Under the initial hormonal influences of the corpus luteum, the uterine spiral arteries elongate and coil. Erosion of the decidua induces lateral looping of the already convoluted spiral arteries. In late pregnancy, approximately 200 spiral arteries can supply approximately 600 mL/min of blood flow directly to the fetus through the placenta. The vasodilation required to accommodate the increased flow is accomplished through wall replacement by cytotrophoblasts, which incorporate into the arterial wall and replace the elastic and muscular components with an extracellular matrix called the fibrinoid. Tightly coiled spiral arteries are thus transformed into distensible, thin-walled vessels that allow continuous blood supply in the placenta; vessel diameter increases up to 10-fold, while blood velocity and blood pressure decrease. This physiologic conversion is a feature of all normal pregnancies. By contrast, if high blood velocity via nondilated spiral arteries persists, damage to the endothelium and endovascular trophoblast occurs, resulting in relative ischemia and the development of preeclampsia and fetal growth restriction.

The intervillous space is a cavernous expanse that develops from the fusion of the trophoblastic lacunae and the erosion of the decidua by the expanding blastocyst. Folds in the basal plate form septae that divide the space into 13 to 30 anatomic compartments or lobules. Each lobule contains numerous villous trees, which are also known as cotyledons or placentomes . The intervillous space of the mature placenta can accommodate 350 mL of maternal blood.

Maternal arterial blood leaves the funnel-shaped spiral arteries and enters the intervillous space. The blood moves into the low-resistance area, where villi are loosely arranged within the intercotyledonary space before entering a region of densely packed intermediate and terminal villi where placental exchange predominates ( Fig. 4.2 ). Maternal venous blood collects between neighboring villous trees in an area called the perilobular zone. Collecting veins penetrate the maternal basal plate at the periphery of the villous trees to drain perilobular blood from the intervillous space.

The Relationship Between the Villous Tree and Maternal Blood Flow .

Arrows indicate the maternal blood flow from the spiral arteries into the intervillous space and out through the spiral veins.

Modified from Tuchmann-Duplessis H, David G, Haegel P. Illustrated Human Embryology. Volume 1. Embryogenesis . Springer Verlag; 1972:73.

Two coiled umbilical arteries deliver fetal blood to the placenta and subsequently divide into chorionic arteries traversing the chorionic plate to supply the 50 villous trees located among placental lobules. At the base of each villous tree within the chorionic plate, the chorionic arteries are the main villous stem or truncal arteries as first-order vessels, which in turn branch into four to eight cotyledonary arteries as second-order vessels; as they pass toward the maternal basal plate, they further subdivide into ramulus chorii as third-order vessels and finally, terminal arterioles. The terminal arterioles lead through a neck region into a bulbous enlargement, where they form two to four narrow capillary loops. Here the large endothelial surface area and the near-absence of connective tissue allow optimal maternal-fetal exchange ( Fig. 4.3 ).

Structure and Cellular Components of Terminal Villi .

Right, Cellular morphology of two terminal villi. Left, higher magnification of the boxed region exhibiting the placental barrier between fetal and maternal blood.

Modified from Kaufmann P. Basic morphology of the fetal and maternal circuits in the human placenta. Contrib Gynecol Obstet . 1985;13:5–17.

The venous end of the capillary loops narrows and returns through the neck region to the collecting venules, which coalesce to form the larger veins in the stem of the villous trees as they perforate the chorionic plate to become chorionic veins. The venous tributaries combine to empty into the one umbilical vein that delivers oxygenated blood back to the fetus.

The main component of the placental parenchyma is the chorionic villus. By the end of pregnancy, five types of villi comprise the placenta (see below). From the mesenchymal villi and immature intermediate villi, about 3 to 5 mature intermediate villi grow from the stem villous, and 10 to 12 branches of the terminal villi grow from the mature intermediate villi. These villi help communication between the chorionic plate and decidua. Most of the villi float freely in the intervillous space maternal blood while anchoring villi attach to the decidua for structural stability of the placenta.

Mesenchymal villi play a significant role early in the first trimester as the most primitive type of villi. The villi are mostly filled with mesenchymal cells that will later differentiate into myofibroblasts, fibroblasts, smooth muscle cells, endothelial cells, blood cells, and macrophages (see Fig. 4.1C ).

