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Review

The anatomy of the normal placenta


B Huppertz
Correspondence to:
Professor B Huppertz, Institute
of Cell Biology, Histology and
Embryology, Centre of Molecular
Medicine, Medical University of
Graz, Harrachgasse 21/7, 8010
Graz, Austria; berthold.
huppertz@meduni-graz.at
Accepted 23 July 2008
Accept for Online First
28 August 2008

ABSTRACT
The placenta is the fetal organ providing the interchange
between mother and fetus. This organ needs to provide
its function such as transport and secretion even during
its development and thus all developmental changes need
to be in accordance with its function. This review
describes development of the placenta during the first
few weeks of pregnancy until the villous trees with their
vasculature are established. The macroscopic anatomy of
the delivered placenta as well as the microscopic
anatomy and histology of this organ are also described.
This includes the different types of villi and the most
important cellular components of the villi such as villous
trophoblast, Hofbauer cells, mesenchymal cells and
endothelium. Fibrinoid and its localisation is also
described.
A brief introduction to the development of the
human placenta is given, followed by a description
of the structural characteristics of a delivered term
placenta.

EARLY STAGES OF PLACENTAL DEVELOPMENT


Pre-implantation stage
During human development, between the stages of
the morula and blastocyst (days 45 post-conception), the trophoblast is the first cell lineage to
differentiate. After establishment of the trophoblast, the blastocyst consists of an inner cell mass
that is surrounded by a single layer of mononucleated trophoblasts. This outer layer surrounds
not only the embryoblast, but also the blastocoel,
the blastocyst cavity. Later during pregnancy, the
trophoblast gives rise to larger parts of the placenta
and fetal membranes, while the inner cell mass
gives rise to the embryo and umbilical cord as well
as the placental mesenchyme. The latter is derived
from extraembryonic mesoderm outgrowing from
the early embryo. At about days 67 post-conception, the blastocyst hatches from the zona pellucida and attaches to the uterine epithelium; at that
stage formation of the placenta begins.1

Prelacunar stage
The localisation of the inner cell mass defines the
part of the trophoblast cover that makes the final
attachment of the blastocyst to the uterine
epithelium (fig 1). Only those trophoblasts overlying the inner cell mass (referred to as polar
trophoblast) seem to be able to finally lead to
implantation.2 Rotation of the blastocyst at that
stage may even lead to failure of pregnancy due to
reduced contact of the polar trophoblast to the
uterine epithelium (fig 1). It has been described
that varying the orientation of the blastocyst at
the time of attachment and implantation results in
abnormalities of umbilical cord insertion into the
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chorionic plate.3 It has been further described that


in pregnancies arising from in vitro fertilisation
techniques, a higher rate of abnormal placental
shapes as well as eccentric umbilical cord insertions
occur.4 It may be speculated that the timing and
normal interaction between maternal and embryonic cells regulating implantation is altered in these
cases.
As soon as the blastocyst has firmly attached to
the uterine epithelium, the polar trophoblast
undergoes the next differentiation step, syncytial
fusion of mononucleated cells to generate the first
oligonucleated syncytiotrophoblast (fig 1). At that
stage of development the syncytiotrophoblast displays an invasive phenotype, and only by means of
this syncytiotrophoblast is the blastocyst able to
penetrate the uterine epithelium.2 During the next
few days the early embryo embeds itself into the
decidual stroma with the syncytiotrophoblast
forming a complete mantle surrounding the conceptus. The remaining mononucleated trophoblasts are now referred to as cytotrophoblast,
which are found in the second row without
contacting maternal tissues. The cytotrophoblasts
act as stem cells, which rapidly divide and
subsequently fuse with the syncytiotrophoblast,
resulting in a continuous expansion of the latter.5
Thus at that stage of development the syncytiotrophoblast is the only embryonic tissue coming
into direct contact with maternal cells and fluids,
which has been hypothesised as a means to reduce
rejection of the embryo.

