I-32: Implantation and Recurrent PregnancyLoss

Background: Recurrent pregnancy loss (RPL), defined as 3 or more consecutive pregnancy failures, is a common and distressing disorder. Chromosome instability in the conceptus is the most common cause whereas uterine factors are invariably invoked to explain nonchromosomal miscarriages. These uterine factors are, however, poorly defined. Materials amd Methods: Laboratory-based analysis of endometrial biopsies, primary endometrial cultures and co-cultures with human blastocysts. Results: Implantation coincides with the differentiation of endometrial stromal cells (ESCs) into specialized decidual cells, which in pregnancy control trophoblast invasion and placenta formation. We investigated the soluble factors involved in crosstalk between decidualizing ESCs and the implanting embryo using a human co-culturemodel. Multiplex immunoassay analysis of culture supernatants demonstrated that decidual cells selectively recognize developmentally impaired embryos and respond by inhibiting the secretion of a panel of implantation and inflammatory modulators. Undifferentiated cells do not mount such a response, suggesting that adequate decidualization of the endometrium is essential not only for normal pregnancy but also for recognition and elimination of compromised conceptions. We demonstrate that the ability of ESCs to express a decidual phenotype is grossly impaired in RPL patients and characterized by prolonged and enhanced expression of the pro-implantation cytokine prokineticin-1 (PROK1) and attenuated prolactin (PRL) production, a sensitive marker of the decidual response. RPL was further associated with a complete dysregulation of PROK1 and PRL expression in response to human chorionic gonadotropin signaling. We postulated that impaired maternal recognition and selection of invasive but compromised embryos would lead to enhanced fecundity, defined by short time-topregnancy (TTP) intervals. To test this hypothesis, we analysed the TTP in 2076 pregnancies reported by 560RPL patients. Woman-based analysis of the mean and mode TTP showed that many RPL patients are highly fecund and 40% of patients can be considered ’superfertile’, defined by a mean TTP of 3 months or less. Conclusion: Decidualization of the endometrium is essential to establish a functional feto-maternal interface. We found that decidual cells also selectively recognize compromised human embryos and, conversely, that failure to express an adequate decidual phenotype disrupts the maternal response to embryonic signals and negates embryo selection at the time of implantation. These observations indicate that the decidualizing endometrium serves as a biosensor for embryo quality and establish a unifying mechanism for both euploidic and aneuploidic recurrent pregnancy failure.