Post on 08-Jun-2020
transcript
Newborn Screening and Congenital
Hypothyroidism UpdatingAlgorithmsandTimelinessofScreening
Sept24,2019MaryMurrayMDUniversityofUtahSchoolofMedicine
Disclosures
• Nothingtodisclose
Background- Congenital Hypothyroidism
• ReportedIncidence:1:1,660to1:2,828livebirthswhichtranslatesto18-40casesperyear
• Goalistomakediagnosisandstarttreatmentquickly• Nationaltimelinessuggesttreatmentshouldbestartedwithin14-21days
• Somestatestestonceandsometesttwicewhichisreflectedinthetimelines• Earlyonsetoftreatmentiskeytopreventingmentalretardation
• Misseddiagnosiscanresultincretinismorseverementalretardation
• Historicalstandardswerebasedupontestingdoneat72hoursofagereflectingthedurationofhospitalizationafterbirth
• Mostbabesarenowdischargedin24-48hours
Background to Current Analysis • EndocrinologistdevelopedanewTSHtestingdeviceandwantedtopromoteit’suseinnewbornscreening
• Statedgoalwastoimprovethetimelinessofscreeningbymakingtestavailablewithalmostimmediateresult
• UndertookananalysisofTSHvaluesinthepediatricpopulation• Reviewedalargeamountoflabdatainchildrenundertheageof2years
• AssumedthatallhighTSHvalues(>20mIU/L)inthisagegroupwereduetocongenitalhypothyroidism
• Nochartreviewwasperformed
• Concludedthatthestatenewbornscreeningprogramismissingcasesandchildreninthestateareinadequatelytreated
• Suggesteddiagnosiswasdelayedin50%ofcasesEhrenkranzJ,ButlerA,SnowG,BachP.OralAbstract19.ThediagnosisandtreatmentofcongenitalhypothyroidisminUtah2006-2015.Presentedat:AmericanThyroidAssociationAnnualMeeting;September21-25,2016;Denver,Colorado
“Missed Cases and Delayed Diagnosis”
• Reviewed5959TSHvaluescollectedatIntermountainHealthcarefacilitiesbetween2006and2016andidentifiedpatientsunderage2yearswithTSH≥20mIU/Lforchartreview.
• 99patientsidentifiedwithTSHover20.• 96patientsanalyzed.
• 72werediagnosedwithCH(75%,)• 62(86%)diagnosedandtreatedappropriately• 10(14%)hadadelayindiagnosisortreatment
• 21(21.9%)didnothaveCH(normallabsonrepeat,intercurrentillness,medication,etc)• 3(3.1%)unabletodeterminediagnosis.
Questions
• Istheprogrammissingcasesoristhediagnosisdelayed?• Whatareourprogramstatistics?
• AredefinedTSHvaluesforbothfirstscreenandsecondscreencorrect?• Arescreensbeingdoneinatimelymanner,egwhenexpected
• Canweimproveourprocesses?• Istherejustificationtodoing2tests?• Isthefollowuptoanabnormalscreenappropriate?
Data Analysis § NBSdatafor359,342infantsbornbetween2010and2016wasanalyzed
§ 359,432firstscreensanalyzed§ Firstscreenrecommendedat24-48hours§ AbnormalisdefinedasTSH>40mIU/L,criticalisdefinedas>230
§ 356,599secondscreensanalyzed§ Secondscreenrecommendedat7-21days§ AbnormalisdefinedasTSH>40mIU/Landcriticalas>230
§ Data reviewed on the babies identified on either screen as having hypothyroidism
§ 130 cases were identified during this time frame § 98 were identified on the first screen and 25 on the second
§ 18-19 cases per year identified average consistent with reported incidence § 7 cases did not have complete TSH data available
§ ThisstudycomparedTSHconcentrationsoftheoverallpopulationto130CHcasesand
performedaretrospectivecut-offanalysistoassesstheimpactofloweringTSHcut-offs3
Characteristics of Newborn Screen Collection
FirstscreenisfairlytimelySecondscreenmuchmorevariable
InclusionCriteria Mean(µIU/mL) StandardDeviation SampleSize FIRST,TSH,0-1Days 14.30 29.44 158581
FIRST,TSH,1-2Days 8.01 8.79 187615
FIRST,TSH,2-3Days 5.27 8.61 7817
FIRST,TSH,3-4Days 4.23 4.97 1473
FIRST,TSH,4-5Days 4.45 20.58 752
TSH Values on Screen #1 by Day
TSH Results by Screening Test
InclusionCriteria
Mean(µIU/mL)
StandardDeviation
SampleSize
FIRST,TSH 10.67 20.91 359432
FIRST,T4C 11.12 4.03 7099
SECOND,TSH 3.85 17.81 356599
SECOND,T4C 11.06 3.45 2662
InclusionCriteria Mean(µIU/mL) StandardDeviation SampleSize
SECOND,TSH,12-13Days 3.94 4.82 28890
SECOND,TSH,13-14Days 3.95 33.06 94087
SECOND,TSH,14-15Days 3.78 5.34 50957
SECOND,TSH,15-16Days 3.73 4.90 31850
SECOND,TSH,16-17Days 3.66 2.62 23923
TSH Values on Screen #2 by Day
Summary • TSHresultsvarybycollectiondate• TSHresultsdonotlookthesameforbothfirstandsecondsample
• Clinicianwouldnotbesurprisedbythisgiventhenormalphysiologyofnewbornthyroid
• Butwehavebeenusingthesamereferenceforbothsamples• CollectiondatesmoreconsistentforfirstsampleandTSHvaluesvaryquiteabitbydayofcollection
• CollectiondatesmorevariableforsecondsamplebutTSHvaluesdonotvarymuchbydayofcollection
• Shouldwebeusingthesamecutoffforbothscreens?
