The Normal and Abnormal Placenta



The Normal and Abnormal Placenta


Yoel Sadovsky

W. Tony Parks



Introduction and a Historical Perspective

In eutherian mammals, the placenta forms the interface between the fetus and the mother, providing essential functions for fetal survival, development, and growth. These functions include regulation of gas exchange, supply of nutrients, removal of waste products, production of essential hormones, and establishment of immunological and mechanical defense.

The term placenta means “cake” in Latin and is derived from plakous, which means “flat cake” in Greek. Although the role of the placenta in supporting the developing fetus was probably recognized as early as the fifth century BCE, the term placenta was coined in the 16th century by Realdo Columbo at the University of Padua in Italy.1 Until the 17th century, it was believed that the maternal and fetal circulations were directly connected through vessel anastomosis. This notion was changed by the work of Harvey and Malpighi, who asserted that such communication was unlikely to exist. Deeper understanding of the two circulations and the intervillous space was later provided by Langhans, who described the placental epithelial multinucleated cells and individual (Langhans) cells, later termed the syncytiotrophoblasts and cytotrophoblast, respectively, by Hubrecht. Insights into placental blood flow and maternal-fetal exchange were made in the 20th century by Ramsey and Donner. A more detailed account of key milestones in the history of placental research was provided by Boyd and Hamilton.1


Anatomy and Morphology

The placenta comprises cells that originated from the conceptus; hence, it shares its genetic origin with the fetus. Maternal cells within the placenta are circulating red and white blood cells and their derivatives, which may become more abundant during a maternal inflammatory response. The placenta is usually round or slightly elliptical, and until 17 weeks, it is larger than the fetus. At term, the placenta weighs approximately 500 g, its mean diameter is 18 to 22 cm, and its thickness is 2.4 cm. These dimensions are fairly variable, and small deviations usually lack clinical significance. The mother-facing plate is called the basal plate, which directly interfaces with the maternal decidua (Figure 6.1).

The basal plate is characterized by grooves that divide the basal plate into 10 to 40 lobes and lobules, called cotyledons. Each groove contains interlobular septa that are directly attached to the decidua basalis. Importantly, each lobe or lobule is not a distinct developmental unit, but each is connected to one or more villous trees. At the center of the fetus-facing chorionic plate is the umbilical cord (UC), which delivers oxygen and nutrients from the placenta to the fetus through its vein, and delivers unoxygenated blood and waste products through the two arteries (Figure 6.1). The chorionic plate is covered by the amnion.

The human placenta is defined as chorioallantoic, which implies that the placental vessels originate in the allantois, the hindgut diverticulum that develops into the UC, and not in the extraembryonic mesoderm that covers the yolk sac, as is found in the marsupial’s choriovitelline placenta. Villous interdigitations also define the human placenta, unlike the labyrinthine interface that defines the placenta of mice and many other rodents. Placental species are also defined by their maternal-fetal barrier interface, which plays a pivotal role in defining the placental transport function. In the noninvasive epitheliochorial interface (Figure 6.2A), the trophoblast is attached to the uterine epithelium, but does not invade into it, or the fetal trophoblast may fuse with the maternal epithelium, yet without invasion
(endotheliochorial interface, Figure 6.2B). In contrast, trophoblast invasion leads to destruction of the uterine epithelium, thus reducing the barrier between the fetal and maternal vessels. The invasive hemochorial interface, characterized by direct contact between trophoblasts and the maternal vessels, is further defined by the number of cell layers separating the maternal and fetal blood: a hemotrichorial interface (Figure 6.2C) characterizes the mouse placenta, and a hemodichorial interface (Figure 6.2D) characterizes the human placenta in early pregnancy. In late human pregnancy, however, the cytotrophoblast cell layer is discontinuous, and the placenta is, therefore, considered a hemomonochorial interface2,3 (Figure 6.2E).







