Patients with low prognosis in ART: a Delphi consensus to identify potential clinical implications and measure the impact of POSEIDON criteria.

BACKGROUND: Currently, there is no consensus on the optimal management of women with low prognosis in ART. In this Delphi consensus, a panel of international experts provided real-world clinical perspectives on a series of literature-supported consensus statements regarding the overall relevance of the POSEIDON criteria for women with low prognosis in ART. METHODS: Using a Delphi-consensus framework, twelve experts plus two Scientific Coordinators discussed and amended statements and supporting references proposed by the Scientific Coordinators (Round 1). Statements were distributed via an online survey to an extended panel of 53 experts, of whom 36 who voted anonymously on their level of agreement or disagreement with each statement using a six-point Likert-type scale (1 = Absolutely agree; 2 = More than agree; 3 = Agree; 4 = Disagree; 5 = More than disagree; 6 = Absolutely disagree) (Round 2). Consensus was reached if > 66% of participants agreed or disagreed. RESULTS: The extended panel voted on seventeen statements and subcategorized them according to relevance. All but one statement reached consensus during the first round; the remaining statement reached consensus after rewording. Statements were categorized according to impact, low-prognosis validation, outcomes and patient management. The POSEIDON criteria are timely and clinically sound. The preferred success measure is cumulative live birth and key management strategies include the use of recombinant FSH preparations, supplementation with r-hLH, dose increases and oocyte/embryo accumulation through vitrification. Tools such as the ART Calculator and Follicle-to-Oocyte Index may be considered. Validation data from large, prospective studies in each POSEIDON group are now needed to corroborate existing retrospective data. CONCLUSIONS: This Delphi consensus provides an overview of expert opinion on the clinical implications of the POSEIDON criteria for women with low prognosis to ovarian stimulation.

Expert Opinion on Refined and Extended Key Performance Indicators for Individualized Ovarian Stimulation for ART.

OBJECTIVE: To assess the adequate ovarian follicular development and oocyte recovery between ovarian potential (antral follicle count [AFC]) before the start of ovarian stimulation (OS) and oocyte quantity and quality at oocyte retrieval. A holistic overview of the current key performance indicators (KPIs) was applied to identify the complementary strengths and identify where the current repertoire can be expanded. DESIGN: Expert opinion. SUBJECTS: Not applicable. INTERVENTION: None. MAIN OUTCOME MEASURES: To formulate a proposal for a refined and expanded repertoire of KPIs for individualized OS for Assisted Reproductive Technology. RESULTS: The performance and outcomes of OS on ovarian follicular development can be evaluated through the application of defined KPIs. Current KPIs for OS are the ovarian sensitivity index (OSI), the follicular output rate (FORT), the oocyte retrieval rate (ORR), and the follicle to oocyte index (FOI). Notably, there are no specific KPIs dedicated to the assessment of follicular development (i.e., recruitment, selection, growth and dominance). In light of this, we recommend expanding the current KPIs for OS to include "Early FORT" (accounting for the number of follicles measuring ≥10-11 mm on Day 5/6 of OS relative to AFC) and "Modified FORT" (the ratio between the number of follicles measuring ≥12 mm at the time of oocyte maturation triggering and AFC); the extension of ORR to include two discrete categories at oocyte retrieval: follicles ≥12 mm and follicles ≥16 mm, to ensure all responsive follicles are accounted for; and FOI to be measured at oocyte maturation triggering and oocyte retrieval ("Advanced FOI"). CONCLUSIONS: Once validated and adopted in clinical practice, we envisage that the proposed expanded KPIs measuring the effect of OS on follicular development (recruitment, selection, growth and dominance) will increase the understanding of the relationship between ovarian reserve measured by AFC and oocyte quantity and quality at oocyte retrieval. This understanding will enable physicians to better evaluate the direct effect of different gonadotropins and doses on ovarian response, leading to a more personalized approach to OS in the context of ART treatment.

Analytical Investigation of the Profile of Human Chorionic Gonadotropin in Highly Purified Human Menopausal Gonadotrophin Preparations.

Highly purified human menopausal gonadotropin (HP-hMG [Menopur®, Ferring Pharmaceuticals, Saint-Prex, Switzerland]) contains a 1:1 ratio of follicle-stimulating hormone (FSH) and luteinizing hormone (LH). This analysis aimed to assess gonadotropin (FSH, LH and hCG) abundance in HP-hMG and clarify the source of hCG by assessing the presence of sulfated glycans, which are diagnostic for pituitary hCG forms due to their distinct glycosylation patterns. Additionally, the purity of each sample, their specific components, and their oxidation levels were assessed. HP-hMG samples (three of Menopur® and two of Menogon® Ferring Pharmaceuticals, Saint-Prex, Switzerland) were included in the current analyses. Brevactid® (urinary hCG; Ferring Pharmaceuticals, Saint-Prex, Switzerland) and Ovidrel® (recombinant hCG; Merck KGaA, Darmstadt, Germany) were used as control samples. Glycopeptide mapping and analysis of impurities were carried out by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Oxidation was assessed through reducing peptide mapping using LC-MS/MS. The FSH and LH in the HP-hMG samples showed sulfated glycans, while no signals of sulfated glycopeptides were detected on any site of the beta subunit of hCG. HP-hMG test samples presented the same hCG glycan distribution as the control sample (placental hCG, Brevactid®) extracted from the urine of pregnant women, suggesting a non-pituitary source of hCG. Protein impurities were estimated to constitute approximately 20-30% of the entire HP-hMG protein content in the test samples. More than 200 non-gonadotropin proteins were identified in the HP-hMG test samples, of which several were involved in embryonic development or pregnancy. The alpha subunit of the tested samples was strongly oxidized, with a relative abundance of 20% of the total gonadotropin content. Without taking into account all the protein impurities, the beta subunit of LH was detected only in traces (0.9-1.2%) in all tested HP-HMG samples, confirming the data obtained by intact molecule analysis, while high levels of beta hCG (18-47%) were observed. Advanced molecular analysis of HP-hMG indicates a primarily placental origin of hCG, as evidenced by the absence of hCG sulfated glycans and the predominance of placental non-sulfated hCG in LH activity. The analysis revealed 20-30% of protein impurities and a significant presence of oxidized forms in the HP-hMG samples. These findings are critical for understanding the quality, safety, and clinical profile of HP-hMG.

