As a major challenge currently plaguing reproductive medicine, recurrent pregnancy loss(RPL) has a variety of causes. Thyroid autoimmunity(TAI) is a prevalent thyroid disorder among women of childbearing age, potentially impacting maternal physiological changes and the balance of the maternal-fetal interface during pregnancy through endocrine and autoimmune pathways, which can lead to abortion and RPL. The selection of therapeutic agents and the effectiveness of treatment for patients experiencing RPL with thyroid autoimmunity remain contentious. Current research have explored the efficacy of medications such as levothyroxine, immunoglobulins, glucocorticoids, cyclosporine, hydroxychloroquine, selenium, and vitamin D for these patients. This review summarizes the correlation between TAI and RPL, as well as the current status of its diagnosis and treatment, with the aim of providing new ideas for clinical diagnosis and treatment.

Intrauterine insemination (IUI) is a common treatment for couples with unexplained infertility. However, the impact of human papillomavirus (HPV) infection on IUI outcomes remains uncertain. This study, therefore, aims to investigate whether HPV infection in women with unexplained infertility affects pregnancy outcomes following IUI. This retrospective cohort study analyzed 435 women with unexplained infertility who underwent intrauterine insemination (IUI) at the Reproductive Centre of Sun Yat-Sen Memorial Hospital between January 2018 and December 2022. Univariate analysis was used to compare the baseline characteristics and assisted conception data between the two groups. Subsequently, a multivariate logistic regression model was employed to further assess the independent association between HPV infection and the key clinical outcome of live birth. Based on their HPV infection status within 1 year prior to treatment, 435 women were categorized into an HPV-positive group (n = 33) and an HPV-negative group (n = 402). Sixty-six women achieved live births and three hundred sixty-nine did not. Cervical cytological abnormalities were more frequent in the HPV-positive group (25.0

Excessive reactive oxygen species (ROS) during assisted reproductive technology (ART) impairs embryonic development, yet the intrinsic molecular mechanisms remain inadequately understood. Through transcriptomic profiling (Drug-seq) of oxidatively stressed mouse embryos, we identified peroxisome proliferator-activated receptor gamma (PPAR1) as a critical regulator whose essential upregulation during zygotic genome activation (ZGA) is suppressed. Functional studies demonstrated that the pharmacological activation of PPAR1 via the agonist GW1929 robustly rescued developmental arrest by scavenging ROS, restoring mitochondrial function, and maintaining metabolic homeostasis. Mechanistically, we demonstrate that PPAR1 activation transcriptionally upregulates GSK3D, which in turn suppresses oxidative stress-induced aberrant Wnt/D-catenin signaling. Our findings establish PPAR1 as a central guardian of embryonic redox and metabolic homeostasis, and propose PPAR1 agonism as a potential strategy to improve ART outcomes by counteracting oxidative injury.

Cervical incompetence occurs when the cervix fails to maintain its normal morphology and function during second-trimester, leading to recurrent second-trimester miscarriages or preterm births. To standardize and guide the clinical diagnosis and treatment of cervical insufficiency in China, the Perinatal Medicine Branch of the Chinese Medical Association and the Obstetrics Group of the Chinese Society of Obstetrics and Gynecology developed this consensus by referencing related research evidence and so on. This consensus provides evidence-based analysis and recommendations on key clinical issues including the diagnosis of cervical incompetence, indications for cervical cerclage, surgical techniques, timing of intervention, perioperative management, and adjunctive therapies, offering evidence-based guidance for obstetric clinical practice.Practice guideline registration:International Practice Guidelines Registry and Transparency Platform (PREPARE-2024CN1155)

