Chapter 3

Chapter 3

Cover Page The handle http://hdl.handle.net/1887/45778 holds various files of this Leiden University dissertation Author: Korndewal, Marjolein Title:...

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The handle http://hdl.handle.net/1887/45778 holds various files of this Leiden University dissertation Author: Korndewal, Marjolein Title: Consequences of congenital cytomegalovirus infection in early childhood Issue Date: 2017-01-24

Chapter3



 

Diseaseburdenofcongenitalcytomegalovirus infectionatschoolentryage:studydesign, participationrateandbirthprevalence

Authors

M.J.Korndewal1,2 A.C.T.M.Vossen2 J.Cremer3 R.S.vanBinnendijk3 A.C.M.Kroes2 M.A.B.vanderSande1,5 A.M.OudesluysͲMurphy4 H.E.deMelker1  

Affiliations 1. 2. 3. 4. 5.  

NationalInstituteofPublicHealthandtheEnvironment(RIVM),CenterforInfectious Diseases,EpidemiologyandSurveillance,Bilthoven,theNetherlands LeidenUniversityMedicalCenter(LUMC),DepartmentofMedicalMicrobiology, Leiden,theNetherlands NationalInstituteofPublicHealthandtheEnvironment(RIVM),CenterforInfectious DiseaseResearch,DiagnosticsandScreening,DepartmentforVirology,Bilthoven,the Netherlands LeidenUniversityMedicalCenter(LUMC),WillemͲAlexanderChildren’sHospital, Leiden,theNetherlands UniversityMedicalCenterUtrecht(UMCU),JuliusCenterforHealthSciencesand PrimaryCare,Utrecht,theNetherlands

EpidemiologyandInfection,2016May;144(7):1520Ͳ1527.

57

Chapter3

Summary

 Background Congenitalcytomegalovirusinfection(cCMV)mayleadtosymptomsatbirthandlongterm consequences.WepresentanationͲwide,retrospectivecohortstudyontheoutcomeof cCMVuptotheageofsixyears.  Methods ForthisstudyweidentifiedcCMV,usingpolymerasechainreaction(PCR),byanalysingthe driedbloodspots(DBS),whicharetakenshortlyafterbirthforneonatalscreening.The groupofchildrenwithcCMVwascomparedtoagroupofchildrenwhowerecCMVnegative atbirth.Datawerecollectedabouttheirhealthanddevelopmentuptosixyearsofage.  Results Parentsof73693childrenwereinvitedtoparticipate,and32486(44.1%)gaveinformed consentfortestingtheirchild'sDBSforCMV.Ofthe31484DBSthatweretested,156(0.5%) werepositiveforcCMV.Amongthese,fourchildren(2.6%)hadbeendiagnosedwithcCMV priortothisstudy.  Conclusion ThisuniqueretrospectivenationͲwidestudypermitstheestimationoflongtermsequelaeof cCMVuptotheageofsixyears.ThebirthprevalenceofcCMVinthisstudywas0.5%,which isinlinewithpriorestimates.Thevastmajorityofchildren(97.4%)withcCMVhadnotbeen diagnosedearlier,indicatingunderdiagnosisofcCMV.  

