placental pathology in neonatal stroke jorina elbers ...manuelosses.cl/bnn/full_patologia...

DOI: 10.1542/peds.2010-1490 2011;127;e722-e729; originally published online Feb 21, 2011; Pediatrics

Moore Jorina Elbers, Sandra Viero, Daune MacGregor, Gabrielle deVeber and Aideen M.

Placental Pathology in Neonatal Stroke

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WHAT’S KNOWN ON THIS SUBJECT: Neonatal stroke isrecognized as a cause of infant morbidity andneurodevelopmental disability. The placenta has become anorgan of interest as a contributor to cerebral palsy andneurologic disability; however, placental pathology has not beensystematically described in stroke.

WHAT THIS STUDY ADDS: This study reviews placental pathologyin patients presenting with neonatal stroke near delivery andcorrelates this with clinical presentation, outcome, and riskfactors. We suggest that multiple risk factors are involved inneonatal stroke, and placental pathology may be a contributor.

abstractOBJECTIVE: Neonatal stroke is increasingly recognized, and risk fac-tors have been identified. The placenta has been implicated as a poten-tial contributor to neonatal stroke; however, pathology has not beenpreviously described. This case series systematically evaluates prena-tal, maternal, and neonatal risk factors and describes placental pathol-ogy in 12 cases of neonatal stroke.

PATIENTS AND METHODS: We reviewed the Canadian Pediatric IschemicStroke Registry from 1992 to 2006, which consists of 186 neonatal strokepatients. Twelve patients with symptomatic cerebral arterial ischemicstroke or sinovenous thrombosis had their placenta available for patho-logic examination. Clinical presentation; maternal, prenatal, and neonatalrisk factors for stroke; andpatient outcomewere collected retrospectivelyfrom patient charts. Gross and microscopic placental pathology was de-scribed and classified into 4 pathologic categories.

RESULTS: Of 12 patients studied, 10 patients were male, 5 patients hadarterial ischemic stroke, and 7 patients had sinovenous thrombosis.Maternal risk factorswere identified in 5 cases, prenatal risk factors in10 cases, and neonatal risk factors in 10 cases. Placental lesions werepresent in 10 cases and were classified as thromboinflammatory pro-cess in 6 cases, sudden catastrophic event in 5 cases, decreased pla-cental reserve in 3 cases, and stressful intrauterine environment in 2cases.

CONCLUSIONS: This study reviews detailed placental pathology in aselected cohort of patients presenting near the time of delivery andcorrelates this with clinical presentation, outcome, and risk factors forneonatal stroke. Our results suggest that multiple risk factors areinvolved in neonatal stroke, and placental pathology may be a contrib-uting factor. The implications of specific placental lesions remain to bedetermined with larger, case-controlled studies. Pediatrics 2011;127:e722–e729

AUTHORS: Jorina Elbers, MD,a Sandra Viero, MD,b

Daune MacGregor, MD,a Gabrielle deVeber, MD, MSc,a andAideen M. Moore, MD, MHScc

aDivision of Neurology, bDepartment of Pediatric LaboratoryMedicine, and cDivision of Neonatology, Department ofPediatrics, Hospital for Sick Children, University of Toronto,Toronto, Ontario, Canada

KEY WORDSneonatal, stroke, placenta, neonatal morbidity, pathogenesis

ABBREVIATIONSAIS—arterial ischemic strokeCSVT—cerebrosinovenous thrombosis

www.pediatrics.org/cgi/doi/10.1542/peds.2010-1490

doi:10.1542/peds.2010-1490

Accepted for publication Nov 22, 2010

Address correspondence to Aideen M Moore, MD, MHSc, Divisionof Neonatology, Department of Pediatrics, Hospital for SickChildren, 555 University Avenue, Toronto, Ontario, M5G 1X8,Canada. E-mail: [email protected]

PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275).

Copyright © 2011 by the American Academy of Pediatrics

FINANCIAL DISCLOSURE: The authors have indicated that theyhave no personal financial relationships relevant to this articleto disclose.