BACKGROUND:Human aneuploid conception, a leading cause of infertility, pregnancy loss, and congenital disorders (e.g. Down's syndrome), arises from errors in chromosome segregation during oocyte meiosis or embryonic mitosis. While advanced maternal age is a well-established risk factor, significant inter-individual variation exists among younger women, suggesting a substantial role for maternal genetic determinants. OBJECTIVE AND RATIONALE:This review summarizes the identified maternal genetic variants associated with aneuploid conceptions and highlights directions for future research. SEARCH METHODS:We systematically searched PubMed, Embase, and the Cochrane Library (up to 12 January 2026), using key terms related to maternal genetics, genetic variants, aneuploidy, and pregnancy. Inclusion criteria were human studies, genetic confirmation of aneuploidy (in oocytes/embryos/products of conception/fetal cells), maternal variants (rare single-nucleotide variations, single-nucleotide polymorphisms, and small indels [≤50 bp]), and English-language publications. Exclusion criteria were non-human studies, structural/non-aneuploid numerical abnormalities, paternal factors, and conference abstracts. Extracted data items included study identifiers, population characteristics, variant details, detection methods, clinical phenotypes, type and origin of aneuploidy, pathogenicity or effect assessment, and gene inclusion in currently commercially available infertility next-generation sequencing (NGS) panels. Rare variants were classified per American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP) guidelines, whereas common variants were evaluated based on effect estimates and functional validation. Study quality was appraised using a modified Newcastle-Ottawa Scale. Supplementary searches explored associations between the identified genes and a broader range of reproductive phenotypes. OUTCOMES:From 28 studies covering the broad clinical spectrum of aneuploid pregnancies (including embryo arrest, implantation failure, pregnancy loss, hydatidiform mole, and fetal aneuploidy), we identified maternal variants associated with aneuploid conceptions. These were functionally categorized into meiotic recombination, spindle dynamics, checkpoint enforcement, and the maternal-to-zygotic transition. Among them, variants in several genes are supported by higher-quality evidence, including likely pathogenic rare variants in KIF18A, ELL3, and CEP120, as well as common variants in PLK4 and CCDC66. Although some identified genes (HFM1, MCM9, MEI1, BUB1B, NLRP2, NLRP7, and TLE6) are included in commercial infertility NGS panels, their direct association with aneuploidy requires further validation. WIDER IMPLICATIONS:This review proposes that 'aneuploidy predisposition' constitutes a critical, mechanism-driven dimension for the genetic diagnosis of infertility, complementing phenotype-based frameworks. This approach would best serve women with unexplained infertility and a normal karyotype who have either a history of recurrent aneuploidy or heterogeneous reproductive phenotypes across different cycles. Adopting this perspective refines clinical genetic testing paradigms and underscores the need to prioritize artificial intelligence-enhanced clinico-genomic association studies and develop polygenic risk models integrated with clinical factors. PROSPERO REGISTRATION NUMBER:CRD42025636217.

Recurrent implantation failure (RIF) remains clinically unresolved at this stage. Hydroxychloroquine, as an immunomodulator, is still lacking clinical evidence, but it is being used by increasing numbers of reproductive centers and physicians worldwide, so a well-designed randomized controlled trial (RCT) is urgently needed to elucidate whether hydroxychloroquine can improve pregnancy outcomes in patients with RIF. In this study, we plan to recruit 686 volunteers who will undergo IVF/ICSI at 5 reproductive centers from 6 December 2022. Participants will be randomized to two parallel groups and treated with hydroxychloroquine sulfate tablets or placebo from the start of endometrial preparation to 14 days after frozen embryo transfer (if not pregnant) or to 12 weeks of pregnancy (if pregnant). The primary outcome is live birth rate, and the secondary outcomes include biochemical pregnancy rate, clinical pregnancy rate, embryo attachment rate, first trimester abortion rate and ongoing pregnancy rate, birth weight, pregnancy and perinatal complications, congenital anomaly, and other adverse events. This study aims to evaluate whether hydroxychloroquine (HCQ) improves pregnancy outcomes in patients with recurrent implantation failure (RIF). Secondary objectives include comparative analysis of gestational complications between the intervention and control groups. ChiCTR2100047584 [Chinese Clinical Trial Registry (ChiCTR): registered on 20 June 2021]. LM2021267 [Ethics Committee of Peking University Third Hospital].