58

DesignoftheCROCUSͲstudy

Introduction

 Cytomegalovirus(CMV)infectionisendemicworldwideandisusuallyasymptomaticin healthyindividuals.Inimmunocompromisedpatientshowever,itcancauseserious complications.[1]Primaryinfections,reinfectionsandreactivationswithCMVduring pregnancycanleadtoinfectioninthefetus.[2]  Congenitalcytomegalovirusinfection(cCMV)isthemostprevalentcongenitalinfection worldwidewithabirthprevalencerangingfrom0.4to2.0%ofallnewborns.[3]An estimated10to15%ofallcongenitallyinfectedinfantshavesignsandsymptomsatbirth, includinghepatosplenomegaly,icterus,petechiae,microcephalyandintracranial calcifications.[4]Longtermsequelae,suchassensorineuralhearingloss,cognitiveand motordevelopmentaldelayandneurologicalproblems,occurin40to58%ofchildrenwho weresymptomaticatbirth.Inaddition,about10to15%ofthechildrenwhowere asymptomaticatbirthdeveloplongtermsequelae.[4]Theseestimatesofsymptomsand sequelaearebasedonametaͲanalysisbyDollardetal,whichmostlyincludedstudieswitha relativelyshortfollowͲupofnomorethanthreeyears.Moreover,mostofthesestudies focusedonlyonhearinglossandgeneraldevelopmentaldelay.Mostinformationonthelong termoutcome(morethanfiveyears)ispresentedbyTownsendetal.,basedonastudyof 176childrenwithcCMVfromtwolargepopulationͲbasedscreeningcohortsinSwedenand theUnitedKingdom.[5]ThesepreviousstudiesontheburdenofcCMVwerebasedonthe prospectivefollowͲupofdifferentcohortsofchildrenwithcCMVdiagnosedatbirth,usually borninasingleregion.  TheCROCUSͲstudy(ConsequencesandRiskfactorsOfcongenitalCytomegalovirUS)was designedspecificallytoaddressthelimitationsofamoreselectedstudypopulation.Itaimed toevaluatethelongtermconsequencesofcCMVintheNetherlandsinanationͲwidegroup ofchildren,retrospectivelydiagnosedattheageoffiveyears.Thedesignofthisstudywill enableustolookatabroadspectrumofoutcomemeasuresacrossthewholerangeof childrenwithcCMV,fromsymptomatictoasymptomatic.Inthispaper,wepresentthis uniquestudydesign,theparticipationrateandthebirthprevalenceofcCMVinthe Netherlands.  

59

Chapter 

3

Chapter3

Methods

 Figure3.1displaysthedesignoftheCROCUSͲstudy,comprisingthestudyelements; identificationofchildrenwithcCMV(1)andcollectionofstudydata(2);andtheregular youthhealthcaresystemforallchildrenintheNetherlandsprovidedbyRegionalPublic HealthServices.   Studyelements

1.IdentifycCMVin Dutchchildrenborn in2008usingDBS

RegularYouthHealthcare



0Ͳ1m

1mͲ4yr





Afterbirth ͲDBS:<1stwk ͲNHS:<1stm

2.Collectdataon developmentand sequelaeofcCMV

CHCvisits ͲGrowth ͲDevelopment ͲVision

4Ͳ5yr

5Ͳ6yr  PHCvisit ͲHearing ͲVision ͲDevelopment

Figure3.1ͲDesignoftheCROCUSͲstudyDesignoftheCROCUSstudy. cCMV:Congenitalcytomegalovirus;CHC:childhealthcenter;DBS:driedbloodspot;NHS:neonatal hearingscreening;PHC:preventivehealthcheck;wk:week;m:month;yr:year.

  IdentificationofchildrenwithcongenitalCMVinfectionandselectionofcontrols Allchildrenbornbetween1January2008and30September2008,livingintheNetherlands wereeligibleforentryintothisstudy(n=139543births,StatisticsNetherlands[6]).All children,livinginregionscoveredbytheRegionalPublicHealthServiceswhowerewillingto participateinthisstudy(n=19;68%oftotal),wereinvitedtotakepartinthisstudy betweenOctober2012andJanuary2013.  Parentsofthiscohortofchildrenwereaskedforconsenttoretrospectivelytesttheirchild’s driedbloodspot(DBS)forCMVDNAbypolymerasechainreaction(PCR).TheDBSwas collectedafterbirthforneonatalscreeningfor18conditions,suchasPhenylketonuria,and wasstoredforfiveyears.TotesttheDBS,arealͲtimemultiplexPCRwaschosen, incorporatingtwoindependentCMVtargetgenes,i.e.UL55andUL123,asdescribedby Boeckhetal.[7]ThismultiplexPCRhada95%detectionlimitof850copiespermilliliterand wascarriedoutattheNationalInstituteforPublicHealthandtheEnvironment(RIVM).All DBSsampleswithsingleordoublepositivePCRresults,andthoseoftheselectedcCMV negativecontrolgroup,weretestedagain,usingaPCRagainstathirddistincttargetregion oftheUL123gene,attheLeidenUniversityMedicalCenter(LUMC).[8]  60

