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. TRIAL REGISTRATION NUMBER: Core Outcome Measures in Effectiveness Trials (COMET) initiative registration No: 1586. Available at www.comet-initiative.org/Studies/Details/1586. TRIAL REGISTRATION DATE: N/A. DATE OF FIRST PATIENT'S ENROLMENT: N/A.

Global epidemiology of Neisseria gonorrhoeae in infertile populations: systematic review, meta-analysis and metaregression.

OBJECTIVE: To provide an in-depth systematic assessment of the global epidemiology of gonorrhoea infection in infertile populations. METHODS: A systematic literature review was conducted up to 29 April 2019 on international databases and WHO regional databases, and reported following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. All prevalence measures of gonorrhoea infection among infertile populations, based on primary data, qualified for inclusion. Infertile populations were broadly defined to encompass women/men undergoing infertility evaluation or treatment (infertility clinic attendees and partners). Pooled mean prevalence by relevant strata was estimated using random-effects meta-analysis. Associations with prevalence and sources of heterogeneity were explored using metaregression. Risk of bias was assessed using four quality domains. FINDINGS: A total of 147 gonorrhoea prevalence studies were identified from 56 countries. The pooled mean prevalence of current gonorrhoea infection was estimated globally at 2.2% (95% CI 1.3% to 3.2%), with the highest prevalence in Africa at 5.0% (95% CI 1.9% to 9.3%). The mean prevalence was higher for populations with tubal factor infertility (3.6%, 95% CI 0.9%-7.7%) and mixed cause and unexplained infertility (3.6%, 95% CI 0.0% to 11.6%) compared with other diagnoses, such as ovarian and non-tubal infertility (0.1%, 95% CI 0.0% to 0.8%), and for secondary (2.5%, 95% CI 0.2% to 6.5%) compared with primary (0.5%, 95% CI 0.0% to 1.7%) infertility. Metaregression identified evidence of variations in prevalence by region and by infertility diagnosis, higher prevalence in women than men and a small-study effect. There was a trend of declining prevalence by about 3% per year over the last four decades (OR=0.97, 95% CI 0.95 to 0.99). CONCLUSIONS: Gonorrhoea prevalence in infertile populations is several folds higher than that in the general population, with even higher prevalence in women with tubal factor infertility and in individuals with secondary infertility. These findings support the potential role of gonorrhoea in infertility and suggest that some infertility is possibly preventable by controlling gonorrhoea transmission. PROSPERO REGISTRATION NUMBER: CRD42018102934.

The Use of Time to Pregnancy for Estimating and Monitoring Human Fecundity From Demographic and Health Surveys.

BACKGROUND: Available studies on the prevalence of infertility have proved to have certain limitations, with a scarcity of population-based studies and inconsistent reporting from surveys in countries at all income levels. We wanted to test the applicability of the current duration approach to data from the important Demographic and Health Surveys (DHS) program, funded by USAID since its inception in 1985, https://dhsprogram.com/. METHODS: The current duration approach assumes that there is a well-defined time of initiation of attempts to get pregnant and defines the current duration of a still ongoing pregnancy attempt as the time interval from initiation to interview. The DHS interviews do not have an explicit question about initiation. We focused on nullipari and substituted date of "establishment of relationship with current partner" for initiation. Our study used the current duration approach on 15 datasets from DHS during 2002-2016 in eight different countries from sub-Saharan Africa, Asia, and Latin America. RESULTS: Well-established statistical techniques for current duration data yielded results that for some countries postulated surprisingly long median times to pregnancy and surprisingly high estimates of infertility prevalence. Further study of the data structures revealed serious deviations from expected patterns, in contrast to our earlier experience from surveys in France and the United States where participants were asked explicitly about time of initiation of attempts to become pregnant. CONCLUSIONS: Using cohabitation as a proxy for the initiation of attempts to get pregnant is too crude. Using the current duration approach with DHS data will require more explicit questions during the DHS interviews about initiation of pregnancy attempt.

IVF and other ART in low- and middle-income countries: a systematic landscape analysis.