This study aimed to evaluate the efficacy of immunotherapies for recurrent implantation failure (RIF), as newly defined by ESHRE 2023. We conducted network meta-analyses of randomized trials on immunomodulatory therapies for well-defined RIF from PubMed, Embase, Web of Science, and Cochrane Library up to October 2024. We assessed clinical outcomes, including clinical pregnancy rate (CPR), live birth rate (LBR), implantation rate (IR), and miscarriage rate (MR), using odds ratios (OR) and 95 % confidence-intervals (CI). Statistical analysis was performed with STATA. Nineteen trials involving 2434 women were included, comparing nine immunotherapies. Compared to controls, low-molecular-weight heparin (LMWH) (OR 4.05, 95 %CI 1.78-9.24, surface under the cumulative ranking curve (SUCRA) 77.1 %) and platelet-rich plasma (PRP) (OR 3.27, 95 %CI 1.42-7.52, SUCRA 66.5 %) significantly improve IR, while sirolimus (OR 3.95, 95 %CI 1.46-10.71, SUCRA 81.9 %) and PRP (OR 3.45, 95 %CI 2.45-4.85, SUCRA 80.3 %) notably increased CPR. Subcutaneous granulocyte colony-stimulating factor (SC-GCSF) (OR 9.00, 95 %CI 1.42-57.12, SUCRA 93.7 %) were associated with higher LBR. LMWH (OR 0.12, 95 %CI 0.02-0.80, SUCRA 84.6 %) and PRP reduced MR (OR 0.15, 95 %CI 0.04-0.50, SUCRA 82.2 %). Subgroup analysis indicated that a 0.5 ml intrauterine PRP dose 48 h before embryo transfer (ET) enhanced CPR (OR 3.96, 95 %CI 2.74-5.74) and reduced MR (OR 0.10, 95 %CI 0.04-0.22). In newly defined RIF patients, sirolimus and PRP effectively enhance CPR, while SC-GCSF optimizes LBR. LMWH is most effective for improving IR and reducing MR. PRP, particularly with a single 0.5 ml intrauterine dose, optimally increases CPR and reduces MR. Intrauterine G-CSF showed no significant benefits. TRIAL REGISTRATION: The protocol was registered on OSF: https://doi.org/10.17605/OSF.IO/GVEP9.

Unexplained recurrent pregnancy loss (URPL) represents a prevalent obstetric complication and remains a challenging condition with poorly understood genetic etiology. Through whole-exome sequencing of 94 URPL patients, we identified enriched MLH3 gene mutations in five individuals (p.G1302Efs21/p.G752E, p.V741F/p.S845G, p.V1220M/p.L1339F, p.T942I/p.G1163D, p.I988M/p.A1426V), with a 5.32

Fertilization and early-cleavage failure are the major causes of assisted reproductive technology failure, but genotype-guided care is underused. We conducted whole-exome sequencing with Sanger confirmation in 20 men from couples with unexplained fertilization and cleavage failure after in vitro fertilization or intracytoplasmic sperm injection (ICSI). Then, further sperm transmission electron microscopy, immunofluorescence, and, where appropriate, embryo quantitative parental contamination test (qPCT) and kinship analysis were integrated in selected cases. Six novel variants were found in four families: two each in dynein axonemal heavy chain 10 ( DNAH10 ) and dynein axonemal heavy chain 12 ( DNAH12 ) and one in cilia and flagella associated protein 47 ( CFAP47 ) and phospholipase C zeta 1 ( PLCZ1 ), respectively. DNAH10/DNAH12 variants segregated with multiple morphological abnormalities of the sperm flagella and showed "9+2" axonemal disruption and reduced dynein signals. Hemizygous CFAP47 c.8006C>T is associated with cleavage failure and altered PLCZ1 localization. Homozygous PLCZ1 c.589C>T in a consanguineous pedigree coincided with multinuclear (≥3 pronuclei) zygotes, and qPCT/kinship indicated excess paternal contribution, consistent with suspected polyspermy in multinuclear zygotes. Management-matched genotype: ICSI restored fertilization in DNAH10/DNAH12 deficiency, whereas ICSI plus assisted oocyte activation (AOA) improved cleavage and yielded ongoing pregnancies in CFAP47/PLCZ1 deficiency. These findings outline potentially actionable clinical strategies-ICSI for axonemal dynein defects and ICSI plus AOA for activation pathway defects-and support targeted genetic testing plus embryo qPCT/kinship in selected cases.