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Neonatal stroke is increasingly recog-nized as a significant cause of infantmorbidity and neurodevelopmentaldisability. With an estimated incidenceof 1 in 2300 live births,1,2 the perinatalperiod confers the highest risk forischemic stroke in patients under 18years of age.3 With increased recogni-tion, risk factors for neonatal strokerecently have been identified. Theserisk factors includematernal conditionssuch as prothrombotic disorders, infer-tility, andpreeclampsia; prenatal factorssuch as fetal heart rate abnormalities,intrauterine growth restriction, chorio-amnionitis, and prolonged rupture ofmembranes; and neonatal factors in-cluding infection, prothrombotic states,and congenital heart disease.4–18 Stud-ies suggest that multiple risk fac-tors may be implicated in neonatalstroke.9,15,19,20

The placenta recently has become anorgan of interest in the search forcauses of cerebral palsy and otherneurologic disabilities. The placentaprovides the sole blood supply for thefetus via an elaborate network of bloodvessels within chorionic villi that pen-etrate the maternal endometrium.These chorionic villi are bathed in ma-ternal blood through surrounding si-nusoidal spaces. The role of the pla-centa in neonatal brain injury hasbeen discussed by Redline andO’Riordan21–23 who described typicalpatterns of placental lesions found inchildren with cerebral palsy.21 Onestudy describing placental lesions in agroup of term infants with adverseneurologic outcomes from amedicole-gal registry showed a significantlyhigher prevalence of chronic villousdegenerative changes, chorioamnioni-tis with severe fetal inflammatory re-sponse, and pathologic umbilical cordabnormalities in case subjects com-pared with healthy control subjects.Overall, 66% of the medicolegal regis-try cases had 1 ormore significant pla-

cental lesions compared with 18% inthe comparison group.24,25 In anotherlarge case-controlled study of patientspresenting with neonatal encephalop-athy, placental lesions of infection,thrombosis, and disturbed uteropla-cental flow were significant indepen-dent factors in the neonatal encepha-lopathy group.26

Neonatal stroke is a recognized causeof hemiplegic cerebral palsy. In con-trast to more diffuse perinatal braininsults underlying cerebral palsy,stroke is attributed to large-vessel ob-struction and is typically a focal injurywithin an otherwise intact brain. Manyauthors12,27–29 have suggested the pla-centa as an additional risk factor forneonatal stroke. Although some stud-ies7,30,31 investigating the incidence ofthrombi in the neonate have estab-lished pathologic findings in the pla-centa, no study has systematically an-alyzed the placenta in neonates withstroke. This study aimed to describeplacental pathology in neonates diag-nosed with either arterial ischemicstroke (AIS) or cerebral sinovenousthrombosis (CSVT). In addition, previ-ously described risk factors for neona-tal stroke were identified to provide aperspective on other factors that maybe implicated in, or contribute to, thepathophysiology of neonatal stroke.

PATIENTS AND METHODS

Case Ascertainment

Patients were identified in the Ca-nadian Pediatric Ischemic StrokeRegistry–Toronto site, part of a pro-spective database containing informa-tion on pediatric stroke patientsacross the country. All patients fromthe Toronto site diagnosed from Janu-ary 1992 to December 2006 were re-viewed, and those with a diagnosis ofneonatal stroke (defined as stroke di-agnosed within the first 28 days oflife) and born term (�37 weeks’ ges-tational age) or late preterm (34–37

weeks’ gestational age) were in-cluded if their placenta was availablefor review. Regional birthing centerstypically only retain placentas at thetime of delivery for newborns withperinatal complications.

Patient Characteristics

Patient records were retrospectivelyreviewed to collect patient character-istics, mode of diagnosis, and distri-bution of cerebral infarcts accordingto vascular territory(ies). Recognizedmaternal, prenatal, and postnatal riskfactors for perinatal stroke4–18 wereidentified. Neuroimaging was com-pleted according to clinical diagnosticstandards. Computed tomographywascompleted acutely in the majority ofcases, with magnetic resonance imag-ing when available. Magnetic reso-nance imaging sequences included T1,T2, fluid-attenuated inversion recov-ery, diffusion weighted, apparent diffu-sion coefficient, and gadolinium.

