Andersons pediatric cardiology 264

impact.Insituationswheretheinnercellmassoftheblastocystisimperfectly
alignedatimplantation,asmallerregionofsyncytiotrophoblastinvasiontakes
place,resultinginasmallerplacentaandadegreeoffetalgrowthrestriction.5
Smallerplacentasarealsoseenwhentheumbilicalcordinsertsatthemarginor
intofetalmembranesinsteadofthecentralplacentalmass.Infantswithsuch
placentashavebeenfoundtobeproportionallysmaller.11Evenwhenthe
umbilicalcordinsertioniseccentricbutnotmarginal,theefficiencyofthe
placentalcirculationisreducedandbirthweightissmallerthanwouldbe
expectedfortheplacentalweight.11
Placentalinsufficiencyisamultifactorialfailureofthematernalandfetal
tissuestoformtheplacenta.Suboptimaluterinepreparation,impaired
decidualization,atypicalmaternalimmuneresponsetotrophoblastinvasion,and
ahostofpotentialaberranciesinthecomplexsignalinginvolvedinplacental
developmentcontributetothespectrumofclinicaldisease.8


PlacentainCongenitalHeartDisease
AgrowingbodyofdatademonstratesthattheplacentasoffetuseswithCHDare
abnormal.Anemergingtheorypointstotheexistenceofa“fetalheart-placental
axis,”inwhichsharedsignalingfactorsandgenesleadtotheabnormal
developmentofbothorgans—heartandplacenta—earlyinfetallife.12Placental
abnormalitiesdevelopalongsideCHDandareapartofthediseasestate.12,13
However,theprecisenatureoftheseabnormalities,andhowtheymayvarywith
theformofstructuralheartdiseasepresent,isnotwellunderstood.
Theplacentaisintrinsicallychallengingtoassessandstudyinutero.Itisa
uniqueorgan,whichdevelops,functions,andisdiscardedoverthecourseofless
thanayear,andisintimatelytiedtothedelicateprocessoffetalgrowthand
development.InvestigatingtheplacentainCHDhasbeenapproachedina
numberofways.Severallargeepidemiologicstudieshavecompellingly
demonstratedasignificantrelationshipbetweenfetuseswithCHDand
preeclampsia,especiallyearlypreeclampsia.14,15Onestudyofover1.9million

pregnanciesinDenmarkdemonstratedasixfoldincreaseintheriskofearly
preeclampsiawhenthefetushadstructuralheartdisease;thiseffectwas
consistentacrossdifferentformsofCHD.15Priorhistoryofearlypreeclampsia
wasassociatedwithasevenfoldincreaseinriskofCHDinsubsequent
pregnancy,whileahistoryoflate-termpreeclampsiaalsodoubledtherisk.In
addition,motherswhohadapriorchildwithCHDincreasedtheriskofearlyand
latepreeclampsiainsubsequentpregnancies.15Theseobservationsnotonly
demonstratethestrongassociationbetweenfetalCHDandplacental
insufficiency,butalsopointtotheexistenceofmaternalorgeneticfactorsinthe
pathogenesisofbothdiseaseprocesses.
Therearelimiteddataexaminingthegrossandmicroscopicpathologyof
placentalabnormalitiesinCHD.Onestudynotedabnormalplacentalcord
insertionassociatedwithCHD,especiallyinthesettingofintrauterinegrowth
restriction.16Anotherstudyoftheplacentasoffetuseswithhypoplasticleftheart
syndromedemonstratedgrossfindingsofsignificantlyreducedplacentalweight
andincreasedfibrindeposition.Histologically,theplacentashadincreased
syncytialnuclearaggregates,decreasedterminalvilli,reducedvasculature,and
increasedleptinexpressioninsyncytiotrophoblastandendothelialcells.17Ona
biomarkerlevel,animbalancebetweenangiogenicandantiangiogenicfactorsin


thematernalandfetalcirculationshasbeenimplicatedinthedevelopmentof
CHD,andmaycauseabnormalangiogenesisintheplacenta.13
Interestingly,althoughthesestrongassociationsbetweenCHDandplacental
anomalieshavebeendemonstrated,theplacentalweighttobirthweightratioor
placentalsizehasnotbeenconsistentlyfoundtobesignificantlydifferentin
CHD.16,18Arecentlarge-scalepopulationmulticenterstudyinDenmark
comparedbirthweightsandplacentalweightsof7569infantsbornwithCHD
overa14-yearperiodtothoseofindividualswithoutCHD.Onlythreetypesof
CHDlesions,largeventricularseptaldefects,double-outletrightventricle,and

tetralogyofFallot,werefoundtobeassociatedwithsignificantlysmaller
placentalsizeatbirth.18
InastudyperformedatTheChildren'sHospitalofPhiladelphia,wefoundthe
placenta-to-birthweightratiosof120fetuseswithcomplexCHDconsisting
primarilyofsingleventricleandconotruncalanomaliestobesignificantlylower
thannormal.19Differencesinfindingsbetweenthesestudiesmayberelatedto
thespecificpopulationsofthetypeofCHDinvestigated,orperhapsvariability
inconsistencyofmethodologyinweighingthepostnatalplacenta.Placentalsize
alonemaybeaninsufficientproxyforthecomplexchangesofthefetalheart–
placentalaxisinCHD.
InourChildren'sHospitalofPhiladelphiastudy,forthe120subjectsoverall,
placental-to-birthweightratioswerelessthanthe10thpercentilefor77%and
lessthanthethirdpercentilefor49%ofsubjects(Fig.11.2).19Chorangiosisis
thepathologicfindingofanabnormallyincreasedcapillarydensityinthe
placentalvilliandisareflectionoftissuehypoxia.Wefoundabnormalitiesof
chorangiosisin18%andhypomaturevilliin15%.Subjectswerecategorized
basedonthetypeofcardiacstructuralmalformation(singleventriclewithaortic
obstruction,singleventriclewithpulmonicobstruction,two-ventricle
conotruncalanomaly,andtranspositionofthegreatarteries).Thelowest
placenta-to-birthweightratiosandthegreatestpercentageofsubjectswithof
chorangiosisandhypomaturevilliwerenotedinthenewbornswithtransposition
ofthegreatarteries.Alsoofgreatinterestwasthefindingthatimportant
placentalthrombosiswaspresentoverallin41%withinfarctionofplacental
tissuein17%.Infarctionwasfocusedpredominantlyintheperipheryofthe
placentainthevascularwatershedregions(Fig.11.3).Therewasnoassociation
betweentheseplacentalabnormalitiesandfetalechocardiography-derived
Dopplertracingsoftheumbilicalarterypulsatilityindex.Thusitappearsthat
detectingplacentalstructuralabnormalitiesisnotreadilyachievablebyassessing