Human Reproduction (Oxford, England)[JOURNAL]

Sun 200 papers

Refined trajectory smoothing and deep learning classification of human sperm motility.

Shahali S, Mortimer ST, McLachlan R … +6 more , O'Bryan MK, Zander-Fox D, Mortimer D, Ackermann K, Neild A, Nosrati R

Hum Reprod · 2026 Mar · PMID 41633817 · Full text

STUDY QUESTION: Can precise trajectory smoothing improve extraction of sperm motility features, and can deep learning on raw trajectory data enable accurate classification of sperm motility patterns? SUMMARY ANSWER: We p... STUDY QUESTION: Can precise trajectory smoothing improve extraction of sperm motility features, and can deep learning on raw trajectory data enable accurate classification of sperm motility patterns? SUMMARY ANSWER: We present an approach that enhances the precision of motility parameter extraction through frequency-domain smoothing and enables accurate classification of sperm motility patterns using a deep learning model trained on raw trajectory data. WHAT IS KNOWN ALREADY: Conventional computer-aided sperm analysis (CASA) systems estimate motility parameters by applying basic smoothing algorithms to derive an average path, which can result in over- or under-smoothing, leading to inaccuracies in key parameters such as beat cross frequency (BCF) and amplitude of lateral head displacement (ALH). Since the identification of hyperactivated spermatozoa relies heavily on these kinematic metrics, such inaccuracies can contribute to misclassification. STUDY DESIGN, SIZE, DURATION: This cross-sectional study analysed 2326 sperm trajectories (1931 progressive, 395 hyperactivated) recorded at 60 frames per second, derived from five individual samples, to develop and evaluate improved motility parameter extraction methods and trajectory-based classification models. PARTICIPANTS/MATERIALS, SETTING, METHODS: We compared Gaussian Process Regression (GPR), moving average, and Discrete Cosine Transform (DCT) smoothing to improve average path estimation. A novel metric, path average width (PAW), was introduced to quantify lateral head displacement. An ensemble of InceptionTime models was trained on (x, y) coordinate sequences to classify spermatozoa as progressive or hyperactivated. Additional classification of motility grades was performed using trajectory endpoints. MAIN RESULTS AND THE ROLE OF CHANCE: The DCT model retaining 12 frequency components (DCT-12) produced the most consistent and symmetric average paths, leading to improved accuracy in the calculation of BCF and ALH. Our introduced PAW metric effectively distinguished between hyperactivated spermatozoa (5.5 ± 1.5 μm) and progressive spermatozoa (2.0 ± 1.3 μm). The InceptionTime-based classification model achieved 89% accuracy in differentiating progressive and hyperactivated trajectories, and 78% accuracy for predicting motility grades. LIMITATIONS, REASONS FOR CAUTION: Models were trained on sperm trajectories recorded in low-viscosity media. Since sperm selection for ICSI is performed in viscous environments like low concentrations of polyvinylpyrrolidone, future training on such data is essential to improve clinical translation. Additionally, the model for classifying progressive and hyperactivated sperm was trained on a single-centre dataset (5 individuals, total of 790 trajectories) and, despite cross-validation and data augmentation, still requires independent, multi-centre validation to confirm generalizability. Absence of personal identifiers and clinical metadata precluded per-person analyses. WIDER IMPLICATIONS OF THE FINDINGS: By integrating refined signal-based feature extraction with trajectory-level classification, our method addresses core limitations of CASA systems and holds potential for real-time application into ART workflows. Training on high-viscosity media could further enhance its applicability to sperm selection for ICSI. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by the Australian Research Council (ARC) Discovery Project Grants (DP210103361 to A.N. and R.N.), the Australian National Health and Medical Research Council (NHMRC) fellowship (Investigator Grant 2017370 to R.N.), and Monash IVF Group support. The authors declare no competing interests. TRIAL REGISTRATION NUMBER: N/A.

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Role of extracellular vesicles in fertility preservation before gonadotoxic exposures to the ovaries and testes.

Cetin E, Alsoud LO, El Mahi Y … +6 more , Park HS, Mathyk B, Omran MM, Salih SM, Al-Hendy A, Liakath Ali FB

Hum Reprod · 2026 Apr · PMID 41632688 · Publisher ↗

Fertility preservation remains a significant concern for individuals undergoing gonadotoxic treatments. While traditional fertility preservation techniques are well-established, these methods can be time-consuming and li... Fertility preservation remains a significant concern for individuals undergoing gonadotoxic treatments. While traditional fertility preservation techniques are well-established, these methods can be time-consuming and limited by various medical or logistical barriers. In recent years, the potential of mesenchymal stem cell (MSC)-derived extracellular vesicles (EVs) has emerged as a promising, paradigm-shifting approach in fertility preservation. Preclinical studies have demonstrated the protective and regenerative properties of EVs in chemotherapy-induced ovarian and testicular damage in animal models. EVs provide a cell-free therapy that can potentially preserve ovarian function in females and spermatogenesis in males without the need for surgery or delay in cancer treatment. Additionally, using MSC-derived EVs offers advantages over traditional stem cell therapies, such as a reduced risk of immune rejection, targeted treatment, and avoidance of safety concerns associated with stem cell-based therapies. Future directions include enhancing the therapeutic potential of MSC-derived EVs through genetic engineering or cell priming techniques to target specific tissues and further optimize their utilization in fertility preservation. Given the potential of MSC-derived EVs to protect fertility in both females and males, this approach could revolutionize treatment in oncofertility. Further research, including clinical trials, is necessary to confirm the safety and efficacy of MSC-derived EVs, focusing on premature ovarian insufficiency. Looking ahead, MSC-derived EVs could revolutionize fertility preservation, offering hope for cancer patients and individuals exposed to various environmental risks affecting reproduction, including in space exploration, where protection from cosmic radiation is essential.

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40th anniversary of Human Reproduction: reflecting on four decades of scientific excellence.

Barratt CLR, Kirkegaard K, Sakkas D … +2 more , Wise LA, Williams AC

Hum Reprod · 2026 Feb · PMID 41630363 · Publisher ↗

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Development of technologies for the non-invasive assessment of single embryo metabolism and viability.

Gardner DK, Leese HJ

Hum Reprod · 2026 Feb · PMID 41630362 · Publisher ↗

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Association between in utero exposure to acetaminophen and external genital tract malformations in boys and girls: a systematic review and meta-analysis.

Eletri L, Joseph-Delaffon K, Dechartres A … +5 more , Damkier P, Richardson J, Elefant E, Mitanchez D, Marin B

Hum Reprod · 2026 Mar · PMID 41615881 · Publisher ↗

STUDY QUESTION: Is the use of acetaminophen during pregnancy associated with external genital tract malformations in boys and girls? SUMMARY ANSWER: This meta-analysis found no evidence linking in utero acetaminophen exp... STUDY QUESTION: Is the use of acetaminophen during pregnancy associated with external genital tract malformations in boys and girls? SUMMARY ANSWER: This meta-analysis found no evidence linking in utero acetaminophen exposure to external genital malformations in boys but further research focusing on girls and considering relevant confounding factors is needed. WHAT IS KNOWN ALREADY: Acetaminophen is widely used by pregnant women, but findings are conflicting regarding a possible increased risk of genital malformations in the offspring of both sexes. STUDY DESIGN, SIZE, DURATION: In this systematic review and meta-analysis, we searched MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, International Clinical Trials Registry Platform, ClinicalTrials.gov on 18 April 2024, and subsequently updated the search on 20 September 2025 for randomized controlled trials and observational studies. This meta-analysis included randomized controlled trials and observational studies focusing on the association between in utero exposure to acetaminophen, with no restriction on publication dates and languages. PARTICIPANTS/MATERIALS, SETTING, METHODS: Two reviewers independently screened studies, extracted data, and assessed risk of bias. The two primary outcomes were a composite endpoint including cryptorchidism, hypospadias, and penile hypoplasia in boys, and a composite outcome including clitoral enlargement, labial fusion, vulvar malformations, and rectovaginal fistula in girls. Secondary outcomes included individual genital malformations and differences in anogenital distance (AGD). GRADE was used to evaluate the level of certainty. MAIN RESULTS AND THE ROLE OF CHANCE: Ten observational studies were included. Regarding boys, meta-analysis of the predefined primary outcome could not be performed as no studies reported penile hypoplasia. Another composite endpoint including cryptorchidism and/or hypospadias was reconstructed and no significant association was found with acetaminophen, pooled crude odds ratio (OR) 1.27 [95% CI (0.18, 8.94), studies = 2, participants = 155 362, I2=79%, phet=0.03, random-effects model (REM)]. No significant association was found for cryptorchidism or hypospadias separately based on adjusted estimates with pooled OR of 1.02 [95% CI (0.78, 1.35), studies = 3, participants = 155 852, I2=32%, phet=0.23, REM] and 1.02 [95% CI (0.89, 1.17), studies = 3, participants = 159 572, I2=40%, phet=0.19, REM], respectively. No significant difference was found for short AGD. No meta-analysis was possible for girls for any of the predefined outcomes due to lack of data. The level of certainty was low to very low. LIMITATIONS, REASONS FOR CAUTION: The predefined primary outcomes in boys and girls could not be fully evaluated. Small study effects could not be assessed as the number of included studies was limited. There was significant heterogeneity in the reporting of results and information regarding maternal characteristics was lacking. Lastly, all included studies had a serious or critical risk of bias due to the limited control of confounding factors and the level of certainty was low to very low. WIDER IMPLICATIONS OF THE FINDINGS: Acetaminophen remains an indispensable medication and abstaining from pain and fever treatment during pregnancy may have harmful effects on the developing fetus. Further research on external genital malformation risks following in utero exposure to acetaminophen should be directed toward developing validated and robust drug-exposure and outcome assessment tools, that control for confounding factors and confounding by indication. STUDY FUNDING/COMPETING INTEREST(S): No funding was used to conduct this study. No relationship or activity could appear to have influenced the submitted work. REGISTRATION NUMBER: CRD42024536483, available from: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42024536483.