The Placental Villus

The main functional unit within the placenta is the villus, with maternal blood cells perfusing the area around the villi, termed the intervillous space. The number of villi in the placenta is highly variable, ranging from several hundreds to the low thousands. They are organized as bifurcating branches that emanate from a stem villus to the terminal villi (Figure 6.1). The outermost layer of each villus, which is directly bathed in maternal blood, comprises the multinucleated syncytiotrophoblast (Figures 6.1 and 6.3). Like most epithelial cells, they exhibit polarity, with a microvillous (“brush border”) membrane facing the maternal blood on the apical side and a basal membrane on the opposite side. Thus, the maternal blood-facing microvillous membrane harbors receptors, channels, and proteins that transmit maternal molecules and signals to the placental villus. Immediately subjacent to this layer are mononucleated cytotrophoblasts (Figure 6.3), constituting 10% to 15% of the total trophoblastic volume.4 The cytotrophoblasts serve as progenitor cells for the syncytiotrophoblast. Cytotrophoblasts may differentiate to replenish the

syncytium, proliferate, or undergo programmed cell death. Each of these processes is highly regulated by intricate signals (eg, hypoxia, epidermal growth factor, cyclic adenosine monophosphate).5,6,7 The process of cytotrophoblast fusion into syncytiotrophoblast involves membrane breakdown. Specific proteins, such as the fusogenic protein syncytin, play key roles in syncytiotrophoblast formation.8 The cytotrophoblasts are separated from the villous core by a basement membrane, which is mainly composed of type IV collagen, heparin sulfate, and fibronectin (Figure 6.3). The villus stroma contains sinusoidal fetal blood vessels lined with endothelial cells, alongside fibroblasts and speciated placental macrophages (Hofbauer cells), which are fetus-derived macrophages that likely originate from villous mesenchymal cells early in gestation and, later, from fetal bone marrow-derived macrophages.9 These stromal structures are further supported by reticular collagen and elastic fibers that are connected to extravascular smooth muscle cells at the base of the stem villi. The fetal villous blood sinusoids coalesce into larger arteries and veins in stem villi.











Villi formation is defined as branching morphogenesis, where villous trees emanate from chorionic plate trabeculae that give rise to villous trunks.10 These trunks bifurcate to either free-floating villi or to anchoring villi that are anchored to the basal plate. The majority of the villi gradually grow in size to form a bifurcating “villous tree”10 (Figure 6.1), from the largest stem villi that mainly provide tensile support to the villous tree; to mesenchymal and immature intermediate villi, characterized by less compact stromal and vascular structures; to mature intermediate villi, which are more differentiated and comprise nearly half the villous volume; to the terminal villi, where most of the maternal-fetal exchange occurs and which is characterized by areas of very thin membranes as well as areas of cell bodies and stromal tissue10 (Figure 6.3).The thin area, which is devoid of cell nuclei and measures only 0.5 to 2 µm between the intervillous space and fetal capillary, is termed the vasculosyncytial membrane11 and comprises the main functional maternal-fetal exchange unit.


The Chorionic and Basal Plates and Nonvillous Support

The entire maternal-fetal interface extends from the chorionic plate and the base of villous tree, across the basal plate, and into junctional zone at the decidua and the inner third of the maternal myometrium. The extravillous trophoblasts are trophoblasts that do not contribute to placental villi. They include the interstitial trophoblasts within the junctional zone and the endovascular trophoblasts within the decidual and myometrial vessels. They are also located within the chorion and chorionic plate, the placental septa in the basal plate, and the placental cell islands. The large stem villi are connected to the basal plate through the trophoblastic cell columns that are established by invasion of the basal plate by cytotrophoblasts early in pregnancy. These structures are called anchoring villi and gradually degenerate until term.