Recommendations from the 2024 Australian evidence-based guideline for unexplained infertility: ADAPTE process from the ESHRE evidence-based guideline on unexplained infertility.

INTRODUCTION: The 2024 Australian evidence-based guideline for unexplained infertility provides clinicians with evidence-based recommendations for the optimal diagnostic workup for infertile couples to establish the diagnosis of unexplained infertility and optimal therapeutic approach to treat couples diagnosed with unexplained infertility in the Australian health care setting. The guideline recommendations were adapted for the Australian context from the rigorous, comprehensive European Society of Human Reproduction and Embryology (ESHRE) 2023 Evidence-based guideline: unexplained infertility, using the ADAPTE process and have been approved by the Australian National Health and Medical Research Council. MAIN RECOMMENDATIONS: The guideline includes 40 evidence-based recommendations, 21 practice points and three research recommendations addressing: definition - defining infertility and frequency of intercourse, infertility and age, female and male factor infertility; diagnosis - ovulation, ovarian reserve, tubal factor, uterine factor, laparoscopy, cervical/vaginal factor, male factor, additional testing for systemic conditions; and treatment - expectant management, active treatment, mechanical-surgical procedures, alternative therapeutic approaches, quality of life. CHANGES IN ASSESSMENT AND MANAGEMENT RESULTING FROM THE GUIDELINE: This guideline refines the definition of unexplained infertility and addresses basic diagnostic procedures for infertility assessment not considered in previous guidelines on unexplained infertility. For therapeutic approaches, consideration of evidence quality, efficacy, safety and, in the Australian setting, feasibility, acceptability, cost, implementation and ultimately recommendation strength were integrated across multidisciplinary expertise and consumer perspectives in adapting recommendations to the Australian context by using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) framework, which had not been used in past guidelines on unexplained infertility to formulate recommendations. The Australian process also included an established data integrity check to ensure evidence could be trusted to guide practice. Practice points were added and expanded to consider the Australian setting. No evidence-based recommendations were underpinned by high quality evidence, with most having low or very low quality evidence. In this context, research recommendations were made including those for the Australian context. The full guideline and technical report are publicly available online and can be accessed at https://www.monash.edu/medicine/mchri/infertility and are supported by extensive translation resources, including the free patient ASKFertility mobile application (https://www.askfertility.org/).

In vitro fertilisation for unexplained subfertility.

