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  1. A sperm is only capable of fertilizing an egg if it first undergoes the
    acrosome reaction. Fertilization can occur if activated sperm meet a
    viable ovum in the fallopian tube.

  2. The first stage of fertilization occurs when an activated sperm fuses
    with the oocyte. The newly fertilized egg then completes its second
    meiotic division, and undergoes the cortical reaction to create a fer­
    tilization membrane which prevents further sperm from fusing with

  3. The newly fertilized egg (the zygote) alerts its mother to its presence
    by secreting a powerful luteotropic hormone, hCG, which prolongs
    the secretory life of rhe corpus luteum. This ensures that progesterone
    continues to be secreted and the specialized endometrial layers of the
    uterus maintained until the pregnancy can be supported by pro­
    gesterone of placental origin. This occurs at around 6—8 weeks of

Fig. 20.4 The placenta, in relation to adjacent structures during early pregnancy. For clarity the placenta and embryo are shown disproportionately large in relation to the uterus.

^ 20.4 The formation of the placenta

All organisms throughout their embryonic development need a large and continuous supply of nutrients. They must also be able to respire and to dispose of the waste products of their meta­bolism. Most mammalian species accomplish this crucial task by the process of placentation. A specialized organ, the placenta, is developed which brings the blood supply of the fetus into close proximity with that of its mother, thereby permitting the exchange of substances between the two circulations. In this way the placenta can perform those functions carried out by the lungs, gastrointestinal tract, and kidneys in the adult. Indeed, the placenta is the only source of nourishment, gas exchange, and waste disposal available to the fetus. It is therefore crucial to the success of a pregnancy that the placenta should develop and function efficiently. Furthermore, placental growth, particularly in the first months of gestation, must keep pace with the requirements of the growing fetus. Without an adequate surface area for transplacental exchange, the growth of the fetus will be

impaired and its life may be threatened. The association between maternal and fetal circulations established by the placenta allows for prolonged development within the uterus and, as a result, delivery of a complex and highly developed baby.

While the anatomical details of placental formation are beyond the scope of this book, it is important to understand how the placenta is adapted structurally for carrying out its role as an organ of exchange. Figure 20.4 illustrates the gross spatial relationships between the fetal and maternal tissues. Essentially, the developing placenta is an association between the uterine endometrium and the embryonic membranes derived from a layer of cells known as the trophoblast.

How is this interface created? Figure 20.5 shows an enlarged view of a section of human placenta soon after the start of embryonic implantation. This is known as the stem-villus stage of development because the fetal tissue grows up into the maternal endometrial tissue in the form of finger-like projections or villi

Fig. 20.5 A simplified drawing to show the stem-villus stage of placental development at around 3 weeks' gestation.

464 20 Fertilization and pregnancy

that are formed from a membrane called the chorion, which is derived from trophoblastic tissue and mesoderm that lies outside the developing embryo (the extraembryonic mesoderm). Blood vessels form within this outgrowth to give rise to the fetal com­ponent of the placental circulation, which will become the umbilical vessels in the umbilical cord. As the trophoblastic tissue invades the endometrium it secretes digestive enzymes that break down the spiral arteries. As a result of this erosion, blood spills out of the maternal vessels to create blood-filled spaces between the chorionic villi. These are called the inter­villous blood spaces. At the same time, the villi themselves become cored with mesoderm (Fig. 20.5) which becomes vas­cularized with fetal vessels that carry fetal blood into close prox­imity to the maternal blood spaces. The essential interface between the maternal and fetal circulations is thus established.

This invasive behavior of the trophoblast during implanta­tion and early placentation is highly aggressive and reminiscent of that of a malignant neoplasm. It has in fact been shown that occasionally fragments of trophoblastic tissue do actually break off and can be found lodged in distant tissues of the mother, par­ticularly the lung, rather in the same way as malignancies tend to metastasize. However, regression of the trophoblastic tissue generally occurs quite rapidly following delivery of the baby.

