British Andrology Society British Fertility Society Society for the Study of Fertility Fertility 2000 Edinburgh 31 July–2 August 2000

Contemporary scientific and clinical knowledges and practices continue to make available new forms of genetic information, and to create new forms of reproductive choice. For example, couples at high risk of passing on a serious genetic condition to their offspring in Britain today have the opportunity to use Preimplantation Genetic Diagnosis (PGD) to select embryos that are unaffected by serious genetic disease. This information assists these couples in making reproductive choices. This article presents an analysis of patients' experiences of making the decision to undertake PGD treatment and of making reproductive choices based on genetic information. We present qualitative interview data from an ethnographic study of PGD based in two British clinics which indicate how these new forms of genetic choice are experienced by patients. Our data suggest that PGD patients make decisions about treatment in a complex way, taking multiple variables into account, and maintaining ongoing assessments of the multiple costs of engaging with PGD. Patients are aware of broader implications of their decisions, at personal, familial, and societal levels, as well as clinical ones. Based on these findings we argue that the ethical and social aspects of PGD are often as innovative as the scientific and medical aspects of this technique, and that in this sense, science cannot be described as "racing ahead" of society.     

Preimplantation genetic diagnosis: State of the art

Preimplantation genetic diagnosis (PGD) is used to analyze embryos genetically before their transfer into the uterus. It was developed first in England in 1990, as part of progress in reproductive medicine, genetic and molecular biology. PGD offers couples at risk the chance to have an unaffected child, without facing termination of pregnancy. Embryos are obtained by in vitro fertilization with intracytoplasmic sperm injection (ICSI), and are biopsied mostly on day 3; blastocyst biopsy is mentioned as a possible alternative. The genetic analysis is performed on one or two blastomeres, by fluorescent in situ hybridization (FISH) for cytogenetic diagnosis, or polymerase chain reaction (PCR) for molecular diagnosis. Genetic analysis of the first or second polar body can be used to study maternal genetic contribution. Only unaffected embryos are transferred into the uterus. To improve the accuracy of the diagnosis, new technologies are emerging, with comparative genomic hybridization (CGH) and microarrays.     

Pre-Implantation Genetic Diagnosis: A Model of Progress and Concern

Pre-implantation genetic diagnosis (PGD) consists of in vitro fertilization (IVF) and embryo biopsy to remove one or two blastomeres, typically from an eight-cell embryo, followed by single cell diagnosis by deoxyribonucleic acid (DNA) amplification or fluorescent in situ hybridization (FISH). The first pregnancies following testing for X-linked recessive diseases were reported in 1990 from the Hammersmith Hospital, London, U.K. In the past four years, capabilities have greatly expanded to include disease-specific and chromosomal methods. At least eight clinical programmes worldwide are now underway, with a recent (June 1994) global estimate of 149 PGD treatment cycles completed and 29 children born. Although PGD may be a welcome alternative to the currently employed methods of prenatal diagnosis, especially for women who are already undergoing IVF, or for whom therapeutic abortion is morally unacceptable, discussion of the ethical and societal issues must not fall behind the rapidly advancing genetic technologies. We must appreciate that these new technologies will inevitably bring greater pressures to bear on the beneficiaries, the practitioners, and society. We must heed the warnings of societal advocates reinforcing the unforeseen dangers when science moves more rapidly than society can comprehend. We must always remember to consider ‬Just because we can, should we?” and determine in a research setting “For what?” and “For whom?” this technology is appropriate and, “What benefits?” and “What harm?” exist, before any new technology becomes part of our clinical armamentarium.     

Analysis of sex chromosomes in preimplantation genetic diagnosis for X-chromosome-linked disorders

Preimplantation genetic diagnosis (PGD) is diagnostic tool to avoid inheritance of genetic disease by transferring unaffected embryos. Recently, PCR and FISH have been mainly applied to the diagnosis of single gene disorders and chromosomal abnormalities, respectively. Since with PGD, only a few cells are available for genetic tests, both gene and chromosomes analysis have to be obtained from the same, limited material. Cell recycling makes it possible to obtain the information on genes as well as chromosomes from the same cells. Therefore cell recycling is an acceptable strategy where in PGD targets large proportions of embryos severe chromosomal abnormalities. The responsible genes of the X-linked disorder and numerical abnormalities of sex chromosomes should be analyzed simultaneously. Gender information is definitely useful because only male affected embryos should be avoided for transfer.     

