The placenta is a complex organ of internal secretion, releasing numerous hormones and enzymes into the maternal bloodstream. In addition, it serves as the organ of transport for all fetal nutrients and metabolic products as well as for the exchange of oxygen and CO2. Although fetal in origin, the placenta depends almost entirely on maternal blood for its nourishment.
The arterial pressure of maternal blood (60–70 mm Hg) causes it to pulsate toward the chorionic plate into the low-pressure (20 mm Hg) intervillous space. Venous blood in the placenta tends to flow along the basal plate and out through the venules directly into maternal veins. The pressure gradient within the fetal circulation changes slowly with the mother's posture, fetal movements, and physical stress. The pressure within the placental intervillous space is approximately 10 mm Hg when the pregnant woman is lying down. After a few minutes of standing, this pressure exceeds 30 mm Hg. In comparison, the fetal capillary pressure is 20–40 mm Hg.
Clinically, placental perfusion can be altered by many physiologic changes in the mother or fetus. When a precipitous fall in maternal blood pressure occurs, increased plasma volume improves placental perfusion. Increasing the maternal volume with saline infusion increases the fetal oxygen saturation. An increased rate of rhythmic uterine contractions benefits placental perfusion, but tetanic labor contractions are detrimental to placental and fetal circulation as they do not allow a resting period in which normal flow resumes to the fetus. An increased fetal heart rate tends to expand the villi during systole, but this is a minor aid in circulatory transfer.
The magnitude of the uteroplacental circulation is difficult to measure in humans. The consensus is that total uterine blood flow near term is 500–700 mL/min. Not all of this blood traverses the intervillous space. It is generally assumed that approximately 85% of the uterine blood flow goes to the cotyledons and the rest to the myometrium and endometrium. One may assume that blood flow in the placenta is 400–500 mL/min in a patient near term who is lying quietly on her side and is not in labor.
As the placenta matures, thrombosis decreases the number of arterial openings into the basal plate. At term, the ratio of veins to arteries is 2:1 (approximately the ratio found in other mature organs).
Near their entry into the intervillous spaces, the terminal maternal arterioles lose their elastic reticulum. Because the distal portions of these vessels are lost with the placenta, bleeding from their source can be controlled only by uterine contraction. Thus uterine atony causes postpartum hemorrhage.
Plasma Volume Expansion & Spiral Artery Changes
Structural alterations occur in the human uterine spiral arteries found in the decidual part of the placental bed. As a consequence of the action of cytotrophoblast on the spiral artery vessel wall, the normal musculoelastic tissue is replaced by a mixture of fibrinoid and fibrous tissue. The small spiral arteries are converted to large tortuous channels, creating low-resistance channels or arteriovenous shunts.
In early normal pregnancy, there is an early increase in plasma volume and resulting physiologic anemia as the red blood cell mass slowly expands. Immediately after delivery, with closure of the placental shunt, diuresis and natriuresis occur. When the spiral arteries fail to undergo these physiologic changes, fetal growth retardation often occurs with preeclampsia. “Evaluating uterine arteries, which serve the spiral arteries and the placenta in the pregnant women, offers an indirect method of monitoring the spiral arteries.” Fleischer and colleagues (1986) reported that normal pregnancy is associated with a uterine artery Doppler velocimetry systolic/diastolic ratio of less than 2:6. With a higher ratio and a notch in the waveform, the pregnancy is usually complicated by stillbirth, premature birth, intrauterine growth retardation, or preeclampsia.
At term, a normal fetus has a total umbilical blood flow of 350–400 mL/min. Thus the maternoplacental and fetoplacental flows have a similar order of magnitude.
The villous system is best compared with an inverted tree. The branches pass obliquely downward and outward within the intervillous spaces. This arrangement probably permits preferential currents or gradients of flow and undoubtedly encourages intervillous fibrin deposition, commonly seen in the mature placenta.
Cotyledons (subdivisions of the placenta) can be identified early in placentation. Although they are separated by the placental septa, some communication occurs via the subchorionic lake in the roof of the intervillous spaces.
Before labor, placental filling occurs whenever the uterus contracts (Braxton Hicks contractions). At these times, the maternal venous exits are closed, but the thicker-walled arteries are only slightly narrowed. When the uterus relaxes, blood drains out through the maternal veins. Hence blood is not squeezed out of the placental lake with each contraction, nor does it enter the placental lake in appreciably greater amounts during relaxation.
