The 2025 World Health Organization (WHO) Guideline for the Prevention, Diagnosis, and Treatment of Infertility represents the first comprehensive global framework integrating male and female contributors to infertility within a unified public health strategy. This commentary examines the male-relevant components of the guideline from the perspective of reproductive biology and translational andrology. The WHO guideline mandates a parallel evaluation of both partners and structures male assessment around the medical history, a focused physical examination and semen analysis as a triage tool. While pragmatic and globally applicable, semen analysis remains a descriptive rather than a mechanistic test, underscoring the need for a deeper investigation into sperm chromatin integrity, epigenetics and molecular function. The guideline's conservative treatment recommendations - limited to clinical varicocele repair and antioxidant therapy - reflect Population, Intervention, Comparison, Outcome prioritization, the GRADE methodology and an emphasis on pregnancy and live-birth outcomes, as well as considerations of equity and feasibility across diverse health systems. By embedding male reproductive health within a global infertility approach, the guideline promotes structured evaluation, early specialist referral and reproductive equity, while highlighting critical gaps in mechanistic understanding that must inform future research and clinical innovation.
Can the analysis of TikTok posts related to fertility and assisted reproduction technology better characterize the types of information shared, potential biases, and relative engagement? Using a new TikTok account posing as a woman of reproductive age in September 2024, posts were gathered using fertility- and infertility-related search terms. Descriptive post statistics were extracted, and reviewers coded each post for perceived patient demographics, creator type, post content, type of fertility treatments mentioned, and emotional tone. In total, 1905 TikTok posts were reviewed, amounting to 1,808,310,047 cumulative views and 117,087,911 cumulative likes. The majority of content creators were patients with fertility challenges (66.82%), followed by physicians (12.39%). Personal posts related to experience were most common (61.36%), followed by educational posts (28.45%). The most popular search terms in terms of both views and likes were 'infertility', 'fertility' and 'IVF' (P < 0.0001). Posts deemed to have a positive emotional tone received significantly more likes than neutral posts (P < 0.05), despite having fewer overall views. While most posts were created by patients with a light skin tone (52.36%), these posts did not differ in emotional tone or receive more engagement. TikTok content about personal infertility experiences is more prevalent than content created by healthcare professionals, and broad terms such as 'infertility' and positive patient stories attract significantly more engagement than medical terminology or neutral information. It is suggested that physicians should use this information to better engage viewers on social media in order to provide balanced content and combat the spread of misinformation.
These guidelines replace the previous (2019) UK guidelines for the medical and laboratory screening of sperm, egg and embryo donors and were achieved by a joint working group composed of representatives from the Association of Reproductive and Clinical Scientists (ARCS), the British Fertility Society (BFS), the British Association for Sexual Health and HIV (BASHH) and the British HIV Association (BHIVA), with review and comments from their respective memberships. It was written to guide best practice in clinics but is not intended as a tool to judge the practice of centres within the UK or beyond. Guidance on core information that should be supplied to all parties involved in donation is provided. Screening tests and standards required are summarized, as are specific considerations for known donation and embryo donation. The assessment of genetic risk and heritable disorders has been fundamentally reviewed in light of technological advances. Extended carrier screening is also discussed, although we do not suggest that this is routinely performed.
