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FetalGrowthRestriction:Overview,CausesofIntrauterineGrowthRestriction,PerinatalImplications
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FetalGrowthRestriction
Author:MichaelGRoss,MD,MPHChiefEditor:CarlVSmith,MDmore...
Updated:Nov10,2015

Overview
Intrauterinegrowthrestriction(IUGR)referstoaconditioninwhichafetusisunable
toachieveitsgeneticallydeterminedpotentialsize.Thisfunctionaldefinitionseeks
toidentifyapopulationoffetusesatriskformodifiablebutotherwisepoor
outcomes.Thisdefinitionintentionallyexcludesoffetusesthataresmallfor
gestationalage(SGA)butarenotpathologicallysmall.SGAisdefinedasgrowthat
the10thorlesspercentileforweightofallfetusesatthatgestationalage.Notall
fetusesthatareSGAarepathologicallygrowthrestrictedand,infact,maybe
constitutionallysmall.Similarly,notallfetusesthathavenotmettheirgenetic
growthpotentialareinlessthanthe10thpercentileforestimatedfetalweight
(EFW).
Ofallfetusesatorbelowthe10thpercentileforgrowth,onlyapproximately40%
areathighriskofpotentiallypreventableperinataldeath(seeimagebelow).
Another40%ofthesefetusesareconstitutionallysmall.Becausethisdiagnosis
maybemadewithcertaintyonlyinneonates,asignificantnumberoffetusesthat

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arehealthybutSGAwillbesubjectedtohighriskprotocolsand,potentially,
iatrogenicprematurity.

Fetalgrowthrestriction.Distributionofsmallfetuses.

Theremaining20%offetusesthatareSGAareintrinsicallysmallsecondarytoa
chromosomalorenvironmentaletiology.Examplesincludefetuseswithtrisomy18,
cytomegalovirusinfection,orfetalalcoholsyndrome.Thesefetusesarelesslikelyto
benefitfromprenatalintervention,andtheirprognosisismostcloselyrelatedtothe
underlyingetiology.
Theclinician'schallengeistoidentifyIUGRfetuseswhosehealthisendangeredin
uterobecauseofahostileintrauterineenvironmentandtomonitorandintervene
appropriately.Thischallengealsoincludesidentifyingsmallbuthealthyfetusesand
avoidingiatrogenicharmtothemortheirmothers.

CausesofIntrauterineGrowthRestriction
MaternalcausesofIUGR(adaptedfromSeverietal,2000)[1]includethefollowing:
Chronichypertension
Pregnancyassociatedhypertension
Cyanoticheartdisease
ClassForhigherdiabetes
Hemoglobinopathies
Autoimmunedisease
Proteincaloriemalnutrition
Smoking
Substanceabuse
Uterinemalformations
Thrombophilias
Prolongedhighaltitudeexposure
PlacentalorumbilicalcordcausesofIUGRincludethefollowing:
Twintotwintransfusionsyndrome
Placentalabnormalities
Chronicabruption
Placentaprevia
Abnormalcordinsertion
Cordanomalies
Multiplegestations
IUGRoccurswhengasexchangeandnutrientdeliverytothefetusarenotsufficient
toallowittothriveinutero.Thisprocesscanoccurprimarilybecauseofmaternal
diseasecausingdecreasedoxygencarryingcapacity(eg,cyanoticheartdisease,
smoking,hemoglobinopathy),adysfunctionaloxygendeliverysystemsecondaryto
maternalvasculardisease(eg,diabeteswithvasculardisease,hypertension,
autoimmunediseaseaffectingthevesselsleadingtotheplacenta),orplacental
damageresultingfrommaternaldisease(eg,smoking,thrombophilia,various
autoimmunediseases).
Evaluationofcausativefactorsforintrinsicdisordersleadingtopoorgrowthmay
includeafetalkaryotype,maternalserologyforinfectiousprocesses,andan
environmentalexposurehistory.

PerinatalImplications
IUGRcausesaspectrumofperinatalcomplications,includingfetalmorbidityand
mortality,iatrogenicprematurity,fetalcompromiseinlabor,needforinductionof
labor,andcesareandelivery.InacohortstudyinSweden,a10foldincreaseinlate

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fetaldeathswasfoundamongverysmallfetuses.Similarly,Gardosietalnotedin
1998thatnearly40%ofstillbornfetusesthatwerenotmalformedwereSGA. [2]
FetuseswithIUGRwhosurvivethecompromisedintrauterineenvironmentareat
increasedriskforneonatalmorbidity.MorbidityforneonateswithIUGRincludes
increasedratesofnecrotizingenterocolitis,thrombocytopenia,temperature
instability,andrenalfailure.Thesearethoughttooccurasaresultofthealteration
ofnormalfetalphysiologyinutero.
Withlimitednutritionalreserve,thefetusredistributesbloodflowtosustainfunction
andtohelpinthedevelopmentofvitalorgans.Thisiscalledthebrainsparingeffect
andresultsinincreasedrelativebloodflowtothebrain,heart,adrenals,and
placenta,withdiminishedrelativeflowtothebonemarrow,muscles,lungs,GItract,
andkidneys.Thebrainsparingeffectmayresultindifferentfetalgrowthpatterns.
In1977,CampbellandThomsintroducedtheideaofsymmetricversusasymmetric
growth. [3]Symmetricallysmallfetuseswerethoughttohavesomesortofearly
globalinsult(eg,aneuploidy,viralinfection,fetalalcoholsyndrome).Asymmetrically
smallfetuseswerethoughttobemorelikelysmallsecondarytoanimposed
restrictioninnutrientandgasexchange.Investigatorssincethenhavedisagreedon
theimportanceofthisdifferentiation.Dasheetalexaminedthisissueamong1364
infantswhowereSGA(20%wereasymmetricallygrown,80%symmetricallygrown)
and3873infantswhowereinthe2575thpercentile(ie,appropriateforgestational
age). [4]TheTableincludesaselectedlistofstatisticallysignificantperinatal
outcomesandeventsamongthesegroups.
Table.PerinatalEventsandOutcomes(OpenTableinanewwindow)

