Eggsurance? A randomized controlled trial of a decision aid for elective egg freezing.

STUDY QUESTION: Does a purpose-designed Decision Aid for women considering elective egg freezing (EEF) impact decisional conflict and other decision-related outcomes? SUMMARY ANSWER: The Decision Aid reduces decisional conflict, prepares women for decision-making, and does not cause distress. WHAT IS ALREADY KNOWN: Elective egg-freezing decisions are complex, with 78% of women reporting high decisional conflict. Decision Aids are used to support complex health decisions. We developed an online Decision Aid for women considering EEF and demonstrated that it was acceptable and useful in Phase 1 testing. STUDY DESIGN, SIZE, DURATION: A single-blind, two-arm parallel group randomized controlled trial was carried out. Target sample size was 286 participants. Randomization was 1:1 to the control (existing website information) or intervention (Decision Aid plus existing website information) group and stratified by Australian state/territory and prior IVF specialist consultation. Participants were recruited between September 2020 and March 2021 with outcomes recorded over 12 months. Data were collected using online surveys and data collection was completed in March 2022. PARTICIPANTS/MATERIALS, SETTING, METHODS: Females aged ≥18 years, living in Australia, considering EEF, proficient in English, and with internet access were recruited using multiple methods including social media posts, Google advertising, newsletter/noticeboard posts, and fertility clinic promotion. After completing the baseline survey, participants were emailed their allocated website link(s). Follow-up surveys were sent at 6 and 12 months. Primary outcome was decisional conflict (Decisional Conflict Scale). Other outcomes included distress (Depression Anxiety and Stress Scale), knowledge about egg freezing and female age-related infertility (study-specific measure), whether a decision was made, preparedness to decide about egg freezing (Preparation for Decision-Making Scale), informed choice (Multi-Dimensional Measure of Informed Choice), and decision regret (Decision Regret Scale). MAIN RESULTS AND THE ROLE OF CHANCE: Overall, 306 participants (mean age 30 years; SD: 5.2) were randomized (intervention n = 150, control n = 156). Decisional Conflict Scale scores were significantly lower at 12 months (mean score difference: -6.99 [95% CI: -12.96, -1.02], P = 0.022) for the intervention versus control group after adjusting for baseline decisional conflict. At 6 months, the intervention group felt significantly more prepared to decide about EEF than the control (mean score difference: 9.22 [95% CI: 2.35, 16.08], P = 0.009). At 12 months, no group differences were observed in distress (mean score difference: 0.61 [95% CI: -3.72, 4.93], P = 0.783), knowledge (mean score difference: 0.23 [95% CI: -0.21, 0.66], P = 0.309), or whether a decision was made (relative risk: 1.21 [95% CI: 0.90, 1.64], P = 0.212). No group differences were found in informed choice (relative risk: 1.00 [95% CI: 0.81, 1.25], P = 0.983) or decision regret (median score difference: -5.00 [95% CI: -15.30, 5.30], P = 0.337) amongst participants who had decided about EEF by 12 months (intervention n = 48, control n = 45). LIMITATIONS, REASONS FOR CAUTION: Unknown participant uptake and potential sampling bias due to the recruitment methods used and restrictions caused by the coronavirus disease 2019 pandemic. Some outcomes had small sample sizes limiting the inferences made. The use of study-specific or adapted validated measures may impact the reliability of some results. WIDER IMPLICATIONS OF THE FINDINGS: This is the first randomized controlled trial to evaluate a Decision Aid for EEF. The Decision Aid reduced decisional conflict and improved women's preparation for decision making. The tool will be made publicly available and can be tailored for international use. STUDY FUNDING/COMPETING INTEREST(S): The Decision Aid was developed with funding from the Royal Women's Hospital Foundation and McBain Family Trust. The study was funded by a National Health and Medical Research Council (NHMRC) Project Grant APP1163202, awarded to M. Hickey, M. Peate, R.J. Norman, and R. Hart (2019-2021). S.S., M.P., D.K., and S.B. were supported by the NHMRC Project Grant APP1163202 to perform this work. R.H. is Medical Director of Fertility Specialists of Western Australia and National Medical Director of City Fertility. He has received grants from MSD, Merck-Serono, and Ferring Pharmaceuticals unrelated to this study and is a shareholder of CHA-SMG. R.L. is Director of Women's Health Melbourne (Medical Practice), ANZSREI Executive Secretary (Honorary), RANZCOG CREI Subspecialty Committee Member (Honorary), and a Fertility Specialist at Life Fertility Clinic Melbourne and Royal Women's Hospital Public Fertility Service. R.A.A. has received grants from Ferring Pharmaceuticals unrelated to this study. M.H., K.H., and R.J.N. have no conflicts to declare. TRIAL REGISTRATION NUMBER: ACTRN12620001032943. TRIAL REGISTRATION DATE: 11 August 2020. DATE OF FIRST PATIENT'S ENROLMENT: 29 September 2020.

Livebirth rate after one frozen embryo transfer in ovulatory women starting with natural, modified natural, or artificial endometrial preparation in Viet Nam: an open-label randomised controlled trial.