Lacunar stage
Eight days after conception, fluid-filled spaces
occur within the syncytiotrophoblast and soon
coalesce to form larger lacunae. The remaining
syncytiotrophoblastic masses between the lacunae
are termed trabeculae and are of great importance
for the further development of the villous trees of
the placenta. As soon as the lacunae have developed, the three fundamental zones of the placenta
can be defined: the early chorionic plate facing the
embryo; the lacunar system together with the
trabeculae developing into the intervillous space
and the villous trees; and the primitive basal plate
in contact with the maternal endometrium.
During implantation the invading syncytiotrophoblast penetrates into the interstitium of the
endometrium and comes into contact with maternal capillaries and the superficial venous plexus of
the endometrium. Erosion of these small vessels
leads to the presence of first maternal blood cells
within the lacunae of the syncytiotrophoblast.6 7
The appearance of first maternal blood cells in
these lacunae has been equated with the onset of
the maternal circulation in the placenta. However,
as was pointed out more than 50 years ago, at that
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Review
From the primitive basal plate they (now termed interstitial
(extravillous) trophoblast) further invade the endometrial
stroma between glands and capillaries. A subset of these cells
(endovascular trophoblast) reaches and invades the walls of
spiral arteries from the interstitium, finally entering the lumen
of these vessels.11 12 This physiological transformation of spiral
arteries involves the destruction of the arterial muscular wall
and the replacement of the endothelium by trophoblast.12

Villous stage

Figure 1 Implantation of the blastocyst. (A) During normal implantation


the blastocyst rotates in such a manner that the polar trophoblast comes
into direct contact with the uterine epithelium. The polar trophoblast
further differentiates into the first invasive syncytiotrophoblast, which
then penetrates the epithelium and thus leads to embedding of the
blastocyst into the uterine decidual stroma. (B) In some conditions
rotation of the blastocyst is not adequate, leading to a reduced
interaction between polar trophoblast and uterine epithelium. Only some
of the polar trophoblasts can form the syncytiotrophoblast, leading to a
reduced mass of the syncytium.
stage of placental development the number of maternal
erythrocytes within the lacunae is extremely low, and arterial
connections with the lacunar system of the syncytiotrophoblast
cannot be found at this stage of placental development.6 8
Rather, the maternal blood flow within the lacunae should be
described as a slow flow of venous blood.
At about day 12 post-conception, implantation may be
considered to be finalised. The embryo and its surrounding
tissues are completely embedded within the endometrium. The
syncytiotrophoblast displays a developmental gradient: it is
thicker with better developed lacunae underneath the embryonic pole, the site of first invasion. The more distal parts towards
the abembryonic pole are thinner, with smaller lacunae and less
developed trabeculae. At that time extraembryonic mesodermal
cells derived from the primitive streak have begun to migrate on
top of the inner surface of the cytotrophoblast cells.9 10 The
combination of extraembryonic mesoderm and cytotrophoblast
is termed chorion.
Starting on day 12 post-conception, cytotrophoblasts of the
chorionic plate penetrate into the syncytiotrophoblastic mass of
the trabeculae, follow their course and reach the maternal side
of the placenta by day 15. This is the first time an embryonic
cell or tissue other than the syncytiotrophoblast comes into
direct contact with maternal tissues. Thus, only at week 5 postmenstruation the first cytotrophoblasts leave the placenta
proper and differentiate into extravillous cytotrophoblasts.
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At about day 13 post-conception the trabeculae begin to develop


first side branches, which may simply be syncytiotrophoblast
protrusions (syncytial sprouts) or which already contain a core
filled with cytotrophoblasts. These purely trophoblastic structures are called primary villi, which now protrude into the
intervillous space, hitherto called lacunae.
Shortly after, the extraembryonic mesodermal cells of the
chorionic plate follow the cytotrophoblasts and also penetrate
into the trabeculae. The mesodermal cells do not reach the
maternal side of the trabeculae but rather stop earlier, leaving
the more distal parts of the trabeculae filled with cytotrophoblasts only. These parts of the trabeculae are referred to as
trophoblastic cell columns, which serve as the proliferating
source of the extravillous trophoblast and which diminish
throughout gestation. The mesodermal cells penetrate into the
primary villi as well, giving them a mesenchymal core and
transforming them into secondary villi.
Within the mesoderm of secondary villi, haematopoietic
progenitor cells develop and start to differentiate. At about day
20 post-conception, first placental blood cells and endothelial
cells develop independent of the vascular system of the embryo
proper.13 14 The development of first placental vessels transforms
the respective villi into tertiary villi.
This classification of villous development only reflects the
very basic stages of development of new villi. This process can
principally be found throughout gestation. But since tertiary
villi accumulate throughout gestation, the relative number of
newly forming primary and secondary villi in a term placenta is
extremely low.15

