DOI: 10.1016/j.fertnstert.2025.03.009
Published: 16 April 2025
Michael P Rimmer, Ruth A Howie, Richard A Anderson, Christopher L R Barratt, Kurt T Barnhart, Yusuf Beebeejaun, Ricardo Pimenta Bertolla, Pietro Bortoletto, Robert E Brannigan, Astrid E P Cantineau, Ettore Caroppo, Barbara L Collura, Kevin Coward, William Colin Duncan, Michael L Eisenberg, Steven A Gellatly, Christian De Geyter, Dimitrios G Goulis, Ralf R Henkel, Vu N A Ho, Alayman F Hussein, Carin Huyser, Jozef H Kadijk , Mohan S Kamath, Shadi Khashaba, Hajra Khattak, Yoshitomo Kobori, Julia Kopeika, Tansu Kucuk, Saturnino Luján, Thabo Christopher Matsaseng, Raj S Mathur, Kevin McEleny, Rod T Mitchell, Ben W Mol, Alfred M Murage, Ernest H Y Ng, Allan Pacey, Antti H Perheentupa, Stefan Du Plessis, Nathalie Rives, Ippokratis Sarris, Peter N Schlegel, Majid Shabbir, Maciej Śmiechowski, Venkatesh Subramanian, Sesh K Sunkara, Basil C Tarlarzis, Frank Tüttelmann, Andy Vail, Madelon van Wely, Mónica H Vazquez-Levin, Lan N Vuong, Alex Y Wang, Rui Wang, James M N Duffy, Cindy M Farquhar, Craig Niederberger
Authors information
1Centre for Reproductive Health, Institute of Regeneration and Repair, University of Edinburgh, Edinburgh, United Kingdom; Edinburgh Fertility Centre, Simpsons Centre for Reproductive Health, Royal Infirmary of Edinburgh, Edinburgh, United Kingdom. Electronic address: michael.rimmer@ed.ac.uk.
2Edinburgh Fertility Centre, Simpsons Centre for Reproductive Health, Royal Infirmary of Edinburgh, Edinburgh, United Kingdom.
3Centre for Reproductive Health, Institute of Regeneration and Repair, University of Edinburgh, Edinburgh, United Kingdom; Edinburgh Fertility Centre, Simpsons Centre for Reproductive Health, Royal Infirmary of Edinburgh, Edinburgh, United Kingdom.
4Reproductive Medicine Research Group, Ninewells Hospital and Medical School, University of Dundee, Dundee, United Kingdom.
5Department of Obstetrics and Gynaecology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.
6King’s Fertility, The Fetal Medicine Research Institute, King’s College London, London, United Kingdom.
7Division of Urology, Department of Surgery, Universidade Federal de Sao Paulo, Sao Paulo, Brazil; Department of Obstetrics and Gynecology, School of Medicine, C.S. Mott Center for Human Growth and Development, Wayne State University, Detroit, Michigan, USA.
8Boston IVF, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA.
9Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA.
10Centre of Reproductive Medicine, University of Groningen, University Medical Centre Groningen, Groningen, The Netherlands.
11ASL Bari, Andrology Outpatients Clinic, Conversano, Italy.
12RESOLVE: The National Infertility Association, USA.
13Nuffield Department of Women’s & Reproductive Health, University of Oxford, Level 3, Women’s Centre, John Radcliffe Hospital, Oxford, United Kingdom.
14Stanford University, Stanford, California, USA.
15Reproductive Medicine and Gynaecological Endocrinology (RME), University Hospital, University of Basel, Basel, Switzerland.
16Units of Human Reproduction and Reproductive Endocrinology, 1st Department of Obstetrics and Gynaecology, Medical School, Aristotle University of Thessaloniki, Thessaloniki, Greece.
17Department of Digestion, Metabolism and Reproduction, Imperial College London, London, United Kingdom; Department of Medical Bioscience, University of the Western Cape, Bellville, South Africa; LogixX Pharma Ltd., Theale, United Kingdom.
18IVFMD and HOPE Research Centre, My Duc Hospital, Ho Chi Minh City, Vietnam.
19Minia University, Minia, Egypt.
20Reproductive Biology Laboratory, Department of Obstetrics and Gynaecology, University of Pretoria, Pretoria, South Africa.
21Freya-Dutch Patient Association for Infertility, Gorinchem, The Netherlands.
22Department of Reproductive Medicine and Surgery, Christian Medical College, Vellore, India.
