First Week of Development

The first week of development coincides with the third week of pregnancy. Pregnancy is dated from the day of the last period (menses) of a woman. Ovulation takes place approximately two weeks after the last menses, i.e. in the 3^rd week of pregnancy’ to be followed by cleavage and subsequent stages of the embryonic development. During the first two weeks of pregnancy there is no developing embryo, but a cohort of ovarian follicles are growing under the influence of FSH in preparation for ovulation of the oocyte which is going to be fertilized. Fertilization takes place in the third week followed by cleavage, morula formation and blastula formation, and implantation in the same week. Thus, the developmental events that take place in the first week of embryonic development are cleavage, morula formation and blastula formation, and implantation. Implantation takes place 6-12 days after ovulation and accordingly may take place in the second week of embryonic development.

Cleavage

Cleavage is the series of rapid mitotic divisions that follow fertilization of and ovum whereby the diploid (2N) ovum proliferates to produce a progeny of diploid embryonic cells known as blastomeres. The cleavage divisions are rapid cell divisions that do not allow for the growth of the daughter cells and thus lead to an increase in the number of cells without an increase in the original size of the zygote. These cleavage divisions take as the zygote moves through the fallopian tube towards the uterine cavity. The mitotic divisions which commence with the first cleavage division will continue throughout the prenatal and postnatal life, but it is only the first few (3-4) divisions that are referred to as the cleavage divisions. The size of the blastomeres decreases gradually as cleavage divisions proceed.   

Fig. 4.1. The illustration on the left two blastomeres that resulted from the first cleavage division; they are surrounded and held together by a prominent zona pellucida. The polar bodies have not completely degenerated. The illustration on the right shows four blastomeres that resulted from the second cleavage division; they are still surrounded and held together by a prominent zona pellucida. The fertilized ovum has so far yielded four cells, but their total size is more or less the same size of the ovum. Cell divisions are rapidly giving no room for daughter cell growth before the succeeding division.

Morula Stage

The cleavage divisions continue almost at the same pace until a solid ball of cells called a morula is formed. This stage is characterized by a compact mass of cells about the size of the zygote and still enclosed by the zona pellucida. The morula blastomeres continue to divide while the morula is rolled down the fallopian tube towards the uterus. It reaches the uterus at about the middle of the first week of embryonic development, around the fourth day after fertilization. By the end of the first week, the zygote transforms into a blastocyst, a hollow ball of cells with a fluid-filled cavity. Until this stage (16 to 32-cell stage) the blastomeres are totipotent capable of producing all the different types of the body cells and the fetal membranes.

Fig. 4.2. The illustrations show the morula as a spherical mass of blastomeres surrounded by the zona pellucida, and about the size of the zygote.

Blastula Stage

As embryonic development proceeds, a fluid begins to accumulate within the morula, forming a central cavity called the blastocoel. Cell junctions (desmosomes and gap junctions) appear between the outer cells of the morula, binding them with each other. These junctions hold the cell tightly and the cell boundaries become indistinct; this process of tightening is called compaction. The cells then gradually differentiate into two distinct populations: an inner collection of cells constituting the inner cell mass or embryoblast, and the outer cell layer known as the trophoblast. This is accompanied by the formation of a distinct fluid filled cavity within the spherical mass of cell. The cavity is known as the blastocoele and thus the solid morula transforms into a hollow spherical body known as blastula or blastocyst. The blastocyst loses the surrounding zona pellucida around the fifth day; this allows the developing embryo to become larger in size in preparation for implantation.  Cells of the inner cell mass are pluripotent and will give rise to all different cell of the body of the embryo. Blastula formation takes place on the 5^th or 6^th day of the first week of embryonic development.

Fig. 4.3. The illustrations show the blastula (blastocyst) as hollow spherical mass of embryonic cells having two populations of cells, cells of the inner mass and cell of trophoblast surrounding the blastocoele. The blastocyst on the right is at a slightly advanced stage compared to the one on the left.

Implantation

Implantation is the process of burrowing of the blastocyst into the uterine wall; it is the process whereby the blastocyst embeds into the endometrial lining of the uterus. It is a crucial step in embryonic development that ensures a connection between the developing embryo and the maternal blood supply. By the 5^th or 6^th day 5-6 day of the first week of embryonic development, the freely floating blastocyst approaches uterine endometrium.

