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OPENING PANDORA’S BOX
Identifying risk of neurodevelopmental impairment in preterm infants
Jessie van Dyk Neonatologist, St Joseph’s Health Centre University of Toronto
Conflictofinterest
Nothingtodeclare…
“Pandora's box had been opened and monsters had come out. But there had been something hidden at the bottom of Pandora's box. Something wonderful.
Hope.”
Lisa Marie Rice,
Breaking Danger
OUTLINE• Whyarethesebabiesatrisk?• Whydoweneedtoidentifythoseatrisk?
• Dowehavetoolsavailabletous?• Arewedoingagoodjobatpresent?
Background
TheBurdenofPrematurity–WHOstatistics
• ±15millionbabiesborn<37completedweeksGA/yr• Thisnumberisrising• Pretermbirthcomplicationsareleadingcauseofdeathamongchildren<5yearsofage~1milliondeathsin2015
• 75%ofthesedeathscouldbepreventedwithcurrent,cost-effectiveinterventions
• Across184countries,therateofpretermbirthrangesfrom5%to18%ofbabiesborn
• InCanada:onlyroughly8%oflivebirthsperyear,butmajorcosttoCanadianHealthcaresystem~CAD587.1millionperyearin2014
Thepreterminfant• Magnitudeappreciatedbygrossinspectionofbrain:
-13wks:fetalcortexsmooth,nosulciorgyri
-26wks:developmentofcentral&lateralsulcus,rudimentaryinsula
-Gyralandsulcalformationincompleteevenat34wks
Etiology
Dysmaturation• Graymatterarchitecturedistorted• Whitematterconnectivityaltered• Cerebellumunder-developed• SensorysystemdisorganizationSecondarycorticaldysplasiaVolpeJJ.Braininjuryinpreterminfants:acomplexamalgamofdestructiveanddevelopmentaldisturbances.JLancet2009;8:110-124.AlywardGP.NeurodevelopmentalOutcomesofInfantsBornPrematurely.JDevBehavPediatr2005;26:427-440.
PrematureBirth• Majorityofpretermsfreeofmajormorbidity• Greatersurvivalatdiminishinggestationalages
• Majormorbidityrelativelystableat6-25%– Cerebralpalsy– Visionimpairment– Hearingimpairment– Cognitiveimpairment
• 50-70%mayhave‘minormorbidities’thataffectschoolperformance
‘MinorMorbidities’• Include:
– Motordelays– Executivedysfunction– Attentiondeficitdisorder– Languagedelays– Learningdisabilities&IQ– Auditorydys-synchrony– Corticalvisualimpairment– Visualmotordifficulties– Behaviorproblems*– Socialemotionaldysregulation*
‘Pretermphenotype’?
• “PrematuritySyndrome”firstreportedbyDrillienin1939
BehavioralphenotypeDescribesaconstellationofbehavioral,cognitive,motor,andsocialstrengths&difficultiesobservedinapopulationwithacommonbiologicaldisorderPrematuresurvivorshaveaphenotypeCommonbiologicaldisorder=alterationsinbraindevelopmentHodappRM,FidlerDJ.SpecialEducationandGenetics:Connectionsforthe21stCentury.TheJSpecEduc1999;33:130-137.BackSA,MillerSP.BrainInjuryinPrematureNeonates:APrimaryCerebralDysmaturationDisorder?AnnNeurol2014:75;469-86.ChurchPT,LutherM,AsztalosE.Theperfectstorm:minormorbiditiesinthepretermsurvivor.CurrPediatrRev,2012;8:142-151
BehaviorProblems
• MultiplestudieshavelookedatbehavioraloutcomeofprematurityVohrB,MsallME,SeminPerinatol1997;21:202-220MarlowN,HennessyEM,BracewellMA,WolkeD.Pediatrics2007;120:793-803.HilleETM,denOudenAL,SaigalSetal.J.Lancet2001;357:1641-1643.
