Induction of Labour

11/29/2015
www.medscape.com/viewarticle/754479_print
www.medscape.com
MethodsofInductionofLabour
ASystematicReview
EllenLMozurkewichJulieLChilimigrasDeborahRBermanUmaCPerniVivianCRomero
ValerieJKingKristieLKeeton
BMCPregnancyChildbirth.201111(84)
AbstractandIntroduction
Abstract
Background:Ratesoflabourinductionareincreasing.Weconductedthissystematicreviewtoassesstheevidencesupporting
useofeachmethodoflabourinduction.
Methods:Welistedmethodsoflabourinductionthenreviewedtheevidencesupportingeach.WesearchedMEDLINEandthe
CochraneLibrarybetween1980andNovember2010usingmultipletermsandcombinations,includinglabor,induced/or
inductionoflabor,prostaglandinorprostaglandins,misoprostol,Cytotec,16,16,dimethylprostaglandinE2orE2,dinoprostone
Prepidil,Cervidil,Dinoprost,Carboprostorhemabateprostin,oxytocin,misoprostol,membranesweepingormembrane
stripping,amniotomy,ballooncatheterorFoleycatheter,hygroscopicdilators,laminaria,dilapan,salineinjection,nipple
stimulation,intercourse,acupuncture,castoroil,herbs.Weperformedabestevidencereviewoftheliteraturesupportingeach
method.Weidentified2048abstractsandreviewed283fulltextarticles.Wepreferentiallyincludedhighqualitysystematic
reviewsorlargerandomisedtrials.Wherenosuchstudiesexisted,weincludedthebestevidenceavailablefromsmaller
randomisedorquasirandomisedtrials.
Results:Weincluded46fulltextarticles.Weassignedaqualityratingtoeachincludedarticleandastrengthofevidence
ratingtoeachbodyofliterature.ProstaglandinE2(PGE2)andvaginalmisoprostolweremoreeffectivethanoxytocinin
bringingaboutvaginaldeliverywithin24hoursbutwereassociatedwithmoreuterinehyperstimulation.Mechanicalmethods
reduceduterinehyperstimulationcomparedwithPGE2andmisoprostol,butincreasedmaternalandneonatalinfectious
morbiditycomparedwithothermethods.Membranesweepingreducedposttermgestations.Mostincludedstudiesweretoo
smalltoevaluateriskforrareadverseoutcomes.
Conclusions:Researchisneededtodeterminebenefitsandharmsofmanyinductionmethods.
Background
Theincidenceoflabourinductionhasincreasedoverthelastdecade. [1]Labourinductionmaybeindicatedbymedicalor
obstetricalcomplicationsofpregnancyormayberequestedorchosenfornonmedicalorsocialreasons.Whenawomanand
hercareproviderdecidethatlaborinductionisdesired,theymustnextchooseamethodofinduction.Severalfactorsmay
influencethechoiceofmethodforinductionoflabourincludingcervicalandmembranestatus,parity,andpatientandprovider
preference.Inthispaperwereviewtheevidenceforeffectivenessofpharmacologic,mechanical,investigational,and
complementaryandalternativemedicinemeansofthirdtrimesterlabourinduction.Wealsoaddresspossibleharmsofeach
method.
Weconductedthisreviewtosummarizethebestevidenceavailableforpregnantwomenrequiringinductionoflaborinthethird
trimesterofpregnancywithalivefetus.Wecomparedeachmethodwithplaceboandwithothermethodsoflaborinduction.
