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OBSTETRICS

Classification of placental lesionsRaymond W. Redline, MD

he placenta is the perennial Holy

Placental pathology can be useful in a variety of ways including immediate diagnosis ofimportant conditions affecting the mother or infant, identifying conditions that are likely torecur in subsequent pregnancies, separating clinical syndromes into distinct pathologicalphenotypes for further investigation, and uncovering the underlying cause of unexpectedadverse outcomes. Classification of placental lesions has evolved from being a purelydescriptive exercise through a stage in which the major pathophysiological processessuch as disorders of maternal implantation and the amniotic fluid infection syndromewere first described to a recently proposed comprehensive classification system thatincludes all of the major maternal and fetal vascular and infectious and idiopathic/im-mune inflammatory processes (Amsterdam Placental Workshop Group). Implementationof this unified system with reproducible grading and staging should help establishevidence-based recommendations for placental submission and facilitate progress instudying the pathogenesis, diagnosis, and treatment of obstetric disorders with an un-derlying placental etiology.

Key words: abruption, adverse pregnancy outcome, chorioamnionitis, clinical impli-cations, delayed villous maturation, fetal vascular, maternal vascular, placenta, placentalpathology, recurrent lesion, underperfusion, vascular lesions of the placenta, villitis

T Grail, a putative diary of intra-uterine life promising to explain themysteries underlying poor pregnancyoutcome. Its practical counterpart,placental pathology, is finally emergingas a respectable specialty after manyyears of confusion related to experts withdivergent views, pathologists with vary-ing levels of interest and relevanttraining, and nomenclature having littlerelationship to either the underlyingbiology or clinical presentation.

Recent progress has been realizedthrough the gradual acceptance of astandardized, reproducible, and biolog-ically based classification system. Muchwork remains to disseminate this newinformation to practicing pathologistsand clinicians.

In this review, I will summarize theutility of placental diagnoses, reviewearly contributions to our understandingof placental pathology, go into moredepth describing the new Amsterdaminternational consensus criteria forplacental diagnosis (Table 1), andconclude by speculating on how furtherprogress in this area could facilitate thegoals of the Human Placental Project todevelop biomarkers and imaging tech-niques that can identify placental diseaseprocesses in real time when targetedintervention may be of benefit.1,2

Utility of placental examinationSubmission of placentas for examinationgenerally follows 1997 College of

From the Department of Pathology, UniversityHospitals Case Medical Center, Cleveland, OH.

Received May 4, 2015; revised May 15, 2015;accepted May 26, 2015.

The author reports no conflict of interest.

Corresponding author: Raymond W. Redline,MD. raymondw.redline@UHhospitals.org

0002-9378/$36.00ª 2015 Elsevier Inc. All rights reserved.http://dx.doi.org/10.1016/j.ajog.2015.05.056

American Pathologists guidelines.3

Approximately 40-50% of all placentasdelivered in a high-risk setting will beexamined according to these criteria.4,5

Additional high-quality evidence isneeded to decide whether these guide-lines are optimal for patient care. Usefulinformation from a competently per-formed placental evaluation falls into thefollowing 4 categories: (1) identificationof previously unsuspected disease pro-cesses in themother or infant that requireimmediate attention (eg, fragmentationsuggestive of retained placenta orplacenta accreta, unusual infections suchas cytomegalovirus or listeria, and find-ings suggestive of aneuploidy or meta-bolic storage diseases); (2) conditionsassociated with a high probability ofrecurrence in subsequent pregnancies(Table 2); (3) information that can guidethe management of future pregnancies orinfluence the long-term care of motherand infant (Table 3); and (4) diagnosesthat provide a specific explanation for anadverse outcome such as fetal death, fetalgrowth restriction (FGR), spontaneouspreterm birth, or central nervous system(CNS) injury.

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These outcomes all have a widedifferential diagnosis that placental pa-thology can sort through for the purposesof quality assurance, risk management,andpatient education (Table 4). Althoughthese benefits are important, a morethorough understanding of placental ab-normalities could both expand and focusthe utility of placental examination.

