JPediatr(RioJ).2016;92(1):1---3
www.jped.com.br
EDITORIAL
‘‘Waste
not,
want
not’’,
or
the
cost
of
doing
the
wrong
thing
夽
,
夽夽
‘‘Waste
not,
want
not’’,
ou
o
custo
da
opc
¸ão
errada
Haresh
Kirpalani
a,b,∗,
John
Zupancic
caDivisionofNeonatology,DepartmentofPediatrics,Children’sHospitalofPhiladelphia,Philadelphia,UnitedStates
bDepartmentClinicalEpidemiology&Biostatistics,McMasterUniversity,Hamilton,Canada cDepartmentofNeonatology,BethIsraelDeaconessMedicalCenter,Boston,UnitedStates
In1995,Sinclairpointedoutthatithadtakenaninordinately longtimetounderstandthatwehadsynthesizedadequate evidence on antenatal corticosteroids (ANCS) to prevent respiratory distress syndrome (RDS) and itscomplications in preterms.1 Secondly, it then took even longer for the
knowledge to bedisseminated into practice. The
dissem-ination problem was addressed by the NIH in a specific
trial to enhance uptake of knowledge on ANCS by the
obstetriccommunityover‘standard’methodsofteaching.2
In that cluster randomized trial, a package of teaching
interventions aimed at the high-risk perinatal caregivers
improvedtheuptakeofANCSintargetpopulationsof
moth-ersatriskofpretermdeliveryby108%.Yetitappearsthat
despite thesetwoseminal ‘wake-upcalls’ tothe
commu-nity---anddespitetherecommendationsofkeybodiessuch
as ACOG3,4 --- the omission of ANCS continues to plague
perinatal---neonatal medicine.Forexample, between2005
and 2007 in California, Lee found that ‘‘of 15,343
eligi-ble neonates, 23.1% did notreceive antenatalsteroids in
2005---2007.’’5 Of these, a higher proportion of Hispanic
mothersdidnotreceiveANCS---25.6%.5Disseminatingthis
knowledge-based practice into poorly resourced or lower
incomecountrieshasbeenevenmorechallenging.6,7
夽 Pleasecitethisarticleas:KirpalaniH,ZupancicJ.‘‘Wastenot,
wantnot’’,orthecostofdoingthewrongthing.JPediatr(RioJ). 2016;92:1---3.
夽夽
SeepaperbyOgataetal.inpages24---31.
∗Correspondingauthor.
E-mail:[email protected](H.Kirpalani).
In this issue of the Jornal de Pediatria, Ogata et al.
re-emphasizetheimportanceoftheuseofANCSinthe
pre-ventionofneonatalprematuredeath,especiallyinthepoor
andmiddle-incomecountries.8Tofurtherconvincethe
peri-natalcommunity,Ogataetal.performedacost-analysisof
the effects of ANCS on total hospital costs in Brazil --- a
middle-incomecountry.8 Ogata etal. have shown us that
thepotential costreductionis stilllarge in a veryrecent
cohort.Insurvivinginfantslessthan30weeksofgestational
age,therewasa38% reductionin totalcosts,presumably
drivenby a 49% reductionin neonatalintensive care unit
(NICU)lengthofstay.8
Previouscost-analysesonANCSwereperformedinan
ear-lierera,9,10butindevelopedandhigh-incomecountries.In
the UK, Mugford appliedexpected odds of death derived
from randomized trials9 to the observed deaths in a UK
hospital. This allowed them to estimate the anticipated
improved survival, and thus the hospital costs per extra
survivor.Theyfoundthatininfantsunder31weeksof
gesta-tionalage(GA),theactualcostpersurvivorwouldhavebeen
reducedby 10%.Thiswasdespitetheprojectedincreased
survivalrate---whichwouldbeexpensive.9Similarly,
mod-eling data from the USA showed projected cost-savings
in 1995 with a minimum of $197,000 savings in hospital
expenditure.10 Thesedataarefromthe1990s.Thefindings
ofOgataetal.strikinglyconfirmtheseearlierreports,but
inamiddle-incomecountry.
Apotentialissue notfullyclarifiedby anyofthe three
studies8---10relatestopossiblemisclassificationofthe
expo-sure to ANCS. Specifically, mothers in the current study
wereclassifiedasreceivingtreatmentiftheyreceivedany
http://dx.doi.org/10.1016/j.jped.2015.11.001
2 KirpalaniH,ZupancicJ
dosesofthemedication.Inaverycomprehensivepopulation
databaseinNovaScotia(from1988to2012),‘‘suboptimal
exposuretoANCS’’(definedaslessthan24hormorethan
sevendaysbeforedelivery)comprised34% ofdeliveries.11
Incompletedosinginthe‘‘treated’’groupwouldpotentially
biastheobservedeffectivenessofANCStowardthenull,so
theactual effectmightbeevenhigherthandemonstrated
here.Conversely, in thegroup whodidnot receiveANCS,
thereisthepotentialforconfoundingbyindication:
moth-erswhodidnotreceivetreatmentmayhavebeentoosick,
orproceededtoprecipitousorcomplicateddeliveries
with-outanydelayforcorticosteroidadministration.Inthiscase,
thenon-treatedinfantsmighthavebeendestinedforworse
outcomes,andtheeffectofANCSwouldbeover-estimated.