Iron overload induces cellular stress and is implicated in diverse pathological conditions. Nevertheless, the epigenetic mechanisms governing mammalian cellular responses to iron overload remain poorly characterized. Using multi-omics profiling in human granulosa cells, we show that the transcriptional signature of iron-stressed granulosa cells recapitulated that of granulosa cells from endometriosis patients. Mechanistically, iron excess triggered a time-dependent, genome-wide reduction in chromatin accessibility, which was associated with broad transcriptional suppression. Furthermore, fine-scale chromatin looping underwent dynamic reorganization, concomitant with dysregulated expression of core iron metabolism genes. We identify SOX4 as a central, dosage-sensitive regulator of this epigenetic reprogramming: its downregulation under iron stress drives chromatin compaction, while ectopic SOX4 expression largely restores accessibility. Moreover, SOX4 is directly regulated by TFEB through binding to the CLEAR motif in its promoter and, in turn, exerts its function by recruiting the SWI/SNF chromatin remodeling complex. Notably, SOX4 also mediated chromatin compaction under high-androgen stimulation, suggesting its universal role as a stress-responsive epigenetic regulator in granulosa cells. These results elucidate a TFEB-SOX4-SWI/SNF regulatory axis that orchestrates iron-responsive chromatin plasticity, and more broadly, uncover SOX4 as a key mediator of chromatin adaptation to pathophysiological stressors, including iron overload and hyperandrogenism.

BACKGROUND:In vitro fertilization has transformed reproductive medicine, yet offspring conceived through in vitro fertilization display elevated risks for diverse long-term health conditions, with underlying mechanisms unclear. Long Interspersed Nuclear Elements-1, a mobile genetic element responsive to environmental stress, represents a potential mediator. OBJECTIVE:This study aimed to test the hypothesis that in vitro fertilization procedures may act as an embryonic stressor that alters Long Interspersed Nuclear Elements-1 dynamics, potentially contributing to genomic instability associated with long-term disease susceptibility. STUDY DESIGN:Umbilical cord blood or peripheral blood from 33 in vitro fertilization and 42 naturally conceived neonates were collected for whole-genome sequencing. Total Long Interspersed Nuclear Elements-1 proportion in individual genome was counted with Bowtie2 software. De novo Long Interspersed Nuclear Elements-1 insertion and Long Interspersed Nuclear Elements-1 deletion were detected with Mobile Element Locator Tool. Three parent-matched in vitro fertilization-naturally conceived sibling pairs were included to control for genetic background. Disease association analysis was performed for genes within 500 kb of differential Long Interspersed Nuclear Elements-1 sites in The Database for Annotation, Visualization and Integrated Discovery (DAVID). Statistical analysis was performed using the R language. RESULTS:In vitro fertilization offspring demonstrate elevated global Long Interspersed Nuclear Elements-1 content compared to naturally conceived controls (P=.04). This finding was corroborated in 3 sibling pairs from identical genetic backgrounds, where in vitro fertilization-conceived children consistently exhibited higher Long Interspersed Nuclear Elements-1 levels than their naturally conceived siblings. Eleven genomic loci with differential Long Interspersed Nuclear Elements-1 insertion frequencies and 14 loci with differential Long Interspersed Nuclear Elements-1 deletion frequencies between in vitro fertilization offspring and naturally conceived controls were identified. Notably, these differential Long Interspersed Nuclear Elements-1 sites demonstrated significant enrichment near genes implicated in metabolic, cardiovascular, neuropsychiatric, and neoplastic diseases, conditions associated with in vitro fertilization conception. CONCLUSION:These findings provide preliminary evidence that in vitro fertilization conception is associated with increased Long Interspersed Nuclear Elements-1 content and altered genomic distribution of Long Interspersed Nuclear Elements-1 elements. The proximity of these differential Long Interspersed Nuclear Elements-1 sites to disease-associated genes suggests a plausible genomic mechanism linking in vitro fertilization-associated embryonic stress to elevated disease risk. This work provides valuable molecular insights that may inform the ongoing discussion about assisted reproductive technology safety and suggests that continued attention to genomic integrity in in vitro fertilization-conceived individuals would be beneficial.

Congenital absence of the vas deferens (CAVD) is a major cause of obstructive azoospermia and male infertility, with its genetic etiology primarily associated with CFTR (autosomal recessive) and ADGRG2 (X-linked) mutations. However, the genetic spectrum and classification of variants in isolated congenital absence of the vas deferens (iCAVD), as well as the risk of CFTR variant carriage in affected couples, remain incompletely understood. In this cross-sectional study, we enrolled 199 Chinese iCAVD patients and 148 female partners between 2012 and 2024. CFTR and ADGRG2 variants were identified in 74.87% of iCAVD patients, with CFTR being the predominant pathogenic gene. Notably, 10.14% of couples carried shared pathogenic or likely pathogenic CFTR variants, highlighting the potential reproductive risks. The most common pathogenic variants were CFTR c.1210-12T (Yu et al., 2012) (5T) and c.4056G > C (p.Gln1352His), whereas c.1666A > G (p.Ile556Val) was classified as likely benign. The c.4056G > C variant exhibited significant regional ethnic characteristics. Furthermore, genotype-phenotype correlation analysis revealed significant differences in semen volume, pH, and fructose levels among different variant subgroups in CBAVD patients. Collectively, these findings provide a comprehensive overview of the genotype-phenotype landscape in a large iCAVD cohort, emphasizing variant classification and reproductive risks associated with CFTR and ADGRG2. This study offers valuable insights for genetic counseling and reproductive planning in affected couples.

