Maternal circulation

The placenta.

Fetal arteries and veins

Chorionic villi

Maternal and fetal blood vessels in the placenta. Chorionic villi are seen dipping down into the maternal circulation. Maternal vessels either envelop a chorionic villus or release spurts of blood directly into the intervillous space. The two circulations are separated by two layers of cells. These cells have microvilli and present a huge surface area for exchange of gases and essential nutrients.

Cylotropho blast

Syncytiotrophoblast

Intervillous space

Chorionic plate

Chorionic villi

Branches of spiral arteries

Maternal veins

Maternal and fetal blood vessels in the placenta. Chorionic villi are seen dipping down into the maternal circulation. Maternal vessels either envelop a chorionic villus or release spurts of blood directly into the intervillous space. The two circulations are separated by two layers of cells. These cells have microvilli and present a huge surface area for exchange of gases and essential nutrients.

Intervillous space

Maternal blood bathes the fetal vessels in the chorionic villi. Some maternal blood circles the fetal villi before draining into the maternal veins; some enters the centre of a villus, and disperses laterally before draining; some is ejected from spiral arteries directly into the intervillous space.

Maternal veins Spiral arteries

Chorion

Desatu rated maternal venous blood

Intervillous space

Saturated maternal arterial blood

Maternal blood bathes the fetal vessels in the chorionic villi. Some maternal blood circles the fetal villi before draining into the maternal veins; some enters the centre of a villus, and disperses laterally before draining; some is ejected from spiral arteries directly into the intervillous space.

With increasing gestation, the cytotrophoblast ceases to be a continuous layer and is represented by individual cells beneath the syncytiotrophoblast. In turn, syncytiotrophoblastic cells unite with fetal capillary endothelial cells to form a vasculosyncytial membrane.

PLACENTAL BLOOD FLOW

Fetal well-being depends on an adequate placental blood flow. At term, the uterine blood flow is approximately 500-700 ml min"1, of which 70-90% is distributed to the placenta.

The smooth muscle in the spiral arteries disappears during pla-centation, thus providing a low resistance to the driving pressure of the maternal cardiac output, which forces blood into the intervillous space.

Placental blood flow depends on the balance between the perfusion pressure across the intervillous space and the resistance of the spiral arteries. Placental perfusion is therefore reduced by changes in cardiac output (e.g. haemorrhage) or uterine hyper-tonicity (e.g. overstimulation by Syntocinon). The spiral and uterine arteries possess a-receptors. Maternal sympathetic stimulation caused by hypotension or catecholamine release resulting from pain may markedly reduce placental perfusion.

Intervillous pressure is increased by intrauterine (i.e. amniotic fluid) pressure and by increased venous pressure (e.g. aortocaval compression).

uterine arterial pressure - (intrauterine pressure + uterine venous pressure)

Placental blood flow = -

intrinsic resistance of spiral arteries + extrinsic resistance (myometrial tone)

The normal fetus may tolerate a 50% reduction in uteroplacental blood flow, because there is good circulatory reserve.

FUNCTIONS OF THE PLACENTA Hormonal

Placental syncytiotrophoblasts secrete human chorionic gonado-trophin (hCG). hCG production commences in very early pregnancy, increases at a remarkable rate, peaks at 8-10 weeks, and declines until a few weeks before term when secretion starts to increase again. The rapid increase in early pregnancy is to stimulate the corpus luteum to secrete progesterone to maintain the viability of the pregnancy. No obvious biological function for hCG in late pregnancy has yet been defined.

Human placental lactogen (hPL) concentration increases from 0.3 pg L"1 at 10-14 weeks to 5.4 pg L"1 by 35-38 weeks. It increases lipolysis, inhibits gluconeogenesis and prevents glucose uptake by maternal tissues (i.e. an anti-insulin effect). hPL can be considered as a metabolic signal by which the fetus obtains nutrients.

Oestrogens. Four oestrogens are secreted: oestrone, oestradiol, oestriol and oestetrol. The role of oestrogens in pregnancy is not entirely clear, although their effect on the breast and the uterus are obvious. They also play a part in fetal development.

Progestogens. Progesterone is the most important hormone in this group and the physiological effects are necessary for the initiation and maintenance of maternal adaptation to pregnancy. Its role in late pregnancy has not been elucidated.

Other hormones. The placenta secretes alkaline phosphatase, cystine aminopeptidase and several other protein hormones. Their role in the physiology of pregnancy is not yet clear.

