Events Leading to the Establishment of Pregnancy and Placental Formation: The Need to Fine-Tune the Nomenclature on Pregnancy and Gestation

Abstract

Today, there is strong and diversified evidence that in humans at least 50% of early embryos do not proceed beyond the pre-implantation period. This evidence comes from clinical investigations, demography, epidemiology, embryology, immunology, and molecular biology. The purpose of this article is to highlight the steps leading to the establishment of pregnancy and placenta formation. These early events document the existence of a clear distinction between embryonic losses during the first two weeks after conception and those occurring during the subsequent months. This review attempts to highlight the nature of the maternal-embryonic dialogue and the major mechanisms active during the pre-implantation period aimed at "selecting" embryos with the ability to proceed to the formation of the placenta and therefore to the completion of pregnancy. This intense molecular cross-talk between the early embryo and the endometrium starts even before the blastocyst reaches the uterine cavity, substantially initiating and conditioning the process of implantation and the formation of the placenta. Today, several factors involved in this dialogue have been identified, although the best-known and overall, the most important, still remains Chorionic Gonadotrophin, indispensable during the first 8 to 10 weeks after fertilization. In addition, there are other substances acting during the first days following fertilization, the Early Pregnancy Factor, believed to be involved in the suppression of the maternal response, thereby allowing the continued viability of the early embryo. The Pre-Implantation Factor, secreted between 2 and 4 days after fertilization. This linear peptide molecule exhibits a self-protective and antitoxic action, is present in maternal blood as early as 7 days after conception, and is absent in the presence of non-viable embryos. The Embryo-Derived Platelet-activating Factor, produced and released by embryos of all mammalian species studied seems to have a role in the ligand-mediated trophic support of the early embryo. The implantation process is also guided by signals from cells in the decidualized endometrium. Various types of cells are involved, among them epithelial, stromal, and trophoblastic, producing a number of cellular molecules, such as cytokines, chemokines, growth factors, and adhesion molecules. Immune cells are also involved, mainly uterine natural killer cells, macrophages, and T cells. In conclusion, events taking place during the first two weeks after fertilization determine whether pregnancy can proceed and therefore whether placenta's formation can proceed. These events represent the scientific basis for a clear distinction between the first two weeks following fertilization and the rest of gestation. For this reason, we propose that a new nomenclature be adopted specifically separating the two periods. In other words, the period from fertilization and birth should be named "gestation", whereas that from the completion of the process of implantation leading to the formation of the placenta, and birth should be named "pregnancy".

Keywords: early embryonic loss; early pregnancy factor; embryo-derived platelet-activating factor; gestation; pre-implantation factor; pregnancy.

Figure 1

Schematic representation of the main phases of human implantation: apposition, adhesion/attachment, invasion/penetration, and decidualization. (A) (Apposition): the blastocyst expresses L-selectin that reacts with its ligands. The presence of Mucin-1 repels the blastocyst and prevents it from attaching outside of the window of receptivity. (B) (Adhesion): the blastocyst promotes cleavage of Mucin-1 at the implantation site to ensure successful attachment. (C) (Invasion): blastocyst trophoblast cells penetrate the endometrial epithelium and reach the stroma. As soon as implantation is initiated and the embryo reaches the stromal cells surrounding the embryo, these transform into decidualized cells. (D) (Decidualization): during the decidualization process, immune cells, such as macrophages and uterine natural killer (uNK) cells, play an important role promoting an environment conducive to successful implantation. Reprinted with permission from: Ochoa-Bernal and Fazleabas (2020) [42].

Figure 2

Positive and negative mechanisms contribute actively to the selection of human embryos at implantation. (A) Developmentally competent human embryos secrete serine proteases that activate epithelial Na1 channel (ENaC) that induce genes involved in implantation and post-implantation embryo development. (B) Developmentally compromised embryos By contrast, induce excessive protease activity, leading to accumulation of misfolded proteins and ER stress, compromising decidual cell functions and triggering early maternal rejection. From: Brosens JJ et al. (2014) [44].