Michael P. Rimmer

Extracellular vesicles (EVs) are lipid-bound nanostructures that play important roles in reproduction as universal mediators of bidirectional cell-to-cell communication. EVs transfer diverse cargoes between reproductive cells, influencing fundamental reproductive processes such as gametogenesis and pregnancy. In the male reproductive tract, specialized EVs such as epididymosomes and prostasomes regulate sperm activation, motility, and capacitation, exerting some of these effects within the female reproductive tract as well. In the female reproductive tract, EVs found in follicular fluid, oviduct, and uterus aid in oocyte maturation, fertilization, and the vital embryo development and embryo-maternal cross talk necessary for successful implantation, including after in vitro fertilization. With advancing gestation, EVs continue to play crucial roles in mediating communication between maternal, placental, and fetal compartments with the ultimate aim of promoting immunotolerance and development of the allogeneic fetus. Focusing on the human reproductive system, the development of obstetric conditions such as preeclampsia and gestational diabetes is marked by a significant increase in EV release and systemic impacts, including endothelial dysregulation, perturbation of metabolic homeostasis, and disruption to the blood-brain barrier. Disruption of EV-mediated signaling is linked to reproductive pathologies, but detailed etiologies are not yet defined. Importantly, EVs offer an exciting avenue for both biomarker discovery and therapeutic applications. Our advancing understanding of how EVs deliver their molecular cargo and influence gene expression in recipient cells holds promise for manipulating these processes and improving the diagnosis and treatment of infertility and pregnancy complications.

Human sex ratios at birth are remarkably stable, yet may be sensitive to events during fertilisation and early embryo development. Intracytoplasmic sperm injection (ICSI) bypasses sperm-zona interaction by injecting a selected sperm directly into the oocyte and is increasingly used beyond severe male-factor infertility. We analysed anonymised UK Human Fertilisation and Embryology Authority registry data for 2005–2018 to test whether fertilisation method is associated with the secondary sex ratio among singleton live births. The cohort included 164,684 singleton live births after conventional IVF or ICSI with recorded infant sex. Multivariable logistic regression adjusted for maternal age, treatment year, number of embryos transferred, and fresh or frozen embryo transfer. The adjusted proportion of male live births was 52.6% after IVF and 49.2% after ICSI, an absolute difference of 3.4 percentage points (95% CI 2.8–3.9); the adjusted odds ratio for male live birth after ICSI versus IVF was 0.88 (95% CI 0.86–0.89). The association was consistent across single-embryo transfers, fresh and frozen cycles, cycles without recorded male-factor infertility, and analyses excluding preimplantation genetic testing and donor-gamete cycles. These data identify a small association between fertilisation method and the proportion of male singleton live births within this ART cohort. They do not establish that ICSI causes a shift in the secondary sex ratio in the wider population and should not alter individual counselling, but support deeper study of sex-specific selection across fertilisation, embryo culture, transfer, and early survival.