BackgroundPlacental pathology in its earliest stagesfocused on macroscopic abnormalitiessuch as battledore placentas, succen-turiate lobes, and velamentous insertionsof the umbilical cord (UC). Althoughdistinctive, these conditions proved notto be closely related to adverse outcomes.A series of seminal studies publishedbetween 1970 and 1995 laid thegroundwork for our present under-standing of placental pathology. Pijnen-borg et al6 established the conceptualframework for disorders of placentalimplantation and their sequelae. Blanc7

first delineated the sequence ofplacental changes that characterize am-niotic fluid infection. Harris8 distin-guished marginal venous abruption

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TABLE 1Placental classification (incorporating the 2014 Amsterdam PlacentalWorkshop Group criteria)1. Placental vascular processes

a. Maternal stromal-vascular lesionsDevelopmental

Superficial implantation/decidual arteriopathyIncreased immature extravillous trophoblast

MalperfusionGlobal/partial

Early: distal villous hypoplasiaLate: accelerated villous maturation

Segmental/completeVillous infarct(s)

Loss of integrityAbruptio placenta (arterial)Marginal abruption (venous)

AcuteChronic

b. Fetal stromal-vascular lesionsDevelopmental

Villous capillary lesionsDelayed villous maturation (maturation defect)Dysmorphic villi

MalperfusionGlobal/partial

Obstructive lesions of umbilical cordRecent intramural fibrin in large fetoplacental vesselsSmall foci of avascular or karyorhectic villi

Segmental/completeChorionic plate or stem villous thrombiLarge foci of avascular or karyorhectic villi

Loss of integrityLarge vessel rupture (fetal hemorrhage)Small vessel rupture (fetomaternal hemorrhage)Villous edema

2. Placental inflammatory-immune processesa. Infectious inflammatory lesions

AcuteMaternal inflammatory response: chorioamnionitis, subchorionitisFetal inflammatory response: chorionic/umbilical vasculitis

ChronicVillitis (CMV, others)Intervillositis (malaria, others)

b. Immune/idiopathic inflammatory lesionsVillitis of unknown etiology and related/associated lesions

Chronic villitisChronic chorioamnionitisLymphoplasmacytic deciduitisEosinophil T-cell fetal vasculitis

Chronic histiocytic intervillositis3. Other placental processes

Massive perivillous fibrin(oid) deposition (maternal floor infarction)Abnormal placental shape or umbilical insertion siteMorbidly adherent placentas (accreta)Meconium-associated changesIncreased circulating nucleated red blood cells

CMV, cytomegalovirus.

Redline. Classification of placental lesions. Am J Obstet Gynecol 2015.

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from the much less common syndromeof arterial rupture and abruptio placenta.Benirschke and colleagues9,10 described

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how early marginal venous abruptionscould progress to the chronic abruption-oligohydramnios sequence and was the

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first to describe the important lesionknown as maternal floor infarction.Stallmach et al11 demonstrated the as-sociation between delayed villous matu-ration (maturation defect) and fetaldeath. Altshuler and Russell12 broughtidiopathic chronic villitis to attention,and Altshuler13 was the first to describevillous chorangiosis. Finally, Sander14

described the patterns that would latercome to be known as fetal thromboticvasculopathy (now segmental fetalvascular malperfusion).

A more systematic approach toplacental diagnosis was undertakenby thePerinatal Section of the Society of Pedi-atric Pathology beginning in 1998.15-17

Ensuing publications proposed and vali-dated the grading and staging of lesionsrelated to amniotic fluid infection and thematernal and fetal vascular disorders.Building on this work, a schematicframework for all placental lesions waspresented at the International Federationof Placenta Associations meeting in2006.18 These efforts provided the back-ground for a comprehensive system pro-posed by 26 placental pathologists fromaround the worldwhomet inAmsterdamin September 2014.1 The consensus rec-ommendations agreed upon during thismeeting and in subsequent online dis-cussions are incorporated into the nextsection and have been submitted forpublication.

