J. Pediatr. (Rio J.) vol.93 número3

www.jped.com.br

ORIGINAL

ARTICLE

Detecting

congenital

hypothyroidism

with

newborn

screening:

the

relevance

of

thyroid-stimulating

hormone

cutoff

values

夽

Stela

Maris

Silvestrin

,

Claudio

Leone

,

Cléa

Rodrigues

Leone

a_{UniversidadeFederaldeMatoGrosso(UFMT),FaculdadedeMedicina,DepartamentodePediatria,Cuiabá,MT,Brazil} b_{UniversidadedeSãoPaulo(USP),FaculdadedeSaúdePública,DepartamentodeSaúdeMaterno-Infantil,SãoPaulo,SP,Brazil} c_{UniversidadedeSãoPaulo(USP),FaculdadedeMedicina,DepartamentodePediatria,SãoPaulo,SP,Brazil}

Received16February2016;accepted4July2016 Availableonline23December2016

KEYWORDS

Congenital hypothyroidism; Newbornscreening; Neonatalscreening; Thyrotropin

Abstract

Objectives: Toassesstheprevalenceofcongenitalhypothyroidismandtheabilityofvarious neonatalthyroid-stimulatinghormone(TSHneo)cutoffvaluestodetectthisdisease.

Methods: Thiscohortstudywasbasedontheretrospectivecollectionofinformationavailable fromtheReferenceServicefor NewbornScreeningdatabase foralllivebirthsfromJanuary 1,2010,toDecember31,2012,assessedusingtheNewbornScreeningProgramofaBrazilian state,Brazil.Theinfantsweredividedintotwogroups:I---Control:infantswithnormal new-bornscreeningtestsandII---Study:infantswithcongenitalhypothyroidism.Analysisincluded comparingtheTSHneolevelsfrombothgroups.Areceiveroperatingcharacteristic(ROC)curve wasconstructedtoassesstheTSHneocutoffvalues.

Results: UsingaTSHneo cutoffvalueof5.0␮IU/mL,50outof111,705screenedinfantshad

diagnosisofcongenitalhypothyroidism(prevalence1:2234livebirths).TheROCcurveshowed thatTSHneovalueof5.03␮IU/mLhad100%sensitivityandthegreatestassociatedspecificity

(93.7%).Theareaunderthecurvewas0.9898(p<0.0001).

Conclusions: TheROCcurveconfirmedthattheTSHneocutoffvalueof5.0␮IU/mLadoptedby

theNewbornScreeningProgramofaBrazilian statewasthemostappropriatefor detecting congenitalhypothyroidismandmostlikelyexplainsthehighprevalencethatwasfound. ©2017SociedadeBrasileiradePediatria.PublishedbyElsevierEditoraLtda.Thisisanopen accessarticleundertheCCBY-NC-NDlicense(http://creativecommons.org/licenses/by-nc-nd/ 4.0/).

夽

Pleasecitethisarticleas:SilvestrinSM,LeoneC,LeoneCR.Detectingcongenitalhypothyroidismwithnewbornscreening:therelevance

ofthyroid-stimulatinghormonecutoffvalues.JPediatr(RioJ).2017;93:274---80.

∗_{Correspondingauthor.}

E-mail:[email protected](S.M.Silvestrin). http://dx.doi.org/10.1016/j.jped.2016.07.006

PALAVRAS-CHAVE

Hipotireoidismo congênito; Triagemde recém-nascidos; Triagemneonatal; Tirotropina

Detecc¸ãodehipotireoidismocongênitopelatriagemneonatal:arelevância dosvaloresdecortedehormônioestimulantedatireoide

Resumo

Objetivos: Avaliaraprevalênciadohipotireoidismocongênitoeacapacidadedeváriosvalores decortedohormônioestimulantedatireoidedeneonatos(TSHneo)paradetectaressadoenc¸a.

