comparativemorphologicaldi썒erencesbetweenumbilicalcords ...age 27.7±4.6 28.3±4.4 27.6±5.3...
TRANSCRIPT
ComparativeMorphologicalDierencesbetweenUmbilicalCordsfromChronicHypertensiveandPreeclampticPregnancies
SevincInan ,MuzaerSancı,DenizCan,SedaVatansever,OzgurOztekin,andSivekarTinar
DepartmentofHistology&Embryology,CelalBayarUniversity,FacultyofMedicine,Manisa,Turkey,DepartmentofObstetrics&Gynecology,AegeanSocialSecurityHospital,Izmir,Turkey,and
DepartmentofRadiology,TepecikSocialSecurityHospital,Izmir,Turkey
Tocomparemorphologicalchangesintheumbilicalcordsfrom chronichypertensiveandpree-clampticpatientshavingnormalorpathologicalumbilicalarteryDopplerultrasonographicresults.Umbilicalcordsfrom34normotensive,31chronichypertensiveand70preeclampticwomenwithnormalandabnormalDopplerflowvelocitywaveforms(FVW)at35-40gestationalweekswerestudied.Morphologicalchangesintheumbilicalcordswereexaminedonformalin-fixed,para n-embeddedsections.Thetotalumbilicalcordarea,totalvesselarea,andwallthicknessofumbilicalvesselsweremeasuredinsystematicrandom samplesusingunbiasedstereologymethods.AnANOVAtestwasusedforstatisticalanalysis.InthechronichypertensiveandpreeclampticgroupswithnormalDopplerFVW,thethicknessoftheumbilicalcordvesselsremainednearlyconstant,whereasboththetotalareaandthelumenareawerereduced.Thesechangescorrelatewiththehistopathologicalfindings,suggestingamainlyvasoconstrictiveeect.Bycontrast,analysisofthepreeclampticgroupwithpathologicDopplerFVW showedacomparablereductionofallparametersoftheumbilicalcord.Histopathologicalfindingswererelatedtosmaller,contractedsmoothmusclecellsofthevesselwall,whichissuggestiveofapredominanthypoplasticmechanism.Asaresultofreduceduteroplacentalperfusion,fetalhypoxiaandintrauterinegrowthretardationbecomeun-avoidableinpreeclampsia.ThehistopathologicalchangesintheumbilicalcordbetweenthechronichypertensiveandpreeclampticpatientsdependontheDopplerresults.Inconclusion,theumbilicalarteryDopplerFVW indicesprovidegoodvaluesforpredictingintrauterinegrowthretardationinpreeclampticpatients.
Keywords:umbilicalcord,morphometry,hypertensiveinducedpregnancy
H ypertensivedisordersinpregnancyarerespon-sibleforasignificantamountofmaternaland
perinatalmorbidityandmortality.Theetiologyofthesedisordersisstillunknown.Itcomplicatesabout6-20
ofallpregnancies.Preeclampsiaandeclampsiaconstituteabout70 ofthesedisorders,whereaschronichyperten-sionrepresentstheremaining30 ofhypertensivedis-ordersinpregnancy[1,2].Althoughpreeclampsiaisoneofthemajorcausesof
maternaldeath,especiallyindevelopingcountries,per-inataloutcomesarealsonotfavorable.Intrauterinegrowthretardation,prematuredelivery,lowbirthweight,
ReceivedNovember12,2001;acceptedApril18,2002.Correspondingauthor.Phone:+90-236-237-64-40;Fax:+90-236-237-64-49E-mail:sevincinan@yahoo.com(S.Inan)
http://www.lib.okayama-u.ac.jp/www/acta/
ActaMed.Okayama,2002Vol.56,No.4,pp.177-186
OriginalArticle
Copyrightc2002byOkayamaUniversityMedicalSchool.
