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As the normative objections to (human) germline genome editing cannot convincingly justify a categorical prohibition of such editing, its present prohibition should be replaced by a strict regulation, i.e. a conditional allowance. If safe and effective, germline genome editing may become a useful reproductive option.

In a research setting (TRIDENT-2), Dutch pregnant women undergoing prenatal screening for trisomies 21, 18 and 13 with the Non-Invasive Prenatal Test (NIPT), are offered the choice to also receive information about incidental findings. In a recent report, the Health Council of the Netherlands has recommended to retain this option, but to only report those incidental findings that very probably will lead to serious health outcomes for the child. A working group has been appointed to draw up a guideline for this. In this article we argue that actively searching for desired 'incidental findings' in fact amounts to broadening the scope of the screening and that a justification of this choice is still lacking. A core issue is whether the benefits of such broader screening outweigh the drawback of inevitably also generating findings that do not fit in with the aim of the screening: providing meaningful reproductive choices.

BACKGROUND: Studying the human peri-implantation period remains hindered by the limited accessibility of the in vivo environment and scarcity of research material. As such, continuing efforts have been directed towards developing embryo-like structures (ELS) from pluripotent stem cells (PSCs) that recapitulate aspects of embryogenesis in vitro. While the creation of such models offers immense potential for studying fundamental processes in both pre- and early post-implantation development, it also proves ethically contentious due to wide-ranging views on the moral and legal reverence due to human embryos. Lack of clarity on how to qualify and regulate research with ELS thus presents a challenge in that it may either limit this new field of research without valid grounds or allow it to develop without policies that reflect justified ethical concerns.OBJECTIVE AND RATIONALE: The aim of this article is to provide a comprehensive overview of the existing scientific approaches to generate ELS from mouse and human PSCs, as well as discuss future strategies towards innovation in the context of human development. Concurrently, we aim to set the agenda for the ethical and policy issues surrounding research on human ELS.SEARCH METHODS: The PubMed database was used to search peer-reviewed articles and reviews using the following terms: 'stem cells', 'pluripotency', 'implantation', 'preimplantation', 'post-implantation', 'blastocyst, 'embryoid bodies', 'synthetic embryos', 'embryo models', 'self-assembly', 'human embryo-like structures', 'artificial embryos' in combination with other keywords related to the subject area. The PubMed and Web of Science databases were also used to systematically search publications on the ethics of ELS and human embryo research by using the aforementioned keywords in combination with 'ethics', 'law', 'regulation' and equivalent terms. All relevant publications until December 2019 were critically evaluated and discussed.OUTC

BACKGROUND: Studying the human peri-implantation period remains hindered by the limited accessibility of the in vivo environment and scarcity of research material. As such, continuing efforts have been directed towards developing embryo-like structures (ELS) from pluripotent stem cells (PSCs) that recapitulate aspects of embryogenesis in vitro. While the creation of such models offers immense potential for studying fundamental processes in both pre- and early post-implantation development, it also proves ethically contentious due to wide-ranging views on the moral and legal reverence due to human embryos. Lack of clarity on how to qualify and regulate research with ELS thus presents a challenge in that it may either limit this new field of research without valid grounds or allow it to develop without policies that reflect justified ethical concerns.OBJECTIVE AND RATIONALE: The aim of this article is to provide a comprehensive overview of the existing scientific approaches to generate ELS from mouse and human PSCs, as well as discuss future strategies towards innovation in the context of human development. Concurrently, we aim to set the agenda for the ethical and policy issues surrounding research on human ELS.SEARCH METHODS: The PubMed database was used to search peer-reviewed articles and reviews using the following terms: 'stem cells', 'pluripotency', 'implantation', 'preimplantation', 'post-implantation', 'blastocyst, 'embryoid bodies', 'synthetic embryos', 'embryo models', 'self-assembly', 'human embryo-like structures', 'artificial embryos' in combination with other keywords related to the subject area. The PubMed and Web of Science databases were also used to systematically search publications on the ethics of ELS and human embryo research by using the aforementioned keywords in combination with 'ethics', 'law', 'regulation' and equivalent terms. All relevant publications until December 2019 were critically evaluated and discussed.OUTC