Event

Appropriate
Asymmetrically Symmetrically for
SGA
SGA
Gestational
Age

Anomalies

14%

4%

3%

SurvivorsNoserious
morbidity

86%

95%

95%

Laborinduction(<36wk)

12%

8%

5%

Intrapartumhighblood
pressure(<32wk)

7%

2%

1%

Cesareandeliveryfor
nonreassuringfetalheartrate

15%

8%

3%

Intubatedindeliveryroom

6%

4%

3%

NeonatalICUadmission

18%

9%

7%

Respiratorydistresssyndrome

9%

4%

3%

Intraventricularhemorrhage
(gradeIIIorIV)

2%

<1%

<1%

Neonataldeath

2%

1%

1%

Gestationalageatdelivery

36.6wk3.5
wk

37.8wk2.9
wk

37.1wk3.3
wk

Pretermbirth32wk

14%

6%

11%

ThesymmetricallygrowninfantswhowereSGAhadoutcomesverysimilartothe
infantswhowereappropriateforgestationalageandverydifferentprognosesthan
theasymmetricallySGAfetuses,thusreinforcingtheconceptofusinggrowth
parametersfordiagnosticandoutcomecounseling.
Severalstudieshaveaddressedprognosticfactorsinfluencingoutcomeandhave
consistentlyreportedthatthedominantinfluenceonsurvivalisgestationalageat
birth.MadazlireportedexperiencewithIUGRfetuseswithabsentenddiastolicflow.
Nofetuslessthan28weeks'andlessthan800gsurvived.Madazlialsonotedthat
allfetuseswithabsentenddiastolicflowgreaterthan31weeks'survived.The
variableperiodforsurvivaloccurredbetweenthesegestationalages,withantenatal
andneonatalsurvivalratesat2831weeks'ofapproximately54%. [5]
ThestressthatresultsinIUGRhasbeenpostulatedtoalsoresultinadvanced
maturationofthefetus,resultingindecreasedperinatalmorbiditycomparedwith
agematchednormallygrownneonates.Bernsteinetalexaminedthisissueby
identifyingalmost20,000whiteorAfricanAmericanneonatesfrom196centerswho
werebornat2530weeks'gestationwithoutmajoranomalies. [6]Theycategorized
infantsasIUGRatlessthanthe10thpercentileusingraceandsexspecificgrowth
charts.Theseresultsdonotsupporttheconceptofastressrelatedprotectiveeffect
ofIUGR.
RelativerisksassociatedwithIUGRusingmorbidityandmortalityparameters,from
thestudybyBernsteinetal,areasfollows:
Relativeriskofdeath,2.7795%confidenceinterval(CI),2.313.33
Relativeriskofrespiratorydistresssyndrome,1.1995%CI,1.031.29
Relativeriskofintraventricularhemorrhage,1.1395%CI,0.991.29
Relativeriskofsevereintravascularhemorrhage,1.2795%CI,0.981.59
Relativeriskofnecrotizingenterocolitis,1.2795%CI,1.051.53
Increasingly,datasupporttheideathatlongtermconsequencesofIUGRlastwell
intoadulthood.Severalauthorshavenotedthattheseindividualshaveagreater

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predispositiontodevelopametabolicsyndromelaterinlife,manifestingasobesity,
hypertension,hypercholesterolemia,cardiovasculardisease,andtype2diabetes.
Severalhypotheseshavebeenproposedtoexplainthisrelationship.Halesand
Barkerproposedthesocalledthriftyphenotypein1992.Thisideasuggeststhat
intrauterinemalnutritionresultsininsulinresistance,lossofpancreaticbetacell
mass,andanadultpredispositiontotype2diabetes.
OtherauthorsfoundthatprepubertalindividualswhohadIUGRatbirthshowa
greaterinsulinresponsethanprepubertalindividualswhohadhealthygrowthas
infants.Thissuggeststhattheincreasedriskoftype2diabetesinadultswhohad
restrictionasinfantsstems,instead,fromincreasedperipheralinsulinresistance
allowingthebrainsparingphysiologytooccurbutwithapermanentreductionin
skeletalmuscleglucosetransport.Thisultimatelyresultsinbetacellburnout.
Althoughthecausativepathophysiologyisuncertain,theriskofametabolic
syndromeinadulthoodisclearlyincreasedamongindividualswhohadIUGRat
birth.
Organsystemspecificmorbidity,asaresultofgrowthrestriction,isnowbeing
evaluatedusingdifferentanimalspeciesandmodels.Humanstudieshaveclearly
showorganspecificsequelaeofIUGR.Kaijseretal,usingalargecohort,wereable
todemonstrateanassociationbetweenlowbirthweightandadultriskofischemic
heartdisease. [7]Hallanetaldemonstratedthatadultkidneyfunctionisadversely
affectedbyrestrictedintrauterinegrowth. [8]
Inadditiontoanincreasedriskforphysicalsequelae,mentalhealthproblemshave
beenfoundmorecommonlyinchildrenwithgrowthrestriction.Inastudyperformed
inWesternAustralia,Zubricketalshowedthatchildrenbornbelowthesecond
percentileforweightwereatsignificantriskformentalhealthmorbidity(oddsratio,
2.995%CI,1.187.12),academicimpairment(oddsratio,695%Cl,2.2516.06),
andpoorergeneralhealth(oddsratio,5.195%Cl,1.6915.52). [9]Specifically,
Tidemanetalhaveshownthatimpairedfetalcirculation,asdemonstratedby
Dopplerstudies,inassociationwithIUGR,resultsinworsenedcognitivefunctionin
adulthood. [10]