The basal plate is found on the placental side after placental separation at delivery.12 At the junction of the trophoblasts and the compact portion of the decidua basalis is the layer of fibrin-type fibrinoid called Rohr layer. Deeper, at the junction of the compact and spongy layers of the decidua is the fibrin-type fibrinoid, Nitabuch layer, which normally forms the placenta-decidua separation layer. The deeper part of the junctional zone, closer to the maternal uterine wall, is termed the “placental bed” and harbors a mixture of necrotic decidual cells and extravillous trophoblasts. Lastly, extensions of the basal plate into the intervillous space are termed placental septa, which harbor maternal components, including decidual cells and even small maternal veins.12


Placental Blood Flow

At term, the placental bed is perfused by an average of 100 spiral arteries and drained by 50 to 200 veins. Remodeling of the feeding spiral arteries to maintain their full dilation is essential for optimal flow even in the face of vasoconstricting signals. Prior to extravillous trophoblast invasion toward the decidual maternal vessels, there is already marked vascular smooth muscle disorganization, endothelial vacuolization, and lumen dilation. These changes are bolstered by interstitial trophoblast invasion toward spiral vessels in the decidua and the inner third of the myometrium,13 causing deposition of fibrinoid and further replacement of the vessel endothelial intima and muscularis with endovascular trophoblasts,14 thus converting the narrow, high-resistance vessels to dilated, low-resistance vessels.


The intervillous space receives arterial blood through openings of the maternal spiral arteries within the basal plate (Figure 6.1), with flow initiated at the lobular center and progressing peripherally. When compared to intravascular flow, blood flow in the intervillous space is characteristically very slow, with multiple irregularly shaped lakes, clefts, and fusions among neighboring villi, and influenced by villous fetal capillary flow. Within each lobule, uterine veins drain blood from the intervillous space to the uterine veins. In the intravillous, fetal side, blood perfusion is initiated by differentiation of hemangiogenic cells within mesenchymal villi, which takes place in a hypoxic environment and is regulated by vascular endothelial growth factor (VEGF), placental growth factor (PlGF), and their receptors.15,16 Villus arterioles and venules transform into coiled capillary loops within mature intermediate villi and terminal villi, and capillary sinusoids form at interspersed regions and reduce blood flow resistance.

Changes in oxygen levels may impact the development and maintenance of the villous tree.17 Placental hypoxia is normal in early pregnancy (see below) and promotes the invasion and migration of extravillous trophoblasts toward the oxygen-enriched environment near decidual blood vessels.13,17,18 Hypoxia after weeks 12 to 14 of pregnancy has been implicated in diverse villous injury pathways. Villous cell hypoxia may also stem from hypobaric (eg, high-altitude) hypoxia, maternal heart or lung diseases, maternal vascular disease, hypoxia-reperfusion injury, or reduced exchange surface area stemming from a damaged trophoblastic interface.19 Although knowledge of the precise mechanisms underlying such injuries is lacking, it is clear that such injuries may result in altered villous architecture and cellular morphology, culminating in cellular dysfunction.20 For example, first-trimester injury may lead to reduced villous terminal bifurcation, enhanced cytotrophoblast proliferation, and reduced trophoblast fusion, resulting in histological changes consistent with villous ischemia and infarct.21 Injury later in gestation may lead to localized damage and scarring. Chronic hypoxia throughout gestation elicits an adaptive response that consists of increased vascularization of terminal villi, cytotrophoblast proliferation, villous membrane thinning, and reduced deposition of perivillous fibrin, all contributing to maintenance of maternal-fetal exchange.22


Placental Development

Our understanding of the pivotal steps that shape placental development is central to our grasp of placental function and dysfunction in clinically relevant diseases. Whereas descriptive and observational embryology studies have been performed in humans and other primates, mechanistic molecular and metabolic studies commonly depend on rodent and other animal models. This section provides a brief overview, and the reader is referred to key references that provide additional details.