A secondary goal of the meeting wasto establish sampling guidelines forplacental evaluation. Although not thefocus of this review, the following rec-ommendations were made: submit 4blocks as a minimum; one to include 2cross-sections of the UC and a roll of theextraplacental membranes includingpart of the marginal parenchyma; 3others containing full-thickness sectionsof normal-appearing placenta paren-chyma taken fromwithin the central twothirds of the disc including one adjacentto the UC insertion site.

The proposed new framework forplacental classification (Table 1) is dis-cussed in the following text.

Placental vascular processesThe placenta is essentially an interhemalmembrane mediating the exchange of

TABLE 2Placental lesions with significant recurrence risk in subsequentpregnanciesRare

Chronic histiocytic intervillositis (75e90%)53

Massive perivillous fibrin(oid) deposition (maternal floor infarction) (40e60%)64

More common

Villitis of unknown etiology (25e50%)46

Placenta accreta (25e30%)65

Severe global/partial maternal malperfusion (10e25%)66

Spontaneous preterm birth with histological chorioamnionitis (10e25%)67

Redline. Classification of placental lesions. Am J Obstet Gynecol 2015.

TABLE 3Management implications of current placental diagnoses: selectedexamplesSevere global/partial maternal vascular malperfusion

Evaluate maternal cardiovascular status, glucose tolerance, thrombophilia, and renalfunction; suggest weight loss; consider ASA therapy, uterine artery Doppler, early third-trimester placental ultrasound, early delivery in subsequent pregnancies

Spontaneous preterm delivery with histological chorioamnionitis

Extend neonatal antibiotics, treat underlying periodontal disease or chronic endometritis,early second-trimester cervical ultrasound, cerclage

Idiopathic/immune lesions (chronic villitis [VUE]), massive perivillous fibrin(oid) deposition([maternal floor infarction] chronic histiocytic intervillositis)

Genetic counseling; maternal autoimmune testing; weight loss; consider low-molecular-weight heparin, aspirin, and/or immunosuppressive therapy; intensive early pregnancysurveillance; elective early delivery

Complete/segmental fetal vascular malperfusion with neonatal sequelae

Maternal/neonatal thrombophilia workup, diabetes screen, maternal platelet evaluation

Delayed villous maturation

Diabetes screen, suggest weight loss, perform third-trimester fetal movement counts,consider delivery prior to 40 weeks

ASA, aspirin; VUE, villitis of unknown etiology.

Redline. Classification of placental lesions. Am J Obstet Gynecol 2015.

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nutrients and waste products betweenthe maternal and fetal circulations. It istherefore not surprising that abnormal-ities in the structure and function ofthese circulatory beds are dominantpatterns of placental injury.

Maternal stromal-vascular lesionsDevelopmental abnormalities of thematernal stromal-vascular compartmentof the placenta have recently beenreviewed and contribute to placentaldysfunction via malperfusion and lossof integrity (discussed below).19 Forthe purposes of this review, I will sayonly that developmental abnormalitiesall appear to involve defects in theappropriate differentiation and expan-sion of trophoblast, both extravillous(shallow implantation, lack of spiral ar-tery remodeling, increased trophoblastislands and cysts in the intervillous space)and villous (persistent cytotrophoblast).Although some of these defects may beintrinsic to the trophoblast, most evi-dence suggests that they are caused bypoorly understood maternal genetic orenvironmental factors that shape theearly intrauterine environment.

Maternal vascular malperfusion de-velops as a consequence of abnormalspiral artery flow and can be separatedinto 2 subgroups.16 The first, global/partial maternal vascular malperfusion,leads to accelerated villous maturation(Figure, A). Accelerated maturation isthe term agreed upon to encompass all ofthe histological changes seen in portionsof the villous tree deprived of the low-velocity, high-volume maternal bloodflow that characterizes normal placentas.