DiagnosisandSurveillance
CriteriafordiagnosisofIUGR
Formostpurposes,anEFWatorbelowthe10thpercentileisusedtoidentify
fetusesatrisk.Importantly,however,understandthatthisisnotadefinitivecutoff
foruteroplacentalinsufficiency.Acertainnumberoffetusesatorbelowthe10th
percentilemaybeconstitutionallysmall.Inthesecases,shortmaternalorpaternal
height,theneonate'sabilitytomaintaingrowthalongastandardizedcurve,anda
lackofothersignsofuteroplacentalinsufficiency(eg,oligohydramnios,abnormal
Dopplerfindings)canbereassuringtotheclinicianandparents.Customizedgrowth
curvesforethnicity,parentalsize,andgenderareindevelopmentsoastoimprove
sensitivityandspecificityofdiagnosingIUGR. [11,12]
Importantly,reviewthedatingcriteriabeforeofferinginterventiontotreatgrowth
restrictioninafetus.Ifdatesareuncertainorunknown,obtainingasecondgrowth
assessmentovera2to4weekintervalmaybeofvalueunlessstrongsupportive
dataorriskfactorswarrantanimmediatechangeinmanagementplans.

Screeningthefetusforgrowthrestriction
AlthoughnosinglebiometricorDopplermeasurementiscompletelyaccuratefor
helpingmakeorexcludethediagnosisofgrowthrestriction,screeningforIUGRis
importanttoidentifyatriskfetuses.Dependentuponthematernalcondition
associatedwithIUGR(seeMaternalcausesofIUGR)patientsmayundergoserial
sonographyduringtheirpregnancies.Aninitialscanmaybeobtainedinthemiddle
ofthesecondtrimester(at1820wk)toconfirmdates,evaluateforanomalies,and
identifymultiplegestations.Arepeatscanmaybescheduledat2832weeks'
gestationtoassessfetalgrowth,evidenceofasymmetry,andstigmataofbrain
sparingphysiology(eg,oligohydramnios,abnormalDopplerfindings).
ScreeningforIUGRinthegeneralpopulationreliesonsymphysisfundalheight
measurements.Thisisaroutineportionofprenatalcarefrom20weeks'untilterm.
Althoughrecentstudieshavequestionedtheaccuracyoffundalheight
measurements,particularlyinobesepatients,adiscrepancyofgreaterthan3cm
betweenobservedandexpectedmeasurementsmaypromptagrowthevaluation
usingultrasound. [13]Theclinicianshouldbeawarethatthesensitivityoffundal
heightmeasurementislimited,andheorsheshouldmaintainaheightened
awarenessforpotentialgrowthrestrictedfetuses.Inanunselectedhospital
population,only26%offetusesthatwereSGAweresuggestedtobeSGAbased
onclinicalexaminationfindings.
Onestudyusingfundalheightcurvesthatcustomizedformaternalweight,height,
andethnicitywasabletoincreasethedetectionratefrom29.2%inthecontrol
groupto47.9%inthestudypopulation.AsYoshidaetalindicated,these
inaccuraciesoccur(1)becauseofthelimitedaccuracyofpredictingbirthweight
within10%usingultrasonographyinthethirdtrimester,(2)becausenotallfetuses
thatareSGAhaveIUGR,(3)becauseindividualandunpredictablechangesin
growthpotentialoccur,and(4)becausegrowthdistributionisacontinuum. [14]

Biometryandamnioticfluidvolumes
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Mostultrasonographicmachinesreportaggregategestationalagemeasurements
andindividualparameters.Assessingindividualvaluesisimportanttoidentifya
fetusthatisgrowingasymmetrically.Inthepresenceofnormalheadandfemur
measurements,abdominalcircumference(AC)measurementsoflessthan2
standarddeviationsbelowthemeanappeartobeareasonablecutofftoconsidera
fetusasymmetric.BaschatandWeinershowedthatalowACpercentilehadthe
highestsensitivity(98.1%)fordiagnosingIUGR(birthweight<10thpercentile).The
sensitivityofEFW(birthweightbelowthe10thpercentile)is85.7%however,an
ACbelowthe2.5percentilehadthelowestpositivepredictivevalue(36.3%),while
alowEFWhada50%positivepredictivevalue. [15]
Supportingevidenceofahostileintrauterineenvironmentcanbeobtainedby
specificallylookingatamnioticfluidvolumes(AFVs).Chauhanetalfoundthatina
groupofnormalpregnanciesgreaterthan24weeks',therateofIUGRwas19%
withanamnioticfluidindex(AFI)oflessthan5and9%withanAFIhigherthan5
(oddsratio,2.1395%CI,1.104.16). [16]BanksandMilleralsonotedasignificantly
increasedriskofIUGRinagroupoffetuseswithborderlineamnioticfluid(AFIof5
10)relativetoagroupofnormalfetuses(AFI>10)(13%vs3.6%rateratio,3.9
95%CI,1.216.2). [17]TheseresultsconfirmmuchearlierworkbyChamberlainetal.
[18]

