Maternal selection of human embryos in early gestation: Insights from recurrent miscarriage

Abstract

Compared to most mammals, human pregnancy is unusual in that it involves chromosomally diverse embryos, cyclical breakdown and regeneration of the uterine mucosa, and intimate integration of fetal and maternal cells at the uteroplacental interface. Not surprisingly, pregnancy often falters in early gestation. Whether these losses result in clinical miscarriages depends on the origins and impacts of chromosomal errors on fetal development and the ability of the decidualizing endometrium to engage in embryo biosensing and selection. Aneuploidy originating in oocytes during meiosis drives the age-related risk of miscarriage. By contrast, the frequency of endometrial cycles with an impaired decidual response may account for the stepwise increase in miscarriage rates with each pregnancy loss independently of maternal age. Additional physiological mechanisms operate in early gestation to ensure that most failing pregnancies are lost before vascular maternal-fetal connections are established by the end of the first trimester. Here, we summarise how investigations into the mechanisms that cause miscarriage led to new insights into the processes that govern maternal selection of human embryos in early gestation.

Keywords: Aneuploidy; Decidualization; Embryo; Endometrium; Miscarriage; Placenta; Selection.

Figure 1.

Risks of miscarriage. (A) Composite graph showing risk of miscarriage according to maternal age. Superimposed are the age-dependent incidences of oocyte/embryo aneuploidy and aneuploid miscarriage. The composite graph is based on data extracted from several studies [, –9]. (B) Miscarriage rates increase with maternal age and with each additional miscarriage. The term ‘recurrence risk’ of miscarriage denotes the stepwise increase in miscarriage rates, independently of maternal age, interpregnancy interval, or a previous live birth. Adapted from Kolte and colleagues [6], with permission.

Figure 2.

Tests for success. (A) Several physiological mechanisms limit the risk of prolonged maternal investment in a failing pregnancy. The ‘blastocyst checkpoint’ refers to embryo-intrinsic mechanisms that balances developmental arrest with self-correction in response to different levels of mosaicism. The ‘implantation checkpoint’ involves biosensing of the conceptus by encapsulating maternal decidual cells, whereas the ‘fitness checkpoint’ refers to the maintenance of ovarian progesterone production in response to embryonic fitness signals, such as hCG. Marked vascular changes impose a further stress-test on the decidual-placental interface at the end of the first trimester. EpC, epithelial cells; DSC, decidualized stromal cells; SCT, syncytiotrophoblast; VCT, villous cytotrophoblast; CS, cytotrophoblast shell; EVT, extravillous cytotrophoblast; TGC, trophoblast giant cells; LMP, last menstrual period. (B) Transition of the cycling endometrium into the decidua of pregnancy requires cooperation between decidual cells and uNK cells to eliminate senescent decidual cells. SASP, senescence-associated secretory phenotype; IL-15, interleukin 15. (C) Endometrial fate decisions at implantation pivot on the balance between decidual subsets. Lack of BMPC and /or loss of uterine natural killer (uNK) cell activity drive a pro-senescent decidual response that renders uteroplacental interface vulnerable to tissue breakdown.

Figure 3.

Predicted impact of implantation checkpoint failure on recurrence risk of miscarriage. (A) The implantation checkpoint hypothesis posits that the decidualizing endometrium mounts a tailored response to individual embryos, eliminating developmentally compromised embryos (leading to occult losses) but supporting competent embryos (leading to successful pregnancies). Checkpoint failure means that aneuploid embryos will escape detection (leading to aneuploid miscarriages), whilst euploid pregnancies will fail because the endometrium is unsupportive and prone to breakdown (leading to euploid miscarriages). Four scenarios can be considered in which the embryo is either euploid (E) or aneuploid (A) and the endometrium has either a normal (N) or failed (F) checkpoint, leading to three clinical outcomes: no pregnancy (occult loss), miscarriage, or live birth. (B) Predicted miscarriage rates with increasing frequency of cycles with implantation checkpoint failure. The predicted rates are compared to reported miscarriage rates associated with increasing number of pregnancy losses. *Based on 30% aneuploidy rate; ^†indicated number of previous miscarriages or more; ^‡two and three previous miscarriages were combined in this study.