• Overall,documentedincreased:– ADHD– Withdrawnsocially– Anxiety– Depression– Dysregulation
AttentionDeficitHyperactivityDisorder(ADHD)
• 2.5-4timesgreaterriskinpreterms• Inattentionmostfrequentlycited• Nostudieslookingatstimulantsandpreterminfants
• Inconsistentdataonwhetherpersistsintoadulthood
ExecutiveFunction
• Mentalprocessesthatdevelopto:– enableself-regulation– problemsolving– goaldirectedactions
• Internalconductor
ExecutiveDysfunction• VictorianInfantCollaborativeStudyGroup
– AndersonPJ,DoyleLWetal.Pediatrics2004;114:50-57
• ELBW’s2-3xmorelikelytohaveexecutivedysfunction-↓GAà↑difficulty
• Globaldysfunction,notonesetpattern
• Difficultywith:-Startingnewactivities-Organizinginformation-Planningasequenceofactivities-Transitioningfromonetasktoother
SocialEmotional
Socialemotionaldysregulation
• Increasinglyreported
• Childrenare…emotionallylabilehavedifficultywith
transitionslowfrustrationtolerancepoorpersistencetotask
Internalizingconditions• Lessrisktakingdueto:
– Underlyinganxiety– Greaterparentalmonitoring– Diminishedpeerrelationships
• Morelikelytoliveathomeasyoungadults
HackM,FlanneryDJ,SchluchterM,CartarL,BorawskiE,KleinN.NEJM2002;346:149-157.
AcademicOutcome
• Lesslikelytoattend4yearcollege,lowerscoresonstandardizedassessmentsofeducationalachievement
• Unemploymentsame– Jobincomehoweverinverselyrelatedtogestationalage
• HackM.JDevBehavPediatr2009;30:460-470.• HackM,FlanneryDJ,SchluchterM,CartarL,BorawskiE,KleinN.NEJM2002;346:149-157.
AutismSpectrumDisorder–DSMV
Deficitsinsocialcommunicationandsocialinteraction• Socialemotionalreciprocity• Nonverbalcommunication• Difficultymaking,sustaining,orunderstandingrelationships
Restrictedrepetitivepatternsofbehavior• Stereotypedmovementpatterns• Inflexibleadherencetoroutines• Fixatedinterestswithabnormalintensityandfocus
AutismSpectrumDisorder&theprem
• ManystudiesevaluatingriskfactorsforASD• Fewstudiesevaluatingprevalenceofautismamidst
prematuresurvivors
• Signsmaypresentinearlyinfancy,caninclude:-abnormalsocialinteractions-atypicalcommunication-restrictedinterests/play-splinterskillsmaydevelop-sensoryhypo/hypersensitivity
• 103enrolledinfants– MRIattermCAobtained
• Birthweight<1500g
• Followupdata:– ModifiedChecklistforAutisminToddlers(M-CHAT)
– VinelandAdaptiveBehaviorScale(VABS)– ChildBehaviorChecklist(CBCL)
PositiveScreeningforAutisminEx-PretermInfantsLimperopoulos,Pediatrics2008
• 26%positiveonM-CHAT• 70%ofthosepositivefoundtofail2criticalitems• Abnormalscorescorrelatedhighlywith:-InternalizingbehavioralproblemsonCBCL-SocializationandcommunicationdeficitsontheVinelandScales.• Factorssignificantlyassociatedwithabnormalscreen:-LowerbirthweightorGA-Malegender-Chorioamnionitis-Acuteintrapartumhemorrhage-Illnessseverityonadmission-AbnormalMRI
PositiveScreeningonM-CHATinELGAN’sKubanetal,J.Pediatrics,2009
• 21%screenedpositiveonM-CHAT
• 16%positivewithoutmotor,vision,orhearingimpairment
• 10%positivewithoutco-existingimpairment*
CerebellarHemorrhage(CH)&ASD
Limperopoulos,Pediatrics2007
• Retrospective,casecontrolled(isolatedCH,lessthan32wk)controlsmatchedforGA,gender,yearofbirth
• MRItoconfirmdiagnosis• 60infantseligible,51survivedtostudy• CHvscontrols:positiveASDscreener37%vs0%,internalizingbehavioralproblems34%vs9%
Latepreterminfant
Latepreterminfant• Brainweightat34weeksonly65%oftermbrain
• Gyral&sulcalformationincomplete
• Corticalvolumeincreases50%between34-40weeks