BACKGROUND: Infertility affects 48.5 million couples worldwide with a prevalence estimated at 3.5-16.7% in low- and middle-income countries (LMIC), and as high as 30-40% in Sub-Saharan Africa. ART services are not accessible to the majority of these infertile couples due to the high cost of treatments in addition to cultural, religious and legal barriers. Infertility and childlessness, particularly in LMIC, have devastating consequences, which has resulted in considerable interest in developing affordable IVF procedures. However, there is a paucity of evidence on the safety, efficiency and ability to replicate techniques under different field conditions, and how to integrate more affordable ART options into existing infrastructures. OBJECTIVE AND RATIONALE: This review was performed to investigate the current availability of IVF in LMIC and which other ART options are under development. This work will unfold the landscape of available and potential ART services in LMIC and is a key element in positioning infertility more broadly in the Global Public Health Agenda. SEARCH METHODS: A systematic literature search was performed of articles and gray literature on IVF and other ART options in LMIC published between January 2010 and January 2020. We selected studies on IVF and other ART treatments for infertile couples of reproductive age (18-44 years) from LMIC. The review was limited to articles published after 2010, based on the recent evolution in the field of ART practices in LMIC over the last decade. Citations from high-income countries, including data prior to 2010 and focusing on specialized ART procedures, were excluded. The literature search included PubMed, Popline, CINHAL, EMBASE and Global Index Medicus. No restrictions were applied with regard to study design or language. Two reviewers independently screened the titles and abstracts, and extracted data. A search for gray literature was performed using the 'Google' search engine and specific databases (worldcat.org, greylit.org). In addition, the reference lists of included studies were assessed. OUTCOMES: The search of the electronic databases yielded 3769 citations. After review of the titles and abstracts, 283 studies were included. The full texts were reviewed and a further 199 articles were excluded. The gray literature search yielded 586 citations, most of which were excluded after screening the title, and the remaining documents were excluded after full-text assessment due to duplicate entries, not from LMIC, not relevant or no access to the full document. Eighty-four citations were included as part of the review and separated into regions. The majority of the studies were observational and qualitative studies. In general, ART services are available and described in several LMIC, ranging from advanced techniques in China to basic introduction of IVF in some African countries. Efforts to provide affordable ART treatments are described in feasibility studies and efficacy studies; however, most citations were of low to very low quality. We found no studies from LMIC reporting the implementation of low-cost ART that is effective, accessible and affordable to most of those in need of the services. WIDER IMPLICATIONS: The World Health Organization is in a unique position to provide much needed guidance for infertility management in LMIC. This review provides insight into the landscape of ART in LMIC in various regions worldwide, which will guide efforts to improve the availability, quality, accessibility and acceptability of biomedical infertility care, including ART in these countries.

Estimating the government public economic benefits attributed to investing in assisted reproductive technology: a South African case study.

Limited resources and high treatment costs are arguments often used in many public health systems in low- and middle-income countries to justify providing limited treatments for people with infertility. In this analysis, we apply a government public economic perspective to evaluate public subsidy for in-vitro fertilization (IVF) in South Africa. A fiscal model was developed that considered lifetime direct and indirect taxes paid and government transfers received by a child conceived by IVF. The model was constructed from public data sources and was adjusted for mortality, age-specific educational costs, participation in the informal economy, proportions of persons receiving social grants, and health costs. Based on current proportions of individuals receiving social grants and average payments, including education and health costs, we estimate each citizen will receive ZAR513,165 (USD35,587) in transfers over their lifetime. Based on inflated age-specific earnings, we estimate lifetime direct and indirect taxes paid per citizen of ZAR452,869 (USD31,405) and ZAR494,521 (USD34,294), respectively, which also includes adjustments for the proportions of persons participating in the informal economy. The lifetime net tax after deducting transfers was estimated to be ZAR434,225 (USD31,112) per person. Based on the average IVF investment cost needed to achieve one live birth, the fiscal return on investment (ROI) for the South African Government is 5.64. Varying the discount rate from 4% to 7%, the ROI ranged from 9.54 to 1.53, respectively. Positive economic benefits can emanate from public financing of IVF. The fiscal analytic framework described here can be a useful approach for health services to evaluate future public economic benefits.

Should home-based ovulation predictor kits be offered as an additional approach for fertility management for women and couples desiring pregnancy? A systematic review and meta-analysis.