23University of New South Wales, Sydney, Australia; IVF Australia, Sydney, Australia.
24Department of Reproductive Health, Elizabeth Garrett Anderson Institute for Women’s Health, University College London, London, United Kingdom.
25Dokkyo Medical University Saitama Medical Center, Koshigaya, Japan.
26Guy’s & St Thomas’ Hospital NHS Trust, London, United Kingdom.
27Acibadem Maslak Hospital, Istanbul, Turkey.
28Urology Department, Hospital Universitari i Politècnic La Fe, Valencia, Spain.
29Department of Obstetrics & Gynaecology, Stellenbosch University, Stellenbosch, Western Cape, South Africa; Tygerberg Academic Hospital, Cape Town, South Africa.
30Manchester University Foundation Trust, Manchester Academic Health Sciences Centre, Manchester, United Kingdom.
31Newcastle Fertility, The Newcastle upon Tyne Hospitals NHS Trust, Newcastle, United Kingdom.
32Centre for Reproductive Health, Institute of Regeneration and Repair, University of Edinburgh, Edinburgh, United Kingdom.
33Department of Obstetrics and Gynaecology, Monash University, Clayton, Australia.
34Harley Street Fertility Centre, Nairobi, Kenya.
35Department of Obstetrics and Gynaecology, The University of Hong Kong, Hong Kong Special Administrative Region, Hong Kong, China.
36School of Medical Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United Kingdom.
37Department of Obstetrics and Gynaecology, University of Turku and Turku University Hospital, Turku, Finland.
38College of Medicine, Mohammed Bin Rashid University of Medicine and Health Sciences, Dubai, UAE; Medical Physiology, Stellenbosch University, Tygerberg, South Africa.
39Univ Rouen Normandie, Inserm U1239, NorDIC, Team “Adrenal and Gonadal Pathophysiology”, Rouen University Hospital, Biology of Reproduction-CECOS Laboratory, Rouen, France.
40King’s Fertility, The Fetal Medicine Research Institute, King’s College London, London, United Kingdom; Faculty of Life Sciences and Medicine, King’s College London, London, United Kingdom.
41New York Men’s Health, PLLC, New York, New York, USA.
42Association for Infertility Treatment and Adoption Support “Our Stork”, Warsaw, Poland; Fertility Europe VZW, Evere, Belgium.
43Faculty of Life Sciences and Medicine, King’s College London, London, United Kingdom.
44Centre of Medical Genetics, Institute of Reproductive Genetics, University of Münster, Münster, Germany.
45Centre for Biostatistics, University of Manchester, Manchester Academic Health Science Centre, Manchester, United Kingdom.
46Netherlands Satellite of the Cochrane Gynaecology and Fertility Group, Centre for Reproductive Medicine, Amsterdam, Netherlands; Reproduction & Development Research Institute, Amsterdam University Medical Centre, Amsterdam, Netherlands.
47Laboratorio de Estudios de Interacción Celular en Reproducción y Cáncer. Instituto de Biología y Medicina Experimental (IBYME), Consejo Nacional de Investigaciones Científicas y Técnicas de Argentina (CONICET), Buenos Aires, Argentina.
48Department of Obstetrics and Gynaecology, University of Medicine and Pharmacy at Ho Chi Minh City, Ho Chi Minh City, Vietnam.
49Faculty of Health, University of Technology Sydney, Sydney, Australia.
50NHMRC Clinical Trials Centre, University of Sydney, Sydney, Australia.
51Centre for Reproductive Medicine, St Bartholomew’s Hospital, Barts Health NHS Trust, London, United Kingdom; Department of Women’s Health, Kings College London, London, United Kingdom.
52Cochrane Gynaecology and Fertility Group, Auckland, New Zealand; Department of Obstetrics and Gynaecology, University of Auckland, Auckland, New Zealand.
53Department of Urology, University of Illinois at Chicago, Chicago, Illinois, USA; Department of Bioengineering, University of Illinois at Chicago College of Engineering, Chicago, Illinois, USA.
Abstract
STUDY QUESTION
Can a core outcome set be developed through a global consensus to standardize outcome selection, collection, comparison, and reporting in future male infertility trials?
SUMMARY ANSWER
A minimum dataset, known as a ‘core outcome set’, has been developed for randomized controlled trials (RCTs) and systematic reviews evaluating potential interventions for male infertility.