During the height of an average first-stage contraction, most of the cotyledons are devoid of any flow and the remainder are only partially filled. Thus, intermittently—for periods of up to a minute—maternoplacental flow virtually ceases. Therefore, it should be evident that any extended prolongation of the contractile phase, as in uterine tetany, could lead to fetal hypoxia.
Secretions of the Maternal– Placental–Fetal Unit
The placenta and the maternal–placental–fetal unit produce increasing amounts of steroids late in the first trimester. Of greatest importance are the steroids required in fetal development from 7 weeks' gestation through parturition. Immediately after conception and until 12–13 weeks' gestation, the principal source of circulating gestational steroids (progesterone is the major one) is the corpus luteum of pregnancy.
After 42 days, the placenta assumes an increasingly important role in the production of several steroid hormones. Steroid production by the embryo occurs even before implantation is detectable in utero. Before implantation, production of progesterone by the embryo may assist ovum transport.
Once implantation occurs, trophoblastic hCG and other pregnancy-related peptides are secreted. A more sophisticated array of fetoplacental steroids is produced during organogenesis and with the development of a functioning hypothalamic–pituitary–adrenal axis. Adenohypophyseal basophilic cells first appear at approximately 8 weeks in the development of the fetus and indicate the presence of significant quantities of adrenocorticotropic hormone (ACTH). The first adrenal primordial structures are identified at approximately 4 weeks, and the fetal adrenal cortex develops in concert with the adenohypophysis.
The fetus and the placenta acting in concert are the principal sources of steroid hormones controlling intrauterine growth, maturation of vital organs, and parturition. The fetal adrenal cortex is much larger than its adult counterpart. From midtrimester until term, the large inner mass of the fetal adrenal gland (80% of the adrenal tissue) is known as the fetal zone. This tissue is supported by factors unique to the fetal status and regresses rapidly after birth. The outer zone ultimately becomes the bulk of the postnatal and adult cortex.
The trophoblastic mass increases exponentially through the seventh week, after which time the growth velocity gradually increases to an asymptote close to term. The fetal zone and placenta exchange steroid precursors to make possible the full complement of fetoplacental steroids. Formation and regulation of steroid hormones also take place within the fetus itself.
In addition to the steroids, another group of placental hormones unique to pregnancy are the polypeptide hormones, each of which has an analogue in the pituitary. These placental protein hormones include hCG and human chorionic somatomammotropin. The existence of placental human chorionic corticotropin also has been suggested.
A summary of the hormones produced by the maternal–placental–fetal unit is shown in Table 8–2.
Table 8–2. Summary of Maternal–Placental–Fetal Endocrine-Paracrine Functions. ||Download (.pdf)
Table 8–2. Summary of Maternal–Placental–Fetal Endocrine-Paracrine Functions.
Peptides of exclusively placental origin
Human chorionic gonadotropin (hCG)
Human chorionic somatomammotropin (hCS)
Human chorionic corticotropin (hCC)
Pregnancy-associated plasma proteins (PAPP)
Pregnancy-associated β1 macroglobulin (β1 PAM)
Pregnancy-associated α2 macroglobulin (α2 PAM)
Pregnancy-associated major basic protein (pMBP)
Placental proteins (PP) 1 through 21
Placental membrane proteins (MP) 1 through 7.
MP1 also known as placental alkaline phosphatase (PLAP)
Hypothalamic-like hormone (β-endorphin, ACTH-like)
Steroid of mainly placental origin
Hormones of maternal–placental–fetal origin
Estradiol 50% from maternal androgens
Hormone of placental–fetal origin
Hormone of corpus luteum of pregnancy
Fetal adrenal zone hormones
Corticotropin intermediate lobe peptide
Anterior pituitary hormone
Adrenocorticotropic hormone (ACTH)
Tropic hormones for fetal zone of placenta
Human Chorionic Gonadotropin
hCG was the first of the placental protein hormones to be described. It is a glycoprotein that has biologic and immunologic similarities to the luteinizing hormone (LH) from the pituitary. Recent evidence suggests that hCG is produced by the syncytiotrophoblast of the placenta. hCG is elaborated by all types of trophoblastic tissue, including that of hydatidiform moles, chorioadenoma destruens, and choriocarcinoma. As with all glycoprotein hormones (LH, follicle-stimulating hormone, thyroid-stimulating hormone [TSH]), hCG is composed of 2 subunits, α and β. The α subunit is common to all glycoproteins, and the β subunit confers unique specificity to the hormone.
Antibodies have been developed to the β subunit of hCG. This specific reaction allows for differentiation of hCG from pituitary LH. hCG is detectable 9 days after the midcycle LH peak, which occurs 8 days after ovulation and only 1 day after implantation. This measurement is useful because it can detect pregnancy in all patients on day 11 after fertilization. Concentrations of hCG rise exponentially until 9–10 weeks' gestation, with a doubling time of 1.3–2 days.