MACROSCOPIC ANATOMY OF THE DELIVERED PLACENTA


The full-term human placenta is a circular discoidal organ with
a diameter of about 22 cm, a central thickness of 2.5 cm, and an
average weight of 470 g (fig 2). There is considerable variation
from placenta to placenta, which strongly depends on the mode
of delivery. Especially when planning a morphometric analysis
of the placenta, factors such as when and where the umbilical
cord has been clamped are critical because loss of maternal and/
or fetal blood clearly affects the dimensions of the placenta.16

Fetal surface of the placenta


The chorionic plate represents the fetal surface of the placenta,
which in turn is covered by the amnion. The amnion is
composed of a single layered epithelium and the amnionic
mesenchyme, an avascular connective tissue. The amnionic
mesenchyme is only weakly attached to the chorionic mesenchyme and can easily be removed from the delivered placenta.
The umbilical cord mostly inserts in a slightly eccentric
position into the chorionic plate. The chorionic mesenchyme
contains the chorionic vessels that are continuous with the
vessels of the umbilical cord. Deriving from the two umbilical
arteries the chorionic arteries branch in a centrifugal pattern
into their final branches, which supply the villous trees. The
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chorionic veins are direct continuations of the veins of the
villous trees and usually cross the chorionic arteries underneath.
The chorionic veins give rise to the single umbilical vein.

Maternal surface of the placenta


The basal plate represents the maternal surface of the placenta.
It is an artificial surface, which emerged from the separation of
the placenta from the uterine wall during delivery. The basal
plate is a colourful mixture of fetal extravillous trophoblasts and
all kinds of maternal cells of the uterine decidua, including
decidual stroma cells, natural killer cells, macrophages and other
immune cells. The basal plate also contains large amounts of
extracellular matrix, fibrinoid and blood clots.
A system of flat grooves or deeper clefts subdivides the basal
plate into 1040 slightly elevated regions called lobes. Inside the
placenta, the grooves correspond to the placental septa, which
only trace the lobar borders as irregular pillars or short sails.
The lobes that are visible on the maternal surface of the
placenta show a good correspondence with the position of the
villous trees arising from the chorionic plate into the intervillous
space. In a full-term placenta, 6070 villous trees (or fetal
lobules) arise from the chorionic plate. Thus, each maternal lobe
is occupied by one to four fetal lobules.2 17 The occurrence of a
single villous tree occupying a single lobe was defined as
placentone.18
At the placental margin chorionic and basal plates merge and
form the smooth chorion, the fetal membranes or the chorion
laeve. The chorion laeve is composed of three layers: the amnion
with its epithelium and mesenchyme; the chorion with a layer
of mesenchyme and a layer of extravillous trophoblast; and the
decidua capsularis.

MICROSCOPIC ANATOMY OF THE DELIVERED PLACENTA


Villous types
The fetal lobules (villous tree) arise from the chorionic plate by a
thick villous stem, which in the central region of the placenta is
derived from a trabecula during very early placental development. The branches of the stems continue branching, leading to
a large number of stem villi generations and further branches,
finally ending as freely floating villi in the intervillous space. A
few branches may reach and contact the basal plate as
anchoring villi, which contain the trophoblastic cell columns.
The freely floating villi have been divided into five types of villi
on the basis of their calibre, stromal characteristics, vessel
structure and appearance during pregnancy (fig 3).2 1921

Mesenchymal villi
Mesenchymal villi (100250 mm in diameter) are the forerunners of the intermediate villi and can be found predominantly in
the earliest stages of pregnancy.22 23 Up to six weeks postmenstruation, mesenchymal villi are the only villous type
present in the developing placenta. Their stromal core is only
weakly organised and contains a large number of mesenchymal
cells and developing vessels, the latter sometimes still lacking a
vessel lumen. Mesenchymal villi persist until delivery, but due
to their ongoing differentiation into intermediate villi, their
number becomes extremely low after the first trimester of
pregnancy.

