Study and Validation of a Model
of Fetoplacental Circulation

1.2. Fisiologia della circolazione feto-placentare Physiology of Fetoplacental Circulation |
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La placenta costituisce l'anello di collegamento tra l'organismo della madre e quello del feto.
Realizza le funzioni di scambio di materia e di termoregolazione.
La corretta perfusione del letto placentare è una prerogativa indispensabile per una completa crescita e per lo sviluppo del feto; una conoscenza specifica e il controllo di questa circolazione sono dunque un fondamentale supporto per l'assistenza delle pazienti gravide.
Ci si potrà rendere conto di un problema che sempre si incontra affrontando questo tipo di studi: l'estrema varietà e discordanza di dati disponibili nella letteratura medica in particolare per quanto riguarda gli aspetti morfologici della placenta e del feto.

1.2. Physiology of Fetoplacental Circulation |
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The placenta is the link between a fetus and its mother about the exchange of substances and the thermoregulation.
Fig.5: Placental functions.
At the childbirth it will be replaced by digestive system, lungs and kidneys of the newborn, for the exchange of substances.
The thermoregulation will be driven by the central nervous system through the control of blood circulation and of the metabolism.
Other placental functions:
* Production of hormones
* Transmission of chemical messages
* Regulation of the resistances of the fetal circulation
* Regulation of oxygenation of the fetal blood.
How and how much these functions are achieved is still mainly unknown.
The proper perfusion of the placental vessels is a prerequisite for the complete growth of the fetus. The specific knowledge and the ability to control this circulation are the fundamental support for the assistance to pregnant patients.
This type of research always faces with a problem: the big variety and and the presence of conflicts among the available data of the medical literature in particular about the morphology of the placenta. The following description refers mainly to data from studies developed by well-known researchers, compared also to the data obtained during our experiments on several placentas as described in Part 2.

1.2.1. Fetal Circulation . |
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In the fetus, the systemic, pulmonary and umbilical circulations have several links. The umbilical and placental circulations are a temporary system for the life and the growth of the fetus, that is abandoned at the childbirth, when drastic changes take place transferring the function of gas exchange from the placenta to the lungs.
The right and left ventricles, for the existence of two vascular links, the foramen ovalis and the arterial duct, work in parallel in order to pump oxygenated blood from the placenta through the umbilical vein [9] to the aorta; about 50% of it (saturated to 80% approximately) do not cross the liver but the venous duct reaching the inferior cave vein [10], where also blood coming from the legs flows, lowering therefore the saturation to 70% approximately. Then it flows mainly into the ascending aorta through the foramen ovalis. The flow of the superior cave vein, rather poor of oxygen, flows from the right atrium to the right ventricle and subsequently into the descendant aorta through the arterial duct (Botallo).
The saturation of blood in the descendent aorta and in the following arteries is about 60%.
The blood flow in the first part of the aortic arc is coming from the left atrium. Here, with a modest amount of blood coming from the lungs (that behave as oxygen consumers in the fetus), also a big part of the flow of the inferior cave vein (with oxygenated blood from the placenta) arrives. Therefore the heart and the brain receive a better oxygenation than the organs of the low part of the body.
The aortic blood flows for 60% [11][12] to the placenta and for 40% to the other organs.
Other differences versus the situation of the adult are the relatively high value of cardiac flow, the high frequency of the heart and the low arterial pressure [9]; the cardiac flow of the fetus is varied exclusively by the frequency of the pulsations, since the fetus cannot vary the real volume of the cardiac pulse [13].
From the right ventricle, also the pulmonary circulation is originated, characterized by a high vascular resistance and a reduced volume of blood.
The pressure in the pulmonary artery is several mmHg higher than in aorta, so a consistent part of blood flows from the pulmonary artery into the aorta through the arterial duct.
The pressures in the fetal districts are subject to an increment because of the pressure of the amniotic fluid, which can change according to the maternal intra-abdominal pressure. Therefore we prefer to consider the values of pressure not relatively to the atmospheric pressure, but to the intra-amniotic one, as in the figure 7.
Increasing the pressure of the amniotic fluid, an equivalent increase of the pressure of the intervillous space [14] takes place. The pressure value in the intervillous space is approximately 10-13 mmHg [14], as confirmed by other authors [15]: in our model this value will be 12 mmHg.
The modifications that happen after the childbirth are evidenced in the schematic diagram in figure 8; during the birth, the interruption of the placental circulation, the occlusion of the foramen ovalis and of the arterial duct, and the beginning of the pulmonary activity take place.
After the occlusion of the umbilical vein, the expansion of lungs produces a strong reduction of the vascular resistance; therefore a marked increase of the pulmonary blood flow [10] can be observed. The pressure of the left atrium of the fetus reaches values higher than inside the right atrium, causing the occlusion of the foramen ovalis. Also the arterial duct closes, disappearing within few days.