BACKGROUND: Use of frozen embryo transfer (FET) in in-vitro fertilisation (IVF) has increased. However, the best endometrial preparation protocol for FET cycles is unclear. We compared natural and modified natural cycle strategies with an artificial cycle strategy for endometrial preparation before FET. METHODS: In this randomised, open-label study, we recruited ovulatory women aged 18-45 years at a hospital in Ho Chi Minh City, Viet Nam, who were randomly allocated (1:1:1) to natural, modified natural, or artificial cycle endometrial preparation using a computer-generated random list and block randomisation. The trial was not masked due to the nature of the study interventions. In natural cycles, no oestrogen, progesterone, or human chorionic gonadotropin (hCG) was used. In modified natural cycles, hCG was used to trigger ovulation. In artificial cycles, oral oestradiol valerate (8 mg/day from day 2-4 of menstruation) and vaginal progesterone (800 mg/day starting when endometrial thickness was ≥7 mm) were used. Embryos were vitrified, and then one or two day-3 embryos or one day-5 embryo were warmed and transferred under ultrasound guidance. If the first FET cycle was cancelled, subsequent cycles were performed with artificial endometrial preparation. The primary endpoint was livebirth after one FET. This trial is registered at ClinicalTrials.gov, NCT04804020. FINDINGS: Between March 22, 2021, and March 14, 2023, 4779 women were screened and 1428 were randomly assigned (476 to each group). 99 first FET cycles were cancelled in each of the natural and modified cycle groups, versus none in the artificial cycle group. The livebirth rate after one FET was 174 (37%) of 476 in the natural cycle strategy group, 159 (33%) of 476 in the modified natural cycle strategy group, and 162 (34%) of 476 in the artificial cycle strategy group (relative risk 1·07 [95% CI 0·87-1·33] for natural vs artificial cycle strategy, and 0·98 [0·79-1·22] for modified natural vs artificial cycle strategy). Maternal and neonatal outcomes did not differ significantly between groups, as the power to detect small differences was low. INTERPRETATION: Although the livebirth rate was similar after natural, modified natural, and artificial cycle endometrial preparation strategies in ovulatory women undergoing FET IVF, no definitive conclusions can be made regarding the comparative safety of the three approaches. FUNDING: None.

Barriers and enablers to a healthy lifestyle in people with infertility: a mixed-methods systematic review.

BACKGROUND: While there is a recognized role of optimizing lifestyle (diet and physical activity) behaviours in the management of infertility, the best practice remains unknown and factors influencing the lifestyle of people with infertility are not well understood. OBJECTIVE AND RATIONALE: This systematic review evaluated barriers and enablers to a healthy lifestyle in people with infertility, from the perspectives of people with infertility and health professionals, in order to inform optimal behavioural change strategies. SEARCH METHODS: Ovid MEDLINE(R), PsycINFO, EMBASE, EBM Reviews, and CINAHL were searched from inception to 28 August 2023. Eligible studies were qualitative and quantitative primary studies that explored barriers and/or enablers to lifestyle for infertility management. Quality assessment was performed using the Centre for Evidence-Based Management Critical Appraisal of a Survey Tool and the Critical Appraisal Skills Programme Qualitative Checklist. Data were analysed by thematic analysis with themes mapped to the Capability, Opportunity, Motivation and Behaviour (COM-B) model and Theoretical Domains Framework (TDF). OUTCOMES: After screening 12 326 abstracts and 99 full-texts, 27 studies were included (12 quantitative, 6 qualitative and 9 mixed-methods) with 22 studies of women with infertility (n = 2524), 11 studies of men with infertility (n = 1407), and 6 studies of health professionals (n = 372). We identified barriers and enablers relating to capability (e.g. strategies for behaviour change), opportunity (e.g. limited time, resources, and money), and motivation (e.g. interplay between lifestyle and emotional state). Based on the identified themes, suggested intervention components to integrate into lifestyle management of infertility include facilitating development of self-management skills to support lifestyle change (e.g. self-monitoring, action planning, and goal setting) and incorporating mental health strategies (e.g. providing information about the benefits of healthy lifestyle behaviours for mental health and encouraging patients to reframe healthy lifestyle behaviours as self-care strategies). WIDER IMPLICATIONS: The findings have identified important factors that influence lifestyle management in people with infertility and have suggested relevant intervention components to consider when designing interventions. Given the paucity of qualitative studies identified, more research is needed to further understand the complex and interacting factors that shape lifestyle during the fertility journey.

Money matters: a critique of 'informed financial consent'.

In recent years, concerns about the financial burdens of health care and growing recognition of the relevance of cost to decision making and patient experience have increasingly focused attention on financial 'transparency' and disclosure of costs to patients. In some jurisdictions, there have been calls not only for timely disclosure of costs information, but also for 'informed financial consent'. However, simply putting the 'financial' into 'informed consent' and invoking an informed consent standard for cost information encounters several ethical, legal, and practical difficulties. This article will examine the viability and desirability of 'informed financial consent', and whether it is possible to derive ideas from traditional informed consent that may improve decision making and the patient experience. We argue that, while there are important legal, ethical, and practical challenges to consider, some of the principles of informed consent to treatment can usefully guide financial communication. We also argue that, while medical practitioners (and their delegates) have an important role to play in bridging the gap between disclosure and enabling informed (financial) decision making, this must be part of a multi-faceted approach to financial communication that acknowledges the influence of non-clinical providers and other structural forces on discharging such obligations.

Polycystic ovary syndrome.

Despite affecting ~11-13% of women globally, polycystic ovary syndrome (PCOS) is a substantially understudied condition. PCOS, possibly extending to men's health, imposes a considerable health and economic burden worldwide. Diagnosis in adults follows the International Evidence-based Guideline for the Assessment and Management of Polycystic Ovary Syndrome, requiring two out of three criteria - clinical or biochemical hyperandrogenism, ovulatory dysfunction, and/or specific ovarian morphological characteristics or elevated anti-Müllerian hormone. However, diagnosing adolescents omits ovarian morphology and anti-Müllerian hormone considerations. PCOS, marked by insulin resistance and hyperandrogenism, strongly contributes to early-onset type 2 diabetes, with increased odds for cardiovascular diseases. Reproduction-related implications include irregular menstrual cycles, anovulatory infertility, heightened risks of pregnancy complications and endometrial cancer. Beyond physiological manifestations, PCOS is associated with anxiety, depression, eating disorders, psychosexual dysfunction and negative body image, collectively contributing to diminished health-related quality of life in patients. Despite its high prevalence persisting into menopause, diagnosing PCOS often involves extended timelines and multiple health-care visits. Treatment remains ad hoc owing to limited understanding of underlying mechanisms, highlighting the need for research delineating the aetiology and pathophysiology of the syndrome. Identifying factors contributing to PCOS will pave the way for personalized medicine approaches. Additionally, exploring novel biomarkers, refining diagnostic criteria and advancing treatment modalities will be crucial in enhancing the precision and efficacy of interventions that will positively impact the lives of patients.