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In vitro fertilization outcomes in transgender individuals with prior testosterone therapy.

Rubin ES, Kornfield M, Palmor M … +6 more , Luck MB, Garg B, Wu D, O'Leary T, Krieg S, Amato P

Hum Reprod · 2026 Mar · PMID 41591849 · Publisher ↗

STUDY QUESTION: Do transgender and gender diverse patients with prior testosterone gender affirming hormone therapy (T-GAHT) have oocyte cryopreservation and IVF outcomes that differ from those without prior T-GAHT? SUMM... STUDY QUESTION: Do transgender and gender diverse patients with prior testosterone gender affirming hormone therapy (T-GAHT) have oocyte cryopreservation and IVF outcomes that differ from those without prior T-GAHT? SUMMARY ANSWER: Prior T-GAHT was associated with a decrease in the total number of blastocysts after adjusting for age, but not with a difference in the number of mature oocytes. WHAT IS KNOWN ALREADY: Many TGD people pursue oocyte cryopreservation or IVF after previously initiating T-GAHT for fertility preservation and/or a partner-carried pregnancy; however, data regarding embryo outcomes are scarce. Retrospective cohort studies suggest high mature oocyte yields in oocyte cryopreservation following T-GAHT, but it is unknown whether embryos from patients with prior T-GAHT have a normal capacity to fertilize, cleave, and form blastocysts. STUDY DESIGN, SIZE, DURATION: This was a retrospective observational cohort study of 46 ovarian stimulation cycles initiated for TGD patients assigned female at birth with and without prior T-GAHT from January 2013 to March 2024. PARTICIPANTS/MATERIALS, SETTING, METHODS: This study included 36 TGD patients assigned female at birth, 25 undergoing IVF and 11 undergoing oocyte cryopreservation. Prior T-GAHT timing, duration, and discontinuation, as well as stimulation cycle characteristics and outcomes collected from the electronic health record retrospectively. Cycles outcomes of TGD people with prior T-GAHT were compared to those without prior T-GAHT. The first completed cycle was used for statistical analysis, with the first initiated cycle (intention to treat) and all cycles as sensitivity analyses. The primary outcome was the number of mature oocytes retrieved for all patients and the total number of blastocysts for patients undergoing IVF. Our secondary outcomes were maturity rate, number of top-quality blastocysts (AB or better), and cumulative live birth rate. A sub-analysis of subjects with prior T-GAHT was performed assessing discontinuation timing and IVF outcomes. MAIN RESULTS AND THE ROLE OF CHANCE: Of the 36 TGD patients included, 14 subjects (20 cycles) had prior T-GAHT, 22 patients (26 cycles) had no prior T-GAHT. Accounting for multiple cycles in 10 subjects, a total of 17 IVF and 3 oocyte cryopreservation cycles were initiated in the prior T-GAHT cohort, and 18 IVF and 8 oocyte cryopreservation cycles in the no T-GAHT cohort. After adjusting for age, in the first cycle, prior T-GAHT was associated with a decrease in the total number of blastocysts (coefficient -0.62, 95% CI: -0.95, -0.30) and number of top-quality blastocysts (coefficient -1.09, 95% CI: -1.68, -0.51) but was not associated with a difference in the number of mature oocytes or maturity. Modeling using the first initiated cycle and including all 46 cycles demonstrated the same results. The first cycle cumulative live birth rate was 60% in the prior T-GAHT cohort and 87.5% in those without T-GAHT (P = 0.20). In patients with prior T-GAHT pursuing IVF for transfer, 80% were ultimately able to achieve a live birth. In the first completed IVF cycle for patients with prior T-GAHT, T-GAHT cessation of <6 months was associated with fewer top-quality blastocysts (P = 0.01) and fewer BB or better quality blastocysts (P = 0.049). LIMITATIONS, REASONS FOR CAUTION: This study is primarily limited by its small sample size and retrospective study design, introducing risk of selection bias and sampling error and limiting our ability to adjust for multiple factors. Limited specificity and reliance on recall in T-GAHT initiation and discontinuation timing is a limitation in this study as it is a recurrent limitation in retrospective studies of TGD patients. WIDER IMPLICATIONS OF THE FINDINGS: Prior T-GAHT was not associated with differences in mature oocyte number, consistent with prior literature. However, we found that prior T-GAHT and shorter discontinuation were associated with poorer embryo outcomes. This may suggest that patients undergoing oocyte cryopreservation after only brief T-GAHT discontinuation may need to cryopreserve a greater number of oocytes to yield high-quality embryos. Overall, these results add to the growing body of reassuring fertility outcomes for TGD patients with prior T-GAHT, as the majority of these patients pursuing IVF for transfer were able to achieve a live birth. STUDY FUNDING/COMPETING INTEREST(S): Dr Rubin's time is partially supported through the Reproductive Scientist Development Program, with full funds supplied by the American Society for Reproductive Medicine. The authors have no competing interest to disclose. TRIAL REGISTRATION NUMBER: N/A.

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Embryonic ploidy correction: an update on mechanisms and insights from mosaic embryo transfer.

Mantzouratou A, Mania A

Hum Reprod · 2026 Mar · PMID 41543933 · Publisher ↗

Preimplantation human embryos frequently exhibit aneuploidy and chromosomal mosaicism, yet emerging evidence suggests they may possess mechanisms for ploidy correction that can mitigate these abnormalities. Several poten... Preimplantation human embryos frequently exhibit aneuploidy and chromosomal mosaicism, yet emerging evidence suggests they may possess mechanisms for ploidy correction that can mitigate these abnormalities. Several potential pathways have been proposed, including selective apoptosis of abnormal cells, cellular exclusion of aneuploid blastomeres, compartmentalization of abnormal cells into extraembryonic tissues, and chromosomal rescue events (such as trisomic or monosomic rescue), while in some embryos, no correction occurs, leading to persistence of aneuploid cell lineages. Follow-up studies on mosaic embryo transfer outcomes indicate that some embryos can eliminate or segregate aneuploid cells, leading to successful live births. However, the extent to which self-correction occurs, and the precise biological mechanisms underlying these processes, remain poorly understood. The likelihood of successful correction depends on the proportion and distribution of aneuploid cells as current evidence shows that embryos with high-level mosaicism have reduced developmental potential. This mini-review integrates current biological insights into ploidy correction mechanisms with clinical outcome data from mosaic embryo transfers, highlighting both the potential and limitations of embryonic self-correction hypotheses. By examining the interplay between mechanism studies and clinical observations, it underscores the challenges in predicting embryo viability and the necessity for standardized approaches in ART. Future research could help in defining the molecular and developmental pathways governing ploidy correction to improve embryo selection strategies and refine ART guidelines.

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Fertility preservation and counselling in prepubertal and pubertal girls with Turner syndrome.