fetaldeathandneonataldeathduetoprematurebirtharecommon complications. Predicting preeclampsia isdicultinearlypregnancy,butsomeepidemiologicalriskfactorsareknown,suchasnulliparity,previouspre-eclampsia,familyhistory,blackrace,obesity,diabetesmellitus,multi-fetalpregnancies,ageofmother(<18and>35),andpreviousrenaldisease[3].Althoughtheetiologyofpreeclampsiaisstillunknown,
theplacentaplaysacrucialroleinthedevelopmentofthedisease[4,5].Preeclampsiaisassociatedwithincreasedvascularresistanceanddecreaseduteroplacentalperfusion.Accordingtothedegreeofdecreaseinuteroplacentalperfusion,fetalhypoxiaandintrauterinegrowthretarda-tioncanbecomeunavoidable[6].Manystudieshavedemonstratedsignificantdierencesinthemorphologicalstructuresoftheplacentaandumbilicalcordvesselsbetweennormalandpreeclampticpregnantwomen[7-12].Mostofthewomenwithpreeclampsiashowhis-tologicalandbiochemicalevidenceofpoorplacentationandischemia.Bruchetal.reportedthatgrowth-retardedfetuseswithorwithoutumbilicalarteryDopplerabnor-malitieshaveasmallerumbilicalcordcross-sectionalareaatdeliverythandonormalhealthyfetuses[10].DiNarofoundthatthediametersandareasofumbilicalcordschangedduringgestation,andthesedierencesdependedonthereductionofWhartonjellyratherthantheumbilicalvesselsthemselves[11].Juneketal.demonstratedthatumbilicalarterieswerethickerinthepreeclampticgroupthaninuncomplicatedpregnancies.Thesedierenceswereespeciallyobservedinthetunicaintimaandmedia.Thesedierenceswereacceptedasaresultoftheadapta-tionsystemoftheumbilicalcordarteriesunderthealteredhomodynamicconditionsinpreeclampsia[12].Itwasobservedthatumbilicalarterialvasoconstriction
wasinducedbyanexcessofeitherendothelium orplatelet-derivedthromboxaneA2,asdescribedinIUGR[13].AhigherproductionofendothelininIUGRwasalsodescribed[14].Butthedegreeofdefectiveplacenta-tionandplacentalischemiamaynotadjusttotheseverityofpreeclampsia.Thereforesomeotherpreexistingfactorsmustalsobepresent.Thesealterationsintheplacentaandumbilicalcordvesselsmaydevelopasaresultofadecreaseinavasodilatorsubstanceoranincreaseinvasoconstrictorsduetoapathophysiologicevent[15-18].Anabnormalendothelialhyperstimulationanddysfunctionmightbethemainevent,andpreeclampsiacanbeanacuteformofsuchasituation.Bothpreeclamp-siaandchronichypertensionincludesimilarriskfactors
andbiochemicalalterations.Althoughtheperinatalriskforwomenwithchronichypertensionislessthanforpreeclampticwomen,thehistopathologicaldierencesinbothgroupsmaybeimportantforthedevelopingfetus.Theaimofthisstudywastocomparethemorphologicalchangesintheumbilicalcordvesselsinnormotensivepregnancies,chronichypertensivepregnanciesandpre-eclampticpatientswithandwithoutpathologicumbilicalarteryDopplerultrasoundstudyresults.
MaterialsandMethods
TheEthicsCommitteeoftheResearchCenterofAegeanSocialSecurityHospitalapprovedtheprotocol.Studieswereperformedontheumbilicalcordsof135newborns,deliveredbetween35-40weeksofgestation.Inallcases,10cm longsectionsoftheumbilicalcordwerecut,beginningfromtheirplacentalend,formorphometricstudyoftheumbilicalcordves-sels.Patientswereseparatedinto4groups.Therewerenostatisticallysignificantdierencesinthemean(±SD)ageofthewomenamongthegroups.Patientcharacteris-ticsaregiveninTable1.Forallpatients,arterialumbilicalflowvelocitywaveforms(FVW)from24hto1weekbeforedeliverywererecordedwithToshiba250pulse-wavedDopplerUSG,usinga5MHzabdominaltransducer.NormalumbilicalDopplerindicesweredefinedasasystolic/diastolicvaluebetween5 and95 withrespecttogestationalage.Valuesoutofthisrangeweretakenasabnormal.Group1:Thecontrolmaterialwastakenfromnew-
bornsdeliveredbyhealthymothers,aged23-32,withnormalbloodpressure(systolic100-135mmHg,diastolic60-85)andhavingnormalumbilicalDopplerFVW(n=34).Exclusioncriteriaincludedmultiplepregnancies,essentialhypertension,diabetes,chronicrenaldisease,plateletdisorders,andepilepsy.Themeanbodyweightofthenewbornswas3,261.7±418.3grams.Group2:Inthisgroup,theumbilicalcordswere
takenfromnewbornsdeliveredbymothers,aged24-33,withessentialhypertensionbeforethe20thweekofpregnancyandhavingnormalumbilicalDopplerFVW(n=31).Themeanbodyweightofthesenewbornswas3,153.2±314.8grams.Group3:Inthisgroup,theumbilicalcordswere
takenfromnewbornsdeliveredbymothers,aged22-32,withpreeclampsia.Womenwerediagnosedwithpre-eclampsiaiftheyhadbloodarterialpressureasfollows:
Inanetal. ActaMed.Okayama Vol.56,No.4178
systolic>140mmHg,diastolic>90mmHgmeasuredon2ormoreoccasionsatleast4hapartafterthe20thweekofgestation.Proteinuriawasconsideredpresentwhentherewasaurinedipstickvalueofatleast1+(>30mg/dl)on2separateoccasionsatleast6hapart.NoneofthewomenhadanMgSO4orbetamethasoneinjectionbeforethebloodsamplesweredrawn.Thisgroupwassubdividedinto2groupsaccordingtoDopplerFVW results.Group3A:WithnormalumbilicalarteryDoppler
FVW (n=32).Themeanbodyweightofthesenew-bornswas3,015.6±426.6grams.Group3B(4):WithabnormalumbilicalarteryDop-
plerFVW (n=38).Themeanbodyweightofthesenewbornswas2,109.2±589.9grams.