Medicine in the marketplace: clinician and patient views on commercial influences on assisted reproductive technology.

RESEARCH QUESTION: What are the views and experiences of patient and expert stakeholders on the positive and negative impacts of commercial influences on the provision of assisted reproductive technology (ART) services, and what are their suggestions for governance reforms? DESIGN: Semi-structured interviews were conducted with 31 ART industry experts from across Australia and New Zealand and 25 patients undergoing ART from metropolitan and regional Australia, between September 2020 and September 2021. Data were analysed using thematic analysis. RESULTS: Expert and patient participants considered that commercial forces influence the provision of ART in a number of positive ways - increasing sustainability, ensuring consistency in standards and providing patients with greater choice. Participants also considered commercial forces to have a number of negative impacts, including increased costs to government and patients; the excessive use of interventions that lack sufficient evidence to be considered part of standard care; inadequately informed consent (particularly with regard to financial information); and threats to patient-provider relationships and patient-centred care. Participants varied in whether they believed that professional self-regulation is sufficient. While recognizing the benefits of commercial investment in healthcare, many considered that regulatory reforms, as well as organizational cultural initiatives, are needed as means to ensure the primacy of patient well-being. CONCLUSIONS: The views expressed in this study should be systematically and critically examined to derive insights into how best to govern ART. These insights may also inform the design and delivery of other types of healthcare that are provided in the private sector.

Prophecy, prediction, and prognosis - can we improve the advice we give on the chance of pregnancy and treatment options for infertility?

Giving patients an accurate prognosis of their chances of achieving pregnancy is difficult with our current knowledge and technology. We need new approaches and thinking to provide truthful information.

Moral justification for the use of 'add-ons' in assisted reproductive technology: experts' views and experiences.

RESEARCH QUESTION: What factors do assisted reproductive terchnology (ART) providers take into account when they make decisions about offering 'add-ons'? DESIGN: A qualitative analysis of interviews with 31 ART professionals, focusing on their views and experiences in relation to add-ons, including the factors that are considered when doctors make decisions about their use. RESULTS: The participants reported that a range of considerations are taken into account when it comes to justifying the use of a particular add-on in a given circumstance, including the likelihood of benefit and harm, patients' perceived psychological needs and preferences, and organizational expectations. Importantly, patient preferences, psychological factors and low risk of harm appear to be stronger motivations than increasing the likelihood of a live birth or the desire to innovate. CONCLUSIONS: These findings suggest that it cannot be taken for granted that add-ons and innovation are closely linked. One possible response to this would be regulatory reform; for example, only allowing 'unproven' add-ons to be used in the context of formal scientific evaluation. Alternatively, it could be made clear that add-ons that are not undergoing formal evaluation have more in common with other therapies lacking a clear evidence base, such as complementary and alternative medicines, than with conventional medical practice. Practices in relation to add-ons may also require a focus on the responsibilities of corporations, and the standards applying to purveyors of consumer goods and services.

What moral weight should patient-led demand have in clinical decisions about assisted reproductive technologies?

Evidence suggests that one reason doctors provide certain interventions in assisted reproductive technologies (ART) is because of patient demand. This is particularly the case when it comes to unproven interventions such as 'add-ons' to in vitro fertilisation (IVF) cycles, or providing IVF cycles that are highly unlikely to succeed. Doctors tend to accede to demands for such interventions because patients are willing to do and pay 'whatever it takes' to have a baby. However, there is uncertainty as to what moral weight should be placed on patient-led demands in ART, including whether it is acceptable for such demands to be invoked as a justification for intervention. We address this issue in this paper. We start by elucidating what we mean by 'patient-led demand' and synthesise some of the evidence for this phenomenon. We then argue that a doctor's professional role morality (PRM) yields special responsibilities, particularly in commercialised healthcare settings such as ART, because of the nature of professions as social institutions that are distinct from markets. We argue on this basis that, while there may be reasons (consistent with PRM) for doctors to accede to patient demand, this is not always the case. There is often a gap in justification between acceding to patient-led demands and providing contested interventions, particularly in commercial settings. As a result, acceding to demand in such settings needs a strong justification to be consistent with PRM.

The adverse effects of vitrification on mouse embryo development and metabolic phenotype in offspring.

Embryo vitrification is a standard procedure in assisted reproductive technology. Previous studies have shown that frozen embryo transfer is associated with an elevated risk of adverse maternal and neonatal outcomes. This study aimed to explore the effects of mouse blastocyst vitrification on the phenotype of vitrified-warmed blastocysts, their intrauterine and postnatal development, and the long-term metabolic health of the derived offspring. The vitrified-warmed blastocysts (IVF + VT group) exhibited reduced mitochondrial activity, increased apoptotic levels, and decreased cell numbers when compared to the fresh blastocysts (IVF group). Implantation rates, live pup rates, and crown-rump length at E18.5 were not different between the two groups. However, there was a significant decrease in fetal weight and fetal/placental weight ratio in the IVF + VT group. Furthermore, the offspring of the IVF + VT group at an age of 36 weeks had reduced whole energy consumption, impaired glucose and lipid metabolism when compared with the IVF group. Notably, RNA-seq results unveiled disturbed hepatic gene expression in the offspring from vitrified-warmed blastocysts. This study revealed the short-term negative impacts of vitrification on embryo and fetal development and the long-term influence on glucose and lipid metabolism that persist from the prenatal stage into adulthood in mice.

Risk for Congenital Anomalies in Children Conceived With Medically Assisted Fertility Treatment : A Population-Based Cohort Study.