These findings include alternatingareas of agglutinated villi with increasedsyncytial knots and intervillous fibrinand villous paucity due to decreasedvillous branching. When paucity affectsmore than 30% of all distal villi, theprocess is termed distal villous hypo-plasia. The second pattern, segmental/complete maternal vascular malperfu-sion, is characterized by villous infarctswhich represent areas of ischemic ne-crosis overlying occluded spiral arteries.Whereas single infarcts, especially atthe placental margin, are not unusualin term placentas, any infarct in a

preterm placenta should be consideredabnormal.Loss of maternal vascular integrity

encompasses 2 distinct processes. Thefirst, abruptio placenta, frequently occurssecondary to arterial maldevelopmentin preeclampsia and represents the rup-ture of incompletely remodeled spiralarteries due to ischemia-reperfusionor atherosis. Vasoactive drugs (cocaineor nicotine) and shear stress (trauma or

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uterine rupture) can also cause arterialhemorrhages. Abruptio placenta ischaracterized by central location andplacental evidence of high pressure flow(large volume, indentaton of the basalplate, and extension into the intervillousspace). Although most cases lead toimmediate delivery, some arterial hem-orrhages evolve gradually, leading tooverlying recent villous infarction (sub-acute abruptio placenta).

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TABLE 4Common underlying placental causes of specific adverse outcomesPreterm fetal death

Global/partial maternal vascular malperfusion (accelerated maturation), global/partial fetalvascular malperfusion (UC accident), abruptio placenta

Spontaneous preterm birth

Acute chorioamnionitis, marginal abruption, mild global/partial maternal malperfusion(accelerated maturation)

Fetal growth restriction/indicated preterm birth

Global/partial maternal malperfusion (accelerated maturation), chronic villitis (VUE),complete/segmental fetal vascular malperfusion (fetal thrombotic vasculopathy), fetalstromal-vascular developmental lesions

Term fetal death

Abruptio placenta, global/partial fetal vascular malperfusion (UC accident), fetomaternalhemorrhage, delayed villous maturation

CNS injury at term

Complete/segmental fetal vascular malperfusion (fetal thrombotic vasculopathy), global/partial fetal vascular malperfusion (UC accident), chronic villitis (VUE) with obliterative fetalvasculopathy, acute chorioamnionitis with severe fetal cellular inflammatory response,multiple placental lesions

UC, umbilical cord; VUE, villitis of unknown etiology.

Redline. Classification of placental lesions. Am J Obstet Gynecol 2015.

Expert Reviews Obstetrics ajog.org

The second process, marginalabruption, represents the rupture ofmaternal veins, usually at the peripheryof the placenta.8 Risk factors includesudden changes in uterine geometry(rupture of membranes, cervical insuf-ficiency), poor support (lower uterinesegment implantation, abnormal mar-ginal anatomy), increased maternalvenous pressure, and decidual inflam-mation (chorioamnionitis).

Acute marginal abruption is animportant cause of spontaneous pretermbirth but only rarely causes fetal hypoxia.Chronic (marginal) abruption developswhen acute marginal abruption does notprogress to delivery. The hallmarks ofchronic abruption include circumvallatemembrane insertion, organizing mar-ginal blood clots, and hemosiderindeposition. Severe cases show diffusechorioamnionic hemosiderosis, reflect-ing hemorrhage into the amniotic fluid.20

Fetal stromal-vascular lesionsDevelopmental abnormalities of thefetal stromal-vascular compartment ofthe placenta can be separated into 3categories.

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Delayed villous maturation (alsoknown as distal villous immaturity ormaturation defect) is characterized by adecreased fetoplacental weight ratio,excessive villous stroma, and centralcapillaries lacking vasculosyncytialmembranes (Figure, B).21 This patternis seen with diabetes, some cases ofFGR, and chronic umbilical cordobstruction.22 Lack of placental reservein these placentas may increase the riskof fetal death.11

Villous capillary lesions includechorangiosis (hypercapillarization ofterminal villi), chorangioma (a benignplacental vascular tumor arising in stemvilli), and multifocal chorangiomatosis(a more pervasive developmental ab-normality involving small vessels at theperiphery of immature intermediatevilli).23,24 Although distinct, all share arelationship with maternal hypoxemiaand/or excessive fetal growth factorexpression. They sometimes occurtogether in conditions such as BeckwithWiedemann syndrome.25

