Abstract STUDY QUESTION What are the specific metabolic and lipidomic alterations in placental tissue and umbilical cord serum of pregnancies complicated by PCOS, and how do maternal testosterone levels and obesity status interplay with these changes at the maternal-fetal interface? SUMMARY ANSWER Pregnancies affected by PCOS exhibit distinct metabolomic and lipidomic reprogramming in both placental tissue and umbilical cord serum, characterized by alterations in key pathways such as tryptophan metabolism and fatty acid metabolism, with propionic and gluconic acids identified as central metabolic nodes; these changes are significantly associated with maternal testosterone levels and are differentially modulated by maternal obesity. WHAT IS KNOWN ALREADY PCOS is known to adversely affect maternal and fetal metabolic health, carrying risks for intergenerational metabolic programming. However, the precise molecular nature of metabolic and lipidomic dysregulation at the maternal-fetal interface, particularly the specific drivers of hyperandrogenism and its complex interplay with maternal obesity, remains poorly characterized. STUDY DESIGN, SIZE, DURATION This prospective comparative study evaluated 48 pregnant women with PCOS and 50 healthy pregnant controls. All biological samples were collected at the time of term delivery. PARTICIPANTS/MATERIALS, SETTING, METHODS Participants were recruited from a tertiary care center. To minimize labor-induced metabolic confounding, all subjects underwent elective term cesarean sections. Untargeted metabolomics and lipidomics analyses were performed on strictly standardized maternal-side placental tissue and umbilical cord serum using liquid chromatography–mass spectrometry (LC–MS). Statistical analyses included multivariable linear regression to adjust for confounders and LASSO regression for key feature selection. Participants were further stratified by pre-pregnancy BMI (obese: BMI ≥28 kg/m2 vs. non-obese: BMI <28 kg/m2) to assess the impact of maternal adiposity. MAIN RESULTS AND THE ROLE OF CHANCE PCOS pregnancies showed significantly distinct metabolomic and lipidomic profiles compared to controls in both placental tissue (407 differential metabolites, 186 differential lipids; FDR < 0.05) and umbilical cord serum (330 differential metabolites, 314 differential lipids; FDR < 0.05). Key enriched KEGG pathways included tryptophan metabolism, sphingolipid metabolism, and biosynthesis of unsaturated fatty acids. Maternal testosterone levels demonstrated strong and independent correlations with several key differential metabolites and lipids. Propionic acid and gluconic acid were identified as central metabolic nodes. Subgroup analysis revealed that maternal obesity exerts an additive metabolic burden that partially masks the intrinsic PCOS molecular phenotype. The role of chance was minimized by appropriate sample size, statistical adjustment for confounders, and the use of FDR correction for multiple comparisons where applicable. LARGE SCALE DATA N/A LIMITATIONS, REASONS FOR CAUTION The cross-sectional design and single-center setting limit causal and longitudinal inferences. Methodological constraints, including the absence of pre-pregnancy hormonal profiles, the lack of concurrent maternal peripheral blood sampling and the restriction to maternal-side placental tissue and elective cesarean deliveries, necessitate caution when extending these findings to systemic maternal metabolism or vaginal births. WIDER IMPLICATIONS OF THE FINDINGS These findings significantly advance our understanding of the metabolic pathophysiology of PCOS during pregnancy, highlighting specific pathways and molecules at the maternal–fetal interface. This knowledge could pave the way for identifying novel biomarkers for early risk stratification and developing targeted interventions to mitigate adverse metabolic programming in offspring of mothers with PCOS, potentially tailored by maternal obesity status. STUDY FUNDING/COMPETING INTEREST(S) This study was supported by the Sichuan Science and Technology Program (2026NSFSC1657), the “Talent Program” Cultivation Project of Chengdu Women’s and Children’s Central Hospital (No. YC2023002), the Health Commission of Sichuan Province (No. 20PJ184), and the Medical Scientific Research Project Funded by the Chengdu Municipal Health Commission (No. 2024247). The authors declare no competing interests.