Eachumbilicalcordwasimmediatelyclampedatdelivery.Inallcases,10cm-longsectionsofumbilicalcordwerecut,beginningfromtheirplacentalend,formorphometricstudyoftheumbilicalcordves-sels.Fiveblocksofcordcross-sectionswerecut.Aroutineparanprocedurewasdone.Inbrief,tissuesampleswerefixedin10 formalinsolution.Theyweredehydratedinagradedethanolseries,cleanedinxyleneandembeddedinparan.Sectionswerecutat5μmthickness,deparanisedandhydrated.Serialsectionsoftheumbilicalcordswerestainedwithhematoxylinandeosin(H.E).Systematicrandomsamplesofumbilical
cordsectionswereidentifiedunderamicroscope(×40),andunbiasedmorphometricstudywasperformedusinganOlympusmicroscope.Theviewfromthemicroscopewasdirectlyprojectedontothecomputerscreen.Asystematicgridofcrosseswasrandomlythrownontotheviewedobject.Theinter-crossspacinginthexandydirectionisΔxandΔyunits,respectively.Thismeansthateachcrosshasanassociatedareaofa/punits.Thenumberofcrossesthathittheobjectmultipliedbya/pisanunbiasedestimateoftheobject’sarea[18].Thefollow-ingparametersweremeasuredforeachumbilicalcord:totalcordandWhartonjellyareas,totalvesselandlumenareas,andwallthickness.Wall-thicknessmeasurementsexpressthewholethicknessofthevesselwall,fromtheendothelium totheWhartonjelly.Allmorphometricmeasurementsweredoneinablindfashion,withoutpreexistingknowledgeoftheclinicaldata.
Allresultsareexpressedasmeanvalues± SEs.StatisticalanalysisofdataandSEswascalculatedforeachparameterandestimatedineachgroup.ForcomputationweusedtheSPSSAdvancedStatisticalpackage.ThedatawasanalyzedbyanANOVA test,anddierenceswereconsideredsignificantifP<0.05.
Pregnancy,Hypertension,UmbilicalCordAugust2002
Table1 Clinicalcharacteristicsofnormal,chronichypertensiveandpreeclampticpregnancies
GROUP GROUP1 GROUP2 GROUP3A GROUP3B
ControlChronicHTwithnormalDopplerFVW
PreeclampsiawithnormalDopplerFVW
PreeclampsiawithpathologicalDopplerFVW
n=34 N=31 n=32 n=38Age 27.7±4.6 28.3±4.4 27.6±5.3 25.5±3.8Parity(Nullipar/multipar) 21/13 10/21 23/9 26/12Gestationalage(wk) 39.0±0.5# 38.3±1.0 37.3±0.9 36.4±1.1SistolicBloodPressure(mmHg)
107.0±10.8# 148.3±11.8 149.8±11.8 156.5±12.7
DiastolicBloodPressure(mmHg)
69.4±9.9# 95.9±6.1 101.0±11.4 105.1±10.7
Edema 1.0±0.6# 0.9±0.9 2.2±0.4 2.2±0.4Spontantdelivery/
Cesariansection25/9# 16/15 6/26 7/31
APGAR 8.3±0.6# 8.0±0.7 7.4±0.8 6.8±1.2Fetalweight(gm) 3261.7±418.3 3153.2±314.8 3015.6±426.6 2109.2±589.9
#,P<0.05Group1vs.Group2,3A,3B;,P<0.05Group3Avs.Group2;,P<0.05Group3Bvs.Group3A,2.
