The Ethics of Stem Cell-Based Embryo-Like Structures : A Focus Group Study on the Perspectives of Dutch Professionals and Lay Citizens.

In order to study early human development while avoiding the burdens associated with human embryo research, scientists are redirecting their efforts towards so-called human embryo-like structures (hELS). hELS are created from clusters of human pluripotent stem cells and seem capable of mimicking early human development with increasing accuracy. Notwithstanding, hELS research finds itself at the intersection of historically controversial fields, and the expectation that it might be received as similarly sensitive is prompting proactive law reform in many jurisdictions, including the Netherlands. However, studies on the public perception of hELS research remain scarce. To help guide policymakers and fill this gap in the literature, we conducted an explorative qualitative study aimed at mapping the range of perspectives in the Netherlands on the creation and research use of hELS. This article reports on a subset of our findings, namely those pertaining to (the degrees of and requirements for) confidence in research with hELS and its regulation. Despite commonly found disparities in confidence on emerging biotechnologies, we also found wide consensus regarding the requirements for having (more) confidence in hELS research. We conclude by reflecting on how these findings could be relevant to researchers and (Dutch) policymakers when interpreted within the context of their limitations.

[Maternal-fetal therapy: from saving the fetus towards a better life for the future child]. / Ontwikkelingen in maternale-foetale therapie.

Maternal-fetal therapy (MFT) is special because treatment of the fetus is exclusively possible through the body of another person, the pregnant woman. MFT is a broad specialty with diverse interventions. In this manuscript several examples of innovations in MFT are discussed to illustrate the shift of lifesaving interventions to interventions aiming to improve morbidity of the future child. The broadening of the scope and shift towards prenatal treatments improving morbidity result in new ethical challenges. Particularly attention is needed for counseling and (the risk of) therapeutic misconception.

'We Should View Him as an Individual': The Role of the Child's Future Autonomy in Shared Decision-Making About Unsolicited Findings in Pediatric Exome Sequencing.

In debates about genetic testing of children, as well as about disclosing unsolicited findings (UFs) of pediatric exome sequencing, respect for future autonomy should be regarded as a prima facie consideration for not taking steps that would entail denying the future adult the opportunity to decide for herself about what to know about her own genome. While the argument can be overridden when other, morally more weighty considerations are at stake, whether this is the case can only be determined in concrete cases. Importantly, when children grow into adolescents, respect for future autonomy will have to give way to respecting their emerging autonomy. When pediatric exome sequencing is done for complex conditions not involving developmental delay, respect for the child's future or emerging autonomy should be a primary consideration for those charged with deciding on behalf of the child. Building on what Emanuel and Emanuel have termed the 'deliberative model' of shared decision making, we argue that if parents fail to give these considerations their due, professionals should actively invite them to do so. Taking a directive stance may be needed in order to make sure that the future or emerging autonomy of the child are duly considered in the decision-making process, but also to help the parents and themselves to shape their respective roles as responsible care-givers.

Preimplantation genetic testing for more than one genetic condition: clinical and ethical considerations and dilemmas.

