Tutoring at home

Although the fetus is dependent on the mother for nutrition, the fetus also actively participates in providing for its own nutrition. At midpregnancy, fetal glucose concentration is independent of and may exceed maternal levels (Bozzetti and colleagues, 1988). Glucose is a major nutrient for fetal growth and energy. It is thus logical that mechanisms exist during pregnancy to minimize maternal glucose use so that the limited maternal supply is available to the fetus. It is believed that placental lactogen (hPL), a hormone normally present in abundance in the mother but not the fetus, blocks the peripheral uptake and use of glucose while promoting the mobilization and use of free fatty acids by maternal tissues.
Glucose Transport
The transfer of D-glucose across cell membranes is accomplished by a carrier-mediated, stereospecific, nonconcentrating process of facilitated diffusion. Six separate glucose transport proteins (GLUT) have been discovered. They belong to the 12-transmembrane segment transporter superfamily and are characterized further by tissue-specific. Transporter proteins for D-glucose—GLUT-1 and GLUT-3—are located in the plasma membrane of the microvilli of human syncytiotrophoblast. GLUT-1 expression is prominent in human placenta, it increases as pregnancy advances, and it is induced by almost all growth factors (Sakata and colleagues, 1995). GLUT-3 is also localized in human syncytiotrophoblast (Hahn and associates, 1995).
Glucose, Insulin, and Fetal Macrosomia
The precise biomolecular events in the pathophysiology of fetal macrosomia are not defined. Nonetheless, it seems clear that fetal hyperinsulinemia is one driving force (Schwartz and colleagues, 1994). Insulin-like growth factor, as well as fibroblast growth factor, also are involved (Giudice and associates, 1995; Hill and colleagues, 1995). Therefore, a hyperinsulinemic state with increased levels of selected growth factors, together with increased expression of GLUT proteins in syncytiotrophoblast, may promote excessive fetal growth.

Chorionic Villus
Substances that pass from maternal blood to fetal blood must traverse (1) syncytiotrophoblast, (2) stroma of the intravillous space, and (3) fetal capillary wall. Although this histological barrier separates the blood in the maternal and fetal circulations, it does not behave in a uniform manner like a simple physical barrier. Throughout pregnancy, syncytiotrophoblast actively or passively permits, facilitates, and adjusts the amount and rate of transfer of a wide range of substances to the fetus. The walls of the villous capillaries likewise become thinner, and the relative number of fetal vessels increases in relation to the villous connective tissue. It is important to recall that the walls of the fetal placental surface vessels, after branching from the truncal arteries of the chorionic vessels, do not contain smooth muscle cells. Several attempts have been made to estimate the total surface area of chorionic villi in the human placenta at term. From the planimetric measurements made by Aherne and Dunnill (1966) of the villous surface area of the placenta, it is evident that there is a close correlation with fetal weight. The total surface area at term has been estimated to be approximately 10 m2.
Regulation of Placental Transfer
The syncytiotrophoblast is the fetal tissue interface. The maternal-facing surface of this tissue is characterized by a complex microvillus structure. The fetal-facing (basal) cell membrane of the trophoblast is the site of transfer to the intravillous space through which the fetal capillaries traverse. The fetal capillaries are an additional site for transport from the intravillous space into fetal blood, or vice versa.
In determining the effectiveness of the human placenta as an organ of transfer, at least 10 variables are important.
1. The concentration of the substance under consideration in the maternal plasma, and in some instances, the extent to which it is bound to another compound, such as a carrier protein.
2. The rate of maternal blood flow through the intervillous space.
3. The area available for exchange across the villous trophoblast epithelium.
4. If the substance is transferred by diffusion, the physical properties of the tissue barrier interposed between blood in the intervillous space and in the fetal capillaries.
5. For any substance actively transported, the capacity of the biochemical machinery of the placenta for effecting active transfer, for example, specific receptors on the plasma membrane of the trophoblast.