Background: Intracytoplasmic sperm injection (ICSI) is increasingly used in assisted reproductive technology (ART), including in cycles without severe male-factor infertility, yet whether fertilisation method is associated with infant sex ratio remains uncertain. We aimed to determine whether the proportion of male singleton live births differs between ICSI and conventional in-vitro fertilisation (IVF).Methods: We did a national registry cohort study using anonymised data from the UK Human Fertilisation and Embryology Authority (HFEA) for treatment cycles in 2005–2018. We included singleton live births with a recorded infant sex after IVF or ICSI, classifying each cycle by fertilisation method as recorded in the registry; cycles using donor insemination, those without an embryo transfer, and multiple births were excluded. The outcome was male sex at live birth. We estimated the covariate-adjusted proportion of male live births by method and the adjusted odds ratio (aOR) for a male live birth (ICSI vs IVF) using multivariable logistic regression adjusting for maternal age, treatment year, number of embryos transferred, and cycle type (fresh vs frozen), with pre-specified sensitivity and subgroup analyses.Findings: Among 164,684 singleton live births, the covariate-adjusted proportion of male live births was 52·6% after IVF and 49·2% after ICSI, an absolute difference of 3.4 percentage points (95% CI 2.8–3.9); the adjusted odds ratio for a male live birth after ICSI versus IVF was 0·88 (95% CI 0.86–0.89; p<0·0001). The association was consistent across single-embryo transfers (aOR 0.87 CI 0.84-0.89; p<0.001) and cycles without recorded male-factor infertility (aOR 0.86 CI 0.83-0.88; p<0.001), and persisted after excluding preimplantation genetic testing cycles (aOR 0.87 CI 0.85-0.89; p<0.001) and donor-gamete cycles (aOR 0.87 CI 0.85-89; p<0.001). The association did not vary by maternal age (p=0.58) or calendar year (p=0.82).Interpretation: In this large national-registry cohort, ICSI was associated with a modest but statistically significant reduction in the proportion of male singleton live births compared with conventional IVF. Although small in absolute terms, this difference is unlikely to influence counselling for individual couples but is relevant to population-level surveillance of ART outcomes as ICSI use continues to expand and warrants further mechanistic investigation.

Background: Immersive virtual reality (VR) technology offers a non‐invasive, non‐pharmacological approach to reduce pain perception in patients undergoing diagnostic or interventional procedures. Objective: To systematically evaluate the efficacy of immersive VR technology in reducing pain perception during obstetric and gynaecological procedures. Search Strategy: We searched MEDLINE, EMBASE, CENTRAL, and CINAHL databases from inception to January 2025. Selection Criteria: We included randomised controlled trials (RCTs) evaluating VR interventions in women undergoing obstetric or gynaecological procedures. Data Collection and Analysis: We performed meta‐analyses using random‐effects models and assessed risk of bias using the Cochrane risk‐of‐bias tool for randomised trials. Main Results: 49 RCTs (5355 participants) were included. Due to clinical heterogeneity, data were analysed separately. VR resulted in a larger, consistent reduction in pain scores compared with standard care in labour (11 studies; SMD −0.93, 95% CI −1.25 to −0.60) compared to minor procedures (29 studies; SMD −0.64, 95% CI −0.97 to −0.32). VR also significantly reduced anxiety scores in both labour (8 studies; SMD −1.13, 95% CI −1.80 to −0.45) and minor procedures (17 studies; SMD −0.74, 95% CI −1.18 to −0.29). Our analysis was limited by high levels of heterogeneity and variability in procedural protocols. Conclusion: Immersive VR technology appears effective for reducing pain and anxiety during obstetric and gynaecological procedures, particularly during childbirth, despite substantial statistical heterogeneity. Further research is needed to optimise implementation strategies and establish clinical practice guidelines.

Extracellular vesicles (EVs) are increasingly recognized as critical mediators of intercellular communication, not least during cellular stress or therapy. While EV signalling is well-studied in various tissues, its role in the prepubertal testicular environment is not well understood. Chemotherapy, commonly used in paediatric oncology, poses a significant risk to spermatogonial stem cells (SSCs) and may affect long-term fertility in cancer survivors. The role of EVs in chemotherapy-induced testicular damage in these patients is unknown and may be important for developing new fertility preservation methods. Immortalised murine Sertoli (TM4) and spermatogonial (GC1-spg) cell lines were used to investigate cisplatin-induced changes in EV biogenesis, release, and function in an in vitro model of the prepubertal testicular microenvironment. Our findings indicate that cisplatin significantly increases EV secretion and internalisation by recipient cells. Notably, EVs from cisplatin-exposed Sertoli cells exhibit a novel pro-apoptotic phenotype when co-cultured with chemotherapy-naïve Sertoli cells. Proteomic profiling of these EVs shows enrichment of apoptosis-regulatory proteins including caspases, activating Caspase-3/7 in recipient Sertoli cells. Conversely, germ cells exposed to Sertoli cell-derived EVs displayed reduced levels of apoptosis as well as a chemoprotective role to germ cells undergoing treatment with cisplatin. These findings indicate a dual role for Sertoli cell-derived EVs in mediating (1) apoptosis in Sertoli cells and (2) protection of germ cells following cisplatin exposure. The presence of pro-apoptotic molecules, especially caspases, in chemotherapy-induced Sertoli cell EVs provides mechanism for the induction of somatic cell apoptosis. Furthermore, their protective effects on germ cells demonstrate the complexity of EV-mediated signalling between testicular cell types. Manipulating EV biogenesis and cargo loading could be a promising approach to reduce chemotherapy-related gonadotoxicity and preserve fertility in childhood cancer patients.

