ESHRE guideline: number of embryos to transfer during IVF/ICSI†.

STUDY QUESTION: Which clinical and embryological factors should be considered to apply double embryo transfer (DET) instead of elective single embryo transfer (eSET)? SUMMARY ANSWER: No clinical or embryological factor per se justifies a recommendation of DET instead of eSET in IVF/ICSI. WHAT IS KNOWN ALREADY: DET is correlated with a higher rate of multiple pregnancy, leading to a subsequent increase in complications for both mother and babies. These complications include preterm birth, low birthweight, and other perinatal adverse outcomes. To mitigate the risks associated with multiple pregnancy, eSET is recommended by international and national professional organizations as the preferred approach in ART. STUDY DESIGN, SIZE, DURATION: The guideline was developed according to the structured methodology for development and update of ESHRE guidelines. Literature searches were performed in PUBMED/MEDLINE and Cochrane databases, and relevant papers published up to May 2023, written in English, were included. Live birth rate, cumulative live birth rate, and multiple pregnancy rate were considered as critical outcomes. PARTICIPANTS/MATERIALS, SETTING, METHODS: Based on the collected evidence, recommendations were discussed until a consensus was reached within the Guideline Development Group (GDG). A stakeholder review was organized after the guideline draft was finalized. The final version was approved by the GDG and the ESHRE Executive Committee. MAIN RESULTS AND THE ROLE OF CHANCE: The guideline provides 35 recommendations on the medical and non-medical risks associated with multiple pregnancies and on the clinical and embryological factors to be considered when deciding on the number of embryos to transfer. These recommendations include 25 evidence-based recommendations, of which 24 were formulated as strong recommendations and one as conditional, and 10 good practice points. Of the evidence-based recommendations, seven (28%) were supported by moderate-quality evidence. The remaining recommendations were supported by low (three recommendations; 12%), or very low-quality evidence (15 recommendations; 60%). Owing to the lack of evidence-based research, the guideline also clearly mentions recommendations for future studies. LIMITATIONS, REASONS FOR CAUTION: The guideline assessed different factors one by one based on existing evidence. However, in real life, clinicians' decisions are based on several prognostic factors related to each patient's case. Furthermore, the evidence from randomized controlled trials is too scarce to formulate high-quality evidence-based recommendations. WIDER IMPLICATIONS OF THE FINDINGS: The guideline provides health professionals with clear advice on best practice in the decision-making process during IVF/ICSI, based on the best evidence currently available, and recommendations on relevant information that should be communicated to patients. In addition, a list of research recommendations is provided to stimulate further studies in the field. STUDY FUNDING/COMPETING INTEREST(S): The guideline was developed and funded by ESHRE, covering expenses associated with the guideline meetings, the literature searches, and the dissemination of the guideline. The guideline group members did not receive payment. DPB declared receiving honoraria for lectures from Merck, Ferring, and Gedeon Richter. She is a member of ESHRE EXCO, and the Mediterranean Society for reproductive medicine and the president of the Croatian Society for Gynaecological Endocrinology and Reproductive Medicine. CDG is the past Chair of the ESHRE EIM Consortium and a paid deputy member of the Editorial board of Human Reproduction. IR declared receiving reimbursement from ESHRE and EDCD for attending meetings. She holds an unpaid leadership role in OBBCSSR, ECDC Sohonet, and AER. KAR-W declared receiving grants for clinical researchers and funding provision to the institution from the Swedish Cancer Society (200170F), the Senior Clinical Investigator Award, Radiumhemmets Forskningsfonder (Dnr: 201313), Stockholm County Council FoU (FoUI-953912) and Karolinska Institutet (Dnr 2020-01963), NovoNordisk, Merck and Ferring Pharmaceuticals. She received consulting fees from the Swedish Ministry of Health and Welfare. She received honoraria from Roche, Pfizer, and Organon for chairmanship and lectures. She received support from Organon for attending meetings. She participated in advisory boards for Merck, Nordic countries, and Ferring. She declared receiving time-lapse equipment and grants with payment to institution for pre-clinical research from Merck pharmaceuticals and from Ferring. SS-R received research funding from Roche Diagnostics, Organon/MSD, Theramex, and Gedeo-Richter. He received consulting fees from Organon/MSD, Ferring Pharmaceuticals, and Merck Serono. He declared receiving honoraria for lectures from Ferring Pharmaceuticals, Besins, Organon/MSD, Theramex, and Gedeon Richter. He received support for attending Gedeon Richter meetings and participated in the Data Safety Monitoring Board of the T-TRANSPORT trial. He is the Deputy of ESHRE SQART special interest group. He holds stock options in IVI Lisboa and received equipment and other services from Roche Diagnostics and Ferring Pharmaceuticals. KT declared receiving payment for honoraria for giving lectures from Merck Serono and Organon. She is member of the safety advisory board of EDQM. She holds a leadership role in the ICCBBA board of directors. ZV received reimbursement from ESHRE for attending meetings. She also received research grants from ESHRE and Juhani Aaltonen Foundation. She is the coordinator of EHSRE SQART special interest group. The other authors have no conflicts of interest to declare. DISCLAIMER: This guideline represents the views of ESHRE, which were achieved after careful consideration of the scientific evidence available at the time of preparation. In the absence of scientific evidence on certain aspects, a consensus between the relevant ESHRE stakeholders has been obtained. Adherence to these clinical practice guidelines does not guarantee a successful or specific outcome, nor does it establish a standard of care. Clinical practice guidelines do not replace the need for application of clinical judgement to each individual presentation, nor variations based on locality and facility type. ESHRE makes no warranty, express or implied, regarding the clinical practice guidelines and specifically excludes any warranties of merchantability and fitness for a particular use or purpose (full disclaimer available at https://www.eshre.eu/Guidelines-and-Legal).

