Rev. Bras. Hematol. Hemoter. vol.37 número1

Revista

Brasileira

de

Hematologia

e

Hemoterapia

Brazilian

Journal

of

Hematology

and

Hemotherapy

w w w . r b h h . o r g

Original

article

Trends

in

mortality

and

hospital

admissions

of

sickle

cell

disease

patients

before

and

after

the

newborn

screening

program

in

Maranhão,

Brazil

Ana

Ranoy

Gomes

Lima

,

Valdinar

Sousa

Ribeiro

,

Dario

Itapary

Nicolau

a_{UniversidadeFederaldoMaranhão(UFMA),SãoLuís,MA,Brazil}

b_{CentrodeHematologiaeHemoterapiadoMaranhão(HEMOMAR),SãoLuís,MA,Brazil}

a

r

t

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o

Articlehistory: Received2July2014 Accepted17September2014 Availableonline21November2014

Keywords:

Neonatalscreening Anemia,sicklecell

Hospitalinformationsystems Indicatorsofmorbidityand mortality

Earlydiagnosis

a

b

s

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t

Objective:Toassesstheimpactoftheimplementationofneonatalscreeningon hospital-izationanddeathratesduetosicklecelldiseaseinpatientsfromthestateofMaranhão, Brazil.

Methods:Adescriptivestudywasperformedofallinpatientsanddeathsofpatientswith adiagnosisofsicklecelldiseaseinMaranhãobetween1999and2012.Datawerecollected fromtheHospitalInformationSystemoftheBrazilianNationalHealthService(SUS)and theDeathInformationSystemoftheMinistryofHealth.Theimplementationofnewborn screeningtestsinMaranhãotookplacein2005,andsotheperiods1999–2005(pre)and 2006–2012(post)wereanalyzedfortrendanalysisusingamultiplelinearregressionmodel. Fisher’sexacttestwasusedfortheanalysisofcategoricalvariablesandtheKruskal–Wallis testforcontinuousvariables.

Results:Therateofhospitalizationincreasedfrom0.315(pre)to1.832(post),indicating5.82 timesmoreadmissions(p-value=0.04).Themortalityrateincreasedfrom0.115to0.216,that is1.88timeshigher,butthiswasnotstatisticallysignificant(p-value=0.586).Themedian ageatadmissiondroppedfrom11.4yearsto8.7years(p-value=0.0002),whereasthemedian ageatdeathincreasedfrom10yearsto14years(p-value=0.665).

Conclusion:Theincreasesintheratesofhospitalizationanddeathaftertheimplementation ofneonatalscreeningsuggeststhatpreviouslytherewasanunderdiagnosisofsicklecell diseaseandthatscreening,alongwithotherfactors,increased“visibility”inthestateof Maranhão.

©2014Associac¸ãoBrasileiradeHematologia,HemoterapiaeTerapiaCelular.Published byElsevierEditoraLtda.Allrightsreserved.

∗ _{Correspondingauthorat:RuaBarãodeItapary,227,Centro,65020-070SãoLuís,MA,Brazil.} E-mailaddress:anaranoy@ig.com.br(A.R.G.Lima).

http://dx.doi.org/10.1016/j.bjhh.2014.11.009

Introduction

Hemoglobin(Hb)SoriginatedinAfricawherethemutation inthebeta-globingenewasadvantageousinsomuchas het-erozygoteshavemoreresistanceagainstmalaria.1_InBrazil,

sicklecelldisease(SCD),the mostprevalent hereditary dis-ease,affectstheblackpopulationmost.Itisestimatedthat about45% ofthe Brazilianpopulationand 72%ofthe pop-ulationofthestateofMaranhãoisofAfricandescendancy. Moreover,inBrazilthereare25–30,000SCDpatientswith3500 newcasesdiagnosedannually.2_{InMaranhãothereisan}

inci-denceof72casesper100,000livebirths(1:1389)forSCDwith onecarrierofthesicklecelltraitinevery30births.2

