Measles, mumps and rubella (MMR) vaccination has no effect on cognitive development in children : the results of the Polish prospective cohort study

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ContentslistsavailableatSciVerseScienceDirect

Vaccine

j o ur na l h o me pa g e : w w w . e l s e v i e r . c o m / l o c a te / v a c c i n e

Measles, mumps and rubella (MMR) vaccination has no effect on cognitive development in children – The results of the Polish prospective cohort study

Dorota Mrozek-Budzyn

^∗

, Agnieszka Kiełtyka, Renata Majewska, Małgorzata Augustyniak

EpidemiologyandPreventiveMedicine,JagiellonianUniversityMedicalCollege,Kopernika7a,31-034Krakow,Poland

a r t i c l e i n f o

Articlehistory:

Received5December2012

Receivedinrevisedform15February2013 Accepted28March2013

Available online 12 April 2013

Keywords:

Children MMRvaccine Cognitivedevelopment

a b s t r a c t

Objectives:TheaimofthestudywastoexaminethehypothesisthatMMRexposurehasanegative inﬂuenceoncognitivedevelopmentinchildren.Furthermore,MMRwascomparedtosinglemeasles vaccinetodeterminethepotentialdifferenceofthesevaccinessafetyregardingchildren’scognitive development.

Methods:Theprospectivebirthcohortstudywithsampleconsistedof369infantsborninKrakow.Vacci- nationhistoryagainstmeasles(dateandthetypeofthevaccine)wasextractedfromphysicians’records.

ChilddevelopmentwasassessedusingtheBayleyScalesofInfantDevelopment(BSID-II)upto3rdyear oflife,Raventestin5thand8thyearandWechsler(WISC-R)in6thand7thyear.Dataonpossiblecon- founderscamefrommothers’interview,medicalrecordsandanalysesofleadandmercurylevelatbirth andattheendof5thyearoflife.Linearandlogisticregressionmodelsadjustedforpotentialconfounders wereusedtoassesstheassociation.

Results:Nosignificantdifferencesincognitiveandintelligencetestsresultswereobservedbetween childrenvaccinatedwithMMRandthosenotvaccinateduptotheendofthe2ndyearoflife.Chil- drenvaccinatedwithMMRhadsignificantlyhigherMentalBSID-IIIndex(MDI)inthe36thmonththan thosevaccinatedwithsinglemeaslesvaccine(103.8±10.3vs.97.2±11.2,p=0.004).Neitherresultsof RaventestnorWISC-RweresignificantlydifferentbetweengroupsofchildrenvaccinatedwithMMR andwithsinglemeaslesvaccine.Afterstandardizationtochild’sgender,maternaleducation,familyeconomicalstatus,maternalIQ,birthorderandpassivesmokingalldevelopmentaltestswerestatistically insignificant.

Conclusion:TheresultssuggestthatthereisnorelationshipbetweenMMRexposureandchildren’scognitivedevelopment.Furthermore,thesafetyoftripleMMRisthesameasthesinglemeaslesvaccinewith respecttocognitivedevelopment.

1. Introduction

Despitethefactthatanumberofepidemiologicalstudiesfailed toshowanyassociationbetweenMMRvaccineandautism,the controversy over thevaccine safety still exists [1–3]. The anti- vaccine organizations and websites that portraythemselves as officialresourcesforcredibledataonvaccinescontinuetoprovide flawedorbiasedinformationaboutMMR[4,5].Itservestofuelpub- licconcernregardingthesafetyofMMRwhichleadstoincreased ratesofimmunizationrefusalordelayson-timevaccination,and consequentlycausesasignificantriskofoutbreaksofmeaslesin manyEuropeancountriesandtheUnitedStates[6–8].

∗ Correspondingauthor.Tel.:+48124231003;fax:+48124228795.

E-mailaddresses:dorota.mrozek-budzyn@uj.edu.pl(D.Mrozek-Budzyn), mykielty@cyf-kr.edu.pl(A.Kiełtyka),rmajewska@cm-uj.krakow.pl(R.Majewska), malgorzata.augustyniak@uj.edu.pl(M.Augustyniak).

