E-Mail [email protected] Review Fetal Diagn Ther 2014;36:117128
DOI: 10.1159/000359969 Placental Pathology in Early-Onset and
Late-Onset Fetal Growth Restriction William MifsudNeil J. Sebire
Department of Paediatric Histopathology, Great Ormond Street
Hospital,London , UK profile. The histological placental findings
in FGR are there-fore varied, from morphologically unremarkable
through to
severeuteroplacentalvasculopathy,withnosinglepatho-logical feature
associated with high sensitivity or specificity. Severe early-onset
FGR, overlapping with severe early-onset PET, is mainly associated
with features of impaired maternal uteroplacental perfusion
secondary to defective extravillous trophoblast invasion, and its
consequences. Late-onset FGR probably represents a more
heterogeneous group with less
characteristichistologicalchanges.Futureresearchusing
histopathological assessment of aggregated data from mul-tiple
studies into larger datasets with centralised pathology review will
allow delineation of distinctive clinicopathologi-cal associations
and further understanding of pathophysiol-ogy. 2014 S. Karger AG,
Basel Introduction There has been increasing interest in defining
patterns ofplacentalpathologyassociatedwithintrauterinefetal
growthrestriction(FGR),withprogressiveclinicalre-finement of
subgroups of fetuses that are small for gesta-tional age (SGA),
with and without other features of FGR, Key Words Placental
pathology Growth restriction Pre-eclampsia Abstract Several
histopathological features are found more frequent-ly in placentas
from pregnancies complicated by fetal growth
restriction(FGR),includingvillousinfarction,maternalvas-cularchangesandvillousmorphologicalalterations,al-though
around one quarter of placentas associated with FGR
lackanymorphologicalabnormalityonroutineexamina-tion. Since similar
changes may also affect clinically
uncom-plicatedpregnancies,thepositivepredictivevalueofsuch findings
for pathological FGR in an unselected case remains
low.However,thepatternofplacentalpathologiesvaries
withclinicalsubgroup.Thecombinationofplacentalbed
andparenchymallesionsinFGRwithabnormaluterinear-teryDopplervelocimetryisessentiallyidenticaltopreterm
pre-eclampsia(PET),andthereisanassociationbetween FGR with abnormal
umbilical artery Doppler findings and le-sions of fetal stem
arteries and terminal villous hypovascu-larity. Conversely,
placentas from pregnancies complicated by PET or FGR presenting at
or near term have a significantly lower frequency of histological
abnormalities compared to early-onset disease and absence of a
distinctive biochemical Received: January 7, 2014 Accepted after
revision: January 23, 2014 Published online: February 21, 2014
Prof. N.J. Sebire Department of Paediatric Histopathology Great
Ormond Street Hospital Great Ormond Street, London WC1N 3JH (UK)
E-Mail [email protected] 2014 S. Karger AG,
Basel10153837/14/03620117$39.50/0 www.karger.com/fdt Downloaded by:
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Ther 2014;36:117128DOI:
10.1159/000359969118suchasabnormalDopplerultrasoundassessmentand
maternal serum markers such as placental growth factor and fms-like
tyrosine kinase-1. Here, we review the
avail-abledataondocumentedhistopathologicalfeaturesof the placenta
associated with early versus late-onset FGR,
theirsignificance,andtheirrelationshiptofindingsin pre-eclampsia
(PET). We also infer possible pathogenetic
implicationsofthesefindingsandspeculateonfuture work to better
define, understand and manage these con-ditions. General Placental
Histopathological Features Associated with FGR There are numerous
publications describing a range of
morphologicalfeaturesinplacentasfrompregnancies complicated by FGR
(or more specifically SGA, since the vast majority of studies,
especially early studies, defined the FGR group simply based on a
fetal size below a given centile value rather than definitive
features of abnormal fetal growth)[1] . Despite this large
descriptive literature, no reliable and pathognomonic features for
either FGR/SGA or specific aetiologies are documented, but several
lesionsaremorecommoncomparedtocontrolsinthe majority of studies,
and hence appear associated with the clinical phenotype of FGR/SGA.