Platelets are anucleate blood cells vital for hemostasis and immunity. During cell death and aberrant mitosis, nucleated cells release DNA, resulting in “cell-free” DNA in plasma (cfDNA). An excess of cfDNA is deleterious. Given their ability to internalize pathogen-derived nucleic acids, we hypothesized that platelets may also clear endogenous cfDNA. We found that, despite lacking a nucleus, platelets contained a repertoire of DNA fragments mapping across the nuclear genome. We detected fetal DNA in maternal platelets and cancer-derived DNA in platelets from patients with premalignant and cancerous lesions. As current liquid biopsy approaches utilize platelet-depleted plasma, important genetic information contained within platelets is being missed. This study establishes a physiological role for platelets that has not previously been highlighted, with broad translational relevance.

Background: Diabetes in pregnancy is common, affecting 5–10% of pregnant women. Poor glycaemic control in labour is associated with neonatal hypoglycaemia and other adverse outcomes for mother and baby, but tight glucose control is burdensome, intrusive and may not always be necessary. The ideal intrapartum glucose target level is unknown, traditionally ‘tight’ control (target 4–7 mmol/l) has been recommended; however, this increases the risk of maternal hypoglycaemia. Objective: To determine the feasibility of a randomised clinical trial to compare clinical and cost-effectiveness of permissive versus intensive intrapartum glycaemic control in labour in pregnancies complicated by diabetes. Design: A mixed-methods study including audit of clinical guidelines from United Kingdom maternity units, online surveys of women with diabetes and healthcare professionals, service evaluation of intrapartum glycaemic care, Delphi survey and consensus meeting. Data from these work packages led to the design of a clinical trial, and qualitative interviews were held to understand acceptability of the trial. Setting: National Health Service maternity services and online input from service users. Participants: Healthcare professionals and women with type 1 or type 2 diabetes mellitus or gestational diabetes (currently pregnant or having birthed after active labour in past 3 years). Results: There is significant variation in the recommended frequency of testing for gestational diabetes in labour, technologies used to test glucose levels in labour and administer insulin in type 1 diabetes mellitus, and in how neonatal hypoglycaemia is defined. Of surveyed women, 66% would be willing to participate in a future trial, with 23% unsure without further information. The service evaluation showed that once glucose testing had commenced, it was repeated after 1 hour in 18%, 2 hours in 38% and 4 hours in 45% of women. Neonatal hypoglycaemia was considered the most important neonatal outcome for a future trial, with maternal satisfaction the most important maternal outcome. The incidence of neonatal hypoglycaemia (defined as glucose < 2.6 mmol/l) was 47% in type 1 diabetes mellitus, 45% in type 2 diabetes mellitus and 16% in gestational diabetes mellitus. A non-inferiority trial to compare permissive versus intensive glucose control was designed to include all types of diabetes in an umbrella trial (conduct more than one trial simultaneously). Women and healthcare professionals considered the trial design acceptable and feasible, though noted important considerations in the design and conduct. Limitations: Glucose levels may be poorly recorded in maternity notes and in practice tested more frequently than the study suggests. Sample sizes in some of the work packages were smaller than our pre-specified target, attrition in the Delphi survey was greater than anticipated and the study was conducted during the COVID-19 pandemic impacting results. Willingness to participate in a hypothetical trial might not translate into recruitment to a real trial. Conclusions: An umbrella trial using a master protocol was designed to compare tight glycaemic control (standard care) with more permissive control in all types of diabetes. Such a trial is feasible and acceptable to women with lived experience of diabetes during pregnancy and by the women and healthcare professionals who took part in qualitative interviews. Future work: We recommend that a future randomised trial should include an internal pilot phase to test key aspects of trial conduct and clear progression criteria, given the challenges we have identified during this scoping study. Study registration: This study is registered as researchregistry6832. Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: NIHR130175) and is published in full in Health Technology Assessment; Vol. 29, No. 41. See the NIHR Funding and Awards website for further award information.

