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ContemporaryOB/GYNObstetricsGynecology&Women'sHealthIntrauterinegrowthrestriction

DetectionandsurveillanceofIUGR
October01,2013
ByGiancarloMariMD,DanielleL.TateMD

ByDanielleLTate,MD,andGiancarloMari,MD
Dr.TateisaMaternalFetalMedicineFellow,DepartmentofObstetricsandGynecology,Universityof
TennesseeHealthSciencesCenter,Memphis.
Dr.MariisProfessorandChair,DepartmentofObstetricsandGynecology,UniversityofTennessee
HealthSciencesCenter,Memphis.

Intrauterinegrowthrestriction(IUGR)referstoinabilityofafetustoachievefullgrowthpotential
whileinutero.AlthoughIUGRisacommoncomplicationofpregnancy,therelatedterminologyand
diagnosticcriteriaremaincontroversial.OnereasonisthatmostIUGRstudieshavenotdifferentiated
betweenconstitutionallyandpathologicallysmallfetuses.Inaddition,studiesonthepathogenesisof
IUGRoftenassumehomogeneityintheorigin,hamperingunderstandingofunderlyingmechanisms.
TheconsequenceiscontinuedambiguityaboutoptimalmanagementofIUGRfetuses.
Traditionally,populationbasedgrowthcurveshavebeenusedtodefineIUGRintheUnitedStates,with
abirthweightbelowthe10thpercentileforgestationalageusedasastandarddefinition.However,
adverseoutcomesandmortalityareincreasedininfantswithbirthweightsbetween10thand15th
percentile.Conversely,manyneonateswhoseweightsarebelowthe10thpercentilearehealthy.1
SeveraldefinitionsofIUGRareacceptedindifferentareasoftheworld.InEurope,forexample,an
abdominalcircumference(AC)belowthe10thorthe5thpercentileisthepreferreddiagnosticcriteria,
asopposedtousingestimatedfetalweight(EFW)todefineIUGR.Publisheddefinitionsinclude:
weightatbirth<2500g,EFW<10thpercentile,AC<10thpercentile,EFW<10thpercentilewith
abnormalDopplerindicesintheumbilicalarteryormiddlecerebralartery,andAC<10thpercentile
withabnormalumbilicalarteryormiddlecerebralarteryDopplerstudies.Otherdiagnosticcriteria
employthefetusasacontrolforitself2,orusecustomizedfetalgrowthstandards.3
Inaddition,theconsequencesofinuterogrowthdeficiencydonotendatbirthorininfancy,butrather,
continueintochildhoodandadultlife.4Barkerandothershavedescribedanassociationbetweenbirth
weightbelowthe10thpercentileanddevelopmentlaterinlifeofhypertension,hypercholesterolemia,
coronaryheartdisease,impairedglucosetolerance,anddiabetes.4Therefore,thegrowthrestrictedfetus
representsanenormouspotentialburdenforboththeaffectedindividualandforsociety.
EnsuringfetalwellbeinganddeterminingtheoptimaltimingfordeliveryofanIUGRfetusisa
primarygoaloffetalspecialists.However,thetimingofdeliveryofthesefetuses,especiallyatlessthan
32weeks,iscontroversial.Furthermore,theoptimalmethodoffetaltestingisalsodebatableinthe
UnitedStates,themostfrequentlyusedtestisthebiophysicalprofile,whereasinEurope,
cardiotocographyisthepreferredmethod.5
Etiologies
IUGRcanbecausedbyseveraldifferentetiologies,manyofwhichmaynotbedetermineduntiltimeof
postmortemevaluation.Accurateidentificationofthecauseisimportantbecauseitmayaffectfuture
pregnancies.