BACKGROUND: More than 2 million children are conceived annually using assisted reproductive technologies (ARTs), with a similar number conceived using ovulation induction and intrauterine insemination (OI/IUI). Previous studies suggest that ART-conceived children are at increased risk for congenital anomalies (CAs). However, the role of underlying infertility in this risk remains unclear, and ART clinical and laboratory practices have changed drastically over time, particularly there has been an increase in intracytoplasmic sperm injection (ICSI) and cryopreservation. OBJECTIVE: To investigate the role of underlying infertility and fertility treatment on CA risks in the first 2 years of life. DESIGN: Propensity score-weighted population-based cohort study. SETTING: New South Wales, Australia. PARTICIPANTS: 851 984 infants (828 099 singletons and 23 885 plural children) delivered between 2009 and 2017. MEASUREMENTS: Adjusted risk difference (aRD) in CAs of infants conceived through fertility treatment compared with 2 naturally conceived (NC) control groups-those with and without a parental history of infertility (NC-infertile and NC-fertile). RESULTS: The overall incidence of CAs was 459 per 10 000 singleton births and 757 per 10 000 plural births. Compared with NC-fertile singleton control infants (n = 747 018), ART-conceived singleton infants (n = 31 256) had an elevated risk for major genitourinary abnormalities (aRD, 19.0 cases per 10 000 births [95% CI, 2.3 to 35.6]); the risk remained unchanged (aRD, 22 cases per 10 000 births [CI, 4.6 to 39.4]) when compared with NC-infertile singleton control infants (n = 36 251) (that is, after accounting for parental infertility), indicating that ART remained an independent risk. After accounting for parental infertility, ICSI in couples without male infertility was associated with an increased risk for major genitourinary abnormalities (aRD, 47.8 cases per 10 000 singleton births [CI, 12.6 to 83.1]). There was some suggestion of increased risk for CAs after fresh embryo transfer, although estimates were imprecise and inconsistent. There were no increased risks for CAs among OI/IUI-conceived infants (n = 13 574). LIMITATIONS: This study measured the risk for CAs only in those children who were born at or after 20 weeks' gestation. Observational study design precludes causal inference. Many estimates were imprecise. CONCLUSION: Patients should be counseled on the small increased risk for genitourinary abnormalities after ART, particularly after ICSI, which should be avoided in couples without problems of male infertility. PRIMARY FUNDING SOURCE: Australian National Health and Medical Research Council.

Association between ambient temperature exposure and pregnancy outcomes in patients undergoing in vitro fertilization in Shanghai, China: a retrospective cohort study.

STUDY QUESTION: Does ambient temperature exposure affect outcomes including clinical pregnancy and live birth in women undergoing IVF? SUMMARY ANSWER: Both extreme cold and hot ambient temperatures were significantly associated with adverse pregnancy outcomes of IVF cycles. WHAT IS KNOWN ALREADY: Heat exposure has been linked to adverse pregnancy outcomes worldwide. However, the effect of ambient temperature on infertile women undergoing IVF treatment is unclear. STUDY DESIGN, SIZE, DURATION: A retrospective cohort study was conducted from a database of 3452 infertile women who underwent their first fresh or frozen embryo transfer in the Shanghai First Maternity and Infant Hospital from April 2016 to December 2020. PARTICIPANTS/MATERIALS, SETTING, METHODS: Daily mean ambient temperature exposure for each patient was obtained based on their residential address. Temperature-stratified multiple logistic regression analysis was performed to investigate associations between temperature exposure and pregnancy outcomes after controlling for confounders. Vulnerable sub-groups were identified using forest plots. MAIN RESULTS AND THE ROLE OF CHANCE: The clinical pregnancy rate and live birth rate were 45.7% and 37.1%, respectively. Regarding clinical pregnancy, a higher temperature during cold weather was significantly associated with a higher pregnancy rate in the period about 11 weeks before ovarian stimulation (adjusted odds ratio (aOR) = 1.102, 95% CI: 1.012-1.201). Regarding live birth, an increased temperature during cold weather was significantly related to a higher live birth rate in the period after confirmation of clinical pregnancy or biochemical pregnancy, with the aORs of 6.299 (95% CI: 3.949-10.047) or 10.486 (95% CI: 5.609-19.620), respectively. However, a higher temperature during hot weather was negatively associated with the live birth rate in the periods after confirmation of clinical pregnancy or biochemical pregnancy, with the aORs at 0.186 (95% CI: 0.121-0.285) or 0.302 (95% CI: 0.224-0.406), respectively. Moreover, the decline in live birth rates during cold and hot weather was accompanied by increased rates of early miscarriage (P < 0.05). Stratified analyses identified susceptibility characteristics among the participants. LIMITATIONS, REASONS FOR CAUTION: Climate monitoring data were used to represent individual temperature exposure levels according to the patient's residential address in the study. We were not able to obtain information of personal outdoor activity and use of indoor air conditioners in this retrospective study, which may affect actual temperature exposure. WIDER IMPLICATIONS OF THE FINDINGS: This study highlights that the ambient temperature exposure should be taken into account during IVF treatment and afterwards. There is a need to be alert to extremes in cold and hot ambient temperatures, especially during the period of follicle development and pregnancy. With this knowledge, clinicians can scientifically determine the timing of IVF treatment and reinforce patients' awareness of self-protection to minimize adverse pregnancy outcomes associated with extreme temperatures. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by a grant from the Clinical Research Plan of Shanghai Hospital Development Center [SHDC2020CR4080], a grant from the Science and Technology Commission of Shanghai Municipality [19411960500], and two grants from the National Natural Science Foundation of China [81871213, 81671468]. B.W.M. is supported by a NHMRC Investigator grant (GNT1176437). B.W.M. reports consultancy for ObsEva, and research grants from Merck KGaA, Ferring and Guerbet. The other authors have no conflict of interest to declare. TRIAL REGISTRATION NUMBER: N/A.

Recommendations from the 2023 International Evidence-based Guideline for the Assessment and Management of Polycystic Ovary Syndrome†.