Fig.6: The fetal circulation.

Fig.7: Fetal circulation in the sheep:
Circled values = of oxygen saturation,
Remaining values = pressures (max/min) relative to the amniotic pressure.

Fig.8: Changes in the circulation from the fetus to the newborn and the adult.

1.2.2. The Placenta: Morphology and Functions . |
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We will describe the placenta from the anatomical point of view, in order to understand its morphology and its functions, to evaluate the geometric characteristics that will be useful in the development of our model.
The placenta puts in relation the mother with the fetus supplying feeding and respiratory necessities; it is a gas exchanger (oxygen and carbon dioxide) between the maternal and fetal blood, that are always separated; it removes the metabolic products, it controls the temperature of the fetus, it is a filter against virus and harmful factors; it fulfills also endocrine functions carrying and producing hormones.
At the end of the pregnancy the placenta is an organ of disk shape, 20-25 cm in diameter, 3-4 cm in thickness, variable weight between 400 and 600 g [16] and 420-490 cm3 [17] in volume. The fetal circulation is a capillary system in which the relationship surface of membrane / volume is maximized thanks to cylindrical and spherical geometry; the maternal blood flows around the vascular structures (villi) while the fetal blood flows into their inner part. The villi are the only parts of the placenta interested by both the blood flows.
The maternal circulation (intervillous) is a system (maternal pool) where the Fåhreus-Lindqvist effect can be considered negligible [18]. The villi behave like small obstacles in the blood current [19].
The figure 10 represents the diagrams of blood flows in various types of placental systems, according to Faber, Moll and Martin [20].

Fig.9: A placenta used for the incannulation tests.

The system of multivillous exchange of the human placenta is not the most efficient: this is confirmed by the fact that 1 gram of human placenta feeds only 6 grams of fetus, compared to a ratio 1:20 in the guinea-pig.
Anyway the multivillous system has an advantage: it allows in a better way the continuous adaptation to conditions that change heavily during the growth.

Fig.10: Types of placental exchange system.
The white arrows indicate the fetal flow, the black ones indicate the maternal flow, the variation in density of points indicates the efficiency.

1.2.3. Anatomy of the Fetal Side . |
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The fetal surface of the placenta is covered by the amniotic membrane.
The umbilical cord is connected approximately at the center, where, after the chorion, its ramifications originate the villi, a complex vascular net, that extends similarly to roots in the pool of maternal blood.
These ramifications, in their final parts, constitute a capillary net in which the fetal blood is oxygenated. Every main root (main stem villus or stem villus of 1st order) has its own ramifications that cross the pool until they reach the basal plate of the maternal part; every stem villus with its ramifications is called cotyledon.
There is a mismatch in the literature on the number of cotyledons, anyway it is not always the same in every placenta. Wilkin suggests a number between 20 and 40 [21], Novak between 15 and 40 [22], but the probably most reliable number is approximately 50 ~ 70 at the end of the pregnancy [23][20].
The cotyledons are purely vessels; they are in part berthed to the basal plate and in part free to fluctuate in the intervillous space. A schematic diagram of the fetal cotyledons is shown in figure 12 [24].

Fig. 12: Morphology of the villi of the human placenta: a) the cotyledon: ChP: chorionic plate BP: basal plate T: trunk I-IV: rami. b) peripheral ramification of a cotyledon: 1: stem villus 2: mature intermediate villus 3: immature intermediate villus 4: terminal villi. c) section of two terminal villi. d) section of the placental barrier.