TheseauthorsshowedanincreasedrateofIUGRamongfetuseswithdecreasing
maximumverticalpocket(MVP)values.AnMVPmeasurementoflargerthan2cm
wasassociatedwithanIUGRrateof5%,anMVPvaluesmallerthan2cmwas
associatedwithanIUGRrateof20%,andanMVPmeasurementofsmallerthan1
cmwasassociatedwithanIUGRrateof39%.Chamberlainetalconcludedthat
decreasedAFImaybeanearlymarkerofdecliningplacentalfunction. [18]

UterinearteryDopplermeasurement
BotharterialDopplerandvenousDopplerhavebeenusedinrecentliteratureto
supportexpectantmanagementordeliveryofIUGRfetusesandtoidentifyfetuses
atrisk.Dopplervelocimetryhasbeenshowntocontributetotheidentificationof
fetusesatriskofIUGR.TofollowisanoverviewofthevariousDopplertechniques
andtheirclinicalapplications.
Flowpatternsofmaternaluterinearterieshavebeenshowntoreflecttheimpactof
placentationonmaternalcirculation.Albaigesetalsuggestthataonestageuterine
arteryscreeningat23weeks'gestationiseffectiveinidentifyingpregnanciesthat
willhavepoorperinataloutcomespriorto34weeks'gestationrelatedto
uteroplacentalinsufficiency.Intheirstudyof1751womenwhowereseenat23
weeks'gestationforanyreason,anabnormaluterinearterystudyresultincluded
bilateraluterinearterynotchesorameanpulsatilityindex(PI)ofgreaterthan1.45
inbotharteries. [19]
Thesecriteriawereobservedinapproximately7%ofthepopulation.Withinthis7%
were90%ofthewomenwholaterdevelopedpreeclampsiaandrequireddelivery
before34weeks'gestation,70%ofwomenwithafetusbelowthe10thpercentile
whorequireddeliverybefore34weeks'gestation,50%ofplacentalabruptions,and
80%offetaldeaths.Importantly,thenegativepredictivevaluefortheseadverse
eventspriorto34weeks'gestationwashigherthan99%.
Chienandcolleaguesconductedanoverviewofpublishedstudiesontheefficacyof
uterinearteryDopplerfindingsasapredictorofpreeclampsia,IUGR,andperinatal
death. [20]Inreportsofstudiesperformedonlowriskwomen,anabnormaluterine
arteryDopplerresultyieldedalikelihoodratio(LR)ofdevelopingIUGRof3.6(95%
CI,3.24),whileanormaltestresultreducedtherisktobelowbackground,withan
LRof0.8(95%CI,0.080.09).Forwomenathighrisk,anabnormaltestresult
indicatedanLRof2.7(95%CI,2.13.4),whileanormalresultreducedtherisksby
30%(LRof0.795%CI,0.60.9).
Althoughthesemeasurementsappearpromising,thesensitivityandspecificityof
uterinearteryDopplermeasurementsisrelativelylow,and,becausenoproven
interventionsareavailabletopreventIUGR,uterinearterybloodflowmeasurements
arenotincludedinroutinesurveillanceprotocols.

UmbilicalarteryDopplermeasurement
Innormalpregnancies,umbilicalartery(UA)resistanceshowsacontinuousdecline
however,thismaynotoccurinfetuseswithuteroplacentalinsufficiency.Themost
commonlyusedmeasureofgestationalagespecificUAresistanceisthesystolic
todiastolicratioofflow,whichchangesfromabaselinevaluetoanelevatedvalue
withworseningdisease.Astheinsufficiencyprogresses,enddiastolicvelocityislost
and,finally,reversed.Theclinicalsignificanceofthisprogressionhasbeenwell
documentedbyMandruzzatoetal,whoreportedasignificantdifferenceinmean
birthweightandperinatalmortalityforabsentenddiastolicvelocity(20%)versus
reversedenddiastolicvelocity(68%). [21]
ThestatusofUAbloodflowcorroboratesthediagnosisofIUGRandprovidesearly
evidenceofcirculatoryabnormalitiesinthefetus,enablingclinicianstoidentifythe
highriskstatusofthesefetusesandtoinitiatesurveillance(seeManagementand
DeliveryPlanning).
UADopplermeasurementsmayhelpthecliniciandecidewhetherasmallfetusis
trulygrowthrestricted.

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BaschatandWeinerlookedatUAresistancetodetermineifitcanhelpimprovethe
accuracyofdiagnosingIUGRandhelpidentifyasmallfetusatriskofchronic
hypoxemia.Theseinvestigatorsidentified308babiesgreaterthan23weeks'atthe
timeofdeliverywhohadanACoflessthanthe2.5percentile,anEFWoflessthan
the10thpercentile,orbothcriteria.UAmeasurementswereobtainedonallof
thesefetuses.ThepositivepredictivevaluesofACaloneandEFWaloneforthe
diagnosisofIUGRwere36.6%and50%,respectively.AnelevatedUAsystolicto
diastolicratioyieldedapositivepredictivevalueof53.3%forpostnatallyconfirmed
IUGR.
Amongall138identifiedfetuseswithanelevatedUAsystolictodiastolicratio,a
10foldincreaseoccurredintherateofadmissiontoandthedurationofstayin
neonatalICUsandinthefrequencyandseverityofrespiratorydistresssyndrome.
Equallyimportantly,nofetuswithnormalDopplermeasurementswasdeliveredwith
documentedmetabolicacidemia. [15]