STUDY QUESTION: What is the recommended assessment and management of those with polycystic ovary syndrome (PCOS), based on the best available evidence, clinical expertise, and consumer preference? SUMMARY ANSWER: International evidence-based guidelines address prioritized questions and outcomes and include 254 recommendations and practice points, to promote consistent, evidence-based care and improve the experience and health outcomes in PCOS. WHAT IS KNOWN ALREADY: The 2018 International PCOS Guideline was independently evaluated as high quality and integrated multidisciplinary and consumer perspectives from six continents; it is now used in 196 countries and is widely cited. It was based on best available, but generally very low to low quality, evidence. It applied robust methodological processes and addressed shared priorities. The guideline transitioned from consensus based to evidence-based diagnostic criteria and enhanced accuracy of diagnosis, whilst promoting consistency of care. However, diagnosis is still delayed, the needs of those with PCOS are not being adequately met, evidence quality was low and evidence-practice gaps persist. STUDY DESIGN, SIZE, DURATION: The 2023 International Evidence-based Guideline update reengaged the 2018 network across professional societies and consumer organizations, with multidisciplinary experts and women with PCOS directly involved at all stages. Extensive evidence synthesis was completed. Appraisal of Guidelines for Research and Evaluation-II (AGREEII)-compliant processes were followed. The Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) framework was applied across evidence quality, feasibility, acceptability, cost, implementation and ultimately recommendation strength and diversity and inclusion were considered throughout. PARTICIPANTS/MATERIALS, SETTING, METHODS: This summary should be read in conjunction with the full Guideline for detailed participants and methods. Governance included a six-continent international advisory and management committee, five guideline development groups, and paediatric, consumer, and translation committees. Extensive consumer engagement and guideline experts informed the update scope and priorities. Engaged international society-nominated panels included paediatrics, endocrinology, gynaecology, primary care, reproductive endocrinology, obstetrics, psychiatry, psychology, dietetics, exercise physiology, obesity care, public health and other experts, alongside consumers, project management, evidence synthesis, statisticians and translation experts. Thirty-nine professional and consumer organizations covering 71 countries engaged in the process. Twenty meetings and five face-to-face forums over 12 months addressed 58 prioritized clinical questions involving 52 systematic and 3 narrative reviews. Evidence-based recommendations were developed and approved via consensus across five guideline panels, modified based on international feedback and peer review, independently reviewed for methodological rigour, and approved by the Australian Government National Health and Medical Research Council (NHMRC). MAIN RESULTS AND THE ROLE OF CHANCE: The evidence in the assessment and management of PCOS has generally improved in the past five years, but remains of low to moderate quality. The technical evidence report and analyses (∼6000 pages) underpins 77 evidence-based and 54 consensus recommendations, with 123 practice points. Key updates include: i) further refinement of individual diagnostic criteria, a simplified diagnostic algorithm and inclusion of anti-Müllerian hormone (AMH) levels as an alternative to ultrasound in adults only; ii) strengthening recognition of broader features of PCOS including metabolic risk factors, cardiovascular disease, sleep apnea, very high prevalence of psychological features, and high risk status for adverse outcomes during pregnancy; iii) emphasizing the poorly recognized, diverse burden of disease and the need for greater healthcare professional education, evidence-based patient information, improved models of care and shared decision making to improve patient experience, alongside greater research; iv) maintained emphasis on healthy lifestyle, emotional wellbeing and quality of life, with awareness and consideration of weight stigma; and v) emphasizing evidence-based medical therapy and cheaper and safer fertility management. LIMITATIONS, REASONS FOR CAUTION: Overall, recommendations are strengthened and evidence is improved, but remains generally low to moderate quality. Significantly greater research is now needed in this neglected, yet common condition. Regional health system variation was considered and acknowledged, with a further process for guideline and translation resource adaptation provided. WIDER IMPLICATIONS OF THE FINDINGS: The 2023 International Guideline for the Assessment and Management of PCOS provides clinicians and patients with clear advice on best practice, based on the best available evidence, expert multidisciplinary input and consumer preferences. Research recommendations have been generated and a comprehensive multifaceted dissemination and translation program supports the Guideline with an integrated evaluation program. STUDY FUNDING/COMPETING INTEREST(S): This effort was primarily funded by the Australian Government via the National Health Medical Research Council (NHMRC) (APP1171592), supported by a partnership with American Society for Reproductive Medicine, Endocrine Society, European Society for Human Reproduction and Embryology, and European Society for Endocrinology. The Commonwealth Government of Australia also supported Guideline translation through the Medical Research Future Fund (MRFCRI000266). HJT and AM are funded by NHMRC fellowships. JT is funded by a Royal Australasian College of Physicians (RACP) fellowship. Guideline development group members were volunteers. Travel expenses were covered by the partnering organizations. Disclosures of interest were strictly managed according to NHMRC policy and are available with the full guideline, technical evidence report, peer review and responses (www.monash.edu/medicine/mchri/pcos). Of named authors HJT, CTT, AD, LM, LR, JBoyle, AM have no conflicts of interest to declare. JL declares grant from Ferring and Merck; consulting fees from Ferring and Titus Health Care; speaker's fees from Ferring; unpaid consultancy for Ferring, Roche Diagnostics and Ansh Labs; and sits on advisory boards for Ferring, Roche Diagnostics, Ansh Labs, and Gedeon Richter. TP declares a grant from Roche; consulting fees from Gedeon Richter and Organon; speaker's fees from Gedeon Richter and Exeltis; travel support from Gedeon Richter and Exeltis; unpaid consultancy for Roche Diagnostics; and sits on advisory boards for Roche Diagnostics. MC declares travels support from Merck; and sits on an advisory board for Merck. JBoivin declares grants from Merck Serono Ltd.; consulting fees from Ferring B.V; speaker's fees from Ferring Arzneimittell GmbH; travel support from Organon; and sits on an advisory board for the Office of Health Economics. RJN has received speaker's fees from Merck and sits on an advisory board for Ferring. AJoham has received speaker's fees from Novo Nordisk and Boehringer Ingelheim. The guideline was peer reviewed by special interest groups across our 39 partner and collaborating organizations, was independently methodologically assessed against AGREEII criteria and was approved by all members of the guideline development groups and by the NHMRC.