STUDY QUESTIONWhat is the current landscape of randomized controlled trials (RCTs) evaluating stem cell-based therapies for women’s reproductive diseases, and how effectively has preclinical research informed their clinical translation?SUMMARY ANSWERThe current clinical trial landscape for stem cell-based therapies in women’s reproductive diseases is characterized by rapid growth in trial registration, particularly for premature ovarian failure (POF) and intrauterine adhesions (IUA), yet remains predominantly in early-phase, single-center, single-country studies with significant heterogeneity in design and outcome reporting.WHAT IS KNOWN ALREADYStem cell-based therapies show promise in preclinical models for conditions such as POF, IUA, and endometriosis. However, despite increasing clinical interest, the extent to which these therapies have been rigorously evaluated in RCTs and how well clinical trials reflect preclinical evidence remains unclear.STUDY DESIGN, SIZE, DURATIONThis translational analysis integrated a meta-epidemiological approach with bibliometric methods. We searched the International Clinical Trials Registry Platform (ICTRP), ClinicalTrials.gov, EudraCT, and ChiCTR from inception to 1 December 2025, using terms related to ‘stem cells’, ‘reproductive diseases’, and ‘randomized controlled trials’. Only English and Chinese registration records were included.PARTICIPANTS/MATERIALS, SETTING, METHODSTwo reviewers independently screened registration records for RCTs assessing stem cell or derivative therapies in women’s reproductive diseases. Eligible criteria included RCTs that reported the use of stem cells or their derivatives in female patients with reproductive conditions. Data on trial design, disease focus, stem cell type, source, phase, sample size, outcomes, and results were extracted. A hybrid approach combined traditional systematic data extraction with machine learning-assisted screening (ASReview) for basic research. Bibliometric analysis using VoSviewer and CiteSpace mapped research trends, while Health Research Classification System (HRCS) scores assessed translational potential. Consistency in screening and extraction was evaluated using kappa and Cronbach’s alpha.MAIN RESULTS AND THE ROLE OF CHANCEFrom 804 records, 38 RCTs met inclusion criteria. The majority were early-phase (Phase 1/2, 76.3%), single-center (81.6%), and conducted in one country (97.4%), with China (50.0%) and the USA (18.9%) leading. POF (34.2%), ovarian cancer (23.7%), and IUA (18.4%) were the most studied conditions. Umbilical cord-derived mesenchymal stem cells (28.9%) were the most commonly used. While preclinical research shows strong mechanistic support, especially for POF and IUA, there was minimal overlap in primary outcome measures across trials, limiting comparability. Only 36.8% of RCTs included safety as a co-primary endpoint, and 49% had short-term follow-up, raising concerns about long-term risks such as tumorigenicity.LIMITATIONS, REASONS FOR CAUTIONThe analysis may be subject to language bias (English and Chinese only), and some included trials were incomplete, relying on interim reports or press releases not peer-reviewed. The quality of individual RCTs was not formally assessed, and publication bias in basic research may influence bibliometric trends.WIDER IMPLICATIONS OF THE FINDINGSThis study highlights a significant gap between robust preclinical evidence and fragmented clinical evaluation, with over-concentration on POF and underrepresentation of other high-potential conditions like endometriosis and thin endometrium. The findings underscore the need for international collaboration, standardized outcome sets, and harmonized regulatory frameworks to enable large-scale, high-quality trials that can translate regenerative potential into clinical reality.STUDY FUNDING/COMPETING INTEREST(S)This study was supported by the National Natural Science Foundation of China (82301835 and 82371682), the Science and Technology Program of Hunan Province (2024JJ4091 and 2023JJ40956), the Youth Fund of Xiangya Hospital, Central South University, China (2021Q03 and 2209090550121), the Postdoctoral Science Foundation of China (2022M713522 and 2021TQ0372), and the Innovation and Entrepreneurship Training Program for College Students (202510533012, S202410533307, and CXPY2025224). The authors declare no competing interests.REGISTRATION NUMBERhttps://doi.org/10.17605/OSF.IO/JM9EK.