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Geneticfactors
Approximately40%oftotalbirthweightisascribabletogeneticfactors,whereastheother60%isdue
tofetalenvironmentalcontributions.6Althoughbothparentsgenesaffectgrowth,maternalgeneshave
theprimaryinfluenceonbirthweight.Johnstoneetal.reportedthatsistersofwomenwithgrowth
restrictedbabiestendtohavegrowthrestrictedbabiesaswell,aphenomenonnotobservedintheir
brothers.7
Inaddition,womenwhoweregrowthrestrictedorSGAatbirthareatincreasedriskofhavinganIUGR
fetus,andspecificmaternalgenotypicdisorderscancausegrowthrestriction,includingphenylketonuria
anddysmorphicsyndromessuchasdwarfism.Finally,manychromosomalanomalieshavebeen
associatedwithIUGR.Approximately50%offetuseswithTrisomy13orTrisomy18havefetalgrowth
restriction.Inaddition,confinedplacentalmosaicismhasbeenassociatedwithgrowthrestriction.8
Congenitalanomalies
Growthrestrictionisnotedinmanyfetuseswithcongenitalanomalies,includingcardiacmalformations
(asmanyas50%to80%offetuseswithseptaldefects),anencephaly,andumbilicalarteryanomalies,
includingabnormalcordinsertions.Approximately25%offetuseswitha2vesselumbilicalcord
weighlessthan2500gatbirth.9Gastroschisisalsoisoftenassociatedwithgrowthrestrictionandis
presentinupto25%ofcases.10
Infection
Intrauterineinfectionunderlies5%to10%ofIUGR.8Worldwide,malariaaccountsforthemajorityof
infectionrelatedgrowthrestriction.Inaddition,otherprotozoaninfectionsincludingToxoplasma
gondii,Plasmodiumgondii,Plasmodiumsp.andTryanosomacruzihavebeenidentifiedaspotential
causesofIUGR.11Viralinfectiousetiologiesincludecytomegalovirus,rubella,toxoplasmosis,herpes
zoster,humanimmunodeficiencyvirus,varicella,andsyphilis.Todate,therearenospecificbacterial
infectionsassociatedwithIUGR,butchorioamnionitisisstronglyassociatedwithsymmetricgrowth
restrictionbetween28and36weeksgestation,andwithasymmetricgrowthrestrictionafter36weeks
gestation.12
Multiplegestations
Multiplegestationscarrya25%riskofIUGRintwinpregnanciesanda60%riskforhigherorder
gestations.13Inaddition,monochorionicpregnanciesareatanadditionalriskofdiscordantfetalgrowth
restrictionbecauseoftwintwintransfusionsyndromeorunequalplacentalbloodandnutrientsharing.
Maternalnutrition
Studieshaveshownthatseverelydecreasedmaternalcaloricandproteinintakeduringpregnancyis
associatedwithIUGR,especiallywhenitoccursbefore26weeksgestation.Glucoseuptakefrom
maternalcirculationistheprimarysourceforthefetus,andthematernalfetalglucoseconcentrationhas
beenshowntoincreaseingrowthrestriction.14Inaddition,decreasesinserumconcentrationsofzinc
andfolatehavebeenassociatedwithgrowthrestriction.15Themostimportantnutrientdeficiency
causingIUGRisoxygen.Decreasedoxygencontentinhibitsfetalmetabolism,leadingtosuboptimal
growth.16Manymaternalconditions,includinghemoglobinopathies,chronicpulmonarydisease,and
severematernalkyphoscoliosis,increaseriskofIUGR.
Environmentaltoxins
Maternalcigarettesmoking,excessalcoholingestion(ie,2ormoredrinksdaily),andillicitdruguse
(specificallycocaineabuse)havebeenassociatedwithIUGR.Cigarettesmokingsymmetrically
decreasesbirthweightby135to300g,butifstoppedbeforethethirdtrimester,theadverseeffectsare
reduced.17Exposuretocertainprescribedmedications,suchasphenytoin,warfarin,andtrimethadione,
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hasbeenassociatedwithanincreasedIUGRriskdependingonthetiming,dosage,andknown
teratogeniceffect.
