Early placental development

After fertilization and egg cleavage, the morula is transformed into a blastocyst by the formation of a fluid-filled cavity within the ball of cells.

The outer layer of the blastocyst consists of primitive cytotrophoblast and, by day 7, the blastocyst penetrates the endometrium as a result of trophoblastic invasion (Fig. 4.1). The outer layer of trophoblast becomes a syncytium. In response to contact with the syncytiotrophoblast, the endometrial stromal cells become large and pale, a process known as the decidual reaction. Some endometrial cells are phagocytosed by the trophoblastic cells.

The nature and function of the decidual reaction remain uncertain, but it seems likely that the decidual cells both limit the invasion of trophoblastic cells and serve an initial nutritional function for the developing placenta.

During development of the placenta, cords of cytotrophoblast or Langhans cells grow down to the basal layers of decidua and penetrate some of the endometrial venules and capillaries. The formation of lacunae filled with maternal blood presages the development of the intervillous space.

The invading cords of trophoblast form the primary villi, which later branch to form secondary villi and, subsequently, free-floating tertiary villi.

The central core of these villi is penetrated by a column of mesoblastic cells that become the capillary network of the villi. The body stalk attaching the developing fetus to the placenta forms the umbilical vessels, which advance into the villi to join the villous capillaries and establish the placental circulation.

Although trophoblastic cells surround the original blastocyst, the area that develops into the placenta becomes thickened and extensively branched and is known as the chorion frondosum. However, in the area that subsequently expands to form the outer layer of the fetal membranes or chorion laeve, the villi become atrophic and the surface becomes smooth (Fig. 4.2). The decidua underlying the placenta is known as the decidua basalis and the decidua between the membranes and the myometrium as the decidua capsularis.

Further placental development

By 6 weeks after ovulation, the trophoblast has invaded some 40–60 spiral arterioles. Blood from the maternal vasculature pushes the free-floating secondary and tertiary capillaries into a tent-shaped maternal cotyledon. The tents are held down to the basal plate of the decidua by anchoring villi, and the blood from arterioles spurts towards the chorionic plate and then returns to drain through maternal veins in the basal plate. There are eventually about 12 large maternal cotyledons and 40–50 smaller ones (Fig. 4.3).

The villus

Despite the arrangement of villi into maternal cotyledons, the functional unit of the placenta remains the stem villus or fetal cotyledon. The end unit of the stem villus, sometimes known as the terminal or chorionic villus is shown in Figure 4.4. There are initially about 200 stem villi arising from the chorion frondosum. About 150 of these structures are compressed at the periphery of the maternal cotyledons and become relatively functionless, leaving a dozen or so large cotyledons and 40–50 smaller ones as the active units of placental function.

The estimated total surface area of the chorionic villi in the mature placenta is approximately 11 m². The surface area of the fetal side of the placenta and of the villi is enlarged by the presence of numerous microvilli. The core of the villus consists of a stroma of closely packed spindle-shaped fibroblasts and branching capillaries. The stroma also contains phagocytic cells known as Hofbauer cells. In early pregnancy, the villi are covered by an outer layer of syncytiotrophoblast and an inner layer of cytotrophoblast. As pregnancy advances, the cytotrophoblast disappears until only a thin layer of syncytiotrophoblast remains. The formation of clusters of syncytial cells, known as syncytial knots, and the reappearance of cytotrophoblast in late pregnancy are probably the result of hypoxia. There is evidence that the rate of apoptosis of syncytial cells accelerates towards term and is particularly increased where there is evidence of fetal growth impairment.

Structure of the umbilical cord

The umbilical cord contains two arteries and one vein (Fig. 4.5). The two arteries carry deoxygenated blood from the fetus to the placenta and the oxygenated blood returns to the fetus via the umbilical vein. Absence of one artery occurs in about 1 in 200 deliveries and is associated with a 10–15% incidence of cardiovascular anomalies. The vessels are surrounded by a hydrophilic mucopolysaccharide known as Wharton’s jelly and the outer layer covering the cord consists of amniotic epithelium. The cord length varies between 30 and 90 cm.

The vessels grow in a helical shape. This configuration has the functional advantage of protecting the patency of the vessels by absorbing torsion without the risk of kinking or snarling of the vessels.

The few measurements that have been made in situ of blood pressures in the cord vessels indicate that the arterial pressure in late pregnancy is around 70 mmHg systolic and 60 mmHg diastolic, with a relatively low pulse pressure and a venous pressure that is exceptionally high, at approximately 25 mmHg. This high venous pressure tends to preserve the integrity of the venous flow and indicates that the pressure within the villus capillaries must be in excess of the cord venous pressures.

The high capillary pressures imply that, at the point of proximity, the fetal pressures exceed the pressures in the choriodecidual space, so that any disruption of the villus surface means that fetal blood cells enter the maternal circulation and only rarely do maternal cells enter the fetal vascular space.