Amongst the main reasons people at risk for Huntington's disease (HD) have for undergoing predictive genetic testing are planning a family and prevention of passing on an expanded CAG-repeat to future offspring. After having received an unfavourable test result, a couple may consider prenatal testing in the foetus or preimplantation genetic diagnostic testing (PGD) in embryos. Testing of the foetus or embryos is possible by means of direct testing of the expanded repeat. Optimal reliability in testing the foetus or embryos requires the establishment of the origin of the repeats of both parents in the foetus. For PGD the analysis is combined with or sometimes solely based on identification of the at-risk haplotype in the embryo. This policy implies that in the context of direct testing, the healthy partner's CAG repeat lengths in the HD gene are also tested, but with the expectation that the repeat lengths of the partner are within the normal range, with the proviso that the partner's pedigree is free of clinically confirmed HD. However, recent studies have shown that the expanded repeat has been observed more often in the general population than previously estimated. Moreover, we have unexpectedly observed an expanded repeat in the non-HD partner in four cases which had far-reaching consequences. Hence, we propose that in the context of reproductive genetic counselling, prior to a planned pregnancy, and irrespective of the outcome of the predictive test in the HD-partner, the non-HD partner should also be given the option of being tested on the expanded allele. International recommendations for predictive testing for HD should be adjusted.

Amongst the main reasons people at risk for Huntington's disease (HD) have for undergoing predictive genetic testing are planning a family and prevention of passing on an expanded CAG-repeat to future offspring. After having received an unfavourable test result, a couple may consider prenatal testing in the foetus or preimplantation genetic diagnostic testing (PGD) in embryos. Testing of the foetus or embryos is possible by means of direct testing of the expanded repeat. Optimal reliability in testing the foetus or embryos requires the establishment of the origin of the repeats of both parents in the foetus. For PGD the analysis is combined with or sometimes solely based on identification of the at-risk haplotype in the embryo. This policy implies that in the context of direct testing, the healthy partner's CAG repeat lengths in the HD gene are also tested, but with the expectation that the repeat lengths of the partner are within the normal range, with the proviso that the partner's pedigree is free of clinically confirmed HD. However, recent studies have shown that the expanded repeat has been observed more often in the general population than previously estimated. Moreover, we have unexpectedly observed an expanded repeat in the non-HD partner in four cases which had far-reaching consequences. Hence, we propose that in the context of reproductive genetic counselling, prior to a planned pregnancy, and irrespective of the outcome of the predictive test in the HD-partner, the non-HD partner should also be given the option of being tested on the expanded allele. International recommendations for predictive testing for HD should be adjusted.

What do scientists in the field of preimplantation genetic diagnosis (PGD) and preimplantation genetic screening (PGS) consider to be the future direction of comprehensive embryo testing? Although there are many biological and technical limitations, as well as uncertainties regarding the meaning of genetic variation, comprehensive embryo testing will impact the IVF/PGD practice and a timely ethical reflection is needed. Comprehensive testing using microarrays is currently being introduced in the context of PGD and PGS, and it is to be expected that whole-genome sequencing will also follow. Current ethical and empirical sociological research on embryo testing focuses on PGD as it is practiced now. However, empirical research and systematic reflection regarding the impact of comprehensive techniques for embryo testing is missing. In order to understand the potential of this technology and to be able to adequately foresee its implications, we held an expert panel with seven pioneers in PGD. We conducted an expert panel in October 2011 with seven PGD pioneers from Belgium, The Netherlands, Germany and the UK. Participants expected the use of comprehensive techniques in the context of PGD. However, the introduction of these techniques in embryo testing requires timely ethical reflection as it involves a shift from choosing an embryo without a particular genetic disease (i.e. PGD) or most likely to result in a successful pregnancy (i.e. PGS) to choosing the best embryo based on a much wider set of criteria. Such ethical reflection should take account of current technical and biological limitations and also of current uncertainties with regard to the meaning of genetic variance. However, ethicists should also not be afraid to look into the future. There was a general agreement that embryo testing will be increasingly preceded by comprehensive preconception screening, thus enabling smart combinations of genetic testing. The group was composed of seven participants from four

Sequencing an individual's complete genome is expected to be possible for a relatively low sum 'one thousand dollars' within a few years. Sequencing refers to determining the order of base pairs that make up the genome. The result is a library of three billion letter combinations. Cheap whole-genome sequencing is of greatest importance to medical scientific research. Comparing individual complete genomes will lead to a better understanding of the contribution genetic variation makes to health and disease. As knowledge increases, the 'thousand-dollar genome' will also become increasingly important to healthcare. The applications that come within reach raise a number of ethical questions. This monitoring report addresses the issue.

