The Journal of Maternal-Fetal & Neonatal Medicine

ISSN: 1476-7058 (Print) 1476-4954 (Online) Journal homepage: https://www.tandfonline.com/loi/ijmf20

Early development of the human placenta and

pregnancy complications

Kjell Haram, Jan Helge Mortensen, Ole Myking, Bodil Roald, Everett F.
Magann & John C. Morrison

To cite this article: Kjell Haram, Jan Helge Mortensen, Ole Myking, Bodil Roald, Everett
F. Magann & John C. Morrison (2019): Early development of the human placenta and
pregnancy complications, The Journal of Maternal-Fetal & Neonatal Medicine, DOI:
10.1080/14767058.2019.1578745

To link to this article: https://doi.org/10.1080/14767058.2019.1578745

Published online: 27 Feb 2019.

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THE JOURNAL OF MATERNAL-FETAL & NEONATAL MEDICINE
https://doi.org/10.1080/14767058.2019.1578745

REVIEW ARTICLE

Early development of the human placenta and pregnancy complications

Kjell Harama, Jan Helge Mortensena,b, Ole Mykingc, Bodil Roaldd, Everett F. Maganne and
John C. Morrisonf
a
Department of Obstetrics and Gynecology, Haukeland University Hospital, Bergen, Norway; bDepartment of Public Health and
Primary Health Care, University of Bergen, Bergen, Norway; cDepartment of Internal Medicine, Section of Endocrinology, Haukeland
University Hospital, University of Bergen, Bergen, Norway; dDepartment of Pathology, Center for Pediatric and Pregnancy Related
Pathology, Oslo University Hospital, Oslo, Norway; eDepartment of Obstetrics and Gynecology, University of Arkansas for Medical
Sciences, Little Rock, AR, USA; fDepartment of Obstetrics and Gynecology, University of Mississippi Medical Center, Jackson, MS, USA

ABSTRACT ARTICLE HISTORY

An adequately sized placenta at a suitable site with appropriate depth and centripetal progres- Received 18 October 2018
sion of implantation are the major factors for optimal fetal development. The cytotrophoblasts Revised 22 January 2019
surround the blastocyst fuses at the site of the uterine attachment. This forms a second layer of Accepted 1 February 2019
multinucleated syncytiotrophoblasts that constitutes the inner epithelial boundary of the chori-
KEYWORDS
onic villous against the intervillous space. In a normal pregnancy, extravillous cytotrophoblasts Blastocyst; cytotrophoblast;
(EVT) invade and obstruct the spiral arteries and remodel them. Vacuoles in the syncytial cell implantation; placenta;
layer fuse and develop the intervillous space. The inner cell mass (embryoblast) gives rise to the pregnancy complications;
umbilical cord and the mesenchyme in the chorionic villi. Vasculogenesis starts with the forma- spiral artery;
tion of hemangioblastic cords in this mesenchyme. The trophoblastic cell columns anchor the syncytiotrophoblast
placenta. A variety of molecular pathways participate in the placentation process. Placental mor-
phogenesis occurs mainly through complex cellular interactions between the chorionic villous
and the extravillous cytotrophoblasts. The formation of the normal structure of the chorionic
villi, syncytiotrophoblast layer and vasculature is essential for placental function, hormone pro-
duction, and regulation of fetal growth. At each stage of placental development, genetic var-
iants, exposure to infection, poor vascular function, oxidative stress, or failure of normal
development can all lead to abnormal formation resulting in the clinical complications of preg-
nancy such as fetal growth disorders, neonatal neurologic abnormalities, placental adhesions,
and inflammatory problems as well as maternal disease such as preeclampsia.

Introduction information [1,8,9]. Studies regarding placental patho-

physiology have recently provided information on the
The placenta is a complicated organ and several func-
complex interactions between normal regulation of
tions are essential for a successful pregnancy outcome
[1]. Abnormalities may cause serious complications, placental growth and spiral artery remodeling as a
such as fetal growth restriction, fetal neurologic condi- function of apoptosis [1,9,10].
tions, placental adhesion disorders, preeclampsia, and The purpose of this review is to describe the main
inflammatory processes which remain as challenging aspects of placental development in the first half of
clinical problems [2–6]. A number of longitudinal ana- pregnancy and obstetric complications, which can
tomic studies of the placenta have been performed in result if pathophysiologic changes in the pla-
normal as well as abnormal pregnancies and all dem- centa occur.
onstrate the importance of sequential placental devel-
opment [7,8]. The spiral arteries have been a focus in
Early development of the human placenta
many reports, some critically apprizing in vitro examin-
ation of trophoblast invasion and spiral artery remod- The outer blastocyst layer of trophoblast develops into
eling [1]. The placenta has been assessed by electron the placenta and fetal membranes. The inner cell mass
microscopy, flow cytometry, immunohistochemical, (embryoblast) develops into the embryo and umbilical
and endocrinologic methodology to provide additional cord. The embryoblast is surrounded by a single layer

