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Review

The anatomy of the normal placenta


B Huppertz

Correspondence to: ABSTRACT chorionic plate.3 It has been further described that
Professor B Huppertz, Institute The placenta is the fetal organ providing the interchange in pregnancies arising from in vitro fertilisation
of Cell Biology, Histology and between mother and fetus. This organ needs to provide
Embryology, Centre of Molecular
techniques, a higher rate of abnormal placental
Medicine, Medical University of its function such as transport and secretion even during shapes as well as eccentric umbilical cord insertions
Graz, Harrachgasse 21/7, 8010 its development and thus all developmental changes need occur.4 It may be speculated that the timing and
Graz, Austria; berthold. to be in accordance with its function. This review normal interaction between maternal and embryo-
huppertz@meduni-graz.at
describes development of the placenta during the first nic cells regulating implantation is altered in these
few weeks of pregnancy until the villous trees with their cases.
Accepted 23 July 2008
Accept for Online First vasculature are established. The macroscopic anatomy of As soon as the blastocyst has firmly attached to
28 August 2008 the delivered placenta as well as the microscopic the uterine epithelium, the polar trophoblast
anatomy and histology of this organ are also described. undergoes the next differentiation step, syncytial
This includes the different types of villi and the most fusion of mononucleated cells to generate the first
important cellular components of the villi such as villous oligonucleated syncytiotrophoblast (fig 1). At that
trophoblast, Hofbauer cells, mesenchymal cells and stage of development the syncytiotrophoblast dis-
endothelium. Fibrinoid and its localisation is also plays an invasive phenotype, and only by means of
described. this syncytiotrophoblast is the blastocyst able to
penetrate the uterine epithelium.2 During the next
few days the early embryo embeds itself into the
A brief introduction to the development of the decidual stroma with the syncytiotrophoblast
human placenta is given, followed by a description forming a complete mantle surrounding the con-
of the structural characteristics of a delivered term ceptus. The remaining mononucleated tropho-
placenta. blasts are now referred to as cytotrophoblast,
which are found in the second row without
EARLY STAGES OF PLACENTAL DEVELOPMENT contacting maternal tissues. The cytotrophoblasts
Pre-implantation stage act as stem cells, which rapidly divide and
During human development, between the stages of subsequently fuse with the syncytiotrophoblast,
the morula and blastocyst (days 4–5 post-concep- resulting in a continuous expansion of the latter.5
tion), the trophoblast is the first cell lineage to Thus at that stage of development the syncytio-
differentiate. After establishment of the tropho- trophoblast is the only embryonic tissue coming
blast, the blastocyst consists of an inner cell mass into direct contact with maternal cells and fluids,
that is surrounded by a single layer of mononu- which has been hypothesised as a means to reduce
cleated trophoblasts. This outer layer surrounds rejection of the embryo.
not only the embryoblast, but also the blastocoel,
the blastocyst cavity. Later during pregnancy, the Lacunar stage
trophoblast gives rise to larger parts of the placenta Eight days after conception, fluid-filled spaces
and fetal membranes, while the inner cell mass occur within the syncytiotrophoblast and soon
gives rise to the embryo and umbilical cord as well coalesce to form larger lacunae. The remaining
as the placental mesenchyme. The latter is derived syncytiotrophoblastic masses between the lacunae
from extraembryonic mesoderm outgrowing from are termed trabeculae and are of great importance
the early embryo. At about days 6–7 post-concep- for the further development of the villous trees of
tion, the blastocyst hatches from the zona pellu- the placenta. As soon as the lacunae have devel-
cida and attaches to the uterine epithelium; at that oped, the three fundamental zones of the placenta
stage formation of the placenta begins.1 can be defined: the early chorionic plate facing the
embryo; the lacunar system together with the
Prelacunar stage trabeculae developing into the intervillous space
The localisation of the inner cell mass defines the and the villous trees; and the primitive basal plate
part of the trophoblast cover that makes the final in contact with the maternal endometrium.
attachment of the blastocyst to the uterine During implantation the invading syncytiotro-
epithelium (fig 1). Only those trophoblasts over- phoblast penetrates into the interstitium of the
lying the inner cell mass (referred to as polar endometrium and comes into contact with mater-
trophoblast) seem to be able to finally lead to nal capillaries and the superficial venous plexus of
implantation.2 Rotation of the blastocyst at that the endometrium. Erosion of these small vessels
stage may even lead to failure of pregnancy due to leads to the presence of first maternal blood cells
reduced contact of the polar trophoblast to the within the lacunae of the syncytiotrophoblast.6 7
uterine epithelium (fig 1). It has been described The appearance of first maternal blood cells in
that varying the orientation of the blastocyst at these lacunae has been equated with the onset of
the time of attachment and implantation results in the maternal circulation in the placenta. However,
abnormalities of umbilical cord insertion into the 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
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 struc-
tures 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 cytotropho-
blasts 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.
Figure 1 Implantation of the blastocyst. (A) During normal implantation Within the mesoderm of secondary villi, haematopoietic
the blastocyst rotates in such a manner that the polar trophoblast comes progenitor cells develop and start to differentiate. At about day
into direct contact with the uterine epithelium. The polar trophoblast 20 post-conception, first placental blood cells and endothelial
further differentiates into the first invasive syncytiotrophoblast, which cells develop independent of the vascular system of the embryo
then penetrates the epithelium and thus leads to embedding of the proper.13 14 The development of first placental vessels transforms
blastocyst into the uterine decidual stroma. (B) In some conditions the respective villi into tertiary villi.
rotation of the blastocyst is not adequate, leading to a reduced This classification of villous development only reflects the
interaction between polar trophoblast and uterine epithelium. Only some very basic stages of development of new villi. This process can
of the polar trophoblasts can form the syncytiotrophoblast, leading to a
principally be found throughout gestation. But since tertiary
reduced mass of the syncytium.
villi accumulate throughout gestation, the relative number of
newly forming primary and secondary villi in a term placenta is
stage of placental development the number of maternal extremely low.15
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 MACROSCOPIC ANATOMY OF THE DELIVERED PLACENTA
Rather, the maternal blood flow within the lacunae should be The full-term human placenta is a circular discoidal organ with
described as a slow flow of venous blood. a diameter of about 22 cm, a central thickness of 2.5 cm, and an
At about day 12 post-conception, implantation may be average weight of 470 g (fig 2). There is considerable variation
considered to be finalised. The embryo and its surrounding from placenta to placenta, which strongly depends on the mode
tissues are completely embedded within the endometrium. The of delivery. Especially when planning a morphometric analysis
syncytiotrophoblast displays a developmental gradient: it is of the placenta, factors such as when and where the umbilical
thicker with better developed lacunae underneath the embryo- cord has been clamped are critical because loss of maternal and/
nic pole, the site of first invasion. The more distal parts towards or fetal blood clearly affects the dimensions of the placenta.16
the abembryonic pole are thinner, with smaller lacunae and less
developed trabeculae. At that time extraembryonic mesodermal Fetal surface of the placenta
cells derived from the primitive streak have begun to migrate on The chorionic plate represents the fetal surface of the placenta,
top of the inner surface of the cytotrophoblast cells.9 10 The which in turn is covered by the amnion. The amnion is
combination of extraembryonic mesoderm and cytotrophoblast composed of a single layered epithelium and the amnionic
is termed chorion. mesenchyme, an avascular connective tissue. The amnionic
Starting on day 12 post-conception, cytotrophoblasts of the mesenchyme is only weakly attached to the chorionic mesench-
chorionic plate penetrate into the syncytiotrophoblastic mass of yme and can easily be removed from the delivered placenta.
the trabeculae, follow their course and reach the maternal side The umbilical cord mostly inserts in a slightly eccentric
of the placenta by day 15. This is the first time an embryonic position into the chorionic plate. The chorionic mesenchyme
cell or tissue other than the syncytiotrophoblast comes into contains the chorionic vessels that are continuous with the
direct contact with maternal tissues. Thus, only at week 5 post- vessels of the umbilical cord. Deriving from the two umbilical
menstruation the first cytotrophoblasts leave the placenta arteries the chorionic arteries branch in a centrifugal pattern
proper and differentiate into extravillous cytotrophoblasts. into their final branches, which supply the villous trees. The