What do scientists in the field of preimplantation genetic diagnosis (PGD) and preimplantation genetic screening (PGS) consider to be the future direction of comprehensive embryo testing? Although there are many biological and technical limitations, as well as uncertainties regarding the meaning of genetic variation, comprehensive embryo testing will impact the IVF/PGD practice and a timely ethical reflection is needed. Comprehensive testing using microarrays is currently being introduced in the context of PGD and PGS, and it is to be expected that whole-genome sequencing will also follow. Current ethical and empirical sociological research on embryo testing focuses on PGD as it is practiced now. However, empirical research and systematic reflection regarding the impact of comprehensive techniques for embryo testing is missing. In order to understand the potential of this technology and to be able to adequately foresee its implications, we held an expert panel with seven pioneers in PGD. We conducted an expert panel in October 2011 with seven PGD pioneers from Belgium, The Netherlands, Germany and the UK. Participants expected the use of comprehensive techniques in the context of PGD. However, the introduction of these techniques in embryo testing requires timely ethical reflection as it involves a shift from choosing an embryo without a particular genetic disease (i.e. PGD) or most likely to result in a successful pregnancy (i.e. PGS) to choosing the best embryo based on a much wider set of criteria. Such ethical reflection should take account of current technical and biological limitations and also of current uncertainties with regard to the meaning of genetic variance. However, ethicists should also not be afraid to look into the future. There was a general agreement that embryo testing will be increasingly preceded by comprehensive preconception screening, thus enabling smart combinations of genetic testing. The group was composed of seven participants from four

Sequencing an individual's complete genome is expected to be possible for a relatively low sum 'one thousand dollars' within a few years. Sequencing refers to determining the order of base pairs that make up the genome. The result is a library of three billion letter combinations. Cheap whole-genome sequencing is of greatest importance to medical scientific research. Comparing individual complete genomes will lead to a better understanding of the contribution genetic variation makes to health and disease. As knowledge increases, the 'thousand-dollar genome' will also become increasingly important to healthcare. The applications that come within reach raise a number of ethical questions. This monitoring report addresses the issue.

No consensus exists whether women at increased risk for trisomy 21, 13, and 18 should be offered stand-alone rapid aneuploidy detection (RAD) or karyotyping. In this paper, the ethical implications of a fast, relatively cheap and targeted RAD are examined. The advantages of RAD seem less robust than its proponents suggest. Fast test results only give a short-term psychological benefit. The cost advantage of RAD is apparent, but must be weighed against consequences like missed abnormalities, which are evaluated differently by professionals and pregnant women. Since pre-test information about RAD will have to include telling women about karyotyping as a possible alternative, the advantage of RAD in terms of the quantity of information that needs to be given may also be smaller than suggested. We conclude that none of the supposed arguments in favour of RAD is decisive in itself. Whether the case for RAD may still be regarded as convincing when taking these arguments together seems to depend on one's implicit view of what prenatal screening is about. Are we basically dealing with a test for trisomy 21 and a few conditions more? Or are there good grounds for also testing for the wider range of abnormalities that karyotyping can detect? As professionals and pregnant women may have different views about this, we suggest that the best approach is to offer women a choice between RAD and karyotyping. This approach is most in line with the general aim of prenatal screening: providing opportunities for autonomous reproductive choice. European Journal of Human Genetics (2011) 19, 1020-1025; doi:10.1038/ejhg.2011.82; published online 1 June 2011

The great promise of the pending introduction of non-invasive prenatal diagnosis (NIPD) for trisomy 21 (18 and 13) is that it enables one-step, early and safe testing for these abnormalities. The ethical debate so far has been limited to possible drawbacks of routine access to this type of testing: normalization of testing and abortion and adverse effects on autonomous decision-making. We address the ethical implications of the fact that routine NIPD affects the scope and strategy of current prenatal screening cascades. A decision is needed whether complementary (invasive) testing remains in place in order to avoid a loss of information as compared with current practice. If so, the supposed advantages of NIPD may be less significant than generally assumed. Accumulation of tests challenges informed consent and proportionality. Therefore, an ethical evaluation of the implications of NIPD for the prenatal screening strategy as a whole is needed.

