Overview of the Delivered Placenta

At term, the human placenta is usually a discoid organ, 15 to 20 cm in diameter, approximately 3 cm thick at the center, and weighing on average 450 g. Data show considerable individual variation, and placentae are also influenced strongly by the mode of delivery. Macroscopically, the organ consists of two surfaces or plates: the chorionic plate, to which the umbilical cord is attached, and the basal plate that abuts the maternal endometrium. Between the two plates is a cavity that is filled with maternal blood, delivered from the endometrial spiral arteries through openings in the basal plate ( Fig. 1-1 ). This cavity is bounded at the margins of the disc by the fusion of the chorionic and basal plates, and the smooth chorion, or chorion laeve, extends from the rim to complete the chorionic sac. The placenta is incompletely divided into between 10 and 40 lobes by the presence of septa created by invaginations of the basal plate. The septa are thought to arise from differential resistance of the maternal tissues to trophoblast invasion and may help to compartmentalize, and hence direct, maternal blood flow through the organ. The fetal component of the placenta comprises a series of elaborately branched villous trees that arise from the inner surface of the chorionic plate and project into the cavity of the placenta. This arrangement is reminiscent of the fronds of a sea anemone wafting in the seawater of a rock pool. Most commonly, each villous tree originates from a single-stem villus that undergoes several generations of branching until the functional units of the placenta, the terminal villi , are created. These consist of an epithelial covering of trophoblast and a mesodermal core that contains branches of the umbilical arteries and tributaries of the umbilical vein. Because of this repeated branching, the tree takes on the topology of an inverted wine glass, often referred to as a lobule , and two to three of these may “sprout” within a single placental lobe (see Fig. 1-1 ). As will be seen later, each lobule represents an individual maternal-fetal exchange unit. Near term, the continual elaboration of the villous trees almost fills the cavity of the placenta, which is reduced to a network of narrow spaces collectively referred to as the intervillous space (IVS) . The maternal blood percolates through this network of channels and exchanges gases and nutrients with the fetal blood that circulates within the villi before draining through the basal plate into openings of the uterine veins. The human placenta is therefore classified in comparative mammalian terms as being of the villous hemochorial type, although as we shall see, this arrangement only pertains to the second and third trimesters of pregnancy. Prior to that, the maternal-fetal relationship is best described as deciduochorial.

Diagrammatic cross section through a mature placenta shows the chorionic and basal plates that bound the intervillous space. The villous trees arise from stem villi attached to the chorionic plate and are arranged as lobules centered over the openings of the maternal spiral arteries. MC, maternal circulation.

Placental Development

Development of the placenta is initiated morphologically at the time of implantation, when the embryonic pole of the blastocyst establishes contact with the uterine epithelium. At this stage, the wall of the blastocyst comprises an outer layer of unicellular epithelial cells, the trophoblast, and an inner layer of extraembryonic mesodermal cells derived from the inner cell mass; together these layers constitute the chorion. The earliest events have never been observed in vivo for obvious ethical reasons, but they are thought to be equivalent to those that take place in the rhesus monkey.

Attempts have also been made to replicate the situation in vitro by culturing in vitro fertilized human blastocysts on monolayers of endometrial cells. Although such reductionist systems cannot take into account the possibility of paracrine signals that emanate from the underlying endometrial stroma, the profound differences in trophoblast invasiveness displayed by various species are maintained. In the case of the human, the trophoblast in contact with the endometrium undergoes a syncytial transformation, and tongues of syncytiotrophoblast begin to penetrate between the endometrial cells. No evidence suggests cell death is induced as part of this process, but gradually the conceptus embeds into the stratum compactum of the endometrium.

Recent ultrasound and comparative data indicate that upgrowth and encapsulation by the endometrium may be just as important as trophoblast invasion in this process. The earliest ex vivo specimens available for study are estimated to be around 7 days postfertilization, and in these, the conceptus is almost entirely embedded. A plug of fibrin initially seals the defect in the uterine surface, but by days 10 to 12, the epithelium is restored.

By the time implantation is complete, the conceptus is surrounded entirely by a mantle of syncytiotrophoblast ( Fig. 1-2, A ). This multinucleated mantle tends to be thicker beneath the conceptus, in association with the embryonic pole, and it rests on a layer of uninucleate cytotrophoblast cells derived from the original wall of the blastocyst. Vacuolar spaces begin to appear within the mantle and gradually coalesce to form larger lacunae, the forerunners of the IVS. As the lacunae enlarge, the intervening syncytiotrophoblast is reduced in thickness and forms a complex lattice of trabeculae (see Fig. 1-2, B ). Soon after, starting around day 12 after fertilization, the cytotrophoblast cells proliferate and penetrate into the trabeculae. On reaching their tips approximately 2 days later, the cells spread laterally and establish contact with those from other trabeculae to form a new layer interposed between the mantle and the endometrium, the cytotrophoblastic shell (see Fig. 1-2, C ). Finally, at the start of the third week of development, mesodermal cells derived from the extraembryonic mesoderm invade the trabeculae, bringing with them the hemangioblasts from which the fetal vascular circulation differentiates. The mesoderm cells do not penetrate right to the tips of the trabeculae, and these remain as an aggregation of cytotrophoblast cells—the cytotrophoblast cell columns, which may or may not have a covering of syncytiotrophoblast (see Fig. 1-2, C ). Proliferation of the cells at the proximal ends of the columns and their subsequent differentiation contribute to expansion of the cytotrophoblastic shell. Toward the end of the third week, the rudiments of the placenta are therefore in place. The original wall of the blastocyst becomes the chorionic plate, the cytotrophoblastic shell is the precursor of the basal plate, and the lacunae form the IVS ( Fig. 1-2, D ). The trabeculae are the forerunners of the villous trees, and repeated lateral branching gradually increases their complexity.

Schematic representation of early placental development between days 9 and 16 postfertilization. ECC, extracoelomic cavity; EE, extraembryonic; IVS, intervillous space; SYS, secondary yolk sac; YS, yolk sac.