Recommendations From the 2023 International Evidence-based Guideline for the Assessment and Management of Polycystic Ovary Syndrome.

STUDY QUESTION: What is the recommended assessment and management of those with polycystic ovary syndrome (PCOS), based on the best available evidence, clinical expertise, and consumer preference? SUMMARY ANSWER: International evidence-based guidelines address prioritized questions and outcomes and include 254 recommendations and practice points, to promote consistent, evidence-based care and improve the experience and health outcomes in PCOS. WHAT IS KNOWN ALREADY: The 2018 International PCOS Guideline was independently evaluated as high quality and integrated multidisciplinary and consumer perspectives from six continents; it is now used in 196 countries and is widely cited. It was based on best available, but generally very low to low quality, evidence. It applied robust methodological processes and addressed shared priorities. The guideline transitioned from consensus based to evidence-based diagnostic criteria and enhanced accuracy of diagnosis, whilst promoting consistency of care. However, diagnosis is still delayed, the needs of those with PCOS are not being adequately met, evidence quality was low and evidence-practice gaps persist. STUDY DESIGN, SIZE, DURATION: The 2023 International Evidence-based Guideline update reengaged the 2018 network across professional societies and consumer organizations with multidisciplinary experts and women with PCOS directly involved at all stages. Extensive evidence synthesis was completed. Appraisal of Guidelines for Research and Evaluation-II (AGREEII)-compliant processes were followed. The Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) framework was applied across evidence quality, feasibility, acceptability, cost, implementation and ultimately recommendation strength and diversity and inclusion were considered throughout. PARTICIPANTS/MATERIALS, SETTING, METHODS: This summary should be read in conjunction with the full Guideline for detailed participants and methods. Governance included a six-continent international advisory and management committee, five guideline development groups, and paediatric, consumer, and translation committees. Extensive consumer engagement and guideline experts informed the update scope and priorities. Engaged international society-nominated panels included paediatrics, endocrinology, gynaecology, primary care, reproductive endocrinology, obstetrics, psychiatry, psychology, dietetics, exercise physiology, obesity care, public health and other experts, alongside consumers, project management, evidence synthesis, statisticians and translation experts. Thirty-nine professional and consumer organizations covering 71 countries engaged in the process. Twenty meetings and five face-to-face forums over 12 months addressed 58 prioritized clinical questions involving 52 systematic and 3 narrative reviews. Evidence-based recommendations were developed and approved via consensus across five guideline panels, modified based on international feedback and peer review, independently reviewed for methodological rigour, and approved by the Australian Government National Health and Medical Research Council (NHMRC). MAIN RESULTS AND THE ROLE OF CHANCE: The evidence in the assessment and management of PCOS has generally improved in the past five years, but remains of low to moderate quality. The technical evidence report and analyses (∼6000 pages) underpins 77 evidence-based and 54 consensus recommendations, with 123 practice points. Key updates include: i) further refinement of individual diagnostic criteria, a simplified diagnostic algorithm and inclusion of anti-Müllerian hormone (AMH) levels as an alternative to ultrasound in adults only; ii) strengthening recognition of broader features of PCOS including metabolic risk factors, cardiovascular disease, sleep apnea, very high prevalence of psychological features, and high risk status for adverse outcomes during pregnancy; iii) emphasizing the poorly recognized, diverse burden of disease and the need for greater healthcare professional education, evidence-based patient information, improved models of care and shared decision making to improve patient experience, alongside greater research; iv) maintained emphasis on healthy lifestyle, emotional wellbeing and quality of life, with awareness and consideration of weight stigma; and v) emphasizing evidence-based medical therapy and cheaper and safer fertility management. LIMITATIONS, REASONS FOR CAUTION: Overall, recommendations are strengthened and evidence is improved, but remain generally low to moderate quality. Significantly greater research is now needed in this neglected, yet common condition. Regional health system variation was considered and acknowledged, with a further process for guideline and translation resource adaptation provided. WIDER IMPLICATIONS OF THE FINDINGS: The 2023 International Guideline for the Assessment and Management of PCOS provides clinicians and patients with clear advice on best practice, based on the best available evidence, expert multidisciplinary input and consumer preferences. Research recommendations have been generated and a comprehensive multifaceted dissemination and translation programme supports the Guideline with an integrated evaluation program. STUDY FUNDING/COMPETING INTEREST(S): This effort was primarily funded by the Australian Government via the National Health Medical Research Council (NHMRC) (APP1171592), supported by a partnership with American Society for Reproductive Medicine, Endocrine Society, European Society for Human Reproduction and Embryology, and the European Society for Endocrinology. The Commonwealth Government of Australia also supported Guideline translation through the Medical Research Future Fund (MRFCRI000266). HJT and AM are funded by NHMRC fellowships. JT is funded by a Royal Australasian College of Physicians (RACP) fellowship. Guideline development group members were volunteers. Travel expenses were covered by the sponsoring organizations. Disclosures of interest were strictly managed according to NHMRC policy and are available with the full guideline, technical evidence report, peer review and responses (www.monash.edu/medicine/mchri/pcos). Of named authors HJT, CTT, AD, LM, LR, JBoyle, AM have no conflicts of interest to declare. JL declares grant from Ferring and Merck; consulting fees from Ferring and Titus Health Care; speaker's fees from Ferring; unpaid consultancy for Ferring, Roche Diagnostics and Ansh Labs; and sits on advisory boards for Ferring, Roche Diagnostics, Ansh Labs, and Gedeon Richter. TP declares a grant from Roche; consulting fees from Gedeon Richter and Organon; speaker's fees from Gedeon Richter and Exeltis; travel support from Gedeon Richter and Exeltis; unpaid consultancy for Roche Diagnostics; and sits on advisory boards for Roche Diagnostics. MC declares travels support from Merck; and sits on an advisory board for Merck. JBoivin declares grants from Merck Serono Ltd.; consulting fees from Ferring B.V; speaker's fees from Ferring Arzneimittell GmbH; travel support from Organon; and sits on an advisory board for the Office of Health Economics. RJN has received speaker's fees from Merck and sits on an advisory board for Ferring. AJoham has received speaker's fees from Novo Nordisk and Boehringer Ingelheim. The guideline was peer reviewed by special interest groups across our 39 partner and collaborating organizations, was independently methodologically assessed against AGREEII criteria and was approved by all members of the guideline development groups and by the NHMRC.

