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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
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Conflictofinterest
Nothingtodeclare…
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“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
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OUTLINE• Whyarethesebabiesatrisk?• Whydoweneedtoidentifythoseatrisk?
• Dowehavetoolsavailabletous?• Arewedoingagoodjobatpresent?
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Background
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TheBurdenofPrematurity–WHOstatistics
• ±15millionbabiesborn<37completedweeksGA/yr• Thisnumberisrising• Pretermbirthcomplicationsareleadingcauseofdeathamongchildren<5yearsofage~1milliondeathsin2015
• 75%ofthesedeathscouldbepreventedwithcurrent,cost-effectiveinterventions
• Across184countries,therateofpretermbirthrangesfrom5%to18%ofbabiesborn
• InCanada:onlyroughly8%oflivebirthsperyear,butmajorcosttoCanadianHealthcaresystem~CAD587.1millionperyearin2014
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Thepreterminfant• Magnitudeappreciatedbygrossinspectionofbrain:
-13wks:fetalcortexsmooth,nosulciorgyri
-26wks:developmentofcentral&lateralsulcus,rudimentaryinsula
-Gyralandsulcalformationincompleteevenat34wks
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Etiology
Dysmaturation• Graymatterarchitecturedistorted• Whitematterconnectivityaltered• Cerebellumunder-developed• SensorysystemdisorganizationSecondarycorticaldysplasiaVolpeJJ.Braininjuryinpreterminfants:acomplexamalgamofdestructiveanddevelopmentaldisturbances.JLancet2009;8:110-124.AlywardGP.NeurodevelopmentalOutcomesofInfantsBornPrematurely.JDevBehavPediatr2005;26:427-440.
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PrematureBirth• Majorityofpretermsfreeofmajormorbidity• Greatersurvivalatdiminishinggestationalages
• Majormorbidityrelativelystableat6-25%– Cerebralpalsy– Visionimpairment– Hearingimpairment– Cognitiveimpairment
• 50-70%mayhave‘minormorbidities’thataffectschoolperformance
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‘MinorMorbidities’• Include:
– Motordelays– Executivedysfunction– Attentiondeficitdisorder– Languagedelays– Learningdisabilities&IQ– Auditorydys-synchrony– Corticalvisualimpairment– Visualmotordifficulties– Behaviorproblems*– Socialemotionaldysregulation*
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‘Pretermphenotype’?
• “PrematuritySyndrome”firstreportedbyDrillienin1939
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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
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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
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AttentionDeficitHyperactivityDisorder(ADHD)
• 2.5-4timesgreaterriskinpreterms• Inattentionmostfrequentlycited• Nostudieslookingatstimulantsandpreterminfants
• Inconsistentdataonwhetherpersistsintoadulthood
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ExecutiveFunction
• Mentalprocessesthatdevelopto:– enableself-regulation– problemsolving– goaldirectedactions
• Internalconductor
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ExecutiveDysfunction• VictorianInfantCollaborativeStudyGroup
– AndersonPJ,DoyleLWetal.Pediatrics2004;114:50-57
• ELBW’s2-3xmorelikelytohaveexecutivedysfunction-↓GAà↑difficulty
• Globaldysfunction,notonesetpattern
• Difficultywith:-Startingnewactivities-Organizinginformation-Planningasequenceofactivities-Transitioningfromonetasktoother
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SocialEmotional
Socialemotionaldysregulation
• Increasinglyreported
• Childrenare…emotionallylabilehavedifficultywith
transitionslowfrustrationtolerancepoorpersistencetotask
Internalizingconditions• Lessrisktakingdueto:
– Underlyinganxiety– Greaterparentalmonitoring– Diminishedpeerrelationships
• Morelikelytoliveathomeasyoungadults
HackM,FlanneryDJ,SchluchterM,CartarL,BorawskiE,KleinN.NEJM2002;346:149-157.
