Human reproduction open最新文献

{"title":"Long-term systemic outcomes of postmenopausal hormone replacement therapy by age at menopause: a real-world cohort study.","authors":"Ting-Fang Lu, Chien-Hsing Lu, Yu-Hsiang Shih, Yen-Fu Chen, Chun-Ting Fan, Shao-Jing Wang, Shih-Tien Hsu, Chih-Ku Liu, Lou Sun, Sheau-Feng Hwang, Tsung-Hsien Lee","doi":"10.1093/hropen/hoag072","DOIUrl":"https://doi.org/10.1093/hropen/hoag072","url":null,"abstract":"<p><strong>Study question: </strong>Does postmenopausal hormone replacement therapy (HRT), initiated within 1 year after menopause diagnosis, confer differential long-term health effects according to age at menopause?</p><p><strong>Summary answer: </strong>Long-term postmenopausal HRT was associated with age-dependent clinical outcomes, with broadly consistent cardiovascular and skeletal associations across age groups, but more variable metabolic and oncological associations according to age at menopause.</p><p><strong>What is known already: </strong>The 'timing hypothesis' suggests that HRT initiated closer to menopause may have more favorable cardiometabolic associations than later initiation, but evidence across distinct age-at-menopause strata remains limited.</p><p><strong>Study design size duration: </strong>This retrospective new-user cohort study utilized de-identified data from the TriNetX Research Network, which provided access to electronic medical records for ∼111 million patients globally. To establish a relatively healthy baseline cohort, we included women aged 30-90 years without prior major systemic diseases who had a documented diagnosis of menopause. To ensure adequate time for the development of hard clinical endpoints, we required that the index event (initial menopause diagnosis) occurred at least 10 years before data extraction (31 December 2025), thereby guaranteeing a minimum follow-up period of one decade. To reduce immortal time bias and survivor bias inherent in prevalent-user designs, we employed a new-user, time-to-event cohort design. Women with a pre-existing history of type 2 diabetes mellitus (T2DM), cardiovascular disease (CVD), osteoporosis, compression fracture, venous thromboembolism (VTE), breast cancer, or colorectal cancer on or before the index date were excluded.</p><p><strong>Participants/materials setting methods: </strong>Women who initiated postmenopausal HRT containing estrogen and/or progestogen within 1 year after menopause diagnosis were propensity score-matched 1:1 with non-users using baseline demographic, clinical, and laboratory covariates. Primary matching yielded 83 670 matched pairs in women who experienced menopause at age ≤60 years and 12 175 matched pairs in women who experienced menopause at age >60 years. Time-to-event analyses using Cox proportional hazards regression were conducted across four clinically defined menopausal age strata: premature ovarian insufficiency (POI, <40 years), early menopause (40-45 years), normal menopause (46-60 years), and late menopause (>60 years). Hazard ratios (HRs) were calculated for incident T2DM, CVD, compression fracture, breast cancer, colorectal cancer, and VTE. Interaction <i>P</i>-values were calculated using the normal menopause group (46-60 years) as the reference for interaction testing. Sensitivity analyses were conducted in both the overall ≤60-year and >60-year cohorts using an alternative 1:1 matching strategy based only on age, race, an","PeriodicalId":73264,"journal":{"name":"Human reproduction open","volume":"2026 3","pages":"hoag072"},"PeriodicalIF":8.6,"publicationDate":"2026-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13493047/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148802516","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Association between body roundness index and pregnancy outcomes of IVF.","authors":"Yuan Fang, Yufang Yang, Ning Li, Jialin Zou, Yue Niu, Dingying Zhao, Sirui Liao, Yanran Liu, Zi-Jiang Chen, Daimin Wei","doi":"10.1093/hropen/hoag068","DOIUrl":"https://doi.org/10.1093/hropen/hoag068","url":null,"abstract":"<p><strong>Study question: </strong>Is there an association between the body roundness index (BRI) and pregnancy outcomes of IVF, and can it provide complementary information beyond body mass index (BMI)?</p><p><strong>Summary answer: </strong>Higher BRI was associated with a lower likelihood of live birth following IVF, particularly among women with normal BMI.