An overview of the current and emerging platforms for preimplantation genetic testing for aneuploidies (PGT-A) in in vitro fertilization programs

Preimplantation genetic testing for aneuploidies (PGT-A) and PGT for monogenic disorders (PGT-M) have currently been used widely, aiming to improve IVF outcomes. Although with many years of unsatisfactory results, PGT-A has been revived because new technologies have been adopted, such as platforms to examine all 24 types of chromosomes in blastocysts. This report compiles current knowledge regarding the available PGT platforms, including quantitative PCR, array CGH, and next-generation sequencing. The diagnostic capabilities of are compared and respective advantages/disadvantages outlined. We also address the limitations of current technologies, such as assignment of embryos with balanced translocation. We also discuss the emerging novel PGT technologies that likely will change our future practice, such as non-invasive PGT examining spent culture medium. Current literature suggest that most platforms can effectively reach concordant results regarding whole-chromosome ploidy status of all 24 types of chromosomes. However, different platforms have different resolutions and experimental complexities; leading to different turnaround time, throughput and differential capabilities of detecting mosaicism, segmental mutations, unbalanced translocations, concurrent PGT-A and PGT-M etc. Based on these information, IVF staff can more appropriately interpret PGT data and counsel patients, and select suitable platforms to meet personalized needs. The present report also concisely discusses some crucial clinical outcomes by PGT, which can clarify the role of applying PGT in daily IVF programs. Finally the up-to-date information about the novel use of current technologies and the newly emerging technologies will also help identify the focus areas for the design of new platforms for PGT in the future.     

植入前遗传学诊断/筛查技术指征进展

植入前遗传学诊断/筛查(PGD/PGS)技术发展多年,其指征始终存在争议。PGD指征较为明确,单基因遗传病、染色体异常人群、人类白细胞抗原(HLA)配型为其适用人群。PGS的指征争议较多,主要面向反复流产、反复植入失败、高龄人群,目的是提高妊娠率及活产率。然而第一代PGS技术[PGS#1,卵裂球活检及荧光原位杂交(FISH)-PGS]技术未显示明显效果,甚至降低了妊娠率及活产率。第二代PGS技术(PGS2.0)增加了严重男性因素不育为指征,其核心为囊胚活检及全染色体筛查(CCS),对上述人群的临床效果较为明显,降低了流产风险并提高了成功率及活产率。PGS2.0已极大地改变了辅助生殖技术(ART)面貌,可能成为未来生殖中心对所有患者的一个常规项目。目前仍然需要多中心前瞻性随机病例对照研究重新评估PGS。     

Reproductive options for individuals at risk for transmission of a genetic disorder

The basis of human growth and development has long been considered to be one of the great mysteries of science and mankind. The portal to understanding this mystery was achieved by the Human Genome Project and Celera Genomics in 2001, with their joint announcement of the sequencing of 99% of the human genome map. Current reproductive options, however, remain restricted to the prevention of transmitting an at-risk gene or genes, but do not include treatment or cure. It is anticipated that this state of "halfway technology" will continue for years to come. As such, the scientific and ethical issues associated with each of these reproductive options will continue to affect the decision making of at-risk individuals. As the omnipresent health care provider, nurses have a duty to know and disseminate accurate and current information about reproductive options for individuals at risk for transmission of a genetic disorder. Nurses also have a duty to advocate for and ensure the privacy and confidentiality of genetic information.     

Ambivalent attitudes towards pre-implantation genetic diagnosis in Germany

BACKGROUND: Pre-implantation genetic diagnosis (PGD) is a modern technique in reproductive medicine which can be used to diagnose genetic disorders of an embryo. PGD is currently not legal in Germany, still there are debates being held regarding the issue of legalization. Both the internationally "accepted" indications and new or alternative approaches can lead to complex ethical dilemmas. The attitudes towards PGD have rarely been assessed in the general population. METHODS: In our study, 2110 persons aged 18-50 years were interviewed about their attitudes towards PGD and related topics. We assumed that religion, world views and the evaluation of PGD would influence the attitude a person has towards this procedure. RESULTS AND CONCLUSIONS: In our survey, the majority of respondents would agree to a restricted legalization of PGD in Germany. Our results also confirmed some of our assumptions but religion did not have the expected influence. The evaluation of costs and benefits of PGD and the feelings associated with this technique explained more of the final attitude whether PGD should remain prohibited in Germany or not. The agreement to a restricted legalization may be connected to an overall rejection of prohibitions made by the state concerning the individual reproductive autonomy.     