CONTACT Everett F. Magann [email protected] Department of Obstetrics and Gynecology, UAMS, Markham St. Slot # 518, Little Rock,
AR, USA
This paper honors Dr. Kjell Haram, recently deceased, who was a leading clinical researcher in the field of Obstetrics and Gynecology. His innovative
thought process, keen interest in new ideas, and energetic scientific methods will be missed.
ß 2019 Informa UK Limited, trading as Taylor & Francis Group
2 K. HARAM ET AL.

of mononucleated trophoblasts, which also embraces within the syncytiotrophoblast [13,15]. Syncytial fusion
the blastocele and the blastocyst cavity. During is dependent on commencement of the apoptotic cas-
human development, between the stages of the mor- cade in the chorionic villous cytotrophoblasts and in
ula and blastocyst (days 4–5 postconception), the the syncytiotrophoblasts [15]. The syncytium has a
trophoblast is the first cell lineage to differentiate [11]. high turnover rate and the syncytial knots are shed
After the establishment of the trophoblasts, the into maternal blood. Anomalies in the syncytiotropho-
blastocyst consists of an inner cell mass that is sur- blast layer may impede placental function and can
rounded by a single layer of mononucleated tropho- lead to fetal growth restriction [16,17].
blasts. This outer layer surrounds not only the In the first trimester, cytotrophoblast stem cells
embryoblast but also the blastocoel and the blastocyst push forward through the syncytiotrophoblastic mass
cavity. The placental mesenchyme is derived from an and reach the maternal side of the placenta. The
extraembryonic mesoderm outgrowth of the early maternal tissue reorganizes and develops, with suffi-
embryo. At about days 6–7 postconception, the cient oxygen, into multilayered structures which will
blastocyst hatches from the zona pellucida and become the trophoblastic cell columns that anchor
attaches to the uterine epithelium and at that stage the placenta to the wall of the uterus [18] At around
formation of the placenta begins [8]. Only the tropho- day 14 postconception, the cytotrophoblasts begin to
blasts overlying the inner cell mass (referred to as invade the underlying decidua (interstitial invasion)
polar trophoblasts) lead to blastocyst implantation [8]. from this anchoring column as extravillous cytotropho-
Immediately after implantation, the first invasion of blasts (EVTs) [19]. The EVTs accumulate around the spi-
the endometrium is performed by the early syncytio- ral arteries and expand laterally to form the
trophoblasts [11,12]. cytotrophoblast shell and then they stop proliferation
The cytotrophoblasts differentiate along the fusion and begin invasion because of differentiation. The
or the invasion pathway. The cytotrophoblasts have depth of trophoblast invasion initiated at the center of
the ability to change from the proliferation to invasion the placenta becomes more shallow at the periphery,
state by adjusting the adhesion molecule phenotype which is noted around midgestation. Appropriate
[13]. Both types of trophoblasts keep a subset of cells placement of the placenta at a suitable site, with nor-
in direct contact with the villous basal membrane. mal depth and centripetal progression of implantation,
They retain their generative potential and the ability are essential for optimal development of the fetus.
to proliferate in response to growth factors [1,3]. The
cytotrophoblasts around the blastocyst fuse at the site
Spiral artery remodeling
of uterine attachment to form a second layer of multi-
nucleated syncytiotrophoblasts, which constitutes the EVTs penetrate and invade the media of the spiral
inner epithelial boundary of the chorionic villus arteries in normal pregnancy. The elastic and add-
against the intervillous space [13,14]. DNA synthesis itional matrix tissue is enzymatically destroyed and
does not occur in syncytiotrophoblasts, indicating that replaced by fibrinoid material [19] After breaking
the syncytial nuclei are unable to replicate [14]. Once through the artery barricade, the cytotrophoblasts
formed, the syncytiotrophoblasts grow by means of migrate along the inner luminal surfaces of the endo-
steady incorporation of new mononucleated tropho- thelium and transiently coexist with the endometrium
blasts from a proximal subset of stem cells, which on the walls of partially modified spiral arteries before
renews the syncytiotrophoblasts. The fusion process replacing the endothelium. The remodeling of the spi-
integrates the cytoplasm content, proteins, and RNA ral arteries involves endothelial apoptosis induced by
as well as membranes and nuclei from cytotropho- EVTs through Fas/FASL interactions [20]. Fas expres-
blasts into the syncytiotrophoblast [1,3]. The final sion is detected in spiral artery endothelial cells,
event of the apoptosis cascade process inside the syn- smooth muscle cells and decidual endothelial cells.
cytiotrophoblast is the packaging of old and later Fas/FASL interactions are involved in trophoblast
apoptotic nuclei into protrusions of the apical mem- induction of endothelial apoptosis. Loss of endothelial
brane of the syncytiotrophoblast, called syncytial knots cells from the lumen of the maternal uterine spiral
[15]. The process of syncytial fusion is linked to the arteries is a prerequisite for a successful pregnancy
“initiator stage” of the apoptotic cascade process [19]. If abnormalities occur early in the process of spi-
within the cytotrophoblast cells. The extrusion of syn- ral artery changes, severe forms of preeclampsia can
cytial knots from the syncytiotrophoblast is the result occur [21]. The trophoblasts transform their adhesion
of final “execution stages” of the apoptotic process receptor phenotype similar to the endothelial cells
 THE JOURNAL OF MATERNAL-FETAL & NEONATAL MEDICINE 3