Immature intermediate villi


Developing from differentiating mesenchymal villi, immature
intermediate villi (100400 mm in diameter) are large, bulbous
villi that dominate the villous trees between weeks 8 and 22 of
pregnancy.20 They further develop into stem villi by fibrosation
of the stroma from the centre to the periphery. Immature
intermediate villi possess a highly characteristic stroma. The
mesenchymal stroma cells display long processes that link
together to form matrix-free channels oriented parallel to the
long axis of these villi. These stromal channels contain large
numbers of placental macrophages (Hofbauer cells) that seem to
be able to move along and cross between these channels.
Immature intermediate villi only contain smaller arterioles and
venules and capillaries. After mid-gestation the number of
immature intermediate villi decreases in parallel to the
mesenchymal villi and only a few can be found at term. If a
larger number of such villi can be found in a term placenta, it is
important to note that they are recognised as immature
intermediate villi rather than being wrongly interpreted as
oedematous villi.

Stem villi
Stem villi derive from differentiation of immature intermediate
villi and are the villi with the largest diameter (1003000 mm in
diameter). They serve to give mechanical support to the villous
tree.2 20 Their villous core is characterised by centrally located
arteries and veins in a dense fibrous stroma.24 25 Capillaries are
rare, and thus it is speculated that this villous type plays only a
small part in materno-fetal exchange. Rather, their physiological
significancebesides their role to mechanically stabilise the
villous treeslies in the fact that their vascular system is
surrounded by a perivascular contractile sheath.26 27 Vessel
media and sheath act together as a functional myofibroelastic
unit, which contributes to support tensile and/or contracting
forces within the stem villus blood vessels.

Mature intermediate villi

Figure 2 Macroscopic view of a normally grown full term placenta


after delivery. (A) The umbilical cord inserts into the fetal surface where
chorionic arteries intersect on top of chorionic veins (white arrow).
(B) The maternal surface of the placenta is grouped into maternal lobes
(dotted lines), which correspond to the fetal lobules, the villous trees
within the placental parenchyma.
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Starting at about mid-gestation, long slender mature intermediate villi (80120 mm in diameter) differentiate from
mesenchymal villi that emerge from stem villi.21 The gently
curving mature intermediate villi give rise to terminal villi at
intervals. Their villous core consists of a loose stroma with a
few small peripheral vessels and capillaries. All vessels present in
a villous cross section occupy maximally half the villous cross
sectional area.

Terminal villi
Terminal villi are the final branches of the villous trees. They
have a length of up to 100 mm and a diameter of about 80 mm,
and originate from mature intermediate villi.2 20 One of their
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Figure 3 Types of placental villi.
(A) Mesenchymal villi are rich in
mesenchymal cells and show syncytial
sprouting. (B) Immature intermediate villi
are characterised by stromal channels
containing fetal macrophages, Hofbauer
cells. (C) Stem villi are the largest villi and
show a perivascular contractile system
around their central vessels. (D) Mature
intermediate villi only contain smaller
vessels and capillaries in a loose stroma.
(E) Terminal villi possess sinusoids and
capillaries with a thin vasculo-syncytial
membrane. Light grey structure encircling
the villi, syncytiotrophoblast; dark grey
cells next to the syncytiotrophoblast,
cytotrophoblast; white centre of villi,
villous stroma; grey and dark grey cells in
stroma stromal cells; light grey cells in
stromal channels (B), macrophages; dark
grey circles and ovals with cells,
placental blood vessels with endothelial
cells; grey circles in centre of stroma (C),
central vessels (artery and vein) of stem
villi.