TheoutcomesofthisreviewweretheclinicallyimportantbenefitsandharmsoflaborinductionspecifiedbytheCochrane
Collaboration'sPregnancyandChildbirthGroupintheirgenericprotocolforinductionoflabour. [2]
Methods
WeconductedacomprehensiveliteraturesearchoftheEnglishlanguageliteratureusingMedlineandtheCochraneDatabase
ofSystematicReviews.ThesearchcoveredtheperiodfromJanuary1980toNovember2010.Weusedcombinationsofthe
followingsearchterms"labor,induced/orinductionoflaborprostaglandinorprostaglandins,misoprostolCytotec16,16,
dimethylprostaglandinE2orE2dinoprostonePrepidilCervidil:DinoprostCarboprostorhemabateprostin,oxytocin,
misoprostol,prostaglandins,membranesweepingormembranestripping,amniotomy,ballooncatheterorFoleycatheter,
hygroscopicdilators,laminaria,dilapan,salineinjection,nipplestimulation,intercourse,acupuncture,castoroil,herbs".Titles
http://www.medscape.com/viewarticle/754479_print
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andabstractswerereviewedforpossibleexclusionbytworeviewers(KKorEMandJC).Ifbothreviewersexcludedacitation,
weeliminatedthatpublicationfromfurtherreview.Ifatleastonereviewerfeltthecitationmightbeincludedoriftherewas
insufficientinformationtomakeadeterminationfromthetitleandabstract,weobtainedthefullarticleforreview.Weidentified
additionalarticlesforconsiderationofinclusionthroughcrosschecksofrelevantbibliographies.Referencelistswerecreated
andfulltextarticleswereretrievedforfurtherconsiderationforinclusion.
Inaccordancewithpublishedguidelinesfora"bestevidence"review, [35]thisstudyincludedhighqualitysystematicreviews
andrandomisedcontrolledtrialsinahierarchicalfashion.Ifahighqualitysystematicreviewwasavailable,onlyrandomised
controlledtrials(RCT)publishedafterthesearchdateforthesystematicreviewwereincluded,exceptintheinstanceinwhich
wefoundaRCTthathadnotbeenidentifiedbythesystematicreview'ssearchoraRCTthathadbeenidentifiedbythe
systematicreview'ssearchbutwhichwasawaitingclassification.Inaddition,weincludedstudieswithatleastoneother
comparisongroup(control,placebooranothermethod)forwomenundergoinginductionoflabourattermwithalivefetus.We
excludedsystematicreviewsdealingexclusivelywithsubgroupsofparticipants,suchasnulliparasorwomenwithprelabour
ruptureofmembranesorwithonlyaparticulardoseorformulationofthemethodunderstudy(i.e.lowdoseorsustained
releasepreparations).Weexcludeddoserangingstudies,comparisonsoftwodifferentformulationsofthesamemethodand
studiesinwhichsubjectsinoneormoretreatmentarmreceivedseveraldifferentmethodsoflabourinduction.Wedidnot
excludestudiesinwhichsubjectsreceivedoxytocinaugmentationaftercervicalripening.
Iffiveormorerandomisedcontrolledtrialsinvolvingamethodofinductionwerepublishedsubsequenttothesearchdateofthe
mostrecentincludedsystematicrevieworwere"awaitingclassification"inthesystematicreview,weconductedmetaanalyses
oftheprimaryoutcomesreportedinthesestudies.Twoauthors,VRandUPextracteddataindependently.Differenceswere
resolvedbyathirdreviewer(EM)aftercarefulreviewofeachmanuscript.Thenewdatawereaddedtothedataonthe
comparisonavailableintheCochranereview.Wecomputedriskratiosand95%confidenceintervalsforthemainoutcome
measuresreportedinthesesubsequentstudiesusingComprehensiveMetaAnalysis,Version2,Englewood,NJ.Weusedthe
fixedeffectsmethodfortheseanalysesinordertomatchthemeasuresofeffectreportedbytheincludedCochranereviews.
