IronDeficiencyandNeurologicalConsequencesforChildren

ClinicalPediatrics&PediatricSurgeryJune2017

DawnSHartfieldBScMed,MPH,MD,FRCPCAssociateProfessor

DepartmentofPediatricsCollegeofMedicineandDentistry

UniversityofAlbertaEdmonton,Alberta,Canada

PresenterDisclosure

• Relationshipswithcommercialinterests:• Grants/ResearchSupport:None• SpeakersBureau/Honoraria:None• ConsultingFees:None• Other:None

Objectives:• Understandtheepidemiology,etiology,andconsequences

ofirondeficiency

• Understandbrainironmetabolismandtheimpactofitsdeficiencyonthedevelopingbrain

• Identifyneurologicalconditionswhichareassociatedwithirondeficiencytoensurepromptdiagnosisandtreatment

• 24.8%ofpopulation(1.62billion)• Highestinpre-schoolagedchildren47.4%(CI:45.7-49.1)• School-agedchildren25.4%(CI:19.9-30.9)• Pregnantwomen41.8%(CI:39.0–43.8)

• CanadianEstimates:• Pre-schoolagedchildren7.6%(CI:1.6–28.9%)• Pregnantwomen11.5%(CI:2.4-40.9%)

deBenoistBetal.,eds.Worldwideprevalenceofanaemia 1993-2005.WHOGlobalDatabaseonAnaemia Geneva,WorldHealthOrganization,2008.http://www.who.int/vmnis/anaemia/prevalence/summary/anaemia_data_status_t2/en/

GlobalEpidemiologyofAnemia

HowCommonisIronDeficiency?

• Morecommonindevelopingcountries• Alsooccursinindustrializednations

• Edmontonstudyof32,06912to59montholdchildrenMay2002-June2008

• 7.69%of19month-oldchildrenhadIDA;11.65%IDPaediatricsandChildHealth.2009May/June;Vol14Suppl14A:44A

• Canadianhighriskpopulations- excessof50%• Mostvulnerable- poorest,youngest,leasteducated,female-athighestrisk

WhatCausesofIronDeficiency?• Life-stages

• Menarche• Infancy/earlychildhood

• Nutritionaldeficiency• Culturalpractices• Parasites

• Hookworm• H.Pylori

HowisIronUtilized?• Ironexistsastwopools:

• Storediron(2/3)• Functionaliron(1/3)

• Hemoglobin70%• Transportiron25%• Myoglobin4%• Enzymerelated1%

• BiochemicaleffectsofID• DECREASED:

• Hemeproteins• Ironcontainingenzymes• Ironascofactor

WhyisIronImportant?

• Vitalmicronutrient• Hormones• Neurotransmitters• RNAandDNAmetabolism• Myelinproduction• energymetabolism

• Productionofhemoglobin

IRONDEFICIENCY:SpectrumofHematologicalChanges

Mild Iron Deficiency

Decrease Iron Stores

Increased RDW

Moderate Iron Deficiency

Decrease Iron Transport

Decreased Serum Iron, Changes in Transport Proteins

Severe Iron Deficiency

Iron Deficient Erythropoiesis

Hypochromic Microcytic Anemia

EnsuringAdequateIronIntakeisImportant

• Ironmaintainsnormalcellularfunction

• Deficiencyeffectseveryorgansystem

• Mostobviousclinicaleffectisanemia

• Criticaltodiagnoseandtreatearlyinchildren

IRONINTHEDEVELOPINGBRAIN

BrainIron• Ironentersbrainviareceptormediatedendocytosis• 50%ofbrainironisacquiredduringthefirst3weeksoflife• Transportwithinbrainpoorlyunderstood

• Mostassociatedwithtransferrin,ferritin,lactoferrin,enzymes• “Free”ironhasbeenimplicatedinthepathophysiologyofanumberofbraindiseases

• Distributionisuneven• Presentingreyandwhitematter• Mostcommonlyfoundinoligodendrocytes

• Normaloligodendrocytes,brainiron,andirontransportarerequiredformyelinproductionandmaintenance