STUDY QUESTION: Which clinical and ethical aspects of preimplantation genetic testing for monogenic disorders or structural rearrangements (PGT-M, PGT-SR) should be considered when accepting requests and counselling couples for PGT when applied for more than one condition (combination-PGT; cPGT-M/SR)? SUMMARY ANSWER: cPGT is a feasible extension of the practice of PGT-M/SR that may require adapting the criteria many countries have in place with regard to indications-setting for PGT-M/SR, while leading to complex choices that require timely counselling and information. WHAT IS KNOWN ALREADY: Although PGT-M/SR is usually performed to prevent transmission of one disorder, requests for PGT-M/SR for more than one condition (cPGT-M/SR) are becoming less exceptional. However, knowledge about implications for a responsible application of such treatments is lacking. STUDY DESIGN, SIZE, DURATION: Retrospective review of all (40) PGT-M/SR applications concerning more than one genetic condition over the period 1995-2018 in the files of the Dutch national PGT centre. This comprises all relevant national data since the start of PGT in the Netherlands. PARTICIPANTS/MATERIALS, SETTING AND METHODS: Data regarding cPGT-M/SR cases were collected by means of reviewing medical files of couples applying for cPGT-M/SR. Ethical challenges arising with cPGT-M/SR were explored against the background of PGT-M/SR regulations in several European countries, as well as of relevant ESHRE-guidance regarding both indications-setting and transfer-decisions. MAIN RESULTS AND THE ROLE OF CHANCE: We report 40 couples applying for cPGT-M/SR of which 16 couples started their IVF treatment. Together they underwent 39 IVF cycles leading to the birth of five healthy children. Of the couples applying for cPGT, 45% differentiated between a primary and secondary condition in terms of perceived severity. In the light of an altered balance of benefits and drawbacks, we argue the 'high risk of a serious condition' standard that many countries uphold as governing indications-setting, should be lowered for secondary conditions in couples who already have an indication for PGT-M/SR. As a consequence of cPGT, professionals will more often be confronted with requests for transferring embryos known to be affected with a condition that they were tested for. In line with ESHRE guidance, such transfers may well be acceptable, on the condition of avoiding a high risk of a child with a seriously diminished quality of life. LIMITATIONS, REASONS FOR CAUTION: We are the first to give an overview of cPGT-M/SR treatments. Retrospective analysis was performed using national data, possibly not reflecting current trends worldwide. WIDER IMPLICATIONS OF THE FINDINGS: Our observations have led to recommendations for cPGT-M/SR that may add to centre policy making and to the formulation of professional guidelines. Given that the introduction of generic methods for genomic analysis in PGT will regularly yield incidental findings leading to transfer requests with these same challenges, the importance of our discussion exceeds the present discussion of cPGT. STUDY FUNDING/COMPETING INTEREST(S): The research for this publication was funded by the Dutch Organization for Health Research and Development (ZonMw), project number: 141111002 (Long term safety, quality and ethics of Preimplantation Genetic Diagnosis). None of the authors has any competing interests to declare.

Ethical issues surrounding the transplantation of organs from animals into humans.

In this paper, the authors provide an analysis of the ethical issues surrounding the transplantation of organs from animals into humans. The main objections to xenotransplantation relate to safety concerns for the recipient; public health concerns about new viruses spreading from animals to humans; the possibility of animals developing human features; concerns about human dignity; and the fact that animals must be sacrificed so humans can benefit from their organs. Despite these objections, the urgency of the organ shortage situation is such that xenotransplantation may be justified, if further advances make it a realistic possibility.

Les auteurs analysent les questions éthiques suscitées par la transplantation chez l'homme d'organes provenant d'animaux. Les principales objections contre la xénotransplantation se réfèrent aux risques pour la santé du receveur, aux problèmes de santé publique liés à une éventuelle propagation chez l'homme de virus émergents d'origine animale, au risque que des animaux acquièrent des caractéristiques humaines, au respect de la dignité humaine et à la nécessité de sacrifier des animaux pour que des êtres humains puissent bénéficier de leurs organes. Malgré ces objections, le déficit d'organes est tel que la xénotransplantation pourrait se justifier à condition que les avancées scientifiques en garantissent la faisabilité à l'avenir.

Los autores proponen un análisis de las cuestiones éticas que rodean el trasplante de órganos animales al ser humano. Las principales objeciones que suscita el xenotrasplante tienen que ver con: la preocupación por la seguridad del receptor; la problemática de salud pública ligada a la eventual propagación de nuevos virus que pasen de los animales al ser humano; la posibilidad de que los animales adquieran atributos humanos; consideraciones vinculadas a la dignidad humana; y el hecho de que haya que sacrificar a animales para que los humanos se beneficien de sus órganos. Pese a todas estas objeciones, la urgencia de la situación de penuria de órganos es de tal magnitud que los xenotrasplantes podrían estar justificados si se sigue progresando lo bastante como para hacer de ellos una perspectiva realista.

Recent developments in genetics and medically assisted reproduction: from research to clinical applications.

Two leading European professional societies, the European Society of Human Genetics and the European Society for Human Reproduction and Embryology, have worked together since 2004 to evaluate the impact of fast research advances at the interface of assisted reproduction and genetics, including their application into clinical practice. In September 2016, the expert panel met for the third time. The topics discussed highlighted important issues covering the impacts of expanded carrier screening, direct-to-consumer genetic testing, voiding of the presumed anonymity of gamete donors by advanced genetic testing, advances in the research of genetic causes underlying male and female infertility, utilisation of massively parallel sequencing in preimplantation genetic testing and non-invasive prenatal screening, mitochondrial replacement in human oocytes, and additionally, issues related to cross-generational epigenetic inheritance following IVF and germline genome editing. The resulting paper represents a consensus of both professional societies involved.