Dysmorphic villi represent a morepervasive disorder encompassing ab-normalities in villous architecture that

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resemble features seen in aneuploidgestations. These include irregular con-tour, trophoblast inclusions, cysticdegeneration, stromal overgrowth,proximal-distal villous disproportion,and abnormal vascular patterning.26,27

Mesenchymal dysplasia is the most dra-matic example of this pattern.28 Somecases of dysmorphic villi may representexamples of confined placentalmosaicism.29

Fetal vascular malperfusion can beseparated into 2 subgroups.30 Global/partial, often associated with potentiallyobstructive umbilical cord lesions suchas hypercoiling, stricture, abnormalplacental insertion site, or long-standingfetal entanglements, is characterized byhistological features suggestive ofincreased venous pressure (dilatation ormural fibrin deposition in large fetopla-cental veins; Figure, C) and poor circu-lation in the most distal portions of thevillous tree (scattered small foci ofavascular villi; Figure, D). Its clinicalcorrelate, chronic partial/ intermittentumbilical cord obstruction, has beenassociated with CNS injury.31,32

The second pattern, segmental/com-plete occlusion of large fetoplacentalvessels by thrombi, leads to larger fociof degenerating downstream villi.33,34

These villi initially show degenerativechanges (stromal-vascular karyorrhexis)and eventually lose all vessels (avascularvilli) (Figure, E). When extensive, thispattern has been called fetal thromboticvasculopathy and has been associatedwith CNS injury and other adverseoutcomes.

Loss of fetal vascular integrity en-compasses 2 processes: hemorrhage andedema. Fetal hemorrhages can involvelarge vessels (eg, ruptured vasa previa)or smaller vessels in the distal villi(fetomaternal hemorrhage). The lattercan present as intervillous thrombi.35,36

Significant amounts of fetomaternalhemorrhage may be associated withincreased fetal nucleated red blood cells(NRBC) in the placenta and a positivematernal Kleihauer Betke test. Edemaof the placental villi accompanieshydrops fetalis, and placental pathologycan contribute to differential diagnosisby highlighting coexisting fetal anemia

FIGUREClinically significant placental lesions

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(increased NRBC) or identifying aspecific etiology (eg, parvovirusinclusions).

A second pattern of edema seen inthe immature intermediate villi of verypremature placentas has been associatedwith perinatal death, CNS injury,and long-term neurodevelopmentaldisability (Figure, F).37-39 A recent studysuggests that a third pattern, patchynonspecific edema of distal villi, iscorrelated with severe fetal acidemia interm infants.40

A, Accelerated villous maturation: clusters of

agglutinated distal villi with increased syncytial

knots and intervillous fibrin alternate with areas

of villous paucity (magnification, �10). B,

Delayed villous maturation: distal villi show

excessive stroma, central capillaries, and

decreased vasculosyncytial membranes

(magnification, �10). C, Global/partial fetal

vascular malperfusion (1): recent intramural

fibrin is seen below the endothelium in a large

fetoplacental vessel (magnification, �40). D,Global/partial fetal vascular malperfusion (2): a

small cluster of distal villi lacking fetal vessels

(avascular villi) is surrounded by normal villi

(magnification, �20). E, Complete/segmental

fetal vascular malperfusion: a large branching

tree of proximal and distal villi lacking fetal

vessels (avascular villi) is flanked by normal villi

(magnification, �10). F, Villous edema: prox-imal villi are expanded by excessive extracel-

lular fluid (magnification, �10). G, Acute

chorioamnionitis with severe fetal cellular in-

flammatory response: confluent neutrophils

with associated endothelial damage distort the

upper (amniotic fluid facing) wall of a large

chorionic plate vessel (magnification, �20).

