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WHO|Antenataladministrationofcorticosteroidsforwomenatriskofpretermbirth

HelpusimproveRHLtakethisshortsurvey
Antenataladministrationofcorticosteroids
forwomenatriskofpretermbirth
Theadministrationofcertaincorticosteroidstowomenatriskof
pretermbirthcausesaconsiderablereductionintherisksof
complicationsofprematuritysuchasrespiratorydistresssyndrome,
intraventricularhaemorrhageandperinataldeath.Corticosteroidtherapy
shouldbeincorporatedintocomprehensivematernalhealthcare
servicesandofficialguidelinesformaternitycare.

RHLCommentarybyHofmeyrGJ

1.INTRODUCTION
Pretermbirthisaleadingcauseofperinataldeathanddisabilityandis
animportantpublichealthproblemglobally(1).Pretermbirthoccurs
mostcommonlyineconomicallydisadvantagedcommunitiesandthose
withhighratesofurinaryandgenitaltractinfection.Theproblemof
pretermbirthinunderresourcedsettingsiscompoundedbyalackof
neonatalhealthcarefacilitiesandaccesstoexpensiveinterventions
suchassurfactanttherapy.Informationontheeffectivenessof
antenatalcorticosteroids,acomparativelyinexpensiveintervention,is
thusparticularlyrelevantforthesesettings.Thiscommentarycovers
threeCochranereviewsthatsoughtto:(i)"assesstheeffectsonfetal
andneonatalmorbidityandmortality,onmaternalmortalityand
morbidity,andonthechildinlaterlifeofadministeringcorticosteroidsto
themotherbeforeanticipatedpretermbirth"(2)"assessthe
effectivenessandsafetyofarepeatdose(s)ofprenatalcorticosteroids"
(3)and"assesstheeffectsofdifferentcorticosteroidregimensfor
womenatriskofpretermbirth"(4).

2.METHODS
AllthreeCochranereviewsusedappropriate,standardCochrane
methodology,includingacomprehensivesearchfortrials,inclusionof
trialsaccordingtopredefinedqualitycriteria,transparentdataextraction
andprespecifiedanalyses.

3.RESULTS
3.1Antenatalcorticosteroidsforacceleratingfetallung
maturationforwomenatriskofpretermbirth
ThisCochranereviewwasupdatedin2006,withtheinclusionof21
studiesinvolving3885womenand4269infants.Thereviewfoundthat
theadministrationofcertaincorticosteroidstowomenatriskofpreterm
deliveryproducesaconsiderablereductionintherisksofcomplications
ofprematuritysuchascombinedfetalandneonataldeath,respiratory
distresssyndrome,cerebroventricularhaemorrhage,necrotizing
enterocolitis,systemicinfectionsandchildhooddevelopmentaldelay.
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Benefitswerefoundwhentreatmentwascommencedbetween26and
35weeksofgestation,andforbabiesborn17daysaftercommencing
treatment,andalsoforsubsetsofwomenwithprematureruptureofthe
membranesandwithhypertensivedisorders.Combinedfetaland
neonataldeathswerereducedevenininfantsbornlessthan24hours
afteradministrationofthefirstdose.
Nobenefitsweredemonstratedfortreatmentcommenced,orinfants
born,before26weeksofgestation,norforthosebornmorethanseven
daysaftertreatment.Forbabiesbornafter36weekstherewasatrend
toincreasecombinedfetalandneonataldeath.
Birthweightwasreducedininfantsborn17days,andmorethanseven
daysafterthefirsttreatment.Onetrialthathadrecruitedwomenwith
severepreeclampsiasuggestedthatthetreatedwomenwereat
increasedriskofgestationaldiabetes.
Evidencefromepidemiologicalandanimalstudiessuggeststhatthere
maybelongtermadverseeffectsofprenatalcorticosteroidexposure,
includingimpairedglucosetoleranceandhypertension.Animalstudies
havealsosuggestedimpairmentofbraingrowth.
Followupoftheoffspringofonetrialatage30yearsfoundanincrease
ininsulinreleaseinresponsetoa75gglucoseload,butnoother
morbidity.
Corticosteroidregimensshowntobeeffectiveinclude:betamethasone
12mgintramuscularly,2doses24hoursapartordexamethasone6mg
intramuscularly4doses12hourly.Studiesusingmethylprednisolone
wereexcludedbecausethissteroidhasbeenshowntohavealtered
placentaltransfer.Thereviewfoundindirectevidencesuggestinga
greaterreductionofrespiratorydistresssyndromewithbetamethasone
thanwithdexamethasonetreatment,anddexamethasonesignificantly
increasedtheriskofpuerperalsepsis(seeiiibelow).