Immature intermediate villi are prevalent in the mid-first trimester. These reticular structures contain fluid as well as macrophages called Hofbauer cells . Small arterioles and venules develop within the stroma.

Stem villi appear condensed with collagen fibers during the mid-first trimester. Additionally, there are fibroblasts and macrophages as well as muscularized arteries and veins, which define this type of villi.

Mature intermediate villi in mid-gestation are bundles of connective tissue with numerous peripheral capillaries, as well as some small terminal arterioles and collecting venules.

Terminal villi mainly evolve late in the second trimester through the third trimester. These villi have no stroma and predominantly contain sinusoidal capillaries.

Villous maturation develops to reduce the distance between the maternal blood and fetal vessels to enhance maternal-fetal exchanges. The primary site of maternal-fetal exchange is the villous surface, especially at vascular syncytial membranes ( VSMs ; see Fig. 4.3 ), which are thinner areas of the placental villous membrane where the maternal and fetal circulations are separated by as little as 1 to 2 µm. Increased VSM thickness, as witnessed in mothers with diabetes, predisposes to fetal hypoxia.

Maternal blood enters the intervillous cotyledon space at a pressure of 70 to 80 mm Hg in areas of the intervillous space that have relatively few villi. The pressure rapidly diminishes to 10 mm Hg and the velocity of blood flow decreases as blood passes into an area of higher resistance, created by the densely packed villi of the placentome.

The maternoplacental circulation relies on anatomical modifications of spiral arterioles to increase flow, while the increase in fetoplacental blood flow is primarily caused by vascular growth. Fetal perfusion of the placenta is not autoregulated and the placental vasculature is not innervated by the sympathetic nervous system. However, the fetus can modulate fetoplacental perfusion via (1) adrenomedullin release by the fetal adrenal glands, which maintains vascular tone; (2) net efflux and influx of water regulated by fetal blood pressure; and (3) local autoregulatory effects mediated by the paracrine vasodilators nitric oxide and acetylcholine . Fetal blood pressure changes cause net influx and efflux of water across the placenta to affect fetal intravascular volume and perfusion. Maternal hyperglycemia and hypoxemia can alter regional fetal blood flow. Endothelium-derived relaxing factors, especially prostacyclin and nitric oxide, are important in the control of the fetoplacental circulation. Hypoxia-induced fetoplacental vasoconstriction is mediated by a reduction in the basal release of nitric oxide. This vasoconstrictor activity is functionally similar to that found with hypoxic pulmonary vasoconstriction in the lung and allows optimal fetal oxygenation through redistribution of fetal blood flow to better-perfused lobules. The placental vasculature constricts in response to graded hypoxia and may be more dependent on angiotensin II than catecholamines.

Paracellular transport refers to transport that occurs between cells and involves solute passage through intercellular shunt pathways described as placental channels. As the syncytiotrophoblast presents a contiguous surface membrane without lateral cell borders, the etiology of the paracellular route for passive diffusive transport is debated. Brownbill et al. reported that channels proposed to be passage pathways within the syncytiotrophoblast were not apparent morphologically, but denudations of the surfacing trophoblast, some secondary to apoptosis, provided a functional passage available for diffusive transport. Placental channels allow nanoparticles smaller than 50 nm to cross the placenta via paracellular transport, based on the diffusion coefficient in water. Enhanced passage of substances was observed when placental structure and function were damaged by inflammation. Paracellular transport appears to be exclusively passive and downhill, occurring by diffusion or convection, and is driven by existing transepithelial gradients. For example, the paracellular route is the major urate transport pathway across the blood-placental barrier.

Transcellular transport occurs through cells, routed sequentially through membranes and the intervening cytoplasm. It occurs through the lipid membrane (e.g., lipophilic molecules and water) or within protein channels that traverse the lipid bilayer (e.g., charged substances such as ions). There are two main ways that water can cross cell membranes: (1) simple diffusion through the lipid bilayer or transit through water-selective channels and (2) facilitated diffusion. The passive transfer of solutes across a membrane depends on (1) concentration and electrochemical differences across the membrane, which drive diffusion; (2) molecular weight; (3) lipid solubility; (4) degree of ionization; and (5) membrane surface area and thickness. Passive diffusion is a key mechanism for the transplacental transfer of lipophilic drugs with a molecular weight < 600 Daltons.