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Does the type of endometrial preparation protocol influence reproductive outcomes in women with thin endometrium (<7 mm) undergoing single blastocyst embryo transfer (SET). Retrospective cohort study including infertile women aged 25-48 years with thin trilaminar endometrium (<7 mm) who underwent blastocyst SET between January 2021 and December 2024. Patients were allocated to the modified natural cycle (mNC) or artificial cycle groups according to endometrial preparation protocol. Only patients undergoing SET with euploid blastocysts from autologous PGT-A or donor oocyte cycles were included. Primary outcome was live birth rate (LBR); secondary outcomes included positive beta-HCG test, clinical pregnancy and miscarriage rates. A total of 762 SETs were carried out in 619 patients (mNC [n = 106], artificial cycle [n = 656). Patients who underwent artificial cycles were significantly older (P < 0.001); endometrial thickness and preparation time were comparable. The artificial cycle group showed more day-5 blastocyst transfers (P = 0.03). Reproductive outcomes, including LBR, did not differ between mNC and artificial cycles in the overall cohort and in subgroups (autologous and oocyte donation). Multivariate analysis confirmed no effect of endometrial preparation; day-6 transfers and low blastocyst grade were independently associated with decreased outcomes. Reproductive outcomes in women with thin endometrium (<7 mm) were comparable and sustainable after mNC and artificial cycle preparation, suggesting that this condition is not an absolute contraindication to embryo transfer. The practice of cancelling embryo transfers in cases of thin endometrium and shifting to an alternative preparation protocol is not supported.
How can the effectiveness of exome sequencing be improved for diagnosing infertility, and what are the key challenges and lessons learned from analysing nine unrelated cases? Nine unrelated infertility cases referred between 2019 and 2024 were analysed in this study. Exome sequencing was conducted on probands and other family members when needed. Sanger sequencing was used for segregation analysis, and consequences on splicing were investigated on mRNA from patient cells and minigene assay. Nine causative variants were identified, including six novel, in nine genes, TUBB8, PATL2, CCDC39, STAG3, KIAA0319, FBXO43, AGBL5/BBS7, PLCZ1 and HS6ST1, across diverse reproductive phenotypes, including oocyte maturation arrest, early embryonic arrest, spermatogenic failure and syndromic infertility. KIAA0319 was also identified as a novel candidate gene for male infertility. Variant segregation in family members and the possibility of re-contacting the patients for further evaluations and questions were crucial to maximize diagnostic yield and reach robust conclusions. This study underscores the need for multidisciplinary collaboration between reproductive medicine specialists and geneticists to facilitate the complexity of infertility, improve its diagnostic yield and counsel patients.
Polycystic ovary syndrome (PCOS) and its underlying features remain poorly understood. In this genetic study (n = 544,513), we expand the number of genetic loci from 16 to 29, and additionally identify 31 associated plasma proteins. Many risk-increasing loci were associated with later age at menopause, underscoring the reproductive longevity related to an increased oocyte number and/or availability across the lifespan. Hormonal regulation in the etiology of this condition, through metabolic and reproductive features, was emphasized. The proteomic analysis highlighted metabolic biology known to be related to PCOS. A polygenic risk score (PRS) was associated with adverse cardiometabolic outcomes, with differing relevance of testosterone and body mass index in women and men. Finally, while oligo-anovulation and anovulatory infertility are features of PCOS, we observed no impact of PCOS susceptibility on childlessness. We suggest that PCOS susceptibility confers balanced pleiotropic influences on fertility in women, and life-long adverse metabolic consequences in both sexes.
France's universal public funding of assisted reproductive technology represents a major achievement for reproductive equity. By removing financial barriers, it has broadened access to fertility care while ensuring high standards of safety, traceability and clinical outcomes. Public oversight has further strengthened quality assurance through mandatory ISO 15189 accreditation of IVF laboratories and implementation of EU Tissues and Cells regulations. However, expanding entitlement without a proportional reinforcement of resources, staffing, laboratory capacity, reimbursement levels and donor availability has generated structural tensions. Complex regulatory demands impose substantial administrative and financial burdens on centres, diverting time and investment from patient care. Inadequate funding of IVF units, persistent shortages of gamete donors and rising overhead costs have created waiting lists and inequitable delays. France also prohibits certain internationally accepted procedures, such as preimplantation genetic testing for aneuploidies, restricting clinical autonomy and patient choice. These unintended effects risk undermining the very principles of universality, equity and quality that underpin France's policy. Comparison with Belgium, the UK, Spain and Quebec, systems that pair broad coverage with more flexible regulation or reimbursement, helps identify ways to rebalance access, oversight and innovation. We propose pragmatic policy adjustments, including realistic reimbursement of laboratory costs, streamlined accreditation, targeted donor-recruitment incentives and evidence-based reconsideration of prohibited techniques.
