Formation and development of the placenta

The placenta is the organ of respiration, nutrition and excretion of the fetus. It produces hormones that ensure the normal vital activity of the mother and protect the fetus from immunological aggression from the mother, preventing its rejection, including preventing the passage of maternal immunoglobulins of class G (IgG).

[ 1 ], [ 2 ], [ 3 ], [ 4 ]

Development of the placenta

After implantation, the trophoblast begins to grow rapidly. The completeness and depth of implantation depend on the lytic and invasive capacity of the trophoblast. In addition, already at these stages of pregnancy, the trophoblast begins to secrete hCG, PP1 protein, and growth factors. Two types of cells are isolated from the primary trophoblast: cytotrophoblast - the inner layer and syncytiotrophoblast - the outer layer in the form of symplast, and this layer is called "primitive" or "previllous forms". According to some researchers, the functional specialization of these cells is already revealed in the previllous period. If syncytiotrophoblast is characterized by invasion into the depths of the endometrium with damage to the wall of maternal capillaries and venous sinusoids, then primitive cytotrophoblast is characterized by proteolytic activity with the formation of cavities in the endometrium, where maternal erythrocytes from the destroyed capillaries enter.

Thus, during this period, numerous cavities filled with maternal erythrocytes and the secretion of the destroyed uterine glands appear around the sunken blastocyst - this corresponds to the previllous or lacunar stage of early placenta development. At this time, active restructuring occurs in the endoderm cells and the formation of the embryo proper and extraembryonic formations, the formation of the amniotic and yolk vesicles begins. The proliferation of primitive cytotrophoblast cells forms cellular columns or primary villi covered with a layer of syncytiotrophoblast. The appearance of primary villi coincides in timing with the first absent menstruation.

On the 12th-13th day of development, the primary villi begin to transform into secondary ones. On the 3rd week of development, the process of vascularization of the villi begins, as a result of which the secondary villi transform into tertiary ones. The villi are covered with a continuous layer of syncytiotrophoblast, have mesenchymal cells and capillaries in the stroma. This process is carried out along the entire circumference of the embryonic sac (annular chorion, according to ultrasound data), but to a greater extent where the villi come into contact with the implantation site. At this time, the layer of provisional organs leads to the bulging of the entire embryonic sac into the lumen of the uterus. Thus, by the end of the 1st month of pregnancy, the circulation of embryonic blood is established, which coincides with the beginning of the embryonic heartbeat. Significant changes occur in the embryo, the rudiment of the central nervous system appears, blood circulation begins - a single hemodynamic system has formed, the formation of which is completed by the 5th week of pregnancy.

From the 5th to 6th week of pregnancy, the placenta is formed extremely intensively, since it is necessary to ensure the growth and development of the embryo, and for this, it is necessary, first of all, to create the placenta. Therefore, during this period, the rate of development of the placenta outpaces the rate of development of the embryo. At this time, the developing syncytiotrophoblast reaches the spiral arteries of the myometrium. The establishment of uteroplacental and placental-embryonic blood flow is the hemodynamic basis for intensive embryogenesis.

Further development of the placenta is determined by the formation of the intervillous space. The proliferating syncytiotrophoblast cytotrophoblast lines the spiral arteries, and they turn into typical uteroplacental arteries. The transition to placental circulation occurs by the 7th-10th week of pregnancy and is completed by the 14th-16th week.

Thus, the first trimester of pregnancy is a period of active differentiation of the trophoblast, the formation and vascularization of the chorion, the formation of the placenta and the connection of the embryo with the maternal organism.

The placenta is fully formed by the 70th day from the moment of ovulation. By the end of the pregnancy, the mass of the placenta is V, of the child's body mass. The blood flow rate in the placenta is approximately 600 ml/min. During pregnancy, the placenta "ages", which is accompanied by the deposition of calcium in the villi and fibrin on their surface. The deposition of excess fibrin can be observed in diabetes mellitus and Rhesus conflict, as a result of which the nutrition of the fetus worsens.