Tocounter theseanti-vaccination advocatesand topromote greater acceptance of vaccination (not exclusively MMR) the evidence-basedinformationconcerningthebeneﬁtsandtherisk ofimmunizationisrequired[9–12].ThehypothesisthatMMRas atriplelivevaccineismoredetrimentalforchildren’sneurodevel- opmentincomparisontosinglemeaslesvaccinewasdevelopedin thepast[13–15].Nevertheless,thestudieshavenotprovidedevi- denceagainstMMRimmunization[16–24].Whileearlierstudies focusedonmoreadvancedhealthproblemslikeautism[18,21,22], currentlyepidemiologicalstudieslookformoresubtleneurode- velopmentaloutcomesthatcouldbepotentiallylinkedtovaccines exposure.Thosecanbedetectedbypsychologicaltestsbeingsuf- ﬁciently sensitiveto monitor even minor, subclinical disorders inchildren.Additionallyessentialisinclusionofawiderangeof potentialconfoundersthatmayhaveanimpactonchildren’sneu- rodevelopment,likematernalage,educationandIQ,mercuryand leadexposureduringpregnancyandotherprenatalandpostnatal factors.

http://dx.doi.org/10.1016/j.vaccine.2013.03.057

Open access under CC BY-NC-ND license.

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DuringthelastyearsinPolandtherewasagoodopportunity toconductthestudiesontheMMRsafetybecausethepopula- tionof children wasdiversiﬁed interms of vaccination history againstmeasles. Thepart ofinfants wasvaccinated withMMR asa voluntaryoption(charged extramoney)andsomeofthem werevaccinatedonlywithsinglemeaslesvaccinewhichwasused accordingtothenationalmandatoryimmunizationscheduleupto 2004.Obviously,somechildrenfordifferentreasonshavenotbeen vaccinatedagainstmeaslesatall.

TheaimofthisstudywastoexaminethehypothesisthatMMR exposurehasa negativeinﬂuence oncognitivedevelopmentin children.Furthermore,MMRwasassessedincomparisontosingle measlesvaccineexposure,todeterminethepotentialdifferenceof thesevaccinessafetyregardingchildren’scognitivedevelopment.

2. Materialsandmethods

Thisis aprospectivecohortstudy,combiningenvironmental monitoringandmolecularapproacheswithcomprehensiveneu- rodevelopmentassessments.In theanalysiswe useddatafrom anearlierestablishedKrakowbirthcohortofchildren,beingpart ofongoing,collaborativestudywithColumbiaUniversityinNew York,on the vulnerability of fetus and child to environmental factors.Thestudyhasreceivedtheapproval of theJagiellonian UniversityEthicalCommittee.

Theenrolment(November3,2000–August22,2003)included onlynon-smokingwomen,aged18–35years,withsingletonpreg- nancywithoutillicitdruguseandHIVinfection,freefromchronic diseasessuchasdiabetesorhypertensionandresidinginKrakow foratleastoneyearpriortopregnancy.Theinfantswerefollowed upto8thyearoflife.Eachyearmotherswereaskedtoprovideinfor- mationoninfants’healthandhouseholdcharacteristicsbytrained interviewers,whocarriedoutdetailed,face-to-facestandardized interviews.TheTestofNonverbalIntelligence,Thirdedition(TONI-3) wasadministeredtomothers.Wehaveincludedthisinstrumentto adjusttothematernalcontributiontochildcognitivedevelopment.

2.1. Vaccinationdata

Thedataoninfants’vaccinationhistory(dateofvaccinationand typeofvaccine)wereextractedfromthephysician’srecords.The vaccinationstatuswasbasedonmeaslesvaccinationduringthe secondyearoflife.

2.2. Biologicalsamplesandanalysis

Concentrationsofcotinineandheavy metals(mercury,lead) wereexaminedin Cord blood (at delivery)and capillary blood (5-year-old children). Whole blood lead concentrations were determinedusinginductivelycoupledplasmamassspectrometry CLIA’88method“BloodleadcadmiummercuryICPMSITB001A”.

Thismulti-element analytical technique is based onquadruple ICP-MStechnology [25]. Mercurylevels were measured at the CDCbyZeemangraphitefurnaceatomic absorptionspectrome- try,using aphosphate/TritonX-100/nitric acidmatrix modiﬁer.