IronDeficiencyandtheDevelopingBrain• Decreasedbrainironandferritin

• Compensatoryincreaseintransferrin• Non-homogeneousdecreaseinbrainiron

• AbnormalMyelination• Ironisacofactorforlipidandcholesterolbiosynthesis• Ratswithprenatalandlactational irondeficiencyhaveadelayedrateofmyelinationandhypomyelination

• NeurochemicalAbnormalities• GABA,dopamine,serotonin,phenylalanine

• AbnormalNeurodevelopment• Ratandmurinemodels- irreversible changesinmotorandcognitivedevelopment

• Ratmodel- associationbetweenirondeficiencyandSNHL• Hippocampus– disruptedplasticity

NeurologicalConsequencesofIronDeficiencyinChildren

DEVELOPMENTALDELAY

DEVELOPMENTALABNORMALITIES

• IDnegativeimpactoncognition,behaviorandmotorskills• ID,IDAandnon-IDanemiacancausecognitivedefectsatanyage

• Hemoglobinlevelcorrelatestocognitiveperformance• Impactofirontherapytoimprovecognitivefunctionisunclear

• LozoffandcolleaguesfollowedacohortofCostaRicanchildrenfrominfancytoadolescencetodeterminetheearlyeffectsofirondeficiencyonchildhooddevelopment

FIRSTSTUDY:Infantsandtoddlers• 191wellinfants12to23months• Baseline,1&12wk posttherapylabworkandBSID• InfantswithmoderatetosevereIDAhadlowerbaselineMDIandPDIscores

• 1week- nochangeinMDIorPDIscores• 12weeks- moderatetosevereIDA

• lackofcorrectionofironstoreswithcorrectionofanemia(25/34patients)correlatedwithpersistenceoflowerMDIandPDIscores

• Irontherapytocorrectanemiaaloneisnotadequatetocorrectneurodevelopmentaldisturbances

Conclusion:Early,severe,chronicirondeficiencyismorelikelytoresultinneurodevelopmentalabnormalitiesPediatrics1987;79:981-995

SECONDSTUDY:School-AgeChildren• Follow-upstudyat5yearsofagetodetermineeffectsofirondeficiencyininfancyonlaterdevelopment

• Retentionrate:85%•Allhadnormalgrowthandnutritionalstatus•moderatelysevereanemiaininfancyresultedinsignificantlylowerscoresonmentalandmotortesting

CONCLUSION:Childrenwithirondeficiencyanemiaininfancyareatriskforlong-lastingdevelopmentalsequelaeNEJM1991;325:687-694

THIRDSTUDY:Adolescents• Longitudinalfollow-uptodetermineeffectsofirondeficiencyininfancyonlaterintellectualfunctioning

• Retentionrate:87%• Adolescencewithmoderatelysevereirondeficiencyininfancy:

• hadlowertestscoresinnumerousareas• morelikelytohaverepeatedagrade/receivedtutoring• morebehaviorproblems

CONCLUSION:Severechronicirondeficiencyininfancyidentifieschildrenatriskforabnormalitiesinbehavior,cognitionandmotorskillsmorethantenyearsafterirontherapyPediatrics2000;105(4):1-11

HOWDOESIRONDEFICIENCYRESULTINDEVELOPMENTALDELAY?

• Alterationsinhippocampus• Mitochondrialdamage• Abnormalmyelination• Neurotransmitterabnormalities

• Braindopaminemetabolism• Behavioralabnormalitiesduetoirondeficiencyimpairlearningcapability

NeurologicalConsequencesofIronDeficiencyinChildren

CEREBROVASCULAREVENTS

HowCommonareCerebrovascularEventsinChildren?

• Incidence:2- 3/100000childrenperyear• Noetiologyfound

• 20- 36%ischemicstroke• 16%hemorrhagicstroke

• Manycasereportsandlargerstudiesdemonstrateanassociationbetweenirondeficiencyandpediatricstrokeinotherwisewellchildren

IRONDEFICIENCY:ACAUSEOFSTROKEINCHILDREN• Retrospectivereviewofchildrenfromtheneonatalperiodtoage15yearswhopresentedwithstrokebetween1985and1995.

