STUDY QUESTION Can consensus definitions for the core outcome set for infertility be identified in order to recommend a standardized approach to reporting? SUMMARY ANSWER Consensus definitions for individual core outcomes, contextual statements and a standardized reporting table have been developed. WHAT IS KNOWN ALREADY Different definitions exist for individual core outcomes for infertility. This variation increases the opportunities for researchers to engage with selective outcome reporting, which undermines secondary research and compromises clinical practice guideline development. STUDY DESIGN, SIZE, DURATION Potential definitions were identified by a systematic review of definition development initiatives and clinical practice guidelines and by reviewing Cochrane Gynaecology and Fertility Group guidelines. These definitions were discussed in a face-to-face consensus development meeting, which agreed consensus definitions. A standardized approach to reporting was also developed as part of the process. PARTICIPANTS/MATERIALS, SETTING, METHODS Healthcare professionals, researchers and people with fertility problems were brought together in an open and transparent process using formal consensus development methods. MAIN RESULTS AND THE ROLE OF CHANCE Forty-four potential definitions were inventoried across four definition development initiatives, including the Harbin Consensus Conference Workshop Group and International Committee for Monitoring Assisted Reproductive Technologies, 12 clinical practice guidelines and Cochrane Gynaecology and Fertility Group guidelines. Twenty-seven participants, from 11 countries, contributed to the consensus development meeting. Consensus definitions were successfully developed for all core outcomes. Specific recommendations were made to improve reporting. LIMITATIONS, REASONS FOR CAUTION We used consensus development methods, which have inherent limitations. There was limited representation from low- and middle-income countries. WIDER IMPLICATIONS OF THE FINDINGS A minimum data set should assist researchers in populating protocols, case report forms and other data collection tools. The generic reporting table should provide clear guidance to researchers and improve the reporting of their results within journal publications and conference presentations. Research funding bodies, the Standard Protocol Items: Recommendations for Interventional Trials statement, and over 80 specialty journals have committed to implementing this core outcome set. STUDY FUNDING/COMPETING INTEREST(S) This research was funded by the Catalyst Fund, Royal Society of New Zealand, Auckland Medical Research Fund and Maurice and Phyllis Paykel Trust. Siladitya Bhattacharya reports being the Editor-in-Chief of Human Reproduction Open and an editor of the Cochrane Gynaecology and Fertility Group. J.L.H.E. reports being the Editor Emeritus of Human Reproduction. R.S.L. reports consultancy fees from Abbvie, Bayer, Ferring, Fractyl, Insud Pharma and Kindex and research sponsorship from Guerbet and Hass Avocado Board. B.W.M. reports consultancy fees from Guerbet, iGenomix, Merck, Merck KGaA and ObsEva. C.N. reports being the Editor-in-Chief of Fertility and Sterility and Section Editor of the Journal of Urology, research sponsorship from Ferring, and a financial interest in NexHand. E.H.Y.N. reports research sponsorship from Merck. A.S. reports consultancy fees from Guerbet. J.W. reports being a statistical editor for the Cochrane Gynaecology and Fertility Group. A.V. reports that he is a Statistical Editor of the Cochrane Gynaecology & Fertility Review Group and of the journal Reproduction. His employing institution has received payment from Human Fertilisation and Embryology Authority for his advice on review of research evidence to inform their ‘traffic light’ system for infertility treatment ‘add-ons’. N.L.V. reports consultancy and conference fees from Ferring, Merck and Merck Sharp and Dohme. The remaining authors declare no competing interests in relation to the work presented. All authors have completed the disclosure form. TRIAL REGISTRATION NUMBER Core Outcome Measures in Effectiveness Trials Initiative: 1023.

