposing to a late‐onset disorder or to be HLA unmatched, a couple would have to make an extremely difficult decision about pregnancy termination, which could hardly be justified by such a finding. Alternatively, PGT technology allows genetic testing of human eggs and embryos before pregnancy is established, making it totally realistic to establish only HLA‐matched or potentially normal pregnancies without genetic predisposition to late‐onset disorders.
Notwithstanding the foregoing considerations, PGT has become an established clinical option in reproductive medicine and is applied using separate consent forms and research protocols approved by institutional ethics committees. Despite recent controversy regarding the quantitation of the impact of PGT‐A on clinical outcome, thousands of cases have been performed, resulting in the birth of thousands of healthy children born after PGT‐A. However, these protocols still require confirmatory CVS or amniocentesis and follow‐up monitoring of their safety and accuracy. Although PGT will help solve some of the longstanding ethical problems, such as the abortion issue (which could largely be avoided as a result of this approach), other issues could become a serious obstacle, particularly those related to “designer babies.” These considerations are highly relevant to the subject of PGT, as well as to any other new methods as we proceed with further development of appropriate technology for avoiding genetic disability.
Conclusion
Although the introduction of first‐trimester prenatal diagnosis by CVS has considerably improved the possibility of avoiding genetic diseases, selective abortion is an issue in the case of an affected fetus. PGT has been initiated to provide the option of avoiding the birth of an affected child without the need for abortion as an obligatory component in the prevention program. This chapter describes these important developments with the emphasis on addressing the problems of implementation of PGT into clinical practice.
Currently, PGT has been applied clinically for up to 600 different conditions, with thousands of unaffected children born after PGT performed for single‐gene and chromosomal disorders. Among the approaches to PGT introduced, blastocyst biopsy is now a standard. This became possible due to the progress in micromanipulation and biopsy and genetic analysis of single cells or small number of cells by PCR and currently by next‐generation technologies. The available experience has already demonstrated the practical utility of PGT, and the reliability and safety of this relatively new technology in assisted reproduction. The indications for PGT have been expanded beyond those used in prenatal diagnosis to include couples at high risk of having a child with a genetic disorder (in the face of antipathy toward elective abortion), poor‐prognosis IVF patients, couples at risk for producing offspring with late‐onset genetic disorders, and preimplantation HLA matching. Because of the high prevalence of chromosomal abnormalities in early pregnancy, the introduction of PGT‐A will not only make it possible to avoid the risk of age‐related aneuploidies, but will also considerably improve the embryo recovery and pregnancy outcome following PGT and should improve the effectiveness of IVF programs in general. Introduction of NGS‐based PGT‐A, which uses WGA as the first step of the technique, also makes it possible to perform PGT‐M with or without PGT‐HLA in the same biopsy material. Concomitant PGT‐A with PGT‐M, PGT‐SR, and PGT‐HLA are thus becoming standard procedures toward comprehensive PGT for genetic and chromosomal disorders.
References
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