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AcademicOutcome
• Lesslikelytoattend4yearcollege,lowerscoresonstandardizedassessmentsofeducationalachievement
• Unemploymentsame– Jobincomehoweverinverselyrelatedtogestationalage
• HackM.JDevBehavPediatr2009;30:460-470.• HackM,FlanneryDJ,SchluchterM,CartarL,BorawskiE,KleinN.NEJM2002;346:149-157.
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AutismSpectrumDisorder–DSMV
Deficitsinsocialcommunicationandsocialinteraction• Socialemotionalreciprocity• Nonverbalcommunication• Difficultymaking,sustaining,orunderstandingrelationships
Restrictedrepetitivepatternsofbehavior• Stereotypedmovementpatterns• Inflexibleadherencetoroutines• Fixatedinterestswithabnormalintensityandfocus
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AutismSpectrumDisorder&theprem
• ManystudiesevaluatingriskfactorsforASD• Fewstudiesevaluatingprevalenceofautismamidst
prematuresurvivors
• Signsmaypresentinearlyinfancy,caninclude:-abnormalsocialinteractions-atypicalcommunication-restrictedinterests/play-splinterskillsmaydevelop-sensoryhypo/hypersensitivity
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• 103enrolledinfants– MRIattermCAobtained
• Birthweight<1500g
• Followupdata:– ModifiedChecklistforAutisminToddlers(M-CHAT)
– VinelandAdaptiveBehaviorScale(VABS)– ChildBehaviorChecklist(CBCL)
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PositiveScreeningforAutisminEx-PretermInfantsLimperopoulos,Pediatrics2008
• 26%positiveonM-CHAT• 70%ofthosepositivefoundtofail2criticalitems• Abnormalscorescorrelatedhighlywith:-InternalizingbehavioralproblemsonCBCL-SocializationandcommunicationdeficitsontheVinelandScales.• Factorssignificantlyassociatedwithabnormalscreen:-LowerbirthweightorGA-Malegender-Chorioamnionitis-Acuteintrapartumhemorrhage-Illnessseverityonadmission-AbnormalMRI
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PositiveScreeningonM-CHATinELGAN’sKubanetal,J.Pediatrics,2009
• 21%screenedpositiveonM-CHAT
• 16%positivewithoutmotor,vision,orhearingimpairment
• 10%positivewithoutco-existingimpairment*
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CerebellarHemorrhage(CH)&ASD
Limperopoulos,Pediatrics2007
• Retrospective,casecontrolled(isolatedCH,lessthan32wk)controlsmatchedforGA,gender,yearofbirth
• MRItoconfirmdiagnosis• 60infantseligible,51survivedtostudy• CHvscontrols:positiveASDscreener37%vs0%,internalizingbehavioralproblems34%vs9%
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Latepreterminfant
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Latepreterminfant• Brainweightat34weeksonly65%oftermbrain
• Gyral&sulcalformationincomplete
• Corticalvolumeincreases50%between34-40weeks
• 25%ofcerebellardevelopmentafter34weeksGA
• Synaptogenesis&dendriticarborizationincomplete
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Specificlong-termissues
Medical
Cognition
Motordeficits
Behaviour
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Earlyoutcomedata
• 124LPTvs33terminfants• AlbertaInfantMotorscale(AIMS)at6mo&GriffithsMental
DevelopmentScales(GMDS)at12mochronologicalage• LPTperformedsignificantlyloweronallsubscalesofGMDS• Similarscoreswhencorrectedforprematurity
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• LPTinfantsvstermcontrols• BayleyScalesofInfantDevelopmentShortForm-ResearchEdition(BSF-R)at24monthschronologicalage
• LPThadhigheroddsofmental(OR1.52)orphysical(OR1.56)developmentaldelay
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24monthoutcomes
Comparedtoterminfants,increasedoddsofhaving:
• Moreseverementaldelay(52%)• Mildermentaldevelopmentaldelay(43%)• Severepsychomotordevelopmentaldelay(43%)
• Milderpsychomotordevelopmentaldelay(58%)
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Comparedtoterminfants:• Riskfordevelopmentaldelayordisability36%higher• Riskforsuspensioninkindergarten19%higher• Riskfordisabilityinpre-kindergarten(3-4years)• Riskforexceptionalstudenteducation
10-13%higher• Riskforretentioninkindergarten
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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
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Threefoldincreasedriskfordevelopingcerebralpalsy in LPT infants compared with terminfants (RR 3.1, 95% confidence interval2.3-4.2)
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ChildrenbornLPT>3timesaslikelyasterminfantstobediagnosedwithcerebralpalsy(hazardratio
3.39,95%CI2.54-4.52)
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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)
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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)
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Whytrytodeterminerisk?