STUDY QUESTION Can a core outcome set to standardize outcome selection, collection and reporting across future infertility research be developed? SUMMARY ANSWER A minimum data set, known as a core outcome set, has been developed for randomized controlled trials (RCTs) and systematic reviews evaluating potential treatments for infertility. WHAT IS KNOWN ALREADY Complex issues, including a failure to consider the perspectives of people with fertility problems when selecting outcomes, variations in outcome definitions and the selective reporting of outcomes on the basis of statistical analysis, make the results of infertility research difficult to interpret. STUDY DESIGN, SIZE, DURATION A three-round Delphi survey (372 participants from 41 countries) and consensus development workshop (30 participants from 27 countries). PARTICIPANTS/MATERIALS, SETTING, METHODS Healthcare professionals, researchers and people with fertility problems were brought together in an open and transparent process using formal consensus science methods. MAIN RESULTS AND THE ROLE OF CHANCE The core outcome set consists of: viable intrauterine pregnancy confirmed by ultrasound (accounting for singleton, twin and higher multiple pregnancy); pregnancy loss (accounting for ectopic pregnancy, miscarriage, stillbirth and termination of pregnancy); live birth; gestational age at delivery; birthweight; neonatal mortality; and major congenital anomaly. Time to pregnancy leading to live birth should be reported when applicable. LIMITATIONS, REASONS FOR CAUTION We used consensus development methods which have inherent limitations, including the representativeness of the participant sample, Delphi survey attrition and an arbitrary consensus threshold. WIDER IMPLICATIONS OF THE FINDINGS Embedding the core outcome set within RCTs and systematic reviews should ensure the comprehensive selection, collection and reporting of core outcomes. Research funding bodies, the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) statement, and over 80 specialty journals, including the Cochrane Gynaecology and Fertility Group, Fertility and Sterility and Human Reproduction, have committed to implementing this core outcome set. STUDY FUNDING/COMPETING INTEREST(S) This research was funded by the Catalyst Fund, Royal Society of New Zealand, Auckland Medical Research Fund and Maurice and Phyllis Paykel Trust. The funder had no role in the design and conduct of the study, the collection, management, analysis or interpretation of data, or manuscript preparation. B.W.J.M. is supported by a National Health and Medical Research Council Practitioner Fellowship (GNT1082548). S.B. was supported by University of Auckland Foundation Seelye Travelling Fellowship. S.B. reports being the Editor-in-Chief of Human Reproduction Open and an editor of the Cochrane Gynaecology and Fertility group. J.L.H.E. reports being the Editor Emeritus of Human Reproduction. J.M.L.K. reports research sponsorship from Ferring and Theramex. R.S.L. reports consultancy fees from Abbvie, Bayer, Ferring, Fractyl, Insud Pharma and Kindex and research sponsorship from Guerbet and Hass Avocado Board. B.W.J.M. reports consultancy fees from Guerbet, iGenomix, Merck, Merck KGaA and ObsEva. C.N. reports being the Co Editor-in-Chief of Fertility and Sterility and Section Editor of the Journal of Urology, research sponsorship from Ferring, and retains a financial interest in NexHand. A.S. reports consultancy fees from Guerbet. E.H.Y.N. reports research sponsorship from Merck. N.L.V. reports consultancy and conference fees from Ferring, Merck and Merck Sharp and Dohme. The remaining authors declare no competing interests in relation to the work presented. All authors have completed the disclosure form. TRIAL REGISTRATION NUMBER Core Outcome Measures in Effectiveness Trials Initiative: 1023.

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STUDY QUESTION What is the methodological validity and usefulness of randomised controlled trials (RCTs) on pain relief during oocyte retrieval for IVF and ICSI? SUMMARY ANSWER Key methodological characteristics such as randomisation, allocation concealment, primary outcome measure, and sample size calculation were inadequately reported in 33 to 43% of the included RCTs, and a broad heterogeneity is revealed in the studied outcome measures. WHAT IS KNOWN ALREADY A Cochrane review on conscious sedation and analgesia (CSA) for women undergoing oocyte retrieval concluded that the overall quality of evidence was low or very low, mainly owing to poor reporting. This, and heterogeneity of studied outcome measures limits generalisability, and eligibility of results for meta-analysis. STUDY DESIGN, SIZE AND DURATION For this review, a systematic search for RCTs on pain relief during oocyte retrieval was performed on July 20th 2020 in CENTRAL CRSO, MEDLINE, Embase, PsycINFO, CINAHL, ClinicalTrials.gov, WHO ICTRP, Web of science, Portal Regional da BVS, and Open Grey. PARTICIPANTS/MATERIALS, SETTING, METHODS RCTs with pain or patient satisfaction as an outcome were included and analysed on a set of methodological and clinical characteristics, to determine their validity and usefulness. MAIN RESULTS AND THE ROLE OF CHANCE Screening of 2531 articles led to an inclusion of 51 RCTs. Randomisation was described inadequately in 33% of the RCTs. A low-risk method of allocation concealment was reported in 55% of the RCTs. Forty-nine percent of the RCTs reported blinding of participants, 33% of blinding personnel, and 43% of blinding the outcome assessor. In 63% of the RCTs, the primary outcome was stated, but a sample size calculation was described in only 57%. Data was analysed according to the intention-to-treat principle in 73%. Treatment