Miscarriage is generally defined as the loss of a pregnancy before viability. An estimated 23 million miscarriages occur every year worldwide, translating to 44 pregnancy losses each minute. The pooled risk of miscarriage is 15•3% (95% CI: 12•5% -18•7%) of all recognised pregnancies. The population prevalence of women with one miscarriage is 10•8% (95% CI 10•3% -11•4%), two miscarriages is 1•9% (95% CI 1•8% -2•1%) and three or more miscarriages is 0•7% (0•5% -0•8%).Risk factors for miscarriage include very young or older female age, older male age, very low or very high body mass index, black ethnicity, previous miscarriages, smoking, alcohol, stress levels, night shift working, air pollution and exposure to pesticides. The consequences of miscarriage are both physical, such as bleeding or infection, and psychological.Psychological consequences include increases in the risk of anxiety, depression, post-traumatic stress disorder and suicide. Miscarriage, and especially recurrent miscarriage, is also a sentinel risk marker for obstetric complications, including preterm birth, fetal growth restriction, placental abruption and stillbirth in future pregnancies, and a predictor of longer-term health problems, such as cardiovascular disease and venous thromboembolism.The costs of miscarriage affect individuals, healthcare systems and society at large. The short-term national economic cost of miscarriage is estimated to be £471 million per year in the United Kingdom. As recurrent miscarriage is a sentinel marker for various obstetric risks in future pregnancies, women should receive care in pre-conception and high-risk obstetric clinics. As psychological morbidity is common after pregnancy loss, effective screening instruments and treatment options for mental health consequences of miscarriage need to be available. We recommend that miscarriage data are gathered and reported to facilitate comparison of rates amongst countries, to accelerate research, and to improve patient care and policy development.

During the implantation window, the endometrium becomes poised to transition to a pregnant state, a process driven by differentiation of stromal cells into decidual cells (DC). Perturbations in this process, termed decidualization, leads to breakdown of the feto-maternal interface and miscarriage, but the underlying mechanisms are poorly understood. Here, we reconstructed the decidual pathway at single-cell level in vitro and demonstrate that stromal cells first mount an acute stress response before emerging as DC or senescent DC (snDC). In the absence of immune cell-mediated clearance of snDC, secondary senescence transforms DC into progesterone-resistant cells that abundantly express extracellular matrix remodelling factors. Additional single-cell analysis of midluteal endometrium identified DIO2 and SCARA5 as marker genes of a diverging decidual response in vivo. Finally, we report a conspicuous link between a pro-senescent decidual response in peri-implantation endometrium and recurrent pregnancy loss, suggesting that pre-pregnancy screening and intervention may reduce the burden of miscarriage.

SummaryThe fate of the human endometrium is determined during the mid-luteal window of implantation, coinciding with differentiation of endometrial stromal cells (EnSCs) into specialized decidual cells.In response to successful embryo implantation, differentiating EnSCs transform the endometrium into a decidua that maintains the placenta throughout gestation; whereas falling progesterone levels in the absence of pregnancy lead to tissue destruction and menstrual shedding. We used single-cell

Decidual remodelling of midluteal endometrium leads to a short implantation window after which the uterine mucosa either breaks down or is transformed into a robust matrix that accommodates the placenta throughout pregnancy. To gain insights into the underlying mechanisms, we established and characterised endometrial assembloids, consisting of gland-like organoids and primary stromal cells. Single-cell transcriptomics revealed that decidualized assembloids closely resemble midluteal endometrium, harbouring differentiated and senescent subpopulations in both glands and stroma. We show that acute senescence in glandular epithelium drives secretion of multiple canonical implantation factors, whereas in the stroma it calibrates the emergence of anti-inflammatory decidual cells and pro-inflammatory senescent decidual cells. Pharmacological inhibition of stress responses in pre-decidual cells accelerated decidualization by eliminating the emergence of senescent decidual cells. In co-culture experiments, accelerated decidualization resulted in entrapment of collapsed human blastocysts in a robust, static decidual matrix. By contrast, the presence of senescent decidual cells created a dynamic implantation environment, enabling embryo expansion and attachment, although their persistence led to gradual disintegration of assembloids. Our findings suggest that decidual senescence controls endometrial fate decisions at implantation and highlight how endometrial assembloids may accelerate the discovery of new treatments to prevent reproductive failure.