BACKGROUND: In vitro fertilisation (IVF) is a treatment for unexplained subfertility but is invasive, expensive, and associated with risks. OBJECTIVES: To evaluate the effectiveness and safety of IVF versus expectant management, unstimulated intrauterine insemination (IUI), and IUI with ovarian stimulation using gonadotropins, clomiphene citrate (CC), or letrozole in improving pregnancy outcomes. SEARCH METHODS: We searched following databases from inception to November 2021, with no language restriction: Cochrane Gynaecology and Fertility Register, CENTRAL, MEDLINE, Embase, PsycINFO, CINAHL. We searched reference lists of articles and conference abstracts. SELECTION CRITERIA: Randomised controlled trials (RCTs) comparing effectiveness of IVF for unexplained subfertility with expectant management, unstimulated IUI, and stimulated IUI. DATA COLLECTION AND ANALYSIS: We followed standard Cochrane methods. MAIN RESULTS: IVF versus expectant management (two RCTs) We are uncertain whether IVF improves live birth rate (LBR) and clinical pregnancy rate (CPR) compared to expectant management (odds ratio (OR) 22.0, 95% confidence interval (CI) 2.56 to 189.37; 1 RCT; 51 women; very low-quality evidence; OR 3.24, 95% CI 1.07 to 9.8; 2 RCTs; 86 women; I2 = 80%; very low-quality evidence). Adverse effects were not reported. Assuming 4% LBR and 12% CPR with expectant management, these would be 8.8% to 9% and 13% to 58% with IVF. IVF versus unstimulated IUI (two RCTs) IVF may improve LBR compared to unstimulated IUI (OR 2.47, 95% CI 1.19 to 5.12; 2 RCTs; 156 women; I2 = 60%; low-quality evidence). We are uncertain whether there is a difference between IVF and IUI for multiple pregnancy rate (MPR) (OR 1.03, 95% CI 0.04 to 27.29; 1 RCT; 43 women; very low-quality evidence) and miscarriage rate (OR 1.72, 95% CI 0.14 to 21.25; 1 RCT; 43 women; very low-quality evidence). No study reported ovarian hyperstimulation syndrome (OHSS). Assuming 16% LBR, 3% MPR, and 6% miscarriage rate with unstimulated IUI, these outcomes would be 18.5% to 49%, 0.1% to 46%, and 0.9% to 58% with IVF. IVF versus IUI + ovarian stimulation with gonadotropins (6 RCTs), CC (1 RCT), or letrozole (no RCTs) Stratified analysis was based on pretreatment status. Treatment-naive women There may be little or no difference in LBR between IVF and IUI + gonadotropins (1 IVF to 2 to 3 IUI cycles: OR 1.19, 95% CI 0.87 to 1.61; 3 RCTs; 731 women; I2 = 0%; low-quality evidence; 1 IVF to 1 IUI cycle: OR 1.63, 95% CI 0.91 to 2.92; 2 RCTs; 221 women; I2 = 54%; low-quality evidence); or between IVF and IUI + CC (OR 2.51, 95% CI 0.96 to 6.55; 1 RCT; 103 women; low-quality evidence). Assuming 42% LBR with IUI + gonadotropins (1 IVF to 2 to 3 IUI cycles) and 26% LBR with IUI + gonadotropins (1 IVF to 1 IUI cycle), LBR would be 39% to 54% and 24% to 51% with IVF. Assuming 15% LBR with IUI + CC, LBR would be 15% to 54% with IVF. There may be little or no difference in CPR between IVF and IUI + gonadotropins (1 IVF to 2 to 3 IUI cycles: OR 1.17, 95% CI 0.85 to 1.59; 3 RCTs; 731 women; I2 = 0%; low-quality evidence; 1 IVF to 1 IUI cycle: OR 4.59, 95% CI 1.86 to 11.35; 1 RCT; 103 women; low-quality evidence); or between IVF and IUI + CC (OR 3.58, 95% CI 1.51 to 8.49; 1 RCT; 103 women; low-quality evidence). Assuming 48% CPR with IUI + gonadotropins (1 IVF to 2 to 3 IUI cycles) and 17% with IUI + gonadotropins (1 IVF to 1 IUI cycle), CPR would be 44% to 60% and 28% to 70% with IVF. Assuming 21% CPR with IUI + CC, CPR would be 29% to 69% with IVF. There may be little or no difference in multiple pregnancy rate (MPR) between IVF and IUI + gonadotropins (1 IVF to 2 to 3 IUI cycles: OR 0.82, 95% CI 0.38 to 1.77; 3 RCTs; 731 women; I2 = 0%; low-quality evidence; 1 IVF to 1 IUI cycle: OR 0.76, 95% CI 0.36 to 1.58; 2 RCTs; 221 women; I2 = 0%; low-quality evidence); or between IVF and IUI + CC (OR 0.64, 95% CI 0.17 to 2.41; 1 RCT; 102 women; low-quality evidence). We are uncertain if there is a difference in OHSS between IVF and IUI + gonadotropins with 1 IVF to 2 to 3 IUI cycles (OR 6.86, 95% CI 0.35 to 134.59; 1 RCT; 207 women; very low-quality evidence); and there may be little or no difference in OHSS with 1 IVF to 1 IUI cycle (OR 1.22, 95% CI 0.36 to 4.16; 2 RCTs; 221 women; I2 = 0%; low-quality evidence). There may be little or no difference between IVF and IUI + CC (OR 1.53, 95% CI 0.24 to 9.57; 1 RCT; 102 women; low-quality evidence). We are uncertain if there is a difference in miscarriage rate between IVF and IUI + gonadotropins with 1 IVF to 2 to 3 IUI cycles (OR 0.31, 95% CI 0.03 to 3.04; 1 RCT; 207 women; very low-quality evidence); and there may be little or no difference with 1 IVF to 1 IUI cycle (OR 1.16, 95% CI 0.44 to 3.02; 1 RCT; 103 women; low-quality evidence). There may be little or no difference between IVF and IUI + CC (OR 1.48, 95% CI 0.54 to 4.05; 1 RCT; 102 women; low-quality evidence). In women pretreated with IUI + CC IVF may improve LBR compared with IUI + gonadotropins (OR 3.90, 95% CI 2.32 to 6.57; 1 RCT; 280 women; low-quality evidence). Assuming 22% LBR with IUI + gonadotropins, LBR would be 39% to 65% with IVF. IVF may improve CPR compared with IUI + gonadotropins (OR 14.13, 95% CI 7.57 to 26.38; 1 RCT; 280 women; low-quality evidence). Assuming 30% CPR with IUI + gonadotropins, CPR would be 76% to 92% with IVF. AUTHORS' CONCLUSIONS: IVF may improve LBR over unstimulated IUI. Data should be interpreted with caution as overall evidence quality was low.

Number of oocytes and IVF outcomes: Real-world evidence.

Randomized controlled trials (RCTs) are gold standard to study the effect of an intervention and establish causation between the treatment and outcomes. However, RCTs have the disadvantage of being expensive, entailing high resource investments and involving only selected patient populations under experimental settings. Real-world evidence (RWE) from real-world data (RWD) involves a heterogenous patient population in real-world settings. RWE is less expensive and quicker than RCTs; it can provide complimentary evidence if methodological challenges, such as residual confounding and susceptibility to bias, are considered when interpreting the findings. This review examines RWE regarding the association between the number of oocytes following ovarian stimulation and IVF outcomes into shaping current IVF practices.