Sage A, Rives N, Levadé R … +8 more , Réal-Lhommet A, Letailleur M, Jumeau F, Liard A, Joly-Hélas G, Cuny A, Castanet M, Feraille A

Hum Reprod · 2026 Mar · PMID 41535243 · Publisher ↗

STUDY QUESTION: What are the outcomes for prepubertal and pubertal girls with Turner syndrome (TS) in terms of fertility counselling and preservation? SUMMARY ANSWER: Fertility counselling is crucial for prepubertal and... STUDY QUESTION: What are the outcomes for prepubertal and pubertal girls with Turner syndrome (TS) in terms of fertility counselling and preservation? SUMMARY ANSWER: Fertility counselling is crucial for prepubertal and pubertal girls with TS, as it can facilitate their pursuit of fertility preservation (FP), primarily through oocyte cryopreservation (OC) and is particularly relevant for patients with blood karyotype abnormality with good prognosis for future fertility. WHAT IS KNOWN ALREADY: TS is a common genetic condition affecting ∼1 in 2500 live-born girls. One consequence of TS is premature ovarian insufficiency, significantly impacting the quality of life in adulthood. Therefore, appropriate counselling and effective FP or solutions are essential. When OC is proposed, the role of anti-Müllerian hormone (AMH) and FSH in predicting the outcomes of OC has been examined in the literature with controversial data. STUDY DESIGN, SIZE, DURATION: This retrospective observational study was conducted at the Reproductive Biology Laboratory-CECOS of Rouen University Hospital, evaluating the follow-up of 40 prepubertal and pubertal girls with TS referred for fertility counselling. Clinical and biological data were collected from medical records between January 2008 and December 2022. PARTICIPANTS/MATERIALS, SETTING, METHODS: Prepubertal and pubertal patients with TS attended a fertility counselling consultation, accompanied by their parents or legal guardian if they were under the age of 18 years. The impact of TS on future fertility and potential FP procedures, including OC, were explained. An assessment of ovarian reserve was conducted. Based on the results and depending on the patient's pubertal status, FP could be initiated immediately in TS patients with spontaneous menarche or follow-up could continue until spontaneous puberty and menarche occur. MAIN RESULTS AND THE ROLE OF CHANCE: In terms of FP, 25% (10/40) of the patients underwent OC. On average, 4.9 ± 3.8 oocytes per controlled ovarian hyperstimulation cycle were cryopreserved. No relationship was found between basal FSH or AMH serum level, karyotype abnormalities, and the number of mature oocytes retrieved. Conversely, a positive correlation was observed between the peak estradiol level at the time of triggering and the number of mature oocytes retrieved. In the multiple linear regression analysis with cross-validation, the peak estradiol level at triggering remained the only variable independently associated with mature oocyte yield. Most patients were aware of the impact of TS on future fertility but were uninformed about available parenthood alternatives. LIMITATIONS, REASONS FOR CAUTION: The number of TS patients included in our study is a limitation, as well as the monocentric and retrospective nature of the study. Therefore, our data should be interpreted with caution. WIDER IMPLICATIONS OF THE FINDINGS: Fertility counselling and FP are essential for prepubertal and pubertal TS patients. Regular and systematic follow-up of ovarian reserve and function should be implemented in their medical care. OC is a feasible option for some TS patients and should be considered after menarche but delayed until further pubertal maturation to allow robust patient engagement in the decision-making process. Further studies are needed to evaluate factors influencing the number of mature oocytes retrieved and the optimal number of oocytes necessary to ensure a good chance of pregnancy. STUDY FUNDING/COMPETING INTEREST(S): This work had institutional financial support from Rouen University Hospital. The authors have no conflicts of interest to declare. TRIAL REGISTRATION NUMBER: N/A.

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The need to understand the underlying mechanisms associated with mitochondrial therapies in assisted reproduction before further clinical trials are performed.

St John JC, Rodgers RJ

Hum Reprod · 2026 Apr · PMID 41528357 · Full text

Over a number of years, there has been growing interest in the introduction of more invasive ARTs, such as nuclear transfer, otherwise referred to as mitochondrial donation, and mitochondrial supplementation/transfer int... Over a number of years, there has been growing interest in the introduction of more invasive ARTs, such as nuclear transfer, otherwise referred to as mitochondrial donation, and mitochondrial supplementation/transfer into clinical medicine. They have been proposed to overcome repeated failed fertilization or developmental arrest or to prevent carriers of mitochondrial DNA disease from having affected children. These technologies require considerable manipulation of the oocyte, which can affect its epigenetic programming that was established as it grew and developed into a fertilizable oocyte. Consequently, when a nucleus is transferred into an enucleated oocyte or pronuclei are transferred into an enucleated zygote, the nucleus must adapt to its new cytoplasmic environment in readiness for the waves of DNA demethylation and methylation that take place during preimplantation development. As a result, some key developmental gene networks are affected. Additionally, these approaches also affect patterns of mitochondrial DNA inheritance, with some embryos and offspring possessing mitochondrial DNA carried over into the oocyte with the nucleus, as well as the mitochondrial DNA from the donor oocyte. Similar outcomes result from the addition of extra mitochondrial DNA into oocytes through mitochondrial supplementation. We provide a background as to how these technologies evolved and discuss recent outcomes associated with clinical work so far undertaken within these approaches and their consequences for the offspring. We conclude that these technologies are not simply replacing or replenishing defective ooplasms with new or extra mitochondria but rather induce a series of genomic and epigenomic events that we do not yet fully understand. To our minds, these issues should be first addressed before clinical trials are continued.

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Sexual functioning and its determinants in individuals and their partners with unexplained infertility.

Dreischor F, Dancet E, Laan ETM … +6 more , Goddijn M, den Hartog JE, van Hooff MHA, Lambalk CB, van Wely M, Custers IM

Hum Reprod · 2026 Mar · PMID 41527942 · Publisher ↗

STUDY QUESTION: What is the prevalence of sexual dysfunction, and what are the determinants of sexual (dys)functioning in couples with newly diagnosed unexplained infertility? SUMMARY ANSWER: At least one in four couples... STUDY QUESTION: What is the prevalence of sexual dysfunction, and what are the determinants of sexual (dys)functioning in couples with newly diagnosed unexplained infertility? SUMMARY ANSWER: At least one in four couples are at risk of sexual dysfunction, and higher age, longer infertility duration, higher sperm quality, and poorer personal and relational well-being were associated with decreased sexual functioning. WHAT IS KNOWN ALREADY: Many couples diagnosed with unexplained infertility have the ability to conceive naturally over time, but infertility is linked to reduced sexual functioning, which can hinder conception. Surprisingly, sexual functioning, its risk factors, and partner interdependence are still understudied in unexplained infertility, while knowing the risk factors for reduced sexual functioning would enable fertility specialists to timely diagnose, prevent, or treat sexual dysfunction, and in this way improve natural conception rates. STUDY DESIGN, SIZE, DURATION: A cross-sectional survey, which also serves as the baseline assessment of a randomized controlled trial (RCT, 2016-2021). A total of 700 heterosexual couples were addressed. PARTICIPANTS/MATERIALS, SETTING, METHODS: Dutch heterosexual couples (female age 18-38 years) who were able to have coitus and were recently diagnosed with unexplained infertility in secondary or tertiary clinics were eligible. The main outcome measures were sexual functioning as a continuous variable and female and erectile dysfunction based on cut-off scores of the Female Sexual Function Index and International Index of Erectile Function. Determinants included demographic, lifestyle, and diagnostic factors, as well as personal and relational well-being, which were assessed with the Hospital Anxiety and Depression Scale and the Revised Dyadic Adjustment Scale. Sexual (dys)functioning and determinants were subjected to dyadic analysis followed by linear regression. MAIN RESULTS AND THE ROLE OF CHANCE: A total of 581 (83%) women and 478 (68%) men completed the questionnaires. Complete couple data were available for 451 (68.9%) couples. About 1 in 4 women (24.3%) and 1 in 14 men (7.3%) were at risk for, respectively, female sexual dysfunction and erectile dysfunction after a fertility work-up. Couples had a mean coital frequency of seven times per month (SD: 2.7). Higher female and male sexual desire (β: 0.04, P < 0.01 and β: 0.02, P < 0.02) and satisfaction (β: 0.03, P < 0.01 and β: 0.06, P < 0.01), but not orgasm, were significantly associated with increased coital frequency. Lower female sexual functioning (β) or dysfunction (OR) was associated with own age (β: -0.64, OR: 1.12), anxiety (β: -9.47, OR: 4.22), depression (β: -7.61, OR: 3.23), relationship distress (β: -8.97, OR: 2.04), and total motility sperm count (β: -4.88). Lower male sexual functioning was associated with anxiety (β: -5.03), depression (β: -3.65), relationship distress (β: -5.77), and partner's age (β: -0.46) and couple's duration of infertility (β: -0.24, OR: 1.06). LIMITATIONS, REASONS FOR CAUTION: The study is prone to selection bias given the inclusion of couples seeking medical help and consenting to an RCT. Not all previously identified determinants of sexual functioning were studied due to factors such as missing data, low case numbers, or not being assessed in the Pleasure&Pregnancy (P&P) RCT. WIDER IMPLICATIONS OF THE FINDINGS: Clinicians advising couples with unexplained infertility to continue natural conception, given their good prognosis, need to be aware that at least one in four couples are at risk for a sexual dysfunction. Clinicians should consider risk factors of reduced sexual functioning, take a sexual anamnesis, and advise face-to-face or digital (e.g. via website or app) sex counselling and treatment, if indicated. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by the Netherlands Organization for Health Research and Development (ZonMW reference: 843001605), University of Amsterdam and Flanders Research Foundation. The funders have no role in considering the design of the study, or collection, analysis, and interpretation of the data, or writing of the report. C.B.L. was the Editor-in-Chief of Human Reproduction until 1 January and has received speakers honorarium and travel support from Merck and Organon. TRIAL REGISTRATION NUMBER: Baseline assessment of the P&P RCT with trial registration number NTR5709.