groups were not treated identically other than the intervention of interest in 10% of the RCTs. The primary outcome was intraoperative pain in 28%, and postoperative pain in 2%. The visual analogue scale (VAS) was the most used pain scale, in 69% of the RCTs in which pain was measured. Overall, nine other scales were used. Patient satisfaction was measured in 49% of the RCTs, for which 12 different methods were used. Occurrence of side-effects and complications were assessed in 77% and 49% of the RCTs: a definition for these was lacking in 13% and 20% of the RCTs, respectively. Pregnancy rate was reported in 55% of the RCTs and, of these, 75% did not adequately define pregnancy. To improve the quality of future research, we provide recommendations for the design of future trials. These include use of the VAS for pain measurement, use of validated questionnaires for measurement of patient satisfaction, and the minimal clinically relevant difference to use for sample size calculations. LIMITATIONS, REASONS FOR CAUTION Consensus has not been reached on some methodological characteristics, for which we formulated recommendations. To prevent further heterogeneity in research on this topic, recommendations were formulated based on expert opinion, or on the most used method thus far. Future research may provide evidence to base new recommendations on. WIDER IMPLICATIONS OF THE FINDINGS Use of the recommendations given for design of trials on this topic can increase the generalisability of future research, increasing eligibility for meta-analyses, and preventing wastefulness. STUDY FUNDING/COMPETING INTEREST(S) No specific funding was obtained for this study. S.B. reports being the editor-in-chief of Human Reproduction Open. For this manuscript, he was not involved with the handling process within Human Reproduction Open, or with the final decision. Further, S.B. reports personal fees from Remuneration from Oxford University Press as editor-in-chief of Human Reproduction Open, personal fees from Editor and contributing author, Reproductive Medicine for the MRCOG, Cambridge University Press. The remaining authors declare no conflict of interest in relation to the work presented. TRIAL REGISTRATION NUMBER Not applicable.

Study question In high-income country settings, what is the evidence supporting economic evaluations of in vitro fertilisation (IVF) interventions? Summary answer Most interventions associated with IVF are high cost for minimal improvement in effectiveness, leading to excessively high acceptability thresholds. What is known already The economic burden of infertility, and approaches to reduce costs and increase access have been identified in the top 10 research priorities for future infertility research. Meanwhile, there has been exponential growth in use of ART for infertility, especially in high-income countries. Therefore, it is important to map the landscape of economic evaluations in IVF research to inform health policy and future research. Study design, size, duration A systematic review of studies of an IVF intervention together with an economic evaluation conducted in high income countries between 2011 and 2022 was completed. Seven electronic databases were searched for eligible studies (MEDLINE, PUBMED, EMBASE, COCHRANE, ECONLIT, SCOPUS or CINAHL). Participants/materials, setting, methods Studies assessing a component of IVF with a cost effectiveness, cost benefit, cost utility or cost minimization assessment were included. Studies were examined to assess their chosen outcome measure, perspective, completeness of reporting and cost effectiveness of the intervention studied. Cost data were converted to USD, taking inflation into consideration. Main results and the role of chance Of the 40 included studies, 62% evaluated an unselected population and 68% used livebirth as the effectiveness outcome measure. Modelling studies predominated (65%) over those alongside trials. Most (80%) spoke from a health funder perspective. There were 11 IVF interventions assessed together with an economic evaluation. The incremental cost effectiveness ratio was greatest for those interventions where the intervention did not improve efficacy significantly. The intervention of PGT-A was assessed as either less effective and more expensive, or more effective, but costing up to $600,000 USD for each additional livebirth. Likewise, intracytoplasmic sperm injection for non-male factor infertility, conferred minimal benefit but cost up to $72000 USD per additional livebirth. Choice of agents for ovarian hyperstimulation were assessed in 15 included papers. Recombinant FSH is more effective and slightly more expensive than biosimilars. The direction of effect of the cost effectiveness findings was the same for the groups of studies assessing IVF, ICSI, PGT-A and embryo transfer number, increasing confidence in the findings across different settings and funding models. Limitations, reasons for caution Systematic reviews of economic evidence rely on assumptions of evidence in included studies. The data on health outcomes (e.g. pregnancy rates) were sometimes optimistic compared with findings in evidence from large trials or systematic reviews. There is variable reporting quality which might increase uncertainty around the cost effectiveness results. Wider implications of the findings Economic evaluation of IVF interventions is important for state funders and individuals who pay for treatment. Awareness of the real price per outcome allows consideration for funding to be applied more effectively. Multi-faceted decision making is needed. Cost effectiveness alone should not champion interventions that may otherwise have adverse consequences. Trial registration number not applicable