STUDY QUESTIONWhat is the clinical and genetic overlap across subtypes of congenital gonadotropin (Gn) deficiency?SUMMARY ANSWERThis study reveals substantial clinical and genetic overlap among Gn deficiency disorders, with shared genetic and developmental features across congenital hypogonadotropic hypogonadism (CHH), combined pituitary hormone deficiency (CPHD), and syndromic forms of Gn deficiency.WHAT IS KNOWN ALREADYCongenital Gn deficiency includes a subset of hypogonadotropic hypogonadism (HH) and can result from defects at the level of the hypothalamus or the pituitary. It includes (i) CHH, further classified into normosmic CHH (nCHH) and Kallmann syndrome (KS); (ii) CPHD; and (iii) syndromic forms such as CHARGE syndrome and septo-optic dysplasia (SOD).STUDY DESIGN, SIZE, DURATIONThe study included all probands with Gn deficiency recruited at a tertiary care center between 2011 and 2024 (n = 568), including 276 KS, 247 nCHH, 29 CPHD, and 16 syndromic Gn deficiency cases. All individuals underwent detailed clinical phenotyping followed by DNA sequencing.PARTICIPANTS/MATERIALS, SETTING, METHODSGenetic analysis focused on pathogenic (P) and likely pathogenic (LP) variants and variants of uncertain significance (VUS) within established CHH and CPHD genes. Oligogenicity was assessed in the CHH/syndromic HH cohort (n = 523) compared with controls from 1000 Genomes (n = 601). Genetic overlap among CHH, CPHD, and syndromic Gn deficiency was systematically investigated.MAIN RESULTS AND THE ROLE OF CHANCECleft lip/palate, dental agenesis, and ear abnormalities were recurrent across all Gn-deficient groups. Notably, some CPHD and SOD patients exhibited anosmia and a preserved Gn response to LH-releasing hormone (LHRH) stimulation, indicating a hypothalamic component to their HH. Rare variants in CHH genes were identified in 53% of KS probands (40% P/LP, 13% VUS) and 33% of nCHH probands (23% P/LP, 10% VUS). FGFR1, ANOS1, and PROKR2 were most frequently mutated in KS, while GNRHR, FGFR1, and KISS1R predominated in nCHH. Oligogenic inheritance was detected in 15% of CHH cases, with variants in FGFR1 being most commonly involved. Importantly, a substantial proportion (14%) of CHH patients without a molecular diagnosis carried rare variants predicted to be P or LP in genes typically associated with CPHD (e.g. ROBO1, BRAF, FAT2, and DCHS2). Conversely, several CHH-associated genes such as FGFR1 and FGF8, already implicated in CPHD, were also identified in patients with CPHD and syndromic GN deficiency, further supporting a shared genetic architecture between CHH and CPHD.LARGE SCALE DATAN/ALIMITATIONS, REASONS FOR CAUTIONNon-coding and copy number variants were not studied. Functional studies of the new candidate genes for CHH were not undertaken.WIDER IMPLICATIONS OF THE FINDINGSThis study highlights the importance of comprehensive clinical evaluation and broadened genetic testing in patients with Gn deficiency.STUDY FUNDING/COMPETING INTEREST(S)This work was supported by the Swiss National Foundation (NP) (Grant No. 310030B_201275 to N.P.) and the Natural Science Foundation of Beijing (Grant No. 7244338 to Y.W.). The authors declare no competing interests.

