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!

jvandyk@stjoestoronto.ca