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org

Pathophysiology of placental-derived fetal

growth restriction
Graham J. Burton, MD, DSc; Eric Jauniaux, MD, PhD, FRCOG

Introduction
The kinetics of placental and fetal Placental-related fetal growth restriction arises primarily due to deficient remodeling of
growth are closely interrelated, and are the uterine spiral arteries supplying the placenta during early pregnancy. The resultant
important features predicting postnatal malperfusion induces cell stress within the placental tissues, leading to selective sup-
health and in particular cardiovascular pression of protein synthesis and reduced cell proliferation. These effects are com-
adaptations in childhood.1,2 Fetal pounded in more severe cases by increased infarction and fibrin deposition.
growth is dependent on nutrient Consequently, there is a reduction in villous volume and surface area for maternal-fetal
availability, which in turn is related to exchange. Extensive dysregulation of imprinted and nonimprinted gene expression oc-
the maternal diet, uteroplacental blood curs, affecting placental transport, endocrine, metabolic, and immune functions. Sec-
supply, placental villous development, ondary changes involving dedifferentiation of smooth muscle cells surrounding the fetal
and the capacity of the villous arteries within placental stem villi correlate with absent or reversed end-diastolic um-
trophoblast and fetoplacental circula- bilical artery blood flow, and with a reduction in birthweight. Many of the morphological
tion to transport these nutrients. At changes, principally the intraplacental vascular lesions, can be imaged using ultrasound
birth, the fetoplacental weight ratio or magnetic resonance imaging scanning, enabling their development and progression
gives a retrospective indication of the to be followed in vivo. The changes are more severe in cases of growth restriction
efficiency of the placenta to support associated with preeclampsia compared to those with growth restriction alone,
growth of the fetus, and estimates the consistent with the greater degree of maternal vasculopathy reported in the former and
potential risks for chronic diseases more extensive macroscopic placental damage including infarcts, extensive fibrin
in later life through developmental deposition and microscopic villous developmental defects, atherosis of the spiral arteries,
programming.2,3 and noninfectious villitis. The higher level of stress may activate proinflammatory and
Fetal growth restriction (FGR) is apoptotic pathways within the syncytiotrophoblast, releasing factors that cause the
defined as the failure of the fetus to maternal endothelial cell activation that distinguishes between the 2 conditions.
achieve its genetically determined Congenital anomalies of the umbilical cord and placental shape are the only placental-
growth potential.4 FGR can have many related conditions that are not associated with maldevelopment of the uteroplacental
causes, but the majority of cases that are circulation, and their impact on fetal growth is limited.
not associated with fetal congenital
malformations, fetal genetic anomalies, Key words: AKT/mTOR, apoptosis, atherosis, chorion laeve, electron transport chain,
or infectious etiology are thought to arise extravillous trophoblast, failure of physiologic transformation, fetal growth restriction,
from compromise of the uterine circu- fetoplacental weight ratio, hemochorial placentation, interstitial trophoblast, intervillous
lation to the placenta. Sufficient dilata- space, intraplacental oxygen concentration, mitochondria, oxidative stress, perivillous
tion of the uteroplacental circulation fibrin deposition, placenta, placental infarct, placental inflammation, placental location,
reactive oxygen species, spiral arteries, ultrasound imaging, unfolded protein response,
villi regression, villous hypoplasia
From the Center for Trophoblast Research,
Department of Physiology, Development, and
Neuroscience, University of Cambridge,
Cambridge (Dr Burton), and EGA Institute for together with rapid villous angiogenesis techniques have been used extensively in
Women’s Health, Faculty of Population Health are the key factors necessary for adequate the screening of placental-related com-
Sciences, University College London, London placental development and function, plications of pregnancy, such as pre-
(Dr Jauniaux), United Kingdom. and subsequent fetal growth. eclampsia,8,9 and the management of
Received Sept. 18, 2017; revised Nov. 13, The etiopathology of FGR due to a fetus presenting with primary or
2017; accepted Nov. 13, 2017. abnormal development of the uteropla- secondary FGR.10 More recently, 3-
The authors report no conflict of interest. cental circulation and its impact on dimensional Doppler imaging11,12 and
Corresponding author: Graham J. Burton, MD, placental development and structure has magnetic resonance imaging (MRI)13
DSc. [email protected] been studied for >5 decades.5 Ultra- have been used to study the develop-
0002-9378/$36.00 sound imaging, and in particular color ment of the placental and fetal circula-
ª 2017 Elsevier Inc. All rights reserved.
https://doi.org/10.1016/j.ajog.2017.11.577
Doppler imaging, has allowed the study tions, but their use in clinical practice
of both the umbilicoplacental and ute- remains limited.
roplacental circulations from the first Placental-related complications of
trimester of gestation onward.6,7 These pregnancy that lead to FGR have their

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in vitro, and most likely play an

FIGURE 1
important role in regulating develop-
Histotrophic nutrition of the placenta during the first trimester ment and differentiation in vivo.18-20
The absence of significant maternal
blood flow at this stage means that
initial development takes place in a low
oxygen concentration, which is physi-
ological and should not be considered
hypoxic.21 This environment is
thought to protect the embryo from
damaging reactive oxygen species
(ROS) during the period of organo-
genesis, but may also serve to maintain
stem cell potential.22 Once the main
organs have differentiated there is a
need for a greater supply of oxygen to
Photomicrographs of archival placenta (P) in situ specimen (H710) at 6 weeks’ gestational age
support faster fetal growth,23 and
demonstrating histotrophic nutrition. A, Gestational sac with developing P is implanted in superficial
hence there must be a switch from
endometrium (E), and was opened during processing to remove embryo. Glands in E beneath sac are
histotrophic nutrition to hemotrophic
highly active, although hemorrhage occurred in some (*). Scale bar ¼ 2 mm. B, Higher power view of
supply from the maternal circulation.
interface between P and E showing opening of E gland (EG) into intervillous space (IVS) through
cytotrophoblastic shell (CS) and developing basal plate. Scale bar ¼ 250 mm. Modified.16,177
M, myometrium.
Development of the uteroplacental
Burton. Placental-derived fetal growth restriction. Am J Obstet Gynecol 2018.
circulation
The human hemochorial form of
placentation poses major hemodynamic
challenges. In particular, a high volume
pathophysiological roots in the early converge on the same intracellular of maternal arterial blood flow has to
stages of placentation and can manifest pathways, and separating the influence be delivered to the placenta at a suffi-
themselves from the end of the first of, for example, glucose as compared to ciently low pressure and velocity to
trimester of pregnancy when the defini- oxygen deprivation during periods of prevent mechanical damage to the
tive placenta is forming.14,15 Consider- ischemia is impossible. delicate villous trees.24 In normal
able remodeling of the placenta takes To provide a coherent account of how pregnancies, the arcuate and radial
place toward the end of the first the FGR phenotype may arise we first arterial components of the uterine
trimester/start of the second trimester, consider the development of the normal vasculature dilate under the combined
associated with onset of the maternal placenta before discussing the molecular effects of estrogen, progesterone,
arterial circulation when the placenta and clinical pathologies. human chorionic gonadotropin, and
becomes fully hemochorial. Events at other hormones and factors secreted by
this time potentially impact the final size Early development of the placenta the placenta. The dilation accommo-
of the placenta, and hence it functional Initial development of the placenta dates the increased uterine flow of
capacity. This concept is supported by takes place within the superficial layer pregnancy, and is so marked that by
findings in utero showing that preg- of the endometrium, and by the end of around 20 weeks of gestation
nancies complicated with FGR, with or the third week postconception villi the diameter of the arcuate arteries is
without accompanying preeclampsia have formed over the entire chorionic equal to that of the uterine artery.25 The
later in pregnancy, have a smaller sac. This precocious growth is sup- more distal elements of the uteropla-
placenta volume and higher uterine ported and stimulated by secretions cental vasculature undergo additional
resistance to blood flow compared to from the underlying endometrial extensive remodeling under the influ-
healthy controls from the beginning of glands (Figure 1),16,17 so-called histo- ence of extravillous trophoblast cells
the second trimester.9 trophic nutrition. The carbohydrate- that migrate out from the placenta
The relationships between abnormal and lipid-rich secretions are delivered during early pregnancy. This remodel-
placental development and FGR are through openings in the developing ing involves the loss of smooth muscle
complex. Isolating the placental causes basal plate into the intervillous space, cells and elastin from the arterial walls,
of FGR can be difficult as many clinical from where they are taken up by and their replacement by fibrinoid
studies are small, retrospective, and the syncytiotrophoblast. As well as material.26 As a result, these segments
often multivariate with confounding providing nutrients, the secretions of the uteroplacental vasculature
factors such as maternal smoking and contain numerous growth factors that become inert flaccid conduits, inca-
ethnicity. Also, many potential stressors stimulate placental cell proliferation pable of vasoconstriction. The

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extravillous trophoblast cells arise from

FIGURE 2
the anchoring villi that are attached to
the developing basal plate, and pass
Endovascular trophoblast plugs spiral arteries during early remodeling
down the lumens of the spiral arteries
as endovascular trophoblast, and
through the decidual stroma as inter-
stitial trophoblast. The migration of
endovascular trophoblast is so extensive
during the first trimester that the cells
effectively plug the mouths of the spiral
arteries, restricting flow to a slow
seepage of plasma through a network of
intercellular spaces (Figure 2).27,28 The
plugs begin to break down toward the
end of the first trimester, and it is only Photomicrograph of placenta in situ specimen (H673) at 8 weeks’ gestational age showing endo-
after approximately 10 weeks of gesta- vascular trophoblast (ET) plugging of spiral artery. A, ET arise from anchoring villi (AV) that attach to
tion that the maternal arterial circula- basal plate, and can be seen virtually occluding lumen in 3 cross-sectional profiles of artery (arrows).
tion to the intervillous space is fully Note deposition of fibrinoid material surrounding artery, characteristic feature of remodeling. Scale
established, as confirmed by measure- bar ¼ 0.5 mm. B, Higher power view of mouth of spiral artery showing ET cells streaming into lumen
ments of the rise in intraplacental ox- from AV. Flow into intervillous space will be restricted to seepage through network of intercellular
ygen concentration.29,30 The interstitial channels. Scale bar ¼ 0.1 mm.
trophoblast cells interact with the EG, endometrial gland.
maternal immune system, in particular Burton. Placental-derived fetal growth restriction. Am J Obstet Gynecol 2018.