Congenital Hypothyroid Infants
• 130infantsdiagnosedwithcongenitalhypothyroidism• 123/130patientshadcompletedata
• 98/123werediagnosedonthefirstscreen• 20%ofthepatientswerediagnosedonthesecondscreen
• 6504falsepositivecasesduringthescreeningperiodwereidentified
Confirmed Congenital Hypothyroidism Population Measurment Screen#1 Screen#2 [p]
Total SampleSize 359432 356599
Mean[µIU/mL]
10.67 3.85 <0.0001
ConfirmedCH SampleSize
130 130
Mean[µIU/mL]
315.29 191.25 <0.0001
[p] <0.0001 <0.0001
Characteristics of Hypothyroid Infants Population Measurement Screen#1 Screen#2 [p]
AbnScreen#1AbnScreen#2
SampleSize 105
Mean[µIU/mL]
386.02 211.51 <0.0001
NormalScreen#1AbnScreen#2
SampleSize 25
Mean[µIU/mL]
23.86 107.60 <0.0001
[p] <0.0001 0.0273
Summary
• Majorityofinfantsarediagnosedonfirstscreen(80%)• However,asignificantnumberhaveanormalfirstscreenandarediagnosedonthesecondscreen
• Whatdotheseinfantslooklikeontesting?• Canwechangethecutoffsoastomakethediagnosisforallinfantsonthefirstscreenandsaveeveryonefromhavingtodothesecondscreen?
0
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0 5 10 15 20 25
TSHconcen
tration[µIU/m
L]
FirstScreen
SecondScreen
AbnormalCut-off[40µIU/mL]
Infants diagnosed on Second Screen
Individual
Effect of lowering Cut-Off for Abnormal
0
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0 5 10 15 20 25 30 35 40
Missedcases[n]
Falsepo
sitiv
es[logn]
Cut-offTSHconcentration[µIU/mL] FalsePositives
MissedCases
Cut-Off AbnSamples
Increase MissedCases
40 6634
30 11170 4536
20 27722 21088 11
10 138241 131607
5 282979 276345 0
CurrentCut-Off
3SD 97thPercentile 98thPercentile 99thPercentile
FIRST,TSH(µIU/mL) 40 73 31 38 53
SECOND,TSH(µIU/mL) 40 57 9 10 11
Possible Cut-off for Abnormal
Summary
• Can’tidentifyalowernumberforfirstscreenthatwillcaptureallthosepickeduponsecondscreenwithoutsignificantincreaseinfalsepositives
• Substantiallyincreasingthenumberoffalsepositiveswillincreasefinancialandemotionalcosts
New Screening Algorithm: Tier 1 FirstNewbornScreen,Day1-2oflife
• Normal=<40µIU/mL• *Elevated=>40µIU/mLand<100µIU/mL(*ifpreemie/sickmarkedtrue)
• Abnormal=>40µIU/mLand<230µIU/mL• Abnormaldefinedas>2SDabovepopulationmeanforstatedata
• Critical=>230µIU/mL• Considerloweringthecriticalvalueafterreviewingthedata
SecondNewbornScreen,Day7-14oflife• Normal=<20µIU/mL• Abnormal=>20µIU/mLand<230µIU/mL
• Abnormalisdefinedas>3SDabovethemeanforUtahdata
Abnormal Screen and Then What?
• PreviouslydidconfirmatorytestingwithaT4atNewbornscreeninglab
• Delaysthereportoutandtheclinicianswantconfirmatorytestingrightawaynomatterwhatthestatescreensays
• Newparadigm:skipthescreeningprogramrepeatandreportitout• Savestheprogrammoneyanddoesnothaveanyimpactuponthecliniciansorfamily
Preterm Low Birthweight infants
Data • TSHvaluesfrominfantsborn<27weeksgestation• 2013-2017• 1489resultsfrom636infants
• MeanBW791gramsmeanGA24weeks,57%male• Samplesobtainedday1,9,40daysoflife
• Preliminaryreviewofthedatademonstrateddifferencesfromnormalnewborns
• MeanTSHwaslowerinpreterminfantsthatnormal(7.2+/-7.4vs10.7+/-3.9µIU/mL)
• 10%ofinfantshadundetectableTSHonfirstNBSandremainedlowin1%.• 51%hadarisingTSHoratleastonevalue>10µIU/mL• Noneofthesepatientswerediagnosedofficiallywithcongenitalhypothyroidismnordidtheyrequirelongtermfollowupwithendocrinology
Conclusions
• Preterminfantsdonotfollowthe“normal”pathway• Newparadigmsneedtobeconsideredforpretermorlowbirthweightinfants
Summary
• Clinicalperspectiveisimportantinunderstandingabnormallabs• ChartreviewsignificantlychangedthedatainterpretationofabnormalTSHinchildrenlessthan2yearsofageandassociationwithcongenitalhypothyroidism
• Understandingtheclinicalcontextallowsbetteranalysisofdataandmayleadtopopulationspecificnormals,egthepreterminfant
• Whenattemptingtoadjustnormalranges,engagementofclinicianscanhelptosupportchangesandhelpthemworkintothepractitionersworkflowwhichmayimprovecompliance
• Collectingsamplesbetween10and14dayswillyieldsameresults,fitinwithnormalWCCvisits,andpreventdelaysinsamplecollection
• Understandingtheimpactof“falsepositives”onfamilies