Attitude of Belgian women towards enucleated egg donation for treatment of mitochondrial diseases and infertility.

RESEARCH QUESTION: What is the attitude of Belgian women of reproductive age towards enucleated egg donation? Does the willingness of women to donate differ when they would donate enucleated or whole eggs? DESIGN: In 2022, an online survey was conducted among a representative sample of 1000 women in Belgium aged 18-50 years. The item on willingness to anonymously donate enucleated eggs was dichotomized into those willing to donate and those not willing to donate or uncertain. RESULTS: No statistically significant difference was found between the willingness to donate enucleated eggs and whole eggs (whether anonymously or identifiably). Anonymity, however, affected the willingness to donate, with considerably fewer women willing to donate identifiably. The respondents were divided about their parental status if they were to donate enucleated eggs, with less than one-half (44%) not considering themselves to be a genetic mother. Women willing to donate enucleated eggs anonymously were less likely to view themselves as a genetic mother of the child compared with others. Fewer than one in five considered the technique unacceptable because the resulting child would carry genetic material of three persons. CONCLUSIONS: Women in the general population did not show a greater willingness to donate enucleated eggs than whole eggs. The fact that the respondents were strongly divided on whether or not they would consider themselves to be a genetic mother of the resulting child may explain this result. Other factors, such as the potential high risk for the child, may also have contributed to less willingness.

The information, control, and value models of mobile health-driven empowerment.

Mobile health tools are often said to empower users by providing them with the information they need to exercise control over their health. We aim to bring clarity to this claim, and in doing so explore the relationship between empowerment and autonomy. We have identified three distinct models embedded in the empowerment rhetoric: empowerment as information, empowerment as control, and empowerment as values. Each distinct model of empowerment gives rise to an associated problem. These problems, the Problem of Interpretation, the Value Alignment Problem, and the Priority Problem, show that mobile health tools in their current form are either insufficient for empowerment or are self-defeating. These digital health technologies encourage users to adopt an individualized conception of autonomy, one that may weaken the doctor-patient relationship and undermine practices in shared decision making, and ultimately may not deliver on improving the health outcomes for those that need it the most.

Age-related hearing loss and "hearables": An agenda for moral considerations.