the uterine natural killer cells. Together,

the extravillous trophoblast and natural
killer cells are thought to release pro- 37% of women showed no pulsatile trophoblast is more extensive in the
teases and cytokines that stimulate inflow into the placenta. center than in the periphery. The early
dedifferentiation and loss of the smooth onset of blood flow in the periphery
muscle cells within the arterial Placental remodeling causes a locally high level of oxidative
walls.31,32 Thus, a degree of activation The early or primitive placenta un- stress (Figure 3, B), which induces
of the natural killer cells is necessary, dergoes extensive remodeling toward activation of the apoptotic cascade.
and genetic studies have revealed that the end of the first trimester. Regres- Consequently, the villi regress, leaving
these immune interactions may regulate sion of villi starts over the superficial only avascular, hypocellular ghosts that
birthweight across the microsomic- pole of the gestational sac (Figure 3, A) are incorporated into the smooth
macrosomic range.33 and gradually extends until only those membranes (Figure 3, C and D).35 At
The arterial remodeling extends as far villi covering the deep pole in contact the same time, expression and activity
as the inner third of the myometrium, with the placental bed remain as the of the principal antioxidant enzymes
and so encompasses the hypercontractile definitive discoid placenta. This pro- within the placenta increase,37 and so
segment of a spiral artery in the found remodeling raises questions villi in the central zone have greater
junctional zone. Consequently, there are regarding how and when the size and defenses when the maternal blood flow
2 principal effects of the remodeling: shape of the placental disc are deter- reaches them.
firstly, dilation of the mouth of the artery mined, and whether further expansion The mature placenta is often
reduces the velocity and pulsatility of and recruitment of spiral arteries can described as discoid; however, there is
the maternal inflow into the placental occur in later pregnancy under adverse considerable debate as to whether the
intervillous space, and secondly the loss conditions. The remodeling is associ- majority are actually circular or ellip-
of smooth muscle reduces the risk of ated with onset of the maternal circu- soid. This may seem a rather academic
spontaneous vasoconstriction.24 lation to the placenta, which starts point, but the risk of chronic disease in
Remodeling of the spiral arteries ex- most commonly in the peripheral re- adult life has been associated with
tends into the second trimester, and gions and extends to the central zone abnormal shape of the placenta
possibly even longer. Ultrasound assess- over the next few weeks.35 This pattern through developmental programming
ment of a cohort of 58 normotensive inversely reflects the degree of extra- of the major organ systems.38 This
women revealed that blood flow from villous trophoblast invasion across the phenomenon may reflect changes in
the mouths of the spiral arteries is pul- placental bed, which is greatest in the placental function, for increased vari-
satile in all cases up to 20 weeks, and that central region where it has been ability in shape has been linked to
pulsatility decreases thereafter with established the longest.36 Hence, plug- reduced placental efficiency as esti-
advancing gestational age.34 By 34 weeks, ging of the arteries by endovascular mated by the ratio of fetal to placental

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more spiral arteries may be tapped

FIGURE 3
within the placental bed during this
Formation of the definitive placenta and smooth membranes process, and of course during normal
pregnancies elaboration and remodel-
ing of the villous trees will increase
the functional capacity to meet fetal
demands.45

Deficient spiral artery remodeling

Deficiencies in extravillous trophoblast
invasion and maternal arterial remod-
eling have been linked to the patho-
physiology of the great obstetric
syndromes, including growth restric-
tion, through malperfusion of the
placenta.46 Studies have reported a
gradient of effects, with absence of
remodeling in the junctional zone and
myometrial segment being associated
with more severe growth restriction
compounded with preeclampsia.46-50
Aberrant remodeling of the more
proximal radial arteries may also
contribute to placental malperfusion in
pathological pregnancies.51 However, it
must be recognized that remodeling is a
Placenta in situ specimen (H916) at 8.5 weeks’ gestational age showing formation of chorion laeve.
continuum, and that examples of defi-
A, Regression of villi can be seen beginning over superficial pole of gestational sac (*). Scale bar ¼ 1
ciently modified spiral arteries may be
cm. B, Diagrammatic representation of how onset of maternal arterial circulation in periphery of
seen in normal pregnancies and vice
placenta (arrows), where plugging of spiral arteries by extravillous trophoblast is least extensive,
versa.52 In addition, histopathological
causes localized oxidative stress (*). Stress induces apoptosis and regression of villi, giving rise to
reporting is generally not performed
chorion laeve. C, Higher power view of area marked by solid-line box (A) over superficial pole of sac
blinded to the clinical condition,
illustrating avascular villi with hypocellular stromal cores. D, Higher power view of area marked by
knowledge of which may influence
dashed-line box (A) over central region display blood vessels, denser stromal core, and thick layer of
interpretation of the findings.53,54
trophoblast. C and D, Scale bars ¼ 0.5 mm. A, reproduced35 and B, modified.178
Nonetheless, within the limitations
DC, decidua capsularis.
that placental bed biopsies provide as
Burton. Placental-derived fetal growth restriction. Am J Obstet Gynecol 2018.
an overview of the maternal blood
supply to the placenta there is general
agreement that deficient spiral artery
weight.39,40 Similarly, eccentricity of Clearly, events during the first remodeling is causal of the placental
the point of insertion of the umbilical trimester are of critical importance, changes that predispose to FGR of
cord into the placenta has been linked and there is increasing evidence from maternal vascular origin.
to reduced efficiency,41 acting possibly ultrasound studies that both growth There are many possible causes for
through hemodynamic effects in the restriction and macrosomia of the deficient spiral artery remodeling, and
fetoplacental circulation. We have placenta are initiated during this the actual cause will undoubtedly differ
speculated that excessive or asymmet- period.43 from case to case. Inadequate histo-
rical regression of the villi due to Given the regression of the periph- trophic nutrition during the first few
aberrant onset of the maternal circu- eral villi that takes place, it is difficult weeks of pregnancy15 or excessive
lation may lead to abnormal placental to envisage how the placental foot- apoptosis within the placental bed55
shapes and cord insertions, and may print might extend further over the could lead to a reduced number of
reflect local variations in the extent of uterine surface during later pregnancy, extravillous trophoblast cells. Other
extravillous trophoblast invasion.22 and in so doing recruit additional studies suggest interstitial trophoblast
Support for this hypothesis comes spiral arteries. Rather, it seems more invasion is normal or even increased in
from the strong correlation between plausible that from 10-12 weeks on- cases of FGR, but that the cells fail to
the shape of the placenta at the end of ward the placenta and the uterine wall penetrate into the walls of the ar-
the first trimester and at term.42 expand together.2,44 It is possible that teries.50 The reason for this is not

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known, but may possibly reflect complications of pregnancy, including

FIGURE 4
abnormal interactions with the uterine preeclampsia and FGR.59-61 Oxidative
natural killer cells, leading to excessive stress is defined as a condition in which
Atherotic changes in a spiral
inhibition and diminished release of the generation of highly reactive species
artery
proteases.56 of oxygen overwhelms a cell’s capacity to
The consequences of deficient spiral detoxify them, leading to indiscriminate
arterial remodeling are multiple. Firstly, damage to any biological molecules in
it will impact adversely on the velocity the immediate vicinity, including pro-
with which the maternal blood enters the teins, lipids, and DNA. Consequently,
placental intervillous space. Mathemat- cell function is impaired, and in the most
ical modeling has shown that the normal severe cases cell death may be induced.
dilation reduces the velocity by an order ROS are generated physiologically as an
of magnitude, from approximately 2-3 inevitable by-product of aerobic respi-
m/se1 to around 10 cm/se1.24 This ration, protein folding, detoxification of
reduction ensures even perfusion of the drugs and xenobiotics by cytochrome
villous trees and adequate transit time P450, the response of nicotinamide
Photomicrograph of spiral artery within decidua
for exchange. In pathological pregnan- adenine dinucleotide phosphate oxidase
from case of preeclampsia displaying acute
cies inflow remains high velocity and to growth factors and cytokines, and
atherosis. Foam cells (FC) accumulate in wall of
pulsatile,34 and causes mechanical various other oxidoreductase and cyclo-
arteries, severely restricting caliber of lumen.
damage to the placenta as will be dis- oxygenase enzymes (Figure 5). The
Scale bar ¼ 50 mm.
cussed later. Secondly, retention of the principal source under normal condi-
Burton. Placental-derived fetal growth restriction. Am J
vascular smooth muscle in the junc- tions is the mitochondria, for during Obstet Gynecol 2018.
tional zone is likely to cause greater passage of electrons along the complexes
intermittent perfusion of the placenta. of the electron transport chain there is
Angiographic studies performed on the leakage on to molecular oxygen, partic- proinflammatory cytokines and even
rhesus macaque, which has a similar ularly from complexes I and III.62 The apoptosis.64-66 Similar changes are seen
uteroplacental circulation to the human, acquisition of an unpaired electron gen- in vivo when placentas are subjected to
revealed that even in normal pregnancies erates the superoxide free radical, and 2% labor, for there is intermittent maternal
blood flow from a spiral artery is inter- of oxygen consumed during quiet respi- perfusion of the intervillous space during
mittent.57 This effect is independent of ration is converted to superoxide. This uterine contractions.67 The balance may
uterine contractions, and thought to be acts as a signaling intermediate, regu- also be perturbed if activity of the anti-
due to spontaneous vasoconstriction lating the activity of redox-sensitive oxidant enzymes is impaired. Transition
of the arteries involved. It might be transcription factors to maintain meta- metals, such as manganese, selenium,
expected, therefore, that the event will be bolic homeostasis in accordance with the copper, and zinc, are required at the active
more frequent in arteries where the prevailing oxygen concentration. How- site of these enzymes to shuttle electrons,
junctional segment has not been ever, because of its potential harmful and a dietary lack of micronutrients has
remodeled, exposing the placenta to actions, excess superoxide is detoxified in been linked to complications of preg-
recurrent ischemia-reperfusion-type in- the mitochondria by the enzyme super- nancy.68 Attempts to redress the balance
sults. Thirdly, deficient remodeling pre- oxide dismutase through conversion to by administration of antioxidant vitamins
disposes the spiral arteries to acute hydrogen peroxide. Being nonpolar, have yielded disappointing results.69 One
atherotic changes, with accumulation of hydrogen peroxide can diffuse out from reason for this lack of success may be that
foam cells and narrowing of the lumen the mitochondria and is then further oxidative stress rarely occurs in isolation,
(Figure 4). These changes are seen distal detoxified by the enzymes catalase and and is closely associated with other forms
to the junctional segment, and may be glutathione peroxidase within the cyto- of cell stress, in particular endoplasmic
induced by the high shear forces expe- plasm (Figure 5). reticulum (ER) stress. There are close
rienced or involvement in the ischemia- Under normal conditions there is physical and functional associations
reperfusion insult, possibly com- thus a homeostatic balance between between mitochondria and the ER,
pounded by dyslipidemia in the mother. generation and detoxification of ROS. mediated principally through calcium
Their effect will be to severely limit blood However, generation of ROS is increased signaling, that integrate the 2 organelles
flow to the placenta, and so not sur- during hypoxia and ischemia- (Figure 6).70
prisingly the lesion is associated with reperfusion, when buildup of electrons The ER is the organelle responsible
poor obstetric outcomes.46,58 on the electron transport chain leads to a for the synthesis, folding, and post-
Malperfusion of any organ is a greater rate of leakage.63 Thus, exposure translational modification of all
powerful inducer of oxidative stress, and of placental explants to cycles of membrane-bound and secreted pro-
the placenta is no exception. Placental hypoxia-reoxygenation is a powerful teins. Because misfolded proteins are
oxidative stress has been linked to generator of oxidative stress, inducing potentially toxic to cells, there is strict

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exchange.76-78 This reduction appears to