How does the risk of placenta accreta spectrum (PAS) in pregnancies from natural cycle (NC-FET), stimulated cycle (SC-FET) and programmed cycle (PC-FET) frozen-thawed embryo transfers compare with that in fresh embryo transfer? A total of 174,591 embryo transfer cycles resulting in singleton live births were obtained from the Japanese assisted reproductive technology (ART) registry from 2017 to 2020. A multivariate logistic regression model compared the risk of PAS across different embryo transfer methods. Adjusted factors were maternal age at embryo transfer, indication for ART, number and stage of embryos transferred, use of assisted hatching, presence of placenta praevia and mode of delivery. The incidence of PAS was 0.16% (39/23,827), 0.17% (66/37,787), 0.14% (11/8,143) and 1.48% (1,549/104,834) for fresh embryo transfer, NC-FET, SC-FET and PC-FET, respectively. PC-FET carried a higher risk of PAS versus fresh embryo transfer (adjusted odds ratio [aOR] 9.12, 95% confidence interval [CI] 6.54-12.73), whereas there was no significantly increased risk with NC-FET and SC-FET. Subgroup analyses revealed that, for single cleavage-stage embryo transfer, PC-FET was associated with a higher risk of PAS versus fresh embryo transfer (aOR 11.19, 95% CI 6.55-19.11). NC-FET and SC-FET showed no significantly increased risk. For single-blastocyst transfer, PC-FET carried a higher risk of PAS versus fresh embryo transfer (aOR 5.44, 95% CI 3.26-9.09), whereas NC-FET and SC-FET had a similar risk to fresh embryo transfer. PC-FET carried a higher risk of PAS than fresh embryo transfer, while NC-FET and SC-FET did not. When planning embryo transfer reproductive physicians should recognize that PC-FET is a potential risk factor for PAS.
The clinical utility and validity of preimplantation genetic testing for aneuploidies (PGT-A) in IVF practice is often questioned. Some major societies (Practice Committees of the American Society for Reproductive Medicine and the Society for Assisted Reproductive Technology 2024) have released ambiguous statements about PGT-A, leaving the potential and benefits of embryo selection, enhanced by chromosome profile assessments, indeterminant. The Preimplantation Genetic Diagnosis International Society (PGDIS) Task Group has gathered the scientific information and critically evaluated the evidence about the clinical value of PGT-A. We considered technical aspects, genetic principles and clinical outcome studies, and conclude that the proper implementation of PGT-A results in increased benefits for IVF embryo selection. It is envisioned that this report will remove some of the confusion surrounding PGT-A, lead to informed choices about the use of PGT-A and ultimately result in improved transfer outcomes.
Is haematopoietic loss of the X chromosome (LOX), which increases with age in women, but whose reproductive relevance is unclear, associated with the likelihood of natural conception? Multicentre case-control study at three hospitals in Osaka, Japan. Cases were women who did not achieve natural conception after exclusion of male-factor infertility (n = 381). Controls were women who conceived naturally (n = 123). The LOX burden in peripheral blood (%LOX) was quantified by multiplex single-cell droplet digital polymerase chain reaction. Serum anti-Müllerian hormone (AMH) was measured by standardized chemiluminescent enzyme assays. The primary outcome was the difference in %LOX between cases and controls. Secondary analyses assessed assisted reproductive technology (ART) outcomes (pregnancy within three embryo-transfer cycles) among a prospectively followed subset. Exploratory analyses examined correlations of %LOX with age and AMH. %LOX increased with age (P < 0.001) and was higher in cases than controls (P < 0.001). This difference remained significant after adjusting for age, body mass index (BMI) and prior pregnancy (β = 0.82, 95% CI 0.70 to 0.96, P = 0.013). Receiver operating characteristic curve analysis identified an optimal %LOX threshold of 0.87% (area under the curve 0.60, 95% CI 0.54 to 0.66). Women with %LOX 0.87% or above had over twofold higher odds of not achieving natural conception (OR 2.16, 95% CI 1.40 to 3.32, P < 0.001; age-stratified, BMI-adjusted). In contrast, %LOX was not associated with pregnancy within three ART cycles (adjusted P = 0.23) and did not correlate with AMH (ρ = ‒0.06; P = 0.25) or FSH (ρ = ‒0.01; P = 0.84) levels. Haematopoietic LOX was associated with a lower likelihood of natural conception, whereas no clear association was found with ART outcomes was observed.