179
Results
Demographicandclinicalfindingsofthecontrolgroup(Group1),chronichypertensive+pregnancy(Group2),preeclampticwithnormalDoppler(Group3A)andpre-eclampticwithabnormalDoppler(Group3B)aresum-marizedinTable1.Asexpectedfromtheinclusionandmatchingcriteria,thepatients’ageswerenotsignificantlydierent,butotherparameterssuchasbloodpressureandedemaweresignificantlyelevated(P<0.05)inthepreeclampticgroup.ThemethodofdeliverywasusuallycesareansectioninGroups3Aand3B.Wealsosawthatthegestationalageandbirthweightweresignificantlylowerinthepreeclampticgroup,especiallyinthepath-ologicDopplerflowpatterns.Relatedwiththesefindings,APGARscoresinGroups2,3Aand3Bwerefoundtobelow.TheresultsofthemorphometricparametersofumbilicalcordsaregiveninTable2.Histologicalexaminationoftheumbilicalcordshows
severaldistinctlayersunderthelightmicroscopeinthecontrolgroup(Fig.1A).Onthesurfaceisawell-definedsinglelayerofsquamoidamnioticepithelium.DeepintheepitheliumthatcomprisesthesurfaceofthecordisthesubstanceknownasWharton’sjelly.EmbeddedwithintheWharton’sjellyaretheumbilicalvessels.Thevas-
culatureoftheumbilicalcordiscomposedof2arteriesandasinglevein.Thearteriespossessnoelasticlaminaandhaveadouble-layeredmuscularwall(Fig.1B).Eachofthesemuscularlayersiscomposedofanetworkofinterlacingsmoothmusclebundles.Theveinhasaninnerelasticlamina(Fig.1C).Theumbilicalvein,whichgenerallyhasalargerdiameter,possessesathinnermuscularcoatconsistingofasinglelayerofcircularsmoothmuscle.Inthecontrolgroup,themeancordareawas63.58±2.00,thetotalareaoftheveinwas6.28±0.44andthewallthicknessoftheveinwas471.75±33.27.Thethicknessesofthearteriesweresimilartoeachother.Themeanwallthicknessofthearterieswas597.08±18.02andtheirtotalareawas2.97±0.18.WhentheumbilicalcordvesselsinGroup2(chronic
hypertensive+pregnancy)wereexaminedunderthelightmicroscope,thehistologicalappearanceappearedtobeclosetonormal(Fig.2A).Theendotheliumandthesubendotheliumoftheumbilicalartery(Fig.2B)andvein(Fig.2C)wereseentobeintheirnormalstate.Althoughafewcontractionsinthenucleuscouldbeseen,thesmoothmusclecellsgenerallyhadtheappearanceofbeingnormalandofnormalsize(Fig.2D).Theintercellulargapshadanunnoticeablewideningbetweenthem.Themorphometricanalysesofthisgroupshowedthatthetotal
Table2 Correlation’scordparameters
GROUP1 GROUP2 GROUP3A GROUP3B
UMBILICALCORDPARAMETERS
ControlChronicHTwithnormalDopplerFVW
PreeclampsiawithnormalDopplerFVW
PreeclampsiawithpathologicalDopplerFVW
n=34 N=31 n=32 n=38
UmbilicalcordTotalcordarea 63.58±2.00# 54.09±2.65 48.99±3.18 41.84±1.58Jellyarea 51.37±1.79# 43.95±2.43 40.39±3.09 35.22±1.77Totalvesselarea 8.44±0.69# 7.01±0.29 6.07±0.22 5.01±0.19Totallumenarea 3.77±0.13# 3.11±0.28 2.58±0.10 1.61±0.11VeinTotalareamm 6.28±0.44# 4.95±0.09 3.61±0.11 2.51±0.22Lumenareamm 2.97±0.29# 2.47±0.05 1.96±0.21 1.10±0.22Wallthicknessμm 471.75±33.27 459.58±11.58 437.75±10.79 398.58±11.54ArteryTotalareamm 2.97±0.18# 2.59±0.14 2.49±0.12 2.06±0.06Lumenareamm 0.40±0.05 0.32±0.04 0.31±0.05 0.25±0.06Wallthicknessμm 597.08±18.02 544.90±17.40 547.58±12.01 426.66±19.22
#,P<0.05Group1vs.Group2,3A,3B;,P<0.05Group3Avs.Group2;,P<0.05Group3Bvs.Group2,3A,1.
Inanetal. ActaMed.Okayama Vol.56,No.4180
cordandjellyarea,andthetotalvesselareaweresignificantlyreduced(Fig.2A).ThewallthicknessoftheumbilicalvesselswasdecreasedinGroup2,butthedierencewiththecontrolgroupwasnotstatisticallysignificant.Itwasobservedthatinpreeclampticpatientshaving
normalDopplerFVW(Group3A),awideningundertheepitheliumofthearteryandbetweenthemusclelayerswaspresentduetotheedema(Fig.3B).Thecontractionofthemusclecellsoccurredwithawave-likeappearanceofthenucleus.Separationsappearedbetweenthemusclecellsduetotheincreaseinfluidbetweenthecells,whichwasassociatedwiththeedema.Thisedemainrelationtotheconnectivetissuebetweenthelayersofmusclemadeitmucheasiertodistinguishbetweenthelayers.Theveinlumenwasseentohavenarrowedduetotheedemaontheveinwallandtothevasoconstriction(Fig.3C,3D).