Métodos: Este estudo de coorte teve como base a coleta retrospectiva de informac¸ões disponíveisnobancodedadosdoServic¸odeReferênciaemTriagemNeonataldetodosos nasci-dosvivosde1◦_{dejaneirode2010a31dedezembrode2012,avaliadosnoProgramadeTriagem}

Neonatal deum estadobrasileiro.Osneonatos foramdivididos emdoisgrupos: I---Controle: neonatoscomtestesdetriagemneonatalnormaiseII---Estudo:neonatoscomhipotireoidismo congênito.Aanáliseincluiuacomparac¸ãoentreosníveisdeTSHneodosdoisgrupos.Umacurva dopoderdiscriminantedoteste(ROC)foicriadaparaavaliarosdiferentesvaloresdecortede TSHneo.

Resultados: UtilizandoumvalordecortedeTSHneode5,0␮IU/mL,50dos111.705neonatos

examinadosforamdiagnosticadoscomhipotireoidismocongênito(prevalênciade1:2.234 nasci-dosvivos).AcurvaROCmostrouqueovalordoTSHneode5,03␮IU/mLpossuíasensibilidade

de 100% e a maior especificidade relacionada (93,7%). A área abaixo da curva foi 0,9898 (p<0,0001).

Conclusões: A curvaROCconfirmouqueovalorde cortedeTSHneode5,0␮IU/mLadotado

peloProgramadeTriagemNeonataldeumestadobrasileirofoiomaisadequadonadetecc¸ão dohipotireoidismocongênitoeprovavelmenteexplicaaaltaprevalênciaconstatada.

©2017SociedadeBrasileiradePediatria.PublicadoporElsevierEditoraLtda.Este ´eumartigo OpenAccesssobumalicenc¸aCCBY-NC-ND(http://creativecommons.org/licenses/by-nc-nd/4. 0/).

Introduction

Congenital hypothyroidism (CH) is a common pediatric endocrinedisorder1,2_{thatcancausementalretardation.}3,4

The importanceof early diagnosis andtreatment, to pre-ventirreparablebraindamage4,5_{andgrowthretardation,}3,6

justifiedtheestablishmentofnewbornscreeningprograms (NSPs)forthedetectionofCH.4,7_{TheseNSPsprovedtobe}

significantlycost-effectivetosocietyatlarge.8,9

Measuringtheconcentrationofthyroid-stimulating hor-mone(TSH)isconsideredthebestscreeningteststrategyfor detectingprimaryCH4_{becauseitexhibitshighsensitivity}4,10

andaccuracy.11_{However,CHdetectiondependsdirectlyon}

the neonatal TSH (TSHneo) cutoff value,4,12 _{which varies}

amongdifferentNSPs13,14_{andmayhaveaninfluenceonthe}

recallrate.13 _{Accordingtoavailable evidence,many cases}

ofCHwouldgoundetectediftheTSHneocutoffvaluewas increased.9,15_{Ontheotherhand,reducingthecutoffvalue}

requirespriorjudiciousassessment ofthelaboratorywork quality15_{andcoststothescreeningprogram.}4,9_Thecriteria

usedforchoosingtheTSHneocutofffordetectingCHshould beadaptedtothetargetdiseasedefinition.4

Some programs worldwide have loweredthe screening test cutoffs5,7 _{in order to increase the sensitivity of the}

assay5_{andtotake changesinitsmethodology.}16 _In

accor-dance withthat, cutoff values closeto 10.0␮IU/mL2,8 _or

aslow as5.0␮IU/mL3,17 _{or 4.5␮IU/mL}18 _{are usedin}

sev-eralNSPsworldwide toimprovethedetection ofchildren atrisk.

The prevalence of CH in Brazil is approximately one caseper2500livebirths;regionalvariationhasbeennoted

and according to the 2010 Brazilian Health Ministry rec-ommendations, a TSH value higher than 15.0␮IU/mL per immunometricassayshouldbeconsideredpositive.19

Becausethe efficiencyof any NSPdependson its abil-itytocoverthe largest possiblepopulation and todetect thelargestnumberofcases,obtainingreliableTSHvalues isnecessary tomaximizethedetectionofCHcases. How-ever, the lack of agreement on TSH cutoff values in the literaturemakesthis taskdifficult. SinceNovember2009, theTSHneovalue of5.0␮IU/mLhasbeen thecutoffpoint adopted by the NSP in Mato Grosso (MT), Brazil. Conse-quently,thepresentstudyaimedtoassesstheCHdetection abilityofseveralTSHneocutoffvaluesandtheireffectson thecurrentscreeningprogram.