Initially, villi form over the entire chorionic sac, but toward the end of the first trimester, they regress from all except the deep pole, where they remain as the definitive discoid placenta. Abnormalities in this process may account for the persistence of villi at abnormal sites on the chorionic sac and, hence, the presence of accessory or succenturiate lobes. Also, excessive asymmetric regression may result in the umbilical cord being attached eccentrically to the placental disc.

Amnion and Yolk Sac

While these early stages of placental development are taking place, the inner cell mass differentiates and gives rise to the amnion, the yolk sac, and the bilaminar germ disc. The amnion, the yolk sac, and the fluid compartment in which they lie play an important role in the physiology of early pregnancy; their development will be described. The initial formation of these sacs has been controversial over the years, due mainly to the small number of specimens available for study. However, there now appears to be consensus that the amnion extends from the margins of the epiblast layer over the future dorsal surface of the germ disc, whereas the primary yolk sac extends from the hypoblast layer around the inner surface of the trophoblast, separated from it by a loose reticulum thought to be derived from the endoderm. Over the next few days, considerable remodeling of the yolk sac occurs that involves three closely interrelated processes. First, formation of the primitive streak in the germ disc and the subsequent differentiation of definitive endoderm lead to displacement of the original hypoblast cells into the more peripheral regions of the primary yolk sac. Second, the sac greatly reduces in size, either because the more peripheral portion is nipped off, or because it breaks up into a number of vesicles. Third, the reticulum splits into two layers of mesoderm except at the future caudal end of the germ disc, where it persists as a mass; this is the connecting stalk that links the disc to the trophoblast. One layer lines the inner surface of the trophoblast, contributing to formation of the chorion, and the other covers the outer surfaces of the amnion and yolk sac. In between these layers is a large fluid-filled space, the exocoelomic cavity (ECC). The net result of this remodeling is the formation of a smaller secondary yolk sac (SYS); connected to the embryo by the vitelline duct, it floats within the ECC (see Fig. 1-2, D ).

The ECC is a conspicuous feature ultrasonographically that can be clearly visualized using a transvaginal probe toward the end of the third week after fertilization (fifth week of gestational age). Between 5 and 9 weeks of pregnancy, it represents the largest anatomic space within the chorionic sac. The SYS is the first structure that can be detected ultrasonographically within that space, and its diameter increases slightly between 6 and 10 weeks of gestation to reach a maximum of 6 to 7 mm, and then it decreases slightly. Histologically, the SYS consists of an inner layer of endodermal cells linked by tight junctions at their apical surface and bearing a few short microvilli. Their cytoplasm contains numerous mitochondria, whorls of rough endoplasmic reticulum, Golgi bodies, and secretory droplets; this gives them the appearance of being highly active synthetic cells. With further development, the epithelium becomes folded to form a series of cystlike structures or tubules, only some of which communicate with the central cavity. The function of these spaces is not known, although it has been proposed that they serve as a primitive circulatory network in the earliest stages of development because they may contain nonnucleated erythrocytes. On its outer surface, the yolk sac is lined by a layer of mesothelium derived from the extraembryonic mesoderm. This epithelium bears a dense covering of microvilli, and the presence of numerous coated pits and pinocytotic vesicles gives it the appearance of an absorptive epithelium. Although no direct evidence has yet been obtained of this function in the human, transport proteins for glucose and folate have been immunolocalized to this layer. Experiments in the rhesus monkey have revealed that the mesothelial layer readily engulfs horseradish peroxidase, and the proposed transport function is reinforced by the presence of a well-developed capillary plexus immediately beneath the epithelium that drains through the vitelline veins to the developing liver.

However, by week 9 of pregnancy, the SYS begins to exhibit morphologic evidence of a decline in function. This appears to be independent of the expansion of the amnion, which is gradually drawn around the ventral surface of the developing embryo. As it does this, it presses the yolk sac remnant against the connecting stalk, thus forming the umbilical cord. By the end of the third month, the amnion abuts the inner surface of the chorion, and the ECC is obliterated. The fusion of the amnion and chorion and elimination of the ECC can be seen by ultrasound at around 15 weeks of gestation.

Maternal-Fetal Relationship During the First Trimester

For the placenta to function efficiently as an organ of exchange, it requires adequate and dependable access to the maternal circulation. Establishing that access is arguably one of the most critical aspects of placental development, and over recent years, it has certainly been one of the most controversial. As the syncytiotrophoblastic mantle enlarges, it soon comes in close proximity to superficial veins within the endometrium. These undergo dilation to form sinusoids, which are subsequently tapped into by the syncytium. As a result, maternal erythrocytes come to lie within the lacunae, and their presence has in the past been taken by embryologists as indicating the onset of the maternal circulation to the placenta. If this is a circulation, however, it is entirely one of venous ebb and flow, possibly influenced by uterine contractions and other forces. Numerous traditional histologic studies have demonstrated that arterial connections are not established with the lacunae until much later in pregnancy, although the exact timing was not known for many years. The advent of high-resolution ultrasound and Doppler imaging has appeared to answer this question, for in normal pregnancies most observers agree that moving echoes indicative of significant fluid flow cannot be detected within the IVS until 10 to 12 weeks of gestation.

It is now well accepted on the basis of evidence from a variety of techniques that a major change in the maternal circulation to the placenta takes place at the end of the first trimester. First, direct vision into the IVS during the first trimester with a hysteroscope reveals the cavity to be filled with a clear fluid rather than with maternal blood. Second, perfusion of pregnant hysterectomy specimens with radiopaque and other media demonstrates little flow into the IVS during the first trimester, except perhaps at the margins of the placental disc. Third, the oxygen concentration within the IVS is low (<20 mm Hg) prior to 10 weeks of pregnancy, and it rises threefold between weeks 10 and 12. This rise is matched by increases in the mRNA concentrations encoding and in activities of the principal antioxidant enzymes in the placental tissues that confirm a change in oxygenation at the cellular level. The mechanism that underlies this change in placental perfusion relates to the phenomenon of extravillous trophoblast invasion.