Wearrangedthemethodsoflabourinductionaccordingtotypesincludingpharmacologicmethods,nonpharmacologic
methods,complementaryandalternativemedicinemethods,andinvestigationalmethods.However,forcomparisonsof
methodswitheachother,wefollowedtheprespecifiedhierarchyusedfortheseriesofinductionoflabourCochraneReviews
andarrangedlabourinductionmethodsinthatspecificorder. [2]Ineachsubsectionofthispaper,wecompareeachmethod
withthosemethodspriortoitonthislist.(see)
Table1.Inductionoflabourmethodshierarchyofcomparisons2
(1)
placebo/notreatment
(2)
vaginalprostaglandinE2
(3)
intracervicalprostaglandinE2
(4)
intravenousoxytocin
(5)
amniotomy
(6)
intravenousoxytocinwithamniotomy
(7)
vaginalmisoprostol
(8)
oralmisoprostol
(9)
mechanicalmethodsincludingextraamnioticFoleycatheter
(10) membranesweeping
(11) extraamnioticprostaglandins
(12) intravenousprostaglandins
(13) oralprostaglandins,excludingmisoprostol
(14) mifepristone
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(15) oestrogenswithorwithoutamniotomy
(16) corticosteroids
(17) relaxin
(18) hyaluronidase
(19) castoroil,bath,and/orenema
(20) acupuncture
(21) breaststimulation
(22) sexualintercourse
(23) homoeopathicmethods
(24) isosorbidemononitrate
(25) buccalorsublingualmisoprostol
(26) hypnoticrelaxation
Allfulltextarticleswereindependentlyreviewedbytwoauthors(EMandKK)forpossibleinclusion.Inordertobeincludedin
thisreview,trialshadtoreportononeormoreoftheoutcomesofinterestspecifiedbytheCochraneCollaborationinductionof
labourgenericprotocol. [2]TheCochranegenericprotocolidentifiedthemostclinicallyimportantbenefitsandharmsoflabor
inductionastheoutcomesofinterest.Theseincludedthefollowingfiveprimaryoutcomeswhichwerefelttobeofmostclinical
importance:vaginaldeliverynotachievedwithin24hours(orperiodspecifiedbyauthors),uterinehyperstimulationwithfetal
heartrate(FHR)changes,caesareansection,seriousneonatalmorbidityorperinataldeath(e.g.seizures,birthasphyxia
definedbytrialists,neonatalencephalopathy,disabilityinchildhood),seriousmaternalmorbidityordeath(e.g.uterinerupture,
admissiontointensivecareunit,septicaemia). [2]
Secondaryoutcomesincludedunfavourableorunchangedcervixafter12or24hours,needforoxytocinaugmentation,uterine
hyperstimulationwithoutFHRchanges,uterinerupture,epiduralanalgesia,instrumentalvaginaldelivery,meconiumstained
amnioticfluid,Apgarscorelessthansevenatfiveminutes,neonatalintensivecareadmission,neonatalencephalopathy,
perinataldeath,disabilityinchildhood,maternalsideeffectsincludingnausea,vomitinganddiarrhea.Othersecondary
outcomesincludedpostpartumhemorrhage,seriousmaternalcomplications,maternalinfectionsincludingchorioamnionitisand
endometritis,andneonatalinfectionsincludingmeningitis,pneumonia,andsepsis.Maternalsatisfactiondatawereincluded
whenavailable.Foreachofthemethodsofinduction,wereportedthesignificantmeasuresofeffect(oddsratiosorriskratios)
onouroutcomesofinterestfromtheincludedsystematicreviewsandRCTs.
Duetothelargenumberofmethods,comparisonsandoutcomes,wedidnotincludediscussionofsubgroupanalyses.
However,becauseoftheimportanceofcervicalstatusasadeterminantoffailureofinductionoflabortoachievevaginalbirth,
wereportedontheeffectofinductionmethodsoncaesareandeliveriesforthesubgroupwithunfavorablecervices,where
availableintheCochranereviews.