Carriers can mediate the transport of relatively lipid-insoluble molecules down their concentration gradient. Specifically, this mode of transfer exhibits (1) competitive and noncompetitive inhibition, (2) stereospecificity, (3) temperature influences, and (4) saturation kinetics. The latter characteristic is derived from the limited amount of membranous carrier protein complexes and the extent of interaction between the carrier and the substance undergoing transport. At high solute concentrations, a maximum rate of transfer is reached; thereafter, further increases in the concentration gradient do not affect the rate of transfer.

Carriers can facilitate the membrane transfer of substrates down concentration gradients (facilitated diffusion) or against them (active transport). Examples of facilitated diffusion and active transport are the transplacental transfer of glucose and removal of doxorubicin from the placenta to maternal blood, respectively.

Placental carrier proteins can be generally divided into two major transporter superfamilies: ABC (adenosine triphosphate binding cassette) and SLC (solute carrier) transporters. Under most circumstances, SLC transporters mediate facilitated diffusion, whereas ABC transporters are involved in active transport. However, exceptions to this classification have been demonstrated.

Placental SLCs mediate the transfer of hormones, nutrients, medications, and other exogenous compounds into and out of trophoblast cells and across the fetal capillaries. Examples include organic anion transporting polypeptides, organic anion and cation transporters, monoamine transporters, and glucose and folate carriers. A nutrient or a drug may be transported across the placenta by several distinct transport mechanisms.

A special type of facilitated diffusion involves the uphill transport of a molecule linked to another substance traveling down its own concentration gradient. As such, the transfer is not directly driven by cellular energy expenditure. In most cases, sodium is the molecule that facilitates transport. For the membrane-bound carrier to transfer these molecules, both molecules must be bound to the carrier. This hybrid system is called secondary active transport or cotransport. The transplacental transport of amino acids appears to occur principally through secondary active transport. Transporters may be affected by disease states (e.g., preeclampsia ) or signaling molecules (e.g., elevated steroid levels).

Active transport involves the movement of a substance across a cell membrane requiring energy from ATP hydrolysis. In general, active transport occurs against a concentration, electrical, or pressure gradient. Active transport also requires a protein membrane carrier that exhibits saturation kinetics and competitive inhibition. The best-known example of primary active ion transport is the translocation of sodium and potassium through the sodium-potassium adenosine triphosphatase (Na ⁺ /K ⁺ ATPase) pump . Unlike most cell types, the placenta can self-generate creatinine, which assists in regeneration of ATP and meeting the high metabolic energy demands of the placenta.

Placental active transport proteins for small molecules include the ABC transporters P-glycoprotein (P-gp), the breast cancer resistance protein (BCRP), and multidrug resistance proteins, as well as SLC transporters such as the sodium/multivitamin transporter and proteins involved in monoamine transport. P-gp and BCRP are expressed on the microvillous surface membrane of the syncytiotrophoblast and play an important role in protecting the fetus from foreign and potentially teratogenic compounds. They additionally prevent compounds such as protease inhibitors from exerting therapeutic effects on the fetus. Other P-gp substrates include all direct-acting oral anticoagulants (e.g., dabigatran ), many immunosuppressive and chemotherapeutic agents, and some cardiovascular drugs (e.g., verapamil ). Inhibition of these transporter proteins (e.g., P-gp inhibition by high-dose cyclosporine ) can increase the fetal transfer of certain drugs.

Endocytosis of solutes by placental trophoblasts can involve pinocytosis and receptor-mediated endocytosis. Pinocytosis is an energy-requiring process in which the cell membrane invaginates around large macromolecules that exhibit negligible diffusion properties. Although the contents of pinocytotic vesicles are subject to intracellular digestion, studies have demonstrated that the vesicles can move across the cytoplasm and fuse with the membrane at the opposite pole, thereby potentially transferring certain molecules across the placenta. Receptor-mediated endocytosis is the selective internalization of extracellular ligands into cytoplasmic vesicles through their interactions with specific receptors. Examples of such receptors include the folate receptor (FR) alpha and the neonatal Fc receptors that bind IgG or IgG-based antibodies and transfer them from the maternal to the fetal circulation.