STUDY QUESTION: How should fertility preservation in child and adolescent males receiving gonadotoxic therapies be managed? SUMMARY ANSWER: There were 44 recommendations formulated to provide guidance on all aspects of fertility preservation in prepubertal boys and adolescent males in whom it is not possible to obtain sperm by established methods including semen cryopreservation and surgical sperm extraction; the recommendations covered topics from setting up a fertility preservation program, determining who is eligible, and counselling, to the practical aspects of the testicular tissue biopsy and cryopreservation. WHAT IS KNOWN ALREADY: For young males facing gonadotoxic treatment, there are limited options for fertility preservation. For those who are unable to produce sperm (children and adolescents) testicular tissue cryopreservation is being increasingly offered prior to gonadotoxic treatment for potential future clinical use to restore fertility. STUDY DESIGN, SIZE, DURATION: This Good Practice Recommendations (GPR) article was developed according to a predefined methodology for ESHRE good practice recommendations. Recommendations are supported by data from the literature, if available. PARTICIPANTS/MATERIALS, SETTING, METHODS: ESHRE appointed a European multidisciplinary working group with expertise in paediatric oncology, paediatric endocrinology, human tissue banking, and surgery, as well as reproductive specialists and researchers, who have demonstrated leadership and expertise in fertility preservation in prepubertal boys and adolescent males. The recommendations were formulated based on the expert opinion of the working group, while taking into consideration the published data. The draft document was then open to ESHRE members for online peer review and was revised in light of the comments received. MAIN RESULTS AND THE ROLE OF CHANCE: The multidisciplinary working group formulated 44 recommendations to provide guidance on all aspects of fertility preservation by testicular tissue cryopreservation, from setting up a fertility preservation program, determining who is eligible and counselling, to the practical aspects of the testicular tissue biopsy and cryopreservation. LIMITATIONS, REASON FOR CAUTION: These guidelines offer valuable direction for healthcare professionals taking care of children and adolescents facing gonadotoxic treatment. Their purpose is to promote knowledge among clinicians and to enable patients to make informed decisions based on realistic expectations. WIDER IMPLICATIONS OF THE FINDINGS: This article provides not only good practice advice but also highlights the areas that need further research. This research, when well-conducted, will be key to making progress in the area of fertility preservation in children and adolescents. STUDY FUNDING/COMPETING INTERESTS: All costs relating to the development process, including meetings and technical support for this project, were funded by the European Society of Human Reproduction and Embryology (ESHRE). There was no external funding of the development process or manuscript production. RTM was supported by a UKRI Future Leader Fellowship. The other authors disclosed no conflicts of interest. TRIAL REGISTRATION NUMBER: N/A. DISCLAIMER: This Good Practice Recommendations document represents the views of ESHRE, which are the result of consensus between the relevant ESHRE stakeholders and are based on the scientific evidence available at the time of preparation. ESHRE GPRs should be used for information and educational purposes. They should not be interpreted as setting a standard of care or be deemed inclusive of all proper methods of care, or be exclusive of other methods of care reasonably directed to obtaining the same results. They do not replace the need for application of clinical judgement to each individual presentation, or variations based on locality and facility type. Furthermore, ESHRE GPRs do not constitute or imply the endorsement, or favouring, of any of the included technologies by ESHRE.

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...