However, comparison of
findingsbetweendifferentstudies,andmoredetailed analysis of the
data, is often not straightforward, due to several reasons. There
is biological variation in the disease process due to several
complex underlying mechanisms resulting in a final common phenotype
of FGR, and in-dividual patient responses may differ in response to
a giv-en underlying cause. There is variation in placental
mor-phology due to the fact that FGR occurs in parallel with many
features of growth and development of the fetopla-cental unit, and
there may be geographical variation be-tween different areas of the
same placenta in relation to
samplingadequacy.Inaddition,studiesmayhaveused different sampling
protocols, with associated bias and er-rors, and the extent of such
regional variations in placen-tal histological changes remains
undefined. Studies have used different definitions and thresholds
for recognising changes as lesions, many of which are based on
subjec-tive assessment by an observer, such that variation in
in-terpretationbetweenstudiesisimpossibletocontrol. However, the
greatest problem is that the study popula-tions examined are
relatively poorly defined and
poten-tiallyheterogeneous.Forexample,anyarbitraryfixed
proportionofapopulation,suchasthesmallest5%of fetuses, will include
a mixture of pathologically growth-restricted fetuses and those who
are constitutively small, with many studies defining inclusion
based on fetal size rather than growth. However, the progressive
refinement ofclinicalsubgroupingforinclusion,throughuseof
Dopplerstudiesandplasmabiomarkers,hasfacilitated
animprovedunderstandingofFGRpathology,and emerging well-defined
subgroups of placental abnormal-ities are now becoming increasingly
recognised. Despitethesepotentialdifficultiesininterpretation,
therearepatternsofplacentalhistologicalchangesthat are well
reported and common to most studies of the pa-thology of FGR.
First, it should be noted that, overall,
ap-proximatelyonequarterofplacentasassociatedwith FGR/SGA (however
defined) lack any morphological ab-normality on routine macroscopic
and histological exam-ination[1] . In those cases with lesions
present, the most
frequentmacroscopicabnormalitythatoccurswithin-creasedfrequencyinFGRplacentasispatchyplacental
infarction, being present in around 25% of term FGR ver-sus 10% of
controls [214] . This finding illustrates a com-mon theme when
interpreting placental findings in FGR,
thatthefrequencyofseverallesionsisincreased,but
sincesuchlesionsareonlypresentinaminorityofaf-fected cases and are
also found in some normal controls, and since non-FGR is far more
frequent than FGR in the population, the positive predictive value
of such findings for pathological FGR in any given unselected case
will be very low. Similarly,severalmicroscopicabnormalitieshave
been reported more frequently in FGR placentas, none of which are
present in the majority of affected cases in any study, and almost
all of which may be encountered in
oth-ernon-FGRpregnancies,including [27,925] :villous infarcts (an
example from a placenta in a case of FGR is shown infigure 1 a, b),
placental abruption/retroplacental
haemorrhage,villousmorphologicalabnormalitiessug-gestiveofreduceduteroplacentaland/orfetoplacental
flow(hypoxiclesion)suchassyncytiotrophoblast
knots,excesscytotrophoblastcells,thickenedtropho-blastic basement
membrane, villous fibrosis, hypovascu-lar terminal villi, reduced
villous volume, reduced
inter-villousspace,andnon-specificinflammatorylesions[villitisofunknownaetiology(VUE)].Inaddition,histologicalfeaturesindicatingdefectiveremodellingof
spiral arteries into uteroplacental vessels may be identi-fied,
such as inadequate physiological change, fibrinoid
necrosisandacuteatherosis(adenseperivascularlym-phocyticinfiltratewithintimalarterialfoamymacro-phages;
see fig.2 a, b) [2628] .Downloaded by: 198.143.39.65 - 8/15/2015
11:01:29 AM Placenta in Early and Late FGRFetal Diagn Ther
2014;36:117128DOI: 10.1159/000359969119 Association of Placental
Pathologies with Clinical Subgroups The use of well-defined
specific clinical subgroups of definite pathological FGR should
allow determination of
anyspecificpatternsofplacentalabnormalities,and
hence,suggestpathophysiologicalpathways.Theintro-ductionofuterineartery(UtA)Dopplerstudiesidenti-fied
FGR cases with evidence of maternal uterine malper-fusion, with
placental bed biopsies in these cases
demon-stratingdefectivespiralarteryremodelling,including inadequate
physiological change and fibrinoid
necrosis/atherosis[27,29].Ferrazzietal. [30]studiedplacentas from
women with FGR and reported that extensive hy-a b Fig. 1. Placental
infarct, secondary to maternal vascular underper-fusion. At low