Coldvaporatomicspectrometryfollowingchemicalreductionof mercurycompoundswasusedtomeasuretotalmercuryinwhole blood.Moredetailsonbloodsamplecollectionandanalysiswere presentedinearlierpublications[26,27].

2.3. Infantsneurodevelopmenttesting

TheFaganTestofInfantIntelligence(FTII)wasconductedin the6thmonthoflife.TheBayleyScalesofInfantsDevelopment, secondedition(BSID-II),wasadministeredinthe12th,24thand 36thmonthsoflife.TheMentalScaleofthattestincludesitems

that assess memory, habituation, problem solving, early num- berconcepts,generalization,classiﬁcation,vocalization,language, and social skills [28].Test scoresare adjusted tochild’sageto obtaintheMentalDevelopmentIndex (MDI).Testresultsarein oneoffourcategories:(1)acceleratedperformance(score>115), (2)withinnormallimits(score85–114),(3)mildlydelayedperfor- mance(score70–84),and(4)signiﬁcantlydelayed(score<69).The outcomesrangeisfrom50to150.

ThetestofRaven’sColoredProgressiveMatrices(Raven)was administeredtwice,in5thand8thyearoflife.Theoutcomesof thetestweremeasuredintermsofcentiles.Becausetheresultsof thistestweregenerallyhigh,thecutpointofpoorresultcategory was74thpercentile,whichmeansmiddleintelligenceoutcomes.

Outputscalewaspresentedincentilesstandardizedtoagegroups.

The Wechsler Intelligence Scale for Children (WISC-R) was administeredin6thand7thyearoflife,andgeneratedverbal,non- verbalandtotalIQforevaluatedchildren.CategorywithIQ<100 wasconsideredasthepooreroutcomes.Theoutcomesrangeisfrom 40to160.

All neurodevelopment tests were conducted in the Depart- mentofEpidemiologyandPreventiveMedicinebycarefullytrained examinersbeingunawareofthechild’sexposure.BayleyScalesas wellasRaventestbothhavewelldeﬁnedcriteriaandwerecon- sideredasfullyconsentbetweendifferentexaminers.Inorderto providefullycomparableassessmentofWISC-Rtest,onepsychol- ogistratedperformedanswersforallchildren.

2.4. Statisticalanalysis

In the descriptive analysis, difference in the distribution of women and newborns’ parameters grouped by measles vacci- nationstatus were testedusing ␹2 (fornominalvariables) and Mann–Whitney and Kruskal–Wallis tests (for continuous vari- ables).

Thecomparisonofthetestsoutcomesaccordingtotheexposure tothetypeofvaccine(MMRvs.monovalentvaccineandMMRvs.

unvaccinatedgroup)wasstudiedusingmultivariatelinearmodels.

Aswellthelogisticmodelswereusedtoassessriskofdevelopmen- taldelay(MDI<85,Raven<74,IQ<100).

AllvariablesfromTable1whichshowedaprobableassociation withmeaslesvaccinationstatus(p<0.1)wereincludedinstatisti- calmultivariablemodels.Bloodleadlevelattheageof5wasused asconfounderinmodelsfor5-year-oldandolderchildren.Addi- tionally,thechild’sgenderwasaddedtoallmodelsasitishighly associatedwithdevelopmentaltests’performance.

StatisticalanalyseswereperformedusingSTATAsoftwarever- sion8.0.

3. Results

3.1. Studypopulation

Theanalyzedpopulationconsistedof369children:52.3%boys and47.7%girls.Fromthatgroup10children(2.7%)wereabsentdur- ingBSID-IItestin24thmonth.Retentionrateinthatgroupduring psychologicaltestsinfurtheryearswasrespectively:94.1%in3rd, 72.6%in5th,58.5%in6th,60.2%in7thand51.2%in8th.Duringthe secondyearoflife(periodofexposureincludedtoanalysis)83.2%

ofchildrenwereexposedtoMMR,8.7%tosinglemeaslesvaccine and8.1%wereunvaccinated.Onlytwochildrenwithknownvacci- nationhistorywerenon-vaccinatedagainstmeaslesuptothe6th yearoflife.

