Background: Recurrent pregnancy loss (RPL), defined as 3 or more consecutive miscarriages, is widely attributed either to
repeated chromosomal instability in the conceptus or to uterine factors that are poorly defined. We tested the hypothesis
that abnormal cyclic differentiation of endometrial stromal cells (ESCs) into specialized decidual cells predisposes to RPL,
based on the observation that this process may not only be indispensable for placenta formation in pregnancy but also for
embryo recognition and selection at time of implantation.
Methodology/Principal Findings: Analysis of mid-secretory endometrial biopsies demonstrated that RPL is associated with
decreased expression of the decidual marker prolactin (PRL) but increased levels of prokineticin-1 (PROK1), a cytokine that
promotes implantation. These in vivo findings were entirely recapitulated when ESCs were purified from patients with and
without a history of RPL and decidualized in culture. In addition to attenuated PRL production and prolonged and enhanced
PROK1 expression, RPL was further associated with a complete dysregulation of both markers upon treatment of ESC
cultures with human chorionic gonadotropin, a glycoprotein hormone abundantly expressed by the implanting embryo. We
postulated that impaired embryo recognition and selection would clinically be associated with increased fecundity, defined
by short time-to-pregnancy (TTP) intervals. Woman-based analysis of the mean and mode TTP in a cohort of 560 RPL
patients showed that 40% can be considered ‘‘superfertile’’, defined by a mean TTP of 3 months or less.
Conclusions: Impaired cyclic decidualization of the endometrium facilitates implantation yet predisposes to subsequent
pregnancy failure by disabling natural embryo selection and by disrupting the maternal responses to embryonic signals.
These findings suggest a novel pathological pathway that unifies maternal and embryonic causes of RPL.