magnification ( a ), the infarct can be seen as an area with severe
reduction of the intervillous space and aggregation of
villi.Intheareasurroundingtheinfarcttheintervillousspaceis
increased and there are several very small villi. At higher
magnifi-cation ( b ), villous aggregation can be better
appreciated, and the
syncytiotrophoblasticshowvariousstagesofdegeneration,with pyknosis,
karyorrhexis and replacement by fibrin-like eosinophil-ic amorphous
(hyaline) material. a b Fig. 2. Lesions of acute atherosis at low (
a ) and high (b )
magnifica-tion.Thearterialwallsareirregular,necroticandreplacedwith
fibrin-like eosinophilic material. In later stages, there are
greater numbersoflipid-ladenmacrophages(lipophages)andthereisa
perivascularmononuclearinflammatoryinfiltrate.Theselesions occur in
vessels with inadequate extravillous trophoblast invasion. Color
version available onlineColor version available onlineDownloaded
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Ther 2014;36:117128DOI:
10.1159/000359969120poxicvillousdamage(morethan30%ofterminalvilli
withoneormoreofthefollowing:syncytiotrophoblast knotting, excess
cytotrophoblast cells, thickened tropho-blastic basement membrane,
villous fibrosis,
hypovascu-larity),non-peripheralinfarctsinvolvingmorethan5%
ofplacentalparenchyma,andplacentalabruptionwere found only in those
FGR cases with abnormal UtA velo-cimetry, regardless of the
presence or absence of
pregnan-cy-inducedhypertension(PIH).UtAvelocimetryis therefore a
marker for defective remodelling of spiral ar-teries with
consequent placental malperfusion and asso-ciated impaired fetal
growth. Abnormal UtA Doppler Is Associated with a Common Set of
Placental Ischaemic Lesions in FGR and Preterm PET
Thecombinationofplacentalbedandparenchymal lesions described in FGR
with abnormal UtA velocimetry
isessentiallyidenticaltolesionsdescribedinpreterm PET, particularly
when subsets of preterm PET and pre-term FGR are compared[12, 15,
26, 2837]. Indeed, ab-normally raised UtA resistance is associated
with defec-tive trophoblast migration on placental bed biopsies
in-dependentofthepresenceorabsenceoftheclinical syndrome of PIH
[38] . Whilst placental findings in preterm PET and FGR are
therefore similar, defining the extent of similarity and its
dependenceonabnormalUtADopplerwouldbebest achieved by a
quantitative meta-analysis, but this is
dif-ficultduetothereasonsdescribedintheIntroduction. Nevertheless,
two studies [12, 35] were performed by the same group on the same
study population (delivering be-tween 22 and 32 weeks gestation);
including 48 cases with FGR(1 vessel not reported 10.0Chronic
maternal vasculitis: 1 vessel only not reported 20.0Absence of
spiral artery physiological changes not reported 30.0Fibrinoid
necrosis and/or atherosis of spiral arteries: multiple arteries
10.424.0 Fibrinoid necrosis and/or atherosis of spiral arteries: 1
artery only 12.5Villous fibrosis: severe* 27.1 82.0Villous
fibrosis: mild 39.6 not reportedVillous hypovascularity: severe*
25.0 72.0Villous hypovascularity: mild 39.6 not reportedVillous
infarction: multiple 37.5 45.0Villous infarction: single 20.8 24.0
(focal)Villous infarct location: peripheral 10% 10.4 11.0Villous
infarct location: central 90% 29.2 36.0Villous infarct location:
peripheral & central 16.7 18.0Syncytiotrophoblast knotting:
severely increased 39.0 40.0Syncytiotrophoblast knotting: mildly
increased 43.8 not reportedProliferation of cytotrophoblast cells:
severe 36.9 42.0Proliferation of cytotrophoblast cells: mild 27.1
not reportedAbruption: frank 10.4 12.0Abruption: consistent with
31.3 37.0Perivillous fibrin deposition: severely increased 45.8
43.0Perivillous fibrin deposition: mildly increased 41.7 not
reportedFetal vascular thrombosis not reported 4.0Haemorrhagic
endovasculitis not reported 12.0Avascular terminal villi:
multifocal 18.8 20.0Avascular terminal villi: focal 29.2
25.0Nucleated erythrocytes: numerous 17.576.0Nucleated
erythrocytes: present, not numerous 56.3* Parameters with a
significant difference between preterm FGR and preterm PET groups,
with respective percentages in bold. Percentages are italicised if
significantly different from control population used in original
study. In the preterm symmetrical FGR study [12], the control
population was preterm placentas from pregnan-cies without FGR (340
cases). In the preterm PET study [35], the control population (353
cases) was a combina-tion of spontaneous premature rupture of
membranes (192 cases) and premature labour with intact membranes
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Mifsud/Sebire Fetal Diagn Ther 2014;36:117128DOI:
10.1159/000359969122esasconsequencesofsuchaprimaryabnormality,and
several other lines of evidence suggest that this is errone-ous.