The vascular venous and arterial structures of the villi are almost symmetrical, like in other organs.
The muscular cells of the vessels are relatively dispersed but they have more intercellular connections: Nikolov and Schiebler (1973) have interpreted this as a muscular system that could be important for an independent local regulation.
Following the blood flow from the umbilical arteries to the terminal capillaries, we will introduce a classification of the placental villi, with reference to Kaufmann (1990) [16] and Arts [25]. Kaufmann has obtained his data analyzing sections of tissue obtained from placentas fixed through immersion in formaline, without perfusion, with the electronic microscope. Arts has analyzed tissues after the perfusion of the placentas with polimetilmetacrilate and their dissolution through immersion in KOH.
Following the description of Arts [25] we can classify the placental vessels as follows:
+ chorionic vessels;
+ vessels of the cotyledons;
+ capillary vessels in the villi;
+ paravascular capillary network.
The villi can be classified in 5 main groups: stem villi, mature and immature intermediate villi, terminal villi and to mesenchimal villi [20].
* Chorionic vessels:
They are arteries and veins pertaining to the chorionic plate of the placenta, which are originated by the extensions of the funicular vessels. They originate vessels that exceed the chorionic plate reaching vascular tree of the cotyledons. They are called vessels of the first order. The average diameter is about 1,5 millimeters for the arteries and 2 millimeters for the veins, their length is 5-10 millimeter. Arts [25], with the exception of a frequent anastomosis between the two umbilical arteries at their insertion to the placenta, did not found any anastomosis between the veins, neither between the arteries, and excluded that arterovenous connections can be found.
* Vessels of the cotyledons:
At the root of each cotyledon, the trunci connect the villous tree to the chorionic plate. From their ramifications 4 orders of rami and 10 of ramuli are originated; the first ones are short, wide, deriving from the trunk near the chorionic plate; the second ones, thinner, span to the periphery of the tree (in fig.12 respectively T, I-IV, 1-10). Trunci, rami and ramuli constitute the stem villi. Among the stem villi there are also several particular ramuli connected to the basal plate [20]. The described villi have the same histological characteristics but differ in the geometric ones: the diameters span from 50-80 µm (smaller ramuli) to 3000 µm (trunci).
The figure 13 shows a stem villus in section. There are 2 main vessels (an arteriola and a venula), and some small paravascular capillary vessels.

Fig.13: Cross-section of a stem villus.

The function of the stem villi is mechanic, as support for the structures of the villous tree; their contribution to the exchange of maternal-fetal mass and the endocrine activity is negligible.
* Capillary in the intermediate villi:
The stem villi split into the intermediate villi, distinguished between immature and mature. The last ones represent the connection between stem villi and terminal villi, and are the great majority in the mature placenta: from their surface more than 95% of the terminal villi take origin [20].
The diameter of the mature intermediate villi is between 60 and 150 µm, in the immature ones between 60 to 200 µm. An important difference is the presence of a bigger number of terminal villi in the mature intermediate villi rather than in the immature ones.
From a functional point of view the immature intermediate villi can be considered as the centers for the development of the villous tree; they represent sites of exchange during the first two trimesters of pregnancy, after that this task is accomplished by the terminal villi, produced by the mature intermediate villi (having about the same diameter of the terminal villi).
For this reason in the model the immature intermediate villi are not considered.
* Capillary in the terminal villi:
From the precapillary arteries of the intermediate villi, blood flows into 3 to 5 terminal villi in series, then into a post-capillary vein.
The terminal villi are the excrescences that fetal capillaries form on the surface of the cotyledons. They develop from the intermediate villi during the last trimester of pregnancy.
The terminal part of the villous tree with the development of fetal capillaries is represented in figure 16. The diagram of capillary vessels made by Kaufmann [26] is characterised by a low degree of ramification.
The estimated length of the capillaries is between 3000 and 5000 µm; the length of the correspondent capillary paravascular network spans from 1000 to 2000 µm.
The measure of the mean diameters of capillary vessels has been executed through the electron microscope and with a technique, already used by Arts, of measurement of stamps of vessels, obtained with perfusion of the cotyledon using a polymer. The measured mean diameter is 12,2 µm with the first method and 14,4 µm with the second one.
There are capillaries with diameters reaching 30 µm, sometimes 50 or even 80 µm; they are called sinusoids. They are located mainly on the terminal-villous crests, where capillary are folded around themselves, and at the points of bifurcation and fusion of vessels. Their surface is 30-40% of the total surface of the villi.
The sinusoids seem to have the task to slow down the blood flow for a better gaseous exchange between fetus and mother. Probably [27] blood is mixed here, including the central zone of the flow, otherwise not involved in the exchange.
The capillaries are rather wide but also short. The consequence is that the difference of pressure between efferent and afferent flow is small. On the number of placental capillaries there is a mismatch in the values calculated by the researchers. Assuming for each capillary a diameter of 15 µm and a length spanning between 3000 and 5000 µm, it is easy to calculate the volume; moreover estimating the volume occupied by the capillary equal approximately to 45 milliliters [28], the ratio of these volumes is the total number of the capillaries. The result is 50 to 80 millions of capillaries. Other researchers propose 50 million approximately (Wilkin and Burzstein).
This description of the terminal villi not absolutely complete, as these structures are extremely variable in terms of characteristics of the villous surface, of capillary membrane and of tissue.
A schematic diagram of the capillary structure in the single villus is shown in figure 17.
* Capillaries in the mesenchimal villi:
At the end of pregnancy, the mesenchimal villi are in small number, mainly on the surface of the immature intermediate villi: they compose less than 1% of the total volume of the villi [20].
* Capillary paravascular network:
It is a network of several capillaries connected by anastomosis, with smaller diameter compared to the capillaries of the villi; they do not originate the sinusoids but are almost linear, 1000-2000 µm long [20].
According to the hypothesis of Arts the paravascular network task is the nutrition for the stem villi. This hypothesis is considered improbable by Kaufmann [20]. This network can be considered a residual of the network present during the early development of the placenta [29]. Due to the development of the terminal villi during the last trimester of pregnancy, the greater part of the paravascular network is not working. For this reason it is neglected in our placental model.