Immunological

The placenta modifies the immune systems of both mother and fetus so that the fetus is not rejected. The mechanism by which this occurs is poorly understood. In pregnancy there is a reduction in cell-mediated immunity. There is a reduction in the activity of T-cytotoxic cells and a reduction in numbers of T-helper cells. The trophoblast acts as an immunologically inert barrier between mother and fetus. However, there is an increase in numbers and activity of neutrophils. IgG is transferred to the fetus in utero and confers some passive immunity. It may produce fetal disease. Modification of the maternal immune system may be the cause of the rapid spread of some cancers during pregnancy and the rapidity with which some viral disorders become life-threatening, e.g. chickenpox with pneumonitis.

Transport of respiratory gases

This is the most important function of the placenta. Gas exchange between mother and fetus takes place in the intervillous space and is governed by the laws of diffusion, aided by the different oxygen affinities of maternal and fetal haemoglobins. Fetal haemoglobin (HbF) has a much higher affinity for oxygen than does adult haemoglobin (HbA). The high affinity of HbF is explained partly by diminished binding of 2,3-DPG in the central cavity which is formed by the gamma chains. Thus 2,3-DPG cannot facilitate release of oxygen in the placenta; HbF can carry more oxygen than can HbA.

The oxyhaemoglobin dissociation curve (ODC) of HbF is to the left: of that for HbA. As the oxygen tension decreases on the normal oxygen cascade, HbA unloads 4.7 ml of oxygen from each 100 ml of blood, whereas HbF unloads only 3.0 ml of oxygen. However, between an oxygen tension of 2.0 kPa (fetal tissue) and 4.5 kPa (placenta), HbF loads 10.3 ml of oxygen to each 100 ml of blood, compared with 8.8 ml for HbA. The loading-unloading advantages of HbF are at low oxygen tensions.

The sequence of events in placental gas transfer is best considered in the following steps:

1. Fetal blood gives up carbon dioxide.

2. Fetal blood becomes more alkaline.

3. Fetal ODC shifts further to the left, increasing oxygen affinity.

4. Fetal carbon dioxide diffuses across to maternal blood.

5. Maternal pH decreases.

6. Maternal ODC shifts to the right (Bohr effect).

7. Oxygen release is facilitated.

8. Oxygen is taken up by left-shifted fetal ODC (double Bohr effect).

9. Within the placenta, HbF becomes more acidic with oxygenation.

10. HbF releases carbon dioxide (Haldane effect).

11. HbA becomes less acidic as it becomes increasingly deoxygenated.

12. HbA binds more carbon dioxide (double Haldane effect).

13. Carbon dioxide enters maternal cells.

14. HC03~ is formed and exchanged for chloride (reversed Hamburger phenomenon).

15. A fetomaternal diffusion gradient is maintained.

16. Maternal blood has carbonic anhydrase.

17. Therefore, maternal blood has higher carbon dioxide binding power.

In the intervillous space, the diffusion gradient for oxygen is approximately 4.0 kPa, and for carbon dioxide is approximately 1.3 kPa.

Placental exchange of oxygen is regulated mainly by a change in oxygen affinities of HbA and HbF caused principally by altered hydrogen ion and carbon dioxide concentrations on both sides of the placenta.

Without the double Bohr and double Haldane effects, the diffusion gradients or placental blood flow would have to be increased considerably to maintain the same efficiency of gas transfer.

PLACENTAL TRANSFER OF DRUGS

The barrier between maternal and fetal blood is a single layer of chorion united with fetal endothelium. The surface area of this is vastly increased by the presence of microvilli. Placental transfer of drugs occurs, therefore, by passive diffusion through cell membranes which are lipophilic. However, this membrane appears to be punctuated by channels which allow transfer of hydrophilic molecules at a rate that is around 100 000 times lower.

Hence drugs cross the placenta by simple diffusion of un-ionized lipophilic molecules. Fick's law of diffusion applies. The rate is directly proportional to the maternofetal concentration gradient and the area of the placenta available for transfer, and inversely proportional to placental thickness. Lipid solubility, degree of ionization and protein binding affect placental transfer, as do the dose and route of administration and absorption, distribution and metabolism in the mother.

Lipid solubility

The placental membrane is freely permeable to lipid-soluble substances which undergo flow-dependent transfer. As the rate of transfer depends on the concentration gradient of the drug across the membrane and blood flow on each side, maternal hypotension reduces placental blood flow and, consequently, transfer of lipid-soluble drugs.

Hydrophilic substances

The placental membrane carries an electrical charge; ionized molecules with the same charge are repelled, while those with the opposite charge are retained within the membrane. The rate of this permeability-dependent transfer is inversely proportional to molecular size. Size limitation for polar substances begins at molecular weights between 50 and 100 Da. Ions diffuse much more slowly. Factors affecting the degree of ionization alter the rate of transfer.

Maternal pH

This alters ionization of a partially ionized drug. The maternal-fetal pH gradient also affects transfer. The degree of ionization of acidic drugs is greater on the maternal side and lower on the fetal side. The converse applies for basic drugs.