</p><p><strong>What is known already: </strong>BMI is widely used to assess obesity-related reproductive risk but does not adequately characterize body fat distribution. BRI, a novel anthropometric index that may better reflect central adiposity, has been associated with cardiometabolic risk, but its relationship with IVF outcomes remains unclear.</p><p><strong>Study design size duration: </strong>This study was a secondary analysis of data from two multicentre randomized controlled trials (RCTs) in China that evaluated live birth rates between freeze-only and fresh embryo transfers. The first trial enrolled 1508 women with polycystic ovary syndrome from 14 centres between June 2013 and May 2014, with follow-up completed in July 2015. The second trial recruited 2157 women with regular menstrual cycles from 20 centres between March 2015 and November 2015, with follow-up completed in March 2017.</p><p><strong>Participants/materials setting methods: </strong>After exclusions, 3523 women who underwent embryo transfer and had complete BRI data were included in the analysis. BRI was calculated from height and waist circumference measured prior to IVF. In the absence of universally accepted clinical thresholds for BRI, the participants were categorized into three groups according to the 33rd and 66th percentiles: <2.54 (n = 1171), 2.54 to <3.54 (n = 1174), ≥3.54 (n = 1178). The primary outcome was live birth, which was defined as the delivery of neonate(s) with signs of life at ≥28 weeks' gestation. Modified Poisson regression with robust variance was used to estimate adjusted risk ratios (aRRs) and 95% confidence intervals (CIs). The models were adjusted for age (continuous), duration of infertility (continuous), cause of infertility, type of embryo transfer, diagnosis of polycystic ovary syndrome (PCOS), number of oocytes retrieved (continuous), and number of embryo(s) transferred. These covariates were selected based on clinical relevance and prior literature to reduce potential confounding.</p><p><strong>Main results and the role of chance: </strong>The rate of live birth was lower among women in the highest BRI group (group 3) compared with those in the lowest group (group 1) (45.2% vs 53.6%; aRR, 0.89; 95% confidence interval [CI], 0.81-0.97; <i>P </i>= 0.008). Women in group 3 also had an increased risk of total pregnancy loss compared with those in group 1 (aRR, 1.31; 95% CI, 1.07-1.61; <i>P </i>= 0.009). In BMI-stratified analyses, higher BRI was associated with a reduced likelihood of live birth (group 2, aRR, 0.89; 95% CI, 0.81-0.98; <i>P </i>= 0.019; group 3, aRR, 0.84; 95% CI, 0.73-0","PeriodicalId":73264,"journal":{"name":"Human reproduction open","volume":"2026 3","pages":"hoag068"},"PeriodicalIF":8.6,"publicationDate":"2026-08-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13493052/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148802336","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Transitioning AI-based sperm assessment from proof-of-concept to clinical practice.","authors":"Erica T Y Leung, Xianghan Mei, Brayden K M Lee, Kevin K W Lam, Cheuk-Lun Lee, Raymond H W Li, Ernest H Y Ng, William S B Yeung, Lequan Yu, Philip C N Chiu","doi":"10.1093/hropen/hoag070","DOIUrl":"10.1093/hropen/hoag070","url":null,"abstract":"","PeriodicalId":73264,"journal":{"name":"Human reproduction open","volume":"2026 3","pages":"hoag070"},"PeriodicalIF":8.6,"publicationDate":"2026-08-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13461642/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148726731","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"AI-predicted zona pellucida binding: shortcut learning and clustered validation may overstate clinical portability.","authors":"Tong Wang, Yue Li, Ran Tong","doi":"10.1093/hropen/hoag069","DOIUrl":"10.1093/hropen/hoag069","url":null,"abstract":"","PeriodicalId":73264,"journal":{"name":"Human reproduction open","volume":"2026 3","pages":"hoag069"},"PeriodicalIF":8.6,"publicationDate":"2026-08-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13461639/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148726777","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Risk factors associated with meiotic errors in blastocysts with mosaic results on biopsy.","authors":"Jialiu Liu, Bing Cai, Yan Xu, Jing Wang, Xixiong Ai, Yanhong Zeng, Jing Guo, Rong Li, Jiafu Pan, Chenhui Ding, Yuanlin Ma, Fang Gu, Yi Zhou, Sijia Lu, Jieliang Ma, Cheng Wan, Jia Fei, Jiucheng Chen, Bingjie Lu, Haoting Zhang, Canquan Zhou, Yanwen Xu","doi":"10.1093/hropen/hoag067","DOIUrl":"10.1093/hropen/hoag067","url":null,"abstract":"<p><strong>Study question: </strong>What are the risk factors associated with meiotic errors in blastocysts with mosaic biopsy results?