Rapid advances in digital hearing technologies, also known as hearables, are expected to disrupt the direct-to-consumer health market. For older adults with higher incidence of hearing loss, such disruption could reduce hearing problems, increase accessibility to hearing aids, and mitigate related stigmas. This paper delves into the intersection of disruptive innovation and hearables within the realm of biomedical ethics. Through a comprehensive exploration, we shed light on the ethical implications surrounding hearables. By critically evaluating the key ethical advantages and drawbacks, we find that no single concern presents an insurmountable a priori objection to hearables. We conclude with some ideas to maximize the benefits of hearables and further promote opportunities for equitable hearing health.

'Do I want children later in life?' Reproductive intentions of 1700 adolescents.

PURPOSE: In the past decades, a positive attitude towards having children has been reported in young people. The current generation of adolescents is increasingly concerned about environmental cataclysm which may have an impact on their desire for children. The purpose of this study is to depict the current attitudes in Flemish adolescents towards having children. MATERIALS AND METHODS: All secondary schools in Flanders (Belgium) were invited to distribute an anonymous online survey among their pupils in the last two years of secondary education. In total, 1700 adolescents participated and provided quantitative and qualitative data on their reproductive intentions. RESULTS: Most pupils expressed a desire for children (60.2%), 24.7% were undecided and 10.8% were not willing to have children. Significantly more boys than girls would like to have children (67.0% versus 61.7%, p < 0.01). Adolescents who were uncertain about having children or not interested, reported financial reasons and loss of freedom as most important reasons. CONCLUSIONS: While most adolescents would like to have children in the future, one in four adolescents is undecided and one in ten indicates a wish to remain childless; reasons for wanting children are rather personal, reasons for not wanting children are rather pragmatic.

A desire for parenthood is no longer the norm: 60% of Flemish adolescents would like to build a family, but many are considering a future without children.

Deconstructing self-fulfilling outcome measures in infertility treatment.

The typical outcome measure in infertility treatment is the (cumulative) healthy live birth rate per patient or per cycle. This means that those who end the treatment trajectory with a healthy baby in their arms are considered to be successful and those who do not are considered to have failed. In this article, we argue that by adopting the healthy live birth standard as the outcome measure that defines a successful fertility treatment, it becomes an interpretative self-fulfilling prophecy: those who achieve the goal consider themselves successful and those who do not consider themselves failures. This is regardless of the fact that having children is only one out of many ways to alleviate the suffering related to infertility and that stopping fertility treatment can also be a positive decision to move on to other goals, rather than a form of "giving up," "dropping out," "nonadherence," or failure. We suggest that those seeking fertility treatment would be served better by an alternative outcome measure, which can be equally self-fulfilling, according to which a successful treatment is one in which people leave the clinic released from the suffering that accompanied their status as infertile when they first entered the clinic. This new outcome measure still implies that walking out with a healthy baby is a positive outcome. What changes is that walking out without a baby can also be a positive outcome, rather than being marked exclusively as a failure.

Watson, autonomy and value flexibility: revisiting the debate.

Many ethical concerns have been voiced about Clinical Decision Support Systems (CDSSs). Special attention has been paid to the effect of CDSSs on autonomy, responsibility, fairness and transparency. This journal has featured a discussion between Rosalind McDougall and Ezio Di Nucci that focused on the impact of IBM's Watson for Oncology (Watson) on autonomy. The present article elaborates on this discussion in three ways. First, using Jonathan Pugh's account of rational autonomy we show that how Watson presents its results might impact decisional autonomy, while how Watson produces knowledge might affect practical autonomy. Second, by drawing an analogy with patient decision aids we identify an empirical way of estimating Watson's impact on autonomy (ie, value-congruence). Lastly, McDougall introduced the notion of value-flexible design as a way to account for the diverging preferences patients hold. We will clarify its relation with the established domain of value-sensitive design. In terms of the tripartite methodology of value-sensitive design, we offer a conceptual clarification using Pugh's account of rational autonomy, an empirical tool to evaluate Watson's impact on autonomy and situate a group of technical options to incorporate autonomy in Watson's design.