What does the Australian public know about mitochondrial donation and think about its potential clinical implementation? 1042 people aged ≥18 years living in Australia completed an online anonymous survey between October and December 2022. Participants were recruited through a market research company. The survey included multiple choice and Likert-scale questions gauging respondents' knowledge and attitudes. Bivariate analysis investigated differences in support for mitochondrial donation based on different sociodemographic groups. Just 19% of respondents had ever heard of mitochondrial donation prior to participation (n = 202). The average level of agreement with the statement 'If the clinical trial proves mitochondrial donation is safe, I support it becoming available in Australia' was 3.36 out of a possible 4, indicating agreement. Significant differences in the average agreement level were reported across the different 'prior use of assisted reproductive technology', 'sexual orientation', 'genetic condition' and 'mitochondrial disease' groups; however, the average level of agreement in each group was consistently >3. The findings indicate broad public support for the clinical implementation of mitochondrial donation in Australia, provided that clinical trials demonstrate its safety. Although these results may not extrapolate directly to other contexts, they may guide other jurisdictions in considering their position towards mitochondrial donation.
Among the many symbols that appear in the medical literature, few have received as much attention as the letter 'P'. It is printed in almost every table, discussed in every result section and often treated as the final word in the interpretation of scientific findings. In reality, the P-value is neither over-rated nor under-rated. It is simply misunderstood. It is an important tool, but it is not the main factor that determines the value of a study. What matters is not the number itself, but how we think about it and what it truly represents. This manuscript revisits the 'value' of the P-value in reproductive medicine.
Despite growing evidence, the contribution of paternal factors to embryo morphokinetics and clinical outcomes in assisted reproductive technology (ART) has been largely overlooked. This systematic review and meta-analysis was conducted to evaluate associations between sperm parameters and embryo morphokinetic events, and to assess their impact on ART outcomes. Studies published between January 2015 and December 2024 were screened in accordance with the PRISMA guidelines. Morphokinetic variables and clinical outcomes were extracted, and random-effects meta-regression was performed to examine the influence of sperm quality on embryo development and clinical endpoints. Nine studies with heterogeneous case-control definitions and 26,111 embryos (8144 cases versus 17,967 controls) met the inclusion criteria. In study-level meta-analysis and meta-regression, early cleavage events were not significantly associated with sperm quality, whereas lower sperm concentration and motility were associated with delays in later developmental stages. The meta-regression showed that sperm motility was positively associated with implantation (β = 0.035, 95% CI 0.014-0.056; P = 0.0012) and live birth (β = 0.041, 95% CI 0.004-0.080; P = 0.031), while sperm concentration was associated with implantation alone (β = 0.025, 95% CI 0.016-0.034; P < 0.001). No significant associations were observed for fertilization, clinical pregnancy or miscarriage. These findings provide meta-analytic evidence linking paternal sperm quality to embryo morphokinetics, and underscore the importance of considering paternal factors in ART outcomes.