Treatment algorithms for high responders: What we can learn from randomized controlled trials, real-world data and models.

A high ovarian response to conventional ovarian stimulation (OS) is characterized by an increased number of follicles and/or oocytes compared with a normal response (10-15 oocytes retrieved). According to current definitions, a high response can be diagnosed before oocyte pick-up when >18-20 follicles ≥11-12 mm are observed on the day of ovulation triggering; high response can be diagnosed after oocyte pick-up when >18-20 oocytes have been retrieved. Women with a high response are also at high risk of early ovarian hyper-stimulation syndrome (OHSS)/or late OHSS after fresh embryo transfers. Women at risk of high response can be diagnosed before stimulation based on several indices, including ovarian reserve markers (anti-Müllerian hormone [AMH] and antral follicle count [AFC], with cutoff values indicative of a high response in patients with PCOS of >3.4 ng/mL for AMH and >24 for AFC). Owing to the high proportion of high responders who are at the risk of developing OHSS (up to 30%), this educational article provides a framework for the identification and management of patients who fall into this category. The risk of high response can be greatly reduced through appropriate management, such as individualized choice of the gonadotropin starting dose, dose adjustment based on hormonal and ultrasound monitoring during OS, the choice of down-regulation protocol and ovulation trigger, and the choice between fresh or elective frozen embryo transfer. Appropriate management strategies still need to be defined for women who are predicted to have a high response and those who have an unexpected high response after starting treatment.

Effect of female body mass index on intrauterine insemination outcomes: a systematic review and meta-analysis.

The prevalence of women with a raised body mass index (BMI) seeking assisted conception treatment is increasing. Findings of existing studies evaluating the effect of female BMI on intrauterine insemination (IUI) treatment outcomes remain inconsistent. This systematic review and meta-analysis evaluate the effect of female BMI on IUI treatment outcomes. Two authors independently conducted data extraction and assessed study quality. Risk ratios (RR) and 95% confidence intervals were calculated using the Mantel-Haenszel approach for dichotomous outcomes. 11 studies involving 23,145 IUI treatment events, comprising 21,211 cycles from 8 studies, and 1,934 participants in three studies, met the inclusion criteria for the meta-analysis. Two cohorts of women undergoing IUI treatment were compared - women with normal BMI < 25 kg/m2 were compared with a second cohort of women with a BMI category ≥ 25 kg/m2. There was no statistically significant difference in live birth rate (LBR) (RR 1.06, 95% CI 0.86-1.307); clinical pregnancy rate (CPR) (RR 0.94, 95% CI 0.78-1.13); miscarriage (RR 0.92, 95% CI 0.31-2.74) or ectopic pregnancy rate (RR 2.20, 95% CI 0.78-6.23). Our meta-analysis showed that a raised female BMI did not affect IUI treatment outcomes. Nevertheless, weight loss counselling should be offered to women with a raised BMI undergoing IUI, to reduce the associated obstetric morbidity.

A meta-analysis of 11 studies found that having a raised female BMI did not change IUI treatment outcomes.

Endometriosis and oocyte quality: an analysis of 13 614 donor oocyte recipient and autologous IVF cycles.

STUDY QUESTION: Does endometriosis affect live birth following donor oocyte recipient versus autologous IVF? SUMMARY ANSWER: There was no significant difference in the live birth rate (LBR) in women with endometriosis undergoing donor oocyte recipient cycles versus autologous IVF cycles. WHAT IS KNOWN ALREADY: For infertile women with endometriosis, IVF is often considered as a treatment option. Lower implantation and pregnancy rates have been observed following IVF in women with endometriosis. It has been debated whether the lower pregnancy rate is due to the effect on oocyte quality or the endometrium, thus affecting implantation. To delineate whether endometriosis affects oocyte quality or the endometrium, we planned a study, using a donor oocyte recipient model, where the recipients were women diagnosed with endometriosis and compared their outcomes with women who underwent autologous IVF, who had also been diagnosed with endometriosis. STUDY DESIGN SIZE DURATION: Human Fertilization and Embryology Authority (HFEA) anonymized data from 1996 to 2016 were analyzed. This comprised of a total of 758 donor oocyte recipients, where the recipients were women diagnosed with endometriosis, and 12 856 autologous IVF cycles where the women were diagnosed with endometriosis as the sole cause of infertility. PARTICIPANTS/MATERIALS SETTING METHODS: Data on all women with endometriosis undergoing donor oocyte recipient and autologous IVF cycles were analyzed to compare live birth outcomes. Logistic regression analysis was performed adjusting for number of previous IVF cycles, previous live birth, period of treatment, day of embryo transfer, number of embryos transferred and fresh or frozen embryo transfer cycle. MAIN RESULTS AND THE ROLE OF CHANCE: There was no significant difference in the LBR in women with endometriosis undergoing donor oocyte recipient fresh embryo transfer cycles compared to women undergoing autologous IVF fresh embryo transfer cycles (31.6% vs 31.0%; odds ratio (OR) 1.03, 99.5% CI 0.79-1.35). After adjusting for confounders, there was no significant difference in LBR in women with endometriosis undergoing donor oocyte recipient fresh embryo transfer cycles versus autologous fresh embryo transfer cycles (adjusted OR (aOR) 1.05, 99.5% CI 0.79-1.41).There was no significant difference in the LBR in women with endometriosis undergoing donor oocyte recipient frozen embryo transfer cycles compared to women undergoing autologous frozen embryo transfer cycles (19.6% vs 24.0%; OR 0.77, 99.5% CI 0.47-1.25). After adjusting for potential confounders, there was no significant difference in the LBR in women undergoing donor oocyte recipient frozen embryo transfer cycles compared with autologous frozen embryo transfer cycles (aOR 0.85, 99.5% CI 0.51-1.41). LIMITATIONS REASONS FOR CAUTION: Although the analysis was adjusted for potential confounders, there was no information on the extent and classification of endometriosis as well as oocyte number. Furthermore, adenomyosis is thought to co-exist in women with endometriosis and may have independent pathophysiological mechanisms affecting fertility, for which there was no information. WIDER IMPLICATIONS OF THE FINDINGS: The study shows no difference in LBR between donor oocyte recipient cycles in which all recipients had endometriosis compared to autologous IVF cycles in women with endometriosis. Therefore, this study finding suggests that there may be a minimal or no effect of oocyte quality on IVF outcomes in women with endometriosis. STUDY FUNDING/COMPETING INTERESTS: No funding was obtained. M.S.K. is an associate editor with Human Reproduction Open. He was not involved in the editorial or peer review process for the manuscript. TRIAL REGISTRATION NUMBER: N/A.