STUDY QUESTIONAre previously proposed vaginal microbial community state types (CSTs) valid predictors of IVF success, or do alternative microbial signatures provide stronger associations?SUMMARY ANSWERPreviously proposed CSTs as predictors of implantation, clinical pregnancy, and live birth were not confirmed, while an interaction between Ureaplasma parvum and Lactobacillus iners emerged as a strong negative predictor.WHAT IS KNOWN ALREADYInfertility affects 17% of the global population. Only one-third of treatment cycles of assisted reproductive technologies result in embryo implantation, and even fewer lead to clinical pregnancy or live births. While early findings have spurred the development of microbiome-based tests for success prediction, evidence on supporting their reliability remains inconclusive.STUDY DESIGN, SIZE, DURATIONThis prospective, single-centre study aimed to validate existing, and identify better, microbial predictors of infertility treatment outcomes. A cohort of 266 infertile female patients (age 18–45 years) undergoing a frozen-thawed embryo transfer cycle in an anovulatory regimen (i.e. a cycle with transfer of an embryo following a previous oocyte retrieval, fertilization, and freezing of embryos) was recruited for the study within a timeframe from May 2017 to March 2019.PARTICIPANTS/MATERIALS, SETTING, METHODSThe female, infertile patients, aged 18–45 years, were undergoing routine care. Vaginal swabs were taken prior to embryo transfer and subjected to DNA isolation for 16S-based microbiota analysis. Extended demographic and treatment data were recorded. Clinical outcomes were defined as: (i) implantation, confirmed by a positive hCG test, (ii) clinical pregnancy, and (iii) live birth (defined as the birth of a viable infant). Sequencing data were processed in mothur following established pipelines, and microbial composition (taxonomy) as well as microbial diversity (dissimilarity analyses) were determined using the open-source software R. A prediction model for implantation success was built using binary logistic regression based on abundance of putatively predictive microbial taxa.MAIN RESULTS AND THE ROLE OF CHANCEThis study suggests that vaginal microbial CSTs, alpha-diversity, and the ratio of dominant Lactobacillus species do not correlate in statistical terms or in a clinically meaningful manner with implantation and clinical pregnancy (as a surrogate for endometrial receptivity) or with live birth (as a surrogate for ongoing pregnancy viability). However, Ureaplasma parvum and Lactobacillus iners abundances were identified as negative predictors of embryo implantation, clinical pregnancy, and live birth. A subset of women colonized by these taxa experienced drastically reduced embryo implantation and completely failed to achieve clinical pregnancy or give birth to live offspring, suggesting a potential role of these organisms in implantation failure and reproductive outcome, independent of other influencing factors such as age, oestradiol levels, endometrial thickness etc.LARGE SCALE DATAThe raw sequencing data used for this manuscript are publicly available at the European Nucleotide Archive under accession number PRJEB107113.LIMITATIONS, REASONS FOR CAUTIONThis study is a single-centre study warranting further validation cohorts. Given the variable nature of the vaginal microbiota, sample sizes need to be enlarged for better refinement of the analyses. Further, the underlying mechanistical basis of our findings is yet elusive and clinical translation has yet to be established.WIDER IMPLICATIONS OF THE FINDINGSWhile this novel association warrants confirmation, the results caution against reliance on previously suggested CSTs as predictors, and highlight the need for refined, reproducible microbiome-based diagnostics in reproductive medicine.STUDY FUNDING/COMPETING INTEREST(S)Financial support was received from the University of Lübeck and the German Center of Infection Research. M.L., A.M., I.P., M.D., and J.R. declare no conflicts of interest. S.G. discloses personal fees from Organon outside the submitted work. T.K.E. discloses honoraria from Ferring; travel support from Ferring, Merck, Theramex, and Gedeon-Richter; and receipt of equipment/materials/laboratory analyses (to institution) from Arthrex, Besins, Merck, and Abbott outside the submitted work. N.H. discloses personal fees from Gedeon Richter, Ferring, and Merck. G.G. reports that his institution received grants or contracts from Besins, Merck, Abbott, Ferring, and Theramex. He has received personal consulting fees, support for travel fees and meeting attendance, and honoraria for lectures or educational events from Organon, Ferring, Merck, Gedeon-Richter, Theramex, Abbott, ReproNovo, Igyxos, OxoLife, Philipps, ReprodWissen, PregLem, Guerbet, Roche, IBSA, and Besins. He also received support for travel and meeting attendance from Merck, Organon, Ferring, Theramex, Gedeon-Richter, and Abbott. Additionally, he holds unpaid leadership positions as a member of the ESHRE Working Group on RIF, the ESHRE Working Group on clinical KPI, and the ESHRE guideline development group on ovarian stimulation. A.S.-M. reports consulting fees and speaker’s fees from Merck, Theramex, and Gedeon-Richter as well as travel support from Merck, Theramex, Gedeon-Richter, IBSA, Ferring, and MSD.