Chronic endometritis is persistent inflammation of the endometrium, often underdiagnosed due to its oligosymptomatic presentation. Both chronic endometritis and adenomyosis share inflammatory and structural alterations of the endometrial-myometrial interface that may impair reproductive outcomes. This systematic review and meta-analysis were conducted in accordance with the PRISMA guidelines, and registered in PROSPERO. MEDLINE, Embase, CENTRAL, Cochrane Database of Systematic Reviews, Scopus and trial registries were searched from 2000 to May 2025 to determine the prevalence of chronic endometritis in women with adenomyosis, and assess the strength of their association. Of 713 identified records, 10 studies (n = 2877 women) met the inclusion criteria. The pooled prevalence of chronic endometritis in women with adenomyosis was 32% (95% CI 16-53; I² = 94%). In subgroup analyses, prevalence varied by the diagnostic method used for adenomyosis: hysterectomy (21%), magnetic resonance imaging (64%), and hysteroscopy (8%). Meta-analysis demonstrated a significantly higher prevalence of chronic endometritis in women with adenomyosis compared with controls (OR = 3.81, 95% CI 2.23-6.50; I² = 11%). This systematic review and meta-analysis suggest that adenomyosis and chronic endometritis frequently coexist, with women with adenomyosis showing a significantly higher risk of chronic endometritis. Standardized diagnostic criteria, adenomyosis subtype classification, and high-quality randomized controlled trials are needed to clarify the underlying mechanisms, and are necessary to demonstrate an association between adenomyosis and chronic endometritis.
Low-Penetrance Copy Number Variants (LP-CNVs) are well-known to contribute to neurodevelopmental disorders and are also found in healthy individuals, presenting significant challenges to genetic counselling. However, data on the clinical management of LP-CNVs in Portugal is lacking. An online questionnaire was administered to Clinical Geneticists in Portugal regarding their management of LP-CNV and ethical issues were addressed. The results showed a significant absence of agreement on LP-CNVs disclosure, particularly concerning whether decisions should be guided by expert panels or individualized for each case. Clinicians acknowledged the substantial challenges patients and families face in understanding genetic information, highlighting the need for a shared decision-making approach. Furthermore, there was considerable variability in ethical perspectives regarding prenatal diagnosis and preimplantation genetic testing for LP-CNVs, emphasizing the need for clear guidelines. Our results strongly advocate for the development of national guidelines mirroring those established in other countries. This work underscores several complex ethical issues requiring urgent exploration internationally. The observed postcode lottery highlights a failure of distributive justice, necessitating equitable access to standardized genomic knowledge across healthcare regions. Furthermore, the uncertainty challenge renders traditional non-directive counseling increasingly unsustainable, requiring a shift toward Shared Decision-Making (SDM) to balance child welfare against parental autonomy in navigating genomic ambiguity.
What is the feasibility of three-dimensional power Doppler ultrasound to predict clinical pregnancy outcome following frozen embryo transfer (FET) in patients with internal adenomyosis (ADM)? This prospective observational study included 61 patients undergoing assisted reproductive technology (ART) who were diagnosed with internal ADM using pelvic magnetic resonance imaging between 10 December 2023 and 1 March 2025. In addition, 116 patients with tubal factor infertility, undergoing ART during the same period, were included as controls. The endometrial blood flow index was measured on ultrasound the day before embryo transfer. The flow index, demographic data and FET outcomes were compared between the two groups. One-way analysis of variance revealed significant differences in the clinical pregnancy rate between the two groups (internal ADM: 20/61, 32.79%; control, 65/116, 56.03%; P = 0.003). The mean ± SD flow index in the internal ADM group (14.74 ± 5.16) was lower than in the control group (17.05 ± 6.65; P = 0.019). Univariate logistic regression analysis revealed that the flow index affected the clinical pregnancy rate significantly, with an OR of 1.126 (95% CI 1.064-1.193; P = 0.001). Multivariable logistic regression of FET outcomes indicated that the flow index affected the clinical pregnancy rate significantly (OR = 1.112, 95% CI 1.049-1.180; P = 0.001). The optimum cut-off value for the flow index to predict pregnancy was 15.84 [area under the curve (AUC) 0.728, 95% CI 0.654-0.802; P = 0.001], and the combination of flow index and cancer antigen 125 (CA125) yielded improved predictive performance (AUC 0.805, 95% CI 0.740-0.870; P = 0.001). Endometrial blood perfusion is reduced in patients with internal ADM, and is associated with a lower pregnancy rate. The combination of flow index and serum CA125 provides an effective predictive model for clinical pregnancy prior to FET in this population.