Placentalfactors
Pooruteroplacentalperfusionasaresultofabnormalplacentationisthemostcommonplacental
etiologyassociatedwithIUGR,aconditiondefinedasplacentalinsufficiency.However,placental
insufficiencymaynotalwaysbethecauseoftheproblem,butrather,theconsequenceofapoorly
understood,moreglobal,diseaseprocess.18
Unfortunately,theprocessthattriggersthecascadeofeventsthatcausesplacentalinsufficiencyisoften
unknown.Placentalinsufficiencyischaracterizedeitherbyalackoftrophoblastmediatedphysiologic
changeinuterinespiralarteriesorbyabnormaldevelopmentofthevillousvasculartree.19Ineither
case,asfetaloxygendemandincreases,oxygendeliverytothefetalcirculationfallsbelowacritical
point,andthefetuscompensatesbyredistributingitsbloodflowfromthebodytothebrain,adrenal
glands,andheart.20TheseeventscanbedetectedbychangesinbloodflowDopplervelocitystudiesof
thefetus,21,22manifestedfirstasanelevatedsystolic/diastolicratio,thenanabsenceofdiastolic
velocity,andfinallybyreverseddiastolicvelocityintheumbilicalartery.23Fetalcardiacperformanceis
thencompromised,whichcanbedetectedbychangesinthevenousflowtotheheart(e.g.absenceor
reverseddiastolicflowoftheductusvenosus).IfalltheseDopplerabnormalitiesarepresent,thefetus
isatanincreasedriskofdeath.5,2427
PlacentalinsufficiencyisthemajorplacentalabnormalityseeninIUGRbuttherearemanyother
placentaldisorders,includingabruption,infarction,hemangioma,chrioangioma,andcircumvallate
shape,thathavebeenimplicated.
Maternalvasculardisease
Maternalmedicalconditionsassociatedwithvasculardiseasehavebeenknowntoresultinfetalgrowth
restriction.Thesedisordersincludediabetes,chronichypertension,pregnancyinducedhypertension,
advancingage,andmorbidobesity.
Detection
Diagnosisbymaternalphysicalexaminationalonehasproventobeinaccurateinupto50%ofcases.A
singlefundalheightmeasurementat32to34weeksgestationhasbeenreportedtobeapproximately
65%to85%sensitiveand96%specificfordetectingthegrowthrestrictedfetus.8WhenIUGRis
suspectedbymaternalfundalheight,ultrasoundforEFWassessmentshouldbeperformedusingfetal
biometry.IftheEFWisbelowthe10thpercentile,furthersonographicevaluationshouldbeperformed,
includingDopplerflowstudies,amnioticfluidassessment,andevaluationforstructuralabnormalities.
Duringinitialevaluation,itisimportanttonotewhethergrowthrestrictionissymmetric,asymmetric,
oramixedpattern.Intrinsicinsultsthatoccurearlyinpregnancyarelikelytoresultinasymmetric
growthrestriction.Incontrast,anextrinsicinsultoccurringlaterinpregnancywilllikelyresultin
asymmetricgrowthrestriction.Everyefforttoidentifyanetiologyshouldbeundertakenoncethe
diagnosisismade.
LimitationsinthecategorizationofIUGRcanbeattributedtotheroutinepracticeofgroupingall
growthrestrictedfetusesbasedonfetalweight.Oneproposedalternativegroupingisasfollows:1)
smallforgestationalage(SGA)referstothosesmallfetuseswithnodiscerniblepathologyandwith
normalumbilicalarteryandmiddlecerebralarteryDopplerresults2)growthrestrictionreferstosmall
fetuseswithrecognizablepathologyandabnormalDopplerstudiesand3)idiopathicgrowthrestriction
appliestosmallfetuseswithnodiscernablepathologyandabnormalDopplerstudies.28
StagingofIUGRhasalsobeenproposed.29Thisclassificationisbasedonfetalbiometry,Doppler
cardiovascularchanges,amnioticfluidvolume,andclinicalparameters.29Inaddition,thestaging
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systemisapplicabletopregnanciesatanygestationalage.Intheproposedstagingsystem:
Stage0includesfetuseswithanEFWoranAC<10thpercentile.Doppleroftheumbilicalartery
andmiddlecerebralarteryisnormal.