</p><p><strong>Summary answer: </strong>Meiotic errors were identified in 3.9% of blastocysts with mosaic biopsy results and were correlated with high-level mosaicism, maternal origin, and advanced maternal age.</p><p><strong>What is known already: </strong>Chromosomal mosaicism mainly arises from postzygotic mitotic errors, except for rare events from rescued meiotic errors. Preimplantation genetic testing for aneuploidy origin (PGT-AO) can distinguish meiotic errors from mitotic errors; however, the clinical value of PGT-AO remains to be explored.</p><p><strong>Study design size duration: </strong>A retrospective cohort of 391 blastocysts with mosaic biopsy results from a university-based fertility centre in China between January 2020 and December 2024 was analysed by PGT-AO. Risk factors associated with meiotic errors in blastocysts with mosaic biopsy results were explored. Pregnancy outcomes following 96 mosaic embryo transfers (METs) of embryos with mitotic errors were compared with those following transfer of 288 matched euploid embryos. Additionally, 7 donated blastocysts were separated for single-cell DNA sequencing.</p><p><strong>Participants/materials setting methods: </strong>The parental origin and cell-division origin were analysed in 391 blastocysts classified as euploid-aneuploid mosaic from a cohort of 8932 blastocysts detected using the single-nucleotide polymorphism (SNP) array. In the prospective study, pregnancy outcomes following METs of embryos with mitotic errors were compared with those following transfer of matched euploid embryos at a 1:3 ratio using propensity score matching. The primary outcome was the live birth/ongoing pregnancy rate (LB/OPR) of METs involving mitotic errors. Multivariate logistic regression analysis was used to evaluate risk factors for pregnancy outcomes. Prenatal and placental samples were analysed by SNP array and/or FISH for genetic verification. Single-cell DNA sequencing of 314 cells separated from 7 donated blastocysts (4 with high-level mosaicism, 2 with meiotic aneuploidy, and 1 with low-level mosaicism) was conducted to assess actual mosaicism. The chromosomal constitution of the blastocysts was comprehensively evaluated at the single-cell level, and concordance with the initial PGT-A results was assessed.</p><p><strong>Main results and the role of chance: </strong>A SNP-based mosaicism quantification platform was established and validated using mixtures of single cells of varying ploidy to mimic clinical mosaic samples. In the retrospective cohort, the error origin was successfully determined for 384 of the 391 blastocysts with euploid-aneuploid mosaicism. The overall meiotic error rate was only 3.9% (15/384). Meiotic error was identified in 9.6% of blastocysts with mosaicism from women of advanced maternal age, which was significantly greater than the 3.0","PeriodicalId":73264,"journal":{"name":"Human reproduction open","volume":"2026 3","pages":"hoag067"},"PeriodicalIF":8.6,"publicationDate":"2026-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13461220/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148714812","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"From a single child to family planning: determinants of returning to ART to build the desired family in a monocentric Italian cohort.","authors":"Francesco Viciglione, Valentina Immediata, Emanuela Morenghi, Carlo Alviggi, Annamaria Baggiani, Federico Cirillo, Paolo Emanuele Levi-Setti","doi":"10.1093/hropen/hoag063","DOIUrl":"https://doi.org/10.1093/hropen/hoag063","url":null,"abstract":"<p><strong>Study question: </strong>What factors are associated with couples' returning to have ART after having a first ART-conceived child?</p><p><strong>Summary answer: </strong>Among returning couples, return was independently associated with younger maternal age, a singleton rather than twin first birth, and the availability of cryopreserved embryos and/or oocytes.</p><p><strong>What is known already: </strong>Long-term family-building trajectories after an initial ART birth remain poorly characterized, despite being essential for counseling couples aiming to achieve their intended family size in the context of declining fertility rates and delayed parenthood in high-income countries. Age-related biological constraints, limited fertility awareness, and overestimation of ART effectiveness contribute to unrealized reproductive intentions; nevertheless, the determinants of couples' return to ART after a first live birth and their association with subsequent live births remain largely unexplored.