DesignoftheCROCUSͲstudy AthreetimesaslargecCMVnegativecontrolgroup,matchedforsex,monthofbirthand postalcoderegion,wasrandomlyselectedforeachchildwithcCMV.Theparentsofthe childrenwithcCMVandtheselectedcCMVnegativecontrolswereinformedandaskedto participateinthesecondpartofstudy,whichconsistedofthecollectionofdataonthe child’shealthanddevelopment.  DatacollectioninthecCMVchildrenandcontrols Allparentswereaskedtofillinquestionnairesandtogivetheirconsenttoretrievedata fromtheyouthhealthcarerecords,teachers,generalpractitionersandotherhealthcare providers.  Parentalquestionnairesonchilddevelopmentandqualityoflife TheChildDevelopmentInventory(CDI)[9,10],translatedintoDutch[11],wasusedtoassess development.ThePediatricQualityofLife™(PedsQL™)[12Ͳ16]andShortͲForm12®(SFͲ12®) [17,18]wereusedtoassesshealthrelatedqualityoflifeforchildrenandparents respectively.Anadditionalquestionnairewasdevelopedtoobtaininformationaboutthe child’smedicalhistoryanddemographicfeaturesofthefamily.  YouthHealthcare Duringthefirstfouryearsoflifethehealth,growthanddevelopmentofchildrenare regularlycheckedattheChildHealthCenter.Attheintake,dataarecollectedconcerning pregnancy,deliveryandthefirstweeksoflife.Neonatalhearingscreeningisperformedat infants’homes,usuallywithinthefirstweekoflife,usingotoͲacousticͲemissions.Testsfor earlydetectionofvisualdisordersareperformedrepeatedlyduringthefirstthreeyearsof life.Aftertheageofthreeyears,apicturevisiontestandlatertheLandoltͲCvisiontestare usedtoassessvisualacuity.Dataondevelopment(focusedonfineandgrossmotorskills, socialskillsandcommunication)arerecordedinachilddevelopmentchart(vanWiechen chart).Lengthorheight,weightandheadcircumferencearemeasuredrepeatedlyandnoted onagrowthchart.Ifanyofthesefindingsdeviatefromnormalvalues,furtherevaluation willbeperformedbyamedicalspecialistorotherhealthcareprovider. Atfiveorsixyearsofage,aPreventiveHealthCheckisperformedbytheschoolphysician. Thischeckincludeshearingscreening,avisualacuitytest(LandoltͲC)andmeasurementof heightandweight.Insomeregionsscreeningofmotorskillsisstandardprocedure,mostly usingtheBaeckeFassaertMotorTest;otherregionsperformextensivemotortestsonly whenindicated.AllthesedatafromtheChildHealthCentervisitsandPreventiveHealth Checkwerecollectedforthisstudy.  School IntheNetherlands,95%ofallregularprimaryschoolsusethesamestudenttrackingsystem (CITO),whileatspecialneedsprimaryschoolsanumberofdifferentmethodsareused.The resultsfromthefirsttwoyearsofprimaryeducationwerecollected.Schoolresultswere dividedintoquintiles(I,II,III,IVandV)inwhichIstandsforthe20%highestscoresorinto quartiles(A,B,CandD/E)withAindicatingthehighest25%scores. 