[Single embryo implantation per IVF cycle: the answer to every request for assisted reproduction?] / Plaatsing van een enkel embryo per ivf: antwoord op elke hulpvraag?

The Dutch eSET-policy is justifiable in case a healthy singleton is the main goal. However, patients who want to create a family of more children may for that reason welcome twins.

Recent developments in genetics and medically-assisted reproduction: from research to clinical applications†‡.

Two leading European professional societies, the European Society of Human Genetics and the European Society for Human Reproduction and Embryology, have worked together since 2004 to evaluate the impact of fast research advances at the interface of assisted reproduction and genetics, including their application into clinical practice. In September 2016, the expert panel met for the third time. The topics discussed highlighted important issues covering the impacts of expanded carrier screening, direct-to-consumer genetic testing, voiding of the presumed anonymity of gamete donors by advanced genetic testing, advances in the research of genetic causes underlying male and female infertility, utilisation of massively-parallel sequencing in preimplantation genetic testing and non-invasive prenatal screening, mitochondrial replacement in human oocytes, and additionally, issues related to cross-generational epigenetic inheritance following IVF and germline genome editing. The resulting paper represents a consensus of both professional societies involved.

A mother's gift of life: exploring the concerns and ethical aspects of fertility preservation for mother-to-daughter oocyte donation.

With the introduction of oocyte vitrification, a special form of intergenerational intrafamilial medically assisted reproduction (IMAR) has now become feasible: fertility preservation for mother-to-daughter oocyte donation (FPMDD). For girls diagnosed with premature ovarian insufficiency (POI), banking of their mothers' oocytes can preserve the option of having genetically related offspring. Since policy documents on IMAR do not discuss specific concerns raised by FPMDD, clinicians can feel at a loss for guidance with regard to handling these requests. Through a comparison of FPMDD with reproductive practices in which similar concerns were raised, proportionality of cryopreservation for self-use and pressure to use the oocytes in fertility preservation in minors, we argue that FPMDD can be acceptable under conditions. The paper ends with recommendations for handling FPMDD-requests, including different options for the legal construction of this form of oocyte donation.

[Making embryos for research: first prohibited, now allowed?] / Embryo's maken voor onderzoek: eerst niet, nu wel?

The Dutch Embryos Act (2000) contains a temporary ban on the creation of embryos for research, meaning that, at present, only research using "spare" IVF embryos is allowed. Recently, the government has announced a plan to lift this ban. This is in line with the original intention of the Act, which already contains conditions for research with specially created embryos that will come into force after the lifting of the ban, including the restriction that the research must be expected to yield new insights in the domains of infertility, assisted reproduction, hereditary or congenital disorders, or transplantation medicine. The government plans announced allow research only in the first three of these domains, adding the further criterion that the research must be 'directly relevant for clinical application'. According to the government, the reason for these additional restrictions was the need to protect 'human dignity'. The authors of this paper are not convinced.

[Foetal therapy for Down syndrome: a pro-active ethical reflection]. / Foetale therapie voor het Down-syndroom.

Prenatal screening for Down syndrome has to date focused on facilitating the informed choice to continue or not with a pregnancy. The non-invasive prenatal test (NIPT) for Down syndrome does potentially offer the option to apply foetal neurocognitive therapy for Down syndrome (FTDS). Current research in animal models looks promising and therefore a proactive ethical reflection in relation to clinical trials is urgently needed. This discussion includes an exploration of the ethical aspects of FTDS. There seem to be no convincing a priori objections on the basis of the social model of disability. Arguments in terms of (respect for) autonomy, wellbeing and justice seem to in principle support such therapy. Still, both the conditions for sound clinical trials and the implications of possible effective therapy for current prenatal screening need further scrutiny.

Genomic futures of prenatal screening: ethical reflection.