H, Chronic villitis with obliterative fetal vas-

culopathy: proximal villus with stromal

lymphocytes, obliteration of fetal arteriolar

lumen, and a few surrounding avascular villi

(magnification, �40). I, Chronic histiocytic

intervillositis: monocyte-macrophages (histio-

cytes) fill the intervillous space surrounding

distal villi (magnification, �40). J, Massive

perivillous fibrin(oid) deposition (maternal floor

infarction): fibrin and fibrinoid extracellular

matrix fills the intervillous space surrounding

distal villi (magnification, �20).

Redline. Classification of placental lesions. Am J ObstetGynecol 2015.

<

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Placental inflammatory-immuneprocessesThe placenta resides at 2 important in-terfaces: with the outside environment(cervicovaginal canal) and betweenantigenically distinct organisms (motherand fetus). An incompletely resolvedtension exists between the need to pro-mote local immune responses to protectagainst exogenous microorganisms andto suppress them to prevent fetal rejec-tion. This results in increased suscepti-bility to infection, occasional breakdownin tolerance leading to immune medi-ated allograft-type responses, and helpsexplain why cellular inflammation isthe major nonvascular abnormalityobserved in the placenta.

Infectious inflammatory lesionsAcute cellular inflammatory responsesto ascending amniotic fluid infections bybacteria and fungi involve 2 separateimmune systems: (1) maternal, withneutrophils entering chorioamnion viadecidual venules in the membranes andthe chorionic plate from the intervillousspace (acute chorioamnionitis) and (2)fetal, with neutrophils entering thechorionic plate and Wharton’s jelly bymigrating through the walls of largechorionic and umbilical vessels (fetaland/or umbilical vasculitis).

The progression of each response isstereotypical and can also be graded forseverity.7,15 The maternal cellular in-flammatory response begins in the sub-chorionic fibrin and at membranouschoriodecidual interface (stage 1),spreads to the fibrous chorion andamnion (stage 2), and eventually leads tonecrosis of the amnionic epithelium(stage 3). The Amsterdam criteriarecognize only stages 2e3 to representa fully developed histological cho-rioamnionitis, with stage 1 being a sen-sitive but less specific early indicator ofevolving amniotic fluid infection.

Fetal cellular inflammation is firstobserved in the chorionic vessels andumbilical vein (stage 1), progresses toinvolve umbilical arteries (stage 2), andfinally enters the umbilical cord stroma(stage 3). Fetal morbidity with cho-rioamnionitis is more commonly relatedto elevated circulating cytokines than

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fetal infection, and arteritis (fetal stage 2)is associated with higher levels ofcytokines than phlebitis alone.41,42

Confluent inflammation (fetal grade 2)and the presence of thrombi in acutelyinflamed chorionic vessels are otherimportant adverse prognostic features(Figure, G).38,43

Chronic cellular inflammatory re-sponses to hematogenous infection byviruses and protozoa are usuallyconfined to the villous stroma andintervillous space.12 Common TORCH(toxoplasmosis, other [hepatitis B],rubella [German measles], cytomegalo-virus, and herpes simplex virus)-typeorganisms such as cytomegaloviruscause a diffuse villitis with edema,fibrosis, and plasma cells. Less commoninfections, such as malaria, are associ-ated with inflammation that surroundsbut does not involve the villi (chronicintervillositis).44 A few infections such aslisteriosis can cause all 3 patterns, cho-rioamnionitis, villitis, and intervillositis,in the same placenta.45 Unlike ascendinginfection, morbidity and mortality withhematogenous infection ismore stronglycorrelated with fetal infection thanelevated cytokines or the extent ofplacental damage.

Immune/idiopathic inflammatorylesionsVillitis of unknown etiology (VUE) is aT-cellemediated disorder targeting thedistal villous tree and characterized bychronic cellular inflammation of villousstroma (villitis) and, in some cases, theintervillous space (intervillositis andperivillous fibrin deposition) and stemvillous vessels (obliterative fetal vascul-opathy) (Figure, G).Based on numerous studies over a 20

year period, VUE is now thought to be amaternal graft vs hostetype response tofetal antigens in the placenta.46,47 High-grade VUE (extensive or associatedwith obliterative fetal vasculopathy) hasbeen associated with FGR, CNS injury,and fetal death. Additional importantaspects of VUE include its high preva-lence (approximately 5-10% of termplacentas), increased incidence andseverity in obese patients, and significantrecurrence risk (25-50%).48-50

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Other chronic inflammatory pro-cesses that are more common in thepresence of VUE include chronic cho-rioamnionitis, lymphoplasmacytic deci-duitis, and eosinophilic T-cell fetalvasculitis.51,52 All can also occur inde-pendently. It has been suggested thatchronic chorioamnionitis may be anunderappreciated cause of spontaneouspreterm birth.