Outcome reporting across randomized controlled trials evaluating potential treatments for male infertility: a systematic review.

STUDY QUESTION: What are the primary outcomes and outcome measures used in randomized controlled trials (RCTs) evaluating potential treatments for male infertility in the last 10 years? SUMMARY ANSWER: Outcome reporting across male infertility trials is heterogeneous with numerous definitions and measures used to define similar outcomes. WHAT IS KNOWN ALREADY: No core outcome set for male infertility trials has been developed. Male infertility trials are unique in that they have potentially three participants, a man, a female partner and their offspring and this will likely lead to significant variation in outcome reporting in randomized trials. STUDY DESIGN SIZE DURATION: A systematic review of RCTs mapping outcomes and outcome measures evaluating potential treatments for men with infertility registered in the Cochrane Register of Controlled Trials (CENTRAL) between January 2010 and July 2021. PARTICIPANTS/MATERIALS SETTING METHODS: Abstract screening and study selection was undertaken in duplicate using a review protocol that was developed prior to commencing the review. No risk of bias assessment was undertaken as this review aims to report on outcome reporting only. MAIN RESULTS AND THE ROLE OF CHANCE: One hundred and seventy-five RCTs were identified, and given the large number of studies we limited our review to the 100 largest trials. Seventy-nine different treatments were reported across the 100 largest RCTs including vitamin and dietary supplements (18 trials), surgical treatments (18 trials) and sperm selection techniques (22 trials). When considering the largest 100 trials (range: 80-2772 participants), 36 primary and 89 secondary outcomes were reported. Forty-seven trials reported a primary outcome and 36 trials clearly defined their primary outcome. Pregnancy outcomes were inconsistently reported and included pregnancy rate (51 trials), pregnancy loss including miscarriage, ectopic pregnancy, stillbirth (9 trials) and live birth (13 trials). Trials consistently reporting the same outcome frequently used different definitions. For example, semen quality was reported by 75 trials and was defined in 7 different ways, including; the World Health Organization (WHO) 2010 criteria (32 trials), WHO 1999 criteria (18 trials), WHO 1992 criteria (3 trials), WHO 1999 and 1992 criteria (1 trial) and the Kruger strict morphology criteria (1 trial). LIMITATIONS REASONS FOR CAUTION: We only evaluated the 100 largest trials published in the last 10 years and did not report outcomes on the remaining 75. An outcome was included as a primary outcome only if clearly stated in the manuscript and we did not contact authors to clarify this. As our review mapped outcomes and outcome measures, we did not undertake an integrity assessment of the trials included in our review. WIDER IMPLICATIONS OF THE FINDINGS: Most randomized trials evaluating treatments for male infertility report different outcomes. Only half of the RCTs reported pregnancy rate and even fewer reported live birth; furthermore, the definitions of these outcomes varies across trials. Developing, disseminating and implementing a minimum data set, known as a core outcome set, for male infertility research could help to improve outcome selection, collection and reporting. STUDY FUNDING/COMPETING INTERESTS: A.P.-chairman of external scientific advisory committee of Cryos International Denmark ApS, member of the scientific advisory board for Cytoswim LDT and ExSeed Health. Guest lecture at the 'Insights for Fertility Conference', funded by MERK SERONO Limited. M.v.W.-holds a ZON-MW research grant. No external funding was obtained for this study.

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.

Risk of breast cancer in women treated with ovarian stimulation drugs for infertility: a systematic review and meta-analysis.