InCalifornia,LeedidfindthatfailuretoreceiveANCSwas
associatedwithsuchfactorsasfetaldistress.5Interestingly,
infantsundergoingvaginaldelivery(vs.cesarean)werealso
associatedwithnon-ANSreceipt.5
Another note of caution concerns the specific
popula-tion that should be targeted in low- and middle-income
countries. This issue has been thrown into recent
con-siderable debate following the Antenatal Corticosteroid
Treatment trial (ACT).12 This cluster randomized clinical
trial (RCT) in six low-to-middle incomecountries showed
ahigher28-day neonatalmortalityinall infantsreceiving
ANCS (RR: 1.12; 95% CI: 1.02---1.22). However, the
pri-maryoutcome ofthetrial was28-daymortalityin infants
<5th percentile, which showed no statistically significant
difference (RR: 0.96; 95% CI: 0.87---1.06). The secondary
outcome of total mortality has of course received much
attention, as the results stand in stark contrast to a
meta-analysis on rates of neonatal death from RDS.6
Mwansa-Kambafwile et al. pooled four trials in
middle-incomecountries(totalnumberofinfants=672)andshowed
a reduction in neonatal mortality [RR: 0.47 (0.35, 0.64)]
which appeared to show even greater effect than that
observedindevelopedcountries(n=3284infantsin14
stud-ies)[RR0.79(95%CI0.65---0.96)].6IntheACT,eligibilitywas
definedby use of a tape-measure of uterine height. It is
possiblethatthisledtomis-classificationofinfants,as
sug-gestedby Visserand DiRenzo.13 It is furtherpossible that
infantsat gestationalagesof >34 weeksareless likelyto
benefit,due tothelowerincidenceof respiratorydistress
syndrome,but might stillbe exposed toas-yet-undefined
risksofthemedication.Indeed,suchexposurewasfrequent
in the Nova Scotia study noted earlier.11 Moreover, ANCS
shouldideallybepart ofa continuumof bestpracticesin
the intrapartum and post-partum period, and suboptimal
resuscitationor hygienemeasures might adversely impact
theeffectivenessofantepartumtreatment.
We should note that the lack of evidence
penetra-tion into practice remains a problem in parts of the
world, despite both efficacy data from the 1990s1 and
theeconomic data for the sameperiod.9,10 Potential cost
reductionsarehuge,andworthy oftheobstetrician’sand
neonatologist’sattention.Manghametal.foundaninverse
relationship between both GA and BW, and the costs of
hospitalization.14 Total United Kingdom costs of newborn
care for the extremely preterm were staggeringly high,
at£94,740(US$146,847)higherthanatermsurvivor.Yet
data on the economic aspects of health care on specific
therapiesisremarkablysparse,andwhatisavailable isof
low methodologicalquality.15,16 Moreover,datafromlarge
methodologically rigorous randomized controlled clinical
trialscanandshouldincorporateeconomicanalyses.17---19
There remains resistance from some physicians to
cost analyses, likely related to multiple factors
includ-ingperceived infringementofautonomy andphilosophical
objectionsto‘limitingcare.’However,giventhatresources
for health care are constrained, particularly in low- and
middle-incomecountries,itisessentialthatthoseresources
arefocusedonthehighest-yieldtherapies. Suchtherapies
haveanacceptablebalanceofcostsandefficacyin
improv-ingoutcomes,assummarizedintheefficacy/costratio,or
‘‘value equation.’’20 To that end, emphasis has recently
been placedoneliminatingpracticesthatarecostlywhile
havingpoor evidenceforeffectiveness. Thisapproachhas
beenusedinthe‘‘ChoosingWisely’’campaign,intheUnited
Statesandelsewhere,inwhichmedicalsubspecialties
iden-tify lists of five practices that should be reconsidered.21
Equallyimportant,however,arethosepracticesthathave
good evidence for efficacy but are not being used in all
eligible patients. Such errors of omission, by foregoing
improvements in outcome that would themselves reduce
costs,arealsowasteful.AsshownbyOgataetal.,
antena-talcorticosteroidsareaprimeexampleofsuchunderused,
buteffective,therapies,andshouldbetargetedinquality
improvementinitiativesinthissetting.