ChildrenvaccinatedwithMMRweremorefrequentlytheﬁrst childinthefamilythanthoseeithervaccinatedwithmonovalent vaccineorunvaccinateduptotheendofthe2ndyearoflife(69.7%,

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Table1

Cohortcharacteristicsofchildrenvaccinatedandunvaccinatedagainstmeaslesupto2ndyearoflife.

MMRvaccine Monovalentvaccine Non-vaccinated p

N % N % N %

Child’sgender:

Boys 160 52.1 18 56.2 15 50.0 0.968

Girls 147 47.9 14 43.8 15 50.0

Maternaleducation

Primary/vocationalschool 57 18.6 15 46.9 9 30.0 0.001

Highschool 18 25.4 10 31.2 6 20.0

University 172 56.0 7 21.9 15 50.0

Maternalmaritalstatus

married 290 94.5 30 93.8 28 93.3 0.730

notmarried 17 5.5 2 6.2 2 6.7

Pooreconomicalstatus 18 5.9 6 18.8 4 13.3 0.016

Birthorder

1 214 69.7 9 28.1 10 33.3 <0.001

2 83 27.0 16 50.0 18 60.0

≥3 10 3.3 7 21.9 2 6.7

Birthweight<250g 10 3.3 1 3.1 1 3.3 1.000

Gestationalage<37weeks 15 4.9 0 – 3 10.0 0.148

Virusinfectionduringpregnancy 74 24.1 5 15.6 10 33.3 0.265

Passivetobaccosmokingduringpregnancy

Non-exposed 231 75.2 11 34.4 20 66.7 <0.001

Upto5cigarettes/day 57 18.6 11 34.4 3 10.0

Above5cigarettes/day 19 6.2 10 31.2 7 23.3

Cordbloodmercurylevel>0.9␮g/L 107 46.5 9 42.9 10 43.5 0.920

Cordbloodleadlevel>1.2␮g/L 143 51.3 18 62.1 15 53.6 0.536

Fishconsumptionduringpregnancyabove100gperweek 81 26.4 11 34.4 6 20.0 0.434

MMRvaccine Monovalentvaccine Non-vaccinated p

Mean SD Mean SD Mean SD

Mother’sageat2ndtrimester 27.7 3.5 27.7 4.5 27.7 3.8 0.971

Maternalnonverbalintelligence(TONI-3) 109.3 16.8 101.0 18.2 110.3 22.8 0.091

Maternaldepressionscaleduringpregnancy 27.4 0.6 28.0 2.5 28.8 2.3 0.811

Cordbloodmercurylevel(␮g/L) 1.08 0.05 0.95 0.13 1.01 0.15 0.561

Cordbloodleadlevel(␮g/L) 1.43 0.04 1.48 0.09 1.61 0.21 0.439

Bloodmercurylevelatageof5years(␮g/L) 0.57 0.32 0.52 0.23 0.44 0.26 0.438

Bloodleadlevelatageof5years(␮g/L) 2.16 0.78 2.53 0.70 2.27 0.65 0.063

Peakbloodmercurylevel(␮g/L) 1.09 0.68 0.88 0.57 0.99 0.68 0.133

Peakbloodleadlevel(␮g/L) 1.94 0.88 1.96 0.78 2.03 1.03 0.811

Fishconsumptionduringpregnancy(g/week) 79.9 63.8 78.8 67.7 75.3 54.4 0.901

28.1%and33.3%,p<0.001)(Table1).Mothersofchildrenvaccinated withmonovalent vaccinehad less frequently universitydegree thanthosevaccinated withMMRor unvaccinated(21.9%,56.0%

and50%,p=0.001)and wereinhigherpercentage bothin poor economicalsituation (18.8%,5.9%, 13.3% respectively, p=0.016) andexposedtopassivetobaccosmokingduringpregnancy(65.6%, 24.8%,33.3%,p<0.001).Nostatisticallysigniﬁcantdifferenceswere observedinothervariablestakenintoconsideration(Table1).