Protein binding

A dynamic equilibrium exists between bound (unavailable) and unbound (available) drug. Protein binding is pH-dependent, e.g. acidosis reduces protein binding of local anaesthetics. Reduced albumin concentration increases the proportion of unbound drug. Many basic drugs are bound to a,-glycoprotein, which is present in much lower concentrations in the fetus.

THE FETUS

The fetus has adapted to life in a hypoxic environment but adjusts quickly to extrauterine life.

Fetal circulation (Fig. 29.7)

Oxygenated blood in the umbilical vein divides into two branches passing though the ductus venosus and the portal sinus. The ductus venosus enters the inferior vena cava, bypassing the liver. The portal sinus supplies the left lobe of the liver. The blood in the right atrium divides into two streams. The main stream enters the left atrium via the foramen ovale and is carried ultimately to the head, brain and heart via the left ventricle and aorta.

A smaller stream, together with superior vena caval blood, enters the right ventricle. The right ventricle is dominant, ejecting 66% of the combined ventricular output. Blood in the right ventricle enters the pulmonary artery, but the high pulmonary vascular resistance ensures that blood is shunted to the aorta via the ductus arteriosus. Mixing of saturated and desaturated blood takes place, and this blood supplies the lower body of the fetus and enters the umbilical arteries. The low systemic vascular resistance of the placenta aids shunting away from the fetal lungs. The fetus has a high cardiac output (160 ml kg-1) and operates a hierarchy of circulation:

1. non-negotiable - brain, heart, lung tissue

2. negotiable - liver, gut, spleen, kidney

3. expendable - bone, muscles, skin.

The non-negotiable blood flow is unreactive to a- and (5-stimula-tion and very sensitive to changes in partial pressures of oxygen and carbon dioxide (Po2■> and pH; the negotiable and expendable circulations are sensitive to neurogenic and hormonal influences.

Fetal lung

Pulmonary circulation is essentially a high-pressure, low-flow circuit with little blood volume. The adult lung is essentially a low-pressure, high-flow circuit which also acts as a reservoir for the left ventricle. In the fetal lung, the vasomotor responses are greater and the large arteriolar muscle mass confers high resistance. There are very few autonomic nerve endings and the pulmonary blood flow is less sensitive to neurogenic and endocrine stimuli.

Surfactant

Although the respiratory function of the lungs is performed by the placenta before birth, blood supply to the fetal lung is much greater than that to the adult lung because alveolar cells are

Fetal circulation showing oxygen saturation (So2, %) and oxygen tension (Po 2, kPa) in different parts of the circulation. SVC, superior vena cava; IVC, inferior vena cava.

Fetal circulation showing oxygen saturation (So2, %) and oxygen tension (Po 2, kPa) in different parts of the circulation. SVC, superior vena cava; IVC, inferior vena cava.

metabolically very active. They manufacture surfactant, a complex glycoprotein which confers stability on alveoli. Surfactant is manufactured from 28 weeks' gestation.

Effects of drugs on the fetus

These effects depend on fetal distribution, metabolism and excretion; for example, polar substances cross the placenta slowly, but when they reach the fetus, they are excreted rapidly into the amniotic fluid. Lipophilic substances are transferred quickly, but it may take up to 40 min for equilibration to occur.

THE FIRST BREATH AND CHANGES IN CIRCULATION

The instant the umbilical cord is cut, the fetus becomes physio logically and legally an independent and separate individual. The events may be summarized as follows:

1. During delivery, the chest wall is squeezed.

2. Recoil of the chest wall assists expansion of the lungs against forces of surface tension; the FRC reaches 75% of its ultimate volume in a few minutes.

3. The first gasps may generate intrapleural pressures of-2 5 to -50 mmHg. Within a few breath's, the fetal Pao2 of 2-3.5 kPa becomes the neonatal Pa02 of 9-13 kPa.

4. As the lungs expand, pulmonary vascular resistance decreases, and pulmonary capillaries and post-alveolar vessels dilate. Arteriolar constriction decreases because of increasing alveolar PO2; pulmonary blood flow increases.

5. Right atrial pressure decreases below left atrial pressure. There is functional closure of the foramen ovale.

6. Clamping the umbilical cord increases systemic vascular resistance, which helps to maintain left atrial pressure.

7. Closure of the foramen ovale results in blood from the venae cavae entering the pulmonary circulation.

8. The rapid increase in pulmonary blood flow is assisted by the developing low pulmonary vascular resistance.

9. Flow through the ductus arteriosus is gradually reduced; this, together with an increasing Pac>2, leads to closure of the ductus.

In the first hour, there may be bidirectional shunting through the ductus but the right-to-left flow gradually decreases. There is a transitional circulation until the adult circulatory pattern is irreversibly developed.

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