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The 2025 WHO infertility guideline: value in focusing on clinical varicocele and recognizing gaps in male diagnosis and treatment.

Esteves SC, De Jonge CJ, Pacey A … +1 more , Vazquez-Levin MH

Hum Reprod · 2026 Mar · PMID 41507099 · Publisher ↗

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A multi-country study to co-design and evaluate digital educational resources to support conversations about ending fertility treatment.

Sousa-Leite M, Gameiro S

Hum Reprod · 2026 Mar · PMID 41499157 · Full text

STUDY QUESTION: How can educational resources be feasibly co-designed and used to support conversations between staff and patients about ending fertility treatment? SUMMARY ANSWER: Co-design workshops allow for the devel... STUDY QUESTION: How can educational resources be feasibly co-designed and used to support conversations between staff and patients about ending fertility treatment? SUMMARY ANSWER: Co-design workshops allow for the development of educational resources that account for all stakeholders' perspectives and are considered sensitive, informative, and helpful to support end-of-treatment conversations, but staff and patients have different views about how these can be used within the treatment pathway. WHAT IS KNOWN ALREADY: Ending treatment without children is a common outcome but seldom discussed with patients. Preventive end-of-treatment care aims to promote healthy transitions at the end of treatment by preparing and helping patients cope with this possible outcome. Nine in ten patients want to receive such care, but only 3 in 10 report receiving it. Knowledge of perceived barriers to implementing preventive end-of-treatment care at clinics and whether digital educational resources can be developed to support its provision is lacking. STUDY DESIGN, SIZE, DURATION: Co-design workshops with fertility staff (March 2022), patients, and patient advocates (March-December 2022) from Europe (Belgium, Finland, Germany, Italy, Portugal, Spain, and UK) and South America (Argentina, Brazil, and Chile). Staff were invited to participate through fertility professional and scientific associations, and patients and advocates via charities and social media. Eligibility criteria were being aged 18 or older and working in fertility care (for staff) or charity (for advocates) or being waiting to initiate, undergoing, or having undergone treatment within 6 months (for patients). PARTICIPANTS/MATERIALS, SETTING, METHODS: A preliminary specification and initial prototypes of digital educational resources to support staff and patients, respectively, in having conversations about ending treatment were developed with relevant stakeholders. Co-design workshops with study participants were conducted. A semi-structured script, following Bowen et al.'s (2009)feasibility framework, was used to guide the workshops. Questions covered: (i) experiences, views, and preferences on the provision of preventive end-of-treatment care at clinics and iterative prototypes of the resources to support this provision (acceptability); (ii) perceived need and benefits (demand); and (iii) perceived barriers and facilitators to its implementation at clinics (practicalities). Workshops were recorded and transcribed verbatim, and data were analysed using Framework Analysis. MAIN RESULTS AND THE ROLE OF CHANCE: Fifteen fertility staff, 34 patients, and 7 advocates participated. Staff were mainly psychologists/counsellors (40.0%) or clinicians (26.7%) working in the field for around 23 years. Patients were mostly women (91.2%), on average aged 38 years. Most were childless (73.5%) and trying to conceive for around 3 years. Framework analysis of data collected during the co-design workshops generated four themes and one meta-theme, reflecting a need for a normative shift across countries towards the routine implementation of preventive end-of-treatment care. Themes reflected: (i) demand for routine provision of holistic psychosocial care, including preventive end-of-treatment care; (ii) different views between staff and patients about the risks and extent of benefits of routinely implementing preventive end-of-treatment care; (iii) patient high clarity about the functions of preventive end-of-treatment care (ensuring patients feel prepared and supported in moving through the grief and cope with short-term challenges; explore other pathways to parenthood and re-orient one's life goals; and ensure informed consent for fertility treatment) versus staff lower clarity, with care being equated to signposting patients for timely psychological support; and (iv) co-designed digital educational resources are helpful to support the routine provision of preventive end-of-treatment care at clinics. LIMITATIONS, REASONS FOR CAUTION: Non-probability sample. Although the patient sample was heterogeneous (heterosexual and same-sex couples; private and public sectors), patients were primarily White, well-educated, employed, and childless women, limiting the generalization and comparisons across gender and other personal characteristics (ethnicity, socioeconomically disadvantaged, and disabled), where access to and acceptance of psychosocial support are expected to be lower. WIDER IMPLICATIONS OF THE FINDINGS: Routine discussions about the end of treatment are needed and beneficial, but staff will require reassurance and training on with whom, when, and how to engage in these. The final version of the digital educational resources is seen as valuable to support a cultural shift in implementing end-of-treatment preventive care at clinics. The co-designed webpages are freely available online in four languages (for staff: www.myjourney.pt/clinics, for patients: www.myjourney.pt/patients). Future research is needed to raise awareness and further investigate how best to support staff in such care provision and measure its impact. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by a Research Wales Innovation Fund from the Higher Education Funding Council for Wales (HEFCW, grant No.: JA1710IF63). M.S.-L. was supported by the Portuguese Foundation for Science and Technology (FCT; fellowship No.: SFRH/BD/144429/2019) and the UK Economic and Social Research Council (ESRC; fellowship No.: ES/Z503125/1). The EPIUnit and ITR were funded by the FTC through the Portuguese State Budget (projects No.: UIDB/04750/2020 and LA/P/0064/2020 and DOI identifiers https://doi.org/10.54499/UIDB/04750/2020 and https://doi.org/10.54499/LA/P/0064/2020). S.G. reports grants from the European Society for Human Reproduction and Embryology (ESHRE), the Wellcome Fund (UK), and the Health and Care Research Wales (UK). Cardiff University holds the Intellectual Property rights for the tool www.myjourney.pt, licensed under a Creative Commons AttributionNonCommercial-ShareAlike 4.0 International Licence (CC BY-NCSA 4.0). TRIAL REGISTRATION NUMBER: n/a.

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Ovarian function compromise in pediatric beta-thalassemia major: a consequence of iron overload-induced mitochondrial and fibrotic damage.

Liu X, Chen P, Li Y … +7 more , Zhao W, Zheng X, Sun P, Guo Y, Fang C, Liang X, Li J

Hum Reprod · 2026 Mar · PMID 41481664 · Publisher ↗

STUDY QUESTION: How does iron overload affect ovarian function in pediatric patients with transfusion-dependent beta-thalassemia major? SUMMARY ANSWER: Iron overload in pediatric patients with beta-thalassemia major is s... STUDY QUESTION: How does iron overload affect ovarian function in pediatric patients with transfusion-dependent beta-thalassemia major? SUMMARY ANSWER: Iron overload in pediatric patients with beta-thalassemia major is strongly associated with decreased ovarian reserve and mitochondrial damage. WHAT IS KNOWN ALREADY: Beta-thalassemia major is a severe blood disorder necessitating frequent blood transfusions, leading to iron overload. Excessive iron causes oxidative stress and damage in various organs, including the ovaries, but its impact on ovarian function in pediatric patients has not been fully explored. STUDY DESIGN, SIZE, DURATION: This study analyzed data from 194 pediatric patients who were treated at The Sixth Affiliated Hospital of Sun Yat-Sen University between January 2021 and January 2024, among whom 138 had beta-thalassemia major. Meanwhile, we conducted experiments using human samples and mouse models of iron overload. PARTICIPANTS/MATERIALS, SETTING, METHODS: The study involved 194 pediatric patients. Clinical assessments measured serum ferritin and ovarian reserve indicators anti-Müllerian hormone (AMH) and antral follicle count. Ovarian tissue from pediatric patients was used for histopathological examination, immunohistochemical (IHC) staining, transmission electron microscopy (TEM), and transcriptome analysis, to investigate the effects of iron overload. For the animal experiments, we utilized 20 newborn female mice to establish an iron overload and control model. These animals underwent comprehensive evaluations, including histopathological examination, TEM, and IHC analyses, to systematically investigate the impact of iron overload on ovarian tissue. MAIN RESULTS AND THE ROLE OF CHANCE: Pubertal pediatric patients with high iron overload had significantly lower AMH, indicating reduced ovarian reserve, accompanied by evident mitochondrial damage and fibrotic remodeling in ovarian tissues, collectively contributing to impaired ovarian function. Decreased AMH and impaired follicular development were also observed in iron-overloaded mice, along with mitochondrial damage and ovarian fibrosis. LARGE SCALE DATA: Transcriptome data are available at China National Center for Bioinformation, reference HRA004373 and HRA013348. LIMITATIONS, REASONS FOR CAUTION: The cross-sectional design limits causality assessment. The sample size for molecular analyses is relatively small, necessitating larger, longitudinal studies to confirm these findings and understand long-term effects. WIDER IMPLICATIONS OF THE FINDINGS: Effective iron management in pediatric patients with beta-thalassemia major is crucial to preserving ovarian function and preventing long-term reproductive issues. These findings can guide clinical practices and therapeutic strategies to mitigate iron overload's adverse effects on ovarian health. In this study, mitochondrial dysfunction may compromise cellular energy production and amplify tissue vulnerability to ischemia-reperfusion injury during transplantation. Additionally, fibrosis-induced structural rigidity may hinder revascularization of transplanted tissue, further reducing success rates. These findings underscore the need to monitor post-transplant survival rates. Further experimental investigations are warranted to explore this critical issue. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by the National Key R&D Program of China (2022YFC2703000); National Natural Science Foundation of China (U24A20662, 82271651); Clinical Research Fund of Guangdong Medical Association (2025SZ-B1001); Postdoctoral Fellowship Program of CPSF (GZC20233216); and Guangdong Basic and Applied Basic Research Foundation (2023A1515110325). The authors declared no competing interests.

