Protocol for developing a core outcome set for male infertility research : an international consensus development study

STUDY QUESTION We aim to develop, disseminate and implement a minimum data set, known as a core outcome set, for future male infertility research. WHAT IS KNOWN ALREADY Research into male infertility can be challenging to design, conduct and report. Evidence from randomized trials can be difficult to interpret and of limited ability to inform clinical practice for numerous reasons. These may include complex issues, such as variation in outcome measures and outcome reporting bias, as well as failure to consider the perspectives of men and their partners with lived experience of fertility problems. Previously, the Core Outcome Measure for Infertility Trials (COMMIT) initiative, an international consortium of researchers, healthcare professionals and people with fertility problems, has developed a core outcome set for general infertility research. Now, a bespoke core outcome set for male infertility is required to address the unique challenges pertinent to male infertility research. STUDY DESIGN, SIZE, DURATION Stakeholders, including healthcare professionals, allied healthcare professionals, scientists, researchers and people with fertility problems, will be invited to participate. Formal consensus science methods will be used, including the modified Delphi method, modified Nominal Group Technique and the National Institutes of Health’s consensus development conference. PARTICIPANTS/MATERIALS, SETTING, METHODS An international steering group, including the relevant stakeholders outlined above, has been established to guide the development of this core outcome set. Possible core outcomes will be identified by undertaking a systematic review of randomized controlled trials evaluating potential treatments for male factor infertility. These outcomes will be entered into a modified Delphi method. Repeated reflection and re-scoring should promote convergence towards consensus outcomes, which will be prioritized during a consensus development meeting to identify a final core outcome set. We will establish standardized definitions and recommend high-quality measurement instruments for individual core outcomes. STUDY FUNDING/COMPETING INTEREST(S) This work has been supported by the Urology Foundation small project award, 2021. C.L.R.B. is the recipient of a BMGF grant and received consultancy fees from Exscentia and Exceed sperm testing, paid to the University of Dundee and speaking fees or honoraria paid personally by Ferring, Copper Surgical and RBMO. S.B. received royalties from Cambridge University Press, Speaker honoraria for Obstetrical and Gynaecological Society of Singapore, Merk SMART Masterclass and Merk FERRING Forum, paid to the University of Aberdeen. Payment for leadership roles within NHS Grampian, previously paid to self, now paid to University of Aberdeen. An Honorarium is received as Editor in Chief of Human Reproduction Open. M.L.E. is an advisor to the companies Hannah and Ro. B.W.M. received an investigator grant from the NHMRC, No: GNT1176437 is a paid consultant for ObsEva and has received research funding from Ferring and Merck. R.R.H. received royalties from Elsevier for a book, consultancy fees from Glyciome, and presentation fees from GryNumber Health and Aytu Bioscience. Aytu Bioscience also funded MiOXYS systems and sensors. Attendance at Fertility 2020 and Roadshow South Africa by Ralf Henkel was funded by LogixX Pharma Ltd. R.R.H. is also Editor in Chief of Andrologia and has been an employee of LogixX Pharma Ltd. since 2020. M.S.K. is an associate editor with Human Reproduction Open. K.Mc.E. received an honoraria for lectures from Bayer and Pharmasure in 2019 and payment for an ESHRE grant review in 2019. His attendance at ESHRE 2019 and AUA 2019 was sponsored by Pharmasure and Bayer, respectively. The remaining authors declare no competing interests. TRIAL REGISTRATION NUMBER Core Outcome Measures in Effectiveness Trials (COMET) initiative registration No: 1586. Available at www.comet-initiative.org/Studies/Details/1586

Protocol for developing a core outcome set for male infertility research: an international consensus development study