Placental Analysis

Placentas were reviewed by a singleobserver, a perinatal anatomic pathol-ogist (Dr Sandra Viero), according to astandardized technique. Gross exami-nation was performed after fixationin 10% formalin. Cord abnormalitieswere described, and 2 sections ofcord, 1 including the placental inser-tion site, were sampled. An extrapla-cental membrane roll including de-cidua was sampled. The trimmed diskweight was recorded. The placentaldisk was sectioned at 1-cm intervalswith at least 2 random sections sam-pled and any lesions sampled. Sec-tions were submitted for routine pro-cessing, paraffin embedding, andstaining with hematoxylin and eosin.

Gross and histologic characteristicswere noted and additionally classifiedaccording to subcategories estab-lished by Redline.21 Placental lesionswere pathologically categorized as (1)

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a sudden catastrophic event, (2) athrombo-inflammatory process, (3) adecreased placental reserve, or (4) anadaptive response to stressful intra-uterine environment. The placental le-sions observed in patients catego-rized under “sudden catastrophicevent” include retroplacental hema-toma and acute umbilical cord occlu-sion, such as by thrombosis, truecord knots, cord overcoiling, or ab-normal cord insertion sites. For thethromboinflammatory processes,placental lesions included acute cho-rioamnionitis, chronic villitis, chori-onic vessel thrombi, stem vesselthrombi, and the presence of avascu-lar fibrotic villi. Decreased placentalreserve was defined by 2 or more ofthe following: multiple placental in-farcts; distal villous immaturity; andplacental weight less than the 10thpercentile for gestational age.32 Thefinal category, indicating adaptiveresponses as a result of a stressfulintrauterine environment, requiredincreased fetal nucleated red bloodcells or an increase in the number offetal capillaries per villous cross-section, termed villous chorangiosis.

Patient Outcome

Patient outcomes at 2 years were col-lected. Outcomes were categorized asnormal, mild motor dysfunction (finemotor problems, mild developmentaldelay), significant motor dysfunction(hemiparesis), language delay, andpresence of seizure disorder.

RESULTS

Patient Characteristics

The Stroke Registry consisted of 186patients with neonatal stroke at theHospital for Sick Children between1992 and 2006. Of those patients, 12had placentas available for pathologicexamination by our pathologist. Of the12 patients studied, 10 were male and5 were diagnosed with AIS and 7 with

CSVT. All were singleton births, with 11infants born at term (�38 weeks) and1 late preterm infant born at 34 weeks’gestation. Birth weights ranged from1.6 kg to 4.17 kg, with a median of 3.41kg. One-minute Apgar scores rangedfrom 1 to 10, with a median of 4.5, and5-minute Apgar scores ranged from 2to 10, with a median of 6.

Clinical Data

Ten patients (83%) presented on thefirst day of life with signs of neonatalencephalopathy. Other presentingsigns can be found in Table 1. Therewas no difference in clinical presenta-tion between the patients with AIS ver-sus CSVT. No patients with AIS weretreated with antithrombotic therapy,whereas 3 patients with CSVT receivedantithrombotic therapy.

Risk factors for neonatal stroke areshown in Table 2. Maternal risk factorswere identified in 5 of 12 cases (42%).No patients had preeclampsia or dia-betes; maternal thrombophilias werenot routinely tested. Prenatal risk fac-tors for neonatal stroke were identi-fied in 10 of 12 cases (83%). Neonatalrisk factors for neonatal stroke werepresent in 10 of 12 cases (83%). Fourpatients had congenital heart diseasewith a right-to-left shunt, 1 was postop-erative day 1 from a cardiac procedureat the time of presentation. Follow-upon coagulation profiles of our study pa-tients did not reveal any significantprothrombotic disorders.

Neuroimaging

The diagnosis of AIS wasmade within amedian of 4 days (range: 1–5 days) andCSVT within a median of 2 days (range:from 1–8 days), according to neuroim-aging findings. Ischemic changes wereconsistent with an arterial or venousdistribution, rather than diffuse hy-poxic injury often seen in hypoxic isch-emic encephalopathy. The distributionof infarction in patients with AIS was

multifocal, involving middle, anterior,and posterior cerebral artery territo-ries in 4 patients (80%) and a singlelesion in the left-middle cerebral ar-tery territory in 1 patient. Magneticresonance angiography was com-pleted acutely (within 3 days of life) in2 patients, both of which were normal.Two patients developed hemorrhagewithin the area of infarcts (40%).