3.2Repeatdosesofprenatalcorticosteroidsforwomenat
riskofpretermbirthforpreventingneonatalrespiratory
disease
Thisreviewincludesfivetrialsinvolving2028women.Inallfivetrials,
whichwereofhighmethodologicalquality,repeatcorticosteroidtherapy
wasgiventowomenwhohadreceivedasinglecourseofcorticosteroids
sevenormoredayspreviously.Fourtrialsusedtwodosesof
betamethasone12mgandoneusedsingledoses,allrepeatedweekly.
Oneormorerepeatcoursesofcorticosteroidswereassociatedwith
reducedseverelungdisease[relativerisk(RR)0.6095%confidence
interval(CI)0.480.75]seriousinfantmorbidity(RR0.7995%CI0.67
0.93).Ontheotherhand,inonetrialtherewasareductioninbirth
weightZscore(RR0.13,95%CI0.260.00)andintwotrialsthere
wasanincreasedriskofbeingsmallforgestationalageatbirth(RR
1.63,95%CI1.122.37)Nootheroutcomeswerestatistically
significant.However,availabledatafromthestudiesdidnotgivethe
reviewsufficientstatisticalpowertoassessimportantrareoutcomes
suchasperinatal/infantdeath(RR0.5395%CI:0.181.57).Inonetrial,
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in160womenwithpretermprematureruptureofthemembranes,there
wasnosignificantreductioninrespiratorydistress,andmaternal
chorioamnionitiswasincreased(RR1.56,95%CI1.052.31).Onetrial
reporteddataonasubgroupofwomenwhoreceivefourormorerepeat
coursesofcorticosteroids:birthweightwassignificantlyreduced(WMD
161,95%CI29131).Benefitsintermsofrespiratorydistressand
evidenceofgrowthimpairmentwereseenbothintrialswithasingle
doseandthosewithtwodoses,allrepeatedweekly.
Theauthorsconcludethat,whiletherewasevidenceofshortterm
respiratorybenefitsfromrepeatedcoursesofcorticosteroids,therewas
insufficientevidenceregardingthepotentialrisksandlongtermeffects
tojustifytheuseofrepeateddosesofcorticosteroidsinclinical
practice,andthatfurtherresultswereneeded(severaltrialsare
continuinglongtermfollowup).

3.3Differentcorticosteroidsandregimensforaccelerating
fetallungmaturationforwomenatriskofpretermbirth
Thisreview,publishedin2008,includestentrialsinvolving1089women
and1161infants.Thereviewfoundthatdexamethasonedecreasedthe
incidenceofintraventricularhaemorrhagecomparedwithbetamethasone
(RR0.44,95%CI0.210.92fourtrials,549infants).Nostatistically
significantdifferenceswereseenforotherprimaryoutcomes,including
respiratorydistresssyndrome,bronchopulmonarydysplasia,severe
intraventricularhaemorrhage,periventricularleukomalacia,perinatal
death,ormeanbirthweight.Resultsforbiophysicalparameterswere
inconsistent,butmostlynoimportantdifferenceswereseenforthoseor
anyothersecondaryoutcomeexceptthat,inonetrialof105infants,
significantlymoreinfantsinthedexamethasonegroupwereadmittedto
aneonatalintensivecareunitcomparedwiththebetamethasonegroup
(RR3.83,95%CI1.2411.87).
Oraldexamethasonecomparedwithintramusculardexamethasone
increasedtheincidenceofneonatalsepsis(RR8.48,95%CI1.11
64.93)inonetrialof183infants.Nostatisticallysignificantdifferences
wereseenforotheroutcomesreported.Inonesmalltrialof69infants,
whichhadcomparedbetamethasoneacetateandphosphatewith
betamethasonephosphate,nodifferenceswereseenforanyofthe
outcomesreported.

4.DISCUSSION
4.1.APPLICABILITYOFTHERESULTS
Mostofthestudiesreviewedwereconductedinindustrializedcountries.
Theriskofrespiratorydistresssyndromeatspecificgestationalages
maydifferindifferentsettings.Itmaythusbenecessarytouselocal
datatoidentifygestationalagesatwhichbabiesareatriskof
respiratorydistresssyndromeorperiventricularhaemorrhage.Thereis
nobiologicalreasontoexpectthatcorticosteroidtherapywillnotbe
equallyeffectiveinallsettingsinimprovingtheoutcomeforfetuses
identifiedasatriskofrespiratorydistressandothercomplicationsof
prematurebirthindifferentpopulations(personalopinion).