61

Chapter 

3

Chapter3 Generalpractitionerandhealthcareproviders IntheNetherlandsthegeneralpractitionerprovidesprimarymedicalcareandkeepstrackof theentiremedicalhistoryandmedicationuseofapatient.Ifthechildattendedthegeneral practitionerorotherhealthcareproviders,thesemedicaldatawereretrieved.  Outcomemeasures Theprimaryoutcomeofthisstudyissensorineuralhearinglossuptotheageofsixyears. Thisisdefinedasmorethan40decibelsnonͲconductivehearinglossinatleastoneear. Secondaryoutcomemeasuresarevisualimpairment,motorimpairment,cognitive impairment,qualityoflifeandgrowthinthefirstsixyearsoflife.Visualimpairmentis definedasbestͲcorrectedvisualacuitylessthan0.3inthebettereye.Cognitiveimpairment, basedontheCDI,isdefinedasadevelopmentalageunderminustwostandarddeviations. Valuesunderminustwostandarddeviationsforheight,weightandheadcircumferenceare consideredgrowthretardationormicrocephaly.  Samplesizecalculation Thesamplesizecalculationwasbasedontheprimaryoutcomeofsensorineuralhearingloss. Weestimatedsamplesizeforunequalgroupsizesusingacontinuitycorrection,sincethe outcomeisrareinthecCMVnegativesubgroup.Todemonstrateadifferenceinhearingloss of10%inthecCMVpositivegroupand0.1%inthecCMVnegativegroupwithapower(ɴ)of 90%andtwoͲsidedalpha(ɲ)of5%weneededcompletedatafrom83cCMVpositiveand 166cCMVnegativechildren.Giventheestimatedresponserateof33%forDBStestingand 75%(cCMVpositive)and50%(cCMVnegative)forapprovalfordatacollection,25000DBS neededtobetested,whichmeantthat75000parentsneededtobeapproachedforthis study.  Ethicalandlegalissues ThisstudywasapprovedbythemedicalethicalcommitteeoftheLeidenUniversityMedical CenterinLeidenandisregisteredinthe“DutchTrialRegister”(NTR3582). Inaccordancewithgoodclinicalpracticeguidelines,studydatawillbestoredfor15years.In theinformedconsentform,parentscouldgiveseparateconsentforDBStesting,approvalof datacollection,storageofthematerials(DBS)for15years,andpermissionforfuture contactconcerningadditionalresearchprojects.Theauthorsassertthatallprocedures contributingtothisworkcomplywiththeethicalstandardsoftherelevantnationaland institutionalcommitteesonhumanexperimentationandwiththeHelsinkiDeclarationof 1975,asrevisedin2008.  Responserate DifferencesinresponseratemayleadtobothanunderͲoroverestimationofthedisease burdenofcCMV.Toassesspotentialdifferences,socioͲdemographiccharacteristics,based onthepostalcoderegion,ofrespondersandnonͲresponderswerecompared,usingdata fromStatisticsNetherlands.  

62

DesignoftheCROCUSͲstudy

Results

 DBStestingͲResponserateandcCMVprevalence Lettersweresenttoparentsof73693children,bornintheNetherlandsbetween1January and30September2008(Figure3.2).Oftheparentsof34105childrenwhoresponded (46.3%),themajority(32486;95.3%)gaveinformedconsenttohavetheirchild’sDBStested forCMV. DBSofintotal31484childrenweretestedforcCMV.DBSthathadbeenobtainedlaterthan 21daysafterbirthwereexcludedfromthestudybecausediagnosisofcCMVwouldbe uncertaininsuchacase,sincetheinfectioncouldhavebeenacquiredafterbirth.CMVDNA wasdetectablein154ofthetestedDBS,basedonthetripletargetPCRconfirmation.In addition,DBSoftwochildrenparticipatinginthestudywerenotavailablefortestingatthe timeofthestudy,buttheyhadbeendiagnosedcCMVpositiveelsewhereshortlyafterbirth. Thisresultedin156confirmedcasesofcCMVandabirthprevalenceof0.50%(95% confidenceinterval:0.42Ͳ0.57). Therewerefewmarkeddifferencesbetweenthedemographicbackgroundsofinhabitants ofthepostalcodeareasofthegroupswhodidanddidnotrespond(Table3.1).Amongthe postalcodeareasofthenonͲresponderstheproportionofmigrants,especiallynonͲWestern migrants,aswellastheproportionofhouseholdswithlowerincomes,weresomewhat highercomparedtothepostalcodeareasofresponders.   Table3.1ͲDifferencesinthegroupofrespondersandnonͲrespondersbasedontheirpostalcode region. Characteristic Responders* NonͲresponders** 

