Standardizing definitions and reporting guidelines for the infertility core outcome set: an international consensus development study

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

Developing a core outcome set for future infertility research: an international consensus development study

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 (RCT) 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, Ferility and Sterility, and Human Reproduction, have committed to implementing this core outcome set

Developing a core outcome set for future infertility research: an international consensus development study

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

Standardizing definitions and reporting guidelines for the infertility core outcome set: an international consensus development study

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

Metabolomics for improving pregnancy outcomes in women undergoing assisted reproductive technologies

Background In order to overcome the low effectiveness of assisted reproductive technologies (ART) and the high incidence of multiple births, metabolomics is proposed as a non‐invasive method to assess oocyte quality, embryo viability, and endometrial receptivity, and facilitate a targeted subfertility treatment. Objectives To evaluate the effectiveness and safety of metabolomic assessment of oocyte quality, embryo viability, and endometrial receptivity for improving live birth or ongoing pregnancy rates in women undergoing ART, compared to conventional methods of assessment. Search methods We searched the Cochrane Gynaecology and Fertility Group Trials Register, CENTRAL, MEDLINE, Embase, CINAHL and two trial registers (Feburary 2018). We also examined the reference lists of primary studies and review articles, citation lists of relevant publications, and abstracts of major scientific meetings. Selection criteria Randomised controlled trials (RCTs) on metabolomic assessment of oocyte quality, embryo viability, and endometrial receptivity in women undergoing ART. Data collection and analysis Pairs of review authors independently assessed trial eligibility and risk of bias, and extracted the data. The primary outcomes were rates of live birth or ongoing pregnancy (composite outcome) and miscarriage. Secondary outcomes were clinical pregnancy, multiple and ectopic pregnancy, cycle cancellation, and foetal abnormalities. We combined data to calculate odds ratios (ORs) for dichotomous data and 95% confidence intervals (CIs). Statistical heterogeneity was assessed using the I² statistic. We assessed the overall quality of the evidence for the main comparisons using GRADE methods. Main results We included four trials with a total of 924 women, with a mean age of 33 years. All assessed the role of metabolomic investigation of embryo viability. We found no RCTs that addressed the metabolomic assessment of oocyte quality or endometrial receptivity. We found low‐quality evidence of little or no difference between metabolomic and non‐metabolomic assessment of embryos for rates of live birth or ongoing pregnancy (OR 1.02, 95% CI 0.77 to 1.35, I² = 0%; four RCTs; N = 924), live birth alone (OR 0.99, 95% CI 0.69 to 1.44, I² = 0%; three RCTs; N = 597), or miscarriage (OR 1.18, 95% CI 0.77 to 1.82; I² = 0%; three RCTs; N = 869). A sensitivity analysis excluding studies at high risk of bias did not change the interpretation of the results for live birth or ongoing pregnancy (OR 0.90, 95% CI 0.66 to 1.25, I² = 0%; two RCTs; N = 744). Our findings suggested that if the rate of live birth or ongoing pregnancy was 36% in the non‐metabolomic group, it would be between 32% and 45% with the use of metabolomics. We found low‐quality evidence of little or no difference between groups in rates of clinical pregnancy (OR 1.11, 95% CI 0.85 to 1.45; I²= 44%; four trials; N = 924) or multiple pregnancy (OR 1.50, 95% CI 0.70 to 3.19; I² = 0%; two RCTs, N = 180). Rates of cycle cancellation were higher in the metabolomics group (OR 1.78, 95% CI 1.18 to 2.69; I² = 51%; two RCTs; N = 744, low quality evidence). There was very low‐quality evidence of little or no difference between groups in rates of ectopic pregnancy rates (OR 3.00, 95% CI 0.12 to 74.07; one RCT; N = 417), and foetal abnormality (no events; one RCT; N = 125). Data were lacking on other adverse effects. A sensitivity analysis excluding studies at high risk of bias did not change the interpretation of the results for clinical pregnancy (OR 1.03, 95% CI 0.76 to 1.38; I² = 40%; two RCTs; N = 744). The overall quality of the evidence ranged from very low to low. Limitations included serious risk of bias (associated with poor reporting of methods, attrition bias, selective reporting, and other biases), imprecision, and inconsistency across trials. Authors' conclusions According to current trials in women undergoing ART, there is no evidence to show that metabolomic assessment of embryos before implantation has any meaningful effect on rates of live birth, ongoing pregnancy, miscarriage, multiple pregnancy, ectopic pregnancy or foetal abnormalities. The existing evidence varied from very low to low‐quality. Data on other adverse events were sparse, so we could not reach conclusions on these. At the moment, there is no evidence to support or refute the use of this technique for subfertile women undergoing ART. Robust evidence is needed from further RCTs, which study the effects on live birth and miscarriage rates for the metabolomic assessment of embryo viability. Well designed and executed trials are also needed to study the effects on oocyte quality and endometrial receptivity, since none are currently available