Changes in the stem villous arteries are strongly sug-gestive of a
response to chronic vasoconstriction [45] , and develop in parallel
with a progressive UA Doppler abnor-mality[45, 55] , and similar
downstream changes in
termi-nalvilliarepresentintheterritoryofanupstreamfetal
vesselwithocclusivethrombus [56,57] .Importantly,in most cases
there is also defective uteroplacental perfusion
withassociatedUtADopplerstudiesprecedingtheUA Doppler changes[46,
47] . Furthermore, experimental ev-idence in sheep demonstrates a
rapid increase in UA re-sistance upon reducing maternal placental
perfusion[58,
59]andthereisexperimentalevidenceofrapidandre-versiblefetalvasoconstrictioninthehumanplacentain
response to hypoxia[60] , in an analogous manner to the
lung,involvinginhibitionofpotassiumchannels [61] .
Similartothepulmonarycirculation,hypoxia-induced andK
+channel-mediateddepolarisationofvascular smooth muscle cells
activates voltage-gated L-type gated Ca 2+ channels, which provides
cytosolic Ca 2+ for activat-ing the contractile apparatus [62] .
Such hypoxic
vasocon-strictionallowsautoregulationtooptimisefetomaternal flow
matching, but when widespread results in increased
globalflowresistance.However,experimentaldemon-strations of
possible fetal hypoxic vasoconstriction in the
placentahavebeenmadewithoxygentensionsthatare higher than those in
the placenta in vivo[6062] , and to
thebestofourknowledge,nostudieshavereportedthe effect of hypoxia at
levels approximating those in the pla-centa, on preparations
including the entire fetal
subchori-onicvasculature.Therehavebeenreportsstudyingpla-cental
levels of hypoxia on isolated chorionic plate arteries and veins
with diameters of 268 13 m (arteries) and 266 19 m (veins) at 2%
oxygen [63, 64] , showing increased chorionic vein vasodilatation
in response to nitric oxide, but no convincing hypoxic chorionic
artery
vasoconstric-tion.However,theisolatedvesselsusedinthesestudies were
too large to represent stem villus vessels, whose di-ameter is
typically in the range of 10100 m in both nor-mal and FGR
pregnancies[54] . Regulation of stem venous
tonemayalsooccurtomaintainwaterbalance [45,6567] . To adequately
test these hypotheses, one would need an experimental system that
can maintain placental coty-ledons at physiological levels of
oxygenation and also tru-ly representative levels of hypoxia, while
allowing for in-dependentvariationofintervillousperfusionpressure
and for measurement of vascular tone across all the
differ-entvesseltypes(arterial,venous,differentcalibres).To date,
such a system has not been reported. More recently, the similarity
of the changes in the stem villus arteries between severe FGR and
preterm PET was further demonstrated by the discovery that in both
clini-cal situations the smooth muscle cells in the stem villus
arteriesshowmarkedlyreducedexpressionofcystathi-one-lyase,
responsible for synthesis of the potent vasodi-lator hydrogen
sulphide (H 2 S). Its reduced expression in the fetal villous
resistance vessels supports the view that there is vasoconstriction
in the fetal stem villi in associa-tion with abnormal umbilical
Doppler profile [68] .
Inter-estingly,cystathione-lyaseisnotonlydownregulatedin cases with
abnormal UA Doppler profile, but shows in-creased expression in PET
with normal UA Doppler find-ings compared to non-PET controls,
although expression in both groups appeared heterogeneous by
Western blot-ting. In addition, the PET cases with normal UA
Doppler findingswerepretermcases(deliveredat29.51.5 weeks), while
the control cases were delivered at term (39 0.6 weeks) [68] .