(n=32486)

(n=41207)

Children(underfiveyearsofage)

6.2%

6.3%

Migrants(personswithforeignbackground)

17.9%

23.6%

Westernmigrants***

8.3%

8.8%

NonͲWesternmigrants****

9.6%

14.9%

2.4

2.3

Averagenumberofpersonsperhousehold



Lowhouseholdincome(lowest40%)

35.0%

38.6%

Middlehouseholdincome(middle40%)

41.5%

40.4%

Highhouseholdincome(upper20%) 24.2% 21.6% Dataarepresentedasaveragepercentageornumberpergroupbasedonpostalcoderegion *Parentswhogaveinformedconsentfordriedbloodspot(DBS)testing **ParentswhodidnotrespondorgavenoinformedconsentforDBStesting ***PersonsfromEurope(exceptTurkey),NorthAmerica,Oceania,JapanandIndonesia ****PersonswithaTurkish,African,AsianandLatinͲAmericanbackground



63

Chapter 

3

Chapter3 DataretrievalͲParticipationrateandcCMVdiagnosis Parentsofthe156childrenwithcCMVwerecontactedtoinformthemofthediagnosisand toinvitethemtotakepartinthesecondpartoftheCROCUSͲstudy.Parentsofonlyfourof these156children(2.6%)wereawarethattheirchildhadcCMVpriortothisphonecall,at whichtimethechildrenwerefiveyearsold.Informedconsentwasgivenfor133(85%)cCMV positivechildrentoparticipateinthesecondpartofthestudy.(Figure3.2) FromthechildrenwhowereconfirmedCMVDNAnegativeatbirth(n=31330),aselection wasmadefromthosewhocouldbematchedtothecCMVpositivechildren(n=468).As soonasinformedconsentwasobtainedfortwomatchedcontrolspercCMVpositivecase furtherinclusionofathirdselectedmatchedcontrolwasceased.Parentsof365ofthese childrenwereaskedforinformedconsentandthiswasgivenfor274(75%)ofthesecCMV negativecontrolchildren.(Figure3.2)   Lettertoparents n=73693 Noresponse

n=39588

Responsefromparents n=34105 Consentfortesting n=32486 NoDBSavailable n=353 Notenoughmaterial n=548

Noconsent Incorrect form

n=825 n = 794

ш21daysafterbirth n=101 DBStestedforCMV n=31484 CMVnegative

n=31330

CMVpositiveDBS n=154 TestedforCMVelsewhere CMVpositive n=2

cCMV n=156

cCMVpositivegroup n = 156

MatchedcCMVnegative n = 468 (365 contacteda)

Consentdataretrieval n = 133

Consentdataretrieval n = 274

Figure3.2ͲFlowchartoftheCROCUSstudy.aInclusionofmatchedcontrolswasceasedwhen informedconsentwasobtainedfortwomatchedcontrols.DBS,Driedbloodspot;CMV, cytomegalovirus;cCMV,congenitalCMVinfection;nindicatesnumberofchildren.