The practice of prenatal screening is undergoing important changes as a result of the introduction of genomic testing technologies at different stages of the screening trajectory. It is expected that eventually it will become possible to routinely obtain a comprehensive 'genome scan' of all fetuses. Although this will still take several years, there are clear continuities between present developments and this future scenario. As this review shows, behind the still limited scope of screening for common aneuploidies, a rapid widening of the range of conditions tested for is already taking shape at the invasive testing stage. But the continuities are not just technical; they are also ethical. If screening for Down's syndrome is a matter of providing autonomous reproductive choice, then why would providing the choice to have a full fetal genome scan be something entirely different? There is a clear need for a sustainable normative framework that will have to answer three challenges: the indeterminateness of the autonomy paradigm, the need to acknowledge the future child as an interested stakeholder, and the prospect of broad-scope genomic prenatal screening with a double purpose: autonomy and prevention.

ESHRE Task Force on Ethics and Law 23: medically assisted reproduction in singles, lesbian and gay couples, and transsexual people†.

This Task Force document discusses ethical issues arising with requests for medically assisted reproduction from people in what may be called 'non-standard' situations and relationships. The document stresses that categorically denying access to any of these groups cannot be reconciled with a human rights perspective. If there are concerns about the implications of assisted reproduction on the wellbeing of any of the persons involved, including the future child, a surrogate mother or the applicants themselves, these concerns have to be considered in the light of the available scientific evidence. When doing so it is important to avoid the use of double standards. More research is needed into the psychosocial implications of raising children in non-standard situations, especially with regard to single women, male homosexual couples and transsexual people.

ESHRE task force on ethics and Law22: preimplantation genetic diagnosis.

This Task Force document discusses some relatively unexplored ethical issues involved in preimplantation genetic diagnosis (PGD). The document starts from the wide consensus that PGD is ethically acceptable if aimed at helping at-risk couples to avoid having a child with a serious disorder. However, if understood as a limit to acceptable indications for PGD, this 'medical model' may turn out too restrictive. The document discusses a range of possible requests for PGD that for different reasons fall outwith the accepted model and argues that instead of rejecting those requests out of hand, they need to be independently assessed in the light of ethical criteria. Whereas, for instance, there is no good reason for rejecting PGD in order to avoid health problems in a third generation (where the second generation would be healthy but faced with burdensome reproductive choices if wanting to have children), using PGD to make sure that one's child will have the same disorder or handicap as its parents, is ethically unacceptable.

ESHRE Task Force on Ethics and Law 21: genetic screening of gamete donors: ethical issues.

This Task Force document explores the ethical issues involved in the debate about the scope of genetic screening of gamete donors. Calls for expanded donor screening arise against the background of both occasional findings of serious but rare genetic conditions in donors or donor offspring that were not detected through present screening procedures and the advent of new genomic technologies promising affordable testing of donors for a wide range of conditions. Ethical principles require that all stakeholders' interests are taken into account, including those of candidate donors. The message of the profession should be that avoiding all risks is impossible and that testing should remain proportional.

ESHRE Task Force on ethics and Law 20: sex selection for non-medical reasons.

This Task Force document revisits the debate about the ethics of sex selection for non-medical reasons in the light of relevant new technological developments. First, as a result of improvement of the Microsort® flow cytometry method, there is now a proven technique for preconception sex selection that can be combined both with IVF and IUI. Secondly, the scenario where new approaches that are currently being developed for preimplantation genetic screening (PGS) may lead to such screening becoming a routine part of all IVF treatment. In that scenario professionals will more often be confronted with parental requests for transfer of an embryo of a specific sex. Thirdly, the recent development of non-invasive prenatal testing based on cell-free fetal DNA in maternal plasma allows for easy and safe sex determination in the early stages of pregnancy. While stressing the new urgency that these developments give to the debate, the Task Force did not come to a unanimous position with regard to the acceptability of sex selection for non-medical reasons in the context of assisted reproduction. Whereas some think maintaining the current ban is the best approach, others are in favour of allowing sex selection for non-medical reasons under conditions that take account of societal concerns about the possible impact of the practice. By presenting these positions, the document reflects the different views about this issue that also exist in the field. Specific recommendations include the need for a wider delineation of accepted 'medical reasons' than in terms of avoiding a serious sex-linked disorder, and for a clarification of the legal position with regard to answering parental requests for 'additional sex selection' in the context of medically indicated preimplantation genetic diagnosis, or routine PGS.