Study question: We aim to develop, disseminate and implement a minimum data set, known as a core outcome set, for future male infertility research.What is known already: Research into male infertility can be challenging to design, conduct and report. Evidence from randomized trials can be difficult to interpret and of limited ability to inform clinical practice for numerous reasons. These may include complex issues, such as variation in outcome measures and outcome reporting bias, as well as failure to consider the perspectives of men and their partners with lived experience of fertility problems. Previously, the Core Outcome Measure for Infertility Trials (COMMIT) initiative, an international consortium of researchers, healthcare professionals and people with fertility problems, has developed a core outcome set for general infertility research. Now, a bespoke core outcome set for male infertility is required to address the unique challenges pertinent to male infertility research.Study design size duration: Stakeholders, including healthcare professionals, allied healthcare professionals, scientists, researchers and people with fertility problems, will be invited to participate. Formal consensus science methods will be used, including the modified Delphi method, modified Nominal Group Technique and the National Institutes of Health's consensus development conference.Participants/materials setting methods: An international steering group, including the relevant stakeholders outlined above, has been established to guide the development of this core outcome set. Possible core outcomes will be identified by undertaking a systematic review of randomized controlled trials evaluating potential treatments for male factor infertility. These outcomes will be entered into a modified Delphi method. Repeated reflection and re-scoring should promote convergence towards consensus outcomes, which will be prioritized during a consensus development meeting to identify a final core outcome set. We will establish standardized definitions and recommend high-quality measurement instruments for individual core outcomes.Study funding/competing interests: This work has been supported by the Urology Foundation small project award, 2021. C.L.R.B. is the recipient of a BMGF grant and received consultancy fees from Exscentia and Exceed sperm testing, paid to the University of Dundee and speaking fees or honoraria paid personally by Ferring, Copper Surgical and RBMO. S.B. received royalties from Cambridge University Press, Speaker honoraria for Obstetrical and Gynaecological Society of Singapore, Merk SMART Masterclass and Merk FERRING Forum, paid to the University of Aberdeen. Payment for leadership roles within NHS Grampian, previously paid to self, now paid to University of Aberdeen. An Honorarium is received as Editor in Chief of Human Reproduction Open. M.L.E. is an advisor to the companies Hannah and Ro. B.W.M. received an investigator grant from the NHMRC, No: GNT1176437 is a paid consultant for ObsEva and has received research funding from Ferring and Merck. R.R.H. received royalties from Elsevier for a book, consultancy fees from Glyciome, and presentation fees from GryNumber Health and Aytu Bioscience. Aytu Bioscience also funded MiOXYS systems and sensors. Attendance at Fertility 2020 and Roadshow South Africa by Ralf Henkel was funded by LogixX Pharma Ltd. R.R.H. is also Editor in Chief of Andrologia and has been an employee of LogixX Pharma Ltd. since 2020. M.S.K. is an associate editor with Human Reproduction Open. K.Mc.E. received an honoraria for lectures from Bayer and Pharmasure in 2019 and payment for an ESHRE grant review in 2019. His attendance at ESHRE 2019 and AUA 2019 was sponsored by Pharmasure and Bayer, respectively. The remaining authors declare no competing interests.</p

Single versus double intrauterine insemination in stimulated cycles for subfertile couples: a systematic review based on a Cochrane review

BACKGROUND: The objective of this review was to determine, from the best available evidence, the difference in outcome using single versus double intrauterine insemination (IUI) in stimulated cycles for subfertile couples. METHODS: The principles of the Cochrane Menstrual Disorders and Subfertility Group were employed. Randomized controlled trials with a parallel design, comparing single versus double IUI in subfertile couples, would be eligible. The main outcome measures included live birth rate and pregnancy rate per couple (and per cycle). RESULTS: Three studies involving 386 women were included. The results of pregnancy rate per couple, of two studies showed no significant effect of using double insemination [Peto odds ratio (OR) 1.45; 95% confidence interval (CI) 0.78-2.70]. The results of pregnancy rate per cycle of the included studies favoured double insemination, however this is not an eligible outcome measure. CONCLUSIONS: Based on the results of two trials, double intrauterine insemination showed no significant benefit over single IUI in the treatment of subfertile couples with partner semen. There are no meaningful data to offer advice on the basis of this review. A randomized controlled trial of single versus double IUI is justified

Long-term effects of radioiodine treatment on female fertility in survivors of childhood differentiated thyroid carcinoma