3.2. Children’scognitivedevelopmentinpre-exposureperiod

Therewerenosignificantdifferencesintestsscoresthatwere performedduringpre-exposureperiod.Theaverageoutcomesof theFagantest,administeredinthe6thmonthoflife,amounted toabout60pointsinallthreegroupsunderanalysis.Theaverage scoresofMDI inthe12thmonthof lifewerealsoonthesimi- larlevel(from98.3to102.7point)(Fig.1).In1-year-oldinfants categories:“MildlyDelayed”or“SignificantlyDelayed”(MDI<85) werereachedbyabout10%ofchildrenanddifferenceswerenot statisticallysignificantbetweenstudiedgroups(Table3).

3.3. MMRandcognitivetestsoutcomes

No signiﬁcantdifferences of cognitiveand intelligence tests resultswere observed between children vaccinated withMMR andunvaccinatedinunivariableanalysis.Theiroutcomeswereon

similarlevel(Fig.1).Afterstandardizationtochild’sgender,maternaleducation,familyeconomicalstatus,maternalIQ,birthorder andpassivetobaccosmoking(aswellasleadlevelincordbloodin theendof5thyearoflifefor5-year-oldandolderchildren)noneof thetestsoutcomesofcognitivedevelopmentorintelligencetests resultswerestatisticallysigniﬁcant(Table2).

ChildrenvaccinatedwithMMRhadsignificantlyhighermental BSID-IIscoresinthe36thmonththanthosevaccinatedwithsingle measlesvaccine(103.8±10.3vs.97.2±11.2,p=0.004)(Fig.1).Nei- therresultsofRaventestnorWISC-Rweresignificantlydifferent betweengroupsofchildrenexposedtoMMRandsinglemeasles vaccine.TheresultsofMDIinthe36thmonthinchildrenvacci- natedwithMMRvs.vaccinatedwithsinglemeaslesvaccinebecame non-significant(ˇ=4.7,p=0.056)afterstandardizationtochild’s gender,maternaleducation,familyeconomicalstatus,maternalIQ, birthorderandpassivetobaccosmoking.ResultsofMDIinthe24th monthaswellasWISC-RandRaveninMMRandmonovalentgroup didn’tdiffersignificantly.

Subjects exposed to monovalent vaccine had a higher per- centageof“MildlyDelayed”or“SigniﬁcantlyDelayed”(MDI<85) outcomesinthe24thmonthandthe36thmonthoflifeincom- parisonwithexposedtoMMRorunvaccinatedchildren(26.7%vs.

8.2%and 11.1%,p=0.009and 20.7%vs.3.5% and4.1%,p=0.023, respectively).Thedifferencesbetweengroupsrelatedtodelayed testsoutcomesinchildren inthe5th,6th, and8th yearsoflife were not statistically signiﬁcant. The percentage of “delayed”

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Fig.1.AveragetestsscoresinMMRormonovalentvaccineexposedandnon-exposedgroups(withstandarddeviation).

Table2

StandardizedtestscoresinMMRandmonovalentexposedandnon-exposedgroups(multivariablelinearregressionmodels).

Test Age MMRvs.non-vaccinated MMRvs.monovalentvaccine

␤^a 95%CI p ␤^a 95%CI p

MDIofBSIDII 24thmonthoflife −3.7 −9.6;2.1 0.212 1.0 −5.1;7.0 0.749

MDIofBSIDII 36thmonthoflife −3.4 −8.2;1.5 0.172 4.7 −0.1;9.5 0.056

Raven(centilles) 5thyearoflife −3.0 −13.5;7.5 0.574 3.1 −7.8;14.0 0.572

WISC−R 6thyearoflife

VerbalIQ^b −2.5 −11.1;6.1 0.568 −3.5 −11.8;4.7 0.394

Non−verbalIQ^b −2.8 −11.1;5.5 0.502 −0.3 −8.4;7.7 0.936

IQ^b −3.0 −11.0;5.1 0.464 −2.23 −10.1;5.6 0.572

WISC-R 7thyearoflife

VerbalIQ^b 3.5 −4.2;11.2 0.370 −0.7 −9.6;8.1 0.867

Non-verbalIQ^b −0.9 −10.1;8.2 0.843 3.4 −7.2;14.1 0.523

IQ^b 1.5 −6.0;9.1 0.688 1.3 −7.4;10.1 0.761

Raven(centilles)^b 8thyearoflife −2.3 −13.9;9.3 0.694 0 −12.8;12.7 0.997

aStandardizedtochild’sgender,maternaleducation,maternalIQ,maternaleconomicalstatus,birthorder(furtherchildvs.ﬁrstone)andexposuretoenvironmental tobaccosmokeduringpregnancy(yesvs.no).

b Additionalstandardizationtobloodleadlevelattheageof5.

verbalIQresultsin7year-oldchildrenwassigniﬁcantlyhigherin groupvaccinatedwithmonovalentvaccinecomparedtoMMRand unvaccinatedsubjects(20%vs.2.6%and7.1%,p=0.012)(Table3).