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chorionic veins are direct continuations of the veins of the Mesenchymal villi
villous trees and usually cross the chorionic arteries underneath. Mesenchymal villi (100–250 mm in diameter) are the forerun-
The chorionic veins give rise to the single umbilical vein. ners of the intermediate villi and can be found predominantly in
the earliest stages of pregnancy.22 23 Up to six weeks post-
menstruation, mesenchymal villi are the only villous type
Maternal surface of the placenta
present in the developing placenta. Their stromal core is only
The basal plate represents the maternal surface of the placenta.
weakly organised and contains a large number of mesenchymal
It is an artificial surface, which emerged from the separation of
cells and developing vessels, the latter sometimes still lacking a
the placenta from the uterine wall during delivery. The basal
vessel lumen. Mesenchymal villi persist until delivery, but due
plate is a colourful mixture of fetal extravillous trophoblasts and
to their ongoing differentiation into intermediate villi, their
all kinds of maternal cells of the uterine decidua, including number becomes extremely low after the first trimester of
decidual stroma cells, natural killer cells, macrophages and other pregnancy.
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 Immature intermediate villi
plate into 10–40 slightly elevated regions called lobes. Inside the Developing from differentiating mesenchymal villi, immature
placenta, the grooves correspond to the placental septa, which intermediate villi (100–400 mm in diameter) are large, bulbous
only trace the lobar borders as irregular pillars or short sails. villi that dominate the villous trees between weeks 8 and 22 of
pregnancy.20 They further develop into stem villi by fibrosation
The lobes that are visible on the maternal surface of the
of the stroma from the centre to the periphery. Immature
placenta show a good correspondence with the position of the
intermediate villi possess a highly characteristic stroma. The
villous trees arising from the chorionic plate into the intervillous
mesenchymal stroma cells display long processes that link
space. In a full-term placenta, 60–70 villous trees (or fetal
together to form matrix-free channels oriented parallel to the
lobules) arise from the chorionic plate. Thus, each maternal lobe
long axis of these villi. These stromal channels contain large
is occupied by one to four fetal lobules.2 17 The occurrence of a
numbers of placental macrophages (Hofbauer cells) that seem to
single villous tree occupying a single lobe was defined as
be able to move along and cross between these channels.
placentone.18
Immature intermediate villi only contain smaller arterioles and
At the placental margin chorionic and basal plates merge and
venules and capillaries. After mid-gestation the number of
form the smooth chorion, the fetal membranes or the chorion
immature intermediate villi decreases in parallel to the
laeve. The chorion laeve is composed of three layers: the amnion
mesenchymal villi and only a few can be found at term. If a
with its epithelium and mesenchyme; the chorion with a layer larger number of such villi can be found in a term placenta, it is
of mesenchyme and a layer of extravillous trophoblast; and the important to note that they are recognised as immature
decidua capsularis. intermediate villi rather than being wrongly interpreted as
‘‘oedematous’’ villi.
MICROSCOPIC ANATOMY OF THE DELIVERED PLACENTA
Villous types Stem villi
The fetal lobules (villous tree) arise from the chorionic plate by a Stem villi derive from differentiation of immature intermediate
thick villous stem, which in the central region of the placenta is villi and are the villi with the largest diameter (100–3000 mm in
derived from a trabecula during very early placental develop- diameter). They serve to give mechanical support to the villous
ment. The branches of the stems continue branching, leading to tree.2 20 Their villous core is characterised by centrally located
a large number of stem villi generations and further branches, arteries and veins in a dense fibrous stroma.24 25 Capillaries are
finally ending as freely floating villi in the intervillous space. A rare, and thus it is speculated that this villous type plays only a
few branches may reach and contact the basal plate as small part in materno-fetal exchange. Rather, their physiological
anchoring villi, which contain the trophoblastic cell columns. significance—besides their role to mechanically stabilise the
The freely floating villi have been divided into five types of villi villous trees—lies in the fact that their vascular system is
on the basis of their calibre, stromal characteristics, vessel surrounded by a perivascular contractile sheath.26 27 Vessel
structure and appearance during pregnancy (fig 3).2 19–21 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