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Earlyintervention
• Optimaltiming<12-15monthsCA• Maximalplasticityimmediatelyaftercompletionofneuralmigrationàdendriticoutgrowth&synapticformationmostactive
• Mixedevidence• Improvefunction
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Earlyintervention• Improvedsocialandcognitiveabilities• Improvedschoolcompletion• Improvedworkforceproductivity• Reducedcrimerates• Reducedteenagepregnancy
• ‘Theearlierinlifetheseinterventionswereintroduced,thehighertheeconomicandsocialreturns’(Heckman,‘Schools,SkillsandSynapses’2010)
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Earlyintervention
• ReviewofEIprogramsforinfantsathigh-riskofdevelopmentaldelay:improvedmotorandcognitivedevelopmentwithspecificdevelopmentalprograms(Blauw-Hospersetal2007)
• Cochranereview:improvedcognitiveoutcomesininfancy,whichwassustainedatpreschoolage,notsustainedatschoolage-heterogeneitybetweenstudieswassignificant(Spittleetal2015)
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Sohowdowedeciderisk?
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Clinicalfactors?• Illnessseverity?• Knownclinicalpredictors:-Preterm:BPD,ROP,braininjury,infection,NEC-Latepreterm:firstbaby,poorfeeding• Notaperfecttool–Schmidtetalcautioned‘limitedclinicalusefulnessoftheindividualriskestimates’– 53%ofcohortwhodevelopedBPDàfavorable18monthoutcome
– 26%ofinfantswithoutBPDàdied/developedneurosensoryimpairment
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NeuroimagingSignificantpredictivevalueinspecificpopulations:egtermHIEPretermpopulation:• Onlycertainmarkers(egwhitematterinjury)predictiveof
laterneurodevelopmentoutcome(mostcommonlyCP)• Dependentonspecialisttrainingandexpertise• Interpretfindingsinconjunctionwithotherclinical
information• MajorityoffindingsonMRINOTsuccessfullylinkedto
long-termimpairment• Upto15%ofchildrenwithCP:‘normal’MRI• Greatstressforparentsofpreterminfants(‘severely
traumatizing’,Pearce2012)
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Screeningtools
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• Noperfecttoolexists• GeneralMovements(GMs),MRI,headultrasound,MovementAssessmentofInfants(MAI),neurologicalexam
• NormalGMassessment:-veryhighnegativepredictivevalueof95-100%-negativelikelihoodratioof0• AbnormalGMs:Pooledsensitivity98%,specificity91%,diagnosticoddsratio(DOR)453(95%CI18-11495)forpredictingcerebralpalsy(CP)at2yearsofage
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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)
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GeneralMovements
• ‘Seriesofgrossmovementsofvariablespeedandamplitudewhichinvolveallpartsofbody’
Prechtl&Nolte,1984• Presentfrom9-10weekspost-menstrualage(PMA)
• Ataround4monthscorrectedageareslowlyreplacedbymoregoal-directedmovements
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Developmentalprogressionandage-specificcharacteristicsofgeneralmovements
Postmenstrualage(weeks)28303234363840424446485052545658
PretermGMsExtremelyvariablemovementsthatincludefrequentpelvictiltsandtrunkmovements(±28weeksto36-38weeksPMA)
WrithingGMsMovementsarenowmoreforcefulandslower,withlesspelvisandtrunkinvolvement(36-38weeksto46-52weeksPMA)
FidgetyGMsAcontinuousflowofsmall,elegantmovementsnowoccurringconstantly,irregularlyalloverthebody,withhead,trunkandlimbsparticipatingequally.Thesemaybesuperimposedonlarger,fastermovements(46-52weeksto54-58weeksPMA)
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AssessmentofQualityofGeneralMovements
classificationcharacteristics
• Complexity-spatialvariationofmovements
• Variability-temporalvariationofmovements
• Fluency-smoothqualityofmovement
‘VariationisfundamentalfeatureoffunctionofhealthyearlyCNS…stereotypyhall-markofearlybraindysfunction…’Touwen1993,Hadders-Algra2000
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ScoringQualityofgeneralmovementonoverall
impressionIstherecomplexity?Istherevariability?