Macroscopically,thecordthicknesswassignificantlyreducedinthisgroupincomparisonwiththecontrolandhypertensivegroups.WhenGroup3AwascomparedwithGroup2,asignificantreductionofthetotalvesselareaofthecordwasobserved.Incontrast,nodierencewasobservedinthewallthicknessofthevessels.Theumbilicalcordvessels,whichweretakenfrom
preeclampticpatientswhohadanabnormalDoppler(Group3B),seemedtobemorphologicallyhypoplastic(Fig.4).Whenexaminedunderalightmicroscope,thediametersofthevesselsweresignificantlyreduced(Fig.4A).Themuscleareaseparatedfromtheconnectivetissues,whichledinturntothesubstantialnarrowingofthediameterofthelumen,whichwasespeciallynoticeableinthearteries(Fig.4B).Thisnarrowingofthelumenresultedinthenarrowingoftheveindiameter(Fig.4C).Themusclecellswereseentobehypoplasticandsmaller
Fig.1 Photomicrographsofumbilicalcordtakenfromanewbornwithanormotensive,healthymother(Controlgroup).Normalappearanceofumbilicalcordandvesselswereseen.Onthesurfaceisawell-definedsinglelayerofamnioticepithelium(a),embeddedwithinthesubstanceofWharton’sjelly(w)aretheumbilicalvessels.Generalviewofumbilicalcordatamagnificationof×10(A);umbilicalcordartery,×40(B);umbilicalvein(V),×40(C).H.E.
181Pregnancy,Hypertension,UmbilicalCordAugust2002
thantheirnormalsize(Fig.4D).Thecontractedsmoothmusclecellswereseentohaveseparatedtheirlinksfromeachotherinsomeparts.Theendotheliumandsuben-dotheliumofthevesselsandtheinnerlayersofmusclewereobservedtohavecompletelyjoinedeachother.Withthisobservation,hypoplasycouldbeclearlydetected.Inthisgroup,itwasobservedthatallparametersoftheumbilicalcordweresignificantlyreducedincomparisontothenormalandhypertensivegroups.Asignificantcorre-lationwasalsoobservedbetweenthethicknessofavesselwallandthepathologicDopplervalues.
Discussion
Theumbilicalcordappearstoplayanimportantroleininteractionsbetweenthemotherandfetusduringpreg-nancy.Pregnancieswithgrowthretardationareassociat-
edwithsmallerplacentasandthinumbilicalcords[7-10].Inthisstudy,thehistopathologicalandmorphometricdierencesassociatedwithpregnancy-inducedhyperten-sion(preeclampsia)andchronichypertensionwereobserv-ed.AbnormalumbilicalcordarterialDopplerFVW wasassociatedwiththereducedumbilicalcorddiameter.ItwasalsoassociatedwithbothreducedtotalcordareasandreducedWhartonjellyareas.Chronichypertensionischaracterizedbyanincreased
vascularresistanceandmodificationsinthemechanicalpropertiesofbloodvessels[20].Vesselscontractviaavarietyofpharmacologicalagentsincludingserotonin,potassiumchloride,bradykinin,angiotensine,oxytosinandothers[21,22].Thesepropertieshavenotbeenfullyinvestigatedinpregnancy-inducedhypertension.Butlikechronichypertensioninpreeclampsia,theinhibitionofprostacyclinesynthesis,hypersensitivitytovasocon-
Fig.2 Photomicrographsofumbilicalcordtakenfromchronichypertensivemother(Group2).Theendotelandsubendotelseemedtolookclosetonormal,thesmoothmusclecellsonthevesselwallswerealsoseentobeontheirnormalstate.Althoughitcouldbeseenthatafewvasocontrictionshadapatchedstateinthenucleus(arrow).Generalviewofumbilicalcordatamagnificationof×10(A);umbilicalcordartery,×40(B);umbilicalvein(V),×40(C);highermagnificationoftheveinwall,×200(D).H.E.