Recommendations from the 2023 International Evidence-based Guideline for the Assessment and Management of Polycystic Ovary Syndrome.

STUDY QUESTION: What is the recommended assessment and management of those with polycystic ovary syndrome (PCOS), based on the best available evidence, clinical expertise, and consumer preference? SUMMARY ANSWER: International evidence-based guidelines address prioritized questions and outcomes and include 254 recommendations and practice points, to promote consistent, evidence-based care and improve the experience and health outcomes in PCOS. WHAT IS KNOWN ALREADY: The 2018 International PCOS Guideline was independently evaluated as high quality and integrated multidisciplinary and consumer perspectives from six continents; it is now used in 196 countries and is widely cited. It was based on best available, but generally very low to low quality, evidence. It applied robust methodological processes and addressed shared priorities. The guideline transitioned from consensus based to evidence-based diagnostic criteria and enhanced accuracy of diagnosis, whilst promoting consistency of care. However, diagnosis is still delayed, the needs of those with PCOS are not being adequately met, evidence quality was low and evidence-practice gaps persist. STUDY DESIGN, SIZE, DURATION: The 2023 International Evidence-based Guideline update reengaged the 2018 network across professional societies and consumer organizations with multidisciplinary experts and women with PCOS directly involved at all stages. Extensive evidence synthesis was completed. Appraisal of Guidelines for Research and Evaluation-II (AGREEII)-compliant processes were followed. The Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) framework was applied across evidence quality, feasibility, acceptability, cost, implementation and ultimately recommendation strength and diversity and inclusion were considered throughout. PARTICIPANTS/ MATERIALS, SETTING, METHODS: This summary should be read in conjunction with the full Guideline for detailed participants and methods. Governance included a six-continent international advisory and management committee, five guideline development groups, and paediatric, consumer, and translation committees. Extensive consumer engagement and guideline experts informed the update scope and priorities. Engaged international society-nominated panels included paediatrics, endocrinology, gynaecology, primary care, reproductive endocrinology, obstetrics, psychiatry, psychology, dietetics, exercise physiology, obesity care, public health and other experts, alongside consumers, project management, evidence synthesis, statisticians and translation experts. Thirty-nine professional and consumer organizations covering 71 countries engaged in the process. Twenty meetings and five face-to-face forums over 12 months addressed 58 prioritized clinical questions involving 52 systematic and 3 narrative reviews. Evidence-based recommendations were developed and approved via consensus across five guideline panels, modified based on international feedback and peer review, independently reviewed for methodological rigour, and approved by the Australian Government National Health and Medical Research Council (NHMRC). MAIN RESULTS AND THE ROLE OF CHANCE: The evidence in the assessment and management of PCOS has generally improved in the past five years, but remains of low to moderate quality. The technical evidence report and analyses (∼6000 pages) underpins 77 evidence-based and 54 consensus recommendations, with 123 practice points. Key updates include: i) further refinement of individual diagnostic criteria, a simplified diagnostic algorithm and inclusion of anti-Müllerian hormone (AMH) levels as an alternative to ultrasound in adults only; ii) strengthening recognition of broader features of PCOS including metabolic risk factors, cardiovascular disease, sleep apnea, very high prevalence of psychological features, and high risk status for adverse outcomes during pregnancy; iii) emphasizing the poorly recognized, diverse burden of disease and the need for greater healthcare professional education, evidence-based patient information, improved models of care and shared decision making to improve patient experience, alongside greater research; iv) maintained emphasis on healthy lifestyle, emotional wellbeing and quality of life, with awareness and consideration of weight stigma; and v) emphasizing evidence-based medical therapy and cheaper and safer fertility management. LIMITATIONS, REASONS FOR CAUTION: Overall, recommendations are strengthened and evidence is improved, but remain generally low to moderate quality. Significantly greater research is now needed in this neglected, yet common condition. Regional health system variation was considered and acknowledged, with a further process for guideline and translation resource adaptation provided. WIDER IMPLICATIONS OF THE FINDINGS: The 2023 International Guideline for the Assessment and Management of PCOS provides clinicians and patients with clear advice on best practice, based on the best available evidence, expert multidisciplinary input and consumer preferences. Research recommendations have been generated and a comprehensive multifaceted dissemination and translation programme supports the Guideline with an integrated evaluation program. STUDY FUNDING/COMPETING INTEREST(S): This effort was primarily funded by the Australian Government via the National Health Medical Research Council (NHMRC) (APP1171592), supported by a partnership with American Society for Reproductive Medicine, Endocrine Society, European Society for Human Reproduction and Embryology, and the Society for Endocrinology. The Commonwealth Government of Australia also supported Guideline translation through the Medical Research Future Fund (MRFCRI000266). HJT and AM are funded by NHMRC fellowships. JT is funded by a Royal Australasian College of Physicians (RACP) fellowship. Guideline development group members were volunteers. Travel expenses were covered by the sponsoring organizations. Disclosures of interest were strictly managed according to NHMRC policy and are available with the full guideline, technical evidence report, peer review and responses (www.monash.edu/medicine/mchri/pcos). Of named authors HJT, CTT, AD, LM, LR, JBoyle, AM have no conflicts of interest to declare. JL declares grant from Ferring and Merck; consulting fees from Ferring and Titus Health Care; speaker's fees from Ferring; unpaid consultancy for Ferring, Roche Diagnostics and Ansh Labs; and sits on advisory boards for Ferring, Roche Diagnostics, Ansh Labs, and Gedeon Richter. TP declares a grant from Roche; consulting fees from Gedeon Richter and Organon; speaker's fees from Gedeon Richter and Exeltis; travel support from Gedeon Richter and Exeltis; unpaid consultancy for Roche Diagnostics; and sits on advisory boards for Roche Diagnostics. MC declares travels support from Merck; and sits on an advisory board for Merck. JBoivin declares grants from Merck Serono Ltd.; consulting fees from Ferring B.V; speaker's fees from Ferring Arzneimittell GmbH; travel support from Organon; and sits on an advisory board for the Office of Health Economics. RJN has received speaker's fees from Merck and sits on an advisory board for Ferring. AJoham has received speaker's fees from Novo Nordisk and Boehringer Ingelheim. The guideline was peer reviewed by special interest groups across our 39 partner and collaborating organizations, was independently methodologically assessed against AGREEII criteria and was approved by all members of the guideline development groups and by the NHMRC.

