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

50

100

150

200

250

300

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

5

10

15

20

25

5000

50000

500000

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