Extravillous Trophoblast Invasion and Physiologic Conversion of the Spiral Arteries

During the early weeks of pregnancy, a subpopulation of trophoblast cells migrates from the deep surface of the cytotrophoblastic shell into the endometrium. Because these cells do not take part in the development of the definitive placenta, they are referred to as extravillous trophoblast . Their activities are, however, fundamental to the successful functioning of the placenta, for their presence in the endometrium is associated with the physiologic conversion of the maternal spiral arteries. The cytologic basis of this phenomenon is still not understood, but the net effect is the loss of the smooth muscle cells and elastic fibers from the media of the endometrial segments of the arteries and their subsequent replacement by fibrinoid. Some evidence suggests that this is a two-stage process. Very early in pregnancy, the arteries display endothelial basophilia and vacuolation, disorganization of the smooth muscle cells, and dilation. Because these changes are observed equally in both the decidua basalis and parietalis, and because they are also seen within the uterus in cases of ectopic pregnancies, they must be independent of local trophoblast invasion. Instead, it has been proposed that these changes result from activation of decidual renin-angiotensin signaling. Slightly later, during the first few weeks of pregnancy, the invading extravillous trophoblasts become closely associated with the arteries and infiltrate their walls. Further dilation ensues, and as a result, the arteries are converted from small-caliber vasoreactive vessels into funnel-shaped flaccid conduits.

The extravillous trophoblast population can be separated into two subgroups: the endovascular trophoblast migrates in a retrograde fashion down the lumens of the spiral arteries, replacing the endothelium; and the interstitial trophoblast migrates through the endometrial stroma. In early pregnancy, the volume of the migrating endovascular cells is sufficient to occlude, or plug, the terminal portions of the spiral arteries as they approach the basal plate ( Fig. 1-3 ). It is the dissipation of these plugs toward the end of the first trimester that establishes the maternal circulation to the placenta. The mechanism of unplugging of the arteries is unknown at present but could potentially reflect changes in endovascular trophoblast motility or alterations in maternal hemodynamics. Trophoblast invasion is not equal across the implantation site; rather it is greatest in the central region, where it has presumably been established the longest. It is to be expected, therefore, that the plugging of the spiral arteries will be most extensive in this region, and this may account for the fact that maternal arterial blood flow is most often first detectable ultrasonographically in the peripheral regions of the placental disc. Associated with this blood flow is a high local level of oxidative stress, which can be considered physiologic because it occurs in all normal pregnancies. It has recently been proposed that this stress induces regression of the villi over the superficial pole of the chorionic sac, so forming the chorion laeve ( Fig. 1-4 ).

During early pregnancy, the tips of the maternal spiral arteries are occluded by invading endovascular trophoblast cells, which impedes flow into the intervillous space. The combination of endovascular and interstitial trophoblast invasion is associated with physiologic conversion of the spiral arteries. Both processes are deficient in preeclampsia, and the retention of vascular smooth muscle may increase the risk of spontaneous vasoconstriction and hence may result in an ischemia-reperfusion type injury to the placenta. MC, maternal circulation.

Onset of the maternal circulation (MC) starts in the periphery of the placenta ( arrows ), where trophoblast invasion—and hence plugging of the spiral arteries—is least developed. The high local levels of oxidative stress are thought to induce villous regression and formation of the chorion laeve. AC, amniotic cavity; D, decidua; ECC, exocoelomic cavity; P, placenta; M, myometrium; SYS, secondary yolk sac.

(Modified from Jauniaux E, Cindrova-Davies T, Johns J, et al. Distribution and transfer pathways of antioxidant molecules inside the first trimester human gestational sac . J Clin Endocrinol Metab. 2004;89:1452-1459.)

Under normal conditions, the interstitial trophoblast cells invade as far as the inner third of the myometrium, where they fuse and form multinucleated giant cells. It is essential that the process is correctly regulated; excessive invasion can result in complete erosion of the endometrium and the condition known as placenta accreta (see Chapter 21 ). As they migrate, the trophoblast cells interact with cells of the maternal immune system present within the decidua, in particular macrophages and uterine natural killer (NK) cells. These interactions may play a physiologic role in regulation of the depth of invasion and in the conversion of the spiral arteries. Uterine NK cells accumulate in the endometrium during the secretory phase of the nonpregnant cycle and are particularly numerous surrounding the spiral arteries at the implantation site. Despite their name, no evidence suggests that they destroy trophoblast cells. On the contrary, their cytoplasm contains numerous granules with a diverse array of cytokines and growth factors. Extravillous trophoblast cells express the polymorphic human leukocyte C-antigen (HLA-C) that binds to killer cell immunoglobulin-like receptors (KIRs) on the NK cells. Recent evidence indicates that a degree of activation of the NK cells is necessary for successful pregnancy, most likely because of the release of factors that mediate spiral artery remodeling. Hence, combinations of HLA-C antigen and KIR subtypes that are generally inhibitory are associated with a high risk of pregnancy complications, which emphasizes the importance of immunologic interactions to reproductive success.

Physiologic conversion of the spiral arteries is often attributed with ensuring an adequate maternal blood flow to the placenta, but such comments generally oversimplify the phenomenon. By itself, the process cannot increase the volume of blood flow to the placenta because it only affects the most distal portion of the spiral arteries. The most proximal part of the arteries, where they arise from the uterine arcuate arteries, always remains unconverted, and will act as the rate-limiting segment. These segments gradually dilate in conjunction with the rest of the uterine vasculature during early pregnancy, most probably under the effects of estrogen; as a result, the resistance of the uterine circulation falls, and uterine blood flow increases from approximately 45 mL/min during the menstrual cycle to around 750 mL/min at term or 10% to 15% of maternal cardiac output.