StageIincludesfetuseswhoseEFWorACis<10thpercentileplusabnormalDopplerflowofthe
umbilicalarteryormiddlecerebralartery.
StageIIincludesfetuseswhoseEFWorACis<10thpercentileplusabsentorreversedDoppler
flowoftheumbilicalartery.
StageIIIincludesfetuseswhoseEFWorACis<10thpercentileplusabsentorreversedDoppler
flowoftheductusvenosus.
Basedontheamnioticfluidindex,eachIUGRfetuswillbeeitherA(AFI<5cm)orB(AFI5cm).
Figures1to3showDopplerchangesinIUGRfetuses.
Stagingsystemandmanagement
Stage0SGAfetuseshaveagoodprognosis.TheyaremanagedasoutpatientwithDoppler
assessmentevery2weeks.IftheDopplerremainsnormal,deliveryisrecommendedatterm.Ifthe
Dopplerbecomesabnormal,thesefetusesaremanagedasStageIIUGRfetuses.
StageIIUGRfetusesareconsideredtohavemildgrowthrestriction,andaffectedmotherswhoare
withoutpreeclampsiaareusuallymanagedasoutpatients.Antenatalcorticosteroidsshouldbegivenat
timeofdiagnosis.Inthesefetuses,twiceweeklyantenataltestingisrecommended.Ifthenonstress
testing(NST)remainsreactiveandtheAFIremains>5.0cm,deliveryisrecommendedat37weeks
gestation.IftheumbilicalarteryDopplerbecomesabsent,thesefetusesshouldbemanagedasStageII
IUGR.
StageIIIUGRfetusesshouldbemanagedasinpatients.Duringhospitaladmission,thefetuses
shouldundergodailyantenataltestingwithtwicedailyNSTanddailybiophysicalprofile(BPP).Ifthe
NSTremainsreassuringandtheBPPscoreremainsbetween6and8of8,continuationofexpectant
managementisrecommended.Inaddition,antenatalcorticosteroidsshouldbegivenattimeof
diagnosis.Deliveryisrecommendedat34weeks.IfanyoftheaforementionedNSTsbecomenon
reassuringoriftheBPPscoreis4of8on2occasionsatleast4hoursapart,immediatedeliveryis
recommended.Deliveryshouldoccurviacesareandeliverybecausefetuseswithanabsent/reversed
flowoftheumbilicalarterywillnottoleratelaborinduction.
StageIIIIUGRfetusesaremanagedthesameasStageIIexceptfordeliveryat32weeks
gestation,regardlessofgestationalageattimeofdiagnosis.AswithStageIandII,antenatal
corticosteroidsshouldbegivenattimeofdiagnosis.
Theadvantageoftheabovescoringsystemisitssimplicity.Onlyfetalbiometry,sonographic
interrogationofthreefetalvessels,andtheamnioticfluidindexareneeded.Italsoallowsclassification
ofallsmallfetuses.OfnoteisthatiftheumbilicalarteryandmiddlecerebralarteryDopplerisnormal,
itisdeterminationofflowvelocitywaveformsoftheductusvenosusisunnecessarybecauseitwillbe
normalaswell.ThepresenceofIUGRinthesettingofpreeclampsiashouldnotdeterstandard
managementofpreeclampsia.