The placenta is a provisional organ of the fetus. In the early stages of development, its tissues differentiate at a faster rate than the embryo's own tissues. Such asynchronous development should be considered an expedient process. After all, the placenta must ensure the separation of maternal and fetal blood flows, create immunological immunity, ensure the synthesis of steroids and other metabolic needs of the developing fetus; the subsequent course of pregnancy depends on the reliability of this stage. If the trophoblast invasion is insufficient during the formation of the placenta, then an incomplete placenta will form - a miscarriage or a delay in fetal development will occur; with incomplete placenta construction, toxicosis of the second half of pregnancy develops; with too deep invasion, placenta accreta is possible, etc. The period of placentation and organogenesis is the most important in the development of pregnancy. Their correctness and reliability are ensured by a set of changes in the mother's body.

At the end of the third and fourth months of pregnancy, along with the intensive growth of villi in the implantation area, degeneration of villi outside it begins. Not receiving adequate nutrition, they are subject to pressure from the growing fetal sac, lose epithelium and become sclerotic, which is a stage in the formation of a smooth chorion. A morphological feature of placenta formation during this period is the appearance of a dark villous cytotrophoblast. Dark cytotrophoblast cells have a high degree of functional activity. Another structural feature of the stroma of the villi is the approach of capillaries to the epithelial cover, which allows for an acceleration of metabolism due to a reduction in the epithelial-capillary distance. At the 16th week of pregnancy, the mass of the placenta and fetus equalizes. Subsequently, the fetus quickly overtakes the mass of the placenta, and this trend remains until the end of pregnancy.

In the 5th month of pregnancy, the second wave of cytotrophoblast invasion occurs, which leads to expansion of the lumen of the spiral arteries and an increase in the volume of uteroplacental blood flow.

At 6-7 months of gestation, further development into a more differentiated type occurs, high synthetic activity of the syncytiotrophoblast and fibroblasts in the stroma of cells around the capillaries of the villi is maintained.

In the third trimester of pregnancy, the placenta does not significantly increase in mass; it undergoes complex structural changes that allow it to meet the increasing needs of the fetus and its significant increase in mass.

The greatest increase in placental mass is noted in the 8th month of pregnancy. The complication of the structure of all placental components, significant branching of the villi with the formation of catyledons are noted.

In the 9th month of pregnancy, a slowdown in the rate of placental mass growth is noted, which is further enhanced at 37-40 weeks. A distinct lobular structure with very powerful intervillous blood flow is noted.

[ 5 ], [ 6 ], [ 7 ]

Protein hormones of the placenta, decidua and fetal membranes

During pregnancy, the placenta produces major protein hormones, each of which corresponds to a specific pituitary or hypothalamic hormone and has similar biological and immunological properties.

Protein hormones of pregnancy

Protein hormones produced by the placenta

Hypothalamic-like hormones

• gonadotropin-releasing hormone
• corticotropin-releasing hormone
• thyrotropin-releasing hormone
• somatostatin

Pituitary-like hormones

• human chorionic gonadotropin
• placental lactogen
• human chorionic corticotropin
• adrenocorticotropic hormone

Growth factors

• insulin-like growth factor 1 (IGF-1)
• epidermal growth factor (EGF)
• platelet-derived growth factor (PGF)
• fibroblast growth factor (FGF)
• transforming growth factor P (TGFP)
• inhibin
• activin

Cytokines

• interleukin-1 (il-1)
• interleukin-6 (il-6)
• colony stimulating factor 1 (CSF1)

Pregnancy-specific proteins

• beta1,-glycoprotein (SP1)
• eosinophil basic protein pMBP
• soluble proteins PP1-20
• membrane-binding proteins and enzymes

Protein hormones produced by the mother

Decidual proteins

• prolactin
• relaxin
• insulin-like growth factor binding protein 1 (IGFBP-1)
• interleukin 1
• colony stimulating factor 1 (CSF-1)
• progesterone-associated-endometrial protein