Methods

Studydesignandpopulation

Thiswasatransversalstudynestedinacohortstudy,based onretrospective informationcollected fromthe database oftheReferenceService for NewbornScreening (RSNS)of MTforalllivebirths,2010---2012,thatwereassessedbythe NSP-MT.Datawerealsocollectedfromtheclinicalrecords ofallindividualswithallformsofCH.

childthatwasincludedinthestudygroup,therewerefive newborninfants withnormal NSTsincluded in thecontrol group.

The children inGroup I wereadmitted totheprogram immediatelybeforethecorrespondingGroupIIcases;they wereborninthesamemonthandhadbirthweight≥2500g. TheseinfantshadtheNSTsamplescollectedwhentheywere 2---6 days old. Potential participants were excluded from GroupIwhentheNSTsampleremainedatthecollectionsite formorethan30daysorthetestdatawereincomplete.

InfantswithconfirmedCHandbirthweight≥2500g com-prisedGroupII,regardlessofthedateofnewbornscreening collection.Theageatcollection’stimeofNSTwasunpaired betweenthetwogroups. Infantswhose NSTsampleswere collectedat24hafterbirthorwhohadcomorbiditiesand/or medicationusethatwerelikelytointerferewiththe labo-ratoryresultswereexcluded.

According tothis NSP’s guidelines, it is recommended thatthe collectionofthe blood sample is takenby punc-turingtheheelwhentheinfantis3---5daysold;onedropof bloodiscollectedonfilterpaper(Schleicher&Schuell,903) andsenttothelaboratoryatMT’sRSNSforbloodspotTSH concentrationmeasurement.

TheTSHneocutoffvaluewasestablishedas5.0␮IU/mL. Values equal to or lower than 5.0␮IU/mL were consid-ered normal, values between 5.0 and 15.0␮IU/mL were reassessedby collectinga newsample, and valueshigher than 15.0␮IU/mL were referred to confirm the diagno-sis.ThosewithTSHneoconcentrationsover5.0␮IU/mL on repeatsamplingwerealsoreferredtotheRSNSforfurther assessment.

The prevalenceofCHwascalculatedastheproportion oflivebirthswithaconfirmeddiagnosisperyearrelativeto thenumberoflivebirthsthatunderwentaNSTthatsame year.Thenumberoftestsperformedduringthestudyperiod wasobtainedfromtheRSNS,andthenumberoflivebirths in the corresponding periodwas obtained from the State Secretary of Health of MT and the Department of Infor-mationTechnology of the Brazilian UnifiedHealth System (DATASUS).

Therewerenorequirements forthe freeandinformed consentbecausetherehasbeen nochangeinmedical pro-cedure,noadditionalbloodsampleswereobtained,andthe participantswerenotidentified,aswellasbecausethiswas achartreview study andtheauthorizationtoconsult the medical records was provided by the clinical director of thehospital.The study wasapprovedbyHuman Research EthicsCommitteesofJúlioMüllerUniversityHospital, Fed-eralUniversityofMatoGrosso,onOctober13,2010,under No.940/CEP-HUJM/2010 and the Commissionfor Analysis ofResearchProjects[ComissãoparaAnálisedeProjetosde Pesquisa(CAPPesq)],ClinicalDirector’sOffice,Clinical Hos-pital,School ofMedicine, UniversityofSãoPaulo, onJuly 19,2011,underNo.307/11.

Biochemicalmethods

The blood spot TSH concentration was measured using a time-resolvedimmunofluorometricassaywithAutoDELFIA® (Perkin Elmer®, Turku, Finland). For cases with values above the established cutoff of 5.0␮IU/mL, a second

assay was performed, and the reported results corre-spond to the mean of both measurements. According to themethod’ssensitivity,thehighestdetectable concentra-tion was 250.00␮IU/mL; higher values were reported as >250.00␮IU/mLandconsideredas251.00␮IU/mLfor anal-ysis.