Invasion of the endometrium and villus formation take place during the first month after conception. The maternal and fetal blood are thus brought into close proximity. In the succeeding month or two, the vascular villi become much more highly branched, thereby increasing the surface area of the fetal capillaries available for transplacental exchange of nutrients and waste products. By the end of the first trimester (3 months) of gestation the placenta is known as the definitive placenta because it will show few further changes to its basic structure for the remainder of the pregnancy.

A diagrammatic and highly simplified representation of the placenta at 3 months is shown in Fig. 20.6. Trophoblastic cells at the outer margins of the villi form a syncytium (the syn-cytiotrophoblasi) while those further from the outer margins retain their individual membranes (the cytotrophoblast). Other important

points to notice are the extensive branching of the primary villi, and the erosion of the maternal spiral arteries which is now so extensive that their blood is simply discharged into the inter­villous spaces. The fetal blood supply runs in the capillaries within the branched villi and the arrangement of the placental blood flow is such that the fetal capillaries essentially dip into the maternal blood spaces and the fetal blood is virtually surrounded by mater­nal blood. This arrangement of the two circulations within the placenta is termed a dialysis pattern and it allows movement of solutes in either direction according to the concentration gradient, over the entire surface of the fetal placental capillaries. This arrangement is shown schematically in Fig. 20.7.

^ 20.5 The placenta as an organ of exchange between mother and fetus

The rate and extent of diffusion of a substance across any cellular barrier depends upon a variety of factors. These include (in addition to the chemical characteristics of the substance itself):

  • the nature and thickness of the barrier to diffusion;

  • the surface area available for exchange;

  • the concentration gradient of the substance.

It may now be helpful to examine each of these factors with reference to the human placenta in order to understand more about the ways in which it is adapted to carry out its functions as an organ of exchange.

The barrier to diffusion in this case is the so-called 'placental barrier' between the maternal and fetal blood. What does this con­sist of? For a substance to diffuse from the maternal blood space to the fetal capillary blood (or vice versa), it must cross the syncytio-trophoblast and the fetal capillary endothelial layer. The latter consists merely of a single layer of cells on a basement membrane and is therefore very thin, but the syncytiotrophoblast contains more layers of cells with no paracellular pathways to act as short­cuts for diffusion, and therefore has a relatively low permeability. Overall, then, the placental barrier is rather impermeable.

Fig. 20.6 A diagrammatic representation of the definitive placenta at the end of the first trimester.

^ 20.5 The placenta as an organ of exchange


This low solute permeability is, however, offset to a great extent by the enormous surface area available for placental exchange created by the extensive branching of the fetal capillar­ies within the villi, and the dialysis arrangement of the two circulations.

Within the placenta, the concentration gradient of any sub­stance between the maternal and fetal blood will be influenced by the blood supply to the maternal and fetal circulations, par­ticularly the relative blood flow rates on either side. The rate of entry of blood to the maternal intervillous spaces is rather difficult to measure since the uterine arteries supply both the uterus and the placenta, making it hard to differentiate between blood destined for the intervillous spaces and that supplying the uterus. Total blood flow in the uterine artery at full term is around 1200mlmin-1, measured just prior to delivery by cesarean section. About 600 ml min~' (or 10 per cent of the total maternal cardiac output at full term) is thought to perfuse the maternal side of the placenta. The maternal blood space has a total volume of about 250 ml, so the blood on the maternal side of the placenta is exchanged roughly 2.5 times each minute. The blood entering the intervillous spaces is at a relatively high pres­sure, about 13kPa (lOOmmHg), as it is discharged from the eroded spiral arteries, thus ensuring a fair degree of turbulence and good mixing.

In a full-term fetus, perfusion of the fetal capillaries in the placental villi is estimated at around 360 ml min-1, roughly half the cardiac output. The total volume of blood in the capillaries is about 45 ml, so the blood in the fetal placental compartment is exchanged about eight times a minute.

To summarize, the maternal blood spaces have a large volume of well-mixed blood, with a moderate turnover, while the fetal capillaries have a much smaller volume but a rather high turnover.