Of 7 patients with CSVT, thrombus wasseen in the transverse sinuses in 5 pa-tients, superior sagittal sinus in 3 pa-tients, torcula in 3 patients, internaljugular vein in 1 patient, and internalvenous system in 1 patient. Six of 7 pa-tients developed parenchymal hemor-rhage (86%).

Placental Analysis

Placental pathology was evident in 10of 12 patients (83%), whereas 2 pla-centas were within normal limits (Ta-ble 3). Placental weights ranged from204 to 808 g, with a median of 487.5 g.Histopathology showed sudden cata-strophic event in 5 patients (42%),thromboinflammatory process in 6 pa-tients (50%), decreased placental re-serve in 3 patients (25%), and stressfulintrauterine environment in 2 patients(15%). Mixed placental lesions werefound in 5 patients (42%). Two patientshad histologic evidence of acute cho-rioamnionitis (Fig 1), 1 had histologicevidence of moderate chorioamnioni-tis, and the other had evidence of se-vere chorioamnionitis, displaying afetal inflammatory response (funisi-tis), and 5 patients had placental fe-tal vessel (Fig 2) or umbilical cordthrombi. Four patients had placentalinfarcts.

Patient Outcome

Of 12 patients in our study, 2 were lostto follow-up. At the 2-year follow-up, 2patients (both with CSVT) were neuro-logically normal, 6 patients (4 had AISand 2 had CSVT) had mild motor dys-



function, and 5 patients (4 had CSVTand 1 had AIS) had language delay. Nopatients had severe hemiparesis orother significant motor dysfunction,and none had a seizure disorder.

DISCUSSION

This is the first study to systematicallyanalyze placental pathology in additionto identifying other potential risk fac-

tors in a cohort of patients with symp-tomatic neonatal AIS and CSVT. Placen-tal lesions identified in 10 of 12 (83%)of our patients with neonatal strokedemonstrate multiple pathologies, in-

TABLE 1 Clinical Features of Neonates With AIS and CSVT

Patient Apgar Score,1 Min, 5 Min

(Age) Clinical presentation Diagnosis (Age) Imaging Modality: Findings(Vascular Territory)

Outcome At 2-YearFollow-Up

1 2, 3 (Days of life: 1) hypotensive, decreasedspontaneous movements

AIS (Days of life: 4) MRI: multifocal, bilateral infarcts withdiffusion restriction (MCA, PCA; no MRA or MRV)

Mild motor dysfunction

2 5, 7 (Days of life: 1) focal seizures, apnea,neonatal encephalopathy

AIS (Days of life: 5) CT: single infarct (left MCA); (Days oflife: 6) MRI: multifocal, unilateral infarcts withrestricted diffusion (left MCA and left ACA); (Daysof life: 6) MRA or MRV: normal

Lost to follow-up

3 4, 6 (Days of life: 1) focal seizures; apnea;decreased movements, right side,neonatal encephalopathy

AIS (Days of life: 1) CT: single infarct (left MCA); (Days oflife: 15) MRI: single infarct without diffusionrestriction (left MCA); (Days of life: 15) MRA: smallleft MCA branches


4 6, 6 (Days of life: 1) focal seizures;hypotension; decreased movements,right side; neonatal encephalopathy

AIS (Days of life: 5) CT: multifocal bilateral infarcts (leftMCA, right MCA, left ACA) Petechial hemorrhagewithin infarcts; (mo of life: 13) MRI: multifocalbilateral infarcts without diffusion restriction(left MCA, right MCA, left ACA); (mo of life:13)MRA: attenuated (left MCA)


5 6, 9 (Days of life: 1) focal seizures, apnea,neonatal encephalopathy

AIS (Days of life: 2) CT: left subdural hemorrhage plussingle infarct (left MCA); (Days of life: 3) MRI:multifocal, bilateral infarcts with restricteddiffusion (left MCA, right PCA); petechialhemorrhage within infarcts; (Days of life: 3)MRA: normal

Mild motor dysfunction,language delay

6 1, 4 (Days of life: 1) focal seizures, apnea,hypotension, neonatalencephalopathy

CSVT (Days of life: 1) CT: diffuse edema; (Days of life: 3)MRI: thrombosis in superior sagittal sinus, torcula,bilateral transverse sinuses, no diffusionrestriction, punctate hemorrhages bilateral basalganglia