OBJECTIVE: To evaluate the evidence addressing the association between the use of ovarian stimulation drugs and the risk of breast cancer. DESIGN: Systematic review and meta-analysis. SETTING: Not applicable. PATIENT(S): Women without any previous history of breast cancer undergoing ovarian stimulation. INTERVENTION(S): Electronic databases were searched from 1990 until January 2020. All cohort studies reporting new incidences of breast cancer in infertile women using ovarian stimulating drugs were included. Treated (exposed) infertile women were compared with the unexposed general population with unexposed infertile women as controls. MAIN OUTCOME MEASURE(S): New diagnosis of breast cancer within an infertile and general population after exposure to ovarian stimulation drugs. RESULT(S): Overall, the quality of evidence was very low because of the serious risk of bias and indirectness (nonrandomized studies). There was no significant increase in the risk of breast cancer among women treated with any ovarian stimulation drug for infertility compared with that in unexposed controls from the general population and the infertile population (pooled odds ratio 1.03, 95% Confidence interval 0.86 to 1.23, 20 studies, I2 = 88.41%, very low quality of evidence). Furthermore, no significant increase in the risk of breast cancer was found with the use of clomiphene citrate or gonadotropins, alone or in combination. CONCLUSION(S): The current study found that the use of clomiphene citrate and gonadotropins in infertile women was not associated with an increased risk of breast cancer.

Optimising Follicular Development, Pituitary Suppression, Triggering and Luteal Phase Support During Assisted Reproductive Technology: A Delphi Consensus.

Background: A Delphi consensus was conducted to evaluate global expert opinions on key aspects of assisted reproductive technology (ART) treatment. Methods: Ten experts plus the Scientific Coordinator discussed and amended statements plus supporting references proposed by the Scientific Coordinator. The statements were distributed via an online survey to 35 experts, who voted on their level of agreement or disagreement with each statement. Consensus was reached if the proportion of participants agreeing or disagreeing with a statement was >66%. Results: Eighteen statements were developed. All statements reached consensus and the most relevant are summarised here. (1) Follicular development and stimulation with gonadotropins (n = 9 statements): Recombinant human follicle stimulating hormone (r-hFSH) alone is sufficient for follicular development in normogonadotropic patients aged <35 years. Oocyte number and live birth rate are strongly correlated; there is a positive linear correlation with cumulative live birth rate. Different r-hFSH preparations have identical polypeptide chains but different glycosylation patterns, affecting the biospecific activity of r-hFSH. r-hFSH plus recombinant human LH (r-hFSH:r-hLH) demonstrates improved pregnancy rates and cost efficacy versus human menopausal gonadotropin (hMG) in patients with severe FSH and LH deficiency. (2) Pituitary suppression (n = 2 statements): Gonadotropin releasing hormone (GnRH) antagonists are associated with lower rates of any grade ovarian hyperstimulation syndrome (OHSS) and cycle cancellation versus GnRH agonists. (3) Final oocyte maturation triggering (n=4 statements): Human chorionic gonadotropin (hCG) represents the gold standard in fresh cycles. The efficacy of hCG triggering for frozen transfers in modified natural cycles is controversial compared with LH peak monitoring. Current evidence supports significantly higher pregnancy rates with hCG + GnRH agonist versus hCG alone, but further evidence is needed. GnRH agonist trigger, in GnRH antagonist protocol, is recommended for final oocyte maturation in women at risk of OHSS. (4) Luteal-phase support (n = 3 statements): Vaginal progesterone therapy represents the gold standard for luteal-phase support. Conclusions: This Delphi consensus provides a real-world clinical perspective on the specific approaches during the key steps of ART treatment from a diverse group of international experts. Additional guidance from clinicians on ART strategies could complement guidelines and policies, and may help to further improve treatment outcomes.

Improving Reporting of Clinical Studies Using the POSEIDON Criteria: POSORT Guidelines.

The POSEIDON (Patient-Oriented Strategies Encompassing IndividualizeD Oocyte Number) criteria were developed to help clinicians identify and classify low-prognosis patients undergoing assisted reproductive technology (ART) and provide guidance for possible therapeutic strategies to overcome infertility. Since its introduction, the number of published studies using the POSEIDON criteria has increased steadily. However, a critical analysis of existing evidence indicates inconsistent and incomplete reporting of critical outcomes. Therefore, we developed guidelines to help researchers improve the quality of reporting in studies applying the POSEIDON criteria. We also discuss the advantages of using the POSEIDON criteria in ART clinical studies and elaborate on possible study designs and critical endpoints. Our ultimate goal is to advance the knowledge concerning the clinical use of the POSEIDON criteria to patients, clinicians, and the infertility community.

Systematic review and meta-analysis of female lifestyle factors and risk of recurrent pregnancy loss.

It is known that lifestyle factors affect sporadic miscarriage, but the extent of this on RPL (recurrent pregnancy loss) is less well known. A systematic review and meta-analysis was performed to assess the associations between lifestyle factors and RPL. Studies that analysed RPL in the context of BMI, smoking, alcohol and caffeine intake were included. The primary and secondary outcomes were odds of having RPL in the general population and odds of further miscarriage, respectively. Underweight and women with BMI > 25 are at higher odds of RPL in the general population (OR 1.2, 95% CI 1.12-1.28 and OR 1.21, 95% CI 1.06-1.38, respectively). In women with RPL, having BMI > 30 and BMI > 25 has increased odds of further miscarriages (OR 1.77, 95% CI 1.25-2.50 and OR 1.35, 95% CI 1.07-1.72, respectively). The quality of the evidence for our findings was low or very low. Being underweight and BMI > 25 contributes significantly to increased risk of RPL (general population). BMI > 25 or BMI > 30 increases the risk of further miscarriages (RPL population). Larger studies addressing the effects of alcohol, cigarette smoking and caffeine on the risk of RPL with optimisation of BMI in this cohort of women are now needed.