Starting at about mid-gestation, long slender mature inter-
mediate villi (80–120 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.
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). Terminal villi
(B) The maternal surface of the placenta is grouped into maternal lobes Terminal villi are the final branches of the villous trees. They
(dotted lines), which correspond to the fetal lobules, the villous trees have a length of up to 100 mm and a diameter of about 80 mm,
within the placental parenchyma. 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 their basal surface, while their apical surface always stays in
a cross section, more than 50% of the overall villous cross contact with the overlying syncytiotrophoblast. As soon as
sectional area is occupied by vessels. Together with their partly these cells lose contact to the basement membrane during
extremely thin placental barrier, this makes them the physio- invasion, they differentiate into the extravillous phenotype.
logically most important components of the villous tree of a Furthermore, if villous cytotrophoblasts lose their contact to the
human placenta. In terminal villi capillaries often dilate into syncytiotrophoblast due to damage of the syncytial layer, they
sinusoids, which are covered by a vasculo-syncytial membrane transform into extravillous trophoblasts. In this situation
(separating maternal and fetal circulations) with a thickness of maternal blood clotting results in the deposition of fibrin-type
0.5–2.0 mm.28 This vasculo-syncytial membrane consists of the fibrinoid on the surface of these cells separating them again
syncytiotrophoblast and the endothelium of the capillary, from direct contact to maternal blood.29 30 Thus even in villous
separated by a joint basement membrane. tissues, extravillous trophoblasts can be found.
In placental specimens from the first trimester of pregnancy,
Basic villous structures the villous cytotrophoblast is present as a complete cell layer
Villous trophoblast below the multinucleated syncytial layer. Thus at that stage of
From the time of the early villous stages until delivery, the pregnancy all villi are covered by a two-layered trophoblast
placental villi are covered by an epithelium-like layer, the villous epithelium. As pregnancy progresses, the cytotrophoblasts seem
trophoblast. This layer rests on a basement membrane, which to reduce in number since at term they only contribute about
separates it from the stromal core of the villi (fig 4). 15% to the total volume of the villous trophoblast.31
Stereological studies have clearly shown that the total number
Villous cytotrophoblast of cytotrophoblasts steadily increases during pregnancy from
The mononucleated villous cytotrophoblasts (Langhans cells) about 16109 cytotrophoblast nuclei at 13–16 weeks of gestation
always stay in direct contact with the basement membrane by to about 66109 at 37–41 weeks of gestation.31 32 Due to steady