• 25%ofcerebellardevelopmentafter34weeksGA
• Synaptogenesis&dendriticarborizationincomplete
Specificlong-termissues
Medical
Cognition
Motordeficits
Behaviour
Earlyoutcomedata
• 124LPTvs33terminfants• AlbertaInfantMotorscale(AIMS)at6mo&GriffithsMental
DevelopmentScales(GMDS)at12mochronologicalage• LPTperformedsignificantlyloweronallsubscalesofGMDS• Similarscoreswhencorrectedforprematurity
• LPTinfantsvstermcontrols• BayleyScalesofInfantDevelopmentShortForm-ResearchEdition(BSF-R)at24monthschronologicalage
• LPThadhigheroddsofmental(OR1.52)orphysical(OR1.56)developmentaldelay
24monthoutcomes
Comparedtoterminfants,increasedoddsofhaving:
• Moreseverementaldelay(52%)• Mildermentaldevelopmentaldelay(43%)• Severepsychomotordevelopmentaldelay(43%)
• Milderpsychomotordevelopmentaldelay(58%)
Comparedtoterminfants:• Riskfordevelopmentaldelayordisability36%higher• Riskforsuspensioninkindergarten19%higher• Riskfordisabilityinpre-kindergarten(3-4years)• Riskforexceptionalstudenteducation
10-13%higher• Riskforretentioninkindergarten
At6years• Latepretermvstermcontrolsmatched• InadjustedmodelsLPTbirthassociatedwithincreasedriskof-FullscaleIQ<85(aOR2.35,95%CI1.20-4.61)-PerformanceIQ<85(aOR2.04,95%CI1.09-3.82)àLPTbirthassociatedwithlowerIQat6years,independentof
maternalIQ,residentialsettingandsociodemographics
• TalgeNMetal.Late-Pretermbirthanditsassociationwithcognitiveandsocioemotionaloutcomesat6yearsofage.Pediatrics
2010;126:1124-1131
Threefoldincreasedriskfordevelopingcerebralpalsy in LPT infants compared with terminfants (RR 3.1, 95% confidence interval2.3-4.2)
ChildrenbornLPT>3timesaslikelyasterminfantstobediagnosedwithcerebralpalsy(hazardratio
3.39,95%CI2.54-4.52)
Other• Executivefunctiondeficitsespeciallyrelatedtocomplex
memorytasks(Baronetal,2012)• Higherlevelsofinternalizingandattentionproblems(Van
Baaretal,2009;Talgeetal,2010)• At3,5&8yrs20%ofLPTscoredinclinicallysignificant
rangeonCBCLvsexpected10%(Grayetal,2004)• AmongLPT’s,thoseadmittedtoNICUhadhigherscoreson
CBCLat3yrs,especiallyforaggressivebehaviorandexternalizingproblems(Boylanetal,2014)
Social
• Slightlyhigherrisktoreceivesocialsecuritybenefitsearlyadulthood(RR1.15,95%CI1.12-1.17)(Teuneetal,2011)
• HelsinkiBirthCohortStudy:comparedwiththosebornatterm,LPTinfantsweremorelikelyto…
-bemanualworkers-haveabasicoruppersecondaryleveleducation-belongtothelowestthirdbasedonincome-bedownwardlymobileintheircareer-haveloweroccupationsthantheirfathers(Heinonenatal,
2013)
• Lesslikelytocompletehighschool(RR0.96),lesslikelytocompleteuniversity(OR0.87)(Teuneetal,2011)
Whytrytodeterminerisk?
Earlyintervention
• Optimaltiming<12-15monthsCA• Maximalplasticityimmediatelyaftercompletionofneuralmigrationàdendriticoutgrowth&synapticformationmostactive
• Mixedevidence• Improvefunction
Earlyintervention• Improvedsocialandcognitiveabilities• Improvedschoolcompletion• Improvedworkforceproductivity• Reducedcrimerates• Reducedteenagepregnancy
• ‘Theearlierinlifetheseinterventionswereintroduced,thehighertheeconomicandsocialreturns’(Heckman,‘Schools,SkillsandSynapses’2010)
Earlyintervention
• ReviewofEIprogramsforinfantsathigh-riskofdevelopmentaldelay:improvedmotorandcognitivedevelopmentwithspecificdevelopmentalprograms(Blauw-Hospersetal2007)
• Cochranereview:improvedcognitiveoutcomesininfancy,whichwassustainedatpreschoolage,notsustainedatschoolage-heterogeneitybetweenstudieswassignificant(Spittleetal2015)
Sohowdowedeciderisk?