Inanetal. ActaMed.Okayama Vol.56,No.4182
strictorsandendothelialcelldeathwereobserved[23].Dobrinreportedthatbloodvesselsexhibitedcharacter-
isticchangesduringfetaldevelopment[24].Thewiden-ingofthemedia,anincreasednumberandathickeningofelasticlamella,decreasedcellularityandaugmentedcol-lagencontentcharacterizethemorphologicdevelopmentduringthisperiod.Itwasreportedthattheumbilicalperfusiondecreasedinpreeclampsia[25].Thevesselwallscouldreactwiththealterations,buttheircomposi-tiontomaintaintheirtransmuralpressureatanoptimallevelwouldhavetobesustained.Inasituationofin-creasedplacentalresistance,anincreaseinintralumenpressureintheumbilicalarterywilltendtoincreasecomplianceinordertokeeptransmuralpressurerelativelyconstant.Conversely,theintrauterinelumenpressureintheumbilicalveinwilldecrease,andthecomplianceofthe
vesselwilldiminish,againtokeeptransmuralpressureconstant.Romanowiczetal.demonstratedthattheinsolubleelastincontentdecreasedintheumbilicalcordveinsofnewbornsdeliveredbymotherswithpreeclampsia[26].Reconstructingtheumbilicalcordveinwallmaydisturbfetalbloodflowandaectthevascularsysteminadulthood[27].Ourmorphometricresultswereinagreementwiththe
resultsofpreviousstudiesinthecontrolandpreeclampticgroups[10-23].OurresultsshowthatwhenGroups2and3Awerecompared,thethicknessoftheumbilicalcordvesselsremainednearlyconstant,whereasbothtotalareasandlumenareaswerereducedwithrespecttothecontrolgroup.Thesechangescorrelatewithourhis-topathologicalfindings,whichincludedawideningundertheepithelium,thecontractionofthemusclecells,and
Fig.3 PhotomicrographsofumbilicalcordtakenfrompreeclampticmotherhavingnormalDopplerFVW(Group3A).Awideningundertheepitheliumbetweenthemusclelayersandthecontractionofthemusclecellswasseenwithawavedlikeappearanceofthenucleus.Separationsappearedinbetweenthemusclecellsandinbetweenthelayersofmuscle(arrow).Theveinlumenwasseentohavenarrowed.Generalviewofumbilicalcordatamagnificationof×10(A);umbilicalcordartery,×40(B);umbilicalvein(V),×40(C);highermagnificationoftheveinwall,×200(D).H.E.
183Pregnancy,Hypertension,UmbilicalCordAugust2002
separationsbetweenthemusclecellsassociatedwiththeedema.Thesefindingssuggestamainlyvasoconstrictiveeect.Bycontrast,acomparisonofGroup3BtoGroups2and1showedacomparablereductionofallparametersofthevessels.InGroup3B,ourhistopath-ologicalfindingsarerelatedtothenarrowinglumenofthevesselsandthecontractedsmoothmusclecellsthatweresmallerthantheirnormalsize.Thesefindingsaresugges-tiveofapredominanthypoplasticmechanism.These2mechanisms,vasoconstrictionandahypoplasticeect,maybedierenteventsormayfolloweachother[10].Thefirstresponsetohypoxemiaisvasoconstrictionofthevessels.Ifhypoxemiacontinues,itmaycausemor-phologicalchangessuchashypoplasia.ChangesofthecompositionofWhartonjellysuchas
theglycosaminoglycans,watercontent,andextracellular
matrixcomponentswerethemainresultsofthereductionofthediameteroftheumbilicalcord[11,26-27].Thesechangesmightberesponsibleforthegrowthfactors,whichmodifymyofibroblastproliferationgeneexpression,proteinbiosynthesisand/orotherprocesses.RecentstudieshavesuggestedthatDopplerwaveform
indicesfromtheumbilicalartery,fetalaortaandfetalmiddlecerebralarteriesareusefulinidentifyingIUGRanddeterminingtheriskofsubsequentperinatalmorbidity[28,29].Anabnormalumbilicalartery Dopplerwaveform isastrongpredictorofadverseperinataloutcomeinpatientswithpreeclampsia.A correlationbetweentheumbilicalarteryDopplerindicesandadverseperinataloutcomewasfoundinpreviousstudies[24,29].TheumbilicalarteryDopplerindicesarerelatedtoplacentalvascularresistance. Theseearlierstudies
Fig.4 PhotomicrographsofumbilicalcordtakenfrompreeclampticmotherhavingabnormalFVW(Group3B).Themuscleareawasseentohaveseparatedfromtheconnectivetissues.Themusclecellswereseentobehypoplasticandsmallerthantheirnormalsize.Therewasasignificantdecreaseinthelumenareainthisgroup,comparedtothenormalandchronichypertensivegroup.Generalviewofumbilicalcordatamagnificationof×10(A);umbilicalcordartery,×40(B);umbilicalvein(V),×40(C);highermagnificationoftheveinwall,×200(D).H.E.