To ensure the uniformity and equivalence of the results, the milli-international units per liter (mIU/L) were expressed as micro-international units per milliliter (␮IU/mL). A chemiluminescent assay (ADVIA Centaur® XP ImmunoassaySystem,Siemens,Germany)formeasurement of serum TSH concentrations (␮IU/mL) was used and the resultswereinterpretedaccordingtothereferencevalues perage,i.e.,upto25.000␮IU/mLatthefirstweekoflife and,from0.800to6.000␮IU/mLfrom2ndweekuntil11th months of life. The serumfree T4 concentration (ng/dL) wasmeasuredusingthechemiluminescencemethod(ADVIA Centaur® XPImmunoassaySystem---Siemens),andthe ref-erencevaluevariedfrom0.70to1.80ng/dLforadultsand childrenaccordingtothereferencevaluesgivenbythe sup-portinglaboratory.

Statisticalanalysis

BasedondiseaseprevalencedataprovidedbytheNSP-MT, ˛=0.05 andˇ=0.20(80% power);assuming anareaunder the ROC curve of 90% and a confidence interval (CI) of 70---100%,thesamplesizewasinitiallycalculatedas45 con-firmedcasesofCH.Thisnumberwasreachedintheperiod chosenforthisstudyand,afterapplicationoftheexclusion criteria,44childrenwereanalyzedwithaconfirmed diagno-sisofCH(studygroup).Therewere220infantswithnormal NSTincludedincontrolgroup.

InadditiontotheinfantsincludedinGroupIandGroup II, toconstruct theROC curve, infants withfalse-positive results were alsoincluded (n=24), as well asfiveinfants withanormalNSTforeachfalse-positiveresult(n=120).

Thesensitivity,specificity,positiveandnegative predic-tive value, and likelihood ratio corresponding to various TSHneovalueswerethencalculatedusingMicrosoft® Excel (Microsoft®,version2007,USA)andStata®(StataCorp.2011. Stata Statistical Software: version 12, USA). Continuous dataareshownasmeasuresofcentraltendency(meanand median)anddispersion(standarddeviation---SD,minimum and maximum). To analyzethe relationship between con-centrationsof bothserumTSHandTSHneo,theSpearman correlation test was used. The binomial z-test was used tocompare multiple proportions. To comparethe TSHneo between groups, the non-parametric Mann---Whitney test wasused.Thesignificancelevelwasestablishedasp<0.05.

Results

100 80 60 40 20 0 0.14-0.5 17.27 25.91 35.45 10.91 _6.82 3.64 6.82 11.36 _9.09 61.36

Normal Congenital hypothyroidism 11.36 0.5-1.0 1.0-2.0 2.0-3.0 3.0-4.0 4.0-5.0 TSHneo levels (µlU/mL)

F requency , % 5.0-7.0 7.0-9.0 9.0-15.0 15.0-20.0 >20.0

Figure 1 Distributionof thepercentage frequency accord-ingtoneonatalthyroid-stimulatinghormone(TSHneo)levelsin GroupI(n=220)andthefirstTSHneotestinGroupII(n=44)for infantsassessedusingtheNewbornScreeningProgram,stateof MatoGrosso,Brazil,2010---2012.

and it ranged from 10.07 to >150.00␮IU/mL. The mean (SD)and median of serumfree T4 value were 0.70ng/dL (SD=0.39)and0.62ng/dL,respectively,ranging from0.11 to1.44ng/dL.

Fig. 1depicts thedistribution of theTSHneo valuesin GroupsIandII.TheresultsshowthattheTSHneovaluesof 78.63%oftheinfantswithanormalNSTrangedfrom0.14to 2.0␮IU/mL,whilethevaluesoftheremaining21.37%ranged from2.0to5.0␮IU/mL.AmongtheinfantswithCH,the ini-tialTSHneovalueswerehigherthan9.0␮IU/mLin81.81% of the cases; the vast majority of the infants had values higher than 20.0␮IU/mL. The proportion of false-positive casesdetectedwiththeTSHneocutoffof5.0␮IU/mL corre-spondedtoaproportionof0.02%.