Conflicts
of
interest
Theauthorsdeclarenoconflictsofinterest.
Acknowledgement
WewouldliketothankDr.ElizabethFogliafor hercritical readingofthemanuscript.
References
1.Sinclair JC. Meta-analysis of randomized controlled trials of antenatal corticosteroid for the prevention of respira-tory distress syndrome: discussion. Am J Obstet Gynecol. 1995;173:335---44.
2.LevitonLC,GoldenbergRL,BakerCS,SchwartzRM,FredaMC, FishLJ,etal.Methodstoencouragetheuseofantenatal corti-costeroidtherapyforfetalmaturation:arandomizedcontrolled trial.JAMA.1999;281:46---52.
3.AmericanCollegeofObstetricians,GynecologistsCommitteeon ObstetricPractice.ACOGCommitteeOpinionNo.402: antena-talcorticosteroidtherapyforfetalmaturation.ObstetGynecol. 2008;111:805---7.
4.ACOGCommitteeOpinion.Antenatalcorticosteroidtherapyfor fetalmaturation.Number210,October1998(ReplacesNumber 147,December1994).CommitteeonObstetricPractice. Amer-icanCollegeofObstetriciansandGynecologists.IntJGynaecol Obstet.1999;64:334---5.
5.LeeHC,LyndonA,BlumenfeldYJ,DudleyRA,GouldJB. Antena-talsteroidadministrationforprematureneonatesinCalifornia. ObstetGynecol.2011;117:603---9.
‘‘Wastenot,wantnot’’,orthecostofdoingthewrongthing 3
7.DalzielSR,CrowtherCA,HardingJE.Antenatalcorticosteroids 40yearson:wecandobetter.Lancet.2014;384:1829---31. 8.OgataJF,FonsecaMC,MiyoshiMH,deAlmeidaMF,GuinsburgR.
Costsofhospitalizationinpreterminfants:impactofantenatal steroidtherapy.JPediatr(RioJ).2016;92:24---31.
9.MugfordM,PiercyJ,ChalmersI.Costimplicationsofdifferent approachestothepreventionofrespiratorydistresssyndrome. ArchDisChild.1991;66:757---64.
10.Simpson KN, Lynch SR. Cost savings from the use of ante-natal steroids to prevent respiratory distress syndrome and relatedconditionsinprematureinfants.AmJObstetGynecol. 1995;173:316---21.
11.Razaz N, Skoll A, Fahey J, Allen VM, Joseph KS. Trends in optimal, suboptimal, and questionably appropriate receipt of antenatal corticosteroid prophylaxis. Obstet Gynecol. 2015;125:288---96.
12.Althabe F, Belizán JM, McClure EM, Hemingway-Foday J, BerruetaM,MazzoniA,etal.Apopulation-based,multifaceted strategy to implement antenatal corticosteroid treatment versus standard care for the reduction of neonatal mortal-ity due to preterm birth in low-income and middle-income countries:theACTcluster-randomisedtrial.Lancet.2015;385: 629---39.
13.VisserGH,DiRenzoGC.Antenatalcorticosteroidsforpreterm births in resource-limited settings. Lancet. 2015;385: 1943---4.
14.ManghamLJ,PetrouS,DoyleLW,DraperES,MarlowN.Thecost ofpretermbirththroughoutchildhoodinEnglandandWales. Pediatrics.2009;123:e312---27.
15.PetrouS,EddamaO, ManghamL.Astructuredreviewofthe recent literatureon theeconomic consequences ofpreterm birth.ArchDisChildFetalNeonatalEd.2011;96:F225---32. 16.ZupancicJA,RichardsonDK.Systematicreviewofneonatal
ran-domizedcontrolledtrialsrevealspaucityofancillaryeconomic evaluations.PediatrRes.2001;49:364A.
17.KamholzKL,DukhovnyD,KirpalaniH,WhyteRK,RobertsRS, WangN, etal.EconomicevaluationalongsidethePremature InfantsinNeedofTransfusionrandomisedcontrolledtrial.Arch DisChildFetalNeonatalEd.2012;97:F93---8.
18.DukhovnyD,LorchSA,SchmidtB,DoyleLW,KokJH,RobertsRS, etal.Economicevaluationofcaffeineforapneaofprematurity. Pediatrics.2011;127:e146---55.
19.PetrouS,BischofM,BennettC,ElbourneD,FieldD,McNally H. Cost-effectiveness of neonatal extracorporeal membrane oxygenationbasedon7-yearresultsfromtheUnitedKingdom collaborativeECMOtrial.Pediatrics.2006;117:1640---9. 20.DukhovnyD,PurselyDM,KirpalaniH,HorbarJH,ZupancicJA.
Evidence, quality and waste: solving the value equation in neonatology.Pediatrics.2015[inpress].