FIGURE 5
be due to excessive villous regression
Intracellular generation, detoxification, and actions of reactive oxygen during placental remodeling, com-
species pounded by a slower rate of subsequent
growth.79
In the case of the placenta, members
of the insulin-like growth factor family
are particularly important regulators
of cell proliferation.80 Their actions
are integrated with oxygen and nutrient
supply through the protein kinase B/
mechanistic target of rapamycin (AKT/
mTOR) signaling pathway, a central
regulator of the translation of mRNA into
protein. Activity in this pathway in-
fluences placental growth,81 and is down-
regulated in cases of growth restriction of
maternal vascular origin (Figure 7).82,83
Although this is often attributed to hyp-
oxia secondary to deficient spiral artery
conversion, no measurements have been
performed in vivo to confirm placental, as
opposed to fetal, hypoxia. One situation
Schematic representation of cellular detoxification of reactive oxygen species (ROS). Superoxide
where there is no doubt the placental
anion (O2e) is generated as by-product of aerobic respiration and various oxidoreductase enzymes,
tissues are exposed to a low maternal
and acts at physiological levels as signaling intermediate to regulate transcription factors, such as
arterial oxygen concentration is during
hypoxia inducible factor (HIF), nuclear factor kappa-light-chain-enhancer of activated B cells (NFKB),
pregnancy at high altitude. It is notable
and activator protein 1 (AP1). It can be scavenged by naturally occurring antioxidants, such as vi-
that a similar reduction in mTOR activity
tamins C and E, but also converted to hydrogen peroxide (H2O2) by superoxide dismutase (SOD)
is seen in placentas from pregnancies at
enzymes copper/zinc (Cu/Zn) and manganese (Mn) SOD. H2O2 is then detoxified by enzymes
3100 m, where it is accompanied by a
glutathione peroxidase and catalase. Excess levels of ROS can cause widespread damage to bio-
reduction in placental villous volume and
molecules, impairing cell function and leading to cell death.
birthweight.84 The changes can be
Burton. Placental-derived fetal growth restriction. Am J Obstet Gynecol 2018.
mimicked by exposing placental cell lines
to hypoxia in vitro, when there is a
reduction in the proliferation rate
quality control within the ER comprising Synthesis and secretion of proteins commensurate with the metabolic
3 evolutionary conserved signaling has to be closely linked to the meta- activity of the cell type.84
pathways collectively known as the bolism of a cell, and regulated in rela- The AKT/mTOR pathway also regu-
unfolded protein response (UPR).71,72 tion to the supply of oxygen and lates expression and activity of placental
Regulation operates at various levels, nutrients. Hence, the alpha subunit of transporters that are responsible for
but one of the most rapid and sensitive eukaryotic initiation factor 2 arm of the transfer of amino acids, fatty acids, and
responses is to block nonessential pro- UPR controlling translation of mRNA glucose. Many of these transporters
tein synthesis to conserve resources and can also be activated in response to are down-regulated in growth restric-
relieve the burden of nascent proteins on hypoxia, amino acid deprivation, and tion,85-88 which will compound the loss
the ER folding machinery. This is ach- other stressors.73-75 In view of this wider of functional capacity of the placenta
ieved through phosphorylation of a involvement in cell homeostasis, the caused by the reduction in villous surface
key regulatory factor, the alpha UPR is also referred to as the integrated area. Down-regulation precedes the
subunit of eukaryotic initiation factor 2 stress response pathway. growth restriction in response to
(eIF2alpha), that limits assembly of maternal undernutrition in animal
ribosomal complexes on the messenger Placental molecular pathology in FGR models,89 suggesting that it is causal of
RNA (mRNA). Longer-term responses Growth regulatory pathways the condition and not a response.
involve increasing the functional capac- One of the principal features of the
ity of the ER by up-regulation of chap- placenta in cases of FGR is the reduction Stress response pathways
erone proteins and elaborating more in volume, surface area, and vasculari- Given the high endocrine output of
cisternae to meet the synthetic and zation of the intermediate and termi- the placenta, the syncytiotrophoblast
secretory demands of the cell. nal villi that mediate maternal-fetal contains large quantities of ER.

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Activation of the UPR pathways is seen

FIGURE 6
in placentas from high-altitude preg-
nancies, where is can be viewed as a
Interactions between mitochondria and the ER mediated by calcium
homeostatic response to match feto-
signaling
placental growth to oxygen availability.
More severe activation is seen in cases of
growth restriction caused by maternal
vascular compromise,83,84 and the
degree of activation, both in terms of
individual pathways and the number of
the pathways involved, is greatest in
cases of growth restriction accompanied
by preeclampsia. This finding is
consistent with the placentas being
exposed to a more severe maternal
vascular insult due to the greater
deficiency in spiral artery remodeling
described earlier.83
The difference in the degree of acti-
vation may have pathophysiological
significance, for high levels of activation
of the UPR are associated with stimula-
tion of the release of proinflammatory
cytokines, cell senescence, and even
apoptosis (Figure 6).90,91 The nuclear
factor kappa-light-chain-enhancer of
activated B cells (NFkB) pathway can be Interactions between mitochondria and endoplasmic reticulum (ER). Mitochondrial and ER mem-
stimulated either through the inositol- branes are closely approximated at punctate sites rich in calcium transporters and ion channels.
requiring enzyme 1/tumor necrosis Calcium signaling integrates functional activity of these 2 organelles, so that both contribute to
factor receptor-associated factor 2 (IRE- increased production of reactive oxygen species (ROS) during malperfusion. ROS can stimulate
1/TRAF2) pathway,90,92 or more simply secretion of pro-inflammatory cytokines and adoption of senescent-associated secretory phenotype
through suppression of protein synthe- (SASP) through activation of nuclear factor kappa-light-chain-enhancer of activated B cells (NFKB)
sis. The half-life of the inhibitor of kappa and p38 mitogen-activated protein kinases (p-p38), via apoptosis signal-regulating kinase 1 (ASK1)
B (IkB) subunit is shorter than that of and high mobility group box 1 (HMGB1) protein. High levels of activation of UPR pathways inositol-
NFkB, and so prolonged translational requiring enzyme 1 (IRE1) and protein kinase RNA-like endoplasmic reticulum kinase (PERK) also
arrest will inevitably lead to an inflam- activate NFKB and p38 through the TNF Receptor Associated Factor 2 (TRAF2) and eukaryotic
matory response.93 Proinflammatory initiation factor 2 (eIF2a) respectively. Suppression of protein translation by activation of eIF2a leads
cytokines and apoptotic debris have all to reduction of the inhibitory sub-unit of kappa B (IKB) due to its short half-life. Reproduced with
been implicated in causing the maternal permission from179.
endothelial cell activation that charac- Burton. Placental-derived fetal growth restriction. Am J Obstet Gynecol 2018.
terizes preeclampsia, and hence, the
higher level of activation of the UPR may
explain the distinction between FGR syncytiotrophoblast of the FGR subject of particular attention. It is
alone and FGR associated with pre- placenta.95 notable that pleckstrin homology like
eclampsia (Figure 7). For example, domain family A member 2 (PHLDA2)
shedding of proinflammatory micro- Transcriptomic changes that inhibits growth, and mesoderm
particles from the syncytiotrophoblast is Changes in gene expression have been specific transcript (MEST) that pro-
seen in preeclampsia but not in FGR reported for the growth-restricted motes growth, are up-regulated and
alone.94 Exactly when the stress begins placenta employing microarray tech- down-regulated, respectively, in
during pregnancy is difficult to deter- nology,96,97 but in general it has yet to be FGR.98,99 However, no correlation was
mine, but we speculate that it originates determined whether the changes are found between the level of gene
around the time of onset of the maternal responsive to, or causal of, the growth expression and loss of imprinting, sug-
circulation to the placenta toward the disorder. Imprinted genes that are gesting that disorders of imprinting per
end of the first trimester.15 Perturbation expressed in a parent-of-origin fashion se are not causal of the condition.
of ER function could also account for play a key role in the regulation of Indeed, these studies also found wide-
the change in glycosylation seen in the placental growth, and so have been the spread changes in nonimprinted genes

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syncytiotrophoblast can be detected in

FIGURE 7
the peripheral maternal blood, opening
Pathways that may lead to placental-related FGR, and FGR with the possibility of their use as diagnostic
preeclampsia biomarkers of placental dysfunction.97,102

Placental metabolism
Data on placental metabolism in cases of
growth restriction are conflicting.
Placental mitochondrial content has
been reported to be both increased103
and decreased104 based on assays of
mitochondrial DNA content.105 These
findings have been correlated with the
oxygen content in the umbilical vein. By
contrast, we observed no difference in
mitochondrial content in the high-
altitude placenta as determined by the
level of citrate synthase.106 There was,
however, a significant reduction in the
protein, but not mRNA level, of the
complexes of the electron transport
chain, suggesting again a block to protein
translation and a reduction in mito-
chondrial activity. It might be expected,
therefore, that placental metabolism
Schematic representation of possible pathways leading to placental-related fetal growth restriction becomes more dependent on glycolysis,
(FGR) alone or FGR complicated by preeclampsia (PE). See text for details. but there appears to be no change in
EVT, extravillous trophoblast; UPR, unfolded protein response.
glycogen content in the growth-
Burton. Placental-derived fetal growth restriction. Am J Obstet Gynecol 2018.
restricted placenta.107
Autophagy-related proteins are regu-
lated by UPR pathways,108 and have been
involved in endocrine signaling, tissue transcript level. They can also influence reported to be increased in FGR pla-
growth, immune modulation, oxidative translation of the mRNA and so the level centas where they may reflect excessive
metabolism, vascular function, and of the encoded protein. It has been re- levels of organelle stress and recycling, or
metabolite transport.98 A more recent ported that 97 miRs are up-regulated severe nutrient depletion.109 Increased
comprehensive transcriptome-wide and 44 down-regulated in small-for- autophagy has also been observed in the
profiling of normal and growth- gestational-age (SGA) as compared to placental territory of monochorionic
restricted placentas using next- appropriate-for-gestational-age pla- twins with selective FGR, where it was
generation sequencing revealed 5 centas.101 Functional studies of miR- inversely proportional to the umbilical
network modules enriched for similar 10b, -363, and -149, which were either blood flow.110
processes, including cellular respiration, significantly increased or trended to in-
amino acid transport, hormone crease in the growth-restricted pla- The fetoplacental circulation
signaling, histone modifications, and centas, in a trophoblast-like cell line Reduced placental surface area and
gene expression, that were associated showed that these have a negative impact transport are important contributors
with birthweight.100 Furthermore, the on their target genes that encode to placental function and hence FGR,
hub genes for each module were signif- angiogenic factors and amino acid but another important factor is the
icantly associated with growth restric- transporters. When trophoblast-like resistance within the umbilical circula-
tion, and so these networks may play an cells were exposed to nutrient restric- tion. The absence or even reversal of
important role in regulating placental tion, miRs-10b and -149 increased end-diastolic flow in cases of severe
function in these pathological cases. whereas miR-363 decreased, suggesting growth restriction as assessed by
These changes may reflect differences that they respond to multiple cues or Doppler ultrasonography will greatly
in gene transcription, but could also that different cell types within the impair the transport of nutrients to the
potentially arise through epigenetic placenta respond in different ways dur- fetus. These findings are not surprisingly
changes involving microRNAs (miRs). ing growth restriction. associated with fetal hypoxia. Patholog-
Noncoding RNAs can bind to mRNA, Placental-specific mRNAs and miRs ical changes have been reported in the
regulating its stability and hence the thought to be derived from the resistance arteries within the stem villi

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of growth-restricted placentas,111-113 but

FIGURE 8
the molecular mechanism underlying
them has only recently been elucidated.
Ultrasound visualisation of placental lesions in FGR
The smooth muscle cells surrounding
these arteries express the enzyme cys-
tathionine-g-lyase that synthesizes
hydrogen sulfide, a powerful vasodilator
of the fetal placental vasculature that
maintains vascular smooth muscle cells
in their differentiated state.114 This
enzyme is reduced at the mRNA and
protein levels in placentas associated
with absent or reversed end-diastolic Transabdominal color Doppler mapping of placenta (P) in pregnancy at 36 weeks complicated by
flow, and this finding is associated with fetal growth restriction and presenting with multiple cystic lesions (*) corresponding to intervillous
dedifferentiation of the smooth muscle thrombosis on histopathology. A, Increased echogenicity in periphery of lesions due to degenerative
cells, the adoption of a synthetic villous tissue embedded in fibrin deposits. B, Uteroplacental blood arterial supply to lesion from basal
phenotype, and a reduction in the plate (BP). Video clips of same lesions showing pulsatile flow from uteroplacental artery.
lumen-to-wall ratio.115 These changes Burton. Placental-derived fetal growth restriction. Am J Obstet Gynecol 2018.