Item does not contain fulltextBackground: Differentiated thyroid carcinoma (DTC) during childhood is a rare disease. Its excellent survival rate requires a focus on possible long-term adverse effects. This study aimed to evaluate fertility in female survivors of childhood DTC by assessing various reproductive characteristics combined with anti-Müllerian hormone (AMH) levels (a marker of ovarian reserve). Methods: Female survivors of childhood DTC, diagnosed at ≤18 years of age between 1970 and 2013, were included. Survivors were excluded when follow-up time was less than five years or if they developed other malignancies before or after diagnosis of DTC. Survivors filled out a questionnaire regarding reproductive characteristics (e.g., age at menarche and menopause, pregnancies, pregnancy outcomes, need for assisted reproductive therapy). Survivors aged <18 years during evaluation received an altered questionnaire without questions regarding pregnancy and pregnancy outcomes. These data were combined with information from medical records. AMH levels were measured in serum samples and were compared with AMH levels from 420 women not treated for cancer. Results: Fifty-six survivors with a median age of 31.0 (interquartile range, IQR, 25.1-39.6) years were evaluated after a median follow-up of 15.4 (IQR 8.3-24.7) years. The median cumulative dose of (131)I administered was 7.4 (IQR 3.7-13.0) GBq/200.0 (IQR 100.0-350.0) mCi. Twenty-five of the 55 survivors aged 18 years or older during evaluation reported 64 pregnancies, 45 of which resulted in live birth. Of these 55, 10.9% visited a fertility clinic. None of the survivors reported premature menopause. Age at AMH evaluation did not differ between DTC survivors and the comparison group (p = 0.268). Median AMH levels did not differ between DTC survivors and the comparison group [2.0 (IQR 1.0-3.7) μg/L vs. 1.6 (IQR 0.6-3.1) μg/L, respectively, p = 0.244]. The cumulative dose of (131)I was not associated with AMH levels in DTC survivors (r(s) = 0.210, p = 0.130). Conclusions: Female survivors of DTC who received (131)I treatment during childhood do not appear to have major abnormalities in reproductive characteristics nor in predictors of ovarian failure

Intra-uterine insemination for male subfertility

BACKGROUND: Intra-uterine insemination (IUI) is one of the most frequently used fertility treatments for couples with male subfertility. Its use, especially when combined with ovarian hyperstimulation (OH) has been subject of discussion. Although the treatment itself is less invasive and expensive than others, its efficacy has not been proven. Furthermore, the adverse effects of OH such as ovarian hyperstimulation syndrome (OHSS ) and multiple pregnancy are a concern. OBJECTIVES: The aim of this review is to determine whether for couples with male subfertility, IUI improves the live birth rates or ongoing pregnancy rates compared with timed intercourse (TI), with or without OH. SEARCH STRATEGY: We searched the Cochrane Menstrual and Disorders Subfertility Group Trials Special Register, the Cochrane Central Register of Controlled Trials (the Cochrane Library, 2006, issue 3), MEDLINE (1966 to May 2006), EMBASE (1980 to May 2006), SCIsearch and the reference lists of articles. We hand searched abstracts of the American Society for Reproductive Medicine, the European Society for Human Reproduction and Embryology. Authors of identified articles were contacted for unpublished data. SELECTION CRITERIA: Randomised controlled trials (RCT's) with at least one of the following comparisons were included: 1) IUI versus TI or expectant management both in natural cycles 2) IUI versus TI both in cycles with OH 3) IUI in natural cycles versus TI + OH 4) IUI + OH versus TI in natural cycles 5) IUI in natural cycles versus IUI + OH Couples with abnormal sperm parameters only were included. DATA COLLECTION AND ANALYSIS: Two co-reviewers independently performed quality assessment and data extraction. Where possible data were pooled, and a meta-analysis was performed. Sensitivity and subgroup analyses were carried out where possible and appropriate. MAIN RESULTS: Three trials of parallel design, and five trials of cross-over design with pre-cross-over data were included in the meta-analysis. Three compared IUI with TI both in stimulated cycles. The remaining four of these studies compared IUI versus IUI + OH . Three studies reported on our main outcome of interest live birth rate per couple. For the comparison IUI versus TI both in natural cycles no evidence of difference between the probabilities of pregnancy rates per woman after IUI compared with TI was found (Peto OR 5.3, 95% CI 0.42 to 67). No statistically significant of difference between pregnancy rates (PR) per couple for IUI + OH versus IUI could be found (Peto OR 1.47, 95% CI 0.92 to 2.37). For the comparison IUI versus TI both in stimulated cycles there was no evidence of statistically significant difference in pregnancy rates per couple either (Peto OR 1.67, 95% CI 0.83 to 3.37). There were insufficient data available for adverse outcomes such as OHSS, multiple pregnancy, miscarriage rate and ectopic pregnancy to perform a statistical analysis. For the other two comparisons no RCT's were found which reported pregnancy rates per couple. A further 10 studies which included one of the comparisons of interests were found. Since these studies reported pregnancy rates per cycle only these data could not be included in the meta-analysis. AUTHORS' CONCLUSIONS: There was insufficient evidence of effectiveness to recommend or advise against IUI with or without OH above TI, or vice versa. Large, high quality randomised controlled trials, comparing IUI with or without OH with pregnancy rate per couple as the main outcome of interest are lacking. There is a need for such trials since firm conclusions cannot be drawn ye