Clinicalfactors?• Illnessseverity?• Knownclinicalpredictors:-Preterm:BPD,ROP,braininjury,infection,NEC-Latepreterm:firstbaby,poorfeeding• Notaperfecttool–Schmidtetalcautioned‘limitedclinicalusefulnessoftheindividualriskestimates’– 53%ofcohortwhodevelopedBPDàfavorable18monthoutcome
– 26%ofinfantswithoutBPDàdied/developedneurosensoryimpairment
NeuroimagingSignificantpredictivevalueinspecificpopulations:egtermHIEPretermpopulation:• Onlycertainmarkers(egwhitematterinjury)predictiveof
laterneurodevelopmentoutcome(mostcommonlyCP)• Dependentonspecialisttrainingandexpertise• Interpretfindingsinconjunctionwithotherclinical
information• MajorityoffindingsonMRINOTsuccessfullylinkedto
long-termimpairment• Upto15%ofchildrenwithCP:‘normal’MRI• Greatstressforparentsofpreterminfants(‘severely
traumatizing’,Pearce2012)
Screeningtools
• Noperfecttoolexists• GeneralMovements(GMs),MRI,headultrasound,MovementAssessmentofInfants(MAI),neurologicalexam
• NormalGMassessment:-veryhighnegativepredictivevalueof95-100%-negativelikelihoodratioof0• AbnormalGMs:Pooledsensitivity98%,specificity91%,diagnosticoddsratio(DOR)453(95%CI18-11495)forpredictingcerebralpalsy(CP)at2yearsofage
PredictivevalueofneurodevelopmentalassessmentsusedtopredictCPinyoungchildren
Test Number of studies reviewed (n)
Number of participants (n)
Range of cerebral palsy prevalence (%)
Sensitivity [% (95% CI)] or range
Specificity [% (95% CI)] or range
Neurological assessment
4 1190 6.3-52.4 88 (55, 97) 87 (57, 97)
Cranial ultrasound (CUS)
10 2827 5.0-59.0 74 (63, 83) 92 (81, 96)
Brain magnetic resonance imaging (MRI)
3 702 11.5-22.8 86-100% 89-97%
Assessments of general movements (GM)
6 1358 6.3-52.4 98 (74, 100) 91 (83, 93)
GeneralMovements
• ‘Seriesofgrossmovementsofvariablespeedandamplitudewhichinvolveallpartsofbody’
Prechtl&Nolte,1984• Presentfrom9-10weekspost-menstrualage(PMA)
• Ataround4monthscorrectedageareslowlyreplacedbymoregoal-directedmovements
Developmentalprogressionandage-specificcharacteristicsofgeneralmovements
Postmenstrualage(weeks)28303234363840424446485052545658
PretermGMsExtremelyvariablemovementsthatincludefrequentpelvictiltsandtrunkmovements(±28weeksto36-38weeksPMA)
WrithingGMsMovementsarenowmoreforcefulandslower,withlesspelvisandtrunkinvolvement(36-38weeksto46-52weeksPMA)
FidgetyGMsAcontinuousflowofsmall,elegantmovementsnowoccurringconstantly,irregularlyalloverthebody,withhead,trunkandlimbsparticipatingequally.Thesemaybesuperimposedonlarger,fastermovements(46-52weeksto54-58weeksPMA)
AssessmentofQualityofGeneralMovements
classificationcharacteristics
• Complexity-spatialvariationofmovements
• Variability-temporalvariationofmovements
• Fluency-smoothqualityofmovement
‘VariationisfundamentalfeatureoffunctionofhealthyearlyCNS…stereotypyhall-markofearlybraindysfunction…’Touwen1993,Hadders-Algra2000
ScoringQualityofgeneralmovementonoverall
impressionIstherecomplexity?Istherevariability?
Isitfluent?