Inanetal. ActaMed.Okayama Vol.56,No.4184
showedtheuseofumbilicalarteryDopplerwaveformindicesinthepredictionofabnormalneonatalmor-phometry.Dopplerultrasonographyoftheumbilicalarteriesisincreasinginimportanceintheantenataldiagno-sisoffetalwellbeing.Theumbilicalvasculararchitectureisinterestingnotonlyfromamorphologicpointofviewbutalsoasabasisforfunctionalinterpretation.Itissuggestedthatwaveformsreflectplacentalimpedancetobloodflow,andthatchangesofflowpatternsmaybecausedbyhistomorphologicalterationsofthefetoplacentalvesseltree.AbnormalDopplersystolic/diastolicratiosmightreflectapathologicfetalcirculationresultinginintrauterinegrowthretardation,whereasnormalvaluesreflectanormalfetoplacentalcirculationassociatedwithsmallfetalsize[30-34].Inconclusion,theumbilicalarteryDopplerFVW
indicesprovidegoodvaluesforpredictingintrauterinegrowthretardationinpreeclampticpatients.Wealsoobservedthattheumbilicalvessel’swallthicknesseswerereducedinthegroupofpreeclampticpatientswithpatho-logicalDoppler.Itisnotclearwhetherthemorphologicalchangesdisturbtheflowinthevesselsorifareductionoftheflowcausesthemorphologicalchanges.Ifaprogres-siveincreaseinbloodflowwasakeyfactorcontributingtotheembryonicdevelopmentofthevasculartree,aninitialumbilicalvasoconstrictioninresponsetoahypoxicstressproducedareductionintheumbilicalbloodflowandinturnledtoaless-developedarterialtreewithanexpectedincreaseintotalplacentalvascularresistance[10].Chronichypertensionandpreeclampsiamaysharesimilarpathophysiologicevents.Furtherstudiesarenecessarytoelucidatetheexactmechanisms.
References
1. ZuspanFB:Newconceptsintheunderstandingofhypertensivediseasesduringpregnancy.Anoverview.ClinPerinatol(1991) ,653-659.
2. EskenaziB,FensterLandSidneyS:Amultivariateanalysisofriskfactorsforpreeclampsia.JAMA(1991) ,237-241.
3. MittendorfR,LainKY,WilliamsMAandWalkerCK:Urinarytractinfectionsandotherriskfactorsforpreeclampsia.JReprodMed(1996) ,491-496.
4. PieringWF,GarancisJG,BeckerCG,BeresJAandLemannJJr:Preeclampsiarelatedtoafunctioningextrauterineplacenta:Reportofacaseand25-yearfollow-up:AmJKidneyDis(1993) ,310-313.
5. FriedmanSA,TaylorRNandRobertsJM:Pathophysiologyofpre-eclampsia.ClinPerinatol(1991) ,661-682.
6. RobertsJMandRedmanCW:Pre-eclampsia:Morethanpregnancy-inducedhypertension.Lancet(1993) ,1447-1451.
7. LasHerasJ,BaskervilleJC,HardingPGandHaustMD:Mor-
phometricstudiesoffetalplacentalstemarteriesinhypertensivedisorders(‘toxaemia’)ofpregnancy.Placenta(1985),217-227.
8. KaufmannP,LuckhardtMandLeiserR:Three-dimensionalpresenta-tionofthefetalvesselsysteminthehumanplacenta.Res(1988),113-137.
9. JohnstoneFD,Ugaily-ThulesiusL,ThulesiusOandNasratAN:Umbilicalarteryreactivityandultrastructuralchangesinpregnancy-inducedhypertensionandothercomplicatedpregnancies.ClinPhysiol(1987),493-502.
10. BruchJF,SibonyO,BenaliK,ChallierJC,BlotPandNessmannC:Computerizedmicroscopemorphometryofumbilicalvesselsfrompregnancieswithintrauterinegrowthretardationandabnormalumbili-calarteryDoppler.HumPathol(1997) ,1139-1145.
11. DiNaroE,GhezziF,RaioL,FranchiMandD’AddarioV:Umbilicalcordmorphologyandpregnancyoutcome.EurJObstetGynecolReprodBiol(2001) ,150-157.
12. JunekT,BaumO,LauterH,VetterK,MatejevicDandGrafR:Pre-eclampsiaassociatedalterationsoftheelasticfibresysteminumbilicalcordvessels.AnatEmbryol(2000) ,291-303.
13. TempletonAG,KingdomJC,WhittleMJandMcGrathJC:Contractileresponsesofthehumanumbilicalarteryfrompregnanciescomplicatedbyintrauterinegrowthretardation.Placenta(1993) ,563-570.
14. Hartikainen-SorriA,VuolteenahoO,LeppaluotoJandRuskoahoH:Endothelininumbilicalarteryvasospasm.Lancet(1991) ,619.
15. HowardRB,HosokawaTandMaguireMH:Hypoxia-inducedfeto-placentalvasoconstrictioninperfusedhumanplacentalcotyledons.AmJObstetGynecol(1987) ,1261-1266.