Language delay

7 2, 6 (Days of life: 1) hypotension, neonatalencephalopathy

CSVT (Days of life: 4) MRI: thrombosis in left transversesinus, left sigmoid, and left internal jugular vein,restricted diffusion bilateral internal capsule,punctate hemorrhages bilateral basal ganglia

Normal

8 2, 2 (Days of life: 1) hypotension, neonatalencephalopathy

CSVT (Days of life: 6) MRI: right transverse sinus withmultifocal areas of diffusion restriction,subcortical petechial hemorrhage; (Days oflife: 6) CT: thrombosis in bilateral transversesinuses, torcula

Lost to follow-up

9 8, 9 (Days of life: 1) focal seizures, apnea CSVT (Days of life: 1) CT: Superior sagittal sinusthrombosis plus hydrocephalus; (Days of life: 2)MRI: thrombosis in superior sagittal sinus


10 7, 9 (Days of life: 2) focal seizures, apnea CSVT (Days of life: 8) CTV: thrombosis in right transversesinus; (Days of life: 20) MRI: remote left parietalhemorrhagic venous infarct

Language delay

11 10, 10 (Days of life: 6) focal seizures CSVT (Days of life: 7) CTV: Thrombi in vein of Galen andinternal cerebral veins bilateral frontal lobehemorrhage; (Days of life: 8) MRI: thrombi in veinof Galen, internal cerebral veins, torcula, andinferior sagittal sinus

Normal

12 3, 4 (Days of life: 1) focal seizures,decreased spontaneous movement,neonatal encephalopathy

CSVT (Days of life: 2) CT: diffuse cerebral edema, thrombusin superior sagittal sinus, hemorrhage rightcentrum semiovale; (Days of life: 3) MRI/MRV:thrombus in torcula and left transverse sinus,multifocal, bilateral areas of diffusion restriction


MRI indicates magnetic resonance imaging; MCA, middle cerebral artery; PCA, posterior cerebral artery; MRA,magnetic resonance angiography; MRV, magnetic resonance venography; CT,computerized tomography; ACA, anterior cerebral artery.

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cluding decreased placental reserve,thromboinflammatory processes, andsudden catastrophic events. Each ofthese lesion types may contribute toneonatal stroke by either sending em-boli directly into the fetal circulation orby causing an inflammatory, proco-agulant environment in the placentaand fetus promoting diffuse thrombusformation.

The majority of our patients also hadprenatal and neonatal risk factors forneonatal stroke, and it was difficult todetermine a predominant cause. Ourfindings suggest that both AIS andCSVT in the newborn are multifacto-rial, with a combination of predispos-ing and triggering factors. This is con-sistent with previous studies.9,15,19,20 In1 case-control study,9 the presence of 3or more risk factors was associatedwith a 25-fold-increased risk of perina-tal stroke compared with those with-out risk factors.

In our study, 6 patients (50%) presentedwith placental lesions consistent witha thromboinflammatory process. Fetalthrombotic vasculopathy is a term pro-posed by Redline21 to describe ischemicchanges in the fetal capillarybedof largeportions of terminal villi, reflecting pro-longed occlusion of supplying fetal pla-cental vessels. Histologically, it is definedby clusters containing at least 5 avascu-lar villi (Fig 3) and thrombi in stem ves-sels or othermajor placental vessels.23

Fetal thrombotic vasculopathy hasbeen associated with thromboemboliin various organs in the newborn.30,31

In a study of 84 perinatal autopsies, 6of 1 6 patients with fetal thromboticvasculopathy were found to have so-matic visceral thrombi, and cerebralinfarcts were present in 3 patients.30 Of6 patients with a thromboinflamma-tory process in our study group, 2 ful-filled the histologic criteria for fetalthrombotic vasculopathy, 2 had histo-logic evidence of acute chorioamnioni-tis, 4 had chorionic vessel thrombosis,TA

BLE2RiskFactorsIdentifiedinNeonatesWithAISandCSVT

PatientGenderGestational

Age

PlacentalWeight

MaternalRiskFactors

PrenatalRiskFactors

NeonatalRiskFactors

PlacentalRiskFactors

Diagnosis

1Male

40�3wk204g(�10percentile)