6. The amount of the substance metabolized by the placenta during transfer.
7. The area for exchange across the fetal capillaries in the placenta.
8. The concentration of the substance in the fetal blood, exclusive of any that is bound.
9. Specific binding or carrier proteins in the fetal or maternal circulation.
10. The rate of fetal blood flow through the villous capillaries.
Mechanisms of Transfer
Most substances with a molecular mass less than 500 d diffuse readily through placental tissue. Molecular weight is clearly important in determining the rate of transfer by diffusion. Simple diffusion, however, is by no means the only mechanism of transfer of low-molecular-weight compounds. The syncytiotrophoblast actively facilitates the transfer of a variety of small compounds, especially those that are in low concentration in maternal plasma but are essential for normal fetal growth and development. Simple diffusion appears to be the mechanism involved in the transfer of oxygen, carbon dioxide, water, and most (but not all) electrolytes. Anesthetic gases also pass through the placenta rapidly by simple diffusion.
Insulin, steroid hormones, and thyroid hormones cross the placenta, but at very slow rates. The hormones synthesized in situ in the trophoblasts enter both the maternal and fetal circulations, but not equally. For example, concentrations of chorionic gonadotropin and placental lactogen in fetal plasma are much lower than in maternal plasma. Substances of high molecular weight usually do not traverse the placenta, but there are important exceptions, such as immunoglobulin G—molecular weight 160,000 d—which is transferred by way of a specific trophoblast receptor–mediated mechanism.
Transfer of Oxygen and Carbon Dioxide
In their excellent account of placental transport, Morriss and associates (1994) recall that in 1674, Mayow suggested that the placenta served as the fetal lung. In 1796, Erasmus Darwin, only 22 years after the discovery of oxygen, observed that the color of blood passing through lungs and gills became bright red. He deduced, from the structure as well as the position of the placenta, that it appeared to be a respiratory organ by which the fetus becomes oxygenated.
The transfer of oxygen across the placenta is blood-flow limited. The placenta supplies about 8 mL O2/min/kg of fetal weight, and because fetal blood oxygen stores are sufficient for only 1 to 2 minutes, this supply must be continuous (Longo, 1991). Because of the continuous passage of oxygen from maternal blood in the intervillous space to the fetus, its oxygen saturation resembles that in the maternal capillaries. The average oxygen saturation of intervillous blood is estimated to be 65 to 75 percent, with a partial pressure (PO2) of about 30 to 35 mm Hg. The oxygen saturation of umbilical vein blood is similar, but with a somewhat lower oxygen partial pressure.
In general, transfer of fetal carbon dioxide is accomplished by diffusion. The placenta is highly permeable to carbon dioxide, which traverses the chorionic villus more rapidly than oxygen. Near term, the partial pressure of carbon dioxide (PCO2) in the umbilical arteries is estimated to average about 48 mm Hg, or about 5 mm Hg more than in the maternal intervillous blood. Fetal blood has less affinity for carbon dioxide than does maternal blood, thereby favoring the transfer of carbon dioxide from the fetus to the mother. Also, mild hyperventilation by the pregnant woman results in a fall in PCO2, favoring a transfer of carbon dioxide from the fetal compartment to maternal blood.
Selective Transfer and Facilitated Diffusion
Although simple diffusion is an important method of placental transfer, the trophoblast and chorionic villus unit demonstrate enormous selectivity in transfer. This results in different concentrations of a variety of metabolites on the two sides of the villus. The concentrations of a number of substances that are not synthesized by the fetus are several times higher in fetal than in maternal blood. Ascorbic acid is a good example of this phenomenon. This relatively low-molecular-weight substance resembles the pentose and hexose sugars and might be expected to traverse the placenta by simple diffusion. The concentration of ascorbic acid, however, is two to four times higher in fetal plasma than in maternal plasma (Morriss and associates, 1994). The unidirectional transfer of iron across the placenta provides another example of transport and sequestration of selected agents. Typically, iron is present in the plasma of the pregnant woman at a lower concentration than in her fetus.

The fetal bowel contents consist of various products of secretion, such as glycerophospholipids from the lung, desquamated fetal cells, lanugo, scalp hair, and vernix. It also contains undigested debris from swallowed amnionic fluid. The dark greenish-black appearance is caused by pigments, especially biliverdin. Meconium passage can result from normal bowel peristalsis in the mature fetus or from vagal stimulation. It can also occur when hypoxia stimulates argininevasopressin (AVP) release from the fetal pituitary gland. AVP stimulates the smooth muscle of the colon to contract, resulting in intra-amnionic defecation (DeVane and co-workers, 1982; Rosenfeld and Porter, 1985). Small bowel obstruction may lead to vomiting in utero (Shrand, 1972). Fetuses who suffer from congenital chloride diarrhea may have diarrhea in utero, which leads to hydramnios and preterm delivery (Holmberg and associates, 1977).