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4.2.IMPLEMENTATIONOFTHEINTERVENTION
Corticosteroidtherapyisrelativelyinexpensive.Itisfeasibleto
implementcorticosteroidtherapyatprimaryhealthcarelevelprovided
skilledhealthcareprovidersareavailabletoidentifywomenatriskof
pretermbirthandadministerintramuscularinjections.Givena
reasonablehealthserviceinfrastructure,nospecificorganizational
changesareneeded.Corticosteroidtherapyshouldbeincorporatedinto
comprehensivematernalhealthcareservices,andincludedinofficial
guidelinesformaternitycare.Dexamethasoneorbetamethasoneshould
beavailableinallmaternityfacilitiesandshouldbeincludedinnational
essentialdrugslists.OurexperienceinSouthAfricaisthathealthcare
providershavereadilytakenuptheuseofantenatalcorticosteroid
therapy,asisthecaseinotherlowincomecountriessuchasThailand
(5).
Themajorbarriertoimplementationofcorticosteroidtherapyisthe
difficultyofidentifyingwomenatriskofpretermdeliveryintimeto
administercorticosteroids.Thisrequiresaneffectiveandwellutilized
antenatalservice.Successfulimplementationofthisinterventionwould
involve:educationofhealthcareprovidersregardingtheeffectiveness
andimplementationofcorticosteroidtherapyintroductionofprotocols
foritsuseidentificationofwomenatrisk,includingeffectiveantenatal
screeningforhypertensionandproteinuria,aspreeclampsiaisan
importantcauseofpretermdeliveryinlowincomecountriesand
providinginformationtopregnantwomen.Theinformationtopregnant
womenwouldneedtofocusonearlyreportingtoahealthfacilityatthe
firstsignsofpregnancycomplicationssuchaspretermuterine
contractions,pretermruptureofmembranesandsymptomsofpre
eclampsia.
Currentevidencesupportstheuseofdexamethasoneasthefirstchoice
oftreatment:four6mgdosesgiven12hourly.However,if
dexamethosoneisnotavailable,betamethasonemaybeused:two12
mgdosesgiven24hourly.

4.3.IMPLICATIONSFORRESEARCH
Furthertrialsontheeffectivenessofantenatalcorticosteroidtreatment
arenotjustified.Researchshouldinsteadbedirectedtowardsmethods
ofachievingeffectiveimplementationoftheinterventionindifferent
settings.Furtherresearchisalsoneededonthebenefitsandrisksof
repeatedcoursesofcorticosteroidtherapy,andtheoptimaldrug,dose
androuteofadministration.
Sourcesofsupport:EasternCapeDepartmentofHealth,Universitiesof
theWitwatersrandandFortHare,SouthAfricaWHOLongterm
InstitutionalDevelopmentGrant.

References
1. SaigalS,DoyleLW.Anoverviewofmortalityandsequelaeof
pretermbirthfrominfancytoadulthood.TheLancet
2007371(9608):2619.
2. RobertsD,DalzielSR.Antenatalcorticosteroidsforaccelerating
fetallungmaturationforwomenatriskofpretermbirth.Cochrane
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DatabaseofSystematicReviews2006Issue3.Art.No.:
CD004454DOI:10.1002/14651858.CD004454.pub2.
3. CrowtherCA,HardingJE.Repeatdosesofprenatalcorticosteroids
forwomenatriskofpretermbirthforpreventingneonatalrespiratory
disease.CochraneDatabaseofSystematicReviews2007Issue3.
Art.No.:CD003935DOI:10.1002/14651858.CD003935.pub2.
4. BrownfootFC,CrowtherCA,MiddletonP.Differentcorticosteroids
andregimensforacceleratingfetallungmaturationforwomenat
riskofpretermbirth.CochraneDatabaseofSystematicReviews
2008Issue4.Art.No.:CD006764DOI:
10.1002/14651858.CD006764.pub2.
5. SaengwareeP,LiabsuetrakulT.Changingpracticeon
corticosteroids.JournaloftheMedicalAssociationofThailand
200588:30713.

Thisdocumentshouldbecitedas:HofmeyrGJ.Antenatal
corticosteroidsforwomenatriskofpretermbirth:RHLcommentary(last
revised:2February2009).TheWHOReproductiveHealthLibrary
Geneva:WorldHealthOrganization.

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Abouttheauthor
HofmeyrGJ

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