The curious case of "trust" in the light of changing doctor-patient relationships.

The centrality of trust in traditional doctor-patient relationships has been criticized as inordinately paternalistic, yet in today's discussions about medical ethics-mostly in response to disruptive innovation in healthcare-trust reappears as an asset to enable empowerment. To turn away from paternalistic trust-based doctor-patient relationships and to arrive at an empowerment-based medical model, increasing reference is made to the importance of nurturing trust in technologies that are supposed to bring that empowerment. In this article we stimulate discussion about why the move towards patient empowerment may not be able to keep clear of the criticism of trust in traditional patient-doctor relationships. First, we explore how such a shift in trust dynamics might corrode patient empowerment in the name of patient empowerment. Second, we examine how a translocation of trust may at best push the "trust issue" elsewhere and at worst make it harder to evaluate trustworthiness.

An ethical exploration of pregnancy related mHealth: does it deliver?

Many pregnant women use pregnancy related mHealth (PRmHealth) applications, encompassing a variety of pregnancy apps and wearables. These are mostly directed at supporting a healthier fetal development. In this article we argue that the increasing dominance of PRmHealth stands in want of empirical knowledge affirming its beneficence in terms of improved pregnancy outcomes. This is a crucial ethical issue, especially in the light of concerns about increasing pressures and growing responsibilities ascribed to pregnant women, which may, in turn, be reinforced by PRmHealth. A point can be made that it would be ethically askew if PRmHealth does not lead to improved pregnancy outcomes, while at the same time increasing maternal duties to closely monitor fetal development. We conclude that more research is needed to get a view on the benefits and burdens of PRmHealth in order to ethically assess whether the latter are proportionate to the former. If not, there is a case in saying that endorsement of PRmHealth is overdemanding.

Follow-up in the field of reproductive medicine: an ethical exploration.

RESEARCH QUESTION: What ethical implications, issues and concerns play a role in conducting follow-up studies of children born after assisted reproductive technologies (ART)? DESIGN: Literature study and relevant experiences of academic medical centres in Brussels, Belgium, and Maastricht, the Netherlands were used to identify and analyse the most pertinent ethical implications, issues and concerns. RESULTS: According to recommendations from the European Society of Human Reproduction and Embryology, follow-up (ideally long term) of children conceived through medically assisted reproduction (MAR) should be an integral part of introducing new ART. With potentially risky new ART on the horizon, these recommendations need to be taken more seriously. Apart from practical barriers, such as funding, challenges for follow-up include securing active involvement of families of children conceived through MAR, starting with parents of young children, and ideally involving consenting adolescents and adults during a large part of their lives, possibly even into the next generation. CONCLUSIONS: From an ethical viewpoint, the most pertinent issues include the proportionality of the inevitable burdens and risks for families of children conceived through MAR, and the implications of the principle of respect for autonomy. The proportionality requirement is most critical when it concerns incompetent children, who should not be included in research with more than minimal burdens and risks if there is no reasonable expectation of benefit for themselves. With respect for autonomy, we argue that, when seeking voluntary consent for participating in follow-up studies that meet the condition of proportionality, professionals may encourage members of families of children conceived through MAR to partake in follow-up research.

Does human genome editing reinforce or violate human dignity?

Germline genome editing is often disapproved of at the international policy level because of its possible threats to human dignity. However, from a critical perspective the relationship between this emerging technology and human dignity is relatively understudied. We explore the main principles that are referred to when 'human dignity' is invoked in this context; namely, the link with eugenics, the idea of a common genetic heritage, the principle of equal birth and broader equality and justice concerns. Yet the concept is also used in favour of germline genome editing as it might improve the overall well-being of future generations. We conclude that dignity concerns do not justify a complete ban on safe heritable genome editing but should inform the implementation of side constraints to ensure that the value judgements about human traits that are inherent in this practice do not result in a diminished basic respect for those people affected by them.