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The impact of transdermal testosterone treatment on quality of life in women with diminished ovarian reserve: secondary analysis of a randomized controlled trial.

Leathersich SJ, Davis SR, García Martínez S … +9 more , Blockeel C, Martínez F, Gosálvez A, Humaidan P, de la Fuente L, Fàbregues F, Pinborg A, Stoop D, Polyzos NP

Hum Reprod · 2026 Feb · PMID 41461161 · Publisher ↗

STUDY QUESTION: Does transdermal testosterone treatment improve fertility-related quality of life (QOL) in women with diminished ovarian reserve (DOR)? SUMMARY ANSWER: Transdermal testosterone for 9 weeks at a dose of 5.... STUDY QUESTION: Does transdermal testosterone treatment improve fertility-related quality of life (QOL) in women with diminished ovarian reserve (DOR)? SUMMARY ANSWER: Transdermal testosterone for 9 weeks at a dose of 5.5 mg per day did not result in improved fertility-related QOL compared with placebo in women with DOR. WHAT IS KNOWN ALREADY: Reduced QOL is prevalent in women with infertility, many of whom have DOR. Several studies have shown a correlation between DOR and lower testosterone levels, and testosterone is frequently prescribed to women with DOR undergoing fertility treatment. Some studies have reported that testosterone therapy may improve wellbeing in pre- and post-menopausal women, though others have found no benefit. There are no studies evaluating the effect of testosterone on QOL in women undergoing fertility treatment. STUDY DESIGN, SIZE, DURATION: Pre-planned secondary analysis of a double-blind placebo-controlled randomized controlled trial that included 288 participants recruited between April 2015 and August 2022. Of these, 213 completed QOL surveys both before and after treatment and were eligible for inclusion in this analysis. PARTICIPANTS/MATERIALS, SETTINGS, METHODS: Participants were women aged 18-43 years with DOR according to the Bologna criteria and planning to undergo IVF treatment at one of eight fertility clinics in Spain, Belgium, and Denmark. Participants were randomized to 5.5 mg of transdermal testosterone per day as 1% gel (n = 106) or an identical placebo (n = 107), applied for a median of 60 days prior to commencing ovarian stimulation. QOL was assessed using the FertiQoL instrument prior to commencing the intervention, and at the completion of the intervention but prior to commencing ovarian stimulation. QOL scores were compared using a one-way ANCOVA adjusted for age, BMI, parity, history of IVF treatment, and baseline FertiQoL scores. MAIN RESULTS AND THE ROLE OF CHANCE: There were no significant differences in baseline characteristics between the testosterone (n = 106) and placebo (n = 107) groups. After adjustment, testosterone showed no benefit over placebo for the Total FertiQoL score (F(1,204)=0.07, P = 0.79), the Core and Treatment scores, nor for any of the included FertiQoL subscales. Total testosterone levels were higher in the testosterone group than the placebo group at the end of the treatment (3.2 ± 2.7 nmol/l vs 0.6 ± 0.4 nmol/l, P < 0.001). LIMITATION, REASONS FOR CAUTION: QOL was a secondary outcome in this trial, and participants were not recruited based on a low QOL. WIDER IMPLICATIONS OF THE FINDINGS: Considering the available evidence, including the current study, premenopausal women are unlikely to benefit from testosterone treatment with regard to wellbeing and QOL. This study provides further evidence that testosterone should not be seen as a treatment for low wellbeing or QOL. STUDY FUNDING/COMPETING INTEREST(S): The study was supported by unrestricted grants and support from Besins Healthcare, Roche Diagnostics, and Ferring Pharmaceuticals. The study medication and placebo were provided by Besins Healthcare. Funders had no access to patient data and had no role in the interpretation of the data, nor in the writing or approval of the final manuscript. The researchers were independent of the funders and had full access to all the data in the study. S.J.L. has received honoraria from Merck, Organon, and Hologic, consulting fees from Merck, and travel support from Merck, Organon, Besins Healthcare, and Ferring Pharmaceuticals. S.R.D. has received grants from NHMRC Australia, MS Australia, MRFF Australia, the Australian Heart Foundation, and Lawley Pharmaceuticals, consulting fees from Besins Healthcare, Astellas, and Abbott, honoraria from Theramex, Astellas, and Bayer, travel support from Astellas, and drugs/placebo from Lawley Pharmaceuticals for clinical trials; she is an Executive Board Member of the Australian Academy of Health and Medical Sciences. C.B. has received honoraria from Ferring Pharmaceuticals, IBSA, Organon, Merck A/S, and Abbott. A.G. has received honoraria from Lab Seid and travel support from Merck Serono. P.H. has received honoraria from Merck, IBSA, Gedeon Richter, and Besins Healthcare. L.D.L.F. has received consulting fees from Gedeon Richter, Ferring Pharmaceuticals, and Organon, travel support (personal and to institution) from Gedeon Richter, Ferring Pharmaceuticals, IBSA, Merck, Organon, and Theramex, and educational support (to institution) from Gedeon Richter and Merck. A.P. has received grants from Gedeon Richter, Ferring Pharmaceuticals, and Merck A/S, consulting fees from Gedeon Richter and Ferring Pharmaceuticals, honoraria from Ferring Pharmaceuticals, Gedeon Richter, Merck A/S, Abbott, and Organon, and travel support from Gedeon Richter. D.S. has received grants from Organon, Ferring Pharmaceuticals, Besins Healthcare, Gedeon Richter, and Vitrolife, honoraria from Organon, Ferring Pharmaceuticals, Besins Healthcare, Gedeon Richter, and Merck, travel support from Organon, Ferring Pharmaceuticals, Besins Healthcare, Gedeon Richter, and Merck, and is President of the Belgian Society for Reproductive Medicine. N.P.P. has received grants from Merck Serono, Ferring Pharmaceuticals, Theramex, Organon, Besins Healthcare, and Gedeon Richter, consulting fees from Merck Serono, Besins Healthcare, Organon, IBSA, FertilAI, and Alife, and honoraria from Merck Serono, Theramex, IBSA, Ferring Pharmaceuticals, Organon, Roche Diagnostics, and Besins Healthcare. S.G.M., F.M., and F.F. have no interests to declare. TRIAL REGISTRATION NUMBER: NCT02418572 (ClinicalTrials.gov).

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Obstetrical, perinatal, and children's health outcomes following fresh embryo transfer after extended embryo culture.