they replace and the EVTs obstruct the lumen of the circulation in the placenta is crucial for efficient
spiral arteries (endovascular invasion) [19]. During this exchanges of oxygen and nutrition to the fetus and
process, if oxygen status is suboptimal, embryopathies removal of waste products from the fetus [16].
can occur [18]. The cytotrophoblast plugging of spiral Chorionic villi formation starts at about 2 weeks after
arteries may serve as a mechanism to protect the fetus conception. Finger-like outgrowths of trophoblast tra-
and the placenta from free radical-mediated stress beculae proliferate from the chorionic plate into the
[22]. At the same time, the cytotrophoblast obstruc- intervillous space developing the chorionic villous
tion creates a low-oxygen environment in the placen- trees. As long as the villi are composed of only troph-
tal tissue, less than 20 mm Hg until 10–12 weeks of oblasts, they are termed primary villi [28]. At 5 weeks’
gestation [23]. gestation (about 21 days after conception), the primary
At the end of the first trimester, the luminal plugs in chorionic villi are invaded by mesenchyme cells
the spiral arteries begin to disintegrate [22] and they derived from the embryoblast, thereby transforming
are dissolved at about 14 weeks’ gestation with a rise the primary villi into secondary chorionic villi. At the
in placental pO2 to concentrations above 50 mmHg end of the third week, mesenchyme cells begin to dif-
[18,24]. The remodeling processes normally occur dur- ferentiate into blood cells and small blood vessels
ing the first 20–22 weeks of pregnancy leading to spiral (vasculogenesis) which results in the formation of the
artery dilatation, a low-resistance circulatory system and the tertiary chorionic villi. Each tertiary villus has a
increased intervillous blood flow [18]. This process has connective tissue core that contains fetal blood vessels
been termed “physiologic change” which refers to the and numerous macrophages (Hofbauer cells) [28]. As
combination of cytotrophoblasts, accumulated fibrinoid the placenta ages, there will be a normal increase in
material in the spiral artery walls, and loss of musculoe- the stromal connective tissue whereas abnormalities in
lastic tissue in the media of fetal spiral arteries [25]. this process can result in preeclampsia [7,21,29].
However, failure of this process can result in pree- The free-floating chorionic villi can be divided into
clampsia, growth restriction, and vascular anomalies five types on the basis of the caliber and stromal char-
[4,6,16]. Trophoblasts may or may not invade the ven- acteristics as well as vessel structure and appearance
ous wall, even though free floating endoluminal [28]. Mesenchymal villi (100–250 mm in diameter) are
trophoblast have been found in these vessels [26]. the forerunners of the intermediate villi and are pre-
dominantly found in the earliest stages of pregnancy.
They become significantly reduced after the first tri-
The intervillous space
mester. Immature intermediate villi (100–400 mm in
Vacuoles develop in the syncytial cell layer. These fuse diameter) developing from differentiating mesenchy-
and form lacuna (especially at the embryonic pole) mal villi are large bulbous villi that dominate the
and an intercommunicating vascular network. The chorionic villous tree between 8 and 22 weeks of preg-
lacuna is observed 11–12 days after conception and is nancy [28]. Stem chorionic villi derive from differenti-
filled with fluid [9]. The syncytial cells penetrate ation of intermediate villi and are generally the villi
deeply into the stroma and erode the lining of the with the largest diameter (100–300 mm). They serve to
capillaries, which are congested and dilated, thus support the chorionic villous tree. Their villous core is
forming sinusoids [11]. Further development of these characterized by centrally located arteries and veins in
sinusoids leads to the creation and expansion of the a dense fibrous stroma [28]. Mature intermediate villi
intervillous space (second –third gestational week) and starting at about midgestation are long slender
results in the first arterial blood flow from mother to mature intermediate villi (80–120 mm). Terminal villi
the intervillous space [27]. are final branches of the villous tree. They have a
length up to 100 mm, a diameter of about 80 mm, and
originate from mature intermediate chorionic villi [28].
Development of chorionic villi, vasculogenesis,
Vasculogenesis is defined as the process in which a
and angiogenesis
primitive vascular network is established while angio-
The structural and functional unit of the placenta is genesis is the process of new vessel formation from
the chorionic villus [28]. The formation of the normal preexisting vessels [30]. The chorionic vasculogenesis
structure of the chorionic villi, syncytiotrophoblast starts with the formation of hemangioblastic cords
layer and vasculature is essential for placental func- that are the first precursors of fetal endothelium in
tion, hormone production, and regulation of fetal the villous stroma. These so-called hemangioblastic
growth. The relationship between maternal and fetal cell cords can be demonstrated as early as 15–21 days
4 K. HARAM ET AL.