The cord vessels often contain a false knot consisting of a refolding of the arteries; occasionally, blood flow is threatened by a true knot, although such formations are often seen without any apparent detrimental effects on the fetus.

In the full-term fetus, the blood flow in the cord is approximately 350 mL/min.

Uteroplacental blood flow

Trophoblastic cells invade the spiral arterioles within the first 10 weeks of pregnancy and destroy some of the smooth muscle in the wall of the vessels which then become flaccid dilated vessels. Maternal blood enters the intervillous space and, during maternal systole, blood spurts from the arteries towards the chorionic plate of the placenta and returns to the venous openings in the placental bed. The intervillous space is characterized by low pressures, with a mean pressure estimated at 10 mmHg and high flow. Assessments of uterine blood flow at term indicate values of 500–750 mL/min (Fig. 4.6).

Placental transfer

The placenta plays an essential role in growth and development of the fetus and in regulating maternal adaptation to pregnancy. The placenta is an organ of fetal nutrition, excretion, respiration, and of hormone synthesis.

Transfer of materials across the placental membrane is governed by molecular mass, solubility and the ionic charge of the substrate involved. Actual transfer is achieved by simple diffusion, facilitated diffusion, active transport and pinocytosis (Fig. 4.7).

Simple diffusion

Transfer between maternal and fetal blood is regulated by the trophoblast, and it must be remembered that the layer separating fetal from maternal blood in the chorionic villus is not a simple semipermeable membrane but a metabolically active cellular layer. However, with regard to some substances, it does behave like a semipermeable membrane and substances pass by simple diffusion.

Although there are some exceptions, small molecules generally cross the placenta in this way and movement is determined by chemical or electrochemical gradients. The quantity of solute transferred is described by the Fick diffusion equation:

< ?xml:namespace prefix = "mml" />Qt=KA(C1−C2)L

where is the quantity transferred per unit of time, K is a diffusion constant for the particular substance, A is the total surface area available, C¹ and C² indicate the difference in concentrations of solute and L represents the thickness of the membrane.

This method is applicable particularly to transfer of gases, although the gradient of oxygen, for example, is exaggerated by the fact that oxygen is extracted by the villous trophoblast.

Placental function

The placenta has three major functions:

Gaseous exchange

As the transfer of gases occurs by simple diffusion, the major determinants of gaseous exchange are the efficiency and flow of the fetal and maternal circulation, the surface area of the placenta that is available for transfer and the thickness of the placental membrane.

Oxygen transfer

The average oxygen saturation of maternal blood entering the intervillous space is 90–100% at a PO₂ of 90–100 mmHg and these high levels of oxygen favour transfer to the fetal circulation. After the placenta itself has utilized some of this oxygen, the remainder is available to the fetal circulation. Fetal haemoglobin has a higher affinity for oxygen than does adult haemoglobin and haemoglobin concentration is higher in the fetus. All of these factors favour the rapid uptake of oxygen by the fetus at PO₂ levels as low as 30–40 mmHg. The extent to which haemoglobin can be saturated by oxygen is affected by hydrogen ion concentration. The increase that occurs in deoxygenated blood arriving in the placental circulation from the fetus favours the release of maternal oxygen in the fetoplacental bed. The oxygen dissociation curve is shifted to the right by the increase in H⁺ concentration, PCO₂ and temperature and this is known as the Bohr effect (Fig. 4.8). Oxygen is predominantly transported in the form of oxyhaemoglobin as there is little free oxygen in solution.

Carbon dioxide transfer

Carbon dioxide is readily soluble in blood and transfers rapidly across the placenta. The partial pressure difference is about 5 mmHg. Transport of carbon dioxide may occur in solution as either bicarbonate or carbonic acid. It is also transported as carbaminohaemoglobin. The binding of CO₂ to haemoglobin is affected by factors that influence oxygen release. Thus, an increase in carbaminohaemoglobin results in the release of oxygen. This is known as the Haldane effect.

Acid–base balance

Factors involved in the regulation of acid–base balance such as H⁺, lactic acid and bicarbonate ions also move across the placenta. As a consequence, acidosis associated with starvation and dehydration in the mother may also result in acidosis in the fetus. However, the fetus may become acidotic as the result of oxygen deprivation in the presence of normal maternal acid–base balance.

Up to 10 weeks gestation, a massive increase in cell numbers occurs in the developing embryo but the actual gain in weight is small. Thereafter a rapid increase in weight occurs, until the full-term fetus reaches a final weight of around 3.5 kg.

Protein accumulation occurs in the fetus throughout pregnancy. However, the situation is very different as far as fetal adipose tissue is concerned. Free fatty acids are stored in brown fat around the neck, behind the scapulae and the sternum and around the kidneys. White fat forms the subcutaneous fat covering the body of the full-term fetus. Fat stores in the fetus between 24–28 weeks gestation make up only 1% of the body weight whereas by 35 weeks it makes up 15% of body weight.