The ethics of ectogenesis-aided foetal treatment.

In this paper, we aim to stimulate ethical debate about the morally relevant connection between ectogenesis and the foetus as a potential beneficiary of treatment. Ectogenesis could facilitate foetal interventions by treating the foetus independently of the pregnant woman and provide easier access to the foetus if interventions are required. The moral relevance hereof derives from the observation that, together with other developments in genetic technology and prenatal treatment, this may catalyse the allocation of a patient status to the foetus. The topic of foetal medicine is of growing interest to clinicians, and it also deserves due attention from an ethical perspective. To the extent that these developments contribute to the allocation of a patient status to the foetus (and to its respective interests for medical treatment), normative questions arise about how moral responsibilities towards foetal interests should be balanced against the interests of the pregnant woman. We conclude that, even if ectogenesis could facilitate foetal therapy, it is important to remain sensitive to the fact that it would not circumvent the key ethical concerns that come with in utero foetal treatment and that it may even exacerbate potential conflicts between directive treatment recommendations and the pregnant woman's autonomous decision to the contrary.

Ethical values supporting the disclosure of incidental and secondary findings in clinical genomic testing: a qualitative study.

BACKGROUND: Incidental findings (IFs) and secondary findings (SFs), being results that are unrelated to the diagnostic question, are the subject of an important debate in the practice of clinical genomic medicine. Arguments for reporting these results or not doing so typically relate to the principles of autonomy, non-maleficence and beneficence. However, these principles frequently conflict and are insufficient by themselves to come to a conclusion. This study investigates empirically how ethical principles are considered when actually reporting IFs or SFs and how value conflicts are weighed. METHODS: A qualitative focus group study has been undertaken, including a multidisciplinary group of professionals from Belgian centres for medical genetics. The data were analysed thematically. RESULTS: All eight Belgian centres participated in this study. Ethical values were frequently referred to for disclosure policies on IFs and SFs. Participants invoked respect for patient autonomy to support the disclosure of IFs and opt-out options for IFs and SFs, non-maleficence for the professional delineation of reportable IFs and opt-out options for IFs and SFs and (the particular scope of) beneficence for the mandatory reporting of actionable IFs, the delineation of reportable IFs and a current decline of actively pursued SFs. Professional assumptions about patients' genetic literacy were an important factor in the weighing of values. CONCLUSIONS: In line with the traditional bioethical discourse, the mandatory reporting of actionable IFs might be interpreted as a "technological, soft paternalism". Restricting patients' choices might be acceptable, but then its motives should be valid and its beneficent outcomes highly plausible. Hence, the presuppositions of technological, soft paternalism - patients' inability to make informed decisions, normative rationality, the efficacy of beneficent outcomes and the delineated spectrum of beneficence - should be approached critically. Moreover, distributive justice should be considered an important value in the delineation of the current scope of the ethical debate on IFs and SFs. This study of guiding values may stimulate the debate on the ethical grounds for a solid policy on IFs and SFs internationally.

Expanded Preconception Carrier Screening in Clinical Practice: Review of Technology, Guidelines, Implementation Challenges, and Ethical Quandaries.

In the last 10 years, expanded preconception carrier screening has become widely available and helps patients/couples make more informed decisions with regard to their reproductive options and facilitates more effective preconception planning, prenatal diagnosis, condition-specific counseling, and condition-specific care. This review provides an overview of expanded preconception carrier screening's high-throughput genotyping and sequencing approaches, current guidelines, implementation challenges and evolving ethical quandaries.

In vitro gametogenesis and reproductive cloning: Can we allow one while banning the other?

In vitro gametogenesis (IVG) is believed to be the next big breakthrough in reproductive medicine. The prima facie acceptance of this possible future technology is notable when compared to the general prohibition on human reproductive cloning. After all, if safety is the main reason for not allowing reproductive cloning, one might expect a similar conclusion for the reproductive application of IVG, since both technologies hold considerable and comparable risks. However, safety concerns may be overcome, and are presumably not the sole reason why cloning is being condemned. We therefore assess the non-safety arguments against reproductive cloning, yet most of these can also be held against IVG. The few arguments that cannot be used against IVG are defective. We conclude from this that it will be hard to defend a ban on reproductive cloning while accepting the reproductive use of IVG.

