Early pregnancy loss is defined as the termination of pregnancy before 20 weeks of gestation or a foetal weight of less than 500g. It is a very common incident with the majority of spontaneous miscarriages happening within the first 12 weeks of pregnancy. It accounts for over 50,000 hospital admissions in the UK annually where 85% of spontaneous miscarriages occur within the first trimester, (Newson, 2015). The maximum chance of getting pregnant with optimum conditions is 30-40% during a normal menstrual cycle but subsequently it usually results in an early loss of pregnancy, (Macklon et al, 2002). There are many factors which contribute to this loss, chromosomal, endocrine and uterine abnormalities as well as many lifestyle factors.
Before any early embryo development fertilisation must occur to form a conceptus. Fertilisation is the combination of two different gametes to produce a conceptus with a diploid set of chromosomes. Fertilisation occurs in the ampulla region of the uterine tube. The facilitation of the movement of the newly formed conceptus is provided by the cilia present in the uterine tube which help transport the conceptus down the tube in uterine fluid ready for implantation into the endometrium. Within 24 hours of fertilisation quick mitotic cell divisions happen, known as cleavage, (Schoenwolf & Larsen, 2009). These allow the subdivision of cells but prevent the conceptus growing due to the zona pellucida preventing any further growth. The subdivisions of cells are blastomeres. The cells continue to divide but by 16-32 cells a process known as compaction occurs where the conceptus is known as a morula. This is due to the fact that there is a polar phenotype developing, an apical and basal domain. These domains allow the differentiation of two new cell types, trophoblasts and inner cell mass. Trophoblasts are the outer layer of cells surrounding the conceptus which provides nutrients before the establishment of the placenta and then later on develops into the placenta. The inner cell mass are a small cluster of cells which will eventually become the definitive structures of the foetus, lying in the blastocoelic cavity, (figure 1). Together these make the blastocyst which is what will leave the uterine tube by the end of the 6th day after fertilisation, and will subsequently implant into the endometrium, (Watson & Barcroft, 2001).
Figure 1 shows the steps undertaken to form a blastocyst once fertilisation has happened, (https://ib-biology2010-12.wikispaces.com/Human%20Reproduction)
Before implantation, the blastocyst must hatch out of zona pellucida to facilitate implantation. The zona pellucida is vital for the maintenance of the conceptus but also to prevent 2 genetically different conceptuses from interacting with one another. However, the stretched zona pellucida develops a crack allowing the blastocyst to use enzymes to squeeze out by a process known as Zona hatching. The blastocyst is now able to directly interact with the endometrium (Schoenwolf & Larsen, 2009).
Changes in Endometrium
Implantation is the attachment of a conceptus to the endometrium lining of the uterus for successful growth and survival.
For successful implantation, both the blastocyst and the endometrium need to be ready for the changes which will subsequently occur. The endometrium is constantly changing due to the menstrual cycle under the influence of hormones, primarily as progesterone and oestrogen. Subsequently, there is only a small period of receptivity of the endometrium to allow implantation of the blastocyst, the implantation window lasting for only 4 days, (Elnashar & Aboul-Eneih, 2004). During the early stages of implantation and pregnancy, progesterone is needed to maintain the endometrium and allowing it to be in a receptive state ready for the conceptus.
Endometrial microvilli briefly fuse to become large ectoplasmic protrusions, known as pinopodes; they are initiated by the influence of progesterone to help endocytose uterine fluid, decreasing the overall volume of the uterus, bringing in the walls closer for the conceptus to adhere and remain fixed on the wall. They help to show how receptive the endometrium is towards a conceptus in a human, (Nikas & Psychoyos, 1997).
There is also an increase in secretions from epithelial glands which is also due to increasing progesterone levels. The secretions help to secrete nutrients into the uterine cavity, used by conceptus whilst there has been no decidualisation or placenta formation yet.
Progesterone is constantly being secreted by the corpus luteum to maintain pregnancy by helping to change the receptiveness of the endometrium. Decidualisation is a process in which the endometrium thickens and becomes vascularised to support the blastocyst when it attaches to the wall. The main difference is the stromal cell as the overall cell morphology changes going from a small spindle shape to a much larger, plumper secretory decidual cell. These decidual cells form a pericellular rim of extracellular matrix which is required for the trophoblasts to move towards arteries and myometrium. It is under the influence of a protein, Insulin like growth factor binding protein-1 (IGFBP-1), (King, 2000). The decidua remains during the first trimester but will be subsequently replaced by the placenta later on.
The Luteo-placental shift is a very important event which happens in regards to the production of progesterone and oestrogen. Originally the corpus luteum secretes mainly progesterone during the early stages, but the corpus luteum has a very short life span of only a couple of weeks. This would mean that after a few weeks, there would be a significant drop in progesterone secretion leading to loss of conceptus as the endometrium cannot maintain the pregnancy, (Johnson & Everitt, 2007). Human Chorionic Gonadotrophin hormone (hCG) is produced by the synctiotrophoblast and helps to rescue the corpus luteum, binding to the corpus luteum receptors producing progesterone, until the seventh week of pregnancy. By the seventh week the placenta is developed and will take over progesterone secretion throughout the rest of the pregnancy, (Finlayson, 2007).
Implantation begins when the blastocyst comes into contact with the uterine wall and tends to happen in 3 steps- : Apposition, Adhesion and Invasion.
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