after conception [1]. In the human placenta, the for- factors in normal and preeclamptic gestations [28,38].
mation of endothelial tubes from hemangiogenic In addition, decidual changes in the endometrial
cords starts at about 21 days after conception by focal stoma and myometrium precede trophoblast invasion
enlargement of centrally located intercellular clefts and remodeling, which particularly in adolescent preg-
which later fuse to become a larger lumen [31]. nancies, can result in spontaneous preterm labor and
Apoptosis contributes to physiologic vascular lumen growth restriction [39,40]. Human cytotrophoblasts
formation and vascular branching in human placental produce both the urokinase-type plasminogen activa-
vasculogenesis [32]. Abnormalities of placental vaculo- tor and different matrix metalloproteinases – (MMPs),
genesis can cause idiopathic recurrence, spontaneous particularly important in those who develop pree-
miscarriages, although the most frequent cause of clampsia [2]. The MMP-9 protease activity is required
such early losses is chromosomal abnormalities [33,34]. for cytotrophoblast degradation and invasion through
Likewise, if the anchoring villi are abnormal, placenta Matrigel. Cytokines and growth factors modulate the
abruption can occur later in pregnancy and lead to MMP expression and the proteolytic activity [2]. Either
stillbirth or an increased prevalence of major fetal con- syncytiotrophoblasts or the inner villous cytotropho-
genital malformation [35,36]. blast layer expresses a number of transforming growth
In the normal human pregnancy, capillary growth is factor beta (TGFb) superfamily ligands [41]. By modu-
biphasic, involving an initial phase of branching angio- lating the syncytial fusion, they play important roles in
genesis (formation of tightly looped capillaries) fol- the decidual regulation of the EVT invasion [4]. Several
lowed by increased nonbranching angiogenesis hormones such as estrogen, progesterone, human
(formation of longer capillaries) [7]. New branches may chorionic gonadotropin (hCG), prolactin, leptin, human
be created by sprouting angiogenesis (lateral spouting placental lactogen (hPL), and different cytokines par-
from existing vessels) or by intussusceptive angiogen- ticipate in the regulation of the cytotrophoblast differ-
esis (formation of transvascular epithelial pillars which entiation, proliferation, and invasion [42]. IL-6 also
partition one lumen into two or more lumina) [7]. contributes to the regulation of hormone production
These cords develop into a richly branched chorionic and appears to be involved in angiogenesis. Following
villous capillary bed. Formation of a capillary vascular implantation, invasion of the decidua by EVTs is tightly
network occurs from 32 days after conception until 25 modulated by cytokines [4]. Plasmin may activate spe-
weeks’ gestation by branching angiogenesis. cific procollagenases and facilitate the EVT invasion in
Regression of terminal capillary webs and formation of the decidua.
central stem vessels primarily occurs mainly through Activin promotes, while TGFb and macrophage
15–32 weeks post conception. From about 25 weeks inhibitory cytokine-1 (MIC-1) (expressed in the
after conception until term, the patterns of chorionic decidua) inhibits trophoblast migration in vitro, sug-
villous vascular growth switch from branching angio- gesting that a relative balance of the TGFb superfamily
genesis to nonbranching angiogenesis and to the for- members participate in modulating the extent of
mation of capillary loops [7]. The human placenta decidual cytotrophoblast invasion [43]. By the end of
experiences a dramatic growth including elongation of the first-trimester follistatin is inhibitory whereas acti-
the terminal villi during the second trimester. The vin A stimulates the invasive potential of cytotropho-
chorionic villi undergo substantial changes as charac- blasts prior to 10 weeks’ gestation [3]. Oxygen is also
terized by an estimated 56-fold increase in capillary a key regulator of placental development. The tropho-
volume in peripheral chorionic villi by term, mostly blast migration and invasive capacity are modulated
due to an increase of the mean length of the villi by oxygen tension and low-tissue PO2 maintains the
[28,37]. The remodeling of the vessels in the chorionic trophoblasts in a proliferative, noninvasive state
villi includes loss of elastic membranes, thinner muscu- [18,44]. The localization of the cell columns at the bor-
lar coats, dispersion of muscle cells and also the loss der between low-oxygen placenta (promoting prolifer-
of the muscoelastic coat of the vessel wall (disruption ation) and the high-oxygen decidua (promoting
of the tunica media) [28]. invasion) is needed for the shift from the ability to
proliferate in the proximal part of the cell column to
the capability for invasion at the distal part [8].
Molecules involved early placental formation
Hypoxia is a potent stimulus for the induction of VEGF
and function
gene expression, while hypoxia-inducible factor-1 (HIF-
Trophoblast invasion of the decidua and maternal vas- 1) is an up-regulating factor. The EVTs express numer-
culature is regulated by trophoblastic and decidual ous VEGF family members. VEGF ligands and receptors
 THE JOURNAL OF MATERNAL-FETAL & NEONATAL MEDICINE 5