Other Placental Histological Lesions Associatedwith FGR In addition
to the typical uteroplacental and
fetopla-centalvascularlesionsdescribedabove,severalstudies have
reported an excess frequency of VUE in FGR, with widely varying
rates ranging from 8 to 90% [5, 11, 13, 16, Fig. 3. Fetal stem
arteries (within the large villi) showing narrow-ing of their
luminal diameters and thickened walls and associated
terminalvillouschangesofhypovascular,small,straightvilli. These
changes are associated with abnormal UA Doppler profiles. Color
version available onlineDownloaded by: 198.143.39.65 - 8/15/2015
11:01:29 AM Placenta in Early and Late FGRFetal Diagn Ther
2014;36:117128DOI: 10.1159/00035996912319, 6972] . VUE is
characterised by patchy villous infil-tration by chronic
inflammatory cells, mainly histiocytes and lymphocytes, especially
in basal/maternal floor villi, in the absence of an identifiable
infective cause. It is
pos-tulatedthatVUErepresentsanabnormalmaternofetal
immunereaction,withconsequentlyincreasedriskof VUE recurrence[7377]
. VUE is approximately twice as common and more diffuse in
multigravidity[78] , and it has a higher than expected concordance
in twin pregnan-cies [79]
.ThepathologicalfeaturesofVUEarewellre-viewedelsewhere [80]
,althoughthereisconsiderable
variationamongstexpertpathologistsinrecognising this histological
lesion[81] . Nevertheless, there is a con-sistently increased
frequency of VUE in FGR, and also in placentas from cases of PIH
and PET, with and without associated FGR, despite the majority of
cases being asso-ciated with normal pregnancy outcome [82, 83] .
The pre-cise mechanism by which patchy inflammation may lead to
impaired fetal growth remains undetermined. Pathology Associated
with Late-Onset FGR and PET In the context of the subtypes of FGR
defined by Dopp-ler abnormalities, and the similarity of placental
findings in early-onset FGR and PET, it is interesting to note
in-creasing recognition of clinical groups of PET with differ-ent
features and outcomes, Doppler findings, biochemi-cal profile and
placental abnormalities. PET presenting at term is associated with
a lower fre-quency and severity of FGR compared to early-onset PET
[84] . This phenomenon could therefore represent either
themanifestationofdifferentpathophysiologicalpath-waysleadingtoasimilarmaternalsyndromeinearly-
versus late-onset PET, or may represent the same disease process at
different stages or rates of evolution. Late-onset PET could
therefore be hypothesised to represent a pro-cess leading to
maternal endothelial damage which is un-related to impaired early
trophoblast invasion, or
associ-atedwithrelativelymildimpairmentoftrophoblasticinvasionofthespiralarteries,orwithadefectinuteroplacentalperfusionthatbecomesfunctionallysig-nificantonlylateringestation,orwithsimilarimpair-mentoftrophoblasticinvasiontothatseeninpreterm
PET,butwithadelayedorreducedmaternalresponse
(althoughthislatterexplanationwouldnotexplainthe lower incidence
and severity of FGR with late-onset PET). Without definitive
evidence for and against these possi-bilities, it is possible that
each may contribute to a propor-tion of PET with late presentation.
Pathological Features Multiplestudieshavereportedthatplacentasfrom
PETpresentingattermhaveasignificantlylowerfre-quencyofhistologicallesionsassociatedwithimpaired
maternal uteroplacental perfusion compared to early-on-set disease.
In an early study of 158 PET placentas there was an inverse
relationship between gestation at delivery and the frequency of
non-peripheral infarcts, villous hy-permaturity and decidual
arteriopathy[85] and another
studyof37PETplacentasconfirmedasignificantlyre-duced frequency of
non-peripheral infarcts in cases pre-senting near term[86] . A
large study (with >900 PET cas-es and >7,000 controls) also
reported an inverse
relation-shipbetweenthefrequencyofplacentallesionsof
maternalunderperfusion(villousinfarction,villousag-glutination,
increased syncytial knots, increased intervil-lous fibrin, distal
villous hypoplasia, persistent
vasculari-sationofbasalplatearteries,muralhypertrophyofde-cidualarterioles,acuteatherosis),andgestationalage.
Despite this inverse relationship, even in PET delivered at or
beyond 37 weeks gestation, the frequency of maternal underperfusion
lesions was relatively high at around 30% [87] . In another series
of >1,200 PET placentas, a compa-rable figure of 26% was
reported[88] ; in this study, the
authorsalsoshowedanassociationoflowplacental weight (