16. StuartMJ,ClarkDA,SunderjiSG,AllenJB,YamboT,ElradHandSlottJH:Decreaseprostacyclineproduction:A characteristicofchronicplacentalinsuciencysyndromes.Lancet(1981) ,1126-
1128.17. BodelssonG,MarsalKandStjernquistM:Reducedcontractileeect
ofendothelin-1andnoradrenalininhumanumbilicalarteryfrompregnancieswithabnormalumbilicalarteryflowvelocitywaveforms.EarlyHumDev(1995) ,15-28.
18. RobertsJM:Endothelialdysfunctioninpreeclampsia.SeminReprodEndocrinol(1998) ,5-15.
19. HowardCVandReedMG:UnbiasedStereology.Three-DimentionalMeasurementinMicroscopy.1stEd,BIOSScientificPublishersLtd,Oxford,UK(1998)pp28-37.
20. MeekinsJW,PijnenborgR,HanssensM,McFadyenIRandvanAssheA:Astudyofplacentalbedspiralarteriesandtrophoblastinvasioninnormalandseverepre-eclampticpregnancies.BrJObstetGynaecol(1994) ,669-674.
21. NasiellJ,NisellH,BlanckA,LunelNOandFaxenM:PlacentalexpressionofendothelialconstitutivenitricoxidesynthasemRNAinpregnancycomplicatedbypreeclampsia.ActaObstetGynecolScand(1998) ,492-496.
22. KhongTY,DeWolfF,RobertsonWBandBrosensI:Inadequatematernalvascularresponsetoplacentationinpregnanciescomplicatedbypre-eclampsiaandbysmall-for-gestationalageinfants.BrJObstetGynaecol(1986) ,1049-1059.
23. BertrandC,DuperronLandSt-LouisJ:Umbilicalandplacentalvessels:Modificationsoftheirmechanicalpropertiesinpreeclampsia.AmJObstetGynecol(1993) ,1537-1546.
24. DobrinPB:Mechanicalpropertiesofarterises.PhysiolRev(1978) ,397-460.
25. BiagiottiR,SgambatiEandBrizziE:Placentalmorphometryinpregnanciescomplicatedbyintrauterinegrowthretardationwithabsentorreversedenddiastolicflowintheumbilicalartery.ItalJAnatEmbryol(1999) ,201-207.
185Pregnancy,Hypertension,UmbilicalCordAugust2002
26. RomanowiczLandSobolewskiK:Extracellularmatrixcomponentsofthewallofumbilicalcordveinandtheiralterationsinpre-eclampsia.JPerinatMed(2000) ,140-146.
27. RomanowiczL,BankowskiE,SobolewskiKandJaworskiS:Activitiesofsomeglycosaminoglycan-degradingenzymesinWharton’sjellyandtheiralterationinEPH-gestosis(Pre-eclampsia).BiolNeonate(1999),144-152.
28. MitraSC,SeshanSVandRiachiLE:PlacentalvesselmorphometryingrowthretardationandincreasedresistanceoftheumbilicalarteryDopplerflow.JMaternFetalMed(2000),282-286.
29. YoonBH,LeeCM andKim SW:Anabnormalumbilicalarterywaveform:Astrongandindependentpredictorofadverseperinataloutcomeinpatientswithpreeclampsia.AmJObstetGynecol(1994),713-721.
30. BarthaJL,Comino-DelgadoR,Gonzalez-MenaC,LopezIandArrabalJ:Umbilicalbloodflowandneonatalmorphometry:Amultivariateanalysis.EurJObstetGynecolReprodBiol(1998) ,27-33.
31. AtkinsonMW,MaherJE,OwenJ,HauthJC,GoldenbergRLand
CopperRL:ThepredictivevalueofumbilicalarteryDopplerstudiesforpreeclampsiaorfetalgrowthretardationinapreeclampsiapreventiontrial.ObstetGynecol(1994) ,609-612.
32. BerkowitzGS,ChitkaraU,RosenbergJ,CogswellC,WalkerB,LahmanEA,MehalekKEandBerkowitzRL:SonographicestimationoffetalweightandDoppleranalysisofumbilicalarteryvelocimetryinthepredictionofintrauterinegrowthretardation:Aprospectivestudy.AmJObstetgynecol(1988) ,1149-1153.
33. ChangTC,RobsonSC,SpencerJAandGallivanS:Identificationoffetalgrowthretardation:ComparisonofDopplerwaveformindicesandserialultrasoundmeasurementsofabdominalcircumferenceandfetalweight.ObstetGynecol(1993) ,230-236.
34. McCowanLM,HardingJEandStewartAW:UmbilicalarteryDopplerstudiesinsmallforgestationalagebabiesreflectdiseaseseverity.BJOG(2000) ,916-925.
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