MiddlecerebralarteryDoppler
Fongandcolleaguesidentified297singletonpregnanciesinwhichEFWwasbelow
the10thpercentileinanatomicallynormalfetuses.Theseinvestigatorsstudied
middlecerebralartery(MCA),renalartery,andUADopplerfindings.They
addressedoutcomes,includingcesareandeliveryforfetaldistress,cordpHless
thanorequalto7.10,andApgarscorelessthanorequalto7at5minutes.They
concludedthatanormalMCADopplerfindingmaybeusefultohelpidentifysmall
fetusesthatarenotlikelytohaveamajoradverseoutcomewithareportednegative
predictivevalueof86%. [22]
HershkovitzetalalsolookedatMCADopplerfindsinsmallfetuses.Theyfound
thatthosefetuseswithabnormalMCAstudyresultshadearlierdeliveries,lower
birthweights,fewervaginaldeliveries,andincreasedadmissionstoneonatalICUs.
Importantly,only7of16fetuseswithDopplerevidenceofbrainsparingphysiology
hadelevatedUADopplerfindings.Thisemphasizedthepossiblepresenceofa
gradientinthedegreeoffetalredistributionandthatwhenperformingDoppler
studies,evaluatingonlytheUAsmaynotbesufficient. [23]
SpecificMCADopplerchangeswereevaluatedbyMarietal.Theyspecifically
evaluatedMCApeaksystolicvelocity(PSV)andpulsatilityindex(PI)ingrowth
restrictedfetusesthatwerelongitudinallyevaluated.Theyfoundthatwhilean
abnormalPIprecededanabnormalPSV,thePIdemonstratedaninconsistent
pattern.MCAPSV,however,consistentlyshowedanincreaseinbloodvelocityand
immediatelypriortodemise,adecrease.TheyconcludedthatMCAPSVisabetter
predictorofIUGRassociatedperinatalmortalitythananyothersingle
measurement. [24]

VenousDopplerwaveforms
VenousDopplerhasbeenmeasuredattheductusvenosus(DV),umbilicalvein
(UV),inferiorvenacava(IVC),and7othersites.Thisprovidesinformationabout
fetalcardiovascularandrespiratoryresponsestoitsintrauterineenvironment.These
measurementshavebeenreportedtobecomeconsistentlyabnormalwhenafetus
isseverelycompromised,thusprovidingevidenceinsupportofanexpedited
delivery.Bilardoetalcompletedaprospectivestudyofthecardiotocography,UA,
andDVvaluesof70IUGRfetusesandtheiroutcomes. [25]Theyreportedthatonly
theDVmeasurementsconsistentlypredictedadverseperinataloutcomesfrom07
dayspriortodelivery.WhiletheoptimalvesselforuseforvenousDoppler
evaluationshasnotbeenidentified,theknowledgegainedfromthese
measurementsmayprovideadditionalinformationforthetimingofdelivery,
especiallyinextremelypremature(<32wk)gestations.

Threedimensionalultrasonography
Withtheintroductionanduseofobstetrical3dimensionalultrasonography,many
newapplicationsforthistechnologyareconstantlyexplored.Theuseofthese
techniquesintheevaluationofthegrowthrestrictedfetushasbeenevaluatedas
well.AsfetalfemurdysplasiaisassociatedwithIUGR,Changetalused3
dimensionalultrasonographytomeasurefetalfemurvolumeasapredictorofIUGR.
Theyfounda10thpercentilefemurvolumethreshold,whichdifferentiatesgrowth
restrictedfetusesfromnormalfetuses.Usingthistechnique,theyobtaineda
sensitivityof71.4%,specificityof94.1%,positivepredictivevalueof62.5%,
negativepredictivevalueof96.0%,andaccuracyof91.3%inpredictionofgrowth
restriction.Asasinglebiometricmeasurement,fetalfemurvolumeisbetterin
predictionofgrowthrestrictionthanfetalACandbiparietaldiameter. [26]Changetal
alsoevaluated3dimensionalultrasonographicmeasurementoffetalhumerus
volumeinevaluationofIUGR.Again,a10thpercentilehumerusvolumethresholdwas
foundtodifferentiategrowthrestrictedfetusesfromnormalfetuses. [27]

Therapeuticoptions
Althoughmultipletherapeuticstrategieshavebeentestedtopromoteintrauterine
growthanddecreaseperinatalmorbidityandmortality,limited,ifany,successhas
beenachievedinthisarea.Glmezogluetalreportedresultsofmetaanalysesof
studies,thegoalsofwhichweretotreatimpairedgrowth.Inthisreview,3
interventionswereshowntobehelpful.First,behavioralstrategiestoquitsmoking
resultinalowerrateoflowbirthweightinbabiesattermamongmotherswho
smoke.Second,balancednutritionalsupplementsinundernourishedwomenand