Concentrations peak at 60–90 days' gestation. Afterward, hCG levels decrease to a plateau that is maintained until delivery. The half-life of hCG is approximately 32–37 hours, in contrast to that of most protein and steroid hormones, which have half-lives measured in minutes. Structural characteristics of the hCG molecule allow it to interact with the human TSH receptor in activation of the membrane adenylate cyclase that regulates thyroid cell function. The finding of hCG-specific adenylate stimulation in the placenta may mean that hCG provides “order regulation” within the cell of the trophoblast.
Human Chorionic Somatomammotropin
Human chorionic somatomammotropin (hCS), previously referred to as designated human placental lactogen, is a protein hormone with immunologic and biologic similarities to the pituitary growth hormone. It is synthesized in the syncytiotrophoblastic layer of the placenta. It can be found in maternal serum and urine in both normal and molar pregnancies. However, it disappears so rapidly from serum and urine after delivery of the placenta or evacuation of the uterus that it cannot be detected in the serum after the first postpartum day. The somatotropic activity of hCS is 3%, which is less than that of human growth hormone (hGH). In vitro, hCS stimulates thymidine incorporation into DNA and enhances the action of hGH and insulin. It is present in microgram-per-milliliter quantities in early pregnancy, but its concentration increases as pregnancy progresses, with peak levels reached during the last 4 weeks. Prolonged fasting at midgestation and insulin-induced hypoglycemia are reported to raise hCS concentrations. hCS may exert its major metabolic effect on the mother to ensure that the nutritional demands of the fetus are met.
It has been suggested that hCS is the “growth hormone” of pregnancy. The in vivo effects of hCS owing to its growth hormonelike and anti-insulin characteristics result in impaired glucose uptake and stimulation of free fatty acid release, with resultant decrease in insulin effect.
A number of proteins thought to be specific to the pregnant state have been isolated. The most commonly known are the 4 pregnancy-associated plasma proteins (PAPPs) designated as PAPP-A, PAPP-B, PAPP-C, and PAPP-D. PAPP-D is the hormone hCS (described earlier). All these proteins are produced by the placenta and/or decidua. The physiologic role of these proteins, except for PAPP-D, are at present unclear. Numerous investigators have postulated various functions, ranging from facilitating fetal “allograft” survival and the regulation of coagulation and complement cascades to the maintenance of the placenta and the regulation of carbohydrate metabolism in pregnancy. In vitro studies of PAPP-A in knockout mouse models show it functioning as a regulator of local insulin-like growth factor bioavailability.
The placenta may be an incomplete steroid-producing organ that must rely on precursors reaching it from the fetal and maternal circulations (an integrated-maternal– placental–fetal unit). The adult steroid-producing glands can form progestins, androgens, and estrogens, but this is not true of the placenta. Estrogen production by the placenta is dependent on precursors reaching it from both the fetal and maternal compartments. Placental progesterone formation is accomplished in large part from circulating maternal cholesterol.
In the placenta, cholesterol is converted to pregnenolone and then rapidly and efficiently to progesterone. Production of progesterone approximates 250 mg per day by the end of pregnancy, at which time circulating levels are on the order of 130 mg/mL. To form estrogens, the placenta, which has an active aromatizing capacity, uses circulating androgens obtained primarily from the fetus but also from the mother. The major androgenic precursor is dehydroepiandrosterone sulfate (DHEAS). This compound comes from the fetal adrenal gland. Because the placenta has an abundance of sulfatase (sulfate-cleaving) enzyme, DHEAS is converted to free unconjugated DHEA when it reaches the placenta, then to androstenedione, testosterone, and finally estrone and 17β-estradiol.
The major estrogen formed in pregnancy is estriol; however, its functional value is not well understood. It appears to be effective in increasing uteroplacental blood flow, as it has a relatively weak estrogenic effect on other organ systems. Ninety percent of the estrogen in the urine of pregnant women is estriol.
Circulating progesterone and estriol are thought to be important during pregnancy because they are present in such large amounts. Progesterone may play a role in maintaining the myometrium in a state of relative quiescence during much of pregnancy. A high local (intrauterine) concentration of progesterone may block cellular immune responses to foreign antigens. Progesterone appears to be essential for maintaining pregnancy in almost all mammals examined. This suggests that progesterone may be instrumental in conferring immunologic privilege to the uterus.