can be induced by exposing explants of

stem villous arteries to hypoxia-
reoxygenation, indicating that the routine ultrasound became available and placentation.121 A population-based,
in vivo findings are likely secondary to at a time when laboratory investigations retrospective cohort study of 544,734
the oxidative stress caused by the were limited. singleton live births, including 2744
placental malperfusion. The severity of Overall, placental lesions associated placenta previa found, after controlling
the changes correlates with the birth- with FGR have been divided by pathol- for maternal factors including smoking
weight, indicating that they may act as an ogists into different categories: vascular and gestational age, that previa placen-
important component of the placental and nonvascular, macroscopic and tation is associated with a 3.7% rate of
dysfunction in growth restriction microscopic, congenital and acquired or FGR (OR, 1.24; 95% CI, 1.17e1.32) at
(Figure 7). secondary abnormalities.116-118 The birth, independently of the 12% rate of
classification below is based on pathol- preterm delivery.122 By contrast, a retro-
Clinical placentology in FGR ogist standardized diagnostic criteria for spective cohort study of 59,149 women
Many, if not all, placental abnormalities each individual lesion and highlights with singleton pregnancies undergoing
have been found in association with FGR, those lesions that can be diagnosed pre- ultrasound between 15-22 weeks found
but the results of most histopathological natally with ultrasound imaging. no difference in the incidence of FGR
studies are hampered by a number of after adjusting for confounding factors
methodological factors. Most studies are Abnormalities of placentation (adjusted OR, 1.1; 95% CI, 0.9e1.5) in
retrospective based on case-series rather Abnormal placental shapes, in particular the 724 women presenting with placenta
than case-control data and many have those with irregular outlines (extrac- previa.123 The pathophysiology of FGR in
used different clinical definitions of FGR, horial and bilobate placenta) have been cases of abnormal placentation is un-
mixing cases of fetuses constitutionally associated with poor obstetric outcome, known, but one can hypothesize the
small (SGA) and/or born prematurely in particular poor fetal growth.119,120 underdevelopment of the uteroplacental
following inaccurate gestational dating or These anomalies are difficult to circulation and, in particular, the
unknown gestational age (low birth- diagnose in utero by ultrasound scan- recruitment of spiral arteries into the
weight). Specific placental lesions have ning and are not routinely investigated in final placenta is influenced by the density
rarely formed the primary topic of pregnancies complicated by FGR. of the uterine terminal vascular network
investigation, more often being consid- Placental location is an important where the blastocyst implants. There are
ered as a coincidental finding or one of factor; for example, cases of lateral no clinical data on placental weight and
several potential causes of FGR. In addi- placentation are more likely to be asso- volume to support this hypothesis.
tion to these selection biases, confound- ciated with FGR. A case-control study of
ing factors such as maternal smoking and precisely dated singleton pregnancies Macroscopic vascular anomalies
methodologic disparities, such as the found that those complicated by FGR Deficient remodeling of the spiral
location and number of samples taken for are nearly 4-fold more likely to have arteries is associated with greater pulsa-
histopathologic examination, make it had a lateral placentation (odds ratio tility of the jets of maternal blood in SGA
difficult to evaluate the data from many [OR], 3.8; 95% confidence interval pregnancies, as expected.34 More severe
studies, in particular from those early [CI], 1.3e11.2) at 16-20 weeks, vasculopathies of the arteries are associ-
histopathologic studies performed before compared with anterior or posterior ated with a combination of secondary

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stillbirth.116,125-129 A series of 14 cases

TABLE 1 found that subchorial thrombosis
Pathophysiology and prenatal diagnosis of placental macroscopic involving 50% of the chorionic or fetal
vascular anomalies found in cases of fetal growth restriction plate is associated with a 70% incidence
Type of anomaly Pathophysiology Prenatal ultrasound imaging of FGR in those pregnancies that
Intervillous thrombosis Focal coagulation of maternal Echogenic cystic lesions or continue >24 weeks of gestation.128 The
blood inside intervillous space hypoechoic areas on development of an intervillous throm-
ultrasound124,130,131 bosis is often associated with fibrin
Breus’ mole Massive subchorial thrombosis Large echogenic lesions deposition and these lesions are often
involving at least 50% of under fetal placental described as echogenic cystic lesions or
chorionic plate plate124,130,131 hypoechoic areas on ultra-
Infarcts Villous necrosis due to Complex echogenic sound.124,130,131 The ultrasound fea-
obstruction of uteroplacental intraplacental masses tures, ie, echogenicity of an intervillous
artery close to basal plate133-138 thrombosis will change with advancing
Maternal floor Lesion combining parabasal Diffuse hyperechogenic gestation as more and more fibrin
infarction in size villous necrosis, fibrin deposition, lesions increasing with deposition will appear in its periphery
thrombosis, and hematoma advancing gestation134,143,144 and depending on when, or if, the
Burton. Placental-derived fetal growth restriction. Am J Obstet Gynecol 2018. maternal blood clots in its center
(Figure 8, Videos). Large thromboses
have been diagnosed prenatally on
placental macroscopic lesions including blood inside the intervillous space,124,125 MRI.132
intervillous and parabasal thrombi, and are found mainly in areas of lower Placental infarcts are due to the
hematomas, infarcts, and extensive villous density such as under the fetal or complete obstruction of uteroplacental
fibrin deposition (Figure 8).116,117 chorionic plate, in the placental mar- arteries leading to interruption of the
Placental thromboses and infarcts are ginal areas, and in the center of cotyle- maternal blood flow and progressive
the most commonly found lesions in dons.116,117 Isolated small thromboses necrosis of the villous tissue, including
pregnancies complicated by FGR with or are of no clinical significance and are its fetal circulation of the corresponding
without preeclampsia and both have commonly found in the placenta of un- cotyledon(s).116,117,124 Isolated small
been reported on ultrasound examina- complicated pregnancies. Massive sub- infarcts can be found in uncomplicated
tions (Table 1).124 chorial thromboses, also called “Breus’ pregnancies but larger infarcts often
Placental thromboses are the conse- mole,” have been reported in pregnan- associated with intervillous thromboses
quence of focal coagulation of maternal cies complicated by FGR and and extensive fibrin deposition are
found in most pregnancies complicated
by preeclampsia and FGR. These lesions
FIGURE 9 appear as complex echogenic intra-
Ultrasound placental masses close to the basal plate
on ultrasound imaging133-138 and have
also been identified recently on MRI in
pregnancies complicated by uteropla-
cental insufficiency and FGR.139,140
Maternal floor infarction is an
extended lesion combining parabasal
villous necrosis, fibrin deposition,
thrombosis, and hematoma that is asso-
ciated with a high risk of severe FGR and
stillbirth.116,117,141 The disorder is some-
what misnamed, because it is mainly
characterized by heavy deposition of
Transabdominal ultrasound longitudinal view of jellylike placenta (P) at A, 18 and B, 19 weeks in
fibrin in the decidua beneath the placenta
pregnancy complicated by very early-onset fetal growth restriction. P base is very narrow and most of
rather than by arterial occlusion and
P mass contains areas of patchy decrease in echogenicity (*). Video clip of same P at 23 weeks
ischemic necrosis of the villi.142 The fibrin
showing increased thickness and patchy decrease in echogenicity secondary to fetal plate being
deposits in floor infarcts often extend into
pushed up by jetlike blood streams from spiral arteries. Massive subchorial thrombosis involving
the intervillous space, where they envelop
>70% of chorionic plate, extended fibrin deposition, intervillous thrombosis, and villous infarcts
villi, causing them to become atrophic.
were found at birth at 34 weeks.
Burton. Placental-derived fetal growth restriction. Am J Obstet Gynecol 2018.
Similarly, massive fibrin depositions, in
particular if involving >50% of the

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placental mass, are associated with severe

FGR.138 On ultrasound, these lesions TABLE 2
appear as diffuse hyperechogenic lesions Pathophysiology of placental microscopic lesions found in cases of fetal
increasing in size with advancing growth restriction
gestation.134,143,144 Type of lesion Pathophysiology
Placental vascular lesions associated Villous developmental defects Underperfusion or malperfusion of
with FGR have been known to present (hypoplasia, dysmaturity, intervillous space by maternal blood150
with abnormally high levels of maternal capillary dysplasia)
serum alpha-fetoprotein and human Atherosis of spiral arteries Failure of spiral artery remodeling
chorionic gonadotrophin at 15-18 weeks in placental basal plate46,58,155
of gestation.125,145-147 There is also an Villitis of unknown etiology Oxidative stress secondary to
association between the vasculopathies ischemia-reperfusion of
of the spiral arterioles leading to pre- intervillous space24,156-161
eclampsia and FGR, a placental jellylike Burton. Placental-derived fetal growth restriction. Am J Obstet Gynecol 2018.
ultrasound appearance and high
maternal serum alpha-fetoprotein levels
at 18-28 weeks.146 The jellylike appear- these lesions according to their maternal, clinically suspected FGR with normal
ance of the placenta is characterized on fetal, or inflammatory origin.149 Our Doppler features. They found no differ-
ultrasound by a narrow implantation understanding of their pathophysiology ences in the number of tertiary stem villi
basis or basal plate diameter, increased remains restricted by our limited between the group with increased resis-
thickness, and patchy decrease in echo- knowledge of the mechanisms triggering tance to blood flow and the controls,
genicity secondary to the fetal plate being them in early pregnancy. The micro- suggesting that only the villous vascula-
pushed up by jetlike blood streams from scopic lesions below have been the most ture and not the overall anatomy of the
the spiral arteries (Figure 9, Videos). We commonly described in pregnancies villous tree was altered in their cases.
found recently an association among complicated by FGR with or without Other studies have shown correlations
placenta protein A levels in maternal preeclampsia (Table 2). among the pathology of the stem villus
serum, basal surface area measurements Villous developmental defects include arteries, the umbilical Doppler wave-
at 11-14 weeks of gestation, and birth- mainly villous hypoplasia, delayed and form, and birthweight.115 However,
weight centile.148 All 3 parameters were accelerated villous maturation, and more detailed histomorphometric
lower in pregnancies complicated by villous capillary dysplasia. These studies have also shown that placentae
preeclampsia and FGR. These findings morphological alterations of the villous from FGR cases with abnormal umbili-
support the concept of an early disrup- architecture are thought to be secondary cal artery Doppler features have
tion in the normal establishment of the to underperfusion or malperfusion of increased number of villous infarcts,
intervillous circulation starting from the the intervillous space by maternal blood, fibrin deposition, villous hypoplasia,
end of the first trimester with a second- and in particular to fluctuations in the cytotrophoblast proliferation, and
ary maldevelopment of the villous tissue, oxygen tension inside the placenta.
including intraplacental vascular lesions, Villous vascular lesions related to
and presenting clinically with early- maternal underperfusion are more FIGURE 10
onset preeclampsia and FGR. common in early-onset (34 weeks) Ultrasound appearance of a
than in late-onset (>34 weeks) FGR,150 single umbilical artery
Microscopic lesions suggesting a timing effect linked to the
Many different microscopic placental extent of the placental defect at the
lesions have been described in pregnan- beginning of pregnancy. Giles et al151
cies complicated by FGR. Most are non- were the first to correlate fetal umbili-
specific, have been found in villous tissue cal artery flow velocity Doppler wave-
from uncomplicated pregnancies, and forms with placental villi microvascular
the terminology used to describe them anatomy. They correlated the blood flow
has been highly variable. The distribu- resistance in the umbilical circulation
tion of these lesions depends on whether obtained with Doppler ultrasound with
the restricted fetal growth is isolated or the numbers of small muscular arterioles
associated with preeclampsia, and on and tertiary stem villi. They found that
Color flow mapping of fetal abdomen and its
gestational age at onset, with late onset the number of small arterial vessels was
placenta (P) at 12 weeks of gestation showing 2-
leading to a more heterogeneous group lower in pregnancies with a high resis-
vessel umbilical cord.
with less characteristic histological tance to blood flow and was associated
Burton. Placental-derived fetal growth restriction. Am J
changes.118 Recent histological classifi- with a higher incidence of FGR than in Obstet Gynecol 2018.
cations have been proposed separating normal controls or in pregnancies with