Fauque P, Cottenet J, Firmin J … +9 more , Pocate-Cheriet K, Ferreux L, Chargui A, Tapia S, Maignien C, Bourdon M, Santulli P, Patrat C, Quantin C

Hum Reprod · 2026 Mar · PMID 41453370 · Publisher ↗

STUDY QUESTION: Does extended embryo culture (EEC) associate with an increased risk of obstetrical, perinatal, or children's health complications? SUMMARY ANSWER: After thorough adjustment, EEC was not associated with wi... STUDY QUESTION: Does extended embryo culture (EEC) associate with an increased risk of obstetrical, perinatal, or children's health complications? SUMMARY ANSWER: After thorough adjustment, EEC was not associated with widespread increased risks, although a moderate excess risk persisted for a few specific outcomes, notably cardiac anomalies, whereas reduced risks were observed for gestational diabetes, small birthweight, and musculoskeletal-limb anomalies. WHAT IS KNOWN ALREADY: EEC is increasingly used in IVF cycles. While blastocyst transfer (day-5/6) often improves birth rates, concerns remain about its impact on maternal and child health. STUDY DESIGN, SIZE, DURATION: In this nationwide longitudinal cohort study, all live-born singletons conceived through IVF-with or without sperm microinjection-and following fresh embryo transfer between 2014 and 2019 in France were included and followed for up to 8 years. PARTICIPANTS/MATERIALS, SETTING, METHODS: Data were obtained from the French National Health System and the National Biomedicine Agency registries. A comparative study was conducted between singletons conceived at either day-2/3 (cleavage-stage embryos group) or day-5/6 (EEC group). Data from both registries were cross-linked to identify obstetrical, perinatal, and health outcomes, including major congenital malformations, hospitalizations, and surgical interventions. Multivariable logistic and survival models were used to adjust for maternal, paternal, and treatment-related factors. MAIN RESULTS AND THE ROLE OF CHANCE: A total of 41 315 singletons were included (25 816 and 15 499 from day-2/3 and day-5/6 groups, respectively). Most outcomes were similar between groups, notably the incidence of global major congenital malformations. However, EEC was associated with increased risks of placenta praevia (aOR, 1.16; 95% CI, 1.02-1.30), admission in neonatal intensive care unit (aOR, 1.16; 95% CI, 1.05-1.29), and cardiac anomalies at age 3 years (aHR, 1.78; 95% CI, 1.21-2.60). Conversely, the risk of gestational diabetes (aOR, 0.94; 95% CI, 0.88-1.00; P = 0.041) and small birthweight (aOR, 0.94; 95% CI, 0.88-1.00, P = 0.039) was lower, as was the risk of musculoskeletal-limb anomalies (aHR, 0.63; 95% CI, 0.42-0.97)-a finding that persisted up to age 7. Other health outcomes were largely comparable. LIMITATIONS, REASONS FOR CAUTION: One limitation of this study is that the data refer to live-born singletons, with stillbirths and medical terminations excluded from the analyses. Despite extensive adjustments, residual confounding cannot be excluded. Findings for specific pathologies/malformations should be interpreted with caution because the number of cases was small in some sub-groups. WIDER IMPLICATIONS OF THE FINDINGS: In this large and unique study, after adjusting for multiple maternal, paternal, and cycle-related variables, our findings provide some reassurance regarding the safety of prolonged in vitro embryo culture. A moderate risk remained for a few maternal and child health conditions following EEC-warranting further investigation-whereas the risk was notably lower compared to short embryo culture, particularly for musculoskeletal-limb anomalies. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by the AOI of University Hospital of Dijon. The authors have no competing interests to disclose. TRIAL REGISTRATION NUMBER: N/A.

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Automated oocyte retrieval, denudation, sperm preparation, and ICSI in the IVF laboratory: a proof-of-concept study and report of the first live births.

Chavez-Badiola A, Mendizabal-Ruiz G, Flores-Saiffe Farías A … +20 more , Costa-Borges N, Murray A, Alikani M, Silvestri G, Millan C, Hernández-Morales E, Valencia-Murillo R, Medina V, Mestres E, Valadez Aguilar A, Ocegueda-Hernández V, Acosta-Gómez F, Álvarez López A, Acacio M, Matia-Algué Q, Espinoza Figueroa JG, Campos Olmedo LM, Barragan CP, Sánchez-González DJ, Cohen J

Hum Reprod · 2026 Feb · PMID 41453368 · Full text

STUDY QUESTION: Can multiple automated systems sequentially perform Day 0 IVF procedures: (i) sperm preparation, (ii) cumulus-oocyte complex (COC) retrieval and oocyte denudation, and (iii) ICSI? SUMMARY ANSWER: Automate... STUDY QUESTION: Can multiple automated systems sequentially perform Day 0 IVF procedures: (i) sperm preparation, (ii) cumulus-oocyte complex (COC) retrieval and oocyte denudation, and (iii) ICSI? SUMMARY ANSWER: Automated sequential Day 0 procedures achieved fertilization in 64.3% of injected oocytes and 42.2% usable blastocyst formation in 11 cases, resulting in five healthy live births from nine patients with positive pregnancy tests. WHAT IS KNOWN ALREADY: The Day 0 procedures-sperm preparation, oocyte handling (e.g. finding and denudation), and ICSI-rely on embryologist skill. Automation in IVF laboratories has the potential to improve reproducibility, yet its implementation remains limited. Fully automated pipetting workflows replicating embryologist activities have not yet been achieved, though partial automation of key steps such as dish preparation and ICSI has been reported. STUDY DESIGN, SIZE, DURATION: Proof-of-concept pilot study with prospective allocation of sibling oocytes to automated or manual protocols. Here, we report on Day 0 automation in 11 cases using two or three automated systems (nicknamed 'pearls') in sequence. Single vitrified/warmed blastocyst transfers occurred between April and October 2024. This work was part of a larger research programme evaluating automation across multiple IVF laboratory procedures from gamete handling through blastocyst transfer and specifically demonstrates sequential automation across multiple Day 0 procedures within a single workflow. PARTICIPANTS/MATERIALS, SETTING, METHODS: Eleven consenting patients (three autologous, eight donor egg cycles) underwent IVF/ICSI following minimal or mild stimulation. The gametes were processed using either automated or manual protocols. The automated systems-Pearl 1 (sperm preparation), Pearl 2 (COC retrieval and oocyte denudation), and Pearl 3 (sperm selection, laser immobilization, and piezo-ICSI)-were used in various combinations. Multiple AIs were developed and deployed across these systems. This IRB-approved study was conducted at Hope IVF, Guadalajara, México. MAIN RESULTS AND THE ROLE OF CHANCE: The automated systems achieved 64.3% fertilization (45/70) and 42.2% usable blastocyst formation per zygote (19/45), compared to 81% (47/58) and 59.6% (28/47) with manual procedures. Transfers from the automated arm resulted in five live births, three biochemical pregnancies, and one early loss at 7 weeks. The live birth rate per transfer of a single warmed blastocyst in the automated arm was 5/12 (41.7%). LIMITATIONS, REASONS FOR CAUTION: The small sample size prevented statistical comparison between automated and manual procedures. Some steps required operator support via direct intervention or digital control. Autonomy (defined as automated execution without human intervention) was achieved only in sperm preparation and selected ICSI tasks. A larger study using an updated system is underway. WIDER IMPLICATIONS OF THE FINDINGS: This study demonstrates the feasibility of automating Day 0 IVF procedures, with the potential to improve standardization and reduce protocol drift, fatigue, and operator variability. Our findings support a phased integration of automation to meet growing ART demands. STUDY FUNDING/COMPETING INTEREST(S): The study was sponsored by Conceivable Life Sciences. A.C.-B. is an employee, shareholder, and company officer at Conceivable Life Sciences and also holds shares in IVF 2.0. G.M.-R. is a stock option holder at Conceivable Life Sciences and has received consulting fees from both Conceivable Life Sciences and IVF 2.0. A.F.-S.F. is an employee and stock option holder at Conceivable Life Sciences. N.C.-B. is a stock option holder at Conceivable Life Sciences and has received consulting fees from the company, and he is also an employee, shareholder, and company officer at Embryotools. A.M. is a shareholder and company officer at Conceivable Life Sciences and holds shares in TMRW Life Sciences. M.A. is a stock option holder at Conceivable Life Sciences and has received consulting fees and travel support from the company; she has also received consulting fees from TMRW Life Sciences. G.S. is an employee and stock option holder at Conceivable Life Sciences and has received consulting fees from IVF 2.0. C.M. is an employee and stock option holder at Conceivable Life Sciences. E.H.-M. is an employee and stock option holder at Conceivable Life Sciences. R.V.-M. is an employee and stock option holder at Conceivable Life Sciences and has received consulting fees from IVF 2.0. V.M. is an employee and stock option holder at Conceivable Life Sciences. E.M. is an employee of Embryotools. A.V.A. has no conflicts of interest to declare. V.O.-H. is an employee and stock option holder at Conceivable Life Sciences and has received consulting fees from IVF 2.0. F.A.-G. is an employee and stock option holder at Conceivable Life Sciences. A.Á.L. is an employee and stock option holder at Conceivable Life Sciences. M.A. is an employee of Embryotools. Q.M.-A. is an employee of Embryotools. J.G.E.F. is an employee and stock option holder at Conceivable Life Sciences. L.M.C.O. has no conflicts of interest to declare. C.P.B. is an employee and stock option holder at Conceivable Life Sciences. D.J.S.-G. has no conflicts of interest to declare. J.C. is an employee, shareholder, stock option holder, and company officer at Conceivable Life Sciences and holds shares in IVF 2.0, Althea Science, TMRW Life Sciences, Kindbody, and Reproductive Healthcare. Furthermore, A.C.-B., G.M.-R., A.F.-S.F., A.M., A.Á.L., and J.C. declare inventorship on US patent 12,349,940 B2 protecting automated oocyte denudation. A.C.-B., G.M.-R., A.F.-S.F., C.M., R.V.-M., V.O.-H., E.H.-M., V.M., A.M., and J.C. declare inventorship on US patent 12,245,793 B2 protecting robotic handling systems for IVF laboratories. A.C.-B., G.M.-R., A.F.-S.F., C.M., G.S., V.M., J.C., and A.M. declare inventorship on US patent 12,178,475 B1 protecting automated sperm preparation. A.C.-B., G.M.-R., A.M., and J.C. declare inventorship on US patent 12,180,441 B1 protecting laboratory workflow automation. A.C.-B., G.M.-R., A.F.-S.F., A.M., C.M., R.V.-M., V.O.-H., N.C.-B., A.Á.L., and J.C. declare inventorship on US patent 12,268,418 B2 protecting automated oocyte preparation. A.C.-B., G.M.-R., R.V.-M., V.O.-H., N.C.-B., E.H.-M., A.M., J.C., and A.F.-S.F. declare inventorship on US patent 12,310,625 B2 protecting automated ICSI. A.C.-B., G.M.-R., A.F.-S.F., C.M., V.O.-H., and A.M. declare inventorship on US patent 12,253,516 B2 protecting optical systems for IVF automation. A.C.-B., G.M.-R., A.M., J.C., A.F.-S.F., C.M., R.V.-M., V.O.-H., G.S., N.C.-B., and J.G.E.F. declare inventorship on US patent 12,226,125 B2 protecting automated vitrification. A.C.-B., G.M.-R., C.M., R.V.-M., V.O.-H., N.C.-B., V.M., and J.C. declare inventorship on US patent US 12,478,405 B2 protecting automated dish-based sperm preparation. A.C.-B., G.M.-R., C.M., N.C.-B., M.A., A.M., and J.C. declare inventorship on a pending patent application protecting automated dish preparation technology. A.C.-B., G.M.-R., N.C.-B., and J.C. declare inventorship on a pending patent application protecting automated oocyte denudation. N.C.-B., J.C., A.M., E.H.-M., and A.C.-B. declare inventorship on a pending patent application protecting automated vitrification systems. A.C.-B., G.M.-R., V.O.-H., and J.C. declare inventorship on a pending patent application protecting COC detection technology. TRIAL REGISTRATION NUMBER: NCT06074835 (ClinicalTrials.gov, 4 October 2023).