Comparative perspectives: regulating preimplantation genetic diagnosis in Canada and the United Kingdom

Preimplantation genetic diagnosis (PGD) in the United Kingdom is governed by a centralized regulatory agency, while Canada's current approach to regulating PGD is neither integrated nor comprehensive. Though concerns have been raised about state regulation of assisted reproductive technologies (ARTs), Canada's move toward centralized oversight of these technologies will lead to improvements in uniformity and transparency of regulation, and will provide a central forum for policy debate and discussion.     

Preimplantation genetic diagnosis/screening by comprehensive molecular testing

Although embryo screening by preimplantation genetic diagnosis (PGD) has become the standard technique for the treatment of recurrent pregnancy loss in couples with a balanced gross chromosomal rearrangement, the implantation and pregnancy rates of PGD using conventional fluorescence in situ hybridization (FISH) remain suboptimal. Comprehensive molecular testing, such as array comparative genomic hybridization and next‐generation sequencing, can improve these rates, but amplification bias in the whole genome amplification method remains an obstacle to accurate diagnosis. Recent advances in amplification procedures combined with improvements in the microarray platform and analytical method have overcome the amplification bias, and the data accuracy of the comprehensive PGD method has reached the level of clinical laboratory testing. Currently, comprehensive PGD is also applied to recurrent pregnancy loss due to recurrent fetal aneuploidy or infertility with recurrent implantation failure, known as preimplantation genetic screening. However, there are still numerous problems to be solved, including misdiagnosis due to somatic mosaicism, cell cycle‐related background noise, and difficulty in diagnosis of polyploidy. The technology for comprehensive PGD also requires further improvement.     

Preimplantation genetic diagnosis of alpha-thalassemia-SEA using novel multiplex fluorescent PCR

Purpose  

Preimplantation genetic diagnosis (PGD) is an alternative to prenatal diagnosis (PND) giving couples at risk a chance to start a pregnancy with a disease-free baby. This study aimed to develop a new PGD protocol for alpha-thalassemia^-SEA mutation, the commonest Mendelian disorder.     

Preimplantation genetic diagnosis as medical innovation: reflections from The President's Council on Bioethics

In its 2004 report, "Reproduction and Responsibility: The Regulation of New Biotechnologies", The President's Council on Bioethics analyzed ethical issues raised by preimplantation genetic diagnosis (PGD) and made recommendations for improvements.     

Preimplantation genetic diagnosis.

Preimplantation genetic diagnosis (PGD) is an exciting new approach for the prevention of transmission of genetic disorders between generations. The use of genetically screened, healthy embryos to establish a pregnancy avoids the need for termination of an affected pregnancy, a procedure which can be traumatic physically and emotionally for potential patients, and is sometimes not available when needed. PGD usually follows the processes of ovarian hyperstimulation and in vitro fertilization (IVF). After carrying out appropriate genetic tests, only normal embryos are transferred to the patient's uterus to achieve an unaffected pregnancy and the birth of a healthy infant.     

Public, expert and patients' opinions on preimplantation genetic diagnosis (PGD) in Germany

The regulation of reproductive medicine technologies differs significantly among Western industrialized countries. In Germany, preimplantation genetic diagnosis (PGD) is prohibited due to the Embryo Protection Act, which came into force in 1991. In the last 5 years, this prohibition has been vigorously debated. In the present studies, which are part of the German research programme on ethical implications of the Human Genome Project, representative surveys were undertaken to assess the attitudes on PGD in the general population (n = 1017), five relevant expert groups (n = 879), high genetic risk couples (n = 324) and couples undergoing IVF (n = 108). All groups surveyed clearly favoured allowing PGD in Germany. Compared with the results of recently conducted population surveys in the UK and the USA, where PGD is already carried out, public approval of PGD does not differ significantly. The influence of restrictive biopolitics on the apparently liberal public opinion towards new reproductive technology seems to be marginal according to the present data, which should carefully be considered in the ongoing legislation process on human reproduction.     

Experiencing new forms of genetic choice: findings from an ethnographic study of preimplantation genetic diagnosis

Contemporary scientific and clinical knowledges and practices continue to make available new forms of genetic information, and to create new forms of reproductive choice. For example, couples at high risk of passing on a serious genetic condition to their offspring in Britain today have the opportunity to use Preimplantation Genetic Diagnosis (PGD) to select embryos that are unaffected by serious genetic disease. This information assists these couples in making reproductive choices. This article presents an analysis of patients' experiences of making the decision to undertake PGD treatment and of making reproductive choices based on genetic information. We present qualitative interview data from an ethnographic study of PGD based in two British clinics which indicate how these new forms of genetic choice are experienced by patients. Our data suggest that PGD patients make decisions about treatment in a complex way, taking multiple variables into account, and maintaining ongoing assessments of the multiple costs of engaging with PGD. Patients are aware of broader implications of their decisions, at personal, familial, and societal levels, as well as clinical ones. Based on these findings we argue that the ethical and social aspects of PGD are often as innovative as the scientific and medical aspects of this technique, and that in this sense, science cannot be described as "racing ahead" of society.     

