PLACENTAL STRUCTURE AND FUNCTION
Grosser (1909) introduced the classification system for chorio-allantoic placentae still
utilized today. Placentae differ by the presence or absence of maternal tissues, and hence the
number of tissue layers that are left to form the placental membrane between maternal and fetal
blood. Placentae in which all layers are present are called epitheliochorial. Those in which the
maternal surface epithelium is absent are termed syndesmochorial. Those in which only the
endometrial vessel walls are present are classified as endotheliochorial, while those in which
even the vessel walls are absent such that the chorionic villi are bathed in maternal blood are
classified as hemochorial. Other types have been proposed, and most researchers utilize the
classification hemoendothelial, in which the chorionic trophoderm is absent as well as the
maternal tissues, leaving only the fetal capillary endothelium separating the maternal and fetal
The appearance of allanto-chorionic placentae from different species varies greatly in
appearance, however, all are composed of smaller units called cotyledons. In primates,
cotyledons are combined in a single area for nutrient and gas exchange. Placentae from rats,
mice, guinea pigs and rabbits are similar to those in primates. Dogs and cats have zonary
placentae consisting of a comparatively narrow band for maternal-fetal exchange. Cattle, sheep
and goats have cotyledonary placentae, with 30 to 80 cotyledons dispersed across the placental
surface. These attach at specialized areas in the uterus called caruncles that are scattered
throughout the medial sides of the horns of the uterus. A single cotyledon is often supplied by
more than one umbilical cotyledonary artery and more than one vein.
Primate Placental Development
The placenta, except for a small amount of decidua adherant to the fetal membranes or
basal plate, is of fetal origin. It undergoes a series of profound morphological changes during it’s
life span, and in humans weighs approximately 400-600 grams and measures 18 x 16 x 2.5 cm at
term. It functions to deliver oxygen and other nutrients, remove carbon dioxide and other end
products of metabolism, and is an important endocrine organ throughout pregnancy.
Embryonic phase of development
The ovum is fertilized in the ampullar-isthmic junction of the fallopian tube. It takes
about four days to reach the uterus. By this time, several cell divisions have occurred and the
morula (a compact clump of 8 cells or more) has been formed and surrounded by the zona
pellucida. A cavity forms in this solid mass of cells, after which it is called a blastocyst. After
two or three days, the zona pellucida degenerates, secreting protease and uteroglobin, and the
blastocyst becomes implanted in the endometrium. The site of implantation is generally high up
on the posterior wall. Usually implantation begins at about the seventh day after fertilization and
is completed by the tenth day. The wall of the blastocyst is a thin, single cell layer (the
trophoblast), except where there is an aggregation of cells (the inner cell mass) bulging inward
from the wall of the blastocyst into the cavity. The inner cell mass forms the embryo and the
trophoblast forms the placenta.
The inner cell mass differentiates into a layer of small, cuboidal cells adjacent to the
blastocyt cavity (the hypoblast layer), and a layer of high columnar cells adjacent to the amniotic
cavity (the epiblast layer). Together they form a flat disc known as the bilaminar germ disc.
During the third week of development, gastrulation occurs and establishes the three germ layers
of the embryo: the ectoderm, mesoderm, and endoderm. By day 15, the different germ layers are
forming in the embryo, and the mesoderm has grown out from the developing embryo to form a
lining for the shell of the trophoblast. When the trophoblast has gained a lining of mesoderm, it
is called a chorion. The mesoderm then extends into the villi to provide them with a
mesodermal core. At this time, the villi are called secondary or definitive stem villi. These
continue to grow and branch. Fetal blood vessels develop in the mesoderm in their cores, and by
the end of the third week, these vessels become connected to the fetal circulation. The villus is
now known as the tertiary stem villus.
The fetal membranes consist of the amnion and the chorion. The amnion is the
innermost aspect of the embryonic cavity. By 12 weeks, the amniotic cavity completely occupies
the chorionic sac. The cavity remains filled with amniotic fluid, about 5 to 10 ml at 8 weeks,
nearly 1500 ml at 38 weeks and between 500 and 1000 ml at term. This fluid provides a
protective buffer against shock; it is also swallowed by the fetus throughout later periods of
development.. The amnion, although adjacent to the chorion, is not fused to it in the human.
The amnion is avascular.
The chorion forms the base for peripherally radiating villi and serves to encapsulate the
early embryo and developing amnion. It is composed of a connective tissue membrane that
carries the fetal vasculature. It’s inner aspect is bounded by the outer layer of amnion, and it’s
outer aspect is directly associated with the trophoblastic villi that originate from the surface.
The yolk sac produces primordial germ cells and is the primary hematopoietic organ. The
allantois contributes blood vessels to the placenta and eventually becomes the umbilical
circulation. The normal umbilical cord at term measures approximately 55 to 65 cm in length.