Fig. 4.4. The illustration shows a blastocyst approaching the endometrium, with inner cell facing towards endometrial epithelium.

The endometrium and Implantation

The endometrium consists of an epithelium and the underling connective tissue lamina propria. It comprises three layers known as the stratum basale (deepest layer), the stratum spongiosum and the stratum compactum (the superficial most layer). The stratum spongiosum (spongy layer) and the stratum compactum (compact layer) together form the functional layer of the endometrium. The uterine epithelium is a simple columnar epithelium, likewise the uterine glands which are simple tubular glands are lined with a simple columnar epithelium. Morphology of the uterine endometrium fluctuates in response to ovarian hormones forming a uterine endometrial cycle that parallels the ovarian cycle. Whereas the ovarian cycle comprises a follicular phase and a luteal phase, the endometrial cycle comprises a proliferative phase, a secretory phase and a menstrual phase.

Fig. 4.5. The H&E0stained section of the uterine wall on the left show the functional and basal layers of the endometrium and the myometrium. The endometrium consists of an epithelium and the underlying lamina propria. The lamina propria contains tortuous simple tubular uterine glands. The illustration on the right shows the epithelium as a simple columnar epithelium and the lamina propria is loose connective tissue.

During the menstrual phase (day 1-5) the functional layer of endometrium is sloughed off and lost. The proliferative phase of the endometrial cycle (days 5-14) the uterine endometrium thickens in response to an increased level of estrogens. Estrogen induces profound proliferation of the endometrial glandular epithelial cells and stromal cells of the lamina propria. This phase precedes ovulation and prepares the endometrium for implantation of an embryo. The secretory phase begins at ovulation and extends to the of the cycle i.e. it spans between days 15 and 28. During the secretory phase the endometrial glands elongate greatly, become highly coiled, and synthesize large amounts of glycogen. During this phase produce large quantities of a secretion rich glycogen to provide nourishment for the implanted embryo. These changes in the endometrium are brought about by high levels of progesterone produced by the corpus luteum of the ovary.   

Stages of Implantation

The blastocyst implantation is accomplished in several steps or stages; these are the migration, hatching, precontact, attachment, adhesion and invasion.

Migration is the movement of the embryo from the site of fertilization in the oviduct to the site of implantation in the uterine endometrium. Hatching is the process whereby the blastocyst gets rid of the zona pellucida; it occurs 1-3 days after the blastocyst enters the uterus. Hatching makes it possible for the blastocyst to grow in size and to attach itself to the uterine epithelium. It takes place about 6-7 days after fertilization. The attachment or adhesion takes after the endometrium has entered the secretory phase; at this stage the uterine epithelium becomes receptive. The attachment and hence the implantation site is usually in the upper posterior uterine wall in the midsagittal plane. During implantation the endometrial vascular permeability markedly increases; this is mediated by prostaglandins. Stromal cells surrounding the implanting blastocyst differentiate into specialized cells called decidual cells. Adhesion of the trophoblast cells of the blastocyst to endometrial epithelial cells is mediated by cell adhesion molecules including integrins and cadherins. The process of implantation of the blastocyst allows its trophoblast cells to invade and migrate into the maternal decidua. By this time the trophoblast has differentiated into two layers, the cytotrophoblast and the syncytiotrophoblast. The cytotrophoblast is made of single whereas the syncytiotrophoblast is a multinucleated syncytium. The syncytiotrophoblast destroys the walls of the maternal (endometrial) spiral arteries, converting them into large sinusoids lined trophoblasts. Then the placental villi are formed. The trophoblast cells secrete enzymes that erode the endometrial tissue, facilitating deeper penetration. Tissue degradation is brought about by proteinases including proteases and collagenases.

Fig. 4.6. The illustrations show the process of blastocyst attachment to the uterine epithelium (left) and invasion (right) of the blastocyst into the endometrial stroma by the activity of the cytotrophoblast.  

Anomalies of implantation

The process of proper implantation is crucial for the establishment of a successful pregnancy. Abnormalities of implantation occur when the normal process of implantation is disrupted or deviated from its normal path. Abnormalities of implantation pose significant risks to both the mother and the developing embryo.