The fetal circulation is substantially different from that of the adult and functions smoothly until the moment of birth, when it is required to change dramatically. For example, because fetal blood does not need to enter the pulmonary vasculature to be oxygenated, the major portion of the right ventricular output bypasses the lungs. In addition, the fetal heart chambers work in parallel, not in series, which effectively supplies the brain and heart with more highly oxygenated blood than the rest of the body.
Oxygen and nutrient materials required for fetal growth and maturation are delivered to the fetus from the placenta by the single umbilical vein. The vein then divides into the ductus venosus and the portal sinus. The ductus venosus is the major branch of the umbilical vein and traverses the liver to enter the inferior vena cava directly. Because it does not supply oxygen to the intervening tissues, it carries well-oxygenated blood directly to the heart. In contrast, the portal sinus carries blood to the hepatic veins primarily on the left side of the liver, where oxygen is extracted. The relatively deoxygenated blood from the liver then flows back into the inferior vena cava, which also receives less oxygenated blood returning from the lower body. Blood flowing to the fetal heart from the inferior vena cava, therefore, consists of an admixture of arterial-like blood that passes directly through the ductus venosus and less well-oxygenated blood that returns from most of the veins below the level of the diaphragm. The oxygen content of blood delivered to the heart from the inferior vena cava is thus lower than that leaving the placenta.
In contrast to postnatal life, the ventricles of the fetal heart work in parallel, not in series. Well-oxygenated blood enters the left ventricle, which supplies the heart and brain, and less oxygenated blood enters the right ventricle, which supplies the rest of the body. The two separate circulations are maintained by the structure of the right atrium, which effectively directs entering blood to either the left atrium or the right ventricle, depending on its oxygen content. This separation of blood according to its oxygen content is facilitated by the pattern of blood flow in the inferior vena cava. The well-oxygenated blood tends to course along the medial aspect of the inferior vena cava and the less oxygenated blood stays along the lateral vessel wall, facilitating their shunting into opposite sides of the heart. Once this blood enters the atrium, the configuration of the upper interatrial septum, called the crista dividens, is such that it preferentially shunts the well-oxygenated blood from the medial side of the inferior vena cava and the ductus venosus through the foramen ovale into the left heart and then to the heart and brain (Dawes, 1962). After these tissues have extracted needed oxygen, the resulting less oxygenated blood returns to the right heart through the superior vena cava.
The less oxygenated blood coursing along the lateral wall of the inferior vena cava enters the right atrium and is deflected through the tricuspid valve to the right ventricle. The superior vena cava courses inferiorly and anteriorly as it enters the right atrium, ensuring that less well-oxygenated blood returning from the brain and upper body also will be shunted directly to the right ventricle. Similarly, the ostium of the coronary sinus lies just superior to the tricuspid valve so that less oxygenated blood from the heart also returns to the right ventricle. As a result of this blood flow pattern, blood in the right ventricle is 15 to 20 percent less saturated than blood in the left ventricle.
The major portion, almost 90 percent, of blood exiting the right ventricle is then shunted through the ductus arteriosus to the descending aorta. The high pulmonary vascular resistance and the comparatively lower resistance in the ductus arteriosus and the umbilical–placental vasculature ensure that only about 15 percent of right ventricular output (8 percent of the combined ventricular output) goes to the lungs (Teitel, 1992). Thus, one third of the blood passing through the ductus arteriosus is delivered to the body. The remaining right ventricular output returns to the placenta through the two hypogastric arteries, which distally become the umbilical arteries.
In the placenta, this blood picks up oxygen and other nutrients and is then recirculated back through the umbilical vein. After birth, the umbilical vessels, ductus arteriosus, foramen ovale, and ductus venosus normally constrict or collapse. With the functional closure of the ductus arteriosus and the expansion of the lungs, blood leaving the right ventricle preferentially enters the pulmonary vasculature to become oxygenated before it returns to the left heart. Virtually instantaneously, the ventricles, which had worked in parallel in fetal life, now effectively work in series. The more distal portions of the hypogastric arteries, which course from the level of the bladder along the abdominal wall to the umbilical ring and into the cord as the umbilical arteries, undergo atrophy and obliteration within 3 to 4 days after birth. These become the umbilical ligaments, while the intra-abdominal remnants of the umbilical vein form the ligamentum teres. The ductus venosus constricts by 10 to 96 hours after birth and is anatomically closed by 2 to 3 weeks, resulting in the formation of the ligamentum venosum (Clymann and Heymann, 1981).