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magnesiumandfolatesupplementation(insomestudies)decreasetherateofSGA
newborns.Third,ifmalariaistheetiologicagent,maternaltreatmentofmalariacan
increasefetalgrowth. [28]
Pollacketaladditionallyexaminedinhospitalbedrestasawaytopromotefetal
growthandfoundnoimprovement. [29]Newnhametalstudiedwomenreceiving100
mgofaspirinversusplaceboafteradiagnosisofIUGRbasedonabnormalUA
Dopplerfindings,andtheydidnotfindaclinicallysignificantdifference. [30]
Otheroptionshavebeenconsideredwithagoalofdecreasingperinatalmorbidity
andmortality.In2003,Sayetalreviewedmaternalestrogenadministration,
maternalhyperoxygenation,andmaternalnutrientsupplementationastherapiesfor
suspectedimpairedfetalgrowth. [31,32,33]Theyconcludedthatevidencetoevaluate
therisksandbenefitsofthesetherapieswaslacking.However,theydidsuggest
thatfurthertrialsofmaternalhyperoxygenationseemwarranted.
Additionaltherapiesthathavebeenproposedandmaywarrantfurtherstudyare
maternalhemodilutionandintermittentabdominalnegativepressure.Theseare
alsopoorlystudied,carrypotentialmaternalandfetalharm,andshouldbe
consideredexperimental.
Theonlyinterventionthathasbeenshowntodecreaseneonatalmorbidityand
mortalityistheadministrationofsteroidstoprematurefetuseswhendeliveryis
anticipated.Bernsteinetaldescribedtheeffectofmaternalprenatalglucocorticoid
administrationingrowthrestrictedfetusesandfoundthebenefitstobesimilarto
thosefoundingestationalagematched,normallygrownfetuses.
Oddsratioreductionwithsteroids,fromBernsteinetal,isasfollows:
Relativeriskofdeath,0.5495%CI,0.480.62
Relativeriskofrespiratorydistresssyndrome,0.5195%CI,0.440.58
Relativeriskofintraventricularhemorrhage,0.6795%CI,0.610.73
Relativeriskofsevereintravascularhemorrhage,0.595%CI,0.430.57
Relativeriskofnecrotizingenterocolitis,nodifferencenoted
Recently,severalstudieshavequestionedthemetabolicandcardiovascular
responseofIUGRfetusestomaternalglucocorticoidadministration.Simchenetal
performedaprospectivelongitudinalstudyofchromosomallynormalIUGRfetuses
at2434weeks'withabsentorreversedenddiastolicflow.Theyfoundadivergent
responsebetweenthe2groupsoffetusesasmeasuredbyUADoppler.Almost
45%ofthesefetuseshadtransientimprovementintheirDopplerwaveforms,and
thesefetuseshadsignificantlybetteroutcomesthantheircounterpartswhohadno
improvementoftheirwaveforms,eventransiently.Theseauthorssuggestthatdaily
Dopplerbasedmonitoringaftertheadministrationofsteroidscanhelpdelineatea
groupoffetusesatextremelyhighriskofacidosisandmortality.Theyalsosuggest
thatfurtherworkisneededtoelucidatetheefficacyofsteroidsversusimmediate
deliveryinthisveryhighrisksubsetofIUGRfetuses. [34]

ManagementandDeliveryPlanning
OnceIUGRhasbeendetected,themanagementofthepregnancyshoulddepend
onasurveillanceplanthatmaximizesgestationalagewhileminimizingtherisksof
neonatalmorbidityandmortality.Thisshouldincludesteroidadministrationwhenat
allfeasible,basedonthemonitoringanddeliverystrategiesdiscussedbelow(see
imagebelowandHarmanandBaschat'sintegratedfetaltestingforIUGR).Fetal
lungmaturitystudiesbyamniocentesis,infetusesgreaterthan34weeks',may
additionallyinfluencedeliverytiming.
ThegoalinthemanagementofIUGR,becausenoeffectivetreatmentsareknown,
istodeliverthemostmaturefetusinthebestphysiologicalconditionpossiblewhile
minimizingtherisktothemother.Suchagoalrequirestheuseofantenataltesting
withthehopeofidentifyingthefetuswithIUGRbeforeitbecomesacidotic.
Developingatestingscheme,followingit,andhavingahighindexofsuspicionin
thispopulationwhenresultsoftestingareabnormalisimportant.Thepositive
predictivevalueofanabnormalantenataltestresultinfetuseswithIUGRis
relativelyhighbecausetheprevalenceofacidemiaandchronichypoxemiais
relativelyhigh.
Althoughnumerousprotocolshavebeensuggestedforantenatalmonitoringof
IUGRfetuses,themainstayincludesaweeklynonstresstest(NST).Additional
modalitiesmayincludeamnioticfluidvolumedetermination,biophysicalprofiles,
and/orDopplerassessments.Othermorecomplexprotocolshavebeenproposed.
TheprotocolforantenataltestingsuggestedbyKramerandWeiner(seeimage
below)isoneexample.ItreliesheavilyontheuseofUADopplertestingbecause
severelyabnormalDopplerfindings(absentorreversedenddiastolicflow)can
precedeanabnormalfetalheartratebyseveralweeks.HarmanandBaschat
suggestedadifferentproposedantenataltestingstrategy.Thisprotocolintegrates
multiplevenousandarterialDopplermeasurementsandthebiophysicalprofile
score(BPS)thisstrategymaybeusedatinstitutionswherethesemeasurements
areroutinelyobtainedbyqualifiedtechnicians. [35]

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Fetalgrowthrestriction.Sampleprotocolforantenataltestingforintrauterinegrowthrestrictionat
32weeks'gestationorafter.IUGRisintrauterinegrowthrestriction,BPPisbiophysicalprofile,
andEDFisenddiastolicflow.

HarmanandBaschat'sintegratedfetaltestingforIUGR,inincreasingorderof
severityfrom1(leastsevere)to5(mostsevere),isasfollows: [35]

Situation1
Seethelistbelow:
TestresultsAClessthanfifthpercentile,lowACgrowthrate,highratioof
headcircumferencetoACBPSgreaterthanorequalto8andAFVnormal
abnormalUVand/orcerebroplacentalrationormalMCA
InterpretationIUGRdiagnosed,asphyxiaextremelyrare,increasedriskfor
intrapartumdistress
RecommendedmanagementInterventionforobstetricormaternalfactors
only,weeklyBPS,multivesselDopplerevery2weeks

Situation2
Seethelistbelow:
TestresultsIUGRcriteriamet,BPSgreaterthanorequalto8,AFV
normal,UAwithabsentorreversedenddiastolicvelocities,decreasedMCA
InterpretationIUGRwithbrainsparing,hypoxemiapossibleandasphyxia
rare,atriskforintrapartumdistress
RecommendedmanagementInterventionforobstetricormaternalfactors
onlyBPS3timesaweekweeklyUA,MCA,andvenousDoppler

Situation3
Seethelistbelow:
TestresultsIUGRwithlowMCAPIoligohydramniosBPSgreaterthanor
equalto6normalIVC,DV,andUVflow
InterpretationIUGRwithsignificantbrainsparing,onsetoffetal
compromise,hypoxemiacommon,acidemia/asphyxiapossible
RecommendedmanagementIfatmorethan34weeks'gestation,deliver
(routedeterminedbyobstetricfactors).Ifatlessthan34weeks'gestation,
administersteroidstoachievelungmaturityandrepeatalltestingin24
hours.