The rate of fetal growth diminishes towards term. Actual fetal size is determined by a variety of factors, including the efficiency of the placenta, the adequacy of the uteroplacental blood flow and inherent genetic and racial factors in the fetus.

Fetal birth weight is determined by gestational age, race, maternal height and weight and parity. Thus, the projected normal birth weight for an infant is determined by a combination of all of these factors (Fig. 4.9). The normal growth curve therefore varies in each infant and can only be determined by taking into account the history of each individual mother. From all these factors, a nomogram for growth can be calculated. Figure 4.9 has the nomogram constructed for Mrs Small that shows the 5th and 95th centile to be between 35 and 39 cm in fundal height at 41 to 42 weeks, whilst it is 37 to 42 cm for Mrs Average. Hence the same growth trajectory plotted in the Mrs Small’s nomogram shows the fetus to be growing within normal limits and the last plot shows the estimated fetal weight to be about 3.0 kg, but the same plots in Mrs Average’s nomogram results in a fetus that shows growth restriction with progress of gestation.

The characteristic appearance of the fetus at 12 weeks gestation is shown in Figure 4.10. The skin is translucent and there is virtually no subcutaneous fat so that the blood vessels in the skin are easily seen, but even at this stage the fetus reacts to stimuli. The upper limbs have already reached their final relative length and the external genitals are distinguishable externally but remain undifferentiated.

By 16 weeks gestation (Fig. 4.11), the crown–rump length is 122 mm and the lower limbs have achieved their final relative length. The external genitalia can now be differentiated.

By 24 weeks gestation (Fig. 4.12), the crown–rump length is 210 mm. The eyelids are separated, the skin is opaque but wrinkled because of the lack of subcutaneous fat, and there is fine hair covering the body. By 28 weeks, the eyes are open and the scalp is growing hair.

The cardiovascular system

The heart develops initially as a single tube and, by 4–5 weeks gestation, a heartbeat is present at a rate of 65 beats/min. The definitive circulation has developed by 11 weeks gestation and the heart rate increases to around 140 beats/min. In the mature fetal circulation, about 40% of the venous return entering the right atrium flows directly into the left atrium through the foramen ovale (Fig. 4.13). Blood pumped from the right atrium into the right ventricle is expelled into the pulmonary artery, where it passes either into the aorta via the ductus arteriosus or into the pulmonary vessels.

In the mature fetus, the fetal cardiac output is estimated to be 200 mL⁻¹min⁻¹kg body weight. Unlike the adult circulation, fetal cardiac output is entirely dependent on heart rate and not on stroke volume. Autonomic control of the fetal heart rate matures during the third trimester and parasympathetic vagal tonus tends to reduce the basal fetal heart rate.

The amniotic sac develops in early pregnancy and has been identified in the human embryo as early as 7 days. The first signs of the development of the amniotic cavity can be seen in the inner cell mass of the blastocyst.

Early in pregnancy, amniotic fluid is probably a dialysate of the fetal and maternal extracellular compartments and therefore is 99% water. It does have a cellular and protein content as well. There is evidence that up to 24 weeks gestation when keratinization of fetal skin begins, significant transfer of water may occur by transudation across the fetal skin. In the second half of pregnancy after the onset of kidney function, fetal urine provides a significant contribution to amniotic fluid volume. Certainly, when the kidneys are missing, as in renal agenesis, the condition is invariably associated with minimal amniotic fluid volume, a condition known as oligohydramnios.

The role of the fetus in the regulation of amniotic fluid volume in normal pregnancy is poorly understood but the fetus swallows amniotic fluid, absorbs it in the gut and, in later pregnancy, excretes urine into the amniotic sac (Fig. 4.14).

It must be noted that this is a highly dynamic state, as the total volume of water in the amniotic sac is turned over every 2–3 hours. Any factor that interferes with either formation or removal of amniotic fluid may therefore result in a rapid change in amniotic fluid volume.

Congenital abnormalities that are associated with impaired ability to ingest amniotic fluid are commonly associated with excessive amniotic fluid volume, a condition known as polyhydramnios.

In summary, amniotic fluid is formed by the secretion and transudation of fluid through the amnion and fetal skin and from the passage of fetal urine into the amniotic sac. Circulation of amniotic fluid occurs by reabsorption of fluid through the fetal gut, skin and amnion.

Amniocentesis

Amniotic fluid is obtained by the procedure of amniocentesis. This procedure involves inserting a fine-gauge needle under aseptic conditions through the anterior abdominal wall of the mother under local anaesthesia. The procedure, when used for diagnostic testing for chromosomal abnormalities, is commonly performed at 14–16 weeks gestation but can be performed as early as 12 weeks in some circumstances. The procedure must be performed under ultrasound control in order to identify the best and most accessible pool of amniotic fluid and, where possible, to avoid the placenta and the fetus. Up to 10 mL of fluid is withdrawn and the presence of a fetal heart beat is checked both before and after the procedure (Fig. 4.15).