This pattern of circulation emphasizes the dialysis nature of the placental blood flow. It optimizes the conditions for passive exchange of solutes by maximizing concentration gradients. Consider the diffusion of a solute from maternal to fetal blood. The fetal blood flow rate is very high. This means that solute diffusing into the fetal blood from the maternal side will be removed from the placenta rapidly, keeping its concentration low in the fetal capillaries. The maternal blood, however, has a much larger volume, so, despite its slower flow rate, will not become depleted of solute readily. By this arrangement, the concentration gradient for the solute between the maternal and fetal blood is maintained and ensures efficient diffusion.

The dialysis arrangement of the placental blood flow also helps to optimize conditions for the removal of waste products from the fetal circulation by maintaining a steep concentration gradient for the waste substance across the placental barrier. The rapid turnover of blood on the fetal side will ensure a con­stant delivery of waste to the placenta while the relatively large volume of blood in the intervillous spaces will keep the concentration of waste product low on the maternal side.

Towards the end of pregnancy, the exchange capacity of the pla­centa tends to diminish. This is due chiefly to changes in the per­fusion of the organ. Maternal blood flow may be somewhat reduced as the spiral arteries become progressively blocked during preg­nancy. At the same time, the fetal capillaries tend to become blocked with small clots and other debris. This leads to a pro­gressive decline in perfusion towards term. As parts of the chor­ionic villi become poorly perfused, they can no longer participate effectively in exchange and the effective surface area for diffusion is reduced. As a result of this declining efficiency, the placenta is said to become 'senescent' near to term and is less and less able to meet the demands of the fetus. This may be one of the many factors involved in the triggering of parturition (Section 20.7).

Gas exchange across the placenta occurs by diffusion

Oxygen diffuses passively from the maternal to the fetal side of the placenta. Carbon dioxide diffuses in the opposite direction. How efficient is the placenta as an organ of gas exchange? To answer this question, it is necessary to consider the gas tensions on both the maternal and the fetal sides of the placenta. Figure 20.7 shows the values for oxygen and carbon dioxide tensions in each com­partment. The normal arteriovenous differences in partial pres­sures seem to prevail on the maternal side, with a PaO2 of around 12.6 kPa (95 mmHg) in the uterine artery falling to around 5.6 kPa (42 mmHg) in the uterine venous blood. The maternal Pco2 rises from 5-5.6 kPa (38—40 mmHg) in the arterial blood to 6.1 kPa (46 mmHg) on the venous side. Since the maternal blood space is large and the blood well mixed, equilibrium values of gas partial pressures are quickly reached and it is therefore reasonable to assume the blood of the intervillous spaces to have a Po2 of 5.6 kPa (42 mmHg) and a Pco2 of 6.1 kPa (46 mmHg).

On the fetal side, the blood in the umbilical artery which is carrying blood from the fetus, is both highly deoxygenated and hypercapnic, having a Po2 of around 3.2 kPa (24 mmHg) and a

Fig. 20.7 The dialysis organization of the placenta with typical blood gas values. Note that the maternal and fetal circulations are separate and that the blood leaving the placenta via the umbilical vein is not fully equilibrated with the maternal blood.


20 Fertilization and pregnancy

Pco2 of about 6.6 kPa (50 mmHg). Blood returning from the pla­centa to the fetus in the umbilical vein has a Pco2 of 5.8 kPa (44 mmHg) and a Po2 of about 4.25 kPa (32 mmHg). The fetal umbilical venous blood is not in equilibrium with the maternal blood. In this respect, the placenta differs from the lung, in which complete equilibration is normally achieved between the pul­monary blood and the alveolar air. There are two important reasons for this failure to reach equilibrium. First, not all the maternal blood is in contact with the villi (which is the area of gas exchange) and 'shunts' therefore exist which are analogous with a ventila-tion/perfusion mismatch in the lungs (see Chapter 16). Secondly, the placental tissue itself, which is highly metabolically active, uses around 20 per cent of the oxygen in the maternal blood before it has a chance to reach the fetal capillaries. The placenta is therefore a less efficient organ of gas exchange than the lung. This is, however adequate to satisfy the oxygen demand of the fetus because of a variety of specific adaptations to ensure that the transfer of oxygen to the fetal tissues is maximized. These are discussed in Chapter 21.