</p><p><strong>Study design size duration: </strong>Monocentric retrospective cohort study of 5852 couples achieving a first ART-conceived live birth (index birth) from cycles initiated between 2010 and 2020, with follow-up through December 2024 to evaluate return to ART for further family building and subsequent live birth outcomes. As data were retrieved from a complete institutional database, no loss to follow-up occurred.</p><p><strong>Participants/materials setting methods: </strong>Couples achieving a first ART-conceived live birth between 2010 and 2020 at a single fertility center in Italy were included. Donor cycles and PGT were excluded. Participants were followed until December 2024. Couples were classified as returners or non-returners and stratified according to cryopreserved oocyte and/or embryo storage status. Outcomes of interest were return to ART for further family building and live birth achievement among returning couples.</p><p><strong>Main results and the role of chance: </strong>Overall, 1978 couples (33.8%) returned for further ART cycles; among returners, a second live birth was achieved by 49.3%. Return was significantly higher among couples with cryopreserved reproductive material compared with those without stored embryos or oocytes (41.0% vs 23.3%, <i>P</i> < 0.001), particularly among couples with cryopreserved embryos only or with both embryos and oocytes stored (41.6% and 44.3%, respectively). At multivariable analysis, independent predictors of return included lower maternal age (aOR 0.93 per year increase), male-factor infertility (aOR 1.26), singleton rather than twin first live birth (aOR 0.12 for twins), presence of cryopreserved material (aOR 2.21), and higher gestational age at delivery (aOR 1.03). Among couples who returned, the proportion achieving a second live birth varied markedly by cryopreservation status, ranging from 39.5% in couples without stored material to 64.6% in those with both embryos and oocytes ava","PeriodicalId":73264,"journal":{"name":"Human reproduction open","volume":"2026 3","pages":"hoag063"},"PeriodicalIF":8.6,"publicationDate":"2026-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13476075/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148762715","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"<i>HIPK4</i> is a novel gene associated with teratozoospermia and male infertility.","authors":"Sophie Adina Koser, Cynthia Rieck, Isabella Aprea, Claudia Krallmann, Avinash Satish Gaikwad, Julia Wallmeier, Retno Tenardi-Wenge, Sara Di Persio, Nina Neuhaus, Johanna Raidt, Heymut Omran, Sandra Laurentino, Sabine Kliesch, Birgit Stallmeyer, Corinna Friedrich, Frank Tüttelmann","doi":"10.1093/hropen/hoag066","DOIUrl":"https://doi.org/10.1093/hropen/hoag066","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Study question: &lt;/strong&gt;Are pathogenic variants in &lt;i&gt;homeodomain-interacting protein kinase&lt;/i&gt; (&lt;i&gt;HIPK4&lt;/i&gt;) associated with sperm head abnormalities that cause male infertility?&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Summary answer: &lt;/strong&gt;&lt;i&gt;HIPK4&lt;/i&gt; is a novel candidate gene associated with sperm head defects and human male infertility.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;What is known already: &lt;/strong&gt;Numerous genes have been described in which pathogenic variants cause male infertility due to multiple morphological abnormalities of the sperm flagella (MMAF), but the genetic basis of sperm head defects is less well understood.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Study design size duration: &lt;/strong&gt;This study included four infertile brothers displaying varying degrees of quantitatively and/or qualitatively impaired spermatogenesis, their parents, and their fertile brother. We also queried the Male Reproductive Genomics (MERGE) cohort comprising exome/genome sequencing data of &gt;3300 men.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Participants/materials setting methods: &lt;/strong&gt;We performed exome sequencing in all five brothers and their parents. To characterize sperm phenotypes, we carried out standard semen analysis, immunofluorescence staining, and transmission electron microscopy (TEM). Further, we evaluated the impact of the &lt;i&gt;HIPK4&lt;/i&gt; variant in cell culture experiments using HEK293T cells.