None

IUGR,nuchalcord,oligohydramnios

Polycythemia,congenitalheart

disease

Decreasedplacentalreserve

AIS

2Male

38wk

475g(50thpercentile)

None

IUGR,ERC/S

Anemia,congenitalheartdiseaseThromboinflammatoryprocess

AIS

3Male

39wk


Primiparity,GBS

positive(treated)

FHRabnormalities,ERC/S,

feto-maternalhemorrhage

Anemia

Thromboinflammatoryprocess,

stressfulintrauterineenvironment

AIS

4Male

36wk


Primiparity

FHRabnormalities,ERC/S

Anemia,systemicthromboses,

congenitalheartdisease,

Anemia

Suddencatastrophicevent

AIS

5Male

39wk

345g(�10thpercentile)Historyofinfertility

Placentalabruption,ERC/S

Disseminatedintravascular

coagulation

Suddencatastrophicevent,

thromboinflammatoryprocess,

decreasedplacentalreserve

AIS

6Male

38wk


Primiparity,GBS

positive(treated)

Prolongedrupture

ofmembranes

Sepsis,disseminated

intravascularcoagulation

Thromboinflammatoryprocess,

stressfulintrauterineenvironment

CSVT

7Male

37�5wk808g(�90thpercentile)Antepartum

hemorrhage

FHRabnormalities,ERC/S,

chorioamnionitis,ERC/S

Sepsis,anemia

Suddencatastrophicevent,

thromboinflammatoryprocess

CSVT

8Female37

�6wk452g(25thpercentile)

Historyoftrauma

Ruptureduterus,placental

abruption

Anemia,disseminated

intravascularcoagulation

Withinnormallimits

CSVT

9Female34wk

525g(�90thpercentile)None

Prolongedsecond-stagelabor,


None


CSVT

10Male

39�2wk500g(50thpercentile)

None

None

Congenitalheartdisease,

postcardiacsurgery


CSVT

11Male

39wk


None

None

Polycythemia

Withinnormallimits

CSVT

12Male

40�2wk320g(�10thpercentile)None


None

Decreasedplacentalreserve,

thromboinflammatoryprocess

CSVT

IUGRindicatesintrauterinegrowthrestriction;ERC/S,emergencycaesariansection;FHR,fetalheartrate.



3 had stem vessel thrombosis, and 1had umbilical vein thrombosis. Suchthrombi may ultimately travel into fe-tal circulation via the umbilical veinand into large cerebral blood vessels

across the foramen ovale or ductus ar-teriosus, causing embolic cerebral ar-terial infarction.

Placental pathology suggesting de-creased placental reserve was present

in 3of 12patients. Placental insufficiencyand infection can promote cytokine pro-duction,whichmayultimately contributeto neonatal stroke. Cytokines are low–molecular weight signaling molecules.Placental trophoblasts and maternallyderived leukocytes release proinflam-matory cytokines at the placental-decidua interface, such as interleukin-6,interleukin-8, and tumor necrosisfactor-�, in response to infection, vas-cular compromise, and oxidativestress.34–36 In rodents, decidual cyto-kines traverse the placental mem-branes and enter the fetal circulation,potentially affecting the developing fe-tus.37,38 In cases of clinical chorioam-nionitis, cytokine concentrations incord blood have been associated withabnormal neurologic examination andseizures.39 In vitro studies simulatinghypoxia and growth restriction releaseexcess tumore necrosis factor-�,which induces placental apoptosis. Asa result, there is a disproportionatedeposition of fibrin within the placen-tal villus.40 Excess placental fibrin hasthe potential for thrombogenesis byconverting endothelium from a throm-boresistant to a thrombogenic sur-face, activating the coagulation cas-cade. Although the role of cytokines inneonatal brain injury remains unclear,they may play an important role in aninflammatory and coagulopathic re-sponse within placental and fetalcirculation.

