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BACKGROUND Since the birth of the first baby using IVF technology in 1978, over 10 million children have been conceived via ART. Although most aspects of ARTs were developed in animal models, the introduction of these technologies into clinical practice was performed without comprehensive assessment of their long-term safety. The monitoring of these technologies over time has revealed differences in the physiology of babies produced using ARTs, yet due to the pathology of those presenting for treatment, it is challenging to separate the cause of infertility from the effect of treatments offered. The use of systematic review and meta-analysis to investigate the impacts of the predominant ART interventions used clinically in human populations on animals produced in healthy fertile populations offers an alternative approach to understanding the long-term safety of reproductive technologies. OBJECTIVE AND RATIONALE This systematic review and meta-analysis aimed to examine the evidence available from animal studies on physiological outcomes in the offspring conceived after IVF, IVM or ICSI, compared to in vivo fertilization, and to provide an overview on the landscape of research in this area. SEARCH METHODS PubMed, Embase and Commonwealth Agricultural Bureaux (CAB) Abstracts were searched for relevant studies published until 27 August 2021. Search terms relating to assisted reproductive technology, postnatal outcomes and mammalian animal models were used. Studies that compared postnatal outcomes between in vitro-conceived (IVF, ICSI or IVM) and in vivo-conceived mammalian animal models were included. In vivo conception included mating, artificial insemination, or either of these followed by embryo transfer to a recipient animal with or without in vitro culture. Outcomes included birth weight, gestation length, cardiovascular, metabolic and behavioural characteristics and lifespan. OUTCOMES A total of 61 studies in five different species (bovine, equine, murine, ovine and non-human primate) met the inclusion criteria. The bovine model was the most frequently used in IVM studies (32/40), while the murine model was mostly used in IVF (17/20) and ICSI (6/8) investigations. Despite considerable heterogeneity, these studies suggest that the use of IVF or maturation results in offspring with higher birthweights and a longer length of gestation, with most of this evidence coming from studies in cattle. These techniques may also impair glucose and lipid metabolism in male mice. The findings on cardiovascular outcomes and behaviour outcomes were inconsistent across studies. WIDER IMPLICATIONS Conception via in vitro or in vivo means appears to have an influence on measurable outcomes of offspring physiology, manifesting differently across the species studied. Importantly, it can be noted that these measurable differences are noticeable in healthy, fertile animal populations. Thus, common ART interventions may have long-term consequences for those conceived through these techniques, regardless of the pathology underpinning diagnosed infertility. However, due to heterogeneous methods, results and measured outcomes, highlighted in this review, it is difficult to draw firm conclusions. Optimizing animal and human studies that investigate the safety of new reproductive technologies will provide insight into safeguarding the introduction of novel interventions into the clinical setting. Cautiously prescribing the use of ARTs clinically may also be considered to reduce the chance of promoting adverse outcomes in children conceived before long-term safety is confidently documented.

Australia has recently legalised mitochondrial donation. However, key ethical and legal issues still need to be addressed. This paper maps the relevant issues and offers some suggestions for how they ought to be resolved.

Background: Legislation to permit mitochondrial donation (MD) in Australia was introduced into Federal Parliament in early 2021, and the techniques may be legalized and made available soon. MD enables women affected by disease-causing mutations in their mitochondrial DNA to have a genetically related child who is unlikely to inherit these mutations. MD relies on the donation of oocytes. Australia’s oocyte donation system does not meet current demand for oocytes and MD would add to this. Consequently, the implementation of MD would raise critical questions about the system of procuring donors and using their oocytes. The proposed model for implementing MD in Australia does not address these issues. We address two key inter-related concerns – oocyte availability and donor consent – in how best to meet current and future demand for donor oocytes. Aim: To consider ethical, social, and regulatory issues arising from the proposed implementation of MD in Australia, particularly oocyte availability and donor consent issues. Method: We discuss the current system of oocyte donation in Australia and consider likely impacts of MD on this. We review alternative systems that have been proposed to enhance the availability of oocytes, focusing on ethical aspects of these with reference to specific features of the Australian context, donor consent, and MD. Results: MD will increase demand for oocytes if introduced in Australia. Alternative procurement systems to address the shortage of oocytes may be required. Refining the system of consent used for oocyte donation may be an important feature of increasing oocyte availability for MD. Conclusion: As Australia presses ahead with the potential implementation of MD, consideration should be given as to whether the current system for oocyte donation is adequate. We conclude that it is necessary to consider alternative systems for enhancing oocyte availability in Australia, which, in some circumstances, may include changing consent procedures.

Study question What are the clinical characteristics and medical outcomes of cross-border surrogacy (CBS) arrangements? Summary answer CBS practices commonly involve anonymously donated oocytes and multiple embryo transfers which can adversely impact the psychological and physical welfare of the children born. What is known already Intended parents may seek CBS when surrogacy in their home country is prohibited or when access is restricted to heterosexual couples, or when they cannot find a surrogate in their home country. Standards of clinical care can differ between the parents' home country and the CBS destination. Surrogacy is generally unregulated in CBS destinations, making it difficult to monitor clinical practices and the outcomes for the children born. In Australia, where this study is set, anonymous gamete donation and multiple embryo transfers for patients engaged in surrogacy is prohibited. The rate of twin surrogacy deliveries is 2.2%. Study design, size, duration This cross-sectional study collected data through an online, anonymous survey open between April and November 2021. Participants/materials, setting, methods A survey with predominantly fixed-choice questions was developed and informed by the authors’ prior research, the literature, and one author’s experience of surrogacy and surrogacy advocacy. Questions were refined through an iterative process involving consultation with parents through surrogacy. Australian parents through surrogacy were eligible to participate and the study was advertised to personal contacts, members of a surrogacy non-profit organisation and members of a surrogacy related Facebook group. Data were analysed descriptively. Main results and the role of chance One hundred and eight Australian parents through CBS completed the survey. Surrogacy was undertaken in twelve destinations, with approximately half of respondents completing surrogacy in the United States of America (34%, n = 37) or Canada (17%, n = 18). Almost all respondents reported the pregnancy was a result of an embryo transfer (92%, n = 98) and not artificial insemination (8%, n = 10). Of those reporting embryo transfer, 41% reported the transfer of multiple embryos (n = 40) and 79% reported the use of donor oocytes (n = 77). Of the respondents that used donor oocytes, almost half were from an anonymous donor (47%, n = 36) and all but one noted their intent to disclose the use of donor oocytes to their child (97%, n = 76). Pregnancy or birth complications were reported by 29% of respondents (n = 31). There were 12 twin births (11%), 22 preterm births (20%) and 24 births requiring neonatal intensive care (22%). The median time spent in the neonatal intensive care unit was 6 days (range 1-60). All but one twin birth arose from pregnancies resulting from a multiple embryo transfer and the majority were preterm (75%, n = 9) and required neonatal intensive care (59%, n = 7). Limitations, reasons for caution It is not known if those who completed the survey are representative of all parents through CBS. However, the respondents’ sociodemographic characteristics and motivations for surrogacy were similar to those in previously conducted studies, both within Australia and internationally. Wider implications of the findings The welfare of children born through surrogacy can be protected by addressing the barriers to undertaking surrogacy domestically and thereby reducing the number of people crossing borders, and by promoting identity release or known donation and single embryo transfer as best practice in surrogacy internationally. Trial registration number Not applicable