most important features is their high degree of capillarisation. In


a cross section, more than 50% of the overall villous cross
sectional area is occupied by vessels. Together with their partly
extremely thin placental barrier, this makes them the physiologically most important components of the villous tree of a
human placenta. In terminal villi capillaries often dilate into
sinusoids, which are covered by a vasculo-syncytial membrane
(separating maternal and fetal circulations) with a thickness of
0.52.0 mm.28 This vasculo-syncytial membrane consists of the
syncytiotrophoblast and the endothelium of the capillary,
separated by a joint basement membrane.

Basic villous structures


Villous trophoblast
From the time of the early villous stages until delivery, the
placental villi are covered by an epithelium-like layer, the villous
trophoblast. This layer rests on a basement membrane, which
separates it from the stromal core of the villi (fig 4).

Villous cytotrophoblast
The mononucleated villous cytotrophoblasts (Langhans cells)
always stay in direct contact with the basement membrane by
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their basal surface, while their apical surface always stays in


contact with the overlying syncytiotrophoblast. As soon as
these cells lose contact to the basement membrane during
invasion, they differentiate into the extravillous phenotype.
Furthermore, if villous cytotrophoblasts lose their contact to the
syncytiotrophoblast due to damage of the syncytial layer, they
transform into extravillous trophoblasts. In this situation
maternal blood clotting results in the deposition of fibrin-type
fibrinoid on the surface of these cells separating them again
from direct contact to maternal blood.29 30 Thus even in villous
tissues, extravillous trophoblasts can be found.
In placental specimens from the first trimester of pregnancy,
the villous cytotrophoblast is present as a complete cell layer
below the multinucleated syncytial layer. Thus at that stage of
pregnancy all villi are covered by a two-layered trophoblast
epithelium. As pregnancy progresses, the cytotrophoblasts seem
to reduce in number since at term they only contribute about
15% to the total volume of the villous trophoblast.31
Stereological studies have clearly shown that the total number
of cytotrophoblasts steadily increases during pregnancy from
about 16109 cytotrophoblast nuclei at 1316 weeks of gestation
to about 66109 at 3741 weeks of gestation.31 32 Due to steady
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proliferation of cytotrophoblast stem cells throughout pregnancy, the pool of cytotrophoblasts increases and is able to
maintain the second layer, the syncytiotrophoblast.33 The
reason for the seeming reduction in the number of cytotrophoblasts is the rapid expansion of the villous surface leading to a
separation of the single cytotrophoblasts.
Undifferentiated cytotrophoblasts display a cuboidal shape
with a cytoplasm that contains only few organelles.34 35
Differentiation after leaving the cell cycle results in the
formation of intermediate cells, which display a morphological
appearance between the undifferentiated state and the syncytiotrophoblast.34 35 The cytoplasm of these intermediate cells
contains large numbers of mitochondria and free ribosomes
together with high amounts of rough endoplasmic reticulum
and mRNA.36 37 These highly active cells display activities of
enzymes involved in aerobic and anaerobic glycolysis.38 39 The
activity of these cells has also been demonstrated by the
incorporation of high amounts of 3H-uridine in vitro.40 41
The highly differentiated cytotrophoblasts display a concentration of organelles, proteins and mRNA that is much higher
than that of the overlying syncytiotrophoblast.38 These cells will
soon fuse with the syncytiotrophoblast and will become an
integral part of this syncytial layer, incorporating all the
organelles, proteins and nucleic acids into this layer.

