Natural and synthetic progestogens have been commonly used to prevent recurrent pregnancy loss in women with inadequate progesterone secretion or reduced progesterone sensitivity. However, the clinical efficacy of progesterone and its analogs for maintaining pregnancy is variable. Additionally, the underlying cause of impaired endometrial progesterone responsiveness during early pregnancy remains unknown. Here, we demonstrated that uterine-selective depletion of BMI1, a key component of the polycomb repressive complex-1 (PRC1), hampers uterine progesterone responsiveness and derails normal uterine receptivity, resulting in implantation failure in mice. We further uncovered genetic and biochemical evidence that BMI1 interacts with the progesterone receptor (PR) and the E3 ligase E6AP in a polycomb complex–independent manner and regulates the PR ubiquitination that is essential for normal progesterone responsiveness. A close association of aberrantly low endometrial BMI1 expression with restrained PR responsiveness in women who had previously had a miscarriage indicated that the role of BMI1 in endometrial PR function is conserved in mice and in humans. In addition to uncovering a potential regulatory mechanism of BMI1 that ensures normal endometrial progesterone responsiveness during early pregnancy, our findings have the potential to help clarify the underlying causes of spontaneous pregnancy loss in women.

Is the total dose of exogenous gonadotropins associated with blastocyst aneuploidy or live-birth rates in PGS cycles in Chinese women? The total dose of exogenous gonadotropins is not significantly associated with blastocyst aneuploidy or live-birth rates in PGS cycles in Chinese women. The administration of gonadotropins in ovarian stimulation leads to supraphysiological steroid concentrations compared with those seen during natural cycles. The rate of euploid blastocytes is negatively associated with female age. This is a retrospective study using anonymised data on PGS cycles performed in China from 2013 to 2017. Data from 1088 PGS cycles and 3219 embryos were analysed by array-comparative genomic hybridization (array-CGH). The study included 944 women who underwent PGS cycles with COH. All cycles were analysed by the total dose of exogenous gonadotropins (3000 IU), patient age (15 oocytes). In the group of younger women (<35 y.o., 537 PGS cycles), the incidence of aneuploidy ranged from 36.9 to 43.4% when data was stratified by gonadotropins dose. After adjusting for confounding factors, the dose of exogenous gonadotropins was not associated with the blastocyst aneuploidy rate. Similar results were shown in the group of women with advanced maternal age (≥35 y.o., 551 PGS cycles), with no difference in the rate of blastocyst aneuploidy among different gonadotropins dose groups (3000 IU, 59.8%; P = 0.86). The live-birth rates after single cryopreserved blastocyst transfers were also not significantly associated with the gonadotropins dose. Limitations include the retrospective study design and the heterogeneity of the included patients. Additionally, array-CGH may not be able to correctly identify mosaicism. The finding that gonadotropin dosage is not associated with embryonic aneuploidy or live-birth rates in Chinese women suggests that the high doses of gonadotropins used in ART cycles may be safe. The findings are consistent with those of prior studies in other populations. This study was supported by the National Natural Science Foundation of China (81671522) and National Key Research and Development Program of China (2016YFC1000202). N/A.

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.