The pituitary triple hormones correspond to human chorionic gonadotropin (hCG), human chorionic somatomammotropin (HS), human chorionic thyrotropin (HT), and placental corticotropin (PCT). The placenta produces peptides similar to ACTH, as well as releasing hormones (gonadotropin-releasing hormone (GnRH), corticotropin-releasing hormone (CRH), thyrotropin-releasing hormone (TRH), and somatostatin) similar to the hypothalamic ones. It is believed that this important function of the placenta is controlled by hCG and numerous growth factors.

Human chorionic gonadotropin is a pregnancy hormone, a glycoprotein, similar in its action to LH. Like all glycoproteins, it consists of two chains, alpha and beta. The alpha subunit is almost identical to all glycoproteins, and the beta subunit is unique for each hormone. Human chorionic gonadotropin is produced by the syncytiotrophoblast. The gene responsible for the synthesis of the alpha subunit is located on chromosome 6, for the beta subunit of LH there is also one gene on chromosome 19, while for the beta subunit of hCG there are 6 genes on chromosome 19. Perhaps this explains the uniqueness of the beta subunit of hCG, since its lifespan is approximately 24 hours, while the lifespan of betaLH is no more than 2 hours.

Human chorionic gonadotropin is the result of interaction of sex steroids, cytokines, releasing hormone, growth factors, inhibin and activin. Human chorionic gonadotropin appears on the 8th day after ovulation, one day after implantation. Human chorionic gonadotropin has numerous functions: it supports development and function of the corpus luteum of pregnancy up to 7 weeks, participates in production of steroids in the fetus, DHEAS of the fetal zone of the adrenal glands and testosterone by the testes of the male fetus, participating in formation of the sex of the fetus. Expression of the human chorionic gonadotropin gene has been detected in fetal tissues: kidneys, adrenal glands, which indicates participation of human chorionic gonadotropin in development of these organs. It is believed that it has immunosuppressive properties and is one of the main components of the "blocking properties of serum", preventing rejection of the fetus foreign to the immune system of the mother. Human chorionic gonadotropin receptors are found in the myometrium and myometrial vessels, suggesting that human chorionic gonadotropin plays a role in uterine regulation and vasodilation. In addition, human chorionic gonadotropin receptors are expressed in the thyroid gland, explaining the thyroid stimulatory activity of human chorionic gonadotropin.

The maximum level of human chorionic gonadotropin is observed at 8-10 weeks of pregnancy (100,000 IU), then it slowly decreases and is 10,000-20,000 IU/I at 16 weeks, remaining at this level until 34 weeks of pregnancy. At 34 weeks, many note a second peak of human chorionic gonadotropin, the significance of which is unclear.

Placental lactogen (sometimes called chorionic somato-mammotropin) has biological and immunological similarities to growth hormone, synthesized by syncytiotrophoblast. Synthesis of the hormone begins at the moment of implantation, and its level increases in parallel with the mass of the placenta, reaching a maximum level at 32 weeks of pregnancy. Daily production of this hormone at the end of pregnancy is more than 1 g.

According to Kaplan S. (1974), placental lactogen is the main metabolic hormone providing the fetus with a nutritious substrate, the need for which increases with the progression of pregnancy. Placental lactogen is an insulin antagonist. Ketone bodies are an important source of energy for the fetus. Increased ketogenesis is a consequence of decreased insulin efficiency under the influence of placental lactogen. In this regard, glucose utilization in the mother decreases, thereby ensuring a constant supply of glucose to the fetus. In addition, an increased level of insulin in combination with placental lactogen ensures increased protein synthesis and stimulates the production of IGF-I. There is little placental lactogen in the fetus's blood - 1-2% of its amount in the mother, but it cannot be ruled out that it directly affects the metabolism of the fetus.