Whole genome amplification from single cells in preimplantation genetic diagnosis and prenatal diagnosis

The literature on whole genome amplification (WGA) techniques and their application to preimplantation genetic diagnosis (PGD) and prenatal diagnosis is reviewed. General polymerase chain reaction (PCR) fails to provide adequate information from limited cells in PGD and non-invasive prenatal diagnosis. Therefore several WGA techniques, such as primer extension preamplification (PEP) and degenerate oligonucleotide primed PCR (DOP-PCR), have been developed and successfully applied to clinical work during the past decade, especially in PGD and prenatal diagnosis. These techniques can provide ample amplification of genetic sequences from single cells for a series of subsequent PCR analyses such as restriction fragment length polymorphisms (RFLP) and comparative genomic hybridization (CGH), thus opening up a new area for prenatal diagnosis. However, several problems have been reported in the application of these techniques. The ideal WGA technique should have high yield, faithful representation of the original template, complete coverage of the genome, and simply performed procedure. In order to make good use of these techniques in future research and clinical work, it is undoubtedly necessary for an extensive understanding of the merits and pitfalls of these recently developed techniques.     

Preimplantation genetic diagnosis: public policy and public attitudes

This paper summarizes the regulatory framework surrounding preimplantation genetic diagnosis (PGD) in the United States. In addition, the author reports results of surveys that reveal conflicting popular opinions about the moral acceptability of manipulating embryos during PGD. For example, some people who feel that an embryo has as much moral status as a born baby nonetheless feel that using PGD to screen embryos for certain diseases is morally acceptable. The national debate about technologies like PGD is stunted because it is currently cast in the same terms as the debate over abortion rights. If national leaders begin discussions about regulation of PGD and similar technologies, it could help depolarize the debate to more accurately consider the nuanced views of the public.     

Preimplantation genetic diagnosis and 'savior siblings'.

From its emergence, preimplantation genetic diagnosis (PGD) has been opposed by religious, feminist, and disability-rights advocates. PGD has developed, however, to extend beyond genetic diagnosis of embryos to diagnose chromosomal abnormalities. Evidence shows that PGD is safe, children born after in vitro fertilization (IVF) and PGD having no higher rate of birth defects than children of normal pregnancies. Laws may accommodate PGD directly or indirectly, but some prohibit PGD totally or except to identify sex-linked genetic disorders. When children suffer severe genetic disorders and require stem-cell transplantation, compatible donors may be unavailable. Then, IVF and PGD of resulting embryos may identify some whose gestation and birth would produce unaffected newborns, and placental and cord blood from which stem-cells compatible for implantation in sick siblings can be derived. Ethical issues concern conscientious objection to direct participation, discarding of healthy but unsuitable embryos, and valuing savior siblings in themselves, not just as means to others' ends.     

Preimplantation genetic diagnosis for couples with a Robertsonian translocation: practical information for genetic counseling

Purpose  

To evaluate the proportions of abnormal and normal embryos detected by preimplantation genetic diagnosis (PGD) of infertile couples of whom one was a Robertsonian translocation (RT) carrier, and to provide practical information, including details of reproductive outcomes, to aid in genetic counseling of such couples.     

Preimplantation genetic diagnosis and the welfare of the child

Preimplantation genetic diagnosis is a form of very early prenatal diagnosis. The technique combines assisted reproductive technology with molecular genetics and cytogenetics to allow the identification of abnormalities in embryos prior to implantation. Since its introduction in 1990 this approach has been applied to an increasing number of single gene disorders, chromosomal rearrangements, and more recent indications such as aneuploidy screening and HLA matching. Since its inception the technology has attracted much attention: geneticists have expressed concerns about the robustness and validity of diagnosis based on single cell analysis, perinatologists were anxious about the effect of embryo biopsy on normal fetal development; and philosophers and ethicists have argued the cases for and against embryo selection. This article attempts to highlight the difficult choices and ethical challenges confronting patients and clinicians in an effort to balance the recognition of parental autonomy with the obligation of clinics to consider the welfare of any child born as a result of this treatment.