Placenta Previa

Placenta previa is a repercussion of abnormality of implantation. It is a condition where the placenta partially or completely covers the cervix, the opening to the uterus. The improper positioning of the placenta can cause severe bleeding during pregnancy and childbirth, posing danger to both the mother and the child. Based on the extent to which the placenta covers the cervix, placenta is classified into three types; these are complete placenta previa, partial placenta previa and marginal placenta previa. Partial placenta previa means that the cervix is partly blocked, whereas marginal placenta previa means a placenta positioned at the edge of the cervix, touching your cervix, but not covering it. Marginal placenta previa often resolves on its own before parturition. On the other hand, complete placenta previa means that the entire cervix is obstructed. The exact cause of placenta previa is not known, but certain risk factors have been identified, including scarring of the uterine endometrium. previous cesarean sections, multiple pregnancies, and advanced maternal age Management of placenta previa often involves careful monitoring, modifications of activities, and sometimes early delivery via cesarean section to ensure the safety of both mother and child.

Fig. 4.7. The illustrations show the different types of the placenta previa; complete placenta previa on the left, partial placenta previa in the middle and marginal placenta previa on the right.

Ectopic pregnancy

Another notable implantation abnormality is ectopic pregnancy, which occurs when the fertilized ovum (the zygote) implants itself outside the main cavity of the uterus and continues to develop in that abnormal site of implantation; it is a relatively common condition among women in their reproductive age. Its incidence is in the range of 1-3%. The most common site of ectopic pregnancies is the Fallopian tube where more than 95% of ectopic pregnancies take place. This type of  pregnancy is known as tubal pregnancy. Ectopic pregnancy can occur in locations other than the fallopian tube including the abdominal cavity, ovary, and the cervix. The zygote and the developing embryo cannot survive outside the uterine cavity for lack of appropriate blood supply and nutrients, and thus ectopic pregnancies do not proceed normally.

Fig. 4.8. The illustration shows sites of ectopic pregnancy outside the uterus in abdominal cavity (abdominal) in the cervix (cervical), in the ovary (ovarian) or in the Fallopian tube (tuba). The tubal can be in ampulla (ampullary), the isthmus (isthmic) or in the intrauterine part of the tube (interstitial).

Risk factors for ectopic pregnancy include inflammation or infection of the fallopian tubes, previous ectopic pregnancies, pelvic inflammatory disease, fertility treatments, and certain surgical procedures to the fallopian tubes. Diagnosis is typically made through ultrasonography and blood tests for human chorionic gonadotropin (hCG) levels. Treatment of ectopic pregnancy could be therapeutic or surgical. Therapeutic treatment includes medication such as methotrexate that stops embryonic cell growth and eliminates the embryonic cells. Surgical treatment aims to remove the ectopic tissue, especially if the fallopian tube has ruptured.

Nourishment of the Embryo Before and After Implantation

The embryo spends approximately 72 hours in the uterine cavity before implanting into the uterine endometrium. During this period, the cannot receive nourishment directly from the maternal blood. Thus, the embryo relies entirely on nutrients present in secretions of the uterine glands. Secretions of the uterine glands contain several nutrients and biomolecules that are vital for the embryo's development,  including essential nutrients such as iron and fat-soluble vitamins, which are crucial for the normal development of the embryo. Moreover, the uterine glands produce steroid-dependent proteins that play an important role in promoting growth and aiding implantation. Cholesterol and steroids are also secreted by the uterine glands and augment to the complicated process of implantation. Furthermore, the endometrium synthesizes matrix substances, adhesion molecules, and surface receptors for these matrix substances, all of which facilitate the implantation process by creating a conducive environment for the embryo.

Immediately after the implantation of the blastocyst, cells of the trophoblast proliferate and invade the surrounding decidual tissue of the endometrium. The trophoblast cells break through the walls of the maternal capillaries. accordingly blood leaks out of vessels and forms cavities filled with blood. These cavities known as lacunae are bound partly by the trophoblast and partly by the decidua. Thus, blood perfuses the blastocyst and flows around its cells and exchange of oxygen and nutrients occurs.

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