are deregulated in severe preeclampsia and fetal/pla- pregnancy. Ligands such as oxidized low-density lipo-
cental vasculopathy [43]. Also, in the face of cytokine proteins (LDLs) at the implantation site might contrib-
expression, polymorphisms in the tumor necrosis fac- ute to the modulation of trophoblast invasion through
tor alpha and lectin genes have been related to cere- activation of PPARc and liver  nuclear receptor
bral palsy in the offspring, particularly if they are born b [21,27].
preterm [45–47]. Development of the chorionic vasculature in the
Normally, the expression of cell-cell interaction (e.g. placenta depends on the actions of angiogenetic
cadherins, Ig superfamily) and cell-extracellular matrix growth factors and their receptors produced by cells
(e.g. integrin receptors), as well as adhesion molecules and extracellular matrix ingredients near the fetal ves-
(syncytin), are extensively modulated as the EVTs sels. These vessels lack autonomic innervations, so
invade the uterine wall from the outside of the spiral resistance to flow in the maturing vasculature must be
arteries and also retrograde from the cytotrophoblastic regulated by local vasoactive effectors [30]. The bal-
shell [48]. The invasive pathway of trophoblast differ- ance of various angiogenetic factors and several
entiation is associated with a change in adhesion angiogenetic inhibitors mainly regulates angiogenesis.
receptor phenotype away from epithelial cell type Most of the angiogenetic regulators are extrinsic to
adhesion molecules (integrin b4 and b5), to adhesion endothelial cells. Vasohibin, a novel endothelium-
receptors typical for invasive and endothelial cells derived angiogenesis inhibitor, is selectively expressed
(vascular endothelial (VE)-cadherin), b1 and b3 integrin, in endothelial cells and is induced by well-known
vascular cell adhesion molecule 1 (VCAM-1), platelet- angiogenetic factors such as VEGF and fibroblast
endothelial adhesion molecule 1 (PECAM-1), and intra- growth factor 2 (FGF-2) [2,52]. Angiogenesis enhances
cellular adhesion molecule-1 (ICAM). The cytotropho- the development of the vascularity in the chorionic
blast cell-cell fusion into syncytiotrophoblasts during villi and the main factors are VEGF, PlGF, FGF, and the
human placentogenesis is tightly regulated [13]. angiopoietin (Ang) protein family as well as their
Syncytin probably plays a key role in the cell-cell receptors [53]. The extracellular portion of VEGF-A
fusion [13,48]. Syncytin is a membrane protein derived molecule (i.e. the soluble VEGF antagonist, sflt-1) is
from the envelope gene of an endogenous retrovirus required for placental vascular development.
of the HERV-W family, almost exclusively expressed in Histochemical studies have found that the receptor is
the syncytiotrophoblasts [49]. Initiation of the cell-cell expressed on human villous endothelium, villous mac-
fusion takes place either through up-regulation of syn- rophages, and trophoblasts during fetoplacental
cytin in differentiating cytotrophoblasts, through local angiogenesis [37]. PlGF is expressed both in villous
down-regulation of receptors in the syncytiotropho- syncytiotrophoblasts and in the media of larger stem
blasts or through local up-regulation of syncytin in the vessels [54].
syncytiotrophoblasts themselves [47]. The vasculogenesis and angiogenesis early in the
The circulating renin-angiotensin system (RAS) plays placental development are stimulated by VEGF, PlGF,
a key role in regulating blood pressure and electrolyte FGF, and their receptors [54]. PlGF in vivo stimulates
balance [50]. There is a local renin-angiotensin system proliferation of microvascular endothelial cells in the
(RAS) in the placenta. RAS has a critical regulatory role term placenta and PlGF is also a potent stimulator of
in vascular remodeling and in the fetoplacental circula- angiogenesis [8]. PlGF is down-regulated by hypoxia
tion facilitating adequate placental blood flow [50,51]. If and becomes increasingly significant towards the third
the blood flow is abnormal, preeclampsia may occur, trimester as angiogenesis changes from branching to
particularly in the presence of polymorphisms [51]. non-branching type [53].
Decidual tissues are a source of angiotensin II (ANG-II) Basic FGF-2 (or bFGF) is thought to be involved in
production and trophoblasts serve as paracrine targets the recruitment of hemangiogenic progenitor cells
of ANG-II signaling through angiotensin AT1 receptor and their expression in human placental villi [30].
activation. Multiple genes are regulated by AT1 recep- Vascular endothelial growth factor A (VEGF-A of VEGF)
tors associated with trophoblast invasion (e.g. plasmino- is responsible for the growth and aggregation of the
gen-activator inhibitor-1 (PAI-1) and sFlt-1) [47]. The endothelial precursors for the formation of hemangio-
peroxisome proliferator-activated receptor-c (PPARc) is genic cords and is highly expressed in early pregnancy
a member of the nuclear receptor superfamily [54]. Chorionic villous trophoblasts and villous macro-
expressed in the chorionic villi, EVTs, and in the syncy- phages are the main sources of this cytokine [53].
tiotrophoblasts [27]. PPARc has a major role in the con- Angiogenesis is also mediated, in part, by the endo-
trol of human trophoblast invasion during early thelial cell receptor tyrosine kinases (RKTs), Tie-1
6 K. HARAM ET AL.