WHAT IS KNOWN ALREADY
Numerous factors, including a failure to consider the perspectives of men with lived experiences of infertility or their partners when developing and conducting RCTs can limit their clinical utility. Selection of outcomes, variations in outcome definitions, and the selective reporting of outcomes based on statistical analysis make the results of infertility research challenging to interpret, compare, and implement. For male infertility, this is further compounded by there being potentially three participants, the male, their female partner, and any offspring born, all with outcomes to be reported. This has led to significant heterogeneity in trial design and reporting. While a core outcome set for general infertility trials has been developed, there is no such outcome set for male infertility trials.
STUDY DESIGN, SIZE, DURATION
A two-round Delphi survey (334 participants from 39 countries) and consensus development workshops (44 participants from 21 countries).
PARTICIPANTS/MATERIALS, SETTING, METHODS
Healthcare professionals, researchers, and men and women with infertility were brought together in a transparent process using formal consensus science methods.
MAIN RESULTS AND THE ROLE OF CHANCE
The core outcome set for male infertility trials has been developed by the inclusion of specific male-factor outcomes in addition to the general infertility core outcome set. These outcomes include assessment of semen using the World Health Organization recommendations for semen analysis; viable intrauterine pregnancy confirmed by ultrasound (accounting for singleton, twin, and higher multiple pregnancies); 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. Although not a requirement as part of the core outcome set, other outcomes were identified as potentially useful in certain study settings.
LIMITATIONS, REASONS FOR CAUTION
We used consensus development methods in this work, 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, which are inconsistently reported at present. 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 for male infertility trials.
STUDY FUNDING/COMPETING INTEREST(S)
This work was funded by The Urology Foundation, Small Project Fund awarded to Michael P Rimmer at the University of Edinburgh, UK. RTM was supported by a United Kingdom Research and Innovation (UKRI) Future Leaders Fellowship (MR/Y011783/1). C.L.R.B. is the co-editor in chief of Human Reproduction and 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. R.P.B. receives royalties from Flow diagnósticos. M.L.E. is an advisor to the companies Hannah, Illumicell, Next, Legacy, Doveras, Vseat and received a consultancy fee for this. B.W.M. is a paid consultant for Norgine and Organon and has received research funding from Ferring and Merck, he also receives consultancy and travel support from Merck. R.R.H. received royalties from Elsevier for a book, consultancy fees from Glyciome, and presentation fees from GryNumber Health and Aytu Bioscience. 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. has been an associate editor with Human Reproduction Open. K.Mc.E. received funding to attend Fertility 2025 by the British Fertility Society and is the Chair of the British Fertility Society. He is a member of the HFEA’s Scientific and Clinical Advances Advisory Committee and a Committee Member of the NICE Fertility Problems Guideline Group. M.H.V.L. receives consultation fees for the WHO Manual Spanish translation, and travel expenses for the ESHRE MRHI meeting in Budapest. She is a member of the editorial board for Fertility & Sterility, F&S Science, Human Reproduction, and Frontiers in Endocrinology. She is also a panel member of the World Health Organization (WHO) Human Reproduction Programme (HRP) Research Project Review Panel. R.S.M. is a member of the NICE Guideline Committee on Fertility and former chair of the British Fertility Society. A. Perheentupa receives an honoraria for lecturing from Merck for the Tackling Infertility manifest, Gedeon Richter & Ferring. A. Perheentupa declares lecture honoraria from Merck, Gideon Richter, and Ferring; and payment from Merck for the Tackling Infertility manifesto. A. Pacey receives consultancy fees for Carrot Fertility and Cryos International as well as lecturing for IBSA Institut Biochimique SA and Mealis Group—all fees paid to The University of Manchester. He is also a Trustee of Progress Educational. Trust (Charity Number 1139856) and Chairman of UKNEQAS Reproductive Sciences Advisory Committee. F.T. is the recipient of a Bayer research grant, as well as DFG Clinical Research Unit ‘Male Germ Cells’ (CRU326, project number 329621271) and BMBF Junior Scientist Research Centre ‘ReproTrack.MS’ (grant 01GR2303), he has received travel support from IBSA and Organon. M.v.W. is the Editor-in-Chief of Human Reproduction Update. R.W. is a former Deputy Editor of Human Reproduction and is currently a Deputy Editor of Human Reproduction Update.
TRIAL REGISTRATION NUMBER
Core Outcome Measures in Effectiveness Trials (COMET) initiative registration No: 1586. Available at www.comet-initiative.org/Studies/Details/1586.