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FIGURE 11
Schematic of spectrum of pregnancy complications arising from deficient trophoblast invasion

Proposed relationship among degree of oxidative stress and placental development in normal pregnancies, late-onset preeclampsia (PE), early-onset PE,
and miscarriage. In normal pregnancies onset of maternal circulation in periphery causes local oxidative stress, villous regression, and formation of
chorion laeve. In miscarriage extravillous trophoblast (EVT) is severely deficient, leading to incomplete plugging of spiral arteries, premature and
disorganized onset of blood flow, and overwhelming oxidative stress. Situation is intermediate in PE, being more severe in early-onset form of syndrome
associated with fetal growth restriction (FGR). Reproduced.173
Burton. Placental-derived fetal growth restriction. Am J Obstet Gynecol 2018.

thickening of the villous trophoblastic extravillous trophoblast, and arterial term placentas.156 High-grade lesions,
basal membrane.152-154 This highlights endothelial activation.46 Decidual athe- affecting >10 villi per focus, have been
the fact that the placental lesions asso- rosis is the main cause of maternal found in fetuses presenting with
ciated with increased resistance to flow underperfusion of the intervillous space FGR.156,157 Their histologic character-
in the umbilical arterial circulation in leading to fibrin deposition, throm- istics are distinct from infectious villitis
FGR are complex and involve the entire bosis, and villous infarcts. Small lesions and thought to be caused by maternal
anatomy of the villous structure, not appear to occur at points of localized T-lymphocytes, predominantly CD8þ,
only its terminal vasculature. stasis at the basal plate and are probably that inappropriately gain access to
Atherosis of the spiral arteries is pathological markers of more general- the villous stroma.156 VUE is found in
characterized by fibrinoid necrosis of ized disturbances in placental circula- 5-15% of placenta in uncomplicated
the arterial wall, subendothelial lipid- tion or of hypercoagulability in the pregnancies,156,157 15-100% of
filled foam cells, and perivascular intervillous space,155 leading progres- placenta from pregnancies complicated
lymphocytic infiltration (Figure 4). It sively to the macroscopic vascular le- by FGR,158-160 and 20% of placenta in
is histologically similar to early-stage sions described previously. Obstructive pregnancies presenting with FGR and
atherosclerosis and is a common lesions in the myometrial segment of preeclampsia.161 A systematic review
microscopic feature of preeclampsia, spiral bed arteries have been found in including 12 studies focusing on
FGR, fetal death, and spontaneous pre- 70% of the FGR cases associated with placental pathologies associated with
term labor with intact or ruptured preeclampsia.46 intrauterine growth restriction found
membranes.46,58 Failure of spiral artery Noninfectious villitis, also called significant heterogeneity in study
remodeling in the placental basal plate is villitis of unknown etiology (VUE), has design, which can explain the wide
associated with increased frequency of been described as a pattern of placental range in incidence of VUE in FGR
decidual artery atherosis, interstitial injury occurring predominantly in placentas.157 It is not known if these

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lesions are the primary cause of FGR compared to normal cord. The use of late-onset preeclampsia at the opposite
or secondary to mechanical damage to color Doppler imaging has made the extreme where there appears to be min-
the villous surface caused by the aber- diagnosis of SUA accurate in early imal placental involvement.173,176
rant hemodynamics (ischemia-reper- pregnancy,172 but its detection at the Considering these complications of
fusion) of the maternal circulation in first-trimester (Figure 10) or routine pregnancy, and others such as preterm
the intervillous space,24 or oxidative midpregnancy ultrasound has been delivery and premature rupture of the
stress and the corresponding metabolic mainly as part of the fetal aneuploidy membranes,15,46 as a spectrum caused by
and morphological alteration of the screening. There is a need for a pro- poor placentation, highlights 2 main
villous trophoblastic layer. spective case-control study on the conclusions. Firstly, there is an urgent
impact on fetal growth of isolated SUA need for more research into maternal-
Umbilical cord anomalies diagnosed in the first half of fetal interactions during the earliest
FGR has been associated with abnor- pregnancy. phases of pregnancy, to understand not
malities of the umbilical cord insertion, just the pathophysiology of FGR but this
ie: eccentric, marginal, or vela- Conclusion array of disorders as a whole. Secondly,
mentous.119,162 These anomalies are rare The placental changes seen in cases of clinical care should be focused just as
and often associated with abnormalities FGR of noninfective and nongenetic much on the preconceptional and peri-
of the placental shape. Thus, there are no origin form part of a spectrum of pa- conceptional periods as in later preg-
data supporting a direct link between the thology associated with different degrees nancy to ensure that when the conceptus
location of the umbilical cord insertion of deficient remodeling of the uterine implants it does so into an endometrium
and poor fetal growth. spiral arteries.46,173 Deficient remodeling that is in the healthiest state possible. -
The absence of 1 of the 2 normal results in maternal blood entering the
umbilical arteries or single umbilical placental intervillous space in jetlike REFERENCES
artery (SUA) cord is one of the most streams that carve large channels and
1. Jaddoe VW, De Jonge LL, Hofman A,
common congenital fetal malforma- lakes within the villous trees. The high Franco OH, Steegers EA, Gaillard R. First
tions with an incidence of approxi- velocity, uneven and, most likely, inter- trimester fetal growth restriction and cardiovas-
mately 1% of all deliveries (Figure mittent perfusion of the placenta causes cular risk factors in school age children: popu-
10).163,164 SUA occurs 3-4 times more oxidative stress and activation of the UPR lation based cohort study. BMJ 2014;348:g14.
frequently in twins, and almost pathways, suppressing placental growth 2. Burton GJ, Fowden AL, Thornburg KL.
Placental origins of chronic disease. Physiol Rev
invariably accompanies the acardia and compromising its endocrine and 2016;96:1509-65.
malformation and sirenomelia of transport functions. We speculate that the 3. Burkhardt T, Schaffer L, Schneider C,
caudal regression syndrome.163-165 pathophysiology starts toward the end of Zimmermann R, Kurmanavicius J. Reference
Most cases of SUA are part of fetal the first trimester, at the time of onset of values for the weight of freshly delivered term
syndromes with major anatomical de- the maternal circulation. Remodeling of placentas and for placental weight-birth weight
ratios. Eur J Obstet Gynecol Reprod Biol
fects that are largely responsible for the the arteries and onset are linked through 2006;128:248-52.
poor perinatal outcomes. The inci- the endovascular trophoblast that initially 4. Resnik R. Intrauterine growth restriction.
dence of FGR is significantly elevated plug the vessels; a deficiency in one is Obstet Gynecol 2002;99:490-6.
among fetuses with SUA and may likely to be associated with abnormalities 5. Gruenwald P. Abnormalities of placental
develop without any other congenital in the other.15 When endovascular vascularity in relation to intrauterine deprivation
and retardation of fetal growth. Significance of
anomalies in around 15 of the trophoblast is particularly poorly devel- avascular chorionic villi. N Y State J Med
cases.163,164,166-169 A population-based, oped, onset of the maternal circulation is 1961;61:1508-13.
retrospective cohort study of 37,500 premature and disorganized spatially, 6. Jauniaux E, Jurkovic D, Campbell S, Kurjak A,
singleton pregnancies including 223 not following the periphery to center Hustin J. Investigation of placental circulations
SUA diagnosed at birth found a higher progression seen in normal pregnan- by color Doppler ultrasound. Am J Obstet
Gynecol 1991;164:486-8.
incidence of birthweight <10th cies.35,174 There is overwhelming oxida- 7. Jauniaux E, Jurkovic D, Campbell S, Hustin J.
percentile (OR, 2.1; CI, 1.44e2.93) in tive stress throughout the placental Doppler ultrasound features of the developing
isolated SUA.166 A retrospective case- tissues, leading to widespread degenera- placental circulations: correlation with anatomic
control series of 136 SUA diagnosed tion of the trophoblast and to miscarriage findings. Am J Obstet Gynecol 1992;166:585-7.
8. Fleischer A, Schulman H, Farmakides G, et al.
at second-trimester ultrasound (Figure 11).175 We speculate that less
Uterine artery Doppler velocimetry in pregnant
reported isolated SUA to be an inde- severe deficiencies in arterial remodeling women with hypertension. Am J Obstet Gynecol
pendent risk factor for FGR (adjusted result in ongoing pregnancies with 1986;154:806-13.
OR, 11.3; 95% CI, 4.8e25.6) differing degrees of compromise as dis- 9. Velauthar L, Plana MN, Kalidindi M, et al. First-
compared to normal 3-vessel cord.167 cussed earlier. At one extreme will be trimester uterine artery Doppler and adverse
Two recent systematic reviews re- early-onset FGR with preeclampsia where pregnancy outcome: a meta-analysis involving
55,974 women. Ultrasound Obstet Gynecol
ported OR ranging between 1.6 (95% there is excessive villous regression and 2014;43:500-7.
CI, 0.97e2.6)170 and 2.75 (95% CI, extensive infarction due to secondary 10. Alfirevic Z, Stampalija T, Dowswell T. Fetal
1.97e3.83)171 for SGA in isolated SUA atherotic changes, through FGR alone to and umbilical Doppler ultrasound in high-risk