[This corrects the article DOI: 10.1093/hropen/hoaf047.].

STUDY QUESTIONAre endometriotic lesions affecting bilateral organs or anatomical structures distributed symmetrically on both sides of the body?SUMMARY ANSWERThe left-sided preponderance of pelvic endometriotic lesions, and the right-sided dominance of thoracic and inguinal lesions, suggest that endometriotic lesions exhibit a non-random, asymmetric lateral distribution.WHAT IS KNOWN ALREADYEvaluating the anatomical distribution of endometriotic lesions may elucidate the underlying pathogenic mechanism(s) of the disease. If the coelomic metaplasia or embryonic cell remnant theory is correct, a symmetrical right-left pattern would be expected. Conversely, retrograde menstruation would likely result in asymmetrical distribution, influenced by gravity, peritoneal fluid circulation, and anatomical niches.STUDY DESIGN, SIZE, DURATIONThis systematic review with meta-analysis included full-length, English-language articles published up to 10 June 2024. Literature searches were performed in PubMed/Medline and Embase databases with the keyword ‘endometriosis’, ‘lateral’, ‘distribution’, ‘right’, ‘left’, and ‘asymmetry’.PARTICIPANTS/MATERIALS, SETTING, METHODSThe review focused on anatomical structures commonly affected by endometriosis with surgically defined right or left laterality: ovaries, uterosacral ligaments, colon, ureters, inguinal regions, and hemithorax (diaphragm, pleura, lungs). Case reports were excluded. Risk of bias was assessed using ROBINS-I for non-randomized studies and a dedicated tool for case series. Meta-analyses of proportions were conducted in R. Heterogeneity was quantified using the I2 statistic. Funnel plots for publication bias and Egger tests were performed using Stata.MAIN RESULTS AND THE ROLE OF CHANCEOf 6356 articles screened, 154 met the inclusion criteria. A statistically significant left-sided preponderance was observed for ovarian (58%; 95% CI: 57–60%; P < 0.001), uterosacral ligament (56%; 95% CI: 54–59%; P < 0.001), ureteral (71%; 95% CI: 67–76%; P < 0.001), and bowel (72%; 95% CI: 64–79%; P < 0.001) lesions, whereas thoracic (98%; 95% CI: 96–100%; P < 0.001) and inguinal (92%; 95% CI: 83–98%; P < 0.001) lesions were predominantly right-sided. These findings were confirmed in the sensitivity analyses. Egger’s test indicated a possible small study effect only for ovarian lesions (P = 0.012).LIMITATIONS, REASONS FOR CAUTIONThe preponderance of retrospective studies, the variability in surgical procedures, and the potential difficulties in accurately distinguishing unilateral from bilateral lesions may have influenced the magnitude of the estimated difference. However, the large patient cohorts, geographical diversity, and consistent asymmetry across lesion types strengthen the results’ validity and generalizability.WIDER IMPLICATIONS OF THE FINDINGSThe pattern of endometriotic lesion distribution, including the opposite asymmetry observed in the pelvis and upper abdomen/thorax, can be explained by factors influencing dissemination and implantation of refluxed endometrial cells. However, it cannot be explained as well by the coelomic metaplasia or embryonic cell remnant theories. This may have important clinical implications, providing a pathogenic basis for secondary prevention strategies.STUDY FUNDING/COMPETING INTEREST(S)The open access facility of this paper was funded by the Italian Ministry of Health, Current research IRCCS Ca’ Granda Ospedale Maggiore Policlinico. P.V. is a member of the Editorial Board of Human Reproduction Open, Journal of Obstetrics and Gynaecology Canada, and International Editorial Board of Acta Obstetricia et Gynecologica Scandinavica; has received royalties from Wolters Kluwer for chapters in UpToDate. All other authors declare no conflicts of interest.REGISTRATION NUMBERCRD42024511356 (PROSPERO).