(expressed in decidual endothelial cells), Tie-2 ORCID

(expressed in the vascular endothelium), and the Tie-2 Everett F. Magann http://orcid.org/0000-0001-6823-7635
agonist ligand Ang-1, which are essential for a suc-
cessful pregnancy [54]. When these receptors are defi-
cient, angiogenesis is reduced and growth restriction,
diabetes, as well as preeclampsia becomes more References
prevalent. Ang-1 and Ang-2 have been detected in [1] Cartwright JE, Kenny LC, Dash PR, et al. Trophoblast
perivascular cells of the intermediate chorionic villi invasion of spiral arteries: a novel in vitro model.
[55]. In the chorionic villous, establishment and main- Placenta. 2002;23:232–235.
[2] Mlynarczyk M, Chauhan SP, Baydoun HA, et al. The
tenance of the outer part of the vessel walls is, in
clinical significance of an estimated fetal weight
part, controlled by the balance of Ang-1 and Ang-2 below the 10th percentile: a comparison of outcomes
interacting with the Tie-2 receptor [56]. The Ang-2 and of <5th vs. 5th–9th percentile. Am J Obstet Gynecol.
Tie-2 receptor ligand system may play a pivotal role in 2017;217:198.e1–198.e11.
the remodeling of the vessels of the fetal-maternal [3] Murtha AP, Menon R. Regulation of fetal membrane
inflammation: a critical step in reducing adverse preg-
interface [30]. Endothelial growth factor receptor kin-
nancy outcome. Am J Obstet Gynecol. 2015;213:
ase 1 and 2 (VEGFR-1 and VEGFR-2) are also involved 447–448.
in vasculogenesis [42]. The placental-specific transcrip- [4] Redline RW. Severe fetal placental vascular lesions in
tion factor glial cell missing gene (GCM1) is a transac- term infants with neurologic impairment. Am J
tivator for syncytin expression in the placenta [57]. Obstet Gynecol. 2005;192:452–457.
[5] Woodring TC, Klauser CK, Bofill JA, et al. Prediction of
GCM1 promotes vasculogenesis and vascular branch-
placenta accreta by ultrasonography and color
ing and has a distinct role in the maintenance, devel- Doppler imaging. J Matern Fetal Neonatal Med. 2011;
opment, and turnover of the trophoblasts. 24:118–121.
[6] American College of Obstetricians and Gynecologists.
Gestational hypertension and preeclampsia. ACOG
Conclusion Practice Bulletin #200. Obstet Gynecol 2019;133:
The placenta is a unique organ whose vital functions 211–218.
[7] Brosens I, Pijnenborg R, Vercruysse L, et al. The “Great
determine fetal and maternal health. An extensive lit- Obstetrical Syndromes” are associated with disorders
erature on placental development began in the eight- of deep placentation. Am J Obstet Gynecol. 2011;204:
eenth century. The classic publication by Grosser 193–201.
published in 1927 reviewed existing knowledge of [8] Huppertz B. The anatomy of the normal placenta.
implantation at that time [8]. Since that time, a great J Clin Pathol. 2008;61:1296–1302.
[9] Huppertz B, Kadyrov M, Kingdom JC. Apoptosis and
number of publications confirming the importance of
its role in the trophoblast. Am J Obstet Gynecol.
placenta development have been published. The pre- 2006;195:29–39.
sent survey highlights the changes in early placental [10] Whitley GS, Cartwright JE. Trophoblast-mediated spi-
development and the clinical problems during preg- ral artery remodelling: a role for apoptosis. J Anat.
nancy which can occur if this process is abnormal. 2009;215:21–26.
[11] Carter AM, Enders AC, Pijnenborg R. The role of inva-
Formation of the chorionic villi and angiogenesis are
sive trophoblast in implantation and placentation of
important steps in the creation of a normal structure, primates. Philos Trans R Soc Lond B Biol Sci. 2015;
which is essential for a placental function such as hor- 370:20140070.
mone production, removal of waste products from the [12] Pantham P, Askelund KJ, Chamley LW. Trophoblast
fetus, and regulation of fetal growth. The relationship deportation part II: A review of the maternal conse-
quences of trophoblast deportation. Placenta. 2011;
between maternal and fetal circulation in the placenta
32:724–731.
is crucial for efficient exchanges of oxygen and nutri- [13] Po€tgens AJ, Drewlo S, Kokozidou M, et al. Syncytin:
tion to the fetus. Inadequate vascularity in the chori- the major regulator of trophoblast fusion? Recent
onic villi may cause reduced fetal growth, lead to developments and hypotheses on its action. Hum
placental abruption, adhesion problems, stillbirth, pre- Reprod Update. 2004;10:487–496.
[14] Po€tgens AJ, Schmitz U, Bose P, et al. Mechanisms of
eclampsia, HELLP syndrome, fetal respiratory problems,
syncytial fusion: a review. Placenta. 2002;23:
and inflammation [2–5,58,59].
S107–S113.
[15] Huppertz B, Frank HG, Kingdom JC, et al. Villous cyto-
trophoblast regulation of the syncytial apoptotic cas-
Disclosure statement
cade in the human placenta. Histochemistry. 1998;
No potential conflict of interest was reported by the authors. 110:495–508.
 THE JOURNAL OF MATERNAL-FETAL & NEONATAL MEDICINE 7