Effect of Genetic Variants of Gonadotropins and Their Receptors on Ovarian Stimulation Outcomes: A Delphi Consensus.

Background: A Delphi consensus was conducted to evaluate the influence of single nucleotide polymorphisms (SNPs) in genes encoding gonadotropin and gonadotropin receptors on clinical ovarian stimulation outcomes following assisted reproductive technology (ART) treatment. Methods: Nine experts plus two Scientific Coordinators discussed and amended statements plus supporting references proposed by the Scientific Coordinators. The statements were distributed via an online survey to 36 experts, who voted on their level of agreement or disagreement with each statement. Consensus was reached if the proportion of participants agreeing or disagreeing with a statement was >66%. Results: Eleven statements were developed, of which two statements were merged. Overall, eight statements achieved consensus and two statements did not achieve consensus. The statements reaching consensus are summarized here. (1) SNP in the follicle stimulating hormone receptor (FSHR), rs6166 (c.2039A>G, p.Asn680Ser) (N=5 statements): Ser/Ser carriers have higher basal FSH levels than Asn/Asn carriers. Ser/Ser carriers require higher amounts of gonadotropin during ovarian stimulation than Asn/Asn carriers. Ser/Ser carriers produce fewer oocytes during ovarian stimulation than Asn/Asn or Asn/Ser carriers. There is mixed evidence supporting an association between this variant and ovarian hyperstimulation syndrome. (2) SNP of FSHR, rs6165 (c.919G>A, p.Thr307Ala) (N=1 statement): Few studies suggest Thr/Thr carriers require a shorter duration of gonadotropin stimulation than Thr/Ala or Ala/Ala carriers. (3) SNP of FSHR, rs1394205 (-29G>A) (N=1 statement): Limited data in specific ethnic groups suggest that A/A allele carriers may require higher amounts of gonadotropin during ovarian stimulation and produce fewer oocytes than G/G carriers. (4) SNP of FSH ß-chain (FSHB), rs10835638 (-211G>T) (N=1 statement): There is contradictory evidence supporting an association between this variant and basal FSH levels or oocyte number. (5) SNPs of luteinizing hormone ß-chain (LHB) and LH/choriogonadotropin receptor (LHCGR) genes (N=1 statement): these may influence ovarian stimulation outcomes and could represent potential future targets for pharmacogenomic research in ART, although data are still very limited. Conclusions: This Delphi consensus provides clinical perspectives from a diverse international group of experts. The consensus supports a link between some variants in gonadotropin/gonadotropin receptor genes and ovarian stimulation outcomes; however, further research is needed to clarify these findings.

The predicted probability of live birth in In Vitro Fertilization varies during important stages throughout the treatment: analysis of 114,882 first cycles.

RESEARCH QUESTION: How much the variability in patients' response during in vitro fertilization (IVF) may add to the initial predicted prognosis based only on patients' basal characteristics? DESIGN: Anonymous data were obtained from the Human Fertilization and Embryology Authority (HFEA). Data involving 114,882 stimulated fresh IVF cycles were retrospectively analyzed. Logistic regression was used to develop the models. RESULTS: Prediction of live birth was feasible with moderate accuracy in all of the three models; discrimination of the model based only on basal patients' characteristics (AUROC 0.61) was markedly improved adding information of number of embryos (AUROC 0.65) and, mostly, number of oocytes (AUROC 0.66). CONCLUSIONS: The addition to prediction models of parameters such as the number of embryos obtained and especially the number of oocytes retrieved can statistically significantly improve the overall prediction of live birth probabilities when based on only basal patients' characteristics. This seems to be particularly true for women after the first IVF cycle. Since ovarian response affects the probability of live birth in IVF, it is highly recommended to add markers of ovarian response to models based on basal characteristics to increase their predictive ability.

Female causes of infertility are associated with higher risk of preterm birth and low birth weight: analysis of 117 401 singleton live births following IVF.