"Human chorionic growth hormone" or "growth hormone" variant is produced by the syncytiotrophoblast, is determined only in the mother's blood in the second trimester and increases up to 36 weeks. It is believed that, like placental lactogen, it participates in the regulation of IGFI levels. Its biological action is similar to that of placental lactogen.

The placenta produces a large number of peptide hormones that are very similar to the hormones of the pituitary gland and hypothalamus - human chorionic thyrotropin, human chorionic adrenocorticotropin, human chorionic gonadotropin-releasing hormone. The role of these placental factors is not yet fully understood, they can act paracrine, having the same effect as their hypothalamic and pituitary analogues.

In recent years, much attention has been paid in the literature to placental corticotropin-releasing hormone (CRH). During pregnancy, CRH increases in plasma by the time of delivery. CRH in plasma is bound to CRH-binding protein, the level of which remains constant until the last weeks of pregnancy. Then its level decreases sharply, and, in connection with this, CRH increases significantly. Its physiological role is not entirely clear, but in the fetus CRH stimulates the level of ACTH and through it contributes to steroidogenesis. It is assumed that CRH plays a role in inducing labor. Receptors for CRH are present in the myometrium, but according to the mechanism of action, CRH should cause not contractions, but relaxation of the myometrium, since CRH increases cAMP (intracellular cyclic adenosine monophosphate). It is believed that the isoform of CRH receptors or the phenotype of the binding protein changes in the myometrium, which through stimulation of phospholipase can increase the level of intracellular calcium and thereby provoke contractile activity of the myometrium.

In addition to protein hormones, the placenta produces a large number of growth factors and cytokines. These substances are necessary for the growth and development of the fetus and the immune relationship between the mother and fetus, ensuring the maintenance of pregnancy.

Interleukin-1beta is produced in the decidua, colony-stimulating factor 1 (CSF-1) is produced in the decidua and in the placenta. These factors participate in fetal hematopoiesis. Interleukin-6, tumor necrosis factor (TNF), interleukin-1beta are produced in the placenta. Interleukin-6, TNF stimulate the production of chorionic gonadotropin, insulin-like growth factors (IGF-I and IGF-II) participate in the development of pregnancy. The study of the role of growth factors and cytokines opens a new era in the study of endocrine and immune relationships during pregnancy. A fundamentally important protein of pregnancy is insulin-like growth factor binding protein (IGFBP-1beta). IGF-1 is produced by the placenta and regulates the transfer of nutrient substrates through the placenta to the fetus and, thus, ensures the growth and development of the fetus. IGFBP-1 is produced in the decidua and by binding IGF-1 inhibits fetal development and growth. Fetal weight and development rates directly correlate with IGF-1 and inversely with lGFBP-1.

Epidermal growth factor (EGF) is synthesized in the trophoblast and is involved in the differentiation of cytotrophoblast into syncytiotrophoblast. Other growth factors secreted in the placenta include: nerve growth factor, fibroblast growth factor, transforming growth factor, platelet-derived growth factor. Inhibin and activin are produced in the placenta. Inhibin is determined in the syncytiotrophoblast, and its synthesis is stimulated by placental prostaglandins E and F2.

The action of placental inhibin and activin is similar to the action of ovarian ones. They participate in the production of GnRH, hCG and steroids: activin stimulates, and inhibin inhibits their production.

Placental and decidual activin and inhibin appear early in pregnancy and appear to be involved in embryogenesis and local immune responses.

Among the pregnancy proteins, the most well-known is SP1 or beta1-glycoprotein or trophoblast-specific beta1-glycoprotein (TSBG), which was discovered by Yu.S. Tatarinov in 1971. This protein increases during pregnancy like placental lactogen and reflects the functional activity of the trophoblast.

Eosinophilic basic protein pMBP - its biological role is unclear, but by analogy with the properties of this protein in eosinophils, it is assumed that it has a detoxifying and antimicrobial effect. It has been suggested that this protein influences the contractility of the uterus.