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Itisimportanttonotetherateofmortalityinthestagingsystem.29NodeathsoccurredinStage0or
StageIfetuses,whereasthemortalityforstageIIIfetusesishigh(50%iftherewasreversalofflowin
theductusvenosus85%mortalitywasobservedwhenreversalofflowintheductusvenosuswas
presentincombinationwithoneoftheotherparametersthatcharacterizestageIII),whereasthe
mortalityinstageIIIUGRfetuseswasintermediatebetweenstagesIandIII(Figure4).Also,studies
haveshownthatfetusescansurvivefordaysorweekswithreversalofflowintheductusvenosus.29A
recentpreliminarystudyreportedthatfetuseswithreversalofflowintheductusvenosuswillnot
necessarilybeacidemicatbirth.30Inaddition,themajorityofaffectedpregnancieshaveanAFI<5cm
beforefetaldemiseoccurs(Figure5).Thesedatacamefromastudyinwhichwewereabletofollow
veryearlyIUGRfetusesuptothetimeofdemisebecausethepatientshaddeclinedintervention.
Finally,categorizingIUGRbasedongestationalageattimeofdiagnosisisanovelconceptworth
mentioning.IUGRfetusesarecategorizedas:veryearlyIUGR(diagnosedat29weeks),earlyIUGR
(diagnosedbetween>29and<34weeks),andlateIUGRfetuses(diagnosedfollowing34weeks).The
notionofgroupingbasedongestationalageisimportantbecausemorbidityandmortalitydifferbased
ongestationalage,evenintheabsenceofcomplications.Todate,thisgroupingconcepthasnotbeen
studied.However,thisintroductorydiscussionmaystimulatefuturestudiesthatdelveintothis
particularclassificationsystem.
Unfortunately,itisunclearwhytherearedifferenttypesofIUGRbuttherearetwohypothesesthatwe
havepostulated:a)differentcausesfortheIUGRandb)thesamecausebutwithdifferentlevelsof
severity.
Timingofdelivery

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SeveralstudieshaveprovidedrecommendationsastothetimingofdeliveryforIUGRfetuses.Theloss
ofthebrainsparingeffectwasinitiallyconsideredaparametertoguidetimingofdelivery.31Other
studieshavereportedthatthereisatemporalsequenceofDopplerchangesprecedingtheonsetoflate
decelerations.32EarlyDopplerchangesoccurinalltheIUGRfetuses,whereaslateDopplerchanges
occurinidiopathicIUGRandonlyinafewIUGRcasesdiagnosedinpatientswith
preeclampsia(Figures6and7).33InidiopathicIUGRfetuses,thechangesoccuroneaftertheotherand
theyarepredictable.Inpreeclampticpatients,however,thechangesareunpredictable,canoccurina
fewhours,andinmostcases,donotoccurbecausedeliveryisdoneformaternalindication.33
FewrandomizedcontrolledtrialshavebeenperformedaddressingwhentodeliverIUGRfetuses.The
GrowthRestrictionInterventionTrial(GRIT)comparedtwomanagementstrategies:immediateversus
delayeddeliveryinhighriskpregnancieswhenclinicaluncertaintyprevailed.34Theresults
demonstratedthatdifferencesinperinatalmorbidityandmortality,neurologicaloutcome2yearsafter
birth,andlongtermoutcomewerenotstatisticallysignificantbetweenthetwogroups.35However,
antenataltestingviaBPPandDoppler(withtheexceptionoftheumbilicalartery)werenotusedfor
fetalsurveillanceinallcases.Inaddition,thegrowthrestrictedfetusesincludedinthestudy
representedaheterogeneouspopulationbecause,inthisstudy,onefourthofthefetuseshadnormal
umbilicalarteryflowvelocitywaveforms,indicatingtheymayhavesimplybeenSGA.