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proliferation of cytotrophoblast stem cells throughout preg- The syncytial cytoplasm contains a varying number of
nancy, the pool of cytotrophoblasts increases and is able to organelles, ribosomes, pinocytotic vesicles and dense bodies.34 43
maintain the second layer, the syncytiotrophoblast.33 The The highly differentiated syncytiotrophoblast does not show
reason for the seeming reduction in the number of cytotropho- any proliferative activity in any of its nuclei, which also show a
blasts is the rapid expansion of the villous surface leading to a reduced rate of transcriptional activity.41 Thus the maintenance
separation of the single cytotrophoblasts. of this syncytial layer is completely dependent on the
Undifferentiated cytotrophoblasts display a cuboidal shape incorporation of cytotrophoblasts throughout gestation.44
with a cytoplasm that contains only few organelles.34 35 Trophoblast nuclei incorporated into the syncytiotrophoblast
Differentiation after leaving the cell cycle results in the by syncytial fusion undergo morphological changes during their
formation of intermediate cells, which display a morphological stay within this layer. They start as large and ovoid nuclei rich
appearance between the undifferentiated state and the syncy- in euchromatin and develop into denser and smaller nuclei
tiotrophoblast.34 35 The cytoplasm of these intermediate cells during the next 3–4 weeks. Finally they display an annular
contains large numbers of mitochondria and free ribosomes chromatin aggregation pointing to late apoptotic events in parts
together with high amounts of rough endoplasmic reticulum of the syncytiotrophoblast.30 31 45 Such late apoptotic nuclei are
and mRNA.36 37 These highly active cells display activities of packed in so-called syncytial knots, which are shed from the
enzymes involved in aerobic and anaerobic glycolysis.38 39 The apical membrane of the syncytiotrophoblast into the maternal
activity of these cells has also been demonstrated by the circulation.31 45–47
incorporation of high amounts of 3H-uridine in vitro.40 41 During normal pregnancy syncytial knots containing multi-
The highly differentiated cytotrophoblasts display a concen- ple nuclei can be detected in maternal uterine vein blood and in
tration of organelles, proteins and mRNA that is much higher maternal pulmonary vessels.48–50 Due to their size these
than that of the overlying syncytiotrophoblast.38 These cells will corpuscular fragments of the syncytiotrophoblast cannot pass
soon fuse with the syncytiotrophoblast and will become an the lungs and thus cannot be detected in maternal peripheral or
integral part of this syncytial layer, incorporating all the arterial blood.48 51
organelles, proteins and nucleic acids into this layer.
Connective tissue cells of the villous core
Syncytiotrophoblast All villi are composed of a villous trophoblast epithelium
The syncytiotrophoblast is a multinucleated and polar layer separated by a basement membrane from the mesenchymal core
with a basal membrane in contact with cytotrophoblasts or the of the villi. This core is built by fixed and free connective tissue
basement membrane, and a microvillous apical membrane in cells (macrophages) and blood vessels.
direct contact with maternal blood. There is a single syncytio-
trophoblast in a single placenta, which covers all villous trees Fixed connective tissue cells
and also parts of the chorionic and basal plates towards the During early placentation the villous core is mostly filled with
intervillous space. It is a continuous layer without lateral cell mesenchymal cells that have the potential to differentiate into a
borders and, depending on the site, contains variable concentra- variety of other cell types such as endothelial cells and blood
tions of organelles. The microvilli on the entire surface of the cells, macrophages, myofibroblasts, smooth muscle cells and of
syncytiotrophoblast amplify the surface of this syncytial layer course fibroblasts. All of these cell types can be found in
about seven-fold. Underneath the microvilli there is a dense different combinations in the villous stroma, depending on
network of actin filaments, microtubules and microfilaments.42 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.

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The anatomy of the normal placenta


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