STUDY QUESTIONIs maternal pre-existing atherosclerotic cardiovascular disease (ASCVD) associated with neonatal and long-term offspring outcomes?SUMMARY ANSWERMaternal pre-existing ASCVD is independently associated with consistent increases in neonatal and early childhood adverse outcomes.WHAT IS KNOWN ALREADYMaternal cardiovascular health may influence offspring development through intrauterine and early-life mechanisms. However, the impact of maternal pre-existing ASCVD on neonatal and long-term offspring’s neurodevelopmental outcomes remains poorly understood.STUDY DESIGN, SIZE, DURATIONWe conducted a nationwide cohort study linking maternal and child health data from the Korean National Health Insurance Service between 2005 and 2019.PARTICIPANTS/MATERIALS, SETTING, METHODSPre-existing ASCVD was defined by diagnostic codes for myocardial infarction, ischemic stroke, or angina prior to conception. Offspring outcomes included neonatal complications (congenital malformations, sepsis, neonatal intensive care unit admission) and neurodevelopmental disorders (developmental delay, seizure, or attention-deficit hyperactivity disorder), with follow-up through 2020. Among 5 461 222 live births (3 640 815 unique mothers), 145 315 (2.7%) were delivered by women with pre-existing ASCVD before pregnancy. Propensity score matching (1:4) was used to adjust for baseline maternal characteristics.MAIN RESULTS AND THE ROLE OF CHANCEOffspring of mothers with ASCVD had increased risk of congenital malformations (adjusted odds ratio [aOR] 1.09, 95% CI: 1.07–1.12), neonatal intensive care unit admission (aOR 1.19, 95% CI: 1.16–1.22), and neonatal sepsis (aOR 1.11, 95% CI: 1.07–1.15). The risk of neurodevelopmental disorders was also elevated (adjusted hazard ratio 1.08, 95% CI: 1.07–1.10). The absolute risk differences were consistent regardless of the presence of adverse pregnancy outcomes during pregnancy.LIMITATIONS, REASON FOR CAUTIONAs with all observational studies, residual confounding could not be ruled out. Only live births are included.WIDER IMPLICATIONS OF THE FINDINGSMaternal pre-existing ASCVD was associated with modest but consistent increases in neonatal and early childhood adverse outcomes. These associations appeared to persist regardless of the presence of adverse pregnancy outcomes, suggesting a possible independent contribution of maternal ASCVD on offspring development. Our findings suggest the importance of identifying and monitoring pregnancies of women with cardiovascular disease and indicate that early neurodevelopmental surveillance may be considered in affected children.STUDY FUNDING/COMPETING INTEREST(S)This study was supported by the Patient-Centered Clinical Research Coordinating Center (PACEN) funded by the Ministry of Health & Welfare, Republic of Korea (grant number: HC21C0123) and supported by the Bio&Medical Technology Development Program of the National Research Foundation (NRF) funded by the Korean government (MSIT) (No. RS-2024-00440881). No competing interests are reported.TRIAL REGISTRATION NUMBERClinicalTrials.gov, NCT06406998.