Regulatory T (T _reg ) cells play a vital role in maintaining maternal immune tolerance to the semiallogeneic fetus during pregnancy. T _reg cell population heterogeneity and tissue-specific functions in the human decidua remain largely unknown. Here, using single-cell transcriptomic and T cell receptor sequencing of human CD4 ⁺ T cells from first-trimester deciduae and matched peripheral blood of pregnant women, we identified a highly activated, immunosuppressive CCR8 ⁺ T _reg cell subset specifically enriched in the decidua (dT _reg cells). CCR8 ⁺ dT _reg cells were decreased in patients with recurrent pregnancy loss (RPL) and an abortion-prone mouse model. Depletion of CCR8 ⁺ dT _reg cells increased susceptibility to fetal loss, with altered decidual immune profiles. Adoptive transfer of CCR8 ⁺ T _reg cells rescued fetal loss in abortion-prone mice. The CCR8 ligand CCL1 was mainly produced by decidual CD49a ⁺ natural killer cells and was significantly decreased in patients with RPL. Our data demonstrate that CCR8 ⁺ dT _reg cells are required to maintain maternal-fetal tolerance and highlight potential avenues for RPL therapies.

Objective: We evaluate whether next-generation sequencing (NGS)-based preimplantation genetic testing for aneuploidy (PGT-A) improves the cumulative pregnancy outcomes of patients with unexplained recurrent implantation failure (uRIF) as compared to conventional in vitro fertilization or intracytoplasmic sperm injection (IVF/ICSI). Patients and Methods: This was a retrospective cohort study (2015– 2022). A total of 705 couples diagnosed with uRIF were included in the study. 229 women transferred blastocysts based on morphological grading (IVF/ICSI) and 476 couples opted for PGT-A to screen blastocysts by NGS. Women were further stratified according to age at retrieval (< 38 years and ≥ 38 years). The primary outcome was the cumulative live-birth rate after all the embryos were transferred in a single oocyte retrieval or until achieving a live birth. Confounders were adjusted using binary logistic regression models. Results: Cumulative live-birth rate was similar between the IVF/ICSI group and the PGT-A group after stratified by age: IVF/ICSI vs PGT-A in the < 38 years subgroup (49.7% vs 57.7%, adjusted OR (95% CI) = 1.25 (0.84– 1.84), P = 0.270) and in the ≥ 38 years subgroup (14.0% vs 19.5%, adjusted OR (95% CI) = 1.09 (0.41– 2.92), P = 0.866), respectively. Nonetheless, the PGT group had a lower first-time biochemical pregnancy loss rate (17.0% vs 8.7%, P = 0.034) and a higher cumulative good birth outcome rate (35.2% vs 46.4%, P = 0.014) than the IVF/ICSI group in the < 38 years subgroup. Other pregnancy outcomes after the initial embryo transfer and multiple transfers following a single oocyte retrieval were all similar between groups. Conclusion: Our results showed no evidence of favorable effects of PGT-A treatment on improving the cumulative live birth rate in uRIF couples regardless of maternal age. Use of PGT-A in the < 38 years uRIF patients would help to decrease the first-time biochemical pregnancy loss and increase the cumulative good birth outcome.

The aim of the retrospective cohort study was to investigate the prognostic effect of subchorionic hematomas (SCH) in the first trimester on pregnancy outcomes after euploid embryo transfer. We retrospectively analyzed women achieving singleton pregnancy by PGT-A or PGT-SR from January 2017 to January 2022. Patients were enrolled in the study if they had a viable intrauterine pregnancy at ultrasound between 6 0/7 and 8 0/7 weeks of gestation. Pregnancy outcomes as well as the incidence of maternal complications were compared between patients with and without SCH. Logistic regression was used for adjusting for potential confounding factors. A total of 1539 women were included, of which 298 with SCH and 1241 with non-SCH. The early miscarriage rate in SCH group was significantly higher than that in the non-SCH group (10.1% vs. 5.6%, adjusted odds ratio [aOR] 1.99, 95% confidence interval [CI] 1.25–3.16, P = 0.003). The live birth rate in SCH group was significantly lower than that in the non-SCH group. (85.6% vs. 91.2%, aOR 0.57, 95% CI 0.39–0.84, P = 0.005). In addition, SCH group had an increased risk of hypertensive disorder of pregnancy (HDP) (8.9% vs. 5.2%, P = 0.022), especially in hematoma with bleeding (19.3% vs. 6.0%, P = 0.002). The incidence of gestational diabetes mellitus (GDM), major congenital abnormalities rate, normal birth weight rate and low birth weight rate were similar between the two groups. The presence of SCH in the first trimester was associated with worse pregnancy outcomes after euploid embryo transfer, including an increased risk of early miscarriage and hypertensive disorder of pregnancy, along with a reduced live birth rate.

Defective endometrial receptivity represents an important factor in recurrent implantation failure (RIF), though its precise regulatory mechanisms remain unclear. While nicotinamide N-methyltransferase (NNMT) is abundantly expressed in human endometrial tissues, its role in endometrial receptivity and RIF pathogenesis has not been defined. This study demonstrated that NNMT expression was significantly downregulated in midluteal-phase endometrium from RIF patients relative to fertile controls. Functional analyses in human endometrial stromal cells (ESCs) revealed that NNMT knockdown enhanced autophagy flux and disrupted progesterone signaling. Mechanistically, NNMT deficiency elevated H3K9me3 enrichment at the Aldh1a3 promoter, suppressing its expression. Notably, knockdown of ALDH1A3 resulted in similar effects with NNMT downregulation, and exogenous rhALDH1A3 reversed the autophagy alterations and rescued progesterone signaling in NNMT-knockdown cells. In vivo, NNMT inhibition in a murine model reduced embryo implantation rates and decreased ALDH1A3 expression. Collectively, these findings indicate that reduced NNMT impairs endometrial receptivity through H3K9me3-mediated ALDH1A3 repression, leading to aberrant autophagy and disrupted progesterone signaling in decidualized ESCs. This study identifies the NNMT-H3K9me3-ALDH1A3 axis as a key epigenetic-metabolic pathway underlying RIF, offering novel diagnostic and therapeutic targets.