Fig.14: Diagram of a peripheral stem villus.

Fig.16: Longitudinal section of a terminal villus.

Fig.17: Structure of a villus.

Fig.18: Development of the volume of several the types of villi, versus the gestational age:
SV stem villi 31g 11%
transition to intermediate immature villi 24g 9%
VII intermediate immature villi 9g 3%
VM mesenchimal villi 3g 1%
transition to intermediate mature villi 3g 1%
VIM intermediate mature villi 77g 28%
transition to terminal villi 31g 11%
VT terminal villi 95g 35%

1.2.4. Anatomy of the Maternal Side . |
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The external surface of the maternal part is extremely irregular and wrinkled, it is divided in several lobes; its color is dark red.
The placenta at the end of pregnancy is fed by the uterine arteries that split into 60 ~ 120 spiral arteries, connected to the basal plate [30]. The utero-placental flow increases during the pregnancy from 50 cc/min (10 weeks) to 500-600 cc/min. The ratio of uterine blood flow reaching the placenta is not exactly known; in the late pregnancy, the placenta probably receives 90% of the total flow [30].
Fig.19: Schematic diagram of the contribution of blood in the intervillous space.

The maternal blood of the spiral arteries flows into a system of communicating interstices that encircles the cotyledons: the intervillous space. Here oxygen and the nourishing substances of the maternal blood are exchanged with the fetal blood and at the same time the products of the fetal metabolism are acquired. Then the maternal blood flows into the veins of the basal plate ("physiological" model of Ramsey) [31].
Each villous tree depends on its spiral artery: although the intervillous space is a system rather open, the disposition of the villi and the gradient of pressure are linked so that the perfusion depends closely on the original placement of the flows [32]: the occlusion of a spiral artery causes the death of the tissue of the cotyledon that it used to feed.
The blood pressure at the end of the spiral arteries is approximately 70 mmHg, in the intervillous space it is 12-15 mmHg [15] and in the endometrial veins, where blood is drained, it is 8 mmHg: the pressure gap is almost totally in the intervillous space.
The studies of Freese explained that the cotyledons do not grow in uniform way but leave cavities in front of the orifices of the spiral arteries. The maternal blood from the basal plate enters in this empty space and, pushed by the pressure, flows towards the chorion (fig. 14), it passes through the cotyledons not dispersing itself and finally it is drained by the endometrial veins.

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