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Family planning of infertile couples: a systematic review of intentions regarding parenthood and return to ART.

Li Piani L, Esposito G, Reschini M … +3 more , Donnez J, Parazzini F, Somigliana E

Hum Reprod · 2026 Feb · PMID 41428654 · Full text

STUDY QUESTION: What motivations and barriers influence family planning decisions among infertile individuals? SUMMARY ANSWER: In studying the family planning of infertile couples, this review found that a significant ga... STUDY QUESTION: What motivations and barriers influence family planning decisions among infertile individuals? SUMMARY ANSWER: In studying the family planning of infertile couples, this review found that a significant gap persists between desired and achieved family size. WHAT IS KNOWN ALREADY: While ART has traditionally focused on live birth rate (LBR) as a primary success parameter, growing attention has been paid to whether treatments help couples achieve their desired family size. Evidence suggests that many infertile couples do not return to ART for subsequent children, despite having cryopreserved embryos available. STUDY DESIGN, SIZE, DURATION: This review was conducted as a systematic review following PRISMA guidelines. A comprehensive search strategy was developed and implemented across PubMed and Embase databases, covering studies published in English up to May 2025. The search combined free text terms and MeSH/Emtree terms related to 'infertility' and 'family planning'. PARTICIPANTS/MATERIALS, SETTING, METHODS: We included observational studies reporting outcomes related to family size, return to ART, or intentions for subsequent children. Two reviewers independently performed screening, data extraction, and quality assessment using the Newcastle-Ottawa Scale. MAIN RESULTS AND THE ROLE OF CHANCE: Of 2495 screened records, 9 studies were included. Across contexts, infertile couples consistently reported smaller family sizes compared to fertile ones. Return rates to ART for a second child ranged from 25 to 50%, even among those with cryopreserved embryos. Factors associated with return included younger age, availability of embryos, and previous treatment characteristics. However, emotional, financial, and social burdens often discouraged further ART use. Success rates for second ART pregnancies varied, with cumulative LBRs between 38 and 88%, depending on treatment strategy and prior history. LIMITATIONS, REASONS FOR CAUTION: Scarcity of evidence and high heterogeneity across studies, including differences in design, populations, outcomes, and type of ART, may have limited comparability of the studies. WIDER IMPLICATIONS OF THE FINDINGS: The low return rate to ART highlights unmet needs in post-treatment support and counselling. Future research should explore the psychosocial, economic, and systemic barriers that prevent couples from pursuing their reproductive goals, enabling more patient-centred care in reproductive medicine. STUDY FUNDING/COMPETING INTEREST(S): Open access funding was provided by Università degli Studi di Milano within the CRUI-CARE Agreement. This study was in part supported by the Italian Ministry of Health-Current Research IRCCS. E.S. reports receiving grants from Ferring and honoraria for lectures from Merck-Serono, IBSA, and Gedeon-Richter. J.D. has received consulting fees from ObsEva, Gedeon Richter, and Theramex and was a member of the scientific advisory board of ObsEva and Preglem until 2023. L.L.P. reports participation in a training course sponsored by Gedeon Richter, during which she received medical writing assistance for this paper as part of the training course. The remaining authors declare no competing interests. REGISTRATION NUMBER: n/a.

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A homozygous variant in HFM1 causes preimplantation embryo developmental arrest by disrupting zygotic genome activation.

Zhang YW, Zhang XG, Li PY … +13 more , Meng TG, Xu FF, Liu MY, Zhu HJ, Chen LN, Zeng L, Li J, Yang Z, Luo SM, Sun QY, Chen J, Li S, Ou XH

Hum Reprod · 2026 Feb · PMID 41423819 · Full text

STUDY QUESTION: Does a homozygous HFM1 mutation cause human embryonic developmental arrest by disrupting zygotic genome activation? SUMMARY ANSWER: A pathogenic homozygous HFM1 mutation causes aberrant mRNA splicing and... STUDY QUESTION: Does a homozygous HFM1 mutation cause human embryonic developmental arrest by disrupting zygotic genome activation? SUMMARY ANSWER: A pathogenic homozygous HFM1 mutation causes aberrant mRNA splicing and produces a protein that fails to localize to the nucleus, leading to widespread transcriptional dysregulation, failure of zygotic genome activation, and consequent embryonic arrest. WHAT IS KNOWN ALREADY: HFM1 (Helicase 1) is a germ cell-specific gene that plays a pivotal role in meiotic recombination and DNA damage repair, and its mutations are linked to premature ovarian insufficiency. While HFM1 knockout mice exhibit fertility defects, the mechanism by which HFM1 mutations cause preimplantation embryonic arrest in humans, particularly its role in zygotic genome activation, remains unclear. STUDY DESIGN, SIZE, DURATION: This was a case-based experimental study conducted from June to November 2024, involving a single infertile patient carrying a homozygous HFM1 mutation and experiencing recurrent embryonic arrest. Analyses included molecular characterization of patient embryos and functional validation in a mouse model. PARTICIPANTS/MATERIALS, SETTING, METHODS: The patient was recruited from the Reproductive Medicine Centre of the Affiliated Guangdong Second Provincial General Hospital of Jinan University. Whole-exome sequencing identified a homozygous HFM1 mutation. Minigene assays, RNA-seq, immunofluorescence, and confocal imaging were used to characterize the mutation's impact on splicing, protein localization, and transcriptomic and epigenetic states. Functional rescue experiments were performed in mouse embryos. MAIN RESULTS AND THE ROLE OF CHANCE: Functional analysis confirmed that the HFM1 mutation disrupts normal mRNA splicing, leading to the production of a protein variant that is excluded from the nucleus. Transcriptomic and epigenetic profiling of arrested human embryos linked the abnormal localization of this protein to a failure in zygotic genome activation and aberrant retention of H3K27me3. The essential role of HFM1 was further verified in a mouse model, where embryonic defects induced by HFM1 knockdown were specifically rescued by wild-type HFM1 mRNA, but not by the mutant version. LIMITATIONS, REASONS FOR CAUTION: The findings are based on a single clinical case and a limited number of embryos. Further studies with larger cohort studies are needed to validate the prevalence and pathogenicity of such mutations. Further mechanistic studies are also required to fully elucidate how HFM1 regulates gene expression and epigenetic remodeling. WIDER IMPLICATIONS OF THE FINDINGS: This study establishes that nuclear localization of HFM1 may be essential for ZGA and early embryogenesis in humans. It provides a mechanistic link between noncoding HFM1 variants, transcriptional dysregulation, epigenetic dysregulation, and embryonic arrest, expanding the genetic understanding of female infertility and informing future diagnostic approaches. STUDY FUNDING/COMPETING INTEREST(S): This study was supported by National Key R&D Program of China (2022YFC2702200), the National Natural Science Foundation of China (82271728), and the Key Basic and Applied Research Project of Guangdong Province (2023B1515120027). None of the authors have any competing interests. TRIAL REGISTRATION NUMBER: n/a.