The surface is lined by a single layer of amniotic epithelium. The parenchyma of the umbilical
cord is composed of Wharton’s jelly. This is primarily mucopolysaccharides derived from extra-
embryonic mesoblast. It contains evenly distributed spindle-shaped fibroblasts with long
extensions and numerous mast cells. Two arteries and one vein are present in the normal human
umbilical cord. The arteries often spiral in parallel around the vein. They possess no internal
elastic lamina and have a double-layered muscular wall composed of interlacing smooth muscle
bundles. The umbilical vein has an elastic subintimal layer. Compared to the arteries, the vein
has a larger diameter and a thinner muscular layer consisting of a single layer of circular smooth
muscle. The umbilical vessels divide within the chorionic plate and extend beneath this layer to
establish the circulation that ends in the terminal villi. In the chorionic vasculature, arteries
always cross over veins when observed on the fetal surface of the placenta. Remnants of the yolk
sac and urachus can be found in the umbilical cord close to it’s fetal insertion.
By 16 weeks, the placenta is discoid in shape. At term, it occupies almost one third of
the internal surface of the gravid uterus (about 15-25 cm in diameter and 500-600 grams). The
terminal villi are the functional units of the human placenta. Their appearance changes
dramatically over the course of gestation. Immature first trimester villi are large and covered by
two distinct layers of trophoblast, an inner layer of cytotrophoblast and an outer layer of
syncytiotrophoblast. Vessels are small and centrally located. Second trimester villi are one-
third to one-half the diameter of first trimester villi. The syncytiotrophoblast layer is thinner.
The cytotrophoblast does not form a continuous layer and is difficult to find after 16 weeks.
Villous capillaries are larger and more numerous. Mature villi are half again the size of second
trimester villi. The intervillous space develops rapidly to become an enormous blood sinus
bounded on one side by the chorionic plate and on the other side by the decidua basalis. It is
filled with maternal blood and fibrin deposits.
The decidua is the portion of the uterine endometrium that is shed following parturition.
It includes all but the deepest layer of endometrium that is shed when the baby is born. The
decidua that lies between the fetal chorionic sac and the basal layer of the maternal uterine
endometrium is called the decidua basalis (embryonic pole). This becomes the maternal part of
the placenta and is the only part of the placenta that is of maternal origin. The portion of the fetal
chorion that ultimately develops at the embryonic pole to become intimately associated with the
decidua basalis of the uterine endometrium is the chorion frondosum (bushy chorion), the most
highly vascularized portion of the chorion. The endometrium that lies between the fetal
chorionic sac and the maternal uterine myometrium is called the basal plate (decidua basalis plus
the basal layer of the endometrium). The decidua parietalis lines the entire pregnant uterus
except where the placenta is forming. The decidua capsularis is the portion of the uterine
endometrium superficial (abembryonic pole) to the developing embryo. As the embryo develops,
the decidua capsularis has to cover a larger and larger area and becomes thin and atrophic. The
portion of the fetal chorion associated with this abembryonic pole is the chorion laeve, which is
relatively smooth and avascular.
The capillary geometry of placental vessels has been extensively debated and studied for
many years. There are four potential arrangements for maternal and fetal blood vessels:
countercurrent, concurrent, crosscurrent, or a pool-type arrangement. In addition to considering
direction of flow as it influences efficiency of exchange, pulsatility is also a factor. Since maternal
and fetal heart rates are not equal, these pulsations are usually out of phase. This may have serious
implications for efficiency of gas and nutrient transfer. It certainly has implications for tissue
function and survival.
In primates, maternal tissues are eroded above the decidual plate. The spiral arterioles
move blood from the uterine arteries to the maternal side of the placenta. They open into
intervillous spaces, which are basically 50 crevices where blood flow is directed strictly by
hemodynamic gradients. The lumen of the spiral arteries is narrow, so maternal arterial blood
enters these spaces under high pressure and spreads up to the chorionic plate before dispersing
laterally and downward past the fetal capillary bed to the basal plate, where it re-enters the maternal
ciculation through endometrial veins. The fetal capillary bed is a supple, three-dimensional
structure with the terminal portions of the villi anchored to the basal plate. The surface area of the
fetal chorionic villi ranges from 4-14 m2, however, the presence of microvilli greatly expand the
effective surface area for exchange. The geometry of the flow arrangement is a composite of the
arrangements listed above, but most closely resembles crosscurrent flow. About 150 ml of maternal
blood is collectively contained in these intervillous spaces, and this volume is replenished 3-4 times
With most other placental types (cotyledonary, microcotyledonary, or zonary), fetal and
maternal villi interdigitate, presumably to bring vessels from both sides into closer apposition for
more efficient exchange as well as to increase the surface area available for exchange. However,
most of the evidence again supports the idea of a disordered arrangement of vessels rather than
exchange occurring between a single maternal capillary to a contiguous, fixed fetal capillary. It
is more accurate to think of gas and nutrient exchange occurring between two contiguous surface
areas through which capillaries are running in every direction.