Does implementation of the DIVINE dose calculator in routine care reduce treatment risk due to ovarian hyperstimulation whilst maintaining treatment efficacy? A retrospective cohort study comparing assisted reproductive technology outcomes from women treated before and after implementation of the DIVINE dose calculator. Data were collected from two Dutch fertility centres. The dose calculator included female age, anti-Müllerian hormone concentration, and gonadotrophin-releasing hormone-(ant)agonist protocol to select the most appropriate starting dose of FSH between 100 and 225 IU. Baseline characteristics of subfertile women aged <39 years starting their first IVF/intracytoplasmic sperm injection (ICSI) treatment cycle, and fresh cycle treatment outcomes were collected. Inverse propensity weighting was applied to balance potential confounders. Weighted regression was performed using general linear models or ordered logistic regression models, according to the outcome variable. The primary outcome variables were live birth rate and safety risk. Data were obtained for 601 women: 472 in the pre-dose calculator group and 129 in the post-dose calculator group. There was no difference in the live birth rate per fresh cycle before and after implementation of the dose calculator: 25.8% versus 24.0% respectively (OR 0.96, 95% CI 0.62-1.51). The treatment risk due to ovarian hyperstimulation decreased after implementation of the dose calculator from 10.8% in the pre-dose calculator period to 3.1% in the post-dose calculator period (OR 0.28, 95% CI 0.10-0.78), and the incidence of ovarian hyperstimulation syndrome decreased from 6.4% to 0% after implementation of the dose calculator. Implementation of the DIVINE dose calculator significantly reduces treatment risks caused by ovarian hyperstimulation, without affecting treatment efficacy in terms of the live birth rate in first fresh IVF/ICSI cycles.
Does programmed cycle frozen embryo transfer (PC-FET) increase the risk of placenta accreta spectrum (PAS) compared with natural cycle FET (NC-FET), and does this risk vary according to facility-level utilization of PC-FET? This nationwide, cross-sectional study analysed 38,973 frozen embryo transfer deliveries identified in the Japanese perinatal registry database (2020-2022), linked to the assisted reproductive technology registry database (2019-2022). The primary exposure was PC-FET versus NC-FET. Facilities were stratified into tertiles based on the proportion of PC-FET (low, medium and high). The primary outcome was PAS, defined as either clinical or pathological. Morbid PAS was defined as PAS accompanied by haemorrhage >2000 ml or managed with balloon tamponade, compression sutures, embolization, or peripartum hysterectomy. OR and 95% CI were estimated with stabilized inverse probability of treatment weighting and multivariable regression. PAS occurred in 3.6% and 0.7% of PC-FET and NC-FET deliveries, respectively (OR 5.02, 95% CI 3.87-6.53). Morbid PAS occurred in 1.5% and 0.3% of PC-FET and NC-FET deliveries, respectively (OR 5.36, 95% CI 3.51-8.20). Facilities with a high proportion of PC-FET had a higher risk of PAS (OR 1.36, 95% CI 1.16-1.58) and morbid PAS (OR 1.34, 95% CI 1.07-1.70) compared with facilities with a low proportion of PC-FET. This study provides robust evidence that PC-FET increases the risk of PAS. Further research should explore the association between facility variations and the incidence of PAS.