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Main results and the role of chance: &lt;/strong&gt;By analysing the exome data, we could not identify a common genetic cause in all four affected brothers. However, one of the affected brothers was compound heterozygous for two loss-of-function variants in &lt;i&gt;DNAH17&lt;/i&gt; (c.1076_1077dup p.(Lys360*) and c.7752+2T&gt;A p.?), associated with markedly reduced sperm motility and MMAF. The variants' pathogenicity was further validated by TEM of flagellar cross sections revealing an outer dynein arm defect and axonemal disruption. In contrast, his three infertile brothers were homozygous for the start-loss variant c.1A&gt;G in &lt;i&gt;HIPK4&lt;/i&gt;. This gene is expressed during spermiogenesis and is reportedly involved in sperm head shaping in mice. Heterologous expression of (partial) &lt;i&gt;HIPK4&lt;/i&gt; variant cDNA showed that translation was being initiated at an alternative in-frame start codon located 35 amino acids downstream, resulting in an N-terminally truncated protein p.(Met1_Glu35del). The truncated HIPK4 protein lacks parts of its kinase domain and shows reduced protein stability. Corresponding with published mouse models, all three brothers displayed 100% abnormal sperm head morphology with variable defects. Importantly, one brother affected by &lt;i&gt;HIPK4&lt;/i&gt; variants fathered a child after successful ICSI, demonstrating a successful treatment option for HIPK4-related teratozoospermia. No further men from the MERGE cohort were affected by biallelic &lt;i&gt;HIPK4&lt;/i&gt; variants. Taken together, &lt;i&gt;HIPK4&lt;/i&gt; is an autosomal recessive candidate gene in which pathogenic variants are associated with sperm head defects and male infertility.&lt;/p&gt;&lt;p","PeriodicalId":73264,"journal":{"name":"Human reproduction open","volume":"2026 3","pages":"hoag066"},"PeriodicalIF":8.6,"publicationDate":"2026-07-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13470646/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148762931","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Benzodiazepine use during an IVF cycle and its impacts on miscarriage and other pregnancy outcomes.","authors":"HyunJoo Lim, Eun-Young Choi, Yongtai Cho, Hyesung Lee, Azar Mehrabadi, Jung Yeol Han, Seung-Hwan Lee, Ju-Young Shin","doi":"10.1093/hropen/hoag065","DOIUrl":"10.1093/hropen/hoag065","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Study question: &lt;/strong&gt;How does benzodiazepine use during an IVF cycle affect pregnancy outcomes?&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Summary answer: &lt;/strong&gt;Benzodiazepine use was neither positively nor adversely associated with IVF pregnancy outcomes overall.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;What is known already: &lt;/strong&gt;Benzodiazepine use during oocyte retrieval, primarily with midazolam, and diazepam use at the time of embryo transfer (ET) have been reported to yield comparable procedural success rates to those of non-users, respectively. However, these studies focus on exposure at a single time point, necessitating a more comprehensive investigation of benzodiazepine use across the entire IVF treatment period.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Study design size duration: &lt;/strong&gt;A retrospective cohort study was conducted using Korea's Health Insurance Review and Assessment (HIRA) database between October 2017 and June 2024. A total of 99 484 women with a first completed IVF cycle were included.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Participants/materials setting methods: &lt;/strong&gt;Benzodiazepine users were defined as individuals who had at least one prescription during an IVF cycle (from the last menstrual period to ET) (user group, n = 28 649). Non-users were defined as those who had no benzodiazepine prescriptions within 365 days prior to ET to minimize exposure misclassification (non-user group, n = 61 433). The outcomes of interest were four IVF outcomes: clinical pregnancy rate, miscarriage rate, live birth rate, and preterm birth rate. To compare the two groups, propensity score overlap weighting was applied to adjust for potential imbalances in confounders. Relative risks (RRs) with 95% CIs were estimated using Poisson regression in the overlap-weighted at-risk population cohort for each outcome.