The earliest, prelacunar stage of human placental development takes place prior to implantation, which occurs at 6 to 7 days after fertilization. This stage is characterized by the differentiation of the outermost blastocyst cells into a single layer of mononuclear trophoblasts, with the polar trophectoderm overlying the inner cell mass, defining the contact point with the endometrium.6 This trophectoderm, at that contact point, begins fusing with neighboring cells to form the first multinucleated syncytiotrophoblasts, with a complete syncytium surrounding the implanted early embryo by day 10 or 11 after implantation.1

During the lacunar stage, the endometrial epithelium covers the implantation site and fluid-filled spaces (lacunas) form within the implantation site syncytiotrophoblasts. These lacunas form the intervillous space. Trophoblasts near the embryo form the chorionic plate, and trophoblasts at the periphery form the basal plate. The differentiating embryo becomes surrounded by a chorionic sac that includes the extraembryonic mesoderm and trophoblasts. Cytotrophoblasts at the tip of the developing villi invade toward the maternal uterine capillaries and become a source for renewed trophoblastic columns that penetrate the maternal vessels and plug their distal segments. This process blocks the maternal and fetal circulation, maintaining fetoplacental hypoxia and histiotrophic support17,23 until the vascular plugs are lysed between 10 and 14 weeks of pregnancy. After that point, placental perfusion is initiated and oxygen tension rises from less than 20 mm to nearly 55 mm,17 ushering in oxygenation and the hemotrophic support to the embryo (Figure 6.4).

Most molecular processes that shape placental development have been studied in the mouse, which has a short (˜20 days) pregnancy and a hemochorial, discoid (albeit labyrinthine) placenta and is relatively accessible to genomic manipulation.
In addition, many genes that regulate mouse placental development have orthologs in the human placenta,24 and some studies in mice have been recapitulated in human cells in vitro and in observational studies in humans in vivo. For reviews, see Refs 25, 26, 27, 28.






Decidual immune response to the allogeneic fetus is also critical for the establishment of pregnancy. In humans, maternal immune cells are in direct contact with both villous trophoblasts and extravillous (interstitial and endovascular) trophoblasts. Villous trophoblasts do not express human leukocyte antigens (HLA). Extravillous trophoblasts express classic HLA-C and non-classic HLA-E and HLA-G, and these HLA molecules interact with the unique decidual natural killer cells to enhance placental immune protection.29 Immune tolerance at the maternal-placental interface is also regulated by the by specialized decidual macrophages, dendritic cells, and regulatory T cells.30

Diverse epigenomic pathways are also essential for placental development.31,32 Genomic imprinting is a process by which one allele is epigenetically silenced in a parent-of-origin manner.33,34 The “parent-offspring conflict” theory or “kinship theory” postulates that paternally imprinted genes are designed to stimulate fetal growth, whereas maternally imprinted genes tend to limit nutrient supply to the embryo in order to preserve maternal reproductive sources.33,34 Akin to many other organs and tissue types, the placenta expresses diverse types of small noncoding RNAs called microRNAs (miRNAs). Three most abundant miRNA clusters, the chromosome 19 and chromosome 14 miRNA clusters (C19 MC and C14 MC, respectively) and miR-371-3, dominate the placental miRNA landscape.35 Although the full function of these placental miRNAs remains to be determined, their unique abundance in the placenta suggests an important role in trophoblast biology.36



Placental Hormones and Other Signals

The placenta is the most active site of steroid and protein hormone synthesis, which are vital for placental development and function.37,38,39


Progesterone

After 8 to 10 weeks, gestation, the placenta takes over the role of the corpus luteum as the main source of progesterone. At term, placenta-derived progesterone reaches a daily production of 250 mg/day. Placental progesterone is synthesized predominantly from maternal cholesterol and pregnenolone, similar to its production in the ovaries. Progesterone is particularly important for the maintenance of pregnancy and the relaxation of the myometrium and other smooth muscles.37,38,40


Estrogen

The production of estrogen in pregnancy shifts from the ovary to the placenta early in the first trimester, with placental estrogen production rapidly increasing during pregnancy until term. In the absence of 17α-hydroxylase, the placenta cannot produce estrogen precursors from progesterone and relies on the formation of estrogen from the C19 steroids dehydroepiandrosterone and dehydroepiandrosterone sulfate from the fetal adrenal and, to a lesser degree, the maternal adrenal. This is achieved by the serial action of placental steroid sulfatase, 3β-hydroxysteroid dehydrogenase, aromatase (CYP19), and 17β-hydroxysteroid dehydrogenase type 1.40,41,42


