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Abstract
BackgroundRecurrent 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 FindingsAnalysis 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.ConclusionsImpaired 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.
Highlights
Miscarriage is the most common complication of pregnancy
Endometrial Decidualization Is Impaired in Recurrent pregnancy loss (RPL) We speculated that impaired decidualization of the stromal compartment may facilitate delayed implantation of compromised embryos by prolonging the window of endometrial receptivity, as suggested by the population study of Wilcox et al [7]
Transcript levels were determined in endometrial biopsies, timed to span the implantation window, from RPL patients and controls, consisting of either fertile or infertile women without a history of recurrent pregnancy failure (Table S1)
Summary
Miscarriage is the most common complication of pregnancy. It is estimated that 30% of embryos are lost prior to implantation (pre-implantation loss) and a further 30% before 6 weeks gestation (pre-clinical/biochemical pregnancy loss) [1]. Pregnancy loss is widely viewed as a dichotomous disorder, attributed either to maternal factors or chromosomal errors in the conceptus. Between 30 to 60% of miscarriages are attributed to fetal chromosomal anomalies [4] These estimates are based on conventional karyotyping of fetal tissues, suggesting that the true incidence may be higher. If chromosomal instability in the preimplantation embryo is the norm rather than the exception, RPL could primarily reflect inadequate embryo selection, accounting for the high prevalence of aneuploidic miscarriages. 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 be indispensable for placenta formation in pregnancy and for embryo recognition and selection at time of implantation
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