Twoauthors(EMandJC)assignedqualityscorestoeachincludedfulltextarticlebasedontheScottishIntercollegiate
GuidelinesNetwork(SIGN)qualityassessmentinstruments.Thesequalityassessmentinstrumentsaredesignedtoassessthe
internalvalidityofeachstudy,andthedegreetowhichthestudies'performanceminimizedbias. [6]TheScottishIntercollegiate
GuidelinesNetworkpublishesmethodologychecklistsforcriticalappraisalofbothrandomisedcontrolledtrialsandfor
systematicreviews. [6]
Wesystematicallyreviewedbenefitsandharmsofeachinductionmethodandcalculatednumberneededtotreat(NNT)and
numberneededtoharm(NNH)foreachsignificantcomparisonamongmethods.Forcomparisonsincludingonlyonetrial,we
usedthe"treatasonetrial"methodofcalculatingtheNNT. [7]Whenmorethanonetrialwasincludedinthecomparison,we
calculatedNNTfrompooledoddsratiosandriskratiosreportedintheincludedmetaanalysesusingtheVisualRx,version2
thismethodislesspronetobiasthanthe"treatasonetrial"methodofNNTcalculation. [89]ForthepurposeofNNT
calculationsfrompooledestimates,weusedriskratiosoroddsratioswherereportedforadverseoutcomesandoddsratiosto
calculatedNNTfrompositiveoutcomes. [9]Whenoddsratioswerenotavailableinthesourcestudies,wecalculatedthemfrom
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availabledatausingComprehensiveMetaAnalysis,Version2,Englewood,NJ.NNTestimateswereroundeduptothenext
wholenumberwhereasNNHestimateswereroundeddowntothenearestwholenumber. [710]
Foreachmethodofinduction,twoauthors(EMandKK)assignedalevelofevidencebasedonthe"GRADE"(Gradingof
RecommendationsAssessment,DevelopmentandEvaluation)system. [11]Inthissystem,theoverallstrengthofevidenceis
assignednotonlybasedonstudydesignandconduct,butalsoonfactorssuchastheconsistencyandprecisionoftheresults
andthelikelihoodofpublicationbias.OverallstrengthofevidenceisclassifiedintheGRADEsystemashigh,intermediate,
loworverylow.Thelevelsofevidencewereassignedinthefollowingmanner.Ifthepreponderanceofevidencesupportinga
particularmethodoflaborinductionfortheoutcomesofinterestisstrongenoughthatfurtherresearchwouldbeunlikelyto
changethereviewers'confidenceintheestimateofeffect,theevidencequalitywasassessedashigh. [11]Iffurtherresearch
wouldbelikelytohaveanimportantimpactonconfidenceintheestimate,theevidencequalitywasassessedasmoderate. [11]
Iffurtherresearchwouldbeverylikelytohaveanimportantimpactintheestimateofeffect,thequalityofevidencewas
assessedaslow,andiftheestimateofeffectisveryuncertain,theevidencewasassessedasverylow. [11]
Thesesameauthors(EMandKK)alsoassignedabalanceofbenefitsandharmsandagradeofrecommendationaccordingto
GRADEsystemguidelines. [11,12]Foreachclinicalinterventionunderstudy,thebalanceofbenefitsandharmsisassessed,
andagradeofrecommendationisclassifiedasstrongorweak.Thissystematicreviewdoesnothavea"standalone"study
protocol.Inreportingoutcomesfromincludedstudy,wefollowedPRISMAguidelines. [13]
Thisisasystematicreviewofpreviouslypublisheddataandassuchdoesnotrequireethicsapproval.
Results
Wereviewed2048abstracts,ofwhich283fulltextarticleswereexaminedforfurtherconsiderationforinclusionandfromwhich
46studieswereincluded.Thus,weincludedatotalof46studiesinthissystematicreview. [1459]Includedstudiesarelistedin
.TheflowofabstractsandarticlesthroughthereviewprocessisoutlinedinFigure1.Asummaryoftheoverallqualityof
evidenceandstrengthofrecommendationforeachinterventionispresentedin.