Prenatal screening strategies are undergoing rapid changes owing to the introduction of new testing techniques. The overall tendency is towards broadening the scope of prenatal testing through increasingly sensitive ultrasound scans and genome-wide molecular tests. In addition, non-invasive prenatal diagnosis is likely to be introduced in the near future. These developments raise important ethical questions concerning meaningful reproductive choice, the autonomy rights of future children, equity of access and the proportionality of testing.

No consensus exists whether women at increased risk for trisomy 21, 13, and 18 should be offered stand-alone rapid aneuploidy detection (RAD) or karyotyping. In this paper, the ethical implications of a fast, relatively cheap and targeted RAD are examined. The advantages of RAD seem less robust than its proponents suggest. Fast test results only give a short-term psychological benefit. The cost advantage of RAD is apparent, but must be weighed against consequences like missed abnormalities, which are evaluated differently by professionals and pregnant women. Since pre-test information about RAD will have to include telling women about karyotyping as a possible alternative, the advantage of RAD in terms of the quantity of information that needs to be given may also be smaller than suggested. We conclude that none of the supposed arguments in favour of RAD is decisive in itself. Whether the case for RAD may still be regarded as convincing when taking these arguments together seems to depend on one's implicit view of what prenatal screening is about. Are we basically dealing with a test for trisomy 21 and a few conditions more? Or are there good grounds for also testing for the wider range of abnormalities that karyotyping can detect? As professionals and pregnant women may have different views about this, we suggest that the best approach is to offer women a choice between RAD and karyotyping. This approach is most in line with the general aim of prenatal screening: providing opportunities for autonomous reproductive choice. European Journal of Human Genetics (2011) 19, 1020-1025; doi:10.1038/ejhg.2011.82; published online 1 June 2011

The great promise of the pending introduction of non-invasive prenatal diagnosis (NIPD) for trisomy 21 (18 and 13) is that it enables one-step, early and safe testing for these abnormalities. The ethical debate so far has been limited to possible drawbacks of routine access to this type of testing: normalization of testing and abortion and adverse effects on autonomous decision-making. We address the ethical implications of the fact that routine NIPD affects the scope and strategy of current prenatal screening cascades. A decision is needed whether complementary (invasive) testing remains in place in order to avoid a loss of information as compared with current practice. If so, the supposed advantages of NIPD may be less significant than generally assumed. Accumulation of tests challenges informed consent and proportionality. Therefore, an ethical evaluation of the implications of NIPD for the prenatal screening strategy as a whole is needed.

Prenatal screening strategies are undergoing rapid changes owing to the introduction of new testing techniques. The overall tendency is towards broadening the scope of prenatal testing through increasingly sensitive ultrasound scans and genome-wide molecular tests. In addition, non-invasive prenatal diagnosis is likely to be introduced in the near future. These developments raise important ethical questions concerning meaningful reproductive choice, the autonomy rights of future children, equity of access and the proportionality of testing.

This paper explores the ethical implications of introducing non-invasive prenatal diagnostic tests (NIPD tests) in prenatal screening for foetal abnormalities. NIPD tests are easy and safe and can be performed early in pregnancy. Precisely because of these features, it is feared that informed consent may become more difficult, that both testing and selective abortion will become 'normalized', and that there will be a trend towards accepting testing for minor abnormalities and non-medical traits as well. In our view, however, the real moral challenge of NIPD testing consists in the possibility of linking up a technique with these features (easy, safe and early) with new genomic technologies that allow prenatal diagnostic testing for a much broader range of abnormalities than is the case in current procedures. An increase in uptake and more selective abortions need not in itself be taken to signal a thoughtless acceptance of these procedures. However, combining this with considerably enlarging the scope of NIPD testing will indeed make informed consent more difficult and challenge the notion of prenatal screening as serving reproductive autonomy. If broad NIPD testing includes later-onset diseases, the 'right not to know' of the future child will become a new issue in the debate about prenatal screening. With regard to the controversial issue of selective abortion, it may make a morally relevant difference that after NIPD testing, abortion can be done early. A lower moral status may be attributed to the foetus at that moment, given the dominant opinion that the moral status of the foetus progressively increases with its development. European Journal of Human Genetics (2010) 18, 272-277; doi: 10.1038/ejhg.2009.203; published online 2 December 2009