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Main results and the role of chance: &lt;/strong&gt;Compared with non-users, benzodiazepine users had a lower prevalence of prior live birth and a higher prevalence of anxiety disorders, along with greater use of antidepressants before adjustment. The absolute event rates of each outcome were as follows: (i) clinical pregnancy rate: 36.0% of users versus 35.7% of non-users, (ii) miscarriage rate: 14.9% versus 15.2%, (iii) live birth rate: 99.3% versus 99.3%, (iv) preterm birth rate: 13.3% versus 11.6%. Most IVF outcomes were comparable between groups, though a marginally increased risk of preterm birth was observed among users (clinical pregnancy: adjusted RR 1.02 [95% CI 1.00 to 1.05]; miscarriage: 0.99 [0.91 to 1.08]; live birth: 1.00 [1.00 to 1.00]; preterm birth: 1.10 [0.99 to 1.21]). However, stratified analyses by cumulative dose showed no dose-response relationship (≤1.2 mg and &gt;2 mg, respectively-preterm birth: 1.09 [0.99 to 1.21] and 1.01 [0.87 to 1.17]). Additionally, the point estimate was closer to the null among users prescribed both injectable and oral agents during the cycle (preterm birth: 1.04 [0.86 to 1.26]). The robustness of the main findings was supported by analyses accounting for","PeriodicalId":73264,"journal":{"name":"Human reproduction open","volume":"2026 3","pages":"hoag065"},"PeriodicalIF":8.6,"publicationDate":"2026-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13441166/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148681302","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Heterogeneity in semen-mediated tolerogenic responses: defining immunological determinants of reproductive compatibility.","authors":"Shahrokh Paktinat, Michael G Gravett, Sean M Hughes, Abigail L P Spray, Germán G Gornalusse, Florian Hladik, Lucia Vojtech","doi":"10.1093/hropen/hoag064","DOIUrl":"10.1093/hropen/hoag064","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Study question: &lt;/strong&gt;Do particular pairs of individuals modeling sexual pairs exhibit differences in the induction of semen-mediated long-lasting tolerance in support of pregnancy?&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Summary answer: &lt;/strong&gt;Yes, factors from both sexes contribute to the variability in the induction of long-lived regulatory T cells (Tregs) in response to semen, with factors related to the recipient seeming to slightly outweigh the factors related to the semen donor.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;What is known already: &lt;/strong&gt;Semen contains multiple immunomodulatory factors that can influence reproductive tract immunity in the recipient, promote tolerance to antigens from the semen donor (designated henceforth as 'paternal'), and ultimately support successful pregnancy. These factors include the soluble fraction containing prostaglandins and cytokines, as well as a very high concentration of extracellular vesicles (EVs). Both soluble and vesicular fractions of semen have been shown to promote tolerogenic phenotypes and migration in antigen-presenting cells (APCs), and to induce Tregs. This study was undertaken to understand the variation in tolerance induction between pairs of individuals modeling sexually active couples.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Study design size duration: &lt;/strong&gt;We designed an &lt;i&gt;in vitro&lt;/i&gt; pairing study using random semen donors (N = 11) and peripheral mononuclear cells (PBMCs) from random self-identified female recipients (N = 3). Semen was fractionated into vesicle-enriched (semen extracellular vesicles; SEVs) and soluble (vesicle-depleted semen plasma; VDSP) fractions. Monocyte-derived dendritic cells (MoDCs) from each of the recipients were exposed to semen fractions from each donor, then cocultured with autologous naïve T cells to assess tolerogenic responses, specifically, generation of Tregs (FOXP3+ CD25Hi CD127Lo CD4+ T cells) and their phenotypic differences (TIGIT+, PD-1+ CTLA-4+, or AREG+ Tregs). These cells were then screened for T cell receptor-dependent activation by activation-induced marker (AIM) expression assay. These responses were compared across all pairs of semen donors and recipient cells. In addition, semen fractions were screened for candidate mediators of tolerance, such as human leukocyte antigen G (HLA-G) and adenosine-generating enzymes.