The placenta has a high rate of metabolism, with consumption of oxygen and glucose occurring at a faster rate than in the fetus. Presumably, this high metabolism requirement is caused by multiple transport and biosynthesis activities.
The primary function of the placenta is the transport of oxygen and nutrients to the fetus and the reverse transfer of CO2, urea, and other catabolites back to the mother. In general, those compounds that are essential for the minute-by-minute homeostasis of the fetus (eg, oxygen, CO2, water, sodium) are transported very rapidly by diffusion. Compounds required for the synthesis of new tissues (eg, amino acids, enzyme cofactors such as vitamins) are transported by an active process. Substances such as certain maternal hormones, which may modify fetal growth and are at the upper limits of admissible molecular size, may diffuse very slowly, whereas proteins such as IgG immunoglobulins probably reach the fetus by the process of pinocytosis. This transfer takes place by at least 5 mechanisms: simple diffusion, facilitated diffusion, active transport, pinocytosis, and leakage.
Simple diffusion is the method by which gases and other simple molecules cross the placenta. The rate of transport depends on the chemical gradient, the diffusion constant of the compound in question, and the total area of the placenta available for transfer (Fick's law). The chemical gradient (ie, the differences in concentration in fetal and maternal plasma) is in turn affected by the rates of flow of uteroplacental and umbilical blood. Simple diffusion is also the method of transfer for exogenous compounds such as drugs.
The prime example of a substance transported by facilitated diffusion is glucose, the major source of energy for the fetus. Presumably, a carrier system operates with the chemical gradient (as opposed to active transport, which operates against the gradient) and may become saturated at high glucose concentrations. In the steady state, the glucose concentration in fetal plasma is approximately two-thirds that of the maternal concentration, reflecting the rapid rate of fetal utilization. Substances of low molecular weight, minimal electric charge, and high lipid solubility diffuse across the placenta with ease.
Selective transport of specific essential nutrients and amnio acids are accomplished by enzymatic mechanisms.
Electron microscopy has shown pseudopodial projections of the syncytiotrophoblastic layer that reach out to surround minute amounts of maternal plasma. These particles are carried across the cell virtually intact to be released on the other side, whereupon they promptly gain access to the fetal circulation. Certain other proteins (eg, foreign antigens) may be immunologically rejected. This process may work both to and from the fetus, but the selectivity of the process has not been determined. Complex proteins, small amounts of fat, some immunoglobulins, and even viruses may traverse the placenta in this way. For the passage of complex proteins, highly selective processes involving special receptors are involved. For example, maternal antibodies of the IgG class are freely transferred, whereas other antibodies are not.
Gross breaks in the placental membrane may occur, allowing the passage of intact cells. Despite the fact that the hydrostatic pressure gradient is normally from fetus to mother, tagged red cells and white cells have been found to travel in either direction. Such breaks probably occur most often during labor or with placental disruption (abruptio placentae, placenta previa, or trauma), caesarean section, or intrauterine fetal death. It is at these times that fetal red cells can most often be demonstrated in the maternal circulation. This is the mechanism by which the mother may become sensitized to fetal red cell antigens such as the D (Rh) antigen.
Placental Transport of Drugs
The placental membranes are often referred to as a “barrier” to fetal transfer, but there are few substances (eg, drugs) that will not cross the membranes at all. A few compounds, such as heparin and insulin, are of sufficiently large molecular size or charge that minimal transfer occurs. This lack of transfer is almost unique among drugs. Most medications are transferred from the maternal to the fetal circulation by simple diffusion, the rate of which is determined by the respective gradients of the drugs.
These diffusion gradients are influenced in turn by a number of serum factors, including the degree of drug-protein binding (eg, sex hormone binding globulin). Because serum albumin concentration is considerably lower during pregnancy, drugs that bind almost exclusively to plasma albumin (eg, warfarin, salicylates) may have relatively higher unbound concentrations and, therefore, an effectively higher placental gradient. By contrast, a compound such as carbon monoxide may attach itself so strongly to the increased total hemoglobin that there will be little left in the plasma for transport.
The placenta also acts as a lipoidal resistance factor to the transfer of water-soluble foreign organic chemicals; as a result, chemicals and drugs that are readily soluble in lipids are transferred much more easily across the placental barrier than are water-soluble drugs or molecules. Ionized drug molecules are highly water soluble and are therefore poorly transmitted across the placenta. Because ionization of chemicals depends in part on their pH-pK relationships, multiple factors determine this “simple diffusion” of drugs across the placenta. Obviously, drug transfer is not simple, and one must assume that some amount of almost any drug will cross the placenta.