Chronic histiocytic intervillositis is arare idiopathic inflammatory lesiondistinct from VUE and associated le-sions.53 It is characterized by a mono-morphic maternal histiocytic infiltrate inthe intervillous space without accom-panying VUE (Figure, G). Occasionallythis disorder overlaps with maternalfloor infarction (described in thefollowing text). Like maternal floorinfarction, chronic histiocytic inter-villositis is strongly associated withmiscarriage, FGR, indicated pretermbirth, and early intrauterine fetal demise.It has the highest recurrence rate of anyplacental lesion, sometimes affecting 10or more consecutive pregnancies.Limited evidence suggests that affectedpatients may respond to aspirin, hepa-rin, or immunosuppressive therapies.54

Other pathological processesPlacental lesions that do not fitcomfortably into either the vascular orinflammatory categories include abnor-malities of placental shape, morbidlyadherent placentas (accreta), increasedcirculating NRBC, and the effects ofprolonged meconium exposure.55-57

Because of limited space, these will notbe discussed further in this review.

One additional lesion of uncertainpathogenesis deserves comment becauseof its frequent underdiagnosis, strongassociation with adverse outcomes, andhigh recurrence rate: massive perivillousfibrin(oid) deposition, commonlyknown as maternal floor infarction,characterized by large amounts of fibrinand fibrinoid matrix surrounding a sig-nificant proportion of the distal villoustree (at least 30%) (Figure, H). Thisprocess can present at any gestational ageand is strongly associated with recurrentmiscarriage, severe FGR, early fetaldeath, spontaneous and indicated

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preterm birth, and CNS injury.58,59 Itspathogenesis remains obscure, butanecdotal evidence suggests that it mayrepresent a reaction to diffuse tropho-blast damage secondary to a variety ofstressors including autoimmune dis-ease, maternal thrombophilia, gesta-tional hypertension, fetal long-chain3-hydroxyacyl-CoA dehydrogenase mu-tations, and Coxsackie virus A16 infec-tion.60-63 A pathology report with thisdiagnosis should never be ignored.

Future directionsA simple, comprehensive, and widelyaccepted classification system is a pre-requisite for the definition of robust andreproducible placental phenotypes.Defining the clinical relevance of eachphenotype still requires additional studyto more precisely establish the relativeimportance of severity (grade), duration(stage), extent of involvement, anddifferent combinations of placental le-sions. Once clinical context and signifi-cance are better understood, it should bepossible to refine submission guidelinesand decrease the number of unhelpfulplacental examinations, thereby re-ducing costs to the health care system.

The establishment of robust pheno-types is also critical for the interpretationof new genetic and epigenetic data,delineation of mechanistic pathways,and understanding the effects of exoge-nous environmental exposures onplacental function. The goals of therecently initiated Human Placenta Proj-ect, to develop new biomarkers andimaging techniques allowing prospectivediagnosis and the development of noveltargeted therapies, are unlikely to berealized if pathological phenotype anddata from the various “omics” technol-ogies are not considered together.

Even in a hypothetical future sce-nario in which these exciting newdiagnostic and therapeutic modalitiesare realized, placental pathology willlikely continue to play an importantrole, serving as a gold standard fordiagnosis, quality assessment, diag-nostic test evaluation, and comparativeeffectiveness trials, and guiding themanagement of individual patients to

prevent adverse outcomes in subse-quent pregnancies. -

ACKNOWLEDGMENTS

I thank Kurt Benirschke and Shirley Driscoll forencouraging a life-long interest in placentalbiology.

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