The mean TSHneo value of the infants with a nor-mal NST was 1.40␮IU/mL (SD=1.2; ranging from 0.14 to 4.70␮IU/mL). The median TSHneo values differed signifi-cantlybetweenGroupsI(1.15␮IU/mL)andII(26.55␮IU/mL) (p<0.001).

Fig.2depictstheresultsoftheconfirmatorytests(serum TSHandfreeT4).

The ROC curve constructed with the TSHneo values of Groups I and II is depicted in Fig. 3.20 _{A TSHneo}

value of 5.03␮IU/mL exhibited the highest specificity

100 80 60 40 20 0 10.0-15.0 13.95 2.33 83.72 18.6 37.21 13.95 25.58 4.65 15.0-20.0

≥20.0 ≤0.35 0.35-0.70 0.70-1.00 Levels F requency , % 1.00-1.40 ≥1.40

Serum TSH (µIU/mL) Free T4 (ng/dL)

Figure2 Distributionofthepercentagefrequencyaccording tothe serum thyroid-stimulating hormone(TSH) andfree T4 levelsoftheinfants(n=43)inGroupIIwhowereassessedusing theNewbornScreeningProgram,stateofMatoGrosso,Brazil, 2010---2012. 100 80 60 40 20 0

0 20 40 60

100 - specificity

Area under ROC curve (AUC) Standard errora

95% confidence intervalb Z statistic

P=Significance level (area=0.5) Youden’s J index

Associated criterionc

[Sensitivity (100) and Specificity (93.68)] Optimal criteriond,e

[Sensitivity (95.45) and Specificity (96.43)] Sample size

Variable classification

With congenital hypothyroidism (1) Without congenital hypothyroidism (0) Frequency of disease, %

0.989885 0.00365 0.974645 to 0.997163 134.177 <0.0001 0.9368 >5.03 >6.33 408 44 364 10.8 Infants with hypothyroidism

Sensitivity

80 100

Figure3 Receiver operatingcharacteristic (ROC) curve for theneonatal thyroid-stimulating hormone(TSHneo) levels of infants without and with a confirmed diagnosis of congeni-talhypothyroidism,NewbornScreeningProgram,stateofMato Grosso,Brazil,2010---2012.

a_{Hanley&McNeil,}20_1982.

b_{Binomialexact.}

c_{Greaterspecificityforasensitivityof100%.}

d_{Highersensitivityandspecificityassociatedandabove95%.}

e_{Takingintoaccountdiseaseprevalenceandestimatedcosts:}

costfalsepositive:1;costfalsenegative:1;costtruepositive: 0;costtruenegative:0.

(96.68%;95%CI=90.7---96.0)for a sensitivityof100% (95% CI=92.0---100.0). A cutoff value of 6.33␮IU/mL exhib-ited the best combination of sensitivity (95.45%; 95% CI=84.5---99.4)andspecificity(96.45%;95%CI=94.0---98.1). Table1describestheCHprevalenceaccordingto differ-entTSHneocutoffvalues.Theprevalencedecreased consis-tentlyastheTSHneocutoffvalueincreased(p<0.001).

Discussion

Table1 Percentagedistributionaccordingtotheneonatalthyroid-stimulatinghormone(TSHneo)cutoffvalue andthe esti-matedCHprevalenceofthe44infantsinGroupII,NewbornScreeningProgram,stateofMatoGrosso,Brazil,2010---2012.

TSHneo(␮IU/mL) Congenitalhypothyroidism(CH) Estimatedprevalenceb p-Valuec

Withdiagnosis Withoutdiagnosis Totala

n % n % n

>5.0 44 100 0

---44

1:2539

--->10.0 36 81.82 8 18.18 1:3103 <0.001

>15.0 31 70.45 13 29.55 1:3603 <0.001

>20.0 27 61.36 17 38.64 1:4137 <0.001

a_{NumberofCHcasesdetectedduringthestudyperiod.}

b _{Basedonthenumberofneonatalscreeningtests(NSTs)performedduringthethree-yearperiod=111,705tests.}

c _{Binomialz-test.}

assessed using the NSP-MT. The results showed that the prevalence of CH increased over time as the adopted TSHneocutoffvaluedecreased.TheTSHneocutoffvalueof 5.0␮IU/mL proved tobethemost effective for detecting CHintheinvestigatedpopulation.