Inrecentyears,incountriesliketheUSA,therehasbeen asignificantimprovementinthesurvivalofSCDpatients.In 1973,theestimatedmeanageatdeathofSCDpatientsinthe USAwas14.3years,with50%ofdeathsoccurringduringthe firstfiveyearsoflife.3_{In1992,astudyintheUSAshowedthat}

themeanageatdeathhadincreasedto42yearsformenand to48yearsforwomen.Inthisstudy,thepatternof mortal-ityvariedwithageandtherewasapeakincidenceofdeath amongSCDchildrenoccurringbetweenoneandthreeyearsof age;deathsofunder20-year-oldpatientswerepredominantly duetopneumococcalsepsis.4

Measures such as neonatal screening, the use of pro-phylactic penicillin between three months and five years ofage, vaccinationfor pneumococcus,meningococcus and Haemophilus,andtraininginrespecttoearlyrecognitionof splenicsequestration,reducedthemortalityratetolessthan 5%inthefirstfiveyearsoflife.5_{Theauthorsconcludedthat}

thesemeasuresresultedin,onaverage,over85%ofaffected childrensurvivingbeyondtheageof20.5

InBrazil, researchon hemoglobinopathies,in particular sicklecellanemia,occurredafterthegovernmentOrdinance No.822cameintoforceonJune6,2001;thislawwasdesigned toimproveearlydiagnosisandtoprovideadequatetreatment withinthefirstfewmonthsoflife.InDecember2002,atest todiagnosehemoglobinopathieswasimplantedinthestate ofMaranhão.6_{ThetestwasperformedbytheAssociationof}

ParentsandFriendsofExceptionalChildren(APAE)inthecity ofSãoLuís,andby2005itwasappliedto72%ofalllivebirths inthestate.6

Theobjectiveofthecurrentstudywastocomparetrendsin themortalityandhospitaladmissionratesofSCDpatientsin Maranhãobeforeandaftertheimplementationofthe neona-talscreeningtest.

Methods

DatarelatedtothedeathsandhospitalizationsofSCDpatients inMaranhãofrom1999to2012werecollected.Datarelated tothe hospitalizations were obtained from an abbreviated versionoftheHospitalInformationSystem(SIH)ofthe Brazil-ianNationalHealthService(SUS)annualdatabaseanddata relatedtodeathswereobtainedfromtheDeathInformation System(SIM/SUS).Thecaseswereselectedusingthe10th revi-sionofthe InternationalClassificationofDiseases(ICD-10) codes forSCD:D57.0 (SCDwithcrisis), D57.1 (SCDwithout

crisis),D57.2(doubleheterozygoussicklecelldisorders)and D57.8(othersicklecelldisorders).Twoagegroupswere deter-mined:0–19yearsand20yearsormore.Theperiod1999–2005 wasconsideredthepre-screeningtestimplementationperiod

and 2006–2012 was considered the post-implementation

period. Although the test officially started in Maranhãoin December2002,itactuallyachievedtruecoveragefrom2005 onwards.TheratesofhospitalizationandmortalityduetoSCD werecalculatedper100,000inhabitants.Thetotalpopulation servedasthedenominatorbecauseinMaranhãoBlack peo-plemakeup74%ofthepopulationandthismethodologyhas already beenreportedintheliteratureandwillallow com-parisonsbetweentheresultsofthisstudyandothers.7,8_The

annualpopulationdatawereobtainedfromtheBrazilian Insti-tuteofGeographyandStatistics(2000,2010andpopulation estimates)andthetotalpopulationofMaranhãogrewfrom 5,418,354to6,714,314between1999and2012.

TheratesofhospitalizationandmortalityduetoSCDwere calculatedaccordingtothefollowingformula:

Mortalityrate

=

population ×100,000

Hospitalizationrate

=

totalresidentpopulationinyear×100,000

Fisher’sexacttestwasusedtocomparethepercentage dis-tributionofindividualsbygenderandagebetweenthetwo periods.Thenon-parametricKruskal–Wallistestwasusedto comparethemedianagebetweentheperiods.