Afteradjustingtopossibleconfounders,MMRexposuredidn’t affecttheriskofdelayedcognitivedevelopmentcomparedtonei- therunvaccinatedchildrennorthosevaccinatedwithmonovalent measlesvaccine.Theoddsratioofdelayedcognitivedevelopment

wasevensigniﬁcantlylowerinMMRthaninsinglemeaslesvac- cinegroupamong3-year-oldchildren(OR=0.18,95%CI:0.03–0.91) (Table4).

In children olderthan 6year-old it wasimpossibleto build up logistic regression modelsdue to thelack of subjects with developmental delay in monovalent vaccine and unvaccinated group.

Table3

Percentageofchildrenwithmildorsigniﬁcantdevelopmentaldelayaccordingtothetestsoutcomes.

MMR Non-vaccinated Monovalentvaccine p

N % N % N %

MDIofBSIDII 12thmonthoflife 23 7.5 3 10.7 4 12.9 ns

MDIofBSIDII 24thmonthoflife 24 8.2 3 11.1 8 26.7 0.009

MDIofBSIDII 36thmonthoflife 10 3.5 1 4.2 6 20.7 0.003

Raven(centilles) 5thyearoflife 44 19.3 5 26.3 7 35.0 ns

VerbalIQ 13 7.1 2 14.3 2 10.5 ns

Non-verbalIQ 12 6.6 2 14.3 2 10.5 ns

IQ 10 5.5 1 7.1 1 5.3 ns

VerbalIQ 5 2.6 1 7.1 3 20.0 0.012

Non-verbalIQ 8 4.2 0 0.0 1 6.7 ns

IQ 8thyearoflife 5 2.6 0 0.0 1 6.7 ns

Raven(centilles) 8thyearoflife 18 10.8 0 0.0 0 0.0 ns

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Table4

TheriskofdelayeddevelopmentinMMRvs.monovalentvaccineexposedornon-exposedgroups(multivariatelogisticregressionmodels).

Test Age MMRvs.non-vaccinated MMRvs.monovalentvaccine

OR 95%CI p OR 95%CI p

MDIofBSIDII^b 24thmonthoflife 1.35 0.15;12.0 0.786 0.35 0.09;1.37 0.132

MDIofBSIDII^b 36thmonthoflife 0.37 0.03;4.02 0.414 0.18 0.03;0.91 0.038

Raven(centilles)^a 5thyearoflife 1.22 0.23;6.55 0.820 0.45 0.11;.1.81 0.261

VerbalIQ^a 1.23 0.09;17.03 0.875 – – –

Non-verbalIQ^a – – – 1.04 0.09;11.78 0.973

IQ – – – – – –

ORstandardizedtochild’sgender,maternaleducation,maternalIQ,maternaleconomicalstatus,birthorder(furtherchildvs.ﬁrstone)andexposuretoenvironmental tobaccosmokeduringpregnancy(yesvs.no).

aAdditionalstandardizationtobloodleadlevelattheageof5.

bStandardizationwithoutmaternaleconomicalstatus.

4. Discussion

ThestudyaddressestheassociationbetweenMMRandcog- nitivedevelopmentinchildrenduringtheeight-yearobservation sincetheexposure.Becausethepopulationofchildrenunderstudy wasdiversiﬁedintermsofvaccinationhistory,weconcentrated onthesafetyofMMRvs.singlemeaslesvaccine.Noothercoun- tryin Europeand theUSAhad similaropportunity toconduct suchan analysis as MMR vaccinewas introduced there tothe immunizationcalendar much earlierthan inPoland, andsingle measlesvaccinehasnotbeenadministeredsince over20 years there[29,30].