By contrast, the terminal dilation of the arteries will substantially reduce both the rate and pressure with which that maternal blood flows into the IVS. Mathematic modeling has demonstrated that physiologic conversion is associated with a reduction in velocity from 2 to 3 m/sec in the nondilated section of a spiral artery to approximately 10 cm/sec at its mouth. This reduction in the velocity will ensure that the delicate villous trees are not damaged by the momentum of the inflowing blood. Slowing the rate of maternal blood flow across the villous trees will also facilitate exchange, whereas lowering the pressure in the IVS is important to prevent compression and collapse of the fetal capillary network within the villi. Measurements taken in the rhesus monkey indicate that the pressure at the mouth of a spiral artery is only 15 mm Hg and within the IVS is on average 10 mm Hg. The pressure within the fetal villous capillaries is estimated to be approximately 20 mm Hg, providing a pressure differential that favors their distension of 5 mm Hg.

Many complications of pregnancy are associated with defects in extravillous trophoblast invasion and failure to establish the maternal placental circulation correctly. In the most severe cases, the cytotrophoblastic shell is thin and fragmented; this is observed in approximately two thirds of spontaneous miscarriages. Reduced invasion may reflect defects inherent in the conceptus, such as chromosomal aberrations, or it may be due to thrombophilia, endometrial dysfunction, or other problems in the mother. The net result is that onset of the maternal circulation is both precocious and widespread throughout the developing placenta, consequent upon absent or incomplete plugging of the maternal arteries. Hemodynamic forces coupled with excessive oxidative stress within the placental tissues are likely to be major factors that contribute to loss of these pregnancies.

In milder cases, the pregnancy may continue, but it is complicated later by preeclampsia, intrauterine growth restriction (IUGR), or a combination of the two. The physiologic changes are either restricted to only the superficial endometrial parts of the spiral arteries or are absent all together (see Fig. 1-3 ). In the most severe cases of preeclampsia associated with major fetal growth restriction, only 10% of the arteries may be fully converted, compared with 96% in normal pregnancies. There is still debate as to whether this is due to an inability of the interstitial trophoblast to invade the endometrium successfully, or whether having invaded sufficiently deeply, the trophoblast cells fail to penetrate the walls of the arteries. These two possibilities are not mutually exclusive and may reflect different etiologies.

Whatever the causation, there are several potential consequences to incomplete conversion of the arteries. First, because of the absence of the distal dilation, maternal blood will enter the IVS with greater velocity than normal, forming jetlike spurts that can be detected ultrasonographically. The villous trees are often disrupted opposite these spurts, which leads to the formation of intervillous blood lakes, and the altered hemodynamics within the IVS result in thrombosis and excessive fibrin deposition. Second, incomplete conversion will allow the spiral arteries to maintain greater vasoreactivity than normal. Evidence from rhesus monkeys and humans shows that spiral arteries are not continuously patent but that they undergo periodic constriction independent of uterine contractions. It has recently been proposed that exaggeration of this phenomenon due to the retention of smooth muscle in the arterial walls may lead to a hypoxia-reoxygenation–type injury in the placenta, which culminates in the development of oxidative stress. Placental oxidative stress is a key factor in the pathogenesis of preeclampsia, and clinical evidence suggests that hypoxia-reoxygenation is a more physiologic stimulus for its generation than simply reduced uterine perfusion. The third consequence of incomplete conversion is that the distal segments of the arteries are frequently the site of acute atherotic changes. These are likely to be secondary changes, possibly induced by the involvement of these segments in the hypoxia-reoxygenation process or their abnormal hemodynamics; however, if the lesions become occlusive, they will further impair blood flow within the IVS, which contributes to the growth restriction.

Role of the Endometrium During the First Trimester

Signals from the uterine epithelium and secretions from the endometrial glands play a major role in regulating receptivity at the time of implantation, but the potential contribution of the glands to fetal development once implantation is complete has largely been ignored. This has been due to the general assumption that once the conceptus is embedded within the uterine wall, it no longer has access to the secretions in the uterine lumen. However, a review of archival placenta in situ hysterectomy specimens has revealed that the glands discharge their secretions into the IVS through openings in the basal plate throughout the first trimester (see Fig. 1-2 ). The secretions are a heterogenous mix of maternal proteins; carbohydrates, including glycogen; and lipid droplets phagocytosed by the syncytiotrophoblast. Recently, it has been demonstrated that the pattern of sialylation of the secretions changes between the late secretory phase of the nonpregnant cycle and early pregnancy. A loss of terminal sialylic acid caps occurs, which will render the secretions more easily degradable by the trophoblast following their phagocytic uptake. The fact that glycodelin, formerly referred to as PP14 or α ₂ -PEG, is derived from the glands and yet accumulates within the amniotic fluid with concentrations that peak at around 10 weeks’ gestation indicates that the placenta must be exposed to glandular secretions extensively throughout the first trimester.

Ultrasonographic measurements suggest that an endometrial thickness of 8 mm or more is necessary for successful implantation , although not all studies have found such an association. Nonetheless, these measurements are in line with observations based on placenta-in-situ specimens, in which an endometrial thickness of over 5 mm was reported beneath the conceptus at 6 weeks of gestation. Gradually, over the remainder of the first trimester, the endometrium regresses so that by 14 weeks of gestation, the thickness is reduced to 1 mm. Histologically, there is also a transformation in the glandular epithelial cells over this period. During early pregnancy, they undergo characteristic hypersecretory morphologic changes, the so-called Arias-Stella reaction, and their cytoplasm contains abundant organelles and large accumulations of glycogen. These changes are likely a response to placental lactogens and prolactin from the decidua, which represents a servomechanism by which the placenta induces upregulation of its own nutrient supply. However, by the end of the first trimester, the cells are more cuboidal, and secretory organelles are much less prominent, although the lumens of the glands are still filled with secretions.