In Vitro Gametogenesis and the Creation of 'Designer Babies'.

Research into the development of stem cell-derived (SCD) gametes in humans, otherwise known as in vitro gametogenesis (IVG), is largely motivated by reproductive aims. Especially, the goal of establishing genetic parenthood by means of SCD-gametes is considered an important aim. However, like other applications in the field of assisted reproduction, this technology evokes worries about the possibility of creating so-called 'designer babies.' In this paper, we investigate various ways in which SCD-gametes could be used to create such preference-matched offspring, and what this would mean for the acceptability of IVG, if it is premised that it is morally problematic to 'design' offspring. We argue that IVG might facilitate the creation of preference-matched offspring, but conclude that this should not undermine the moral acceptability of IVG altogether-even if one concedes the premise that creating 'designer babies' is morally problematic. In the light of this, we also point at a possible inconsistency for a position that condemns the creation of 'designer offspring,' while accepting the various endeavors to have genetically related offspring.

Getting what you desire: the normative significance of genetic relatedness in parent-child relationships.

People who are involuntarily childless need to use assisted reproductive technologies if they want to have a genetically related child. Yet, from an ethical point of view it is unclear to what extent assistance to satisfy this specific desire should be warranted. We first show that the subjectively felt harm due to the inability to satisfy this reproductive desire does not in itself entail the normative conclusion that it has to be met. In response, we evaluate the alternative view according to which the satisfaction of this desire is regarded as a way to meet one's presumed intermediate need for parenthood. This view presupposes that parenthood is one of those general categories of experiences and activities that contribute an irreplaceable value to people's lives, but the central difficulty is to find those characteristics that mark out parenthood as an irreplaceable constituent of a valuable life. We go on to argue, however, that even if one assumes that parenthood is such an irreplaceable constituent that makes life more valuable, this does not necessarily entail a moral duty to satisfy the desire for genetic parenthood. We conclude that there is a pro tanto obligation to help people conceive a genetically related child (if this is what they prefer), but that this can be outweighed by other moral considerations, such as safety and justice concerns.

Of mice and human embryos: is there an ethically preferred order of preclinical research on new assisted reproductive technologies?

It is widely acknowledged that the responsible introduction of new assisted reproductive technologies (ARTs) requires preclinical safety research, including the use of animal models and human embryos. However, the moral sensitivity of human embryo research has led to regulations and guidance stating that human embryos may only be used for research that cannot also be conducted with animals. We call this the 'use animals first' (UAF) rule. In the field of ART research, this translates into the notion of an ideal chain of consecutive preclinical research steps, where research using human embryos may only be considered as a further step after promising results have been obtained in animals first. This may lead to research ethics committees requiring animal studies that are in fact a waste of time and money, while exposing animals to an infringement of their wellbeing for no good purpose. In this paper, we explore the possible moral arguments behind the UAF-rule and test their validity. We conclude that there are no convincing grounds for upholding this rule and recommend replacing it.

Balancing animal welfare and assisted reproduction: ethics of preclinical animal research for testing new reproductive technologies.

In the field of medically assisted reproduction (MAR), there is a growing emphasis on the importance of introducing new assisted reproductive technologies (ARTs) only after thorough preclinical safety research, including the use of animal models. At the same time, there is international support for the three R's (replace, reduce, refine), and the European Union even aims at the full replacement of animals for research. The apparent tension between these two trends underlines the urgency of an explicit justification of the use of animals for the development and preclinical testing of new ARTs. Considering that the use of animals remains necessary for specific forms of ART research and taking account of different views on the moral importance of helping people to have a genetically related child, we argue that, in principle, the importance of safety research as part of responsible innovation outweighs the limited infringement of animal wellbeing involved in ART research.