Nearly half the patients in our cohorthad clinical and histologic features ofa sudden catastrophic event, such asretroplacental hematoma or umbilicalvessel occlusion. In addition, umbilicalcord entanglements (cord overcoilingor abnormal insertion sites) were in-cluded in this group because they havebeen previously associated with cere-bral palsy.21 Such lesions may lead toblood stasis and thrombus formationwithin umbilical vessels, allowing em-boli access to fetal circulation. One

TABLE 3 Placental Pathology and Associated Lesional Category21

Patient Placental Lesion Category Placental Pathology

1 Decreased placental reserve Chronic villitis, distal villous immaturity, placental infarct,placental weight�3rd percentile

2 Thromboinflammatory process Chronic villitis, chronic intervillositis, villous edema,positive immunostaining for CD68� cells

3 Thromboinflammatory process,stressful intrauterine environment

Chorinonic thrombosis, avascular fibrotic villi, increasednucleated red blood cells

4 Sudden catastrophic event Cord overcoiling, distal villous immaturity5 Sudden catastrophic event,

thromboinflammatory process,decreased placental reserve

Velamentous cord insertion, cord venous congestion,chronic villitis, chronic intervillositis, placentalinfarction, distal villous immaturity, placental weight�10th percentile

6 Thromboinflammatory process,stressful intrauterine environment

Funisitis (severe, diffuse), cord thrombosis (acute), cordvenous congestion, severe chorioamnionitis, chorionicthrombosis, stem villous thrombosis, distal villousimmaturity, villous chorangiosis

7 Sudden catastrophic event,thromboinflammatory process

Retroplacental hematoma, cord hemangioma, moderatechorioamnionitis, avascular fibrotic villi, distal villousimmaturity

8 Placenta within normal limits Villous edema9 Sudden catastrophic event Marginal cord insertion, stem villous thrombosis (acute),

chorionic thrombosis (acute)10 Sudden catastrophic event True cord knot and stricture, acute chorionic thrombosis,

cord thrombosis (acute) retromembranous hematoma11 Placenta within normal limits Chorionic congestion, stem villous congestion, chronic

villitis, placental infarct12 Thromboinflammatory process,

decreased placental reserveCord stricture, stem villous thrombosis (old and acute),chorionic thrombosis (old), placental infarct, distalvillous immaturity, placental weight�10th percentile

FIGURE 1Hematoxylin and eosin stain of placental membranes demonstrating inflammatory cells within fetalmembranes, consistent with acute chorioamnionitis (magnification�200).

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case report describes an acute umbil-ical artery occlusion resulting in aorticembolus in the fetus, in addition tomultiple placental thrombi.41 Two pa-tients in our study showed evidence of

acute superimposed on chronic pla-cental lesions. In these cases, acuteabruption may be a consequence ofunderlying structural lesions in theplacenta resulting in an inability to

compensate for acute vascular injury.Previous studies22,25,42 also have shownthat multiple placental lesions furtherincrease the risk of later neurologicdisability.

Limitations of this study include thelack of data on maternal thrombo-philias and the absence of healthynewborn control subjects for compar-ison. Furthermore, our sample size issmall and biased toward patients witha history of distress in labor or presen-tation within the first 24 hours of life,before disposal of the placenta. It ischallenging to obtain placentas becausemost children with neonatal stroke willpresent clinically with seizures after 12hours of life,43 at which point the pla-centa already may be discarded. Largerbirthing centers may consider retainingplacentas for 48 to 72 hours to allowfor placental examination in neonatespresenting with neurologic symptomswithin the first few days of life.

CONCLUSIONS

We completed a detailed review ofplacental pathology and recognizedrisk factors for a series of selectedpatients with symptomatic neonatalstroke and suggestedmechanisms un-derlying this disorder. The placentamay play an important role in throm-bus formation and cytokine release,contributing to other risk factors forneonatal stroke. Although this is an im-portant first look at the placenta in thispopulation, a larger, prospective studycomparing placentas from healthynewborns to those of distressed new-borns is necessary to further establishthe placenta as a causative factor inneonatal stroke.

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FIGURE 3Hematoxylin and eosin stain of placental membranes, demonstrating avascular fibrotic chorionic villi,seen in patients with fetal thrombotic vasculopathy (magnification�40).



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DOI: 10.1542/peds.2010-1490 2011;127;e722-e729; originally published online Feb 21, 2011; Pediatrics

Moore Jorina Elbers, Sandra Viero, Daune MacGregor, Gabrielle deVeber and Aideen M.


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