STUDY QUESTION: Does the cause of infertility affect the perinatal outcomes preterm birth (PTB) and low birth weight (LBW) following IVF treatment? SUMMARY ANSWER: The risk of PTB and LBW was higher with female causes of infertility-ovulatory disorders, tubal disorders and endometriosis-compared to unexplained infertility but the absolute increase in risk was low. WHAT IS KNOWN ALREADY: Infertility is associated with an increased risk of adverse perinatal outcomes. Risk of adverse perinatal outcomes is also higher following ART compared to spontaneous conceptions. Infertility can result from female and/or male factors or is unexplained when the cause cannot be delineated by standard investigations. Given that infertility and ART are contributory to the adverse perinatal outcomes, it is a matter of interest to delineate if the specific cause of infertility influences perinatal outcomes following IVF treatment. STUDY DESIGN, SIZE, DURATION: Anonymous data were obtained from the Human Fertilization and Embryology Authority (HFEA). The HFEA has collected data prospectively on all ART cycles performed in the UK since 1991. Data from 1991 to 2016 comprising a total of 117 401 singleton live births following IVF with or without ICSI (IVF ± ICSI) for sole causes of infertility were analysed for PTB and LBW. Cycles having more than one cause of infertility and/or multiple births were excluded. PARTICIPANTS/MATERIALS, SETTING, METHODS: Data on all women undergoing stimulated IVF ± ICSI treatment cycles were analysed to compare perinatal outcomes of PTB and LBW among singleton live births based on the cause of infertility (ovulatory disorders, tubal disorders, endometriosis, male factor, unexplained). Logistic regression analysis was performed, adjusting for female age category, period of treatment, previous live births, IVF or ICSI, number of embryos transferred and fresh or frozen embryo transfer cycles. MAIN RESULTS AND THE ROLE OF CHANCE: Compared to unexplained infertility, the risk of PTB was significantly higher with ovulatory disorders (adjusted odds ratio (aOR) 1.31, 99.5% CI 1.17 to 1.46); tubal disorders (aOR 1.25, 99.5% CI 1.14 to 1.38) and endometriosis (aOR 1.17, 99.5% CI 1.01 to 1.35). There was no significant difference in the risk of PTB with male factor causes compared to unexplained infertility (aOR 1.01, 99.5% CI 0.93, 1.10). The risk of LBW was significantly higher with ovulatory disorders (aOR 1. 29, 99.5% CI 1.16 to 1.44) and tubal disorders (aOR 1.12, 99.5% CI 1.02 to 1.23) and there was no increase in the risk of LBW with endometriosis (aOR 1.11, 99.5% CI 0.96 to 1.30) and male factor causes (aOR 0.94, 99.5% CI 0.87, 1.03), compared to unexplained infertility. LIMITATIONS, REASONS FOR CAUTION: Although the analysis was adjusted for several important confounders, there was no information on the medical history of women during pregnancy to allow adjustment. The limitations with observational data would apply to this study, including residual confounding. WIDER IMPLICATIONS OF THE FINDINGS: This is the largest study to address the causes of infertility affecting perinatal outcomes of PTB and LBW. The information is important for the management of pregnancies and the underlying reasons for the associations observed need to be further understood. STUDY FUNDING/COMPETING INTEREST(S): No funding was obtained. There are no competing interests to declare. TRIAL REGISTRATION NUMBER: N/A.

Concordance between systematic reviews of randomized controlled trials in assisted reproduction: an overview.

STUDY QUESTION: Are systematic reviews published within a 3-year period on interventions in ART concordant in their conclusions? SUMMARY ANSWER: The majority of the systematic reviews published within a 3-year period in the field of assisted reproduction on the same topic had discordant conclusions. WHAT IS KNOWN ALREADY: Systematic reviews and meta-analyses have now replaced individual randomized controlled trials (RCTs) at the top of the evidence pyramid. There has been a proliferation of systematic reviews and meta-analyses, many of which suffer from methodological issues and provide varying conclusions. STUDY DESIGN SIZE DURATION: We assessed nine interventions in women undergoing ART with at least three systematic reviews each, published from January 2015 to December 2017. PARTICIPANTS/MATERIALS SETTING METHODS: The systematic reviews which included RCTs were considered eligible for inclusion. The primary outcome was extent of concordance between systematic reviews on the same topic. Secondary outcomes included assessment of quality of systematic reviews, differences in included studies in meta-analyses covering the same search period, selective reporting and reporting the quality of evidence. MAIN RESULTS AND THE ROLE OF CHANCE: Concordant results and conclusions were found in only one topic, with reviews in the remaining eight topics displaying partial discordance. The AMSTAR grading for the majority of the non-Cochrane reviews was critically low whilst it was categorized as high for all of the Cochrane reviews. For three of the nine topics, none of the included systematic reviews assessed the quality of evidence. We were unable to assess selective reporting as most of the reviews did not have a pre-specified published protocol. LIMITATIONS REASONS FOR CAUTION: We were limited by the high proportion of reviews lacking a pre-specified protocol, which made it impossible to assess for selective reporting. Furthermore, many reviews did not specify primary and secondary outcomes which made it difficult to assess reporting bias. All the authors of this review were Cochrane review authors which may introduce some assessment bias. The categorization of the review's conclusions as beneficial, harmful or neutral was subjective, depending on the tone and wording of the conclusion section of the review. WIDER IMPLICATIONS OF THE FINDINGS: The majority of the systematic reviews published within a 3-year period on the same topic in the field of assisted reproduction revealed discordant conclusions and suffered from serious methodological issues, hindering the process of informed healthcare decision-making. STUDY FUNDING/COMPETING INTERESTS: All the authors are Cochrane authors. M.S.K. is an editorial board member of Cochrane Gynaecology and Fertility group. No grant from funding agencies in the public, commercial or not-for-profit sectors was obtained.

Time as an outcome measure in fertility-related clinical studies: long-awaited.

Time taken to achieve a live birth is an important consideration that is central to managing patient expectations during infertility treatment. However, time-related endpoints are not reported as standard in the majority of fertility-related clinical studies and there is no internationally recognized consensus definition for such endpoints. There is, therefore, a need for meaningful discussions around the selection of appropriate time-related treatment outcome measures for studies evaluating fertility treatments that will be relevant to diverse stakeholders (e.g. patients, healthcare professionals, clinical scientists, authorities and industry). Here, we provide a proposal for the evaluation of time-related outcome measures in fertility-related clinical studies, alongside associated definitions.