Table2.IncludedStudies
Author
Year Indication
StudyDesign
SRFinalSearchDate StudyQuality
Kelly[14]
2009 VaginalProstaglandins
SR,MA
May2009
High
Boulvain[15]
2009 CervicalProstaglandins
SR,MA
August2007
High
Alfirevic[16]
2010 Intravenousoxytocin
SR,MA
January2009
High
Kunt[17]
2010 Intravenousoxytocin
RCT
Bricker[18]
2009 Amniotomy
SR,MA
Howarth[19]
Medium
January2007
High
2009 Intravenousoxytocinplusamniotomy SR,MA
September2009
High
Hofmeyr[20]
2010 Vaginalmisoprostol
SR,MA
April2010
High
Alfirevic[21]
2008 Oralmisoprostol
SR,MA
May2008
High
Gaffaney[22]
RCT
High
Nagpal[23]
RCT
High
Muzonzini[24]
2009 Buccalmisoprostol
SR,MA
December2003
High
Bartusevicius[25] 2005 Buccalmisoprostol
SR
2004
High
Souza[26]
SR
February2008
High
Lo[27]
RCT
High
Elhassan[28]
RCT
High
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Boulvain[29]
2010 Mechanicalmethods
SR,MA
April2001
High
Heinemann[30]
SR,MA
November2005
High
Vaknin[31]
SR,MA
April2008
High
MoraesFilho[32] 2010 Mechanicalmethods
RCT
High
Boulvain[33]
2009 Membranesweeping
SR,MA
Kaul[34]
RCT
High
Kashanian[35]
RCT
High
DeMiranda[36]
RCT
High
Hill[37]
RCT
High
Yildirim[38]
RCT
High
Hamdan[39]
RCT
High
Kelly[40]
2009 Castoroil
SR,MA
August2009
High
Smith[41]
2009 Acupuncture
SR,MA
January2008
High
July2009
High
SelmerOlsen[45] 2007 Acupuncture
RCT
High
Smith[42]
2008 Acupuncture
RCT
High
Asher[43]
2009 Acupuncture
RCT
High
Modlock[44]
2010 Acupuncture
RCT
High
Kavanaugh[46]
2009 BreastStimulation
SR,MA
September2009
High
Kavanaugh[47]
2009 SexualIntercourse
SR,MA
June2007
High
Smith[48]
2010 Homeopathicmethods
SR,MA
December2009
High
Omer[49]
1987 Hypnoticrelaxation
Quasirandomised
Hutton[50]
2009 Extraamnioticprostaglandins
SR,MA
June2009
High
Luckas[51]
2010 Intravenousprostaglandins
SR,MA
May2010
High
French[52]
2009 Oralprostaglandins
SR,MA
July2009
High
Hapangama[53]
2009 Mifepristone
SR,MA
May2009
High
Thomas[54]
2008 Oestrogen
SR,MA
January2008
High
Kavanaugh[55]
2006 Corticosteroids
SR,MA
December2005
High
Kelly[56]
2009 Relaxin
SR,MA
August2009
High
Kavanaugh[57]
2009 Hyaluronidase
SR,MA
July2009
High
Osman[59]
2006 Isosorbidemononitrate
RCT
High
Habib[58]
2008 Isosorbidemononitrate
RCT
High
Low
Abbreviations:SRSystematicReviewMAMetaanalysisRCTRandomisedcontrolledtrial
Table3.Summary:QualityofEvidenceandGradesofRecommendation11,12
Method
Qualityofevidence BalanceofBenefits/Harms GradeofRecommendation
VaginalPGE2
Moderate
Tradeoffs
Strong
CervicalPGE2
Moderate
Netbenefits
Strong
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Intravenousoxytocin
Moderate
Tradeoffs
Strong
Amniotomy
Moderate
Uncertaintradeoffs
Weak
IntravenousoxytocinplusAmniotomy Moderate
Tradeoffs
Strong
Vaginalmisoprostol
Moderate
Tradeoffs
Strong
Oralmisoprostol
Moderate
Tradeoffs
Strong
Mechanicalmethods
Moderate
Tradeoffs
Weak
Membranesweeping
Moderate
Netbenefits
Strong
Extraamnioticprostaglandins
Moderate
Nonetbenefit
Strong(against)
Intravenousprostaglandins
Moderate
Netharms
Strong(against)
Oralprostaglandins