During the first 2 months of pregnancy, the embryo consists almost entirely of water. Because of the small amount of yolk in the human ovum, growth of the embryo-fetus from an early stage of development is dependent on nutrients obtained from the mother. During the first few days after implantation, the nutrition of the blastocyst comes from the interstitial fluid of the endometrium and the surrounding maternal tissue. Within the next week, the forerunners of the intervillous space are formed. In the beginning, these are simply lacunae that are filled with maternal blood, but during the third week after fertilization, fetal blood vessels in the chorionic villi appear. During the fourth week, a cardiovascular system has formed, and thereby a true circulation is established both within the embryo and between the embryo and the chorionic villi.
The maternal diet is translated into storage forms that are made available to meet the demands for energy, tissue repair, and new growth, including maternal needs for pregnancy. Three major maternal storage depots—the liver, muscle, and adipose tissue—and the storage hormone insulin are intimately involved in the metabolism of the nutrients absorbed from the maternal gut.
Insulin secretion is sustained by increased serum levels of glucose and amino acids. The net effect is storage of glucose as glycogen primarily in liver and muscle, retention of some amino acids as protein, and storage of the excess as fat. Storage of maternal fat peaks in the second trimester, and then declines as fetal demands increase in late pregnancy (Pipe and colleagues, 1979).
During times of fasting, glucose is released from glycogen, but maternal glycogen stores cannot provide an adequate amount of glucose to meet requirements for maternal energy and fetal growth. However, cleavage of triacylglycerols, stored in adipose tissue, provides the mother with energy in the form of free fatty acids. Lipolysis is activated, directly or indirectly, by several hormones, including glucagon, norepinephrine, placental lactogen, glucocorticosteroids, and thyroxine.

Development during the fetal period of gestation consists of growth and maturation of structures that were formed during the embryonic period.
12 Gestational Weeks
By the end of the 12th week of pregnancy, when the uterus usually is just palpable above the symphysis pubis, the crown-rump length of the fetus is 6 to 7 cm. Centers of ossification have appeared in most of the fetal bones, and the fingers and toes have become differentiated. Skin and nails have developed and scattered rudiments of hair appear. The external genitalia are beginning to show definitive signs of male or female gender. The fetus begins to make spontaneous movements.
16 Gestational Weeks
By the end of the 16th week, the crown-rump length of the fetus is 12 cm, and the weight is 110 g. Gender can be correctly determined by experienced observers by inspection of the external genitalia by 14 weeks.
20 Gestational Weeks
The end of the 20th week is the midpoint of pregnancy as estimated from the beginning of the last normal menstrual period. The fetus now weighs somewhat more than 300 g, and the weight begins to increase in a linear manner. The fetal skin has become less transparent, a downy lanugo covers its entire body, and some scalp hair has developed.
24 Gestational Weeks
By the end of the 24th week, the fetus weighs about 630 g. The skin is characteristically wrinkled, and fat deposition begins. The head is still comparatively large, and eyebrows and eyelashes are usually recognizable. The canalicular period of lung development, during which the bronchi and bronchioles enlarge and alveolar ducts develop, is nearly completed. A fetus born at this time will attempt to breathe, but most will die because the terminal sacs, required for gas exchange, have not yet formed.
28 Gestational Weeks
By the end of the 28th week, a crown-rump length of about 25 cm is attained and the fetus weighs about 1100 g. The thin skin is red and covered with vernix caseosa. The pupillary membrane has just disappeared from the eyes. An infant born at this time moves limbs energetically and cries weakly. The otherwise normal infant of this age has a 90-percent chance of survival without physical or neurological impairment.
32 Gestational Weeks
At the end of 32 gestational weeks, the fetus has attained a crown-rump length of about 28 cm and a weight of about 1800 g. The skin surface is still red and wrinkled. Barring other complications, infants born at this period also usually survive intact.
36 Gestational Weeks
At the end of 36 weeks of gestation, the average crown-rump length of the fetus is about 32 cm and the weight is about 2500 g. Because of the deposition of subcutaneous fat, the body has become more rotund, and the previous wrinkled appearance of the face has been lost. Infants born at this time have an excellent chance of survival with proper care.