Situation4
Seethelistbelow:
TestresultsIUGRwithbrainsparing,oligohydramnios,BPSgreaterthan
orequalto6,increasedIVCandDVindices,UVflownormal
InterpretationIUGRwithbrainsparing,provenfetalcompromise,
hypoxemiacommon,acidemia/asphyxialikely
RecommendedmanagementIfatmorethan34weeks'gestation,deliver
(routedeterminedbyobstetricfactorsandoxytocinchallengetest[OCT]
results).Ifatlessthan34weeks'gestation,individualizetreatmentwith
admission,continuouscardiotocography,steroids,maternaloxygen,and/or
amnioinfusionandthenrepeatalltestingupto3timesadaydependingon
status.

Situation5
Seethelistbelow:
TestresultsIUGRwithacceleratingcompromise,BPSlessthanorequal
to6,abnormalIVCandDVindices,pulsatileUVflow
InterpretationIUGRwithdecompensation,cardiovascularinstability,
hypoxemiacertain,acidemia/asphyxiacommon,highperinatalmortality,

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deathimminent
RecommendedmanagementIffetusisconsideredviablebysize,deliver
assoonaspossibleattertiarycenter.Routedeterminedbyobstetricfactors
andOCTresults.FetusrequireshighestlevelofnatalICUcare.
ThediagnosisofsevereIUGRbefore32weeks'gestationisassociatedwithapoor
prognosis,andtherapymustbehighlyindividualized.Onceadecisionhasbeen
madetoeffectdelivery,themodeofdeliveryisgovernedbyevidenceofacidemia,
gestationalage,andBishopscore.Cesareandeliverywithoutatrialoflabormaybe
appropriate(1)inthepresenceofevidenceoffetaldistressbynonstresstestingor
reverseddiastolicflowor(2)fortraditionalobstetricalindicationsforcesarean
delivery(ie,malpresentation,priorcesareandelivery).
LietalinvestigatedthesuccessrateofinductionoflaborinIUGRfetuseswithand
withoutUAbloodflowchangesandtheneonataloutcomesofinducedfetuseswith
anegativeresultafteranOCT.Theyfoundthatfetuseswithabnormal(butnot
absentorreversed)UAbloodflowwhohadanormalOCTresulthadsimilar
successininductionoflabor,withoutindicationsofdetrimentalfetalhypoxiaor
distress. [36]ThissuggeststhatinfetuseswithalteredUAbloodflow,anOCTmay
beappropriatetoselectfetusesthatwilltoleratelaborinduction.
Whenatrialoflaborisundertaken,continuousheartratemonitoringshould
optimizethesuccessoftheinduction.

FutureDirectionsandPrevention
PreventionofIUGRishighlydesirable,andseveralstudieshaveaddressedthis
potential.Investigatorshavelookedatalteringthethromboxanetoprostacyclinratio
byadministeringaspirinwithorwithoutdipyridamoletomothersoffetuseswith
IUGR.ThestudiesexaminingtheseagentsforpreventionofIUGRaredifficultto
compare.Differentdosesofaspirin,differenttimesofadministrationinpregnancy,
anddifferentindicationsforusemakecomparisonsdifficulthowever,thefollowing
isasummaryofthestudies:
WallenburgetalstudiedapopulationofwomenathighriskforIUGRina
nonrandomizedtrialusinghistoriccontrols.Theynotedadeclineintherate
ofIUGRfrom61.5%inthehistoriccontrolsto13.3%inthosetreatedwith
aspirinanddipyridamole. [37]
Sibaietalstudiedlowrisknulliparouswomeninadoubleblinded,placebo
controlled,randomizedtrial.Patientsweretreatedfromweeks1326with
eitherplaceboor60mg/dofaspirin.Thisstudyshowedasmalldecreasein
therateofpreeclampsiabutnotIUGR(4.6%vs5.8%incontrols),attherisk
ofincreasedchanceofabruption. [38]
IntheEssaiPreeclampsiaDipyridamoleAspirine(EPREDA)randomized
controlledtrial,highriskpatientsreceivedplacebo,aspirinonly,oraspirin
plusdipyridamole.NodifferenceintherateofIUGRwasfoundbetween
thosereceivingaspirinaloneandthosereceivingaspirinplusdipyridamole.
ThecontrolrateofIUGRwas26%inthe2groupsreceivingaspirinwithor
withoutdipyridamole,theratewas13%. [39]
InanItalianstudy,womenconsideredtobeatmoderateriskofIUGRor
pregnancyinducedhypertensionat1632weeks'gestationwererandomly
assignedtoreceiveeither50mgaspirinornotreatment.Nodifferencein
anyoutcomestudiedwasfoundbetweenthe2groups. [40]
HarringtonetalidentifiedpatientswithabnormaluterinearteryDoppler
findingsat20weeks'gestation.Participantswerestartedonaspirin,and
therapywasdiscontinuedat24weeks'ifrepeatDopplerresultsnormalized.
NodifferenceintherateoffetusesthatwereSGAbelowthe10thorthird
percentilewasfoundbetweenthetreatedandcontrolgroups. [41]
Trudingeretalperformedadoubleblinded,randomizedclinicaltrialusing
150mgofaspirininpregnantwomenwithabnormalUADopplerfindings.
Theresultwasanincreaseinbirthweightof516gandanincreasein
placentalweight. [42]
TheCollaborativeLowDoseAspirinStudyinPregnancytrial,which
investigatedbothpreventionandtreatmentofIUGR,showednochangein
therateofIUGRintreatedandcontrolpatientswiththeadministrationof60
mgofaspirin. [43]
Leitichetalperformedametaanalysisof13trialsinwhichwomenwere
enrolledforprophylacticaspirintherapy.Inwomentreated,theoddsratiofor
IUGRwas0.82(95%Cl,0.661.08).Amongthosetrialsinwhichwomen
werehypertensiveorhadotherriskfactors,theriskofIUGRwasclearly
decreased.Leitichetalfoundthatbeginning100150mg/dofaspirinatless
than17weeks'gestationdecreasedtherateofIUGRbyapproximately65%
andtherateofperinatalmortalitybyapproximately60%. [44]
TheDisproportionateIntrauterineGrowthInterventionTrialAtTerm
(DIGITAT)suggeststhatwomenwhohavehadaprevioussingleton
pregnancybeyond36weeksgestationcansafelychooseexpectant
managementwithintensivematernalandfetalmonitoringifinductionisnot
wanted. [45]Choosinginductiontopreventneonatalmorbidityorstillbirthis
reasonable.
Despitethetheoreticalbenefitofaspirininmanystudies,theroleofaspirin,ifany,
inthepreventionofIUGRisstillunclear.Alargerandomizedcontrolledtrialusinga
standardizedhighriskpopulationwithastandardizedtreatmentregimencouldserve
tobetteranswerthisquestion.

