The molecular basis of recurrent pregnancy loss: impaired natural embryo selection

G. Teklenburg 2 Madhuri Salker 1 Cobi Heijnen 2 Nick S. Macklon 0 2 Jan J. Brosens 1 0 Division of Developmental Origins of Adult Diseases (DOHaD) , Level F , University of Southampton, Princess Anne Hospital , Coxford Road, Southampton SO16 5YA , UK 1 Institute of Reproductive and Developmental Biology, Imperial College London, Hammersmith Hospital , London W12 ONN , UK 2 Department of Reproductive Medicine and Gynaecology, University Medical Center Utrecht , PO Box 85500, 3508 GA Utrecht , The Netherlands Recurrent pregnancy loss (RPL) is a common and distressing disorder. Chromosomal errors in the embryo are the single most common cause, whereas uterine factors are invariably invoked to explain non-chromosomal miscarriages. These uterine factors are, however, poorly defined. The ability of a conceptus to implant in the endometrium is normally restricted to a few days in the menstrual cycle. A limited 'window of implantation' ensures coordinated embryonic and endometrial development, thereby minimizing the risk of late implantation of compromised embryos. In this paper, we review emerging evidence, indicating that RPL is associated with impaired differentiation of endometrial stromal cells into specialized decidual cells. From a functional perspective, this differentiation process, termed decidualization, is not only critical for placental development but also signals the end of the implantation window and bestows on the endometrium the ability to recognize, respond to and eliminate implanting compromised embryos. Thus, we propose that spontaneous decidualization of the human endometrium, which inevitably causes menstrual shedding in the absence of a viable conceptus, serves as functional 'window for natural embryo selection'. Conversely, impaired decidualization predisposes to late implantation, negates embryo quality control and causes early placental failure, regardless of the embryonic karyotype. This pathological pathway also explains the common observation that many RPL patients seem exceptionally fertile, often conceiving within one or two cycles. Thus, as the clinical correlate of inappropriate uterine receptivity, 'superfertility' should be considered as a genuine reproductive disorder that requires targeted intervention. - Put simply, pregnancy requires little more than implantation of a developmentally competent embryo into the receptive endometrium. In many species, pregnancy is readily achieved and maintained. In humans, however, the prevalence of subfertility is high and increasing, affecting one in six couples in developed countries (Evers, 2002). Fertility can be measured by the time taken to achieve pregnancy. Time-to-pregnancy (TTP) is expressed in monthly fecundity rates (MFRs), i.e. the probability of achieving pregnancy within one menstrual cycle. The average MFR in humans is, compared with other mammalian species, relatively low at 20% (Stevens, 1997; Viudes-de-Castro and Vicente, 1997; Evers, 2002). On the basis of this MFR, a simple mathematical model predicts that 74, 93 and 100% of normally fertile couples will conceive in 6, 12 and 24 months, respectively. Along the same lines, moderate and severe subfertilities have been defined by MFRs of 5 and 1%, respectively (Evers, 2002). At the other end of the spectrum, superfertility can be characterized with MFRs of 60% or more. According to this model, superfertile couples achieve 94 and 100% of pregnancies within 3 and 6 months, respectively. On the basis of the Tietze model (Tietze et al., 1950; Evers, 2002), it has been estimated that 79% of the population is fertile, 18% subfertile or infertile and 3% superfertile. In addition to subfertility, the incidence of embryo wastage and pregnancy loss is also extraordinarily high in humans, estimated to be 30% prior to implantation (preimplantation loss), a further 30% before 6 weeks gestation (early pregnancy loss or EPL) and 10% of clinical pregnancies, mostly prior to 12 weeks gestation (Chard, 1991; Macklon et al., 2002) (Fig. 1). A recent study has shown that this preclinical pregnancy wastage does not present as subfertility and is therefore an additional reproductive challenge in humans & The Author 2010. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: (Koot et al., 2010). Moreover, 1 2% of couples experience recurrent pregnancy loss (RPL), defined in Europe as three or more consecutive miscarriages (Jauniaux et al., 2006; Rai and Regan, 2006). From a clinical perspective, miscarriage, whether sporadic or recurrent, is widely viewed as a dichotomous disorder, attributed either to chromosomal or other developmental abnormalities in the embryo or to uterine factors. Although numerous anatomical, endocrine, immunological, thrombophilic and genetic perturbations have been invoked to explain non-chromosomal miscarriages, none of these are specific or prevalent (Jauniaux et al., 2006; Rai and Regan, 2006). In fact, the current paradigm of RPL and its management are firmly anchored in the conjecture that pre-existent disease, often much more relevant to subfertility, also underpins RPL. In our clinical experience, however, many women with RPL, especially those who have experienced many consecutive losses, report exceptionally high pregnancy rates. A retrospective analysis of TTP in 560 recurrent miscarriage patients revealed that 40% could be considered as superfertile, here defined as a mean TTP of 3 months or less (Salker et al., 2010). If confirmed, the incidence of superfertile patients suffering from RPL is remarkable, especially as the likelihood of conception is dependent upon many variables, including timing and frequency of coitus and the presence or absence of coexisting disorders, such as suboptimal sperm quality or ovulatory, tubal and uterine defects. Superfertility in humans is currently only an anecdotal concept without obvious clinical connotations. Even in a broader biological context, superfertility is a rare phenomenon, ascribed only to certain breeds of sheep. For example, the Inverdale (FecXI) sheep carries a naturally occurring X-linked mutation in the BMP15 gene, which encodes bone morphogenetic protein 15, that causes an increased ovulation rate and twin and triplet births in heterozygotes (Galloway et al., 2000). Although often referred to as superfertile, reproduction in these animals is in fact characterized by increased prolificacy, not fertility. In the absence of informative animal models, the concept of superfertility as a pathological entity must at least have a plausible biological basis. To examine if there could be a basis for superfertility in humans, we will first discuss the two defined functional periods within the menstrual cycle, one on each side of ovulation, known to determine the rate of conception and pregnancy (Dunson et al., 1999). These functional periods are known as the fertile (...truncated)