[16] Pardi G, Marconi AM, Cetin I. Placental-fetal interrela- [33] Teles TM, Paula CM, Ramos MG, et al. Frequency of
tionship in IUGR fetuses – a review. Placenta. 2002;23: chromosomal abnormalities in products of concep-
S136–S141. tion. Rev Bras Ginecol Obstet. 2017;39:110–114.
[17] American College of Obstetricians and Gynecologists. [34] Banergee P, Ghosh S, Dutta M, et al. Identification of
Fetal growth restriction. ACOG Practice Bulletin #204. key contributory facts responsible for vascular dys-
Obstet Gynecol. 2013;121:1122–1133. function in idiopathic recurrent spontaneous miscar-
[18] Huppertz B, Gauster M, Orendi K, et al. Oxygen as riage. Plos One. 2013;8:le80940.
modulator of trophoblast invasion. J Anat. 2009;215: [35] Riihim€aki O, Mets€aranta M, Ritvanen A, et al.
14–20. Increased prevalence of major congenital anomalies
[19] Zhou Y, Fisher SJ, Janatpour M, et al. Human cytotro- in births with placental abruption. Obstet Gynecol.
phoblasts adopt a vascular phenotype as they differ- 2013;122:268–274.
entiate. A strategy for successful endovascular [36] Pinar H, Goldenberg RL, Koch MA, et al. Placental
invasion? J Clin Invest. 1997;99:2139–2151. findings in singleton stillbirths. Obstet Gynecol. 2014;
[20] Ashton SV, Whitley GS, Dash PR, et al. Uterine spiral 123:325–336.
artery remodeling involves endothelial apoptosis [37] Mayhew TM. Fetoplacental angiogenesis during ges-
induced by extravillous trophoblasts through Fas/FasL tation is biphasic, longitudinal and occurs by prolifer-
interactions. ATVB. 2005;25:102–108. ation and remodelling of vascular endothelial cells.
[21] Zhou Y, McMaster M, Woo K, et al. Vascular endothe- Placenta. 2002;23:742–750.
lial growth factor ligands and receptors that regulate [38] Regnault TR, Galan HL, Parker TA, et al. Placental
human cytotrophoblast survival are dysregulated in development in normal and compromised pregnan-
severe preeclampsia and hemolysis, elevated liver cies – a review. Placenta. 2002;23:S119–S129.
enzymes, and low platelets syndrome. Am J Pathol. [39] Brosens I, Benagiano G, Brosens JJ. The potential peri-
2002;160:1405–1423. natal origin of placentation disorders in the young
[22] Pijnenborg R, Vercruysse L, Hanssens M. The uterine primigravida. Am J Obstet Gynecol. 2015;212:580–585.
spiral arteries in human pregnancy: facts and contro- [40] Knuppel RA, Hassan MI, McDermott JJ, et al. Oxidative
versies. Placenta. 2006;27:939–958. stress and antioxidants: preterm birth and preterm
[23] Burton GJ, Hempstock J, Jauniaux E. Oxygen, early
infants. In: Morrison JC, editor. Preterm birth: mother
embryonic metabolism and free radical-mediated
and child. Rijeka, Croatia: InTech Press; 2012.
embryopathies. Reprod Biomed Online. 2003;6:84–96.
p. 125–150.
[24] Jauniaux E, Gulbis B, Burton GJ. The human first tri-
[41] Jones RL, Stoikos C, Findlay JK, et al. TGF-beta super-
mester gestational sac limits rather than facilitates
family expression and actions in the endometrium
oxygen transfer to the foetus – a review. Placenta.
and placenta. Reproduction. 2006;132:217–232.
2003;24:S86–S93.
[42] Torry DS, Hinrichs M, Torry RJ. Determinants of pla-
[25] Konje JC, Huppertz B, Bell SC, et al. 3-dimensional col-
cental vascularity. Am J Reprod Immunol. 2004;51:
our power angiography for staging human placental
257–268.
development. Lancet. 2003;362:1199–1201.
[43] Mohaupt M. Molecular aspects of preeclampsia. Mol
[26] Espinoza J, Romero R, Mee Kim Y, et al. Normal and
abnormal transformation of the spiral arteries during Aspects Med. 2007;28:169–191.
[44] Caniggia I, Mostachfi H, Winter J, et al. Hypoxia-indu-
pregnancy. J Perinat Med. 2006;34:447–458.
[27] Fournier T, Therond P, Handschuh K, et al. cible factor-1 mediates the biological effects of oxy-
PPARgamma and early human placental develop- gen on human trophoblast differentiation through
ment. Curr Med Chem. 2008;15:3011–3024. TGFbeta(3). J Clin Invest. 2000;105:577–587.
[28] Kingdom J, Huppertz B, Seaward G, et al. [45] Peleja AB, Martinelli S, Ribeiro RL, et al. Fetal throm-
Development of the placental villous tree and its con- botic vasculopathy: a case report and literature
sequences for fetal growth. Eur J Obstet Gynecol review. Rev Assoc Med Bras. 2016;62:687–690.
Reprod Biol. 2000;92:35–43. [46] Gibson CS, MacLennan AH, Goldwater PN, et al. The
[29] Fisher SJ. The placental problem: linking abnormal association between inherited cytokine polymor-
cytotrophoblast differentiation to the maternal phisms and cerebral palsy. Am J Obstet Gynecol.
symptoms of preeclampsia. Reprod Biol Endocrinol. 2006;194:674.e1–674.11.
2004;2:53. [47] Costantine MM, Clark EAS, Lai Y, et al. Association of
[30] Goldman-Wohl DS, Ariel I, Greenfield C, et al. Tie-2 polymorphisms in neuroprotection and oxidative
and angiopoietin-2 expression at the fetal-maternal stress genes and neurodevelopmental outcomes after
interface: a receptor ligand model for vascular remod- preterm birth. Obstet Gynecol. 2012;120:542–550.
elling. Mol Hum Reprod. 2000;6:81–87. [48] Chen CP, Wang KG, Chen CY, et al. Altered placental
[31] Kaufmann P, Mayhew TM, Charnock-Jones DS. syncytin and its receptor ASCT2 expression in placen-
Aspects of human fetoplacental vasculogenesis and tal development and pre-eclampsia. BJOG. 2006;113:
angiogenesis. II. Changes during normal pregnancy. 152–158.
Placenta. 2004;25:114–126. [49] Blond JL, Lavillette D, Cheynet V, et al. An envelope
[32] Tertemiz F, Kayisli UA, Arici A, et al. Apoptosis con- glycoprotein of the human endogenous retrovirus
tributes to vascular lumen formation and vascular HERV-W is expressed in the human placenta and
branching in human placental vasculogenesis. Biol fuses cells expressing the type D mammalian retro-
Reprod. 2005;72:727–735. virus receptor. J Virol. 2000;74:3321–3329.
8 K. HARAM ET AL.