A total of 50 cases of CH were detected during the study period. The corresponding prevalence (1:2234) was fourtimeshigherthantheprevalencefoundbyStranieriand Takano21 _{atthesameNSPin2003---2004,whichwas1:9448}

live births using the TSHneo cutoff value of 15.0␮IU/mL by enzymatic-colorimetric assay. The difference in CH prevalenceamongneonatalscreeningservicesthatuse dif-ferentlaboratory methods for detection is present in the literature.22 _{Using a similar laboratory method, Mengreli}

et al.8 _{found an increased prevalence of permanent CH}

(1:1749 vs. 1:3384) when different TSHneo cutoff values wereused.

Studies conducted in the United States showed that changes in the TSHneo cutoff value13 _{could result in an}

increase in CH prevalence. Therefore, the data reported herestronglyindicatethatthe changein theTSHneo cut-offvalueislikelythemainfactorthatcausedtheincrease inCHprevalenceintheNSPsofMT.

TheaverageofTSHneoconcentrationinBrazilianinfants from the state of Sergipe at age 2 to 6 days old was 1.33±1.08␮IU/mL,23 _{i.e., similarto the TSHneo}

concen-trationin thepresent study (1.40±1.02␮IU/mL). Despite thehighaveragetemperaturein thestateofMT,seasonal variationsandeffectsassociatedwithsamplestorageatthe collectionsitedonotseemtohaveinfluencedtheTSH val-uesin the present study,assamplesthat werestored for morethan30dayswerenotincludedintheanalysis.

TheTSHneovaluewashigherthan20.0␮IU/mLin61.36% of theinfants with CHin the present study,with amean of 93.97±98.15␮IU/mL. These findings agree with those reportedbyRamalhoetal.,23_{whofoundvalueshigherthan}

19.70␮IU/mLin62.5%ofinfantswithCH.

TheefficiencyofanyNSPdependsofthechoiceofthe cutoff values, which should have a high sensitivity while maintainingspecificity.Increasingthecutoffvalueincreases itssensitivity, but therewill alsobe an increase in false-positiveresults.24

In the present study, the TSHneo cutoff value of 5.0␮IU/mLdetected50casesofCHfromwhichmanywould nothavebeendetectedusinghigherTSHcutoffvalues.The

better abilitytodetect CHcasesmight indicatethe diag-nostic power of lower TSH cutoff levels and reflect the structuring ofthe local NSP.Botleret al.25 _analyzed

vari-ousTSHcutoffvaluesfor detectingCHandfound42cases usingacutoffvalueof≥20.0␮IU/mLin2005,but165cases were found in 2007 when the cutoff value was reduced to ≥10.0␮IU/mL. Korada et al.6 _{found 120 infants using}

a TSHneocutoffvalue of 6.0␮IU/mL, unlikethe study by Ramalhoet al.,23 _{where eightcases of CHwere detected}

withcutoffof5.2␮IU/mL.

In the present study, the TSHneo cutoff value of 10.2␮IU/mL,withsensitivityof81.82%(95%CI:67.3---91.8) and specificityof 98.08%(95% CI:96.1---99.2), wouldhave failedtodetectapproximately18%ofthescreenedinfants whorequiredfurtherdiagnosticinvestigation.Inthestudy byTuetal.,26_{thesensitivityoftheTSHneocutoffpointof}

10.0␮IU/mLusingtheDELFIAmethod(immunoassaysystem for routinescreeninganddiagnosticprograms)wasbetter (98.93%) than the sensitivity found in the present study; however,thespecificity(99.48%)wassimilarinbothstudies. Here,withaTSHcutoffvalueof15.5␮IU/mL,almost30.0% oftheCHcaseswouldbemissedbecauseofthelow sensitiv-ityofthetest(68.18%;95%CI:52.4---81.4).However,healthy infantswithvaluesbelow10.2␮IU/mLor15.5␮IU/mLwould becorrectlyidentifiedashealthyin98.0%ofthecases.