FEBRUARY 2018 American Journal of Obstetrics & Gynecology S757

Expert Reviews ajog.org

pregnancies. Cochrane Database Syst Rev 25. Burchell C. Arterial blood flow in the human maternal and fetal vascular pathology. Placenta
2017;6:CD007529. intervillous space. Am J Obstet Gynecol 2010;31:958-62.
11. Luria O, Barnea O, Shalev J, et al. Two- 1969;98:303-11. 41. Yampolsky M, Salafia CM, Shlakhter O,
dimensional and three-dimensional Doppler 26. Pijnenborg R, Vercruysse L, Hanssens M. Haas D, Eucker B, Thorp J. Centrality of the
assessment of fetal growth restriction with The uterine spiral arteries in human pregnancy: umbilical cord insertion in a human placenta in-
different severity and onset. Prenat Diagn facts and controversies. Placenta 2006;27: fluences the placental efficiency. Placenta
2012;32:1174-80. 939-58. 2009;30:1058-64.
12. Moran MC, Mulcahy C, Zombori G, Ryan J, 27. Hustin J, Schaaps JP. Echographic and 42. Salafia CM, Yampolsky M, Shlakhter A,
Downey P, Mcauliffe FM. Placental volume, anatomic studies of the maternotrophoblastic Mandel DH, Schwartz N. Variety in placental
vasculature and calcification in pregnancies border during the first trimester of pregnancy. shape: when does it originate? Placenta
complicated by pre-eclampsia and intra-uterine Am J Obstet Gynecol 1987;157:162-8. 2012;33:164-70.
growth restriction. Eur J Obstet Gynecol 28. Burton GJ, Jauniaux E, Watson AL. 43. Schwartz N, Quant HS, Sammel MD,
Reprod Biol 2015;195:12-7. Maternal arterial connections to the placental Parry S. Macrosomia has its roots in early
13. Zhu MY, Milligan N, Keating S, et al. The intervillous space during the first trimester of placental development. Placenta 2014;35:
hemodynamics of late-onset intrauterine growth human pregnancy; the Boyd Collection revis- 684-90.
restriction by MRI. Am J Obstet Gynecol ited. Am J Obstet Gynecol 1999;181:718-24. 44. Gruenwald P. Expansion of placental site
2016;214:367.e1-17. 29. Rodesch F, Simon P, Donner C, Jauniaux E. and maternal blood supply of primate placentas.
14. Jauniaux E, Poston L, Burton GJ. Placental- Oxygen measurements in endometrial and Anat Rec 1972;173:189-203.
related diseases of pregnancy: involvement of trophoblastic tissues during early pregnancy. 45. Mayhew TM, Jackson MR, Boyd PA.
oxidative stress and implications in human evo- Obstet Gynecol 1992;80:283-5. Changes in oxygen diffusive conductances of
lution. Hum Reprod Update 2006;12:747-55. 30. Jauniaux E, Watson AL, Ozturk O, Quick D, human placental during gestation (10-41 weeks)
15. Burton GJ, Jauniaux E. The cytotropho- Burton G. In-vivo measurement of intrauterine are commensurate with the gain in fetal weight.
blastic shell and complications of pregnancy. gases and acid-base values in early human Placenta 1993;14:51-61.
Placenta 2017;60:134-9. pregnancy. Hum Reprod 1999;14:2901-4. 46. Brosens I, Pijnenborg R, Vercruysse L,
16. Burton GJ, Watson AL, Hempstock J, 31. Harris LK. Review: Trophoblast-vascular cell Romero R. The “great obstetrical syndromes”
Skepper JN, Jauniaux E. Uterine glands provide interactions in early pregnancy: how to remodel are associated with disorders of deep placen-
histiotrophic nutrition for the human fetus during a vessel. Placenta 2010;31(Suppl):S93-8. tation. Am J Obstet Gynecol 2011;204:
the first trimester of pregnancy. J Clin Endocrinol 32. Whitley GS, Cartwright JE. Cellular and 193-201.
Metab 2002;87:2954-9. molecular regulation of spiral artery remodeling: 47. Brosens I, Dixon HG, Robertson WB. Fetal
17. Burton GJ, Jauniaux E, Charnock- lessons from the cardiovascular field. Placenta growth retardation and the arteries of the
Jones DS. Human early placental development: 2010;31:465-74. placental bed. Br J Obstet Gynaecol 1977;84:
potential roles of the endometrial glands. 33. Moffett A, Hiby SE, Sharkey AM. The role of 656-63.
Placenta 2007;28(Suppl):S64-9. the maternal immune system in the regulation of 48. Gerretsen G, Huisjes HJ, Elema JD.
18. Maruo T, Matsuo H, Murata K, Mochizuki M. human birthweight. Philos Trans R Soc Lond B Morphological changes of the spiral arteries in
Gestational age-dependent dual action of Biol Sci 2015;370:20140071. the placental bed in relation to pre-eclampsia
epidermal growth factor on human placenta 34. Collins SL, Birks JS, Stevenson GN, and fetal growth retardation. Br J Obstet
early in gestation. J Clin Endocrinol Metab Papageorghiou AT, Noble JA, Impey L. Mea- Gynaecol 1981;88:876-81.
1992;75:1362-7. surement of spiral artery jets: general principles 49. Khong TY, De Wolf F, Robertson WB,
19. Burton GJ, Scioscia M, Rademacher TW. and differences observed in small-for-gestational- Brosens I. Inadequate maternal vascular
Endometrial secretions: creating a stimulatory age pregnancies. Ultrasound Obstet Gynecol response to placentation in pregnancies
microenvironment within the human early 2012;40:171-8. complicated by pre-eclampsia and by small-for-
placenta. Implications for the etiopathogenesis 35. Jauniaux E, Hempstock J, Greenwold N, gestational age infants. Br J Obstet Gynaecol
of pre-eclampsia. J Reprod Immunol 2011;89: Burton GJ. Trophoblastic oxidative stress in 1986;93:1049-59.
118-25. relation to temporal and regional differences in 50. Lyall F, Robson SC, Bulmer JN. Spiral artery
20. Filant J, Spencer TE. Uterine glands: bio- maternal placental blood flow in normal and remodeling and trophoblast invasion in pre-
logical roles in conceptus implantation, uterine abnormal early pregnancies. Am J Pathol eclampsia and fetal growth restriction: relation-
receptivity and decidualization. Int J Dev Biol 2003;162:115-25. ship to clinical outcome. Hypertension 2013;62:
2014;58:107-16. 36. Pijnenborg R, Bland JM, Robertson WB, 1046-54.
21. Cindrova-Davies T, Van Patot MT, Dixon G, Brosens I. The pattern of interstitial 51. Ong SS, Baker PN, Mayhew TM, Dunn WR.
Gardner L, Jauniaux E, Burton GJ, Charnock- trophoblastic invasion of the myometrium in early Remodeling of myometrial radial arteries in pre-
Jones DS. Energy status and HIF signaling in human pregnancy. Placenta 1981;2:303-16. eclampsia. Am J Obstet Gynecol 2005;192:
chorionic villi show no evidence of hypoxic stress 37. Jauniaux E, Watson AL, Hempstock J, 572-9.
during human early placental development. Mol Bao Y-P, Skepper JN, Burton GJ. Onset of 52. Aardema MW, Oosterhof H, Timmer A, Van
Hum Reprod 2015;21:296-308. maternal arterial blood flow and placental Rooy I, Aarnoudse JG. Uterine artery Doppler
22. Burton GJ, Jauniaux E, Charnock- oxidative stress; a possible factor in human early flow and uteroplacental vascular pathology in
Jones DS. The influence of the intrauterine pregnancy failure. Am J Pathol 2000;157: normal pregnancies and pregnancies compli-
environment on human placental development. 2111-22. cated by pre-eclampsia and small for gestational
Int J Dev Biol 2010;54:303-12. 38. Barker DJ, Thornburg KL. The obstetric or- age fetuses. Placenta 2001;22:405-11.
23. Van Uitert EM, Exalto N, Burton GJ, et al. igins of health for a lifetime. Clin Obstet Gynecol 53. Falco ML, Sivanathan J, Laoreti A,
Human embryonic growth trajectories and 2013;56:511-9. Thilaganathan B, Khalil A. Placental histopa-
associations with fetal growth and birthweight. 39. Salafia CM, Zhang J, Miller RK, Charles AK, thology associated with preeclampsia: a sys-
Hum Reprod 2013;28:1753-61. Shrout P, Sun W. Placental growth patterns tematic review and meta-analysis. Ultrasound
24. Burton GJ, Woods AW, Jauniaux E, affect birth weight for given placental weight. Obstet Gynecol 2017;50:295-301.
Kingdom JC. Rheological and physiological Birth Defects Res A Clin Mol Teratol 2007;79: 54. Sebire NJ. Implications of placental
consequences of conversion of the maternal 281-8. pathology for disease mechanisms; methods,
spiral arteries for uteroplacental blood flow during 40. Salafia CM, Yampolsky M, Misra DP, et al. issues and future approaches. Placenta 2017;52:
human pregnancy. Placenta 2009;30:473-82. Placental surface shape, function, and effects of 122-6.