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Testing the efficacy of a self-guided psychotherapy intervention for infertility-related distress: a randomized controlled trial.

Poulter MML, Wahl TD, Kiviharju MJ … +2 more , Campbell TS, Gordon JL

Hum Reprod · 2026 Feb · PMID 41401817 · Full text

STUDY QUESTION: Is the online 7-week self-help Coping with Infertility (CWI) program more effective than treatment as usual (TAU) at improving mental health for individuals assigned female at birth (AFAB) who are experie... STUDY QUESTION: Is the online 7-week self-help Coping with Infertility (CWI) program more effective than treatment as usual (TAU) at improving mental health for individuals assigned female at birth (AFAB) who are experiencing infertility? SUMMARY ANSWER: AFAB individuals who participated in the CWI program experienced improvements in quality of life, distress, depression, and anxiety relative to TAU; these effects were large among those with poorer quality of life or greater symptoms of depressed mood and anxiety at baseline. WHAT IS KNOWN ALREADY: Existing psychological interventions are associated with small improvements in mental health relative to TAU for individuals experiencing infertility. A newly developed, brief tailored intervention has been well received, yet has not been rigorously tested in a randomized controlled trial (RCT). STUDY DESIGN, SIZE, DURATION: A parallel RCT was conducted between January and November 2024 (start of recruitment and end of data collection, respectively). AFAB adults experiencing infertility were randomly assigned to either the CWI program or a waitlist/TAU control group using a predetermined stratified block randomization scheme. The sample (n = 173) was powered to detect a medium effect on continuous outcomes. PARTICIPANTS/MATERIALS, SETTING, METHODS: There was an approximately equal number of participants assigned to the CWI program (n = 87) as to the waitlist/TAU control group (n = 86). Participants assigned to the CWI program were emailed one 10-minute video module every week for 7 weeks or received access to the videos on a mobile app. Participants in the waitlist/TAU control group continued with their everyday life until the conclusion of the study. Psychological outcomes were assessed at baseline, post-treatment, and biweekly for 16 weeks post-treatment. Fourteen participants were either excluded from analyses or lost to follow-up, leaving 160 (CWI program n = 77, waitlist/TAU control group n = 83) for intent-to-treat analyses. MAIN RESULTS AND THE ROLE OF CHANCE: Participants who engaged with the CWI program reported higher fertility-related quality of life throughout the follow-up period relative to those assigned to the waitlist/TAU control group, M (SE) = 63.2 (0.5) versus 54.5 (0.5), Cohen's d = .53, P < .001; as well as lower infertility-related distress, M (SE) = 21.6 (0.2) versus 23.9 (0.2), d = .35, P < .001; depressed mood, M (SE) = 5.3 (0.2) versus 7.7 (0.2), d = .56, P < .001; and anxiety, M (SE) = 5.1 (0.2) versus 7.7 (0.2), d = .66, P < .001. Treatment effects were pronounced for participants with poorer quality of life or clinically significant symptoms of depressed mood and anxiety at baseline, with large effect sizes ranging between Cohen's d = 0.91-1.10 in these subgroups. Treatment effects on relationship quality, mood and anxiety disorders, and pregnancy rates were not statistically significant (P > .05). LIMITATIONS, REASONS FOR CAUTION: The lack of an active control condition, use of self-report data, heterogenous population, and limited follow-up period limit the empirical conclusions that can be drawn from this study. WIDER IMPLICATIONS OF THE FINDINGS: These results establish the CWI program as an effective short-term therapy option for AFAB individuals who are experiencing reduced quality of life or increased distress, depressed mood, and anxiety during infertility, addressing a significant gap in infertility treatment. STUDY FUNDING/COMPETING INTEREST(S): The development and pilot of the CWI program was supported by a Saskatchewan Health Research Foundation (SHRF) Patient-Oriented Leader Award (#4577). The current study was supported by a Canadian Institutes of Health Research Project Grant (#PJT186221) and a SHRF Research Connections Grant (#6447). Neither funding agency was involved in the study design; collection, management, analysis, and interpretation of data; writing of the report; or the decision to submit the report for publication. The authors are fully responsible for the content of this manuscript, and the views and opinions described reflect solely those of the authors. J.L.G. also receives salary support as a Canadian Institutes of Health Research Canada Research Chair. All authors declare that they have no financial, personal, or professional competing interests in the writing of this project. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov NCT06006936. TRIAL REGISTRATION DATE: 17 August 2023. DATE OF FIRST PATIENT’S ENROLLMENT: 8 January 2024.

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Surrogates 20 years on: long-term psychological health, contact with surrogacy families, and thoughts and feelings about post-birth contact.

Jadva V, Shaw K, Hall P … +2 more , Ross S, Imrie S

Hum Reprod · 2026 Feb · PMID 41385536 · Full text

STUDY QUESTION: What were the psychological health outcomes for surrogates 20 years after the surrogacy pregnancy? SUMMARY ANSWER: Most surrogates did not experience psychological problems 20 years after the pregnancy wi... STUDY QUESTION: What were the psychological health outcomes for surrogates 20 years after the surrogacy pregnancy? SUMMARY ANSWER: Most surrogates did not experience psychological problems 20 years after the pregnancy with many showing positive psychological wellbeing. WHAT IS KNOWN ALREADY: Studies of surrogates from the global north have found that although some surrogates may experience psychological difficulties in the weeks following the birth of the child, this decreases over time, with most surrogates not experiencing psychological problems at 6 months, 1 year or 10 years following the birth. STUDY DESIGN, SIZE, DURATION: Cross-sectional follow-up study of 21 surrogates who had conducted surrogacy ∼20 years previously (M = 20.33 years, SD = 3.31, range 13-26 years). Data are presented from phase 3 of the study. All participants were interviewed and 17 completed psychometric scales. Data were collected between December 2021 and September 2022. PARTICIPANTS/MATERIALS, SETTING, METHODS: Twenty-one surrogates participated in the study. Ten surrogates (48%) had completed only gestational surrogacy arrangements, five (24%) had completed only traditional surrogacy arrangements, and six (29%) had completed both traditional and gestational surrogacy arrangements. All were domestic arrangements for heterosexual couples. Data were collected using semi-structured interviews and standardized psychometric questionnaires to assess experiences of surrogacy and psychological health of surrogates. Data on frequency of contact and relationship with the surrogacy family were also obtained. MAIN RESULTS AND THE ROLE OF CHANCE: Seventeen of the 21 surrogates completed the questionnaires assessing mental health and psychological wellbeing. None of the 17 surrogates who completed the assessments of psychological health showed signs of depression. Four surrogates scored above the cutoff of 5 on the General Health Questionnaire-30 indicating a 50% likelihood of having a psychiatric condition. Two of the four were in contact with a medical professional about their mental health. The mean score for self-esteem as measured by the Rosenberg Self-esteem Scale was within the normal range. The scores on the Scale of Positive and Negative Experience questionnaire showed moderately positive emotional balance for the majority of participants. Most surrogates scored within the normal range for satisfaction with life and flourishing. Thirteen (62%) surrogates had stayed in contact with the child with 11 describing their relationship as positive. LIMITATIONS, REASONS FOR CAUTION: Sample size for this study was relatively small and some participants from previous phases were unable to be contacted or declined. Five surrogates had completed 11 surrogacy arrangements between them since Phase 2. Seven of these were gestational arrangements, however, whether donor gametes were used was not recorded. WIDER IMPLICATIONS OF THE FINDINGS: This is the first study to assess psychological health of surrogates 20 years after the birth of the child. Findings show that the majority of surrogates did not experience psychological problems in the longer term. Future research should focus on understanding what individual and contextual factors contribute to both negative and positive psychological health of surrogates in the longer term. STUDY FUNDING/COMPETING INTEREST(S): This research was funded by the Wellcome Trust (grant number 208013/Z/17/Z) and by the University of Cambridge's Returning Carers Scheme. The authors have no conflicts of interest to declare. TRIAL REGISTRATION NUMBER: N/A.

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