Soluble placental proteins include a group of proteins with different molecular weights and biochemical compositions of amino acids, but with common properties - they are found in the placenta, in the placental-fetal bloodstream, but are not secreted into the mother's blood. There are currently 30 of them, and their role is mainly to ensure the transport of substances to the fetus. The biological role of these proteins is being intensively studied.

In the mother-placenta-fetus system, it is of great importance to ensure rheological properties of the blood. Despite the large contact surface and slow blood flow in the intervillous space, the blood does not thrombose. This is prevented by a complex of coagulating and anticoagulant agents. The main role is played by thromboxane (TXA2, secreted by maternal platelets - an activator of maternal blood coagulation, as well as thrombin receptors on the apical membranes of the syncytiotrophoblast, promoting the conversion of maternal fibrinogen into fibrin. In contrast to the coagulating factors, there is an anticoagulant system, including annexins V on the surface of the syncytiotrophoblast microvilli, at the border of the maternal blood and the epithelium of the villi; prostacyclin and some prostaglandins (PG12 and PGE2), which in addition to vasodilation have an antiplatelet effect. A number of other factors with antiplatelet properties have also been identified, and their role has yet to be studied.

Types of placentas

Marginal attachment - the umbilical cord attaches to the placenta from the side. Vestibular attachment (1%) - the umbilical vessels pass through the syncytiocapillary membranes before attaching to the placenta. When such vessels rupture (as in the case of the vessels of the placenta previa), blood loss occurs from the fetal circulatory system. An accessory placenta (placenta succenturia) (5%) is an additional lobule located separately from the main placenta. If an additional lobule is retained in the uterus, bleeding or sepsis may develop in the postpartum period.

Membranous placenta (placenta membranacea) (1/3000) is a thin-walled sac surrounding the fetus and thus occupying most of the uterine cavity. Situated in the lower segment of the uterus, such a placenta predisposes to bleeding in the prenatal period. It may not separate in the fetal period of labor. Placenta accreta is an abnormal adhesion of all or part of the placenta to the uterine wall.

Placenta previa

The placenta lies in the lower segment of the uterus. Placenta previa is associated with conditions such as a large placenta (eg, twins); uterine anomalies and fibroids; and uterine injury (multiple births, recent surgery including cesarean section). From 18 weeks onwards, ultrasound can visualise low-lying placentas; most of these move to a normal position by the onset of labour.

In type I, the edge of the placenta does not reach the internal os; in type II, it reaches but does not cover the internal os from the inside; in type III, the internal os is covered from the inside by the placenta only when the cervix is closed, but not when it is dilated. In type IV, the internal os is completely covered from the inside by the placenta. Clinical manifestation of placental location anomaly may be bleeding in the prenatal period (antepartum). Overstretching of the placenta, when the overstretched lower segment is the source of bleeding, or the inability of the fetal head to insert (with a high position of the presenting part). The main problems in such cases are related to bleeding and the method of delivery, since the placenta causes obstruction of the uterine orifice and may come away during labor or become accrete (in 5% of cases), especially after a previous cesarean section (more than 24% of cases).

Tests to assess placental function

The placenta produces progesterone, human chorionic gonadotropin, and human placental lactogen; only the latter hormone can provide information on the health of the placenta. If its concentration is below 4 μg/ml after 30 weeks of gestation, this suggests impaired placental function. The health of the fetus/placenta system is monitored by measuring the daily excretion of total estrogens or estriol in the urine or by determining estriol in the blood plasma, since pregnenolone synthesized by the placenta is subsequently metabolized by the adrenal glands and liver of the fetus, and then again by the placenta for the synthesis of estriol. The content of estradiol in the urine and plasma will be low if the mother has severe liver disease or intrahepatic cholestasis or is taking antibiotics; if the mother has impaired renal function, the level of estradiol in the urine will be low and in the blood it will be increased.