Toanalyzethetrend,amodeloftheevolutionoftheresults intheinitialperiodwascreatedusingmultipleregressionto checklinearand quadraticmodels,withandwithout expo-nential growth, and the model that best fit the data was used.Afteranalyzingthetrends,R2_{values,andtheresultsof}

theadjustmentsofregressionanalysis,asimplelineartrend modelwasusedtoanalyzethemortalityandhospitalization rates.Extrapolationwassubsequentlyperformedforthefirst period,whichwouldbethe‘natural’trend.Theeffectofthe ‘natural’trendwasthenremoved(detrended)forbothperiods andthemeansofthetwoperiodswerecomparedusingthe t-testfortwogroups.Avalueofsignificanceof0.05,which corresponds toaconfidencelevel of95%,wasassumedfor statisticalanalysis.

Results

Hospitalizationrates

Totalsof128and840SCDpatientswerehospitalizedinthe pre-test(before2005)andpost-testperiods,respectively.

0.35

0.30

0.25

0.20

0.15

0.10

0.05

0.00

1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012

4.00

3.50

3.00

2.50

2.00

1.50

1.00

0.50

0.00

Mortality rate

Mor

tality r

ate

Hospitalization rate

Hospitalization r

ate

Figure1–Evolutionofmortalityandhospitalizationrates.

Thepercentageofmaleswasslightlyhigherthanthatof females;53.9%inthepre-testperiodand51.9%inthepost-test period.

Figure1showsthatinthepre-testperiodthereweremuch fewerhospitalizations,with amarkedupwardtrendinthe post-test period. The mean hospitalization rate increased 5.82-fold from 0.315 in the pre-test period to 1.832 in the post-testperiod. Thet-testwas usedtocheck ifthe mean hospitalizationrate ofthe newperiodwasdifferent tothe oldconsideringdetrendeddata,i.e.consideringthe‘natural’ trendwhereachangeinthemeanwouldindicateachange inthetrend;adescriptivelevelof0.040wasobtained,from whichitwasconcludedthatthetrendinthehospitalization ratechangedsignificantly.

Figure2showsthefinalmodelforthehospitalizationrate inthe period 1999–2005. Themajority ofpoints from 2006 onwardsareabovetheline,indicatingthattherewasachange, anincreaseintherateofhospitalization.

4.000

3.500

3.000

2.500

2.000

1.500

1.000

0.500

0.000

1998 2000 2002 2004 2006 2008 2010 2012 2014

Hospitalization r

ate

Linear trend Post test

Pre-test

Figure2–Finalmodelforhospitalization.

0.350

0.300

0.250

0.200

0.150

0.100

0.050

0.000

1998 2000 2002 2004 2006 2008 2010 2012 2014

Mor

tality r

ate

Linear trend Post test

Pre-test

Figure3– Finalmodelformortality.

Mortalityrate

Forty-sevenpatientsdiedinthepre-testperiodand107diedin thepost-testperiod.Themedianagesatdeathbyyearranged fromsixto26years.Whentheresultsbetweenthetwoperiods werecompareditwasnotedthatthemedianswerehigherin thepost-testperiod,withthemedianincreasingfrom10years oldinthepre-testperiodto16yearsinthepost-testperiod (p-value=0.247–Kruskal–Wallis).

Figure1showsthetrendindeathsovertheyears;there wasalreadyanincreasingtrendinthepre-testperiodandthis trendcontinuedinthepost-testperiod,butwithgreater vari-ability.Themeanmortalityrateincreasedby1.88timesfrom 0.115inthepre-testperiodto0.216inthepost-testperiod. Detrendeddatawereusedtocheckwhetherthemeaninthe post-testperiodwasdifferentfromthatofthepre-testperiod using thesame procedureasthe hospitalizationrates.The t-testofbothgroupsgaveadescriptivelevel of0.586, from whichitwasconcludedthatthetrendinhospitalizationsdid notchangesignificantly.

Figure3showsthefinalmodelforthemortalityrate.Ifthe deathrate had continuedatthe same level, thevaluesfor futureyearswouldhavebeenclosetotheextrapolatedline. If therehadbeenasignificantchangeinthemortalityrate duetothescreeningtest,themajorityofthepointsfrom2006 onwardswouldbeabovetheline.Inthisgraph,itcanbeseen thatfrom2006onwardssomepointsareabovetheline,others arearoundtheline,andsomearebelow.