Theoddsof findinghealthy infantswithTSHneovalues of 30.8␮IU/mL were zero because of the high specificity (100%;95%CI:99.0---100)andverylowsensitivity(47.73%, 95%CI:32.5---63.3)ofthatcutoffvalue,which wouldhave failedtodetectmorethan50%oftheinfantsatactualrisk ofdisease.

Thatshortcoming notwithstanding, because of its pos-itive predictive value of 100%, TSHneo values above 30.8␮IU/mL reliably indicated the need for treatment beforetheconfirmatorytestresultswereavailable,as dis-easewasconfirmedinalloftheinfantswhoexhibitedvalues above that level. According to Léger et al.,4 _{when the}

TSHneovaluesareabove≥40.0␮IU/mL,itisrecommended tostarttreatmentafteragoodvenoussampleisobtained, withoutwaitingfortheconfirmatorytestresult.

Inthepresent study,TSHneo cutoffvaluesof15.0 and 20.0␮IU/mL would have failed to detect 30% and 40%, respectively,ofthescreenedinfantswhorequired confirma-tionofdisease.Baroneetal.18_{foundthatin24.4%ofinfants}

theirvaluesvariedfrom4.5to5.4␮IU/mL.Inthepresent study,6.82%oftheinfantswithCHexhibitedTSHneovalues from5.0to7.0␮IU/mL.

This analysis was based on a TSH cutoff value of 5.0␮IU/mL,theaccuracyofwhichisshownbytheROCcurve (areaunderthecurve=98.98%)andp<0.0001.Inaddition, thatcutoffvalueexhibited100%sensitivityand93.68% asso-ciatedspecificity.Consideringtheequivalentresultforthese two measures, the Youden index of 0.9368 has indicated thatthechoiceofTSHneocutoffvalueismostlikelytobe correct,asitwasassociatedwiththelowestproportionof misclassification.

Oneofthelimitationsofthisstudyisthenon-inclusionof childrenwhounderwentscreeningbyprivateandcontracted healthcaresystem,andevenasmallproportionwhodidnot performtheexam.However,itmustbestressedthatalllive birthsinthepublichealthcaresystemwhounderwentNST wereincluded. The other limitationis relatedtothe fact thatsomeinfantshavenotyetbeenreassessedfor identify-ingthetransientformofCHbecausetheyareunder3years old.

The results obtained suggest that in the population of infantsscreenedfor CHusingtheNSP-MT,thelowTSHneo cutoff value adopted may have contributed to the high prevalence of the disease found. This study shows that the current threshold of TSHneo at the NSP-MT in terms ofcost-effectivenessisthemostadequatecutoffpointfor thedetectionofCH;itwasabletodetect allcasesofCH, includingthosemilderformsofthedisease.However,this protocol increased the occurrence of false-positive tests that wereassociated withincreased psychological effects onparentalanxiety.Thisproportionoffalse-positivescould bealimitationtotheTSHneocutoffof5.0␮IU/mL,butas it corresponded tosuchasmall proportion(0.02%),it did notcontributetotheincreasedcostsoftheprogram.The possibilityofdetectingthelargestpossiblenumberofcases ofthediseasejustifiedtheadoptionofthiscutoff.

Unfortunately,whetherornottheadditionalmildcases ofCHdetectedinthiswayareassociatedwithadecrease in cognitive performance is not known and, therefore, whetheror nottheyneed tobescreened,ensuring signif-icantincrease inthecostofrecall,is controversialat the present. According to Léger et al.,4 _{the aim of a}

neona-talscreening shouldbetodetectallformsofprimaryCH, especiallythemoresevere.Besidesthat,furtherstudiesare needed toassessthecost-effectivenessof adoptinglower cutoffofTSHneoforthestateprogram.

Conflicts

of

interest

Theauthorsdeclarenoconflictsofinterest.

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