Isitfluent?
Dichotomousclassification:
NormalGMs
Richincomplexity,variability(&fluency)
AbnormalGMs
Lackingincomplexity,variability(&fluency)
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AvailableevidenceReliabilityoftheAQGMSpittleetal,2008
Characteristic Cohen’skappa(κ) Interpretation(accordingtoLandis&Koch)
Inter-raterreliability 1.00 Perfectagreementbetweenraters
Intra-raterreliability 0.84–0.92 Near-perfectagreement
Goodreliabilityevenwithminimaltraining
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• Preterminfantsborn<30weeksGA• GMsassessedduringwrithing&fidgetyphases• ‘Normal’vs.‘abnormal’• Motor,language&cognitivefunction• Strongestassociation:GMqualityat3mocorrectedageàCPat2&4yrs
• Associationwithcognitiveoutcomeslessrobustbutpromising…deservesfurtherresearch
• Benefitofserialassessments?
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Otherassociations
• Minorneurologicaldeficits• Autismspectrumdisorder?
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OURSTUDYAt6weeksCAAt3monthsCAAt18-24monthsCA(±6weeks)(±6weeks)(±12weeks)(WrithingGMphase)(FidgetyGMphase)
NormalAQGM
NormalAQGM
AbnormalAQGM
AbnormalAQGM
NormalAQGM
AbnormalAQGM
Outcomesassessed:
• BSID-III• Comprehensiveneurological
examinationwithdiagnosisofCP
• Presenceofvisualorhearingimpairment
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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)
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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)
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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)
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HammersmithInfantNeurologicalExamination(HINE)
• RecommendedinInternationalClinicalPracticeEarlyDiagnosisofCerebralPalsyGuidelines,particularlyinsituationswherethemostpredictivetools(GeneralMovementsandMRI)notabletobeused
• Infants2-24monthsofage• AHINEscore<57at3months96%predictiveofcerebral
palsy(sensitivity96%;specificity87%)• >5monthsage(corrected)ithas90%predictive
accuracyfordetectingtheriskofcerebralpalsy
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So…dowehaveaclearanswerthen?
• Notreally…• Inthiscase:lessisn’tmore• Combineclinicaldata+imaging+reliablescreeningtoolsappropriateforthechosenpopulation
• Futureresearch:clinicalpredictionrulesforspecificneonatalpopulations?
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Parentalmentalhealth
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Schoolreadiness
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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.
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SowhatamIsupposedtotakeawayfromthis?
• Haveastructuredapproachtofollowingprematureinfants
• Usealltoolsavailabletoyou–MRI/US,GMA,astructuredneurologicalexam(HINE)
• Ifconcerned(youORparents)àREFERforintervention
• Educateparentsonrisksandexpectations,empowerthemtoadvocate
• Educateteacherswheneverpossible!• Don’tforgettoassessparentalwellness
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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/