Human Chorionic Gonadotropin

Human chorionic gonadotropin (hCG) is produced nearly exclusively in the trophoblasts. It is composed of two noncovalently linked subunits, alpha and beta, with the alpha subunit shared with other glycoproteins: follicle-stimulating hormone, luteinizing hormone (LH), and adrenocorticotropic hormone, each with a distinct beta subunit. hCG is a highly glycosylated peptide, which serves to enhance its half-life. Intact hCG peaks in the middle of the first trimester, with variation among pregnant women. There is a gradual decline early in the second trimester, and hCG levels remain low until term. The most important function of hCG in the first trimester is the maintenance of the corpus luteum until the placenta starts producing progesterone. hCG acts like fetal LH and stimulates early fetal testosterone production. It also binds to maternal thyroid-stimulating hormone receptors to stimulate the production of T4.43,44


Human Placental Lactogen

Human placental lactogen (hPL) is similar to human growth hormone and is composed of one polypeptide chain. Although it is detectable as early as 1 week after implantation, its level gradually rises during pregnancy, with accelerated production and release in the second trimester. The major function of hPL is the promotion of maternal adaptation to gestational fetal needs, primarily maternal lipolysis and the release of free fatty acids, as well as insulin resistance. hPL also promotes fetal angiogenesis.45


Other Hormones and Signaling Molecules

The placenta produces other peptide hormones, including hypothalamic releasing hormones such as gonadotropin-releasing hormone, thyrotropin-releasing hormone, growth hormone-releasing hormone, and corticotropin-releasing hormone, growth hormone variant, parathyroid hormone-related protein, leptin, relaxin, serotonin, activin, and inhibin. Oxytocin is also produced by syncytiotrophoblasts, with levels far exceeding those produced by the mother. In addition, trophoblasts produce growth factors: insulin-like growth factor 2, PlGF, and VEGF. The role of many of these signaling molecules is assumed to be related to diverse homeostatic functions during pregnancy, but their precise activity and regulation have not been fully clarified.37,46,47,48,49,50,51


Maternal-Fetal Exchange


General Principles

As with other epithelial surfaces, the transport of ions, molecules, or protein complexes across the placental barriers can take place either between cells, via intercellular water-filled channels, or through cells,52,53 where small or large molecules can traverse the placental surface by the hydrostatic and osmotic pressure gradients. Temporary cellular breaks of the thin vasculosyncytial membranes that result from the action of spiral artery blood jets entering the intervillous space may also add to the transplacental water pathway. Yet, together, these channels and breaks occupy a relatively small part of the placental surface area.


Most transplacental transport is achieved through diffusion, transport mechanisms, and endocytosis/exocytosis. Simple diffusion through the placenta follows Fick law, where diffusion is directly proportional to the exchange surface area, the concentration gradient, and the diffusion capacity of the molecule and inversely proportional to the membrane thickness. The transfer of small, noncharged lipid-soluble molecules (ie, oxygen) across the placental barrier is commonly characterized by flow-limited, receptor-independent pathways, which are also influenced by blood flow, differences in concentrations or electrical gradients, and membrane thickness and composition.54 Larger, water-soluble molecules (ie, proteins) are commonly transported by diffusion-limited, receptor-mediated pathways. When receptor-mediated transport does not require energy expenditure, the transport is termed “facilitated transport” or “facilitated diffusion.” The term “active transport” implies that energy is consumed directly or indirectly. Transport proteins are commonly located in the syncytiotrophoblast’s maternal blood-facing microvillous membrane, the cytoplasm, and the villous core-facing basal membrane. In general, for most substances, the movement across the microvillous membrane and/or basal membrane is the rate-limiting step in transplacental transfer. During gestation, the thickness of the microvillous membrane gradually declines, principally due to expansion of the fetal capillary bed, a process that is associated with increased diffusing capacity.55 Large molecules, such as immunoglobulin G (IgG) or cholesterol, are transported by endocytic pathways.56 The text below serves to highlight key information, and the reader is referred to more focused texts for additional information.