The studies onthe safety of both MMR and single measles vaccine and their link with the risk of cognitive development disorders in children have signiﬁcant value,especially that the growing number of parents are opting out of the MMR vacci- nationoratleastsubstitutingitwithasinglevaccinations[31].

The result is that the MMR vaccination rate has fallen, caus- ingasigniﬁcantriskofoutbreaksofmeaslesinmany countries [7,8]. Our ﬁndings are supporting commonly accepted immunization program against measles and rubella which allows to replacesinglevaccineswithMMRvaccine,ifadequatelycontrolled [32].

Theresultsofthestudiespublishedoverthelast12yearson theassociationbetweenMMRvaccineandautismandourobser- vations have found no evidence for such causal links [17–24].

Despiteadverseopinionsandpressures,theWHOhasnotwith- drawntherecommendationsforMMRvaccine,andmeaslesand rubellapreventionprogramshave beencontinued,though with somedifﬁculties,being a partof theMMRmass immunization policy[33].

ThestudyalsodealswiththeassociationbetweenMMRimmu- nization and development of the vaccinated and unvaccinated children,whichwaspossibleonlyintheearlyexposedinfants,as someofthechildrenfromthiscohortwerevaccinatedwithdelay, overtheageoftwo.Havinginmindpotentiallysignificantroleof thetimeofexposure,weconcentratedontheeffectsofdifferent vaccinationstatusinchildrenattheageoftwo.Untilthisagemost children inPoland became vaccinatedaccording tothemanda- toryimmunizationprogram forpreventingmeaslesandrubella, andasmanyas95%ofchildrenshouldhavealreadyreceivedthe firstdoseofMMR.Therefore,theanalysisofMMRvaccinesafety relatedtotheinfantsexposuretimeiscrucialforfindingthelink betweenthevaccinationandchilddevelopment.Iftherewereno evidencefortheharmfuleffectofMMRvaccineonthedevelop- mentofearlyexposedinfants,itwouldbehardtoanticipatethat thechildrenvaccinatedwithdifferenttimedelaysareatrisk.Inthis studyauthorshavenotconcentratedonthecausallinkbetween MMRand autismalthough thishypothesis caused highlevel of

anxietyaroundtheMMRvaccine.Thereissufﬁcientepidemiologic evidencethatfailedtoshowanylinkbetweenMMRandautism [17–23].Atgenerallylowincidenceratesofautism,weshouldnot anticipatehighratesofautisminaprospectivestudyofthecohort consistingof 500children. Duringa few-yearobservationthere wasonlyasinglecaseofautismthatcorrespondedtotheover- allaverageincidenceofautism.Still,thesizeofthecohortwasbig enoughtoobservethedynamicsofhealthoutcomes,suchasdisor- dersofcognitivedevelopment,psychomotoractivityorbehavior.

Assumingapowerlevel0.8and˛=0.05andthesmallnumberof childrenunvaccinatedorvaccinatedwithmonovalentvaccine,our populationwasbigenoughtoﬁndpossibledifferencesinneurode- velopmentoutcomes,e.g.6-pointdifferenceforMDIoutcomesor 8-pointforWISCRIQ.

Themainpurposeofthestudywastoestablishwhetherthere isanassociationbetweenMMRandearlydevelopmentaldelaysof milderintensity.Thisisthestrongpointofthestudybecausemost oftheepidemiologicanalysesconcentrateonthelinks between MMR and more serious post -vaccination side effects in children. Inouropinion,theanalysesshouldalsocover thosemild sideeffectsordisorders,tobeabletoeitherfindevidenceforor againstthecausalrelationshipbetweenMMRandotherlessseri- oushealthoutcomes.Similarissueshavenotalreadybeenanalyzed inclinicalstudiesconductedsofarandepidemiological surveys donot provideinformation onadverse post-vaccinationeffects andtheirinfluenceonchilddevelopment.Alldevelopmentaltests conductedwithinthestudyprovidedconsistentresultsthatfailed toshowanylinkbetweenMMRandincreasedrisk ofcognitive developmentdelays in children. Theanalysesof child development over theperiod ofseveralyears also didnotprovide the evidencefortheassociationoftestsscoresandthetypeofexpo- sure,MMRorsinglevaccine.ThechildrenvaccinatedwithMMR hadevenslightlyhigherscoresofinfantdevelopmentinBSID-II testsin24thand36thmonth oflifeandinRavenattheageof five.Higherscoresobtainedbythevaccinatedchildrencaninno waylink MMRwithhigherintellectualoutcomes,as thiseffect ismostlikelyassociatedwiththeparents’education,intelligence ormaterialstatus.DuringthetimeofthestudyMMRwasarec- ommendedvaccine,thoughitwaschargedextra,andmaybefor thisreasonitwaschosenbybettereducatedandwell-offparents.