40 Gestational Weeks
Term is reached at 40 weeks from the onset of the last menstrual period. At this time, the fetus is fully developed. The average crown-rump length of the fetus at term is about 36 cm, and the weight is approximately 3400 g.

Prolactin-like activity in the human placenta was first described by Ehrhardt in 1936. The protein responsible for this activity was isolated from extracts of human placenta and retroplacental blood (Ito and Higashi, 1961; Josimovich and MacLaren, 1962). Because of the potent lactogenic and growth hormone–like bioactivity, as well as an immunochemical resemblance to human growth hormone, it was first called human placental lactogen or chorionic growth hormone. It also has been referred to as chorionic somatomammotropin. Recently, most authors have used the original name, human placental lactogen (hPL). Grumbach and Kaplan (1964) found, by immunofluorescence studies, that this hormone, like hCG, was concentrated in the syncytiotrophoblast. It is detected in the trophoblast as early as the second or third week after fertilization of the ovum. As with hCG, hPL also is identified in cytotrophoblasts from before 6 weeks (Maruo and associates, 1992).
Chemical Characteristics
Placental lactogen is a single nonglycosylated polypeptide chain with a molecular weight of 22,279 daltons. It is derived from a precursor of 25,000 daltons that contains a 26-amino-acid signal sequence. There are 191 amino-acid residues in placental lactogen, compared with 188 in human growth hormone (hGH). The amino acid sequence in each hormone is strikingly similar, with 96-percent homology. HPL also is structurally similar to human prolactin (hPRL), with an amino-acid sequence similarity of about 67 percent. For these reasons, it has been suggested that the genes for hPL, hPRL, and hGH evolved from a common ancestral gene—probably that of prolactin—by repeated gene duplication (Ogren and Talamantes, 1994).
Gene Structure and Expression
There are five genes in the growth hormone–placental lactogen gene cluster that are linked and located on chromosome 17. Two of these genes, hPL2 and hPL3, both encode hPL, and the amount of mRNA in the term placenta is similar for each. In contrast, the prolactin gene is located on chromosome 6 (Owerbach and colleagues, 1980, 1981). The production rate of hPL near term, about 1 g/day, is the greatest, by far, of any known hormone in humans.
Serum Concentration
HPL is demonstrable in the placenta within 5 to 10 days after conception and can be detected in maternal serum as early as 3 weeks after fertilization. Maternal plasma concentration rises steadily until about 34 to 36 weeks and this rise is linked mainly to placental mass. The serum concentration reaches higher levels in late pregnancy (5 to 15 g/mL) than those of any other known protein hormone. The half-life of hPL in maternal plasma is between 10 and 30 minutes (Walker and co-workers, 1991).
Very little hPL is detected in fetal blood or in the urine of the mother or newborn. Amnionic fluid levels are somewhat lower than in maternal plasma. Because hPL is secreted primarily into the maternal circulation, with only very small amounts in cord blood, it appears that the role of the hormone in pregnancy, if any, is mediated through actions in maternal rather than in fetal tissues. Nonetheless, there is continuing interest in the possibility that hPL serves select functions in fetal growth.
Regulation of hPL Biosynthesis
The levels of mRNA for hPL in syncytiotrophoblast remain relatively constant throughout pregnancy. This finding is supportive of the idea that the rate of hPL secretion is proportional to placental mass. There are very high plasma levels of hCG in women with trophoblastic neoplasms, but only low levels of hPL in these same women.
Prolonged maternal starvation in the first half of pregnancy leads to an increase in the plasma concentration of hPL. Short-term changes in plasma glucose or insulin, however, have relatively little effect on plasma levels of hPL. In vitro studies using human syncytiotrophoblast suggest that the synthesis of hPL is stimulated by insulin and insulin-like growth factor-1 and inhibited by PGE2 and PGF2 (Bhaumick and colleagues, 1987; Genbacev and colleagues, 1977).
Metabolic Actions
HPL has putative actions in a number of important metabolic processes. These include.
1. Maternal lipolysis and an increase in the levels of circulating free fatty acids, thereby providing a source of energy for maternal metabolism and fetal nutrition.
2. An anti-insulin or “diabetogenic” action, leading to an increase in maternal levels of insulin, which favors protein synthesis and provides a readily available source of amino acids for transport to the fetus.
3. A potent angiogenic hormone; it also may play an important role in the formation of fetal vasculature (Corbacho and co-workers, 2002).