Discussion

reportingofcasesrequiringhospitalcare.Oneofthecauses of under-reporting is the difficulty of making a diagnosis. Thisproblemwasreducedwiththe implementationofthe neonatalscreeningprogram,which probablyfacilitatedthe earlydiagnosisofSCDchildren,therebyraisingthenumber ofhospitaladmissions.Othercausesofunder-reportingcould includepoorhospitalcare,theincorrectuseofICDcodes,and thelackofhospitalregistrationwithnoconsequentrecording intheSIH/SUSsystemofcaseswhichremainedemergencies throughouttheperiodofhospitaltreatment.

Despiteprogress,thehospitalizationrateinMaranhãois stillfarbelowthenationalaverage.ABrazilianstudy,7_based

ondatafromtheSIH/SUSfor2002,reportedhospitalization rates forSCD of1.8 inthe state ofBahia, and 6.0 and 7.0 forthestatesofSãoPauloand RiodeJaneiro,respectively. Thesestateshavethefollowingpercentagesofblack popula-tion:Bahia:78.8%;Maranhão:74.3%;SãoPaulo:45.3%andRio deJaneiro:30.9%.9

GiventhattheoverallprevalenceofSCDintheblack popu-lationis0.22%,9_{theexpectednumberofcasesin2002would}

havebeen11,339inBahia,9486inMaranhão,10,191inRiode Janeiro,and10,918inSãoPaulo.Inotherwords,theexpected numberofcasesinthefourstateswouldbeverysimilar,and thusthehospitalizationratesshouldhavebeenverysimilar. However,theactualhospitalizationratesaremuchhigherin RiodeJaneiroandSãoPaulo.Currently,therateof hospital-izationinMaranhãois1,832,similartothestateofBahia,but about3–4timeslessthanthestatesofSãoPauloandRiode Janeirointhatstudy.7

ItispossiblethatthelowhospitalizationratesinMaranhão occurnotonlyduetounder-reportingofpatientswhorequired hospitaltreatment,butalsoduetothelowlevelofhospital careforpatientswith SCDin thestate. Under-reportingof patientswasreducedaftertheimplementationofthe neona-talscreeningtest.Thisanalysisinfersthatthehospitalization ratesforSCDareareflectionofthequalityofmedicalcare pro-videdtopatientsandthesocialdifferencesthatexistbetween Brazilianregions.

Afterthe implementationofthe neonatalscreeningtest inMaranhãotherewasasignificantreductioninthemedian age of hospitalized SCD patients, from 11.4 years in the pre-test period to 8.7 years in the post-test period. This shows the initial impact of the test on the youngest age groups.Thedatareflectthenationalrealityasthe2002 Brazil-ianstudy7 _{reported thathospitalizations were generally of}

youngerpatients,withmostbeingundertheageof29years, andaround 70%under 19years.Themedianageswere 11 yearsinBahia,and12yearsinRiodeJaneiroandSãoPaulo.

Confirmingareductionintheunder-registrationofdeaths attributedtoSCDcausedbyalackofdiagnosis,thepresent studynotedthattherewasanincrease,albeitinsignificant, inthemeanmortalityrateofalmost200%fromthepre-test periodtothepost-testperiod.Itisbelieved thattherewas nostatisticalsignificanceforthisincreaseduetothe great variabilityinthepost-testperiod(in2009,inparticular,andin 2012thereweredecreases)andthatthenumberofdeathsin eachgroupwassmall.

Themedianageatdeathwasverylow(tenyearsinthe pre-testperiodand14inthepost-testperiod)withnosignificant differencebetweenthetwoperiods.Atthenationallevel,the

medianageatdeathisabouttwicethatinMaranhão.In2002, themedianageatdeathforSCDpatientswas26.5yearsin Bahia;31.5inRiodeJaneiroand30.0inSãoPaulo.7_Thecurrent

situationinMaranhãoiscomparabletothatofBrazilin1996, whenthemedianreportedageatdeathwas18.5years.10