Thereforetoavoidthebias,associatedwithsocialandeconomical inequalities,weincludedavailablefactorssuchasmaternaleduca- tion,maritalstatusandfamilyeconomicalstatusinﬁnalstatistical models.

Wakeﬁeld’shypothesisstatedthatMMRvaccinecausesaseries ofeventsincludingintestinalinﬂammation,lossofintestinalbar- rier function,entranceintothebloodstream ofencephalopathic proteinsandconsequentdevelopmentofautism[15].Thoughithas beenchallengedmanytimes,therearestilldoubtsastoMMRsafety

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intermsofchilddevelopment[11,12].Weestimatethatourstudy isthefirstonethataddressesMMRsafetyinwidersensebeyond autism,andthereforeitcouldbeveryconsiderableforpublicaccep- tanceofimmunization.Theweakpointofourresearchisthatthe resultscannotbecomparedtoanyotherfindingsreportedinthe literature.Onlycertain,limitednumberofqualitycategoriescanbe comparedandtheresultsoftheseobservationsarecompatiblewith thefindingsofotherauthorsinprovidingstrongevidenceagainst associationbetweenMMRand developmentaldelayinchildren withautism[34].

An important advantage of the study is that it compares theresults of developmentaltests beforeMMR exposure (two independent tests assessing cognitive development in children administeredinthe6thand12thmonthoflife)andafterMMR immunization.No signsof cognitivedevelopmental delaywere foundafterMMRexposurecompared tochildren whoreceived singlemeaslesvaccinesandthoseunvaccinated.Allresultsofthe differentdevelopmentaltestsusedinthestudywereconsistent.

Thetestsadministeredinourstudyare highlyreliableandval- idated,themethodologywascarefullyselectedinallcases.The study was blindedduring the collection of questionnaires and therefore the interpretation of the results was objective. Long observationperiod (8years) furtherincreasedreliability of the obtainedresults.

Thestudy is a prospectivecohort observation, which is the mostpowerful tool in terms of formulating conclusions. Study designcoveredassessmentofmultipleagentsthatmightpoten- tiallyinﬂuencechilddevelopment.Widevarietyofavailabledata madepossibletakingintoconsideration multiplepotentialcon- founders, which is a great beneﬁt of the study. The obtained results had as well high level of internal agreement. No evi- dencewasfoundforthelinksbetweenMMRanddevelopmental delay in the children from thecohort. The great advantage of the study is that it is at low risk of bias due to MMR vac- cinemanufacturers.AllMMRvaccines havebeenregistered for theuse in Poland and there wasno preference for any of the vaccines.

In conclusion, ourresults suggest that there is no relation- shipbetweenMMRexposureandchildrencognitivedevelopment.

Furthermore, the safety of triple MMR is similar to single measles vaccine with respect to cognitive development. How- ever,astheresultsareoftheﬁrstepidemiologicalstudyregarding that issue, the interpretation of the effects requires careful assessment.

Acknowledgements

ThestudyreceivedfundingfromaNIEHSR01grantsentitled

“Vulnerability of the Fetus/Infant to PAH, PM2.5 and ETS” and

“Developmentaleffects of early-lifeexposure to airbornePAH”

(R01ES010165andR01ES015282)andfromTheLundinFounda- tion,TheJohnandWendyNeuFamilyFoundation,andTheGladys andRolandHarrimanFoundation.Principalinvestigator:Prof.FP Perera;co-investigator:Prof.WJedrychowski.

Conﬂictsofinterest:Thereisnoconﬂictofinterest.

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