Asecondrandomizedtrial,theDisproportionateIntrauterineGrowthInterventionTrialatTerm
(DIGITAT),wasperformedintheNetherlands.Thisstudycomparedcompositeneonatalmorbidityand
mortalityofIUGRpregnanciesbeyond36weekswhounderwentimmediateinductionoflaborversus
expectantmanagementwithmaternalandfetalmonitoring.Inaddition,thestudyanalyzedsevere
maternalmorbidity,maternalqualityoflifeandcosts,andneurodevelopmentalandneurobehavioral
outcomesat2yearspostnatal.ThestudyconcludedthatinwomenwithsuspectedIUGRatterm,there
werenosignificantdifferencesinadversematernalorneonataloutcomesbetweeninductionoflabor
andexpectantmonitoring.[3640]
ArecentprospectivemulticenterobservationaltrialperformedinIrelandfoundthattheabnormal
umbilicalarteryandanestimatedfetalweight<3rdpercentilewereassociatedwithadverseperinatal
outcome.41
Timingofdeliveryforveryprematuregrowthrestrictedfetuses
Atthecurrenttime,itisnotpossibletoidentifyoptimaltimingofdeliveryforveryprematuregrowth
restrictedfetuses.IntheUnitedStates,mostphysiciansmakethedecisiontodeliveragrowthrestricted
fetusbasedonabnormalantenataltesting,anabnormalBPPoraCategoryIIorIIINST.Intermsof
survivalrate,thegrowthrestrictedfetusdeliveredat>25and<30weeksisthemostproblematic.Inour
experience,growthrestrictedfetusesdeliveredat<25weeksgestationdonotsurviveattheother
extreme,allgrowthrestrictedfetusessurvivedwhendeliveredat>30weeksgestation.42
Ascanbenoted,thereisanabsenceofrobustdatatorelyontodeterminetheoptimaltimingof
deliveryforveryprematuregrowthrestrictedfetuses.Itisourinstitutionspracticetomanageour
growthrestrictedfetusesbasedongestationalstage.WedelivertheveryearlyIUGRfetusesinthe
presenceofeitheraCategoryIIINSToranabnormalBPP(4/8confirmedat2hoursapartinpresence
ofCategoryIINSTorinthepresenceofaBPPof2/8independentlybytheNST).
Dopplerultrasoundasanindicationfordelivery
Asmentionedearlier,fetusesdiagnosedwithStageIorhigherIUGRinvolvingabnormalDoppler
studiesshouldbemonitoredclosely.Antenataltestingisrecommendedandfrequencyrangesfrom
twiceweeklytomultipletimesdaily,dependingonlevelofseverity.Deliverysolelyonthebasisof
abnormalDopplerstudieshasnotbeenprovenbeneficialand,inmostcases,fetuseswithabnormal
Dopplerstudiesdowellinthesettingofreassuringantenataltesting.IfantenataltestingisCategoryIII,
thenimmediatedeliveryiswarranted.
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DeliverymodeforIUGRfetuses
Dataseemtosupportcesareandeliveryforagrowthrestrictedfetuswhenthereisabsentorreversed
flowoftheumbilicalarterybecausethesefetusesrarelytolerateattemptsatvaginaldelivery.Caremust
beindividualized,however,becauseafetus34weekswithanabnormalumbilicalarteryS/Dratiobut
anormalBPPisnotlikelytotoleratelabor.
Summary
IUGRsecondarytoplacentalinsufficiencyremainsamajorcauseofperinatalmorbidityandmortality
intheUnitedStates.Thereisnosingletestthatappearssuperiortotheotheravailabletestsfor
determiningthetimingofdeliveryofthegrowthrestrictedfetus.Atourinstitution,webasethe
decisiononthecategoryoftheNSTorontheabnormalBPP.WemonitorsevereIUGRfetuses
(reversedflowoftheumbilicalarteryand/orreversedflowoftheductusvenosus)with3NST/day
(every8hours)+1BPP/day.Inaddition,administrationofantenatalcorticosteroidsinthesecasesis
ourcommonpractice.Insomecases,thefetalheartrateiscontinuouslymonitored.Webelievethatby
gainingafewdaysoratleastaweekbetween25and30weeksgestation,wecanmakeadifferencein
thefutureoftheIUGRfetus.33

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