Moderate
Netharms
Strong(against)
Mifepristone
Moderate
Netharms
Weak
Oestrogens
VeryLow
Uncertaintradeoffs
Weak
Corticosteroids
VeryLow
Uncertaintradeoffs
Weak
Relaxin
Moderate
Uncertaintradeoffs
Weak
Hyaluronidase
Verylow
Uncertaintradeoffs
Weak
Castoroil
VeryLow
Netharms
Strong(against)
Acupuncture
Moderate
Nonetbenefit
Weak
Breaststimulation
Moderate
Uncertaintradeoffs
Weak
Sexualintercourse
Verylow
Uncertaintradeoffs
Weak
HomeopathicMethods
Verylow
Uncertaintradeoffs
Weak
Isosorbidemononitrate
Moderate
Uncertaintradeoffs
Weak
Buccalorsublingualmisoprostol
Moderate
Tradeoffs
Strong
Hypnosis
Verylow
Nonetbenefit
Weak
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Figure1.
FlowDiagram.
PharmacologicMethods
IntravaginalProstaglandins(PGE2andPGF2a)
OursearchidentifiedoneCochranesystematicreviewofvaginalprostaglandinE2(PGE2)orF2(PGF2). [14]Withinthis
review,37studiescomparedPGE2withplacebo.Ofthese,twotrialswith384womenaddressedtheprimaryoutcomeof
achievingvaginaldeliverywithin24hours.ThesestudiesdemonstratedthatPGE2reducedfailuretoachievevaginaldelivery
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within24hourscomparedwithplacebo(36/199versus183/185RelativeRisk[RR]0.19,95%ConfidenceInterval[CI]0.14to
0.25NNT=2).However,therewassignificantbetweenstudyheterogeneityinthesetwoincludedstudies,(P<0.0001),
possiblyresultingfromdifferencesinbaselinecharacteristicsofincludedwomenanddifferencesindosingregimensstudies. [14]
Thirtyfourtrialswith6399womencomparedratesofcaesareansectionanddemonstratedsimilarratesbetweenPGE2and
placebogroups.Fourteentrialsincluding1259womenreportedthatuterinehyperstimulationwithFHRchangeswasincreased
withvaginalPGE2comparedwithplacebo(28/642versus3/617RR4.14,95%CI1.93to8.90NNH=65).Additionally,13
trialswith3636womendemonstratedthathyperstimulationwithoutFHRchangeswasalsoincreased(26/1846versus7/1790
RR2.48,95%CI1.17to5.26NNH=174).Insufficientdataprohibitedanyconclusionsaboutseriousmaternalorneonatal
morbidityordeath. [14]Threetrialswith387womencomparedPGF2withplacebo.PGF2reducedtheneedforoxytocin
augmentation(2trials,122women,41/76versus41/46RR0.65,95%CI0.53to0.81,NNT=4).PGF2reducedtheriskfor
instrumentalvaginaldeliveryin2trials355women,51of225versus48of130,RR0.60,95%CI0.43to0.84,NNT=7)and
forepiduralanalgesiain3trialswith387women(53/241versus47of146,RR0.72,95%CI0.53to0.98,NNT=17)
comparedwithplacebo.Thesetrialsdidnotdemonstrateadifferenceincesareansectionratesoranyotheroutcomesof
interestbetweenPGF2andplacebo. [14]
UnfavorableCervixSubgroupTheauthorsconductedsubgroupanalysesoftrialparticipantswhohadcervicesunfavorable
forinduction.TherewasnodifferenceintheriskofcaesareandeliverybetweenvaginalPGE2andplacebointhesubgroupof
womenwithunfavorablecervices(22trials,2173women,225/1093versus254/1080,RR0.87,95%CI0.75to1.02). [14]
Summary:Comparedwithplacebo,vaginalPGE2increasesvaginaldeliveryrateswithin24hours.However,overallriskof
cesareansectionwasnotchanged.PGE2increasesuterinehyperstimulationwithFHRchanges.