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Participants/materials setting methods: &lt;/strong&gt;This study used an &lt;i&gt;in vitro&lt;/i&gt; human cell culture approach in which primary blood-derived immune cells were exposed to semen-derived vesicular and non-vesicular fractions. Blood samples were obtained from healthy self-identified female donors, and semen samples were obtained from healthy participants who provided initial screening specimens for a contraceptive study. Semen-derived vesicular and non-vesicular fractions were characterized by western-blot analysis for markers associated with immune tolerance. Primary immune cells were exposed to these semen fractions, and the major endpoints included changes in Tr","PeriodicalId":73264,"journal":{"name":"Human reproduction open","volume":"2026 3","pages":"hoag064"},"PeriodicalIF":8.6,"publicationDate":"2026-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13446728/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148686898","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"An artificial intelligence real-time rare sperm detection system for intraoperative microsurgical testicular sperm extraction.","authors":"Sha Han, Shuai Xu, Haojun Hu, Zijue Zhu, Furong Bai, Cunzhong Deng, Yuhua Huang, Chenwang Zhang, Yifan Sun, Haowei Bai, Chencheng Yao, Fujun Zhao, Zheng Li, Dengyang Zhao, Peng Li","doi":"10.1093/hropen/hoag062","DOIUrl":"10.1093/hropen/hoag062","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Study question: &lt;/strong&gt;How can rare spermatozoa be identified efficiently during microsurgical testicular sperm extraction (micro-TESE)?&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Summary answer: &lt;/strong&gt;An artificial intelligence (AI)-assisted system was developed to flag candidate rare spermatozoa in real time during micro-TESE, and it may support embryologists as a decision-support tool.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;What is known already: &lt;/strong&gt;Patients with non-obstructive azoospermia (NOA) can obtain sperm for procreation through micro-TESE. During this procedure, sperm retrieval primarily relies on embryologists or laboratory technicians visually searching for sperm under a microscope, which is not only laborious and inherently subjective but also susceptible to errors. Although AI technology has been applied to identify trace amounts of sperm, existing models lack sufficient efficiency and true real-time performance.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Study design size duration: &lt;/strong&gt;This study included model development followed by a single-centre clinical evaluation. An improved YOLO (You Only Look Once)-based rare sperm detection model, termed YOLOv11-RSD, was developed using microscopy data from 1165 surgical patients, comprising 1932 image samples containing a total of 5032 annotated sperm objects with confirmed identification. Clinical evaluation was performed between May 2024 and July 2025. Performance was assessed across confidence thresholds in obstructive azoospermia (OA) patients with normal spermatogenesis, and the system was then applied during micro-TESE in NOA patients and compared with routine embryologist assessment.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Participants/materials setting methods: &lt;/strong&gt;The model was developed using testicular sperm microscopy images collected at a single hospital. Real-time clinical feasibility was evaluated in 10 OA cases and 30 NOA cases. Embryologist assessment was used as the reference standard, and performance was assessed using PPV, sensitivity, &lt;i&gt;F&lt;/i&gt;1-score, and 95% confidence intervals. Discordant AI-assisted detections were reviewed by embryologists in real time.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Main results and the role of chance: &lt;/strong&gt;YOLOv11-RSD achieved real-time detection of candidate spermatozoa in microscopy images with high sensitivity and acceptable PPV under the selected operating threshold. Compared with baseline YOLOv11, YOLOv11-RSD showed improved overall detection performance across representative evaluation settings. In OA cases, the system achieved high sensitivity for sperm detection, reaching up to 96.7% across evaluated thresholds. During micro-TESE in NOA patients, at a confidence threshold of 0.50, positive predictive value (PPV), sensitivity, and &lt;i&gt;F&lt;/i&gt;1-score were 80.58%, 96.11%, and 87.66%, respectively. The system highlighted candidate spermatozoa that were not identified during the initial manual assessment in six NOA cases, including two cases initially classified as sperm-negative; these findings were confirmed upon immediate re-","PeriodicalId":73264,"journal":{"name":"Human reproduction open","volume":"2026 3","pages":"hoag062"},"PeriodicalIF":8.6,"publicationDate":"2026-07-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13437015/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148674416","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}