The placenta mediates the exchange of metabolic and gaseous products between the
maternal and fetal compartments. It also serves as an endocrine organ producing hormones that
regulate both fetal and maternal processes. Gas exchange is critical not only for meeting the
xoygen demands of the feto-placental units, but also for removing carbon dioxide resulting from
feto-placental metabolism. Nutrient and electrolyte exchange is carefully regulated to match the
stage of fetal development and account for maternal nutritional status. In primates, transmission
of maternal antibodies is critical for protection of the neonate; however, it is also the basis for
Rh-incompatability problems. Fetal red cells that may “leak” into the maternal system at the
placental barrier may elicit a maternal antibody response. These maternal antibodies that are
specifically directed against fetal red cells are then transported back to the fetus and cause
breakdown of the fetal red blood cells (erythroblastosis fetalis or hemolytic disease).
The placenta converts maternally-supplied cholesterol to progesterone, and becomes the
major organ for progesterone synthesis following luteolysis (by the end of the fourth month).
Progesterone exerts a negative feedback on LH and FSH secretion, preventing growth of ovarian
follicles. Placentally-derived progesterone is converted to DHEA in the fetal adrenal, which is
converted to 16-OH-DHEA sulfate in the fetal liver. This is then transported back to the
placenta and converted to estriol, which is the primary estrogen in the maternal circulation during
pregnancy. High levels produced of estriol produced near the end of pregnancy contribute to
uterine growth and the development of the mammary gland.
Human chorionic gonadotropin (hCG), human placental lactogen (hPL) or
somatomammotropin, and pregnancy-specific beta-l-glycoprotein (SP1) are most widely
distributed in the syncytiotrophoblast. The intermediate trophoblast contains a considerable
amount of both hPL and SP1 throughout pregnancy as well as small amounts of hCG early in
gestation. Most early pregnancy tests confirm pregnancy by binding hCG to a specific antibody
and then to a color producing molecule. Chorionic gonadotropin functions to prolong the life of
the corpus luteum and the production of progesterone. It also stimulates the placental production
of both estrogen and progesterone. After the first trimester, there is a marked decrease of hCG in
both the syncytiotrophoblast and the intermediate trophoblast. In contrast, both hPL and SP1
increase during the second and third trimesters. None of these hormones is localized in the
cytotrophoblast. Placental lactogen is a growth hormone analogue that preferentially partitions
glucose uptake to the fetus, making the mother relatively diabetogenic.
Relaxin is secreted by the corpus luteum and then the placenta. Concentrations of relaxin
increase greatly in late gestation, loosening connective tissue and widening the pubic symphysis
so the fetal head can pass through more easily during delivery. Relaxin also promotes cervical
effacement (the flattening, spreading, and dilation of the cervical os).
Most maternally-produced hormones do not cross the placenta efficiently. Some
synthetic progestins and estrogens readily cross the placental barrier, however, and can induce
many abnormalities in fetal development. Similarly, most drugs and drug metabolites pass
through the placental barrier without difficulty, and many cause serious developmental problems
in the embryo or fetus.
Development of Cotyledonary Placentae
The bovine embryo enters the uterus (via peristaltic contractions) on day 3 or 4 post-
fertilization at the 16-cell stage. Over the next few days, the embryo becomes a blastocyst with
the inner cell mass on one side and a blastcoel, or fluid-filled cavity, on the other. Elongation of
the embryo begins at approximately 2 weeks post-fertilization. The embryo is nourished
throughout this pre-implantation period by specific uterine (endometrial) secretions under the
control of progesterone. Estrogen and progesterone concentrations both have direct effects on
uterine receptivity through control of uterine tone, uterine secretions and uterine oxygen tension.
During the course of a normal estrous cycle, oxygen tension in the lumen of the uterus
undergoes a marked fluctuation, presumably from a combination of changes in uterine blood flow,
endometrial metabolism, and endometrial tissue structure. Oxygen tension will increase from 20-25
mm Hg at estrus (high uterine tone) to nearly 50 mm Hg during diestrus (low uterine tone); these
changes are mediated by changes in estrogen and progesterone. Ovariectomy induces a 2.5-fold
increase in lumenal oxygen tension; progesterone replacement reduces oxygen tension back to
normal luteal phase levels while estrogen reduces oxygen tension back to levels normally seen
during estrus. Reducing oxygen concentrations from 20% (~150 mm Hg) to 5% (~40 mm Hg) or
lower improves in vitro embryonic development, and presumably affects in vivo development in a
similar manner. Uterine tone is also important for embryonic implantation.