• 53patientsdiagnosed• 2.5/100000childrenperyear

• 16/53(30.2%)noetiologyfound• 6/16(37.5%)withetiologyundeterminedwereirondeficient(p<0.01)

• Ofthesechildren:• Allwere6- 18months• Allhadamildviralillness• Notallwereanemic• Notallhadthrombocytosis

CONCLUSION:• Anassociationbetweenirondeficiencyandpediatricstrokeexistsinchildren6to18monthsofageinthesettingofanonspecificviralillness

Hartfield et al. Pediatric Neurology 1997;16(1)50-53

Furtherworkinthisarea:• Azabetal.AnnHematol2014;93(4):57:1-6

• Case-controlstudyof21patientswith100controls• Healthychildrenwithstrokewere3.8timesmorelikelytohaveIDA(p=0.005)• RecommendearlydetectionofIDAforpreventionofhealthproblems

• Maguireetal.Pediatrics2007;120:1053-1057• Case-controlstudyof53patients12-38months• otherwisehealthchildrenwere10timesmorelikelytobeirondeficient• accountedformorethan50%ofstrokeinthecohort• Concludedthatirondeficiencyisariskfactorforstrokeinchildren

• Sebireetal.Brain2005;128:477-489• Studyof42patientswithSVTfrom4strokeregistries• 55%hadanemia;50%hadID• Morecommoninotherwisehealthchildren(p=0.07)• Concluded- nutritionaldeficiencymodifiableriskfactor

MechanismofIDandStroke

• Thrombocytosissecondarytoirondeficiency• Irondeficiencyleadstoahypercoagulablestate• AnemicHypoxia• Abnormalitiesinmitochondrialfunction

NeurologicalConsequencesofIronDeficiencyinChildren

FEBRILESEIZURE

FebrileSeizures

• 2-5%ofchildrenupto5yearsofage• Peakageis18months- similartoID

• Knownriskfactors:• Genetics,fever>39.4celsius,particularinfections,day-careattendance,lowbirthweight,neonatalstay>30days,maternalsmokinginpregnancy

• Susceptibilityofdevelopingbraintoseizuresrelatedtomaturationalchangesinexcitatoryandinhibitoryneurotransmitters

• Inappropriateresponsetocytokinesassociatedwithinfection

RoleofIronDeficiencyinFebrileSeizures

RelevantStudies:• OnestudyfoundIDtodecreasetheriskoffebrileseizuresinchildren

• KobrinskyNL,YagerJY,CheangMS,etal.JChildNeurol.1995(2):105-109

• SixstudiesfoundIDtoincreasetherisk• SharifM,etal.GlobalJofHealthSci20168(2):185-189• PapageorgiouV,etal.EurJPaediatrNeurol201519(5):591-6• Hartfieldetal.ClinicalPediatricsFebruary200948(4):420-426• RehmanN,BillooSG.JCPSP,2005(5):338-340• DaoudAS,BatiehaA,Abu-EkteishF,etal.Epilepsia,2002(7):740-74• PisacaneA,SansoneR,ImpagliazzoN,etal.BMJ,1996(313):343-344

• Difficultieswiththesestudies:• Somearesmallstudies• DiagnosticcriteriausedtodiagnoseID/IDA

• Ironstudiesinaccurateinthesettingoffebrileillness

Consensus:

• Irondeficiencyisariskfactorforfebrileseizure• ChildrenwithfebrileseizuresshouldbescreenedforID/IDA

• Avoidironstudieswhileacutelyunwell

NeurologicalConsequencesofIronDeficiencyinChildren

BREATHHOLDINGSPELLS

BreathHoldingSpells• Occurin27%ofchildren• Proposedtobeduetoautonomicdysregulationandvagallymediatedcardiacarrestwithcerebralanoxia

• IronDeficiencyexacerbatesBHSas:• Anemiadecreasesoxygencarryingcapacitycausingcerebralanoxia• IDchildrenaremoreirritablewhichincreaseslikelihoodofaBHS• Ironisacofactorintheenzymesthatdegradecerebralcatecholamines

• Autonomicdysregulation• Abnormalityinneurotransmitterfunction

IronTherapyandBreathHoldingSpells• Consideredrandomised/quasi-randomised studies• Comparedironsupplementationwithplaceboornotherapyforchildren<18yearswithBHS

• Reductioninfrequencyorseverityorboth• RESULTS:

•2studieswith87children• Irondecreasedfrequency(OR76.4895%CI:15.65-373.76,P<0.00001)

•Meta-analysissolelyexaminedironcausingcompleteresolutionmaintainsignificance(OR53.45:95%CI6.57-434.57,P=0.0002)

• CONCLUSION:• IrontherapyiseffectiveinthetreatmentofBHS

Cochranereview:Zehetner Aetal.CochraneDatabaseSyst Rev201012(5)

• Prospectivestudyof100children6-26monthswithBHS

• 73%resolutionand23%had50%reductioninBHS

• 3mg/kg/dayofironfor12weeks• Factorspredictingpoorresponseonunivariateanalysis:

• Frequencyofattacksandintoleranceofiron• Responseratenotpredictedbypresenceofanemiaorironstatus

Conclude:IrontherapyiseffectivetherapyinBHSregardlessofironstatusJain R et al. J of Paediatr Child Health 2017 June 1 ePub

IsIronTherapyAppropriateforBHSforChildrenWithoutAnemia?

• Investigate for IDA

• Treat those with IDA and ID

• For those without ID/IDA• More research needed!• Discuss risks/benefits of therapy• Trial 3 mg/kg/day• Monitor side-effects

How to Approach Children with BHS?

NeurologicalConsequencesofIronDeficiencyinChildren

OtherLessCommonProblems

IronandDysphagia• Plummer-VinsonSyndromeiswelldescribedinadults

• Rarereportsinchildren- youngest5years• Treatmentisiron• Dysphagiaresolvespriortowebs/rings

• AdultscomplainoforalpainwhenID• Esophagealmanometry(adults)

• AbnormalinIDadultswithdysphagiawithoutwebs/rings

• AnimalmodelsofID• AbnormalesophagealmusclestructureinID• NitricOxide

• requiredfornormalsmoothmusclefunction/peristalsis• decreasedasproductionisirondependent

IDANDDYSPHAGIA:IMPLICATIONSFORINFANTS

• ToddlersdevelopIDAasconsumeexcessivemilk• Typicallyrefusesolids• Mostlythoughtofasa“parenting”issue

• Newhypothesis:MildIDresultsinoralpainanddysphagia.Thiscausesfeedingdysfunction,whichperpetuatestheIDstate.Rapidlyreversiblewithirontherapy

• Supportedbyadultandanimalstudies• WarrantsfurtherstudyHartfield.ClinicalPediatrics,February2010

RecognizedandRare

•Pseudotumorcerebri• Irondeficiencyrecognizedcauseofpseudotumorcerebrisincethe1800’s

• Pathophysiologyuncertain• Tissuehypoxialeadstocerebraledema• AbnormalhemodynamicsresultinincreasedCBFresultinginincreasedICP

• Depletioniniron-containingenzymesmayhaveeffect

• Reversiblewithirontherapy•Cranialnervepalsy

NewandEmerging

•ADHD• Abnormalitiesindopaminergicfunction• Metaanalysis- lowserumferritinandnotironassociatedwithADHD

WangYetal.PLoS One201712(1)

•RestlessLegSyndrome• PublicationsimplicateIDasacontributortoRLS• Meta-analysisofirontherapy– insufficientevidencetodeterminebenefit

Trotti LMetal.CochraneDatabaseSysRev2012May16(5)

Conclusions• Ironisrequiredfor:

• Braindevelopment• Myelination• Neurotransmitterproduction• Hemoglobinsynthesis

• Deficiencyassociatedwithavarietyofneurologicalproblems

Preventionofirondeficiencythroughoutgestation,infancyandchildhoodisimperativefornormalneurodevelopment

andtopreventotherimportantcomplicationsofirondeficiency

StrategiestoPreventIronDeficiency• ScreenandtreatpregnantwomenforID

• Moreprevalentinwomenofchildbearingage• Delayedcordclamping• Ensureappropriatedietatearlycheck-ups

• Ironcontainingfoodintroducedby6months• Avoidcow’smilkuntil1yearofage• Breastfeedorformulawithironbeforethen

• Screenhighriskinfantsandchildren• Indigenous,immigrants,prematureinfants

• Remember- parasitesandH.Pyloricontribute• Timelytherapywithdiagnosis