Stalling of the endometrial decidual reaction determines the recurrence risk of miscarriage risk
In each menstrual cycle, progesterone acting on estrogen-primed endometrium elicits an inflammatory decidual reaction, rendering it poised for embryo implantation and transformation into the decidua of pregnancy. Here, we show that the sequential functions of the decidual reaction - implantation and decidualization - pivot on the time-sensitive loss of progesterone-resistant stromal cells that form a transient implantation niche and reciprocal expansion of progesterone-responsive pre-decidual cells. In parallel, proliferation and differentiation increase the abundance of immunotolerant uterine natural killer (uNK) cells. Examination of pre-pregnancy endometrial biopsies from 924 women revealed that the frequency of cycles culminating in a blunted or stalled decidual reaction closely aligns with the age-independent recurrence risk of miscarriage. Further, analysis of 632 biopsies obtained in different cycles from 316 women indicated that prior miscarriages disrupt intercycle endometrial homeostasis, an observation supported by modelling the impacts of prolonged decidual inflammation in three-dimensional endometrial assembloids. Although stalling of the decidual reaction is often accompanied by a poor expansion of immunotolerant uNK cells, miscarriages do not impact intercycle uNK cell dynamics. Our findings indicate that intrinsic uterine mechanisms hardwire the recurrence risk of miscarriage, underscoring the need for pre-pregnancy diagnostics and therapeutics. One Sentence SummaryThe frequency of menstrual cycles culminating in a suboptimal decidual reaction determines the recurrence risk of miscarriage.