By day 16, differentiation is initiated and formation of the extra-embryonic membranes as
well as formation of all organ systems begins. Four extra-embryonic membranes are formed from
the embryonic trophoblast during differentiation; the amnion, allantois, chorion, and yolk sac. The
amnion is the innermost layer and folds around the embryo, suspending it in fluid. The middle
layer (allantois) contains most of the vascular components and functions to contain the waste
products of the fetus. The allantois slowly displaces the yok sac over time, re-orienting the fetus in
such a way that the fetus is pushed to the top of the uterus as the yolk sac empties. The membranes
and vessels associted with the yolk sac and the allantois now merge together to form the umbilical
cord. This assures that the umbilical cord will be properly oriented to the fetus, with minimal
physical constraints on it’s function, throughout gestation. The chorion is derived from fetal
ectoderm and forms the outermost layer, although it becomes fused with the allantois by the end of
the differentiation period (day 45) to form the chorioallantois or allantochorion. This membrane
becomes the tissue that will fuse with the uterine endometrium. The nutrient-rich yolk sac
disappears by the end of diffentiation.
Implantation occurs near day 28 as the chorioallantois adheres to uterine caruncles. There
are approximately 80 to 100 caruncles in the bovine uterus. A cotyledon (or area of increased
vascular density) is formed by the fetal membranes that surround the uterine caruncle. Placental
attachment becomes complete by day 45. The cotyledons interdigitate with the caruncles through
villi and microvilli to increase surface area for nutrient exchange. The placenta remains attached to
the fetus by way of the umbilical cord, originally formed by the amnion enclosing the yolk sac. It is
composed typically of two arteries and two veins. By term, the allointoic volume will be
approximately 10 liters and the amniotic volume about 3.5 liters.
In mares, the area for fetal-maternal exchange is created in a different manner. A band of
specialized trophoblastic cells is formed in an avascular area of the chorion at the junction of the
yolk sac and the allantoic sac. This begins at the end of the fourth week and is complete by day 35.
Some of these cells invade the maternal endometrium and form endometrial cups. These
endometrial cups produce copius amounts of equine chorionic gonadotropin (eCG), and form a
longitudinal ring along the lateral and medial walls of the caudal umbilical cord horn. The
tremendous quantities of eCG produced by these cups stimulate an increase in size of the corpus
luteum, with an associated increase in progesterone and estrogen production. This serves to
maintain pregnancy until placental production of these hormones is adequate. The endometrial
cups also function to create a suitable uterine environment for the development of the
microcotyledonary attachment of the allantochorionic placenta to the uterine lining. By day 80, the
cups begin to degenerate as their function is no longer necessary.
Placental weight increases at a faster rate than that of the fetus throughout early gestation.
However, as gestation continues, the rate of placental growth decreases while the rate of fetal
development accelerates. Typically, as the rate of placental growth begins to decrease, vascular
density increases allowing for an adequate area for maternal-fetal exchange to support fetal
During the first half of pregnancy, increasing fetal demand for oxygen stimulates
angiogenesis, and increased blood flow is accomplished by increasing numbers of blood vessels..
The angiogenic response is maternally regulated in early gestation. The latter part of gestation,
however, requires increases in blood vessel diameter to meet the needs of the growing fetus.
Lack of arterial compliance will limit fetal growth. Progesterone serves to maintain phasic
contractility of uterine blood vessels throughout pregnancy while estrogens are necessary for
increasing the diameter of arteries and increasing blood flow later in gestation. Progesterone
concentrations are lower during early gestation. If decreased compliance of vessels limits blood
flow to the fetus, fetal size is reduced, fetal organ development is stunted, and labor may be
initiated prematurely. Decreased sites of attachment (uterine caruncles) occur with increasing
parity and are associated with restricted fetal growth during late pregnancy and restricted nutrient
and gas exchange. Because the surface area is limited, there is a greater need for increased blood
flow (both maternal and fetal) in these animals. Nutrient and gas exchange between maternal and
fetal compartments is mediated by placental diffusing capacity, rates of fetal and maternal blood
flow, maternal arterial nutrient concentrations or gas tensions, and vascular geometry of the
placenta. Placental insufficiency leads to intrauterine growth restriction and increased risk of
perinatal mortality. The ability of chorionic binucleate cells to migrate and fuse with the maternal
syncytium is impaired in sheep with placental insufficiency. This results in decreased amounts of
progesterone and placental lactogen being present during the time of maximal placental growth.
Expression of vascular endothelial growth factor is enhanced and placental vascular structure is
altered, with increased vessel coiling and altered arrangement of vessels. These changes are
identical to those seen under conditions of chronic maternal hypoxia. Placental insufficiency
results in an increased incidence of dystocia and higher perinatal mortality rates. Placental
production of relaxin appears to mirror these difficulties; dramatic decreases or variations in
maternal serum relaxin concentrations during the last trimester are a reliable indicator of
placental insufficiency in mares.