Abstract:This study aimed to investigate whether an early LH surge during controlled ovarian stimulation (COS) affects pregnancy outcomes in patients with polycystic ovary syndrome (PCOS) undergoing assisted reproductive technology (ART) and to explore methods for identifying high-risk patients for early intervention. In a retrospective case-control analysis of 786 PCOS cycles, an early LH surge was found to significantly increase the spontaneous abortion rate and reduce the live birth rate in in vitro fertilization and multiple embryo transfer cycles, while also correlating with a higher preterm birth rate in frozen embryo transfer cycles. Using the training set of 786 cycles, three predictive models for LH surge were developed and validated in an independent time validation set of 76 cycles. Among them, model 2 demonstrated optimal performance, with prediction feasible as early as COS day 0 and an AUC of 0.713. The findings indicate that an early LH surge may compromise ART outcomes in specific PCOS subgroups, and the proposed predictive models could aid clinicians in identifying high-risk patients and adapting treatment strategies accordingly. Lay summary:For women with polycystic ovary syndrome (PCOS) undergoing fertility treatment, a premature hormone surge can sometimes disrupt the process. Our study investigated how this early 'luteinizing hormone (LH) surge' affects pregnancy success. We found that women who experienced this early surge had more eggs collected. However, for those who had a fresh embryo transfer, it led to a higher risk of miscarriage and a lower chance of having a baby. If they used frozen embryos in a later cycle, the risk of premature birth was higher. To help patients, we also created a prediction tool. This tool uses simple information collected at the start of treatment - like a woman's body mass index and hormone levels - to identify those at high risk of this early surge. By spotting these patients early, doctors can personalize their treatment to improve their chances of a successful and healthy pregnancy.

Insulin resistance (IR) is increasingly recognized as a modifiable contributor to unexplained recurrent spontaneous abortion (uRSA), yet its routine surrogate, the homeostasis model assessment of insulin resistance (HOMA-IR), requires fasting glucose and insulin measurement and therefore an overnight fast, which is inconvenient in routine reproductive-clinic workflows. HOMA-IR is itself a surrogate index rather than the gold standard for insulin sensitivity (the hyperinsulinaemic–euglycaemic clamp), and any downstream marker must be interpreted accordingly. Adiponectin is an insulin-sensitizing adipokine with low biological variability and limited post-prandial fluctuation. We evaluated whether serum adiponectin, measured in this study from fasting oral-glucose-tolerance-test samples, could serve as an adjunctive marker for HOMA-IR-defined IR in women with uRSA. We performed a single-centre retrospective observational study of women managed for uRSA at a tertiary maternal and child health hospital in Dongguan, southern China. All participants were of Chinese Han ethnicity. Serum total adiponectin was quantified by latex-enhanced immunoturbidimetry (Sekisui Medical Co., Tokyo, Japan; catalogue No. 17083) on a Hitachi 7180 automated analyser, with an intra-assay coefficient of variation (CV) of 3.2