S758 American Journal of Obstetrics & Gynecology FEBRUARY 2018

ajog.org Expert Reviews

55. Kadyrov M, Schmitz C, Black S, randomized placebo-controlled trial. Lancet 85. Sibley CP, Turner MA, Cetin I, et al. Placental
Kaufmann P, Huppertz B. Pre-eclampsia and 2006;367:1145-54. phenotypes of intrauterine growth. Pediatr Res
maternal anemia display reduced apoptosis and 70. Bravo R, Gutierrez T, Paredes F, et al. 2005;58:827-32.
opposite invasive phenotypes of extravillous Endoplasmic reticulum: ER stress regulates 86. Jansson T, Powell TL. IFPA 2005 Award in
trophoblast. Placenta 2003;24:540-8. mitochondrial bioenergetics. Int J Biochem Cell Placentology Lecture. Human placental trans-
56. Hiby SE, Apps R, Sharkey AM, et al. Biol 2012;44:16-20. port in altered fetal growth: does the placenta
Maternal activating KIRs protect against human 71. Ron D, Walter P. Signal integration in the function as a nutrient sensor? A review. Placenta
reproductive failure mediated by fetal HLA-C2. endoplasmic reticulum unfolded protein 2006;27(Suppl):S91-7.
J Clin Invest 2010;120:4102-10. response. Nat Rev Mol Cell Biol 2007;8: 87. Cetin I, Alvino G. Intrauterine growth re-
57. Martin CB, Mcgaughey HS, Kaiser IH, 519-29. striction: implications for placental metabolism
Donner MW, Ramsey EM. Intermittent func- 72. Han J, Kaufman RJ. Physiological/patho- and transport. A review. Placenta
tioning of the uteroplacental arteries. Am J logical ramifications of transcription factors in the 2009;30(Suppl):S77-82.
Obstet Gynecol 1964;90:819-23. unfolded protein response. Genes Dev 2017;31: 88. Gaccioli F, Lager S. Placental nutrient
58. Labarrere CA, Dicarlo HL, Bammerlin E, 1417-38. transport and intrauterine growth restriction.
et al. Failure of physiologic transformation of 73. Fahling M. Surviving hypoxia by modulation Front Physiol 2016;7:40.
spiral arteries, endothelial and trophoblast cell of mRNA translation rate. J Cell Mol Med 89. Jansson N, Pettersson J, Haafiz A, et al.
activation, and acute atherosis in the basal plate 2009;13:2770-9. Down-regulation of placental transport of amino
of the placenta. Am J Obstet Gynecol 2017;216: 74. Wouters BG, Koritzinsky M. Hypoxia acids precedes the development of intrauterine
287.e1-16. signaling through mTOR and the unfolded pro- growth restriction in rats fed a low protein diet.
59. Hubel CA. Oxidative stress in the patho- tein response in cancer. Nat Rev Cancer 2008;8: J Physiol 2006;576:935-46.
genesis of preeclampsia. Proc Soc Exp Biol Med 851-64. 90. Zhang K, Kaufman RJ. From endoplasmic-
1999;222:222-35. 75. Rutkowski DT, Hegde RS. Regulation of reticulum stress to the inflammatory response.
60. Myatt L. Review: Reactive oxygen and basal cellular physiology by the homeostatic Nature 2008;454:455-62.
nitrogen species and functional adaptation of unfolded protein response. J Cell Biol 2010;189: 91. Hotamisligil GS. Endoplasmic reticulum
the placenta. Placenta 2010;31(Suppl): 783-94. stress and the inflammatory basis of metabolic
S66-9. 76. Teasdale F. Idiopathic intrauterine growth disease. Cell 2010;140:900-17.
61. Burton GJ, Jauniaux E. Oxidative stress. retardation: histomorphometry of the human 92. Xu C, Bailly-Maitre B, Reed JC. Endo-
Best Pract Res Clin Obstet Gynaecol 2011;25: placenta. Placenta 1984;5:83-92. plasmic reticulum stress: cell life and death de-
287-99. 77. Mayhew TM, Ohadike C, Baker PN, cisions. J Clin Invest 2005;115:2656-64.
62. Cadenas E, Davies KJA. Mitochondrial free Crocker IP, Mitchell C, Ong SS. Stereological 93. Deng J, Lu PD, Zhang Y, et al. Translational
radical generation, oxidative stress, and aging. investigation of placental morphology in preg- repression mediates activation of nuclear factor
Free Rad Biol Med 2000;29:222-30. nancies complicated by pre-eclampsia with and kappa B by phosphorylated translation initiation
63. Guzy RD, Schumacker PT. Oxygen sensing without intrauterine growth restriction. Placenta factor 2. Mol Cell Biol 2004;24:10161-8.
by mitochondria at complex III: the paradox of 2003;24:219-26. 94. Goswami D, Tannetta DS, Magee LA, et al.
increased reactive oxygen species during hyp- 78. Egbor M, Ansari T, Morris N, Green CJ, Excess syncytiotrophoblast microparticle shed-
oxia. Exp Physiol 2006;91:807-19. Sibbons PD. Pre-eclampsia and fetal growth ding is a feature of early-onset pre-eclampsia,
64. Hung TH, Skepper JN, Burton GJ. In vitro restriction: how morphometrically different is the but not normotensive intrauterine growth re-
ischemia-reperfusion injury in term human placenta? Placenta 2006;27:727-34. striction. Placenta 2006;27:56-61.
placenta as a model for oxidative stress in 79. Hafner E, Metzenbauer M, Hofinger D, et al. 95. Sgambati E, Biagiotti R, Marini M, Brizzi E.
pathological pregnancies. Am J Pathol Placental growth from the first to the second Lectin histochemistry in the human placenta of
2001;159:1031-43. trimester of pregnancy in SGA-fetuses and pre- pregnancies complicated by intrauterine growth
65. Hung T-H, Skepper JN, Charnock- eclamptic pregnancies compared to normal fe- retardation based on absent or reversed dia-
Jones DS, Burton GJ. Hypoxia/reoxygena- tuses. Placenta 2003;24:336-42. stolic flow. Placenta 2002;23:503-15.
tion: a potent inducer of apoptotic changes in 80. Sferruzzi-Perri AN, Owens JA, Pringle KG, 96. Nishizawa H, Ota S, Suzuki M, et al.
the human placenta and possible etiological Roberts CT. The neglected role of insulin-like Comparative gene expression profiling of pla-
factor in preeclampsia. Circ Res 2002;90: growth factors in the maternal circulation centas from patients with severe pre-eclampsia
1274-81. regulating fetal growth. J Physiol 2011;589: and unexplained fetal growth restriction.
66. Cindrova-Davies T, Spasic-Boskovic O, 7-20. Reprod Biol Endocrinol 2011;9:107.
Jauniaux E, Charnock-Jones DS, Burton GJ. 81. Roos S, Powell TL, Jansson T. Placental 97. Whitehead CL, Walker SP, Ye L, et al.
Nuclear factor-kappa B, p38, and stress- mTOR links maternal nutrient availability to fetal Placental specific mRNA in the maternal circu-
activated protein kinase mitogen-activated pro- growth. Biochem Soc Trans 2009;37:295-8. lation are globally dysregulated in pregnancies
tein kinase signaling pathways regulate proin- 82. Roos S, Jansson N, Palmberg I, Saljo K, complicated by fetal growth restriction. J Clin
flammatory cytokines and apoptosis in human Powell TL, Jansson T. Mammalian target of Endocrinol Metab 2013;98:E429-36.
placental explants in response to oxidative rapamycin in the human placenta regulates 98. McMinn J, Wei M, Schupf N, et al. Unbal-
stress: effects of antioxidant vitamins. Am J leucine transport and is down-regulated in anced placental expression of imprinted genes
Pathol 2007;170:1511-20. restricted fetal growth. J Physiol 2007;582: in human intrauterine growth restriction.
67. Cindrova-Davies T, Yung HW, Johns J, et al. 449-59. Placenta 2006;27:540-9.
Oxidative stress, gene expression, and protein 83. Yung HW, Calabrese S, Hynx D, et al. Evi- 99. Diplas AI, Lambertini L, Lee MJ, et al. Dif-
changes induced in the human placenta during dence of placental translation inhibition and ferential expression of imprinted genes in normal
labor. Am J Pathol 2007;171:1168-79. endoplasmic reticulum stress in the etiology of and IUGR human placentas. Epigenetics
68. Rayman MP, Bath SC, Westaway J, et al. human intrauterine growth restriction. Am J 2009;4:235-40.
Selenium status in UK pregnant women and its Pathol 2008;173:451-62. 100. Deyssenroth MA, Li Q, Lacasana M,
relationship with hypertensive conditions of 84. Yung HW, Cox M, Tissot Van Patot M, Nomura Y, Marsit C, Chen J. Expression of
pregnancy. Br J Nutr 2015;113:249-58. Burton GJ. Evidence of endoplasmic reticulum placental regulatory genes is associated with
69. Poston L, Briley AL, Seed PT, Kelly FJ, stress and protein synthesis inhibition in the fetal growth. J Perinat Med 2017;45:887-93.
Shennan AH. Vitamin C and vitamin E in preg- placenta of non-native women at high altitude. 101. Thamotharan S, Chu A, Kempf K, et al.
nant women at risk for pre-eclampsia (VIP trial): FASEB J 2012;26:1970-81. Differential microRNA expression in human

FEBRUARY 2018 American Journal of Obstetrics & Gynecology S759

Expert Reviews ajog.org

placentas of term intra-uterine growth restriction placental vasodilator. Am J Pathol 2013;182: 131. Proctor LK, Whittle WL, Keating S, Viero S,
that regulates target genes mediating angio- 1448-58. Kingdom JC. Pathologic basis of echogenic
genesis and amino acid transport. PLoS One 115. Lu L, Kingdom J, Burton GJ, Cindrova- cystic lesions in the human placenta: role of
2017;12:e0176493. Davies T. Placental stem villus arterial remodel- ultrasound-guided wire localization. Placenta
102. Hromadnikova I, Kotlabova K, Doucha J, ing associated with reduced hydrogen sulfide 2010;31:1111-5.
Dlouha K, Krofta L. Absolute and relative synthesis contributes to human fetal growth re- 132. Linduska N, Dekan S, Messerschmidt A,
quantification of placenta-specific microRNAs striction. Am J Pathol 2017;187:908-20. et al. Placental pathologies in fetal MRI with
in maternal circulation with placental 116. Fox H, Sebire NJ. Pathology of the pathohistological correlation. Placenta 2009;30:
insufficiency-related complications. J Mol Diagn placenta. Amsterdam: Saunders Elsevier; 2007. 555-9.
2012;14:160-7. 117. Benirschke K, Burton GJ, Baergen RN. 133. Jauniaux E, Campbell S. Antenatal diag-
103. Lattuada D, Colleoni F, Martinelli A, et al. Pathology of the human placenta. Heidelberg: nosis of placental infarcts by ultrasonography.
Higher mitochondrial DNA content in human Springer; 2012. p.941. J Clin Ultrasound 1991;19:58-61.
IUGR placenta. Placenta 2008;29:1029-33. 118. Mifsud W, Sebire NJ. Placental pathology 134. Jauniaux E, Campbell S. Fetal growth
104. Poidatz D, Dos Santos E, Duval F, et al. in early-onset and late-onset fetal growth re- retardation with abnormal blood flows and
Involvement of estrogen-related receptor- striction. Fetal Diagn Ther 2014;36:117-28. placental sonographic lesions. J Clin Ultrasound
gamma and mitochondrial content in intrauterine 119. Nordenvall M, Sandstedt B, Ulmsten U. 1990;18:210-4.
growth restriction and preeclampsia. Fertil Steril Relationship between placental shape, cord 135. Levine AB, Frieden FJ, Stein JL,
2015;104:483-90. insertion, lobes and gestational outcome. Acta Pisnanont P. Prenatal sonographic diagnosis of
105. Holland O, Dekker Nitert M, Gallo LA, Obstet Gynecol Scand 1988;67:611-6. placental infarction in association with elevated
Vejzovic M, Fisher JJ, Perkins AV. Review: 120. Toal M, Chan C, Fallah S, et al. Usefulness maternal serum alpha-fetoprotein. J Ultrasound
Placental mitochondrial function and structure in of a placental profile in high-risk pregnancies. Med 1993;12:169-71.
gestational disorders. Placenta 2017;54:2-9. Am J Obstet Gynecol 2007;196:363.e1-7. 136. Barclay D, Evans K, Fox R. Ultrasound-
106. Colleoni F, Padmanabhan N, Yung HW, 121. Kalanithi LE, Illuzzi JL, Nossov VB, et al. diagnosed placental infarction in a woman with
et al. Suppression of mitochondrial electron Intrauterine growth restriction and placental recurrent fetal growth restriction. J Obstet
transport chain function in the hypoxic human location. J Ultrasound Med 2007;26:1481-9. Gynaecol 2005;25:200-1.
placenta: a role for miR-210 and protein 122. Ananth CV, Demissie K, Smulian JC, 137. Theophilou G, Sahashrabudhe N,
synthesis inhibition. PLoS One 2013;8: Vintzileos AM. Relationship among placenta Martindale EA, Heazell AE. Correlation between
e55194. previa, fetal growth restriction, and preterm de- abnormal placental appearance at routine 2nd
107. Akison LK, Nitert MD, Clifton VL, livery: a population-based study. Obstet Gyne- trimester ultrasound scan and histological ex-
Moritz KM, Simmons DG. Review: Alterations in col 2001;98:299-306. amination of the placenta after birth. J Obstet
placental glycogen deposition in complicated 123. Harper LM, Odibo AO, Macones GA, Gynaecol 2012;32:760-3.
pregnancies: current preclinical and clinical evi- Crane JP, Cahill AG. Effect of placenta previa on 138. Aurioles-Garibay A, Hernandez-
dence. Placenta 2017;54:52-8. fetal growth. Am J Obstet Gynecol 2010;203: Andrade E, Romero R, et al. Prenatal diagnosis
108. Bastida-Ruiz D, Aguilar E, Ditisheim A, 330.e1-5. of a placental infarction hematoma associated
Yart L, Cohen M. Endoplasmic reticulum stress 124. Jauniaux E, Campbell S. Ultrasonographic with fetal growth restriction, preeclampsia and
responses in placentationea true balancing act. assessment of placental abnormalities. Am J fetal death: clinicopathological correlation. Fetal
Placenta 2017;57:163-9. Obstet Gynecol 1990;163:1650-8. Diagn Ther 2014;36:154-61.
109. Hung TH, Chen SF, Lo LM, Li MJ, Yeh YL, 125. Jauniaux E, Gibb D, Moscoso G, 139. Bonel HM, Stolz B, Diedrichsen L, et al.
Hsieh TT. Increased autophagy in placentas of Campbell S. Ultrasonographic diagnosis of a Diffusion-weighted MR imaging of the placenta
intrauterine growth-restricted pregnancies. large placental intervillous thrombosis associ- in fetuses with placental insufficiency. Radiology
PLoS One 2012;7:e40957. ated with elevated maternal serum alpha- 2010;257:810-9.
110. Chang YL, Wang TH, Chang SD, Chao AS, fetoprotein level. Am J Obstet Gynecol 140. Messerschmidt A, Baschat A,
Hsieh PC, Wang CN. Increased autophagy in 1990;163:1558-60. Linduska N, et al. Magnetic resonance imaging
the placental territory of selective intrauterine 126. Richards DS, Bennett BB. Prenatal ultra- of the placenta identifies placental vascular
growth-restricted monochorionic twins. Prenat sound diagnosis of massive subchorionic abnormalities independently of Doppler ultra-
Diagn 2013;33:187-90. thrombohematoma. Ultrasound Obstet Gynecol sound. Ultrasound Obstet Gynecol 2011;37:
111. Fok RY, Pavlova Z, Benirschke K, Paul RH, 1998;11:364-6. 717-22.
Platt LD. The correlation of arterial lesions with 127. Fung TY, To KF, Sahota DS, Chan LW, 141. Mandsager NT, Bendon R, Mostello D,
umbilical artery Doppler velocimetry in the pla- Leung TY, Lau TK. Massive subchorionic Rosenn B, Miodovnik M, Siddiqi TA. Maternal
centas of small-for-dates pregnancies. Obstet thrombohematoma: a series of 10 cases. Acta floor infarction of the placenta: prenatal diag-
Gynecol 1990;75:578-83. Obstet Gynecol Scand 2010;89:1357-61. nosis and clinical significance. Obstet Gynecol
112. Salafia CM, Pezzullo JC, Minior VK, 128. Alanjari A, Wright E, Keating S, Ryan G, 1994;83:750-4.
Divon MY. Placental pathology of absent and Kingdom J. Prenatal diagnosis, clinical out- 142. Naeye RL. Maternal floor infarction. Hum
reversed end-diastolic flow in growth-restricted comes, and associated pathology in pregnan- Pathol 1985;16:823-8.
fetuses. Obstet Gynecol 1997;90:830-6. cies complicated by massive subchorionic 143. Devisme L, Chauviere C, Franquet-
113. Mitra SC, Seshan SV, Riachi LE. Placental thrombohematoma (Breus’ mole). Prenat Diagn Ansart H, et al. Perinatal outcome of placental
vessel morphometry in growth retardation and 2013;33:973-8. massive perivillous fibrin deposition: a case-
increased resistance of the umbilical artery 129. Boulis TS, Rochelson BL, Williamson AK. control study. Prenat Diagn 2017;37:323-8.
Doppler flow. J Matern Fetal Med 2000;9: Massive subchorionic placental cyst and poor 144. Alkazaleh F, Viero S, Simchen M, et al.
282-6. fetal growth: a case report. J Reprod Med Ultrasound diagnosis of severe thrombotic
114. Cindrova-Davies T, Herrera EA, Niu Y, 2015;60:458-60. placental damage in the second trimester: an
Kingdom J, Giussani DA, Burton GJ. Reduced 130. Kofinas A, Kofinas G, Sutija V. The role of observational study. Ultrasound Obstet Gynecol
cystathionine gamma-lyase and increased second trimester ultrasound in the diagnosis of 2004;23:472-6.
miR-21 expression are associated with placental hypoechoic lesions leading to poor 145. Jauniaux E, Moscoso G, Campbell S,
increased vascular resistance in growth- pregnancy outcome. J Matern Fetal Neonatal Gibb D, Driver M, Nicolaides KH. Correlation of
restricted pregnancies: hydrogen sulfide as a Med 2007;20:859-66. ultrasound and pathologic findings of placental