The overall picture is that the glands are most prolific and active during the early weeks of pregnancy, and that their contribution gradually wanes during the first trimester. This would be consistent with a progressive switch from histotrophic to hemotrophic nutrition as the maternal arterial circulation to the placenta is established. The glands should not be considered solely as a source of nutrients; their secretions are also rich in growth factors such as leukemia inhibitory factor, vascular endothelial growth factor (VEGF), epidermal growth factor, and transforming growth factor beta (TGF-β). Receptors for these factors are present on the villous tissues, so the glands may play an important role in modulating placental proliferation and differentiation during early pregnancy, as in other species. The change in sialylation in early pregnancy will ensure that any of the secretions that gain access to the maternal circulation via the uterine veins will be rapidly cleared in the maternal liver. Hence, a unique proliferative microenvironment can be created within the IVS of the early placenta without placing the mother’s tissues at risk of excessive stimulation. Attempts to correlate the functional activity of the glands with pregnancy outcome have met with mixed success. Thus reduced concentrations of mucin 1, glycodelin, and leukemia inhibitory factor have been reported in uterine flushings from women who have suffered repeated miscarriages. However, a recent study has shown no significant association between the expression of these markers within the endometrium and outcome. This difference may reflect impairment in the secretory, rather than the synthetic, machinery of the gland cells, although further work is required to confirm this point.

From the evidence available, it would appear that the functional importance of the endometrial glands to a successful pregnancy extends well beyond the time of implantation.

Topology of the Villous Trees

One of the principal functions of the placenta is diffusional exchange, and the physical requirements for this impose the greatest influence on the structure of the organ. The rate of diffusion of an inert molecule is governed by Fick’s law, so it is proportional to the surface area for exchange divided by the thickness of the tissue barrier. A large surface area will therefore facilitate exchange, and this is achieved by repeated branching of the villous trees.

The villous trees arise from the trabeculae interposed between the lacunae (see Fig. 1-2 ) through a gradual process of remodeling and lateral branching. Initially, the different branches have an almost uniform composition, and the villi can be separated only by their relative size and position in the hierarchical branching pattern. At this stage, the mesodermal core is loosely packed, and at the proximal end of the trees, it blends with the extraembryonic mesoderm that lines the ECC. The stromal cells possess sail-like processes that often link together to form fluid-filled channels orientated parallel to the long axis of the villi. Macrophages are often seen within these channels, so it is possible they function as a primitive circulatory system prior to vasculogenesis. In this way proteins derived from the uterine glands could freely pass into the coelomic fluid, and it is notable that the macrophages within the channels are strongly immunoreactive for maternal glycodelin secreted from the glands.

Toward the end of the first trimester, the villi begin to differentiate into their principal types. The connections to the chorionic plate become remodeled to form stem villi, which represent the supporting framework of each villous tree. These progressively develop a compact fibrous stroma and contain branches of the chorionic arteries and accompanying veins. The arteries are centrally located and are surrounded by a cuff of smooth muscle cells. Although these have the appearance of resistance vessels, physiologic studies indicate that under normal conditions, the fetal placental circulation operates under conditions of full vasodilation. Stem villi contain only a few small caliber capillaries, and so they play little role in placental exchange.

After several generations of branching, stem villi give rise to intermediate villi. These are longer and more slender in form and can be of two types: immature and mature. The former are seen predominantly in early pregnancy and represent a persistence of the nondifferentiated form as indicated by the presence of fluid-filled stromal channels. Mature intermediate villi provide a distributing framework, and terminal villi arise at intervals from their surface. Within the core are arterioles and venules but also a significant number of nondilated capillaries, which suggest a limited capacity for exchange.

The main functional units of the villous tree are, however, the terminal villi. There is no strict definition as to where a terminal villus starts, but they are most often short, stubby branches up to 100 µm in length and approximately 80 µm in diameter that arise from the intermediate villi ( Fig. 1-5 ). They are highly vascularized, but by capillaries alone, and they are highly adapted for diffusional exchange, as will be seen later.

Diagrammatic representation of an intermediate villus with terminal villi arising from the lateral surface.

This differentiation of the villi coincides temporally with the development of the lobular architecture, and the two processes are most likely interlinked. Lobules can be first identified during the early second trimester, following onset of the maternal circulation, when it is thought hemodynamic forces may shape the villous tree. Convincing radiographic and morphologic evidence shows that maternal blood is delivered into the center of the lobule and that it then disperses peripherally, as in the rhesus monkey placenta. Consequently, it is to be expected that an oxygen gradient will exist across the lobule, and differences in the activities and expression of antioxidant enzymes within the villous tissues suggest strongly that this is the case. Other metabolic gradients (e.g., glucose concentration) may also exist, and together these may exert powerful influences on villous differentiation. Villi in the center of the lobule, where the oxygen concentration will be highest, display morphologic and enzymatic evidence of relative immaturity, and so this is considered to be the germinative zone. By contrast, villi in the periphery of the lobule are better adapted for diffusional exchange.

Elaboration of the villous tree is a progressive event that continues at a steady pace throughout pregnancy, and by term, the villi present a surface area of 10 to 14 m ² . This may be significantly reduced in cases of IUGR, although this principally reflects an overall reduction in placental volume rather than maldevelopment of the villous tree. In cases of preeclampsia alone, villous surface area is normal and is only compromised with associated growth restriction. Attempts have recently been made to monitor placental growth longitudinally during pregnancy using ultrasound. Although the data show considerable individual variability, they indicate that in cases of growth restriction or macrosomia, placental volume is significantly reduced or increased, respectively, at 12 to 14 weeks. These findings suggest that ultimate placental size has its origins firmly in the first trimester.