Dichotomousclassification:
NormalGMs
Richincomplexity,variability(&fluency)
AbnormalGMs
Lackingincomplexity,variability(&fluency)
AvailableevidenceReliabilityoftheAQGMSpittleetal,2008
Characteristic Cohen’skappa(κ) Interpretation(accordingtoLandis&Koch)
Inter-raterreliability 1.00 Perfectagreementbetweenraters
Intra-raterreliability 0.84–0.92 Near-perfectagreement
Goodreliabilityevenwithminimaltraining
• Preterminfantsborn<30weeksGA• GMsassessedduringwrithing&fidgetyphases• ‘Normal’vs.‘abnormal’• Motor,language&cognitivefunction• Strongestassociation:GMqualityat3mocorrectedageàCPat2&4yrs
• Associationwithcognitiveoutcomeslessrobustbutpromising…deservesfurtherresearch
• Benefitofserialassessments?
Otherassociations
• Minorneurologicaldeficits• Autismspectrumdisorder?
OURSTUDYAt6weeksCAAt3monthsCAAt18-24monthsCA(±6weeks)(±6weeks)(±12weeks)(WrithingGMphase)(FidgetyGMphase)
NormalAQGM
NormalAQGM
AbnormalAQGM
AbnormalAQGM
NormalAQGM
AbnormalAQGM
Outcomesassessed:
• BSID-III• Comprehensiveneurological
examinationwithdiagnosisofCP
• Presenceofvisualorhearingimpairment
NEURODEVELOPMENTALOUTCOMECATEGORIZATION
Diagnosticcriteria Normalormildimpairment
Moderateimpairment Severeimpairment
Cognitive BSID-IIIcognitivecompositescore>85
BSID-IIIcognitivecompositescore70-85
BSID-IIIcognitivecompositescore<70
Motor BSID-IIImotorcompositescore>85orNodiagnosisofCP
BSID-IIImotorcompositescore70-85orDiagnosisofCPwithGMFCSlevel1-2
BSID-IIImotorcompositescore<70orDiagnosisofCPwithGMFCSlevel3-5
Language BSID-IIIlanguagecompositescore>85
BSID-IIIlanguagecompositescore70-85
BSID-IIIlanguagecompositescore<70
Vision Mildvisualimpairment(visualacuitybetterthan20/200inbotheyes)
Bilateralblindness(visualacuity<20/200instrongesteye)
Bilateralblindnessthatcannotbecorrected
Hearing Mildhearingloss(notrequiringamplification/injustoneear)
Bilateralhearingloss(requiringamplification)
Severetoprofoundhearingimpairment(nofunctionalhearingwithamplification)
Table12:UnadjustedandadjustedoddsratioforassociationofAQGMtrajectories,maternalandneonatalcharacteristics,short-termneonatalmorbiditiesandNDI
UnadjustedOR(95%CI)
AdjustedOR(95%CI)
TrajectoryA-AvsN-NA-AvsN-AA-AvsA-NA-NvsN-NA-NvsN-AN-AvsN-N
2.5(1.2,5.3)2.4(1.1,5.4)2.2(1.1,4.4)1.1(0.5,2.8)1.1(0.4,2.8)1.0(0.4,2.8)
1.7(0.8,3.6)2.0(0.9,4.6)2.5(1.2,5.1)0.7(0.2,1.7)0.8(0.3,2.2)0.8(0.3,2.4)
MaternalcharacteristicsMaternalageatdelivery(years)Maternaleducation(post-secondary)Homelanguage(notEnglish)Parentalcircumstance(singleparenthousehold)
1.0(0.95,1.0)0.5(0.2,1.1)1.1(0.6,2.0)1.8(0.8,3.9)
NeonatalcharacteristicsGender(male)Gestationalage(weeks)Birthweight(grams)Modeofdelivery(Caesariansection)Multiplebirth
2.1(1.3,3.3)0.8(0.7,0.9)0.9(0.8,0.9)1.0(0.6,1.6)1.2(0.7,2.0)
2.3(1.4,4.0)
0.9(0.8,1.0)
Short-termneonatalmorbiditiesPresenceofBPD±receivedpostnatalsteroidsPresenceofintraventricularhemorrhagePresenceofretinopathyofprematurityPresenceofnecrotizingenterocolitisPresenceofPDArequiringligation
3.8(2.2,6.8)2.2(1.1,4.3)1.8(0.2,14.8)1.2(0.4,3.5)5.8(2.3,15.0)
2.5(1.3,4.8)1.5(0.7,3.0)
3.8(1.4,10.5)