In addition to supplying oxygen to the fetus, the placenta must, in its capacity as the fetal organ of gas exchange, remove the carbon dioxide produced by metabolism of the fetus. As with O2, the passive movement of CO2 depends on blood flow and diffusion gradients, but the placental barrier is more per­meable to CO2 than it is to O2 and exchange is more or less complete.

Placental exchange of glucose and amino acids is carrier mediated

The placenta is the sole source for the fetus of the nutrients essential for its growth. The most important of these is glucose. Because glucose is a polar molecule, and so rather lipid insolu­ble, it cannot rely solely upon passive diffusion across the lipid-rich placental barrier. Instead, it moves from the maternal to the fetal side by facilitated diffusion, a mechanism that is discussed in Chapter 4. The process is mediated by a carrier that is located in the membrane of the cells of the syncytiotrophoblast. Unless the carrier becomes saturated, fetal levels of glucose will be in equilibrium with those of the mother. While this will normally be desirable, there are circumstances under which this is not the case. Consider the case of poorly controlled maternal diabetes. Here, maternal glucose levels may be abnormally high, and, because of facilitated diffusion across the placenta, fetal levels will also be high. This can lead to overnourishment and obesity of the baby—indeed, the babies of diabetic mothers are often bigger than normal for their gestational age.

Amino acids are vital to the fetus during its development in the uterus. They are needed to support the high rate of protein synthesis that occurs during gestation. Like glucose, amino acids appear to cross the placenta from the maternal blood to the fetal capillaries by facilitated diffusion. At least three separate carriers are known to exist, specific for the acidic amino acids, the small neutrals, and the large neutrals and branched-chain amino acids.

Lipids are of great importance in fetal development. While phospholipids do not pass readily across the placental barrier, free fatty acids are able to do so and it is in this form that the fetus receives most of its lipid. Phospholipid in the maternal blood is hydrolyzed by enzymes on the placental surface to form free fatty acids which diffuse passively down their concentration gradient to the fetal blood. They then pass to the fetal liver where they undergo reconjugation to form new phospholipid.

The excretion of fetal waste products by placental exchange

Like carbon dioxide, which diffuses from the fetal to the maternal blood across the placenta, other fetal waste products are removed in a similar fashion and then excreted along with those of the mother herself. One of the most important of these metabolic waste products is urea, the nitrogenous waste product of protein metabolism. Although much of the metabolism of the fetus is concerned with the synthesis of new structural protein, through­out gestation and fetal development, there is also a fair amount of tissue destruction as developing tissues are remodeled. Indeed, of the total nitrogen that enters the fetus in the form of amino acids transported across the placenta from the maternal blood, about 40 per cent ends up in the form of urea, which must be dis­posed of. Excretion occurs by passive diffusion of urea down the concentration gradient between the fetal and maternal blood.

Another fetal waste product of considerable clinical sig­nificance is bilirubin, which is produced by the breakdown of hemoglobin. In adults, bilirubin is conjugated by hepatic enzymes to form bilirubin glucuronide. This is water soluble and can therefore be excreted without difficulty. However, the fetal liver is relatively immature and does not possess sufficient amounts of the necessary conjugation enzymes. During fetal life, there is significant destruction of red blood cells and the bilirubin produced must be removed. If it is not disposed of but allowed to build up in the fetal blood, bilirubin can cross the blood—brain barrier and cause severe brain damage. The basal ganglia are the most commonly affected regions under these circumstances, giving rise to the condition known as kernicterus, in which there may be permanent impairment of motor function.

^ 20.6 The placenta as an endocrine organ

In addition to its crucial transporting role described above, the placenta is also an extremely important endocrine organ. At full term it normally weighs around 650 g and, at this time, is the largest endocrine organ in the body of a pregnant woman. More significant, however, is its versatility. The placenta secretes a wide variety of different hormones, both peptide and steroid, which are important in the maintenance of pregnancy and for the preparation of the body for parturition and lactation. The major peptide hormones secreted by the placenta are:

  • human chorionic gonadotropin (hCG);

  • human placental lactogen (hPL).

^ 20.6 The placenta as an endocrine organ
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