Integrity of the Villous Membrane

One situation that may alter the balance of the two populations of nuclei is damage to the trophoblast layers and the requirement for repair. Isolated areas of syncytial damage, often referred to as sites of focal syncytial necrosis, are a feature of all placentae, although they are more common in those from pathologic pregnancies. Their origin remains obscure but they could potentially arise from altered hemodynamics within the IVS or from physical interactions between villi. One striking example of the latter is the rupture of syncytial bridges that form between adjacent villi and lead to circular defects on the surface 20 to 40 µm in diameter. Disruption of the microvillous surface leads to the activation of platelets and to the deposition of a fibrin plaque on the trophoblastic basement membrane. Apoptosis of syncytial nuclei has been reported in the immediate vicinity of such plaques, but whether this reflects cause or effect has yet to be determined. With time, cytotrophoblast cells migrate over the plaque, differentiate, and fuse to form a new syncytiotrophoblastic layer. As a result, the plaque is internalized, and the integrity of the villous surface is restored. In the interim, however, these sites are nonselectively permeable to creatinine and may represent a paracellular route for placental transfer.

In the past, more widespread apoptosis in the syncytiotrophoblast has been reported, with the interpretation that this reflects increased turnover of the trophoblast in pathologic conditions. However, recent research has clarified that although rates of apoptosis are increased in preeclampsia and IUGR, the cell death is confined to the cytotrophoblast cells.

Extensive damage to the syncytiotrophoblast is seen in cases of missed miscarriage, in which complete degeneration and sloughing of the layer can occur. Although apoptosis and necrosis are increased among the cytotrophoblast cells, the remaining cells differentiate and fuse to form a new and functional syncytial layer. A similar effect is observed when villi from either first trimester or term placentae are maintained under ambient conditions in vitro.

Thus it is likely that considerable turnover of the syncytiotrophoblast takes place over the course of a pregnancy, although in the absence of longitudinal studies, it is impossible to determine the extent of this phenomenon. Nonetheless, it is clear that the villous membrane cannot be considered an intact physical barrier and that other elements of the villous trees may play important roles in regulating maternal-fetal transfer.

Placental Vasculature

The development of the fetal vasculature begins during the third week after conception (the fifth week of pregnancy) with the de novo formation of capillaries within the villous stromal core. Hemangioblastic cell cords differentiate under the influence of growth factors such as basic fibroblast growth factor and VEGF. By the beginning of the fourth week, the cords have developed lumens, and the endothelial cells become flattened. Surrounding mesenchymal cells become closely apposed to the tubes and differentiate to form pericytes. During the next few days, connections form between neighboring tubes to form a plexus, and this ultimately unites with the allantoic vessels developing in the connecting stalk to establish the fetal circulation to the placenta.

Exactly when an effective circulation is established through these vessels is difficult to determine. First, the connection between the corporeal and extracorporeal fetal circulations is initially particularly narrow, which suggests there can be little flow. Second, the narrow caliber of the villous capillaries, coupled with the fact that the fetal erythrocytes are nucleated during the first trimester and hence are not readily deformable, will ensure that the circulation presents a high resistance to flow. This is reflected in the Doppler waveform obtained during the first trimester, and the resistance gradually falls as the vessels enlarge over the ensuing weeks.

Early in pregnancy, there are relatively few pericytes, and the capillary network is labile and undergoes considerable remodeling. Angiogenesis continues until term and results in the formation of capillary sprouts and loops. Both of these processes contribute to the elaboration of terminal villi. The caliber of the fetal capillaries is not constant within intermediate and terminal villi, and frequently on the apex of a tight bend, the capillaries become greatly dilated and form sinusoids. These regions may help to reduce vascular resistance and facilitate distribution of fetal blood flow through the villous trees. Equally important is the fact that the dilations bring the outer wall of the capillaries into close juxtaposition with the overlying trophoblast. The trophoblast is locally thinned, and as a result, the diffusion distance between the maternal and fetal circulations is reduced to a minimum (see Fig. 1-5 ). Because of their morphologic configuration, these specializations are referred to as vasculosyncytial membranes, and they are considered the principal sites of gaseous and other diffusional exchanges. The arrangement can be considered analogous to that in the alveoli of the lung, where the pulmonary capillaries indent into the alveolar epithelium in order to reduce the thickness of the air-blood diffusion barrier. Thinning of the syncytial layer will not only increase the rate of diffusion into the fetal capillaries, it will also reduce the amount of oxygen extracted by the trophoblast en route. The syncytiotrophoblast is highly active metabolically because of the increased rates of protein synthesis and ionic pumping, but by having an uneven distribution of the tissue around the villous surface, the oxygen demands of the fetus and the placenta can be separated to a large extent.

It is notable that development of vasculosyncytial membranes is seen to its greatest extent in the peripheral regions of a placental lobule, where the oxygen concentration is lowest, and also in placentae from high altitudes. In both instances, it is associated with enlargement of the capillary sinusoids and may be viewed as an adaptive response aimed at increasing the diffusing capacity of the placental tissues. Conversely, an increase in the thickness of the villous membrane is often seen in cases of IUGR and in placentae from cigarette smokers. As mentioned earlier, the hydrostatic pressure differential across the villous membrane is an important determinant of the diameter of the capillary dilations and hence of the villous membrane thickness. Raising the pressure in the IVS not only compresses the capillaries, it also increases the resistance within the umbilical circulation. Both effects will impair diffusional exchange, which highlights the importance of full conversion of the spiral arteries.

Vascular changes are observed in many complications of pregnancy, where they may underpin changes in the topology of the villous tree. Increased branching of the vascular network is observed in placentae from high altitudes, which causes the terminal villi to be shorter and more clustered than normal. At present, no experimental data indicate that this has any impact on placental exchange; but in theory, this shortening of the arteriovenous pathway may lead to increased efficiency.

Physiology of the Secondary Yolk Sac and Exocoelomic Cavity

Now that development of the placenta and the extraembryonic membranes has been covered, we turn to their physiologic roles during pregnancy. Phylogenetically, the oldest membrane is the yolk sac, and the SYS plays a major role in the embryonic development of all mammals. The function of the yolk sac has been most extensively studied in laboratory rodents. It has been demonstrated that it is one of the initial sites of hematopoiesis, it synthesizes a variety of proteins, and it is involved in maternal-fetal transport.