64

DesignoftheCROCUSͲstudy

Discussion

 ThisuniquestudydesigndemonstratesthatpopulationͲbasedlongtermoutcomeofcCMV canbestudiedinarelativelyshorttimeframebyusingneonatalDBStoretrospectively identifyexposed(cCMVpositive)andunexposed(cCMVnegative)children.CurrentlyDBS arestoredforfiveyearsintheNetherlands,butlongerstoragemightbeuseful.Thisis particularlyrelevantforcongenitaldiseasesthatmightnotalwaysbepossibletorecognize atbirth,suchasCMV,rubellaandtoxoplasmosis.[19Ͳ21]Itisclearfromotherstudiesthat somelongtermconsequencesofcCMVbecomeapparentlaterthanfiveyearsafterbirth; forexamplehearinglossmayfirstbecomeobviousupto,orevenafter,theageofsixyears. [22,23]Sucharetrospectivediagnosismaybeofclinicalandepidemiologicalrelevance,and mayguidefutureinterventions.  ThebirthprevalenceofcCMVof0.5%foundinthisstudyisverysimilartoprevious estimatesintheNetherlands(0.54%)[24]andinEurope(0.5%)[25].Birthprevalenceand maternalseroprevalencearedirectlyrelated[3,26]andthefoundbirthprevalenceisalsoin linewiththeoverallseroprevalenceamongwomenofchildbearingageintheNetherlandsof approximately37%.[27]  Remarkably,onlyfour(2.6%)ofthe156childrenwithcCMVhadbeendiagnosedpriortothis study.ThisimpliesthatthemajorityofchildrenwithcCMVaremissedintheNetherlands, despitethefactthattheNetherlandshasanexcellenthealthsystemwhichishighly accessible.ThebroadspectrumandlackofspecificityofclinicalsignsrelatedtocCMVmight havecontributedtothisunderdiagnosis.PreviousstudiesshowthatcCMVissymptomatic atbirthinalmost13%ofcases,andthatlongtermconsequencesoccurinabout17%of cases.However,theseestimatesareallbasedonprospectivestudiesinwhichmore extensiveexaminationsandmonitoringmayleadtoinformationbiaswithanoverestimation ofthesymptoms,signsandsequelaeattributedtocCMV.Inaddition,ithasbeenshownthat medicalpractitionersintheNetherlandshavearelativelylowlevelofawarenessconcerning cCMV.[28,29]Allthesefactorsmaycontributetothehighrateofunderdiagnosisfoundin thisstudy.  Althoughtheretrospectivedesignofthisstudyavoidsinformationbiasforthemajorityof thestudyoutcomes,italsohassomedisadvantages.Themaindrawbackisthehigh probabilityofmissingdata,forexampleacompletephysicalexamafterbirthisoftennot registeredandneonatalsymptomsmightthereforebemissed.Inaddition,selectionbias, suchasdifferencesinresponseratebetweenparentsofchildrenwithandwithouthealth problems,ispossible.Yet,thisbiasmaygobothwaysanditcouldleadtoeitheranoverͲor underestimationofthediseaseburden.Thereareactuallysomedifferencesbetween parentswhoconsenttotheDBStestingandthosewhodidnotrespondordidnotconsent. TheseroprevalenceofCMVintheNetherlandsishigheringroupswithlowerincomeornonͲ Westernorigin,[27]thereforethecCMVbirthprevalencecouldbesomewhathigherinthe nonͲrespondergroup,whichcouldleadtoanunderestimationofthediseaseburden.  