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Conclusion
IUGRremainsachallengingproblemforclinicians.MostcasesofIUGRoccurin
pregnanciesinwhichnoriskfactorsarepresenttherefore,theclinicianmustbe
alerttothepossibilityofagrowthdisturbanceinallpregnancies.Nosingle
measurementhelpssecurethediagnosisthus,acomplexstrategyfordiagnosis
andassessmentisnecessary.Theabilitytodiagnosethedisorderandunderstand
itspathophysiologystilloutpacestheabilitytopreventortreatitscomplications.
Thecurrenttherapeuticgoalsaretooptimizethetimingofdeliverytominimize
hypoxemiaandmaximizegestationalageandmaternaloutcome.Furtherstudymay
elucidatepreventiveortreatmentstrategiestoassistthegrowthrestrictedfetus.

ContributorInformationandDisclosures
Author
MichaelGRoss,MD,MPHProfessorofObstetricsandGynecology,UniversityofCalifornia,LosAngeles,
DavidGeffenSchoolofMedicineProfessor,DepartmentofCommunityHealthSciences,FieldingSchoolof
PublicHealthatUniversityofCaliforniaatLosAngeles
MichaelGRoss,MD,MPHisamemberofthefollowingmedicalsocieties:AmericanAssociationforthe
AdvancementofScience,AmericanCollegeofObstetriciansandGynecologists,PhiBetaKappa,Societyfor
ReproductiveInvestigation,SocietyforMaternalFetalMedicine,SocietyforNeuroscience,AmericanFederation
forClinicalResearch,PerinatalResearchSociety,AmericanGynecologicalandObstetricalSociety,American
PhysiologicalSociety,AmericanPublicHealthAssociation,AssociationofProfessorsofGynecologyand
Obstetrics
Disclosure:Serve(d)asadirector,officer,partner,employee,advisor,consultantortrusteefor:LumaraHealth
CervilenzInc<br/>Receivedincomeinanamountequaltoorgreaterthan$250from:LumaraHealthCervilenz
Inc.
Coauthor(s)
RoyZionMansano,MDDepartmentofObstetricsandGynecology,HarborUCLAMedicalCenter
RoyZionMansano,MDisamemberofthefollowingmedicalsocieties:AmericanCollegeofObstetriciansand
Gynecologists,SocietyforMaternalFetalMedicine,AAGL
Disclosure:Nothingtodisclose.
SpecialtyEditorBoard
FranciscoTalavera,PharmD,PhDAdjunctAssistantProfessor,UniversityofNebraskaMedicalCenterCollege
ofPharmacyEditorinChief,MedscapeDrugReference
Disclosure:ReceivedsalaryfromMedscapeforemployment.for:Medscape.
ChiefEditor
CarlVSmith,MDTheDistinguishedChrisJandMarieAOlsonChairofObstetricsandGynecology,Professor,
DepartmentofObstetricsandGynecology,SeniorAssociateDeanforClinicalAffairs,UniversityofNebraska
MedicalCenter
CarlVSmith,MDisamemberofthefollowingmedicalsocieties:AmericanCollegeofObstetriciansand
Gynecologists,AmericanInstituteofUltrasoundinMedicine,AssociationofProfessorsofGynecologyand
Obstetrics,CentralAssociationofObstetriciansandGynecologists,SocietyforMaternalFetalMedicine,Council
ofUniversityChairsofObstetricsandGynecology,NebraskaMedicalAssociation
Disclosure:Nothingtodisclose.
Acknowledgements
TheauthorsandeditorsofMedscapeReferencegratefullyacknowledgethecontributionsofpreviousauthors
Teresa(Terry)CHarper,MDGarrettLam,MDandNancyCChescheir,MDtothedevelopmentandwritingof
thisarticle.

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