S760 American Journal of Obstetrics & Gynecology FEBRUARY 2018

ajog.org Expert Reviews

anomalies in pregnancies with elevated maternal etiology with stillbirth and fetal growth 169. Naveiro-Fuentes M, Carrillo-Badillo MP,
serum alpha-fetoprotein. Eur J Obstet Gynecol restrictionea systematic review. Placenta Malde-Conde J, Gallo-Vallejo JL, Puertas-
Reprod Biol 1990;37:219-30. 2013;34:856-62. Prieto A. Perinatal outcomes in singleton preg-
146. Jauniaux E, Ramsay B, Campbell S. Ul- 158. Salafia CM, Minior VK, Pezzullo JC, nancies with a single umbilical artery. J Matern
trasonographic investigation of placental Popek EJ, Rosenkrantz TS, Vintzileos AM. In- Fetal Neonatal Med 2016;29:1562-5.
morphologic characteristics and size during the trauterine growth restriction in infants of less 170. Voskamp BJ, Fleurke-Rozema H, Oude-
second trimester of pregnancy. Am J Obstet than thirty-two weeks’ gestation: associated Rengerink K, et al. Relationship of isolated single
Gynecol 1994;170:130-7. placental pathologic features. Am J Obstet umbilical artery to fetal growth, aneuploidy and
147. Alkazaleh F, Chaddha V, Viero S, et al. Gynecol 1995;173:1049-57. perinatal mortality: systematic review and meta-
Second-trimester prediction of severe placental 159. Parant O, Capdet J, Kessler S, Aziza J, analysis. Ultrasound Obstet Gynecol 2013;42:
complications in women with combined eleva- Berrebi A. Chronic intervillositis of unknown eti- 622-8.
tions in alpha-fetoprotein and human chorionic ology (CIUE): relation between placental lesions 171. Kim HJ, Kim JH, Chay DB, Park JH,
gonadotrophin. Am J Obstet Gynecol and perinatal outcome. Eur J Obstet Gynecol Kim MA. Association of isolated single umbilical
2006;194:821-7. Reprod Biol 2009;143:9-13. artery with perinatal outcomes: systemic review
148. Suri S, Muttukrishna S, Jauniaux E. 2D- 160. Kovo M, Schreiber L, Ben-Haroush A, and meta-analysis. Obstet Gynecol Sci
Ultrasound and endocrinologic evaluation of Wand S, Golan A, Bar J. Placental vascular 2017;60:266-73.
placentation in early pregnancy and its rela- lesion differences in pregnancy-induced hyper- 172. Jauniaux E, Campbell S, Vyas S. The use
tionship to fetal birthweight in normal preg- tension and normotensive fetal growth restric- of color Doppler imaging for prenatal diagnosis
nancies and pre-eclampsia. Placenta 2013;34: tion. Am J Obstet Gynecol 2010;202:561.e1-5. of umbilical cord anomalies: report of three
745-50. 161. Veerbeek JH, Nikkels PG, Torrance HL, cases. Am J Obstet Gynecol 1989;161:
149. Redline RW. Classification of placental et al. Placental pathology in early intrauterine 1195-7.
lesions. Am J Obstet Gynecol 2015;213: growth restriction associated with maternal hy- 173. Burton GJ, Jauniaux E. Placental oxidative
S21-8. pertension. Placenta 2014;35:696-701. stress; from miscarriage to preeclampsia. J Soc
150. Kovo M, Schreiber L, Ben-Haroush A, et al. 162. Biswas S, Ghosh SK. Gross morphological Gynecol Invest 2004;11:342-52.
The placental factor in early- and late-onset changes of placentas associated with intrauter- 174. Jauniaux E, Hustin J. Histological ex-
normotensive fetal growth restriction. Placenta ine growth restriction of fetuses: a case control amination of first trimester spontaneous
2013;34:320-4. study. Early Hum Dev 2008;84:357-62. abortions: the impact of materno-embryonic
151. Giles WB, Trudinger BJ, Baird PJ. Fetal 163. Heifetz SA. Single umbilical artery. A sta- interface features. Histopathology 1992;21:
umbilical artery flow velocity waveforms and tistical analysis of 237 autopsy cases and review 409-14.
placental resistance: pathological correlation. Br of the literature. Perspect Pediatr Pathol 1984;8: 175. Hempstock J, Jauniaux E, Greenwold N,
J Obstet Gynaecol 1985;92:31-8. 345-78. Burton GJ. The contribution of placental oxida-
152. Madazli R, Somunkiran A, Calay Z, Ilvan S, 164. Jauniaux E, Demunter C, Pardou A, tive stress to early pregnancy failure. Hum Pathol
Aksu MF. Histomorphology of the placenta and Elkhazen N, Rodesch F, Wilkin P. Ultrasonic 2003;34:1265-75.
the placental bed of growth restricted fetuses study of the single umbilical artery syndrome. A 176. Yung HW, Atkinson D, Campion-Smith T,
and correlation with the Doppler velocimetries of series of 80 cases [in French]. J Gynecol Obstet Olovsson M, Charnock-Jones DS, Burton GJ.
the uterine and umbilical arteries. Placenta Biol Reprod (Paris) 1989;18:341-7. Differential activation of placental unfolded
2003;24:510-6. 165. Hubinont C, Lewi L, Bernard P, Marbaix E, protein response pathways implies heteroge-
153. Vedmedovska N, Rezeberga D, Teibe U, Debieve F, Jauniaux E. Anomalies of the neity in causation of early- and late-onset pre-
Melderis I, Donders GG. Placental pathology in placenta and umbilical cord in twin gestations. eclampsia. J Pathol 2014;234:262-76.
fetal growth restriction. Eur J Obstet Gynecol Am J Obstet Gynecol 2015;213:S91-102. 177. Hempstock J, Cindrova-Davies T,
Reprod Biol 2011;155:36-40. 166. Khalil MI, Sagr ER, Elrifaei RM, Jauniaux E, Burton GJ. Endometrial glands as a
154. Spinillo A, Gardella B, Bariselli S, Alfei A, Abdelbasit OB, Halouly TA. Outcomes of an source of nutrients, growth factors and
Silini E, Dal Bello B. Placental histopathological isolated single umbilical artery in singleton cytokines during the first trimester of human
correlates of umbilical artery Doppler velocimetry pregnancy: a large study from the Middle East pregnancy; a morphological and immunohis-
in pregnancies complicated by fetal growth re- and Gulf region. Eur J Obstet Gynecol Reprod tochemical study. Reprod Biol Endocrinol
striction. Prenat Diagn 2012;32:1263-72. Biol 2013;171:277-80. 2004;2:58.
155. Fitzgerald B, Shannon P, Kingdom J, 167. Mailath-Pokorny M, Worda K, Schmid M, 178. Jauniaux E, Cindrova-Davies T, Johns J,
Keating S. Basal plate plaque: a novel organizing Polterauer S, Bettelheim D. Isolated single um- et al. Distribution and transfer pathways of anti-
placental thrombotic process. J Clin Pathol bilical artery: evaluating the risk of adverse oxidant molecules inside the first trimester hu-
2011;64:725-8. pregnancy outcome. Eur J Obstet Gynecol man gestational sac. J Clin Endocrinol Metab
156. Redline RW. Villitis of unknown etiology: Reprod Biol 2015;184:80-3. 2004;89:1452-9.
noninfectious chronic villitis in the placenta. Hum 168. Battarbee AN, Palatnik A, Ernst LM, 179. Burton GJ, Yung HW, Murray AJ.
Pathol 2007;38:1439-46. Grobman WA. Association of isolated single Mitochondrialeendoplasmic reticulum in-
157. Derricott H, Jones RL, Heazell AE. Inves- umbilical artery with small for gestational age and teractions in the trophoblast: stress and senes-
tigating the association of villitis of unknown preterm birth. Obstet Gynecol 2015;126:760-4. cence. Placenta 2017;52:146-55.

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