65

Chapter 

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Chapter3 AnotherpotentialbiasistheuseofDBSforCMVtesting,whichisdissimilartomanyother studies.TestingtheDBSforCMVislesssensitivethanpostnatalurineCMVtestingandthe sensitivitydependsontheviralload.[30]Largedifferencesinsensitivityhavebeen describedindifferentstudies.[31,32]Recentlyapooledsensitivityof84.4%andspecificity of99.9%,basedonPCRmethodswithreporteddetectionlimitsrangingfrom450to9400 copiespermilliliter,hasbeendemonstratedinametaͲanalysis.[33]Usingahighlyspecific assay,withasensitivityofaround80%,andtakingthebirthprevalenceof0.5%intoaccount, aboutonein1000childrenhadafalsenegativetestresult.Therefore,thechanceissmall thatoneofthechildrenwithacCMVfalsenegativetestresultwasincludedintherelatively smallcCMVnegativecontrolgroup,containingonly274ofthe31330childrenwithacCMV negativetestresult.WeassumethatthechildrenwithcCMV,whohavenotbeendiagnosed byDBStestinginthisstudy,mostlyhadlowviralloads.Therefore,childrenwhowerecCMV positiveinthisstudy,probablyhadaslightlyhigherviralload,whichisknowntobe associatedwithpoorerlongtermoutcomes[34Ͳ36],thantheentiregroupofchildrenwith cCMV.Thismayleadtoanoverestimationofthediseaseburden.  Ourstudydesign,withdatacollectionuptotheageofsixyears,enablesustolookatthe wholerangeofchildrenwithcCMV,includingmainlyasymptomaticchildren,somechildren whomightberetrospectivelyclassifiedassymptomaticandthosewhowereclearly symptomaticatbirth.Thismeansthatthisstudywillproduceinformationonawidediversity ofsequelaerelatedtocCMV.BesidesthewellͲknowncomplicationssuchashearinglossand cognitivedevelopmentaldelay,itallowsustoexploreotheroutcomesthatarepossibly relatedtocCMV.However,thisstudyispoweredwithhearinglossastheprimaryoutcome and,eventhoughtheresponserateswerehigherthanexpectedandtheresultsmaygiveus animpressionofpotentialproblemsrelatedtocCMV,thesamplesizemaynotbesufficient toobtainstatisticallysignificantresultsontheseotheroutcomemeasures.  Inconclusion,thisstudyconfirmsabirthprevalenceofcCMVintheNetherlandsof0.5%.It clearlyshowsthatcCMViscurrentlyunderdiagnosed,sinceonlyfourofthe156children withcCMVhadbeendiagnosedpriortothisstudy.Manyquestionsremainconcerning cCMV.Theinformationcollectedinthisstudyonthelongtermconsequencesofallinfants withcCMV,rangingfromsymptomatictoasymptomatic,canbeusedtoclarifytherelevance andneedforpreventivemeasures,includingneonatalscreening[37].  

66

DesignoftheCROCUSͲstudy Acknowledgement WewouldliketothankthefollowingparticipatingRegionalPublicHealthServicesfortheir contributiontothisstudy:GGDAmsterdam,GGDBrabantͲZuidoost,CareynJeugdenGezin andRivasZorggroep(formerGGDZuidͲHollandZuid),GGDDenHaag,GGDFlevoland,GGD Fryslân,GGDGooienVechtstreek,GGDGroningen,GGDHartvoorBrabant,GGDHollandsͲ Midden,GGDIJsselland,GGDLimburgͲNoord,GGDMiddenͲNederland,GGDRivierenland, GGDRotterdamͲRijnmond,GGDWestͲBrabant,GGDZaanstreek/Waterland,GGDZeeland andGGDZuidͲHollandͲWest. WewouldliketoacknowledgethehelpofPetraOomen,datamanagerofthePraeventis databaseforneonatalscreening,forprovidingtheparents’addressesandthedatarequired tocollectthedriedbloodspots. WewouldliketothankJeroenCremer(RIVM)andLisetteRusman(LUMC)fortesting thousandsofdriedbloodspotsforcytomegalovirus.WeacknowledgeDr.HeinBoot(†)for hisvaluableadviceandextensiveparticipationinthedevelopmentofthecytomegalovirus PCRondriedbloodspots.  Financialsupport ThisresearchwasfundedbyStrategicResearchoftheNationalInstituteofPublicHealthand theEnvironment.  Conflictofinterest None. 

67

Chapter 

3

Chapter3

References  1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18.

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DesignoftheCROCUSͲstudy 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30. 31. 32. 33. 34. 35. 36. 37. 

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