Table14:AssociationbetweenAQGMscoreat6weeks(writhingphase)and3months(fidgetyphase)andmotorimpairment
UnadjustedOR
(95%CI)
AdjustedORfor6weeksCA(95%CI)
AdjustedORfor3monthsCA(95%CI)
AQGMscoreAvsNat6weeksCAAvsNat3monthsCA
2.1(0.9,4.6)2.9(1.3,6.3)
1.8(0.7,4.5)
3.4(1.4,7.9)
MaternalcharacteristicsMaternalageatdelivery(years)Maternaleducation(post-secondary)Homelanguage(notEnglish)Parentalcircumstance(singleparenthousehold)
1.0(0.9,1.0)0.6(0.2,1.6)1.7(0.8,3.4)1.7(0.7,4.1)
NeonatalcharacteristicsGender(male)Gestationalage(weeks)Birthweight(grams)Modeofdelivery(Caesariansection)Multiplebirth
2.0(1.0,3.7)0.8(0.7,0.9)0.9(0.8,1.0)0.5(0.3,1.0)0.8(0.4,1.5)
1.8(0.9,3.7)
1.0(0.9,1.2)
2.1(1.0,4.3)
1.0(0.9,1.2)
Short-termneonatalmorbiditiesPresenceofBPD±receivedpostnatalsteroidsPresenceofintraventricularhemorrhagePresenceofretinopathyofprematurityPresenceofnecrotizingenterocolitisPresenceofPDArequiringligation
3.1(1.6,5.9)8.9(4.2,18.8)7.1(0.9,58.7)0.3(0.04,2.4)4.4(1.7,11.2)
2.3(1.0,5.2)7.8(3.6,17.1)
3.7(1.3,10.6)
3.6(1.2,10.5)8.3(3.7,18.5)
3.6(1.2,10.5)
HammersmithInfantNeurologicalExamination(HINE)
• RecommendedinInternationalClinicalPracticeEarlyDiagnosisofCerebralPalsyGuidelines,particularlyinsituationswherethemostpredictivetools(GeneralMovementsandMRI)notabletobeused
• Infants2-24monthsofage• AHINEscore<57at3months96%predictiveofcerebral
palsy(sensitivity96%;specificity87%)• >5monthsage(corrected)ithas90%predictive
accuracyfordetectingtheriskofcerebralpalsy
So…dowehaveaclearanswerthen?
• Notreally…• Inthiscase:lessisn’tmore• Combineclinicaldata+imaging+reliablescreeningtoolsappropriateforthechosenpopulation
• Futureresearch:clinicalpredictionrulesforspecificneonatalpopulations?
Parentalmentalhealth
Schoolreadiness
KnowledgeofEducatorsEducators(n=138)lessknowledgeableaboutoutcomesofprematurity• 75%awareand/orknowledgeableaboutADHD/ADD• 62.5%awareand/orknowledgeableaboutlearningdisabilities• 60.6%awareand/orknowledgeableaboutASD• 24.8%awareand/orknowledgeableaboutdevelopmental
outcomesofprematurityFactorsthatenhancededucators’knowledge• Havingexperiencewithachildbornpreterm• Havingachildwithanindividualizededucationplan• AdditionaleducatorqualificationsChurchPT,CavanaghA,LeeSK,ShahV.AcademicChallengesforthePretermInfant:Educators’Knowledge,Attitudes,andPerceptionsofIdentifiedBarriers.Prelimdata.
SowhatamIsupposedtotakeawayfromthis?
• Haveastructuredapproachtofollowingprematureinfants
• Usealltoolsavailabletoyou–MRI/US,GMA,astructuredneurologicalexam(HINE)
• Ifconcerned(youORparents)àREFERforintervention
• Educateparentsonrisksandexpectations,empowerthemtoadvocate
• Educateteacherswheneverpossible!• Don’tforgettoassessparentalwellness
Resources• EdinburghPostnatalDepressionScalehttp://med.stanford.edu/content/dam/sm/ppc/documents/DBP/EDPS_text_added.pdf
• ProvincialCouncilforMaternalandChildHealth(PCMCH)http://www.pcmch.on.ca/ontario-neonatal-follow-program/
• SunnybrookHealthSciencesCentreNeonatalFollow-upClinicwebsite–parentandproviderresourceshttp://followup.sunnybrook.ca/
• Neoknowledgehttp://www.neoknowledge.org/
Thankyou!