SCDpatientslivemuchlongerinsomeothercountries.The aforementionedUScohortstudyreportedthatthemedianage atdeathwas42yearsformenand48forwomen.Forpatients withHbSSitwas60,andforpatientswiththeHbSC geno-typeitwas68.4_{AnothercohortstudyperformedinJamaica}

reportedamedianageatdeathof53yearsformenand58.5 yearsforwomenwithHbSS.11_{ThemeanageatdeathinSCD}

patientsseemsnottohavechangedsincestudiesconducted byPlattetal.intheearly1990sbecausearecentstudy exam-iningtheageatdeathusingdeathcertificatedatafromtheUS NationalCenterforHealthStatisticsshowedthatintheUSin 2005,consideringallthegenotypes,themedianageatdeath ofSCDpatientswas42yearsforwomenand38yearsformen.8

Perhapsthisparticularstudyhadaninherentbiasbecauseif patientswithSCDlivelongeritislesslikelythattheirdeath certificatewillincludesicklecelldiseaseasthecause.

Inthecurrentstudy,itwasnotexpectedthattherewouldbe achangeintheageatdeath,butonlyintheabsolutenumberof recordeddeathsduetoimprovednotification.Inafuture anal-ysis,insomedecades,whenpatientsdiagnosedbyscreening reachadulthood,itmaybepossibletoobserveanincreasein themedianageatdeathinMaranhão.

Thepresentstudyhasshownthattheimplementationof aneonatalscreeningtestforhemoglobinopathieshasnotyet resultedinanincreaseinthesurvivalofpatientswithSCD inMaranhão,whenoneconsidersthelowageatdeathand themarkeddifferencebetweentheagesatdeathcomparedto elsewhereinBrazil,andinternationally.

Promptdiagnosisofthediseaseonitsownisnotenough tohaveapositiveimpactonpatientsurvival.Thishasbeen observedintwoBraziliancohortstudiesrelatedtoneonatal screening(oneinthestateofMinasGeraisandtheotherin thestateofRiodeJaneiro)whereitwasobservedthateven withacarefullycontrolledprogram,the probabilityof chil-drenwithHbSSdyingwasstillconsideredtobehigh,with 71.8%ofdeathsoccurringinundertwo-year-oldchildren.12

Infectionsandsplenicsequestration13_{werethemaincauses}

of death, and 23% of deaths occurred outside the hospi-tal environment.12 _{Itisclearthatinadditiontoaneonatal}

screeningtestforhemoglobinopathiesitisnecessaryto opti-mize other measures,suchas family counselingabout the seriouscomplicationsofthedisease,effectivevaccinationand drugdistributionprograms,aswellasaccesstoeffective med-icalcaretotreatclinicalcomplications.Ontheotherhand, thesocioeconomiccharacteristicsofthepopulationalso influ-ence the survival of SCD patients and, according to some researchers,14 _{the presentationand severity ofthe disease}

dependonsocioeconomicstatus,nutrition,preventive meas-uresandaccesstohealthservices.Theseareallrelevantissues inMaranhão,whichhasoneoftheworsthumandevelopment indexes(HDI=0.639)inBrazil;thestatewasinthesecondfrom bottompositionoverallofBrazilianstatesin2010.15

It ispossible that notall the health facilities in the state ofMaranhãothatcareforSCDpatientssystematically regis-tertheiradmissionsintheSIH/SUSsystem.Thisleadstoan under-estimationofthefrequencyofhospitalizations.Failure toproperlycomplete ICDinformationmay wellbeanother limitationinaccuratelycheckingtheoccurrenceof hospital-izationsforSCD.

Theunder-reportingofdeathsisa probleminthe state ofMaranhão.However,thesituationhasimprovedinrecent years,whenthenotificationofdeathsincreasedfrom48.8% in2001to70%in2011.Nevertheless,thisismuchlowerthan instatesinthesouthandsoutheastofBrazil,wherethefigure hasbeencloseto100%since1991.16_{Anotherlimitingfactoris}

thequalityofinformation.

Itisconcludedthatthekeyreasonfortheapparent para-doxofincreasedmortalityandhospitalizationratesafterthe implementationofneonatalscreeningistheincreased ‘visi-bility’ofSCD,whichisprimarilyduetophysicians,whoare responsible forfilling out death certificates and diagnostic datarequiredtoauthorizehospitaladmittance.

Conflicts

of

interest

Theauthorsdeclarenoconflictsofinterest.

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