Oxygen

Oxygen transport is limited by blood flow because oxygen is rapidly transferred from maternal to fetal blood due to the high permeability of the placental barrier to respiratory gases and is facilitated by a marked difference in oxygen tension (po2) between maternal and fetal blood, a higher hemoglobin concentration in the fetal blood, and a higher oxygen affinity of fetal hemoglobin compared to maternal hemoglobin.57


Carbon Dioxide (CO2), Protons, and Lactate

Placental exchange of CO2, protons, and lactate is critical for acid-base balance. The elimination of CO2 is flow limited, mainly by diffusion of dissolved gas, and facilitated by the fetal-maternal concentration gradient. Protons, or acid equivalents, produced by fetal metabolism, cannot be eliminated by transfer of CO2 and require fetal-maternal proton movement. The sodium-proton exchangers58 are the most important family of placental transporter involved in acid-base regulation. Lactate is an important energy source for the fetal heart, brain, and skeletal muscle, and its fetal levels are higher than the maternal levels. It is transported across cell membranes by members of the monocarboxylate transporter family, which mediate H+/lactate cotransport.59


Water

Near term, the fetus accumulates 22 mL of water per day, largely transferred across the placenta from the maternal circulation. Although differences in hydrostatic pressure and colloidal osmotic pressure would favor net water trafficking from the fetal to the maternal side, this is counteracted by the significant water permeability of the trophoblast microvillous membrane. Water movement is regulated by members of the aquaporins family of membrane water channels.60


Key Cations and Anions


Sodium (Na+)

Sodium typically enters trophoblasts via several Na+-dependent cotransporters, with an active efflux step across the basal membrane, mediated by sodium/potassium ATPAse (Na+/K+-ATPase). As the main intracellular cation, potassium (K+) passively exits the syncytium through syncytiotrophoblast membrane channels,61 with Na+/K+-ATPase constituting the primary route for K+ reuptake into syncytiotrophoblasts. The transport of chloride takes place via the microvillous membrane chloride transporters such as anion exchanger 1 (SLC4A1, CFTR, and MDR1 P-glycoprotein).62


Bicarbonate

Bicarbonate is transported by members of the solute carrier (SLC) transporters (SLC4 and SLC26a family of sulfate transporters). SLC4A1 also exchanges maternal blood chloride for syncytial bicarbonate in maternal blood.


Calcium (Ca2+)

Fetal calcium uptake predominates in the third trimester when it is necessary for bone mineralization.
Calcium transfer involves the transient receptor potential channel protein of the vanilloid subtype 6, store-operated channels, and L-type voltage-dependent calcium channels.63 This is followed by Ca2+ mobilization through the cytosol in association with calcium-binding proteins (calmodulin, calbindin) and storage in the endoplasmic reticulum. Calcium is effluxed against a significant electrochemical gradient on the fetal side by the action of plasma membrane Ca2+ ATPase,64 whose activity increases after 32 weeks, accounting for the increased transport capacity during the period of maximal fetal skeletal mineralization.64


Iron

Iron uptake is essential for heme synthesis, mitochondrial energy production, and prevention of oxidative stress. Maternal transferrin-bound iron binds to the microvillous membrane transferrin receptor and is internalized by clathrin-mediated endocytosis. Iron efflux from the endosome is mediated by the divalent metal transporter protein (DMT1, SLC11A2). Within trophoblasts, iron may be used in biosynthetic pathways. It is also stored free or bound to ferritin and transported to the fetal compartment across the basal membrane by ferroportin or metal transport protein (MTP1).65

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Jun 19, 2022 | Posted by in OBSTETRICS | Comments Off on The Normal and Abnormal Placenta

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