INTRODUCTION: To inform the WHO Guideline on self-care interventions, we conducted a systematic review of the impact of ovulation predictor kits (OPKs) on time-to-pregnancy, pregnancy, live birth, stress/anxiety, social harms/adverse events and values/preferences. METHODS: Included studies had to compare women desiring pregnancy who managed their fertility with and without OPKs, measure an outcome of interest and be published in a peer-reviewed journal. We searched for studies on PubMed, CINAHL, LILACS and EMBASE through November 2018. We assessed risk of bias assessed using the Cochrane tool for randomised controlled trials (RCTs) and the Evidence Project tool for observational studies, and conducted meta-analysis using random effects models to generate pooled estimates of relative risk (RR). RESULTS: Four studies (three RCTs and one observational study) including 1487 participants, all in high-income countries, were included. Quality of evidence was low. Two RCTs found no difference in time-to-pregnancy. All studies reported pregnancy rate, with mixed results: one RCT from the 1990s among couples with unexplained or male-factor infertility found no difference in clinical pregnancy rate (RR: 1.09, 95% CI 0.51 to 2.32); two more recent RCTs found higher self-reported pregnancy rates among OPK users (pooled RR: 1.40, 95% CI 1.08 to 1.80). A small observational study found higher rates of pregnancy with lab testing versus OPKs among women using donor insemination services. One RCT found no increase in stress/anxiety after two menstrual cycles using OPKs, besides a decline in positive affect. No studies measured live birth or social harms/adverse events. Six studies presented end-users' values/preferences, with almost all women reporting feeling satisfied, comfortable and confident using OPKs. CONCLUSION: A small evidence base, from high-income countries and with high risk of bias, suggests that home-based use of OPKs may improve fertility management when attempting to become pregnant with no meaningful increase in stress/anxiety and with high user acceptability. SYSTEMATIC REVIEW REGISTRATION NUMBER: PROSPERO registration number CRD42019119402.

Global epidemiology of Neisseria gonorrhoeae in infertile populations: protocol for a systematic review.

INTRODUCTION: A key target of the WHO's 'Global Health Sector Strategy on sexually transmitted infections, 2016-2021' is achieving 90% reduction in Neisseria gonorrhoeae (gonorrhoea for short) incidence globally by 2030. Though untreated, gonorrhoea has been linked to infertility, the epidemiology of this infection in infertile populations remains poorly understood and somewhat a neglected area of reproductive health. Our proposed systematic review aims to fill this gap by characterising comprehensively gonorrhoea infection in infertile populations globally. METHODS AND ANALYSIS: All available studies of gonorrhoea infection in infertile populations, including infertility clinic attendees, will be systematically reviewed informed by Cochrane Collaboration guidelines. Findings will be reported following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Data sources will be searched using broad index terms exploded to cover all subheadings and free text terms with no language or year restriction. Any epidemiological measure in infertile populations based on primary data will be eligible for inclusion. Measures based on different assay types will be extracted as separate studies for different analyses. Only one biospecimen type per assay type will be considered based on a predefined priority order. Samples including fewer than 10 participants or assessing infection in the upper genital tract will be excluded. Quality assessments will be conducted for all measures included in the review. Meta-analyses will be implemented using DerSimonian-Laird random effect models to estimate the mean prevalence of gonorrhoea in infertile populations globally, and stratified by WHO region, assay type, sex, infertility type, infertility diagnosis, among other factors. Detailed heterogeneity assessment will be performed, and potential sources of between-study heterogeneity will be explored using meta-regression. Review will be conducted from 26 March 2018 to 28 July 2019. ETHICS AND DISSEMINATION: An institutional review board clearance is not required as all data are publicly available. The findings will be disseminated through a peer-reviewed publication and international scientific meetings/workshops with key stakeholders. PROSPERO REGISTRATION NUMBER: CRD42018102934.

Mild ovarian stimulation for in vitro fertilization: are we ready to change? A meta-analysis.

OBJECTIVE: To compare the efficacy of mild ovarian stimulation versus conventional stimulation in in vitro fertilization (IVF). DESIGN: Meta-analysis. SEARCH STRATEGY: A systemic literature search was carried out for prospective randomised clinical trials. We electronically searched using PubMed, Medline and Embase for all the studies published from 1990 to December 2011. INTERVENTIONS: Mild ovarian stimulation IVF that uses lower doses and/or shorter duration of gonadotrophins in GnRH antagonist co-treated cycle compared with conventional stimulation IVF. MAIN OUTCOME MEASURES: Live birth rates per started cycle and ongoing pregnancy rates per started cycle of IVF. RESULTS: On live birth rate, there was a significant difference in favour of the conventional stimulation [70/444 (15.7%) mild vs. 78/325 (24%) conventional] (OR 0.59, CI 0.41-0.85, p = 0.004). Similar findings were observed in the ongoing pregnancy data [140/696 (20%) mild vs. 144/547 (26%) in favour of conventional stimulation] (OR 0.72, CI 0.55-0.93, p = 0.01). The sub-analysis of two studies showed a statistically significant reduction of hyperstimulation syndrome in favour of the mild stimulation (OR 0.27, CI 0.11-0.66). CONCLUSION: This analysis presents strong evidence in favour of conventional stimulation IVF, which therefore should currently be considered a treatment of choice for patients requiring IVF treatment.