BACKGROUND:Isolated obstructive azoospermia (iOA) is classified as a type of obstructive azoospermia (OA) where cases remain "unexplained" even after excluding congenital absence of the vas deferens and external factors. This study aimed to determine if certain semen characteristics in iOA patients could indicate underlying genetic variants. OBJECTIVES:To investigate CFTR and ADGRG2 gene variants in patients with idiopathic obstructive azoospermia (iOA) and identify semen parameters associated with these variants to guide genetic testing. MATERIALS AND METHODS:Seventy-six iOA patients were divided into three groups based on variant status: Group I, patients with at least two CFTR variants or a hemizygous ADGRG2 variant; Group II, patients with one CFTR variant and no ADGRG2 variants; Group III, patients without any CFTR or ADGRG2 variants. Associations between genotypes and clinical parameters were analyzed using univariate and multivariate logistic regression to identify potential biomarkers. RESULT(S):Thirty-six of the 76 patients (47.37%) carried one or more CFTR or ADGRG2 variants. Twenty distinct variants, including three novel variants (c.1851A > T and c.2426C > T in CFTR, c.1105G > A in ADGRG2), were identified. The most common variant was c.1210-12T[5] (5T) (18.42%), followed by c.1666A > G (4.61%) and c.4056G > C (3.95%). Group I patients had significantly lower ejaculate volume, pH, and fructose levels compared with Groups II and III. The combined area under the curve (AUC) for fructose, age, pH, and volume was 0.979, with fructose alone achieving an AUC of 0.952. Diagnostic efficacy for variant detection was highest (88.1%) at a fructose cutoff of 0.591 µmol/ejaculate, with a sensitivity of 0.958, a specificity of 0.923, a positive predictive value (PPV) of 0.895 and a negative predictive value (NPV) of 0.877. DISCUSSION AND CONCLUSION:Approximately 47% of iOA patients carry CFTR and ADGRG2 variants, characterized by significantly lower semen volume, fructose, and pH. Fructose was identified as an independent predictor of CFTR and ADGRG2 variants, highlighting its potential utility in guiding genetic testing and clinical decision-making in iOA patients.

BACKGROUND:This study aimed to propose a new classification of focal choroidal excavation (FCE), summarize the clinical and multimodal imaging characteristics of FCE subtypes, and explore the relationship between FCE and choroidal neovascularization (CNV). METHODS:In this retrospective observational study, patients diagnosed with FCE using spectral-domain optical coherence tomography (SD-OCT) were included. FCE was classified according to associated retinochoroidal diseases. Clinical and multimodal imaging features, as well as the association of CNV, were investigated for different subtypes of FCE. RESULTS:The study included 105 eyes with FCE from 93 Chinese patients, with a mean age of 41.66 years (range: 15-75 years). Among the 93 eyes with comprehensive multimodal imaging data, FCE subtypes were classified as retractive (34.41 %), inflammatory (18.28 %), pachychoroidal (23.66 %), atrophic (9.68 %), and idiopathic (13.97 %). Idiopathic FCE patients had significantly better best-corrected visual acuity compared to those with retinochoroidal disease-associated FCE (P < 0.001). Inflammatory FCE was associated with higher myopia (median refractive error:6.00 D, P < 0.001) and reduced choroidal thickness (P = 0.014), whereas pachychoroidal FCE showed increased choroidal thickness. Retractive FCE exhibited the highest CNV rate at baseline (P < 0.001), with CNV more likely in larger greatest linear dimension (GLD) (P = 0.004) and female patients (P = 0.016). Although CNV was present in 50.54 % of cases at baseline, it grew within FCE during follow-up in only 8.60 % of cases, and 9.68 % experienced CNV recurrence. CONCLUSION:Different FCE subtypes exhibit distinct clinical features. Idiopathic FCEs are generally stable, while the emergence of secondary CNV is linked to anatomical alterations caused by FCE and associated retinochoroidal diseases.