The syncytial cytoplasm contains a varying number of


organelles, ribosomes, pinocytotic vesicles and dense bodies.34 43
The highly differentiated syncytiotrophoblast does not show
any proliferative activity in any of its nuclei, which also show a
reduced rate of transcriptional activity.41 Thus the maintenance
of this syncytial layer is completely dependent on the
incorporation of cytotrophoblasts throughout gestation.44
Trophoblast nuclei incorporated into the syncytiotrophoblast
by syncytial fusion undergo morphological changes during their
stay within this layer. They start as large and ovoid nuclei rich
in euchromatin and develop into denser and smaller nuclei
during the next 34 weeks. Finally they display an annular
chromatin aggregation pointing to late apoptotic events in parts
of the syncytiotrophoblast.30 31 45 Such late apoptotic nuclei are
packed in so-called syncytial knots, which are shed from the
apical membrane of the syncytiotrophoblast into the maternal
circulation.31 4547
During normal pregnancy syncytial knots containing multiple nuclei can be detected in maternal uterine vein blood and in
maternal pulmonary vessels.4850 Due to their size these
corpuscular fragments of the syncytiotrophoblast cannot pass
the lungs and thus cannot be detected in maternal peripheral or
arterial blood.48 51

Connective tissue cells of the villous core


Syncytiotrophoblast
The syncytiotrophoblast is a multinucleated and polar layer
with a basal membrane in contact with cytotrophoblasts or the
basement membrane, and a microvillous apical membrane in
direct contact with maternal blood. There is a single syncytiotrophoblast in a single placenta, which covers all villous trees
and also parts of the chorionic and basal plates towards the
intervillous space. It is a continuous layer without lateral cell
borders and, depending on the site, contains variable concentrations of organelles. The microvilli on the entire surface of the
syncytiotrophoblast amplify the surface of this syncytial layer
about seven-fold. Underneath the microvilli there is a dense
network of actin filaments, microtubules and microfilaments.42

All villi are composed of a villous trophoblast epithelium


separated by a basement membrane from the mesenchymal core
of the villi. This core is built by fixed and free connective tissue
cells (macrophages) and blood vessels.

Fixed connective tissue cells


During early placentation the villous core is mostly filled with
mesenchymal cells that have the potential to differentiate into a
variety of other cell types such as endothelial cells and blood
cells, macrophages, myofibroblasts, smooth muscle cells and of
course fibroblasts. All of these cell types can be found in
different combinations in the villous stroma, depending on
stage of gestation and localisation in a specific villous type. The

Figure 4 Turnover of villous trophoblast.


From left to right the different steps
during trophoblast differentiation and
turnover are depicted. Cytotrophoblasts
proliferate; daughter cells leaving the cell
cycle differentiate and finally fuse with
the syncytiotrophoblast. There further
differentiation takes place, resulting in the
expression of various proteins specific for
this layer. Finally aged nuclei are released
from the apical membrane of the
syncytiotrophoblast by means of
syncytial knots. These apoptotic
corpuscular structures are shed and can
be found in maternal blood.

1300

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fibroblasts secrete typical matrix proteins such as collagen types
I and III, as well as proteoglycans such as hyaluronic acid.52

Placental macrophages (Hofbauer cells)


Macrophages can be found in the villous stroma starting at
week 5 post-menstruation. The origin of these cells, which are
also referred to as Hofbauer cells, is: (1) from progenitor cells
within the population of mesenchymal cells in the villous
stroma14 53; and (2) from penetration of embryonic/fetal bone
marrow-derived monocytes into the villous stroma and differentiation into macrophages once the blood flow between
embryo and placenta is established.38

Fetal vessels
A non-fenestrated endothelium lines the placental vasculature
throughout gestation with junctional complexes to link
neighbouring cells and to reduce paracellular transport. Larger
molecules cross the endothelial cells by means of vesicular
transport.54
Capillaries and sinusoids within terminal villi are surrounded
by a basement membrane without any further supporting cells
such as pericytes.14 Arteries and arterioles within stem and
intermediate villi possess a media with smooth muscle cells but
missing elastic laminae. The luminal diameter of placental
vessels has to be controlled by paracrine and autocrine factors
because there is no neural innervation in the placenta.55 The
endothelium of venules and veins has recently been shown to be
composed of a more immature endothelial cell phenotype
compared to placental arteries.56

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Fibrinoid
Fibrinoid is a homogeneous material that preferably binds acid
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surface of the chorionic and basal plates, encasing or partly
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J Clin Pathol 2008;61:12961302. doi:10.1136/jcp.2008.055277

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