The endodermal layer of the human SYS is known to synthesize several serum proteins in common with the fetal liver, such as alpha-fetoprotein (AFP), alpha ₁ -antitrypsin, albumin, prealbumin, and transferrin. With rare exceptions, the secretion of most of these proteins is confined to the embryonic compartments, and the contribution of the SYS to the maternal protein pool is limited. This can explain why their concentrations are always higher in the ECC than in maternal serum. AFP is also produced by the embryonic liver from 6 weeks until delivery; it has a high molecular weight (±70 kDa) and, conversely to hCG, is found in similar amounts on both sides of the amniotic membrane. Analysis of molecular variants of AFP that have an affinity for concanavalin A have demonstrated that AFP molecules within both the coelomic and amniotic fluids are mainly of yolk sac origin, whereas maternal serum AFP molecules are principally derived from the fetal liver. These results suggest that the SYS also has an excretory function and secretes AFP toward the embryonic and extraembryonic compartments. By contrast, AFP molecules of fetal liver origin are probably transferred from the fetal circulation to the maternal circulation, mainly across the placental villous membrane.

The potential absorptive role of the yolk sac membrane has been evaluated by examining the distribution of proteins and enzymes between the ECC and SYS fluids and by comparing the synthesizing capacity of SYS, fetal liver, and placenta for hCG and AFP. The distribution of the trophoblast-specific hCG in yolk sac and coelomic fluids, together with the absence of hCG mRNA expression in yolk sac tissues, provided the first biologic evidence of its absorptive function. Similarities in the composition of the SYS and coelomic fluids suggest that a free transfer for most molecules occurs between the two corresponding compartments. Conversely, an important concentration gradient exists for most proteins between the ECC and amniotic cavity, indicating that transfer of molecules is limited at the level of the amniotic membrane.

These findings suggest that the yolk sac membrane is an important zone of transfer between the extraembryonic and embryonic compartments, and that the main flux of molecules occurs from outside the yolk sac—that is, from the ECC—in a direction toward its lumen and subsequently to the embryonic gut and circulation. The recent identification of specific transfer proteins on the mesothelial covering, and of the multifunctional endocytic receptors megalin and cubilin, lends further support to this concept. When after 10 weeks of gestation, the cellular components of the wall of the SYS start to degenerate, this route of transfer is no longer functional, and most exchanges between the ECC and the fetal circulation must then take place at the level of the chorionic plate.

The development and physiologic roles of the ECC are intimately linked with that of the SYS, for which it provides a stable environment. The concentrations of hCG, estriol, and progesterone are higher in the coelomic fluid than in maternal serum and strongly suggest the presence of a direct pathway between the trophoblast and the ECC. Morphologically, this may be via the villous stromal channels and the loose mesenchymal tissue of the chorionic plate. Protein electrophoresis has also shown that the coelomic fluid results from an ultrafiltrate of maternal serum with the addition of specific placental and SYS bioproducts. For the duration of the first trimester, the coelomic fluid remains straw colored and more viscous than the amniotic fluid, which is always clear. This is mainly due to the higher protein concentration in the coelomic fluid than in the amniotic cavity. The concentration of almost every protein is higher in coelomic fluid than in amniotic fluid, ranging from 2 to 50 times higher depending on the molecular weight of the protein investigated. The coelomic fluid has a very slow turnover, so the ECC may act as a reservoir for nutrients needed by the developing embryo. These findings suggest that the ECC is a physiologic liquid extension of the early placenta and an important interface in fetal nutritional pathways. Molecules such as vitamin B ₁₂ , prolactin, and glycodelin (placental protein 14, PP14) are known to be mainly produced by the uterine decidua. This pathway may be pivotal in providing the developing embryo with sufficient nutrients before the intervillous circulation becomes established.

Some analogies can be drawn between the ECC and the antrum within a developing graafian follicle. It has been suggested that the evolution of the latter was necessary to overcome the problem of oxygen delivery to an increasing large mass of avascular cells. Because the contained fluid has no oxygen consumption, it will permit diffusion more freely than an equivalent thickness of cells. However, because neither follicular nor coelomic fluids contain an oxygen carrier, the total oxygen content must be low. An oxygen gradient will inevitably exist between the source and the target, whether it be an oocyte or an embryo. Measurements in human patients undergoing in vitro fertilization (IVF) have demonstrated that the oxygen tension in follicular fluid falls as follicle diameter, assessed by ultrasound, increases. Thus diffusion across the ECC may be an important route of oxygen supply to the embryo before the development of a functional placental circulation, but it will maintain the early fetus in a low-oxygen environment. This may serve to protect the fetal tissues from damage by O ₂ free radicals and may prevent disruption of signaling pathways during the crucial stages of embryogenesis and organogenesis. The presence in the ECC of molecules with a well-established antioxidant role—such as taurine, transferrin, vitamins A and E, and selenium—supports this hypothesis. Associated with this, the low-oxygen environment may also favor the maintenance of “stemness” in embryonic and placental stem cells. It is notable that the proliferative capacity of the placenta rapidly reduces at the end of the first trimester, which may reflect loss of growth factor stimulation from the endometrial glands or the rise in intraplacental oxygen concentration.

Placental Metabolism and Growth

The critical function of the placenta is illustrated by its high metabolic demands. For example, placental oxygen consumption equals that of the fetus, and it exceeds the fetal rate when expressed on a weight basis (10 mL/min/kg). Glucose is the principal substrate for oxidative metabolism by placental tissues. Of the total glucose leaving the maternal compartment to nourish the uterus and its contents, placental consumption may represent up to 70% . In addition, a significant fraction of placental glucose uptake derives from the fetal circulation. Although one third of placental glucose may be converted to the three-carbon sugar lactate, placental metabolism is not heavily anaerobic. Instead, because the placental tissues are not capable of metabolizing lactate, this may represent a mechanism by which energy resources can be protected for use by the fetal kidneys and liver. During the first trimester, activity is high in the polyol pathways.