Recommendations from the 2023 international evidence-based guideline for the assessment and management of polycystic ovary syndrome.

STUDY QUESTION: What is the recommended assessment and management of those with polycystic ovary syndrome (PCOS), based on the best available evidence, clinical expertise, and consumer preference? SUMMARY ANSWER: International evidence-based guidelines address prioritized questions and outcomes and include 254 recommendations and practice points, to promote consistent, evidence-based care and improve the experience and health outcomes in PCOS. WHAT IS KNOWN ALREADY: The 2018 International PCOS Guideline was independently evaluated as high quality and integrated multidisciplinary and consumer perspectives from 6 continents; it is now used in 196 countries and is widely cited. It was based on best available, but generally very low- to low-quality, evidence. It applied robust methodological processes and addressed shared priorities. The guideline transitioned from consensus-based to evidence-based diagnostic criteria and enhanced accuracy of diagnosis, whilst promoting consistency of care. However, diagnosis is still delayed, the needs of those with PCOS are not being adequately met, the evidence quality was low, and evidence-practice gaps persist. STUDY DESIGN, SIZE, AND DURATION: The 2023 International Evidence-based Guideline update re-engaged the 2018 network across professional societies and consumer organizations with multidisciplinary experts and women with PCOS directly involved at all stages. Extensive evidence synthesis was completed. Appraisal of Guidelines for Research and Evaluation II (AGREEII)-compliant processes were followed. The Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) framework was applied across evidence quality, feasibility, acceptability, cost, implementation, and ultimately recommendation strength, and diversity and inclusion were considered throughout. PARTICIPANTS/MATERIALS, SETTING, AND METHODS: This summary should be read in conjunction with the full guideline for detailed participants and methods. Governance included a 6-continent international advisory and management committee, 5 guideline development groups, and paediatric, consumer, and translation committees. Extensive consumer engagement and guideline experts informed the update scope and priorities. Engaged international society-nominated panels included paediatrics, endocrinology, gynaecology, primary care, reproductive endocrinology, obstetrics, psychiatry, psychology, dietetics, exercise physiology, obesity care, public health, and other experts, alongside consumers, project management, evidence synthesis, statisticians, and translation experts. Thirty-nine professional and consumer organizations covering 71 countries engaged in the process. Twenty meetings and 5 face-to-face forums over 12 months addressed 58 prioritized clinical questions involving 52 systematic and 3 narrative reviews. Evidence-based recommendations were developed and approved via consensus across 5 guideline panels, modified based on international feedback and peer review, independently reviewed for methodological rigour, and approved by the Australian Government National Health and Medical Research Council. MAIN RESULTS AND THE ROLE OF CHANCE: The evidence in the assessment and management of PCOS has generally improved in the past 5 years but remains of low to moderate quality. The technical evidence report and analyses (∼6000 pages) underpin 77 evidence-based and 54 consensus recommendations, with 123 practice points. Key updates include the following: (1) further refinement of individual diagnostic criteria, a simplified diagnostic algorithm, and inclusion of anti-Müllerian hormone levels as an alternative to ultrasound in adults only; (2) strengthening recognition of broader features of PCOS including metabolic risk factors, cardiovascular disease, sleep apnoea, very high prevalence of psychological features, and high risk status for adverse outcomes during pregnancy; (3) emphasizing the poorly recognized, diverse burden of disease and the need for greater healthcare professional education, evidence-based patient information, improved models of care, and shared decision-making to improve patient experience, alongside greater research; (4) maintained emphasis on healthy lifestyle, emotional well-being, and quality of life, with awareness and consideration of weight stigma; and (5) emphasizing evidence-based medical therapy and cheaper and safer fertility management. LIMITATIONS AND REASONS FOR CAUTION: Overall, recommendations are strengthened and evidence is improved but remains generally low to moderate quality. Significantly greater research is now needed in this neglected, yet common condition. Regional health system variation was considered and acknowledged, with a further process for guideline and translation resource adaptation provided. WIDER IMPLICATIONS OF THE FINDINGS: The 2023 International Guideline for the Assessment and Management of PCOS provides clinicians and patients with clear advice on best practice, based on the best available evidence, expert multidisciplinary input, and consumer preferences. Research recommendations have been generated, and a comprehensive multifaceted dissemination and translation programme supports the guideline with an integrated evaluation programme.

In vitro egg maturation and in vitro fertilization-an idea whose time has come?

In vitro maturation of oocytes before their use in assisted reproduction has proved to be difficult and relatively unsuccessful despite a long history of attempts. Recent understanding of natural oocyte maturation, advances in culture media, and improved clinical approaches offer opportunities for a wider use of this technology in human in vitro fertilization.

Offspring physiology following the use of IVM, IVF and ICSI: a systematic review and meta-analysis of animal studies.

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.