Does low serum progesterone levels comprise the clinical outcome of the artificial preparation of frozen embryo transfer with vaginal progesterone In patients with expected good prognosis, low serum progesterone may affect clinical outcome, early miscarriage rates increase and ongoing pregnancy and live birth rates decrease. Previous studies is inconclusive in effect of the low serum progesterone levels on the clinical outcome of the artificial preparation of frozen embryo transfer with vaginal progesterone. This is a prospective pilot study. A total of 465 patients who had serum progesterone checked on the day of embryo transfer from the reproductive center of Sun Yat-sen Memorial Hospital between April 2020 and August 2022 were analyzed. They received the routine luteal phase support of vaginal progesterone 600-800mg/d plus dydrogesterone 20mg/d. There are 388 patients with serum Progesterone (P)≥7.24ng/ml, while the rest of 77 patients with serum P < 7.24ng/ml on the day of embryo transfer. The 77 patients with serum P < 7.24ng/ml on embryo transfer day were randomized to receive additional intramuscular progesterone 40mg per day from the day of embryo transfer（S1=34）or no additional intervention（S2=43）.The primary outcome was ongoing pregnancy rate. Baseline characteristics such as age, BMI, weight, infertility factors, endometrial thickness and serum progesterone in the proliferative phase were comparable between patients with serum P ≥ 7.24ng/ml and serum P < 7.24ng/ml on the day of embryo transfer. Clinical pregnancy rate, ongoing pregnancy rate, early miscarriage rate and live birth rate were similar in the three groups (serum P ≥ 7.24ng/ml, serum P < 7.24ng/ml with extra intramuscular progesterone and serum P < 7.24ng/ml without intervention). In the subgroup of expected good prognosis patients (age <35 years, less than 3 transfer cycles and at least one high quality embryo transferred), baseline characteristics were comparable between patients with serum P ≥ 7.24ng/ml and serum P < 7.24ng/ml on the day of embryo transfer. The clinical pregnancy rate in the serum P < 7.24ng/ml group was not significantly lower than in the serum P ≥ 7.24ng/ml group（55.6% vs 66.0%, p = 0.294）. However, the early miscarriage rate was significantly higher（22.2% vs 3.8%, p = 0.000） and the ongoing pregnancy rate and live birth rate were significantly lower in the serum P < 7.24ng/ml group than that in the serum P ≥ 7.24ng/ml group（OPR 33.3% vs 61.5%, LBR 33.3% vs 60.3%, p < 0.05）. This is a prospective cohort study from a single center. The cut-off serum progesterone on embryo transfer day may be not suitable for all centers due to the progesterone test variation. Serum progesterone on embryo transfer day plays partially important role on the clinical outcome especially in expected good prognosis patients. It is helpful in individualized treatments. Yes

This study utilized single-tube long fragment read whole genome sequencing (stLFR WGS) to identify cryptic chromosomally balanced translocations in preimplantation genetic testing (PGT), aiming to improve outcomes for couples experiencing recurrent pregnancy loss (RPL). G-banded karyotyping initially revealed normal results for Family 1 and a reciprocal translocation for Family 2. However, PGT’s low-coverage WGS uncovered recurrent copy number variations (CNVs) that contradicted the initial findings. Further analysis using stLFR WGS and Sanger sequencing precisely located the breakpoints, revealing a balanced translocation between chromosomes 7 and 13 in Family 1’s male and a complex translocation involving chromosomes 9, 10, and 11 in Family 2’s female. By selecting non-carrier embryos for transfer, the study resulted in successful births of healthy infants. These findings highlight the critical role of PGT in detecting concealed chromosomal rearrangements and demonstrate stLFR WGS as an effective diagnostic tool for breakpoint identification, significantly impacting reproductive decisions for couples with cryptic balanced translocations and RPL.

Recurrent pregnancy loss (RPL) is a multifactorial condition, with nearly half of cases remaining unexplained, and maternal insulin resistance is identified as a significant contributor. This study examined the role of salt-inducible kinase 1 (SIK1) in RPL patients associated with insulin resistance using villi samples, in vitro trophoblast models, and an insulin-resistant mouse model. Our results revealed that a marked increase in miscarriage risk was observed in women with a higher value of homeostatic model assessment for insulin resistance (>2.41). SIK1 expression was elevated in the villous tissues of RPL patients with insulin resistance, as well as insulin-treated trophoblast models. Overexpression of SIK1 impaired trophoblast migration and invasion by downregulating matrix metalloproteinase-2 and matrix metalloproteinase-9 and disrupted decidual natural killer cell-mediated vascular remodeling. Cocultured decidual natural killer cells exhibited altered cytokine expression, leading to endothelial dysfunction. In vivo, insulin-resistant mice showed elevated placental SIK1 expression, reduced pregnancy success, and defective spiral artery remodeling. These findings suggest that SIK1 activation driven by insulin resistance impairs trophoblast and decidual natural killer cell functions, thereby contributing to recurrent pregnancy loss.NEW & NOTEWORTHY Insulin resistance has been clinically linked to RPL, but mechanisms at the maternal-fetal interface remain unclear. This study combines clinical villous samples, in vitro trophoblast-dNK-endothelial coculture systems, and an insulin-resistant mouse model to demonstrate that SIK1 is upregulated in RPL patients with IR and impairs trophoblast invasion and cytokine regulation and endothelial remodeling. These findings implicate SIK1 in immune-vascular dysregulation, offering a mechanistic link between maternal metabolic stress and placental vascular dysfunction.