These phylogenetically old carbohydrate pathways enable nicotinamide adenine dinucleotide (NAD ⁺ ) and nicotinamide adenine dinucleotide phosphate (NADP ⁺ ) to be regenerated independent of lactate production and thereby permit glycolysis to be maintained under the low-oxygen conditions. Metabolomic profiling confirms that first-trimester tissues are not compromised energetically, and the ratio of adenosine triphosphate (ATP) to adenosine diphosphate (ADP) is the same at 8 weeks of gestation as it is at term. The factors that regulate short-term changes in placental oxygen and glucose consumption are uncertain at present, although in pregnancies at high altitudes, the placenta appears to spare oxygen for fetal use at the cost of increased placental utilization of glucose.

The regulation of placental growth is incompletely understood, although dramatic advances have recently been made in the study of imprinted genes. Such genes are expressed in a parent-of-origin manner: paternally expressed genes generally promote placental growth, whereas maternally expressed genes provide restraint. Approximately 100 imprinted genes have been identified at present; these are expressed in the placenta and also in the brain, where they regulate reproductive behaviors such as nest building. Imprinting is achieved through epigenetic mechanisms that are particularly sensitive to environmental factors such as hypoxia, maternal diet, and stress. Perturbations of imprinting therefore represent a possible mechanism linking extrinsic changes to alterations in placental differentiation and function.

Normal term placental weight averages 450 g, which represents approximately one seventh (one sixth with cord and membranes) of the fetal weight. Large placentae, either ultrasonographically or at delivery, may prompt investigation into possible etiologies: increased placental size has been associated with maternal anemia, fetal anemia associated with erythrocyte isoimmunization, and hydrops fetalis secondary to fetal α-thalassemia with hemoglobin Bart’s. The association of a large placenta with maternal diabetes mellitus is also recognized, possibly a result of insulin-stimulated mitogenic activity or enhanced angiogenesis. Enlarged placentae are also found in cloned animals, presumably because of defects in the expression of imprinted genes, and in animals in which specific gene products have been deleted. In humans, an increased ratio of placental size to fetal weight is associated with increased morbidity for the offspring, both in the neonatal period and subsequently.

An array of growth-promoting peptide hormones (factors) have been characterized in placental tissue at the protein and/or receptor levels. These include the insulin receptor, IGF-I and IGF-II, EGF, leptin, placental growth factor, placental growth hormone, placental lactogen, and a variety of cytokines and chemokines, each of which has been shown to play an important role in fetal/placental development. IGF-I and IGF-II are polypeptides with a high degree of homology to human proinsulin; both are produced within the placenta and in the fetus and mother, both circulate bound to carrier proteins, and they are 50 times more potent than insulin in stimulating cell growth. EGF increases RNA and DNA synthesis and cell multiplication in a wide variety of cell types. The integrated physiologic role of these and other potential placental growth factors in regulating placental growth remains to be fully defined; however, the development of null-mutation mouse models for IGF-I, IGF-II, IGF-Ir, and IGF-IIr—as well as for the EGF receptor—have provided evidence in this regard. Specifically, the EGF receptor appears important in placental development, as does IGF-II. Knockout of IGF-II results in diminished placental size, whereas deletion of the H19 gene that regulates imprinting of the IGF-II clearance receptor results in an increase in placental size.

Conversely, exposure to chronic hypoxia at high altitudes, nutrient deprivation, infection, and malperfusion due to deficient remodeling of the spiral arteries all lead to a small placenta and fetal IUGR. Inhibition of protein synthesis through activation of the integrated stress response pathways, formerly referred to as endoplasmic reticulum stress or the unfolded protein response, and deactivation of the mTOR/AKT pathway appears to be a common feature in many cases. Translational arrest also appears to reduce complexes of the mitochondrial electron transport chain at the protein, but not mRNA, level at high altitudes, which renders ATP levels lower in these placentae compared with sea level controls. Modeling these changes in placental cell lines in vitro leads to a reduction in the rate of cell proliferation. Exposure to exogenous corticosteroid may also result in diminished placental size and represents another pathway through which stress and undernutrition may act.

Placental Transport

For the bulk of pregnancy, the chorioallantoic placenta is the major site of exchange of nutrients (including oxygen) and of waste products of fetal metabolism (including carbon dioxide) between mother and fetus. As described above, histotrophic nutrition occurs in early pregnancy, and the yolk sac probably contributes to the uptake of nutrients and their transport to the embryo. However, once blood flow to the IVS begins at around 10 weeks of gestation, exchange across the barrier between maternal and fetal circulations within the villi will be predominant, although there may be some limited transfer between maternal blood in the endometrium and the fluid of the amniotic sac. As discussed below, many of the transport mechanisms required to effect exchange are present in the placenta by 10 weeks, and these may be upregulated or downregulated throughout the rest of pregnancy to meet the requirements of fetal growth and homeostasis. The impact of perturbations of nutrient transport on fetal growth has recently been reviewed.

For a molecule to reach fetal plasma from maternal plasma and vice versa, it must cross the syncytiotrophoblast, the matrix of the villous core, and the endothelium of the fetal capillary ( Fig. 1-6 ). The syncytiotrophoblast is the transporting epithelium and is considered to be the major locus of exchange selectivity and regulation. However, both the matrix and endothelium will contribute to the properties of the placenta as an organ of exchange because both contribute to the thickness of the barrier; they may also act as a size filter in that the finite width of the space between the endothelial cells is likely to restrict the diffusion of larger molecules.

Only gold members can continue reading. Log In or Register to continue

Share this:

• Click to share on Twitter (Opens in new window)
• Click to share on Facebook (Opens in new window)

Related

Related posts:

1. Cesarean Delivery
2. Prolonged and Postterm Pregnancy
3. Collagen Vascular Diseases in Pregnancy
4. Mental Health and Behavioral Disorders in Pregnancy

Stay updated, free articles. Join our Telegram channel

Join