Normal Physiology of Placentation
Erin H. Burnett
INTRODUCTION
The placenta is a unique organ that has numerous functions; however, in order for the placenta to function appropriately, a gamut of precise processes need to occur. The development of the placenta begins at implantation and should be complete by the end of the first trimester.1 The placenta’s primary purpose involves exchange of oxygen and nutrients and the removal of waste. A properly attached placenta and therefore properly functioning placenta is vital, as it must deal with the large majority of uterine blood flow.
Overall, the placenta is a mysterious yet magnificent organ, and although we continue to learn more about it, there are still so many aspects that are puzzling and not fully explained. The aim of this chapter is to describe the “normal” aspect of implantation and placental development to help readers in understanding and recognizing abnormal placentation discussed in other chapters.
PREIMPLANTATION (FIGURE 3-1)
The fallopian tubes most frequently serve as the site of fertilization. The fertilized ovum (zygote) transitions to a solid mass of cells (morula) as it moves through the fallopian tube on its way to the uterus. The embryo has a protective covering called the zona pellucida, which serves as a protective coating during the transit. This coating prevents the embryo from sticking to the sides of the tube. Even before the embryo makes its way to the uterus, decidualization has already begun in the midsecretory phase of the menstrual cycle.2 Rising progesterone levels halt proliferation and cause endometrial and stromal cells to begin to differentiate.2 The glandular cells also prepare for implantation by producing secretory products and cytokines.3,4 Stromal cells also play a role in preparation, and natural killer cells accumulate. The uterine vasculature is directed to have increased permeability, and the capillary network matures in preparation of implantation.5 The overall process of decidualization provides maternal immune tolerance, along with protection to the fetus and regulation of placentation.6
The morula usually arrives in the uterus around 3 days post fertilization.7 The morula becomes more organized at day 5 to 6 and is then referred to as a blastocyst, which contains an inner and outer cell mass. The outer cell mass, the trophoblast, forms the placenta and fetal membrane, and an inner cell mass, forms the embryo (Figure 3-2).8
 FIGURE 3-1 Normal female anatomy depicting the normal location for various stages of fertilization and implantation. (Reprinted with permission from the Anatomical Chart Company. “Infertility Anatomical Chart.” Lippincott Williams & Wilkins; 2004.) |
The blastocyst also has the very distinctive feature of a fluid filled cavity. This fluid helps the blastocyst expand and contract which allows it to “hatch” from the zona pellucida, therefore preparing it for implantation. After hatching, uterine secretions help support the embryo by providing oxygen and nutrients.8 Due to the rapidly increasing demand of the embryo, these secretions will become inadequate within 24 hours; therefore, the cell must implant to survive.
 FIGURE 3-2 Blastocyst with outer trophoblast (green) and inner cell mass (blue) The inner cell mass gives rise to the entire embryo and is displaced to one pole of the blastocyst, the embryonic pole; the outer cell mass forms the outer layer of the blastocyst and contributes to development of the placenta. (Adapted from Sadler TW. Langman’s Essential Medical Embryology. Wolters Kluwer Health and Pharma; 2004 [Figure 2-1].) |
ANATOMY OF THE ENDOMETRIUM
While the blastocyst prepares to implant, estrogen and progesterone prepare the endometrium of the uterus. Stromal cells enlarge and become surrounded by edematous fluid and glycogen fills the glandular cells.1 The endometrium, also known as the decidua, is made up of three layers and will be shed at the end of the pregnancy, the stratum compactum, stratum spongiosum, and stratus basalis. The surface layer (stratum compactum) has very few glands, but the middle, stratum spongiosum, contains many glands and vessels, which serve as the target for the invading blastocyst (Figure 3-3).1
STAGES OF IMPLANTATION
Successful implantation and invasion requires complex interaction between a receptive uterus and a mature and appropriately functioning blastocyst.7 Attraction to certain regions of the endometrium occurs in response to molecular signals expressed on the respective surfaces. Implantation starts around day 6 to 7 and is thought to occur in three stages discussed below.
Stage 1: Apposition
The initial stage involves the initial contact with the endometrium. The blastocyst then rolls against the wall and adhesion of the blastocyst to the uterine wall occurs; this is referred to as apposition.7 The trophoblast, outside layer of the blastocyst, proliferates and divides into layers, the cytotrophoblast and the syncytiotrophoblast. The inner layer, cytotrophoblast, forms the foundation of the chorionic villi and placenta. The outer layer, syncytiotrophoblast, secretes enzymes assisting with implantation and will expand into the placenta parenchyma (Figure 3-4).8
 FIGURE 3-3 Endometrium layers of the uterus. |
 FIGURE 3-4 Blastocyst beginning implantation into the uterus. (Modified from Sadler TW. Langman’s Essential Medical Embryology. © Wolters Kluwer Health and Pharma; 2004 [Figure 2-1].) |
Stage 2: Adhesion
This second stage is known as “adhesion.”7 At day 7 to 8, the cells on the outside of the blastocyst show increased physical attraction and the trophectoderm, a trophoblast that has completed gastrulation, sticks to the uterine epithelium.
Stage 3: Invasion and Uteroplacental Circulation
The third stage known as “invasion” begins during day 8 to 9 and is characterized by the syncytiotrophoblasts penetrating the uterine epithelium (see Figure 3-5). The syncytiotrophoblasts provide the barrier to maternal blood and help regular oxygen and protein transport.9 Invasion stage peaks between weeks 9 to 12 of pregnancy.
At day 10, the blastocyst should be completely buried in the subepithelium and the uterine epithelium has covered the implantation site.10 Interstitial and
endovascular invasion occur next as the cytotrophoblasts exude out of the trophoblastic shell and then invade the endometrium and eventually the maternal uterine vasculature.11
endovascular invasion occur next as the cytotrophoblasts exude out of the trophoblastic shell and then invade the endometrium and eventually the maternal uterine vasculature.11
 FIGURE 3-5 Implantation site at approximately 2 weeks of gestation. The finger-like trophoblastic projections represent primary stem villi and are closely associated with lacunae filled with maternal blood. Note that the endometrial surface has been reepithelialized by this stage of development (lower left). |
This anchoring officially begins the process of placentation, by creating a uteroplacental circulation through placing fetal trophoblasts directly in contact with maternal blood. Trophoblasts are thought to normally invade through the endometrium in the inner third of the myometrium.12 The interstitial trophoblasts target the myometrial tissue, and the endovascular trophoblast aim for remodeling the maternal spiral arteries.
Role of Regulatory Proteins and Decidual Natural Killer Cells in Successful Placentation
In order to assist in the process, proteases breakdown the basement membrane to allow stable anchoring.13 Hepatocyte growth factor14 and epidermal growth factor (EGF)15 serve to stimulate trophoblast migration, while interferon-γ (IFN-γ) and transforming growth factor-β (TGFB) limit trophoblastic invasion.16 Decidual natural killer cells (dNKs) account for 70% of the immune cells recruited during this process, and they assist in regulating cellular interactions.17 dNKs are thought to have significant contribution to successful placentation (see Figure 3-6). One main role includes expressing cytokines and chemokines, which signal to trophoblasts, therefore helping to regulate invasion.18 dNKs also can influence uterine vascular cells via their expression of pro-and antiangiogenic factors.18,19 In order for placentation and remodeling to be successful, a careful balance must be achieved between all the regulatory proteins.14
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