[50] Irani RA, Xia Y. The functional role of the renin-angio- angiopoietin-1, and angiopoietin-2. J Clin Endocrinol
tensin system in pregnancy and preeclampsia. Metab. 2002;87:4213–4224.
Placenta. 2008;29:763–771. [56] Vuorela P, Halmesm€aki E. Vascular endothelial growth
[51] Mello G, Parretti E, Gensini F, et al. Maternal-fetal factor, its receptors, and the tie receptors in the pla-
flow, negative events, and preeclampsia: role of ACE cental bed of women with preeclampsia, diabetes,
I/D polymorphism. Hypertension. 2003;41:932–937. and intrauterine growth retardation. Amer J Perinatol.
[52] Sato Y, Sonoda H. The vasohibin family: a negative 2006;23:255–264.
regulatory system of angiogenesis genetically pro- [57] Anson-Cartwright L, Dawson K, Holmyard D, et al. The
grammed in endothelial cells. ATVB. 2007;27:37–41. glial cells missing-1 protein is essential for branching
[53] Reynolds LP, Redmer DA. Angiogenesis in the pla- morphogenesis in the chorioallantoic placenta. Nat
centa. Biol Reprod. 2001;64:1033–1040. Genet. 2000;25:311–314.
[54] Ahmed A, Dunk C, Ahmad S, et al. Regulation of pla- [58] Muraskas JK, Kelly AF, Nash MS, et al. The role of fetal
cental vascular endothelial growth factor (VEGF) and inflammatory response syndrome and fetal anemia in
placenta growth factor (PlGF) and soluble Flt-1 by nonpreventable term neonatal encephalopathy.
oxygen— a review. Placenta. 2000;21:S16–S24. J Perinatol. 2016;36:362–365.
[55] Geva E, Ginzinger DG, Zaloudek CJ, et al. Human pla- [59] Magann EF, Haram K, Ounpraseuth S, et al. Use of
cental vascular development: vasculogenic and angio- antenatal corticosteroids in special circumstances: a
genic (branching and nonbranching) transformation is comprehensive review. Acta Obstet Gynecol Scand.
regulated by vascular endothelial growth factor-A, 2017;96:395–409.