CervicalPGE2
OursearchidentifiedoneCochranesystematicreviewoftheuseofintracervicalprostaglandinsforcervicalripeningand
inductionoflabourcomparedwithplacebo/notreatment. [15]ThisCochranereviewincluded28trialswith3764womenthat
comparedintracervicalPGE2withplacebo/notreatment.Fourofthestudies(n=198)foundthatuseofcervicalPGE2was
superiortoplaceboindecreasingthenumberofwomenwhodidnotachievevaginaldeliverywithin24hours(44/100versus
71/98RR0.61,95%CI0.47to0.79NNT=4).In27trialsincluding3734women,therewasanonsignificanttrendtoward
decreasedriskofcaesareansectionforwomenreceivingcervicalPGE2(344/1941versus360/1793RR0.8895%CI0.77to
1.01).TherewerenosignificantincreasesinriskofhyperstimulationwithFHRchanges.However,11trialswith2531women
demonstratedsignificantincreasesinhyperstimulationwithoutFHRchanges(67/1344versus37/1187RR1.59,95%CI1.09
to2.33NNH=55).Seriousmaternalandneonatalmorbidityandmortalitywereinfrequentlyreportedandavailabledata
revealedsimilarfindingsinthePGE2andplacebogroups. [15]
Theauthorsidentified29trialsincluding3881womenthatcomparedcervicalPGE2withvaginalPGE2.CervicalPGE2was
lesseffectivethanvaginalPGE2inachievingvaginaldeliverywithin24hours(11trials,2200women,410/1122versus
315/1078RR1.2695%CI1.12to1.41NNH=14).Therewasnodifferenceinanyotheroutcomeofinterest. [15]
SubgroupWithUnfavorableCervixComparedwithplacebo,therewasanonsignificanttrendtowardfewercaesarean
sectionsamongwomenreceivingcervicalPGE2(27studies,3716women,343/1931versus359/1785,RR0.8895%CI,0.77
to1.01).In26trialswith3586womenwhosecervixwereunfavorableforinduction,therewasnodifferenceincaesarean
deliveriesbetweenwomenreceivingintracervicalandintravaginalPGE2. [15]
Summary:IntracervicalPGE2appearsmoreeffectivethanplaceboinachievingvaginaldeliverywithin24hours.
Oxytocin
OursearchidentifiedoneCochranesystematicreviewwhichincluded61trialswith12,819womenandevaluatedoxytocinfor
inductionoflabour. [16]Comparisonsweremadebetweenintravenous(IV)oxytocinversusplacebo/expectantmanagement(25
trials,6660women),IVoxytocinversusvaginalprostaglandin(PGE2)(27trials,4564women),IVoxytocinversusintracervical
prostaglandins(PGE2)(14trials,1331women),andIVoxytocinversusvaginalPGF2(3trials,291women). [16]
Threetrialsincluding399womenreportedthatIVoxytocin,whencomparedwithexpectantmanagement,reducedfailureto
achievevaginaldeliverywithin24hours(16/191versus112/208RR0.16,95%CI0.10to0.25NNT=3).Metaanalysisof24
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trialsincluding6620womenfoundasmallbutstatisticallysignificantincreasedrateofcaesareandeliveryforwomeninthe
oxytocingroup(339/3267versus301/3353RR1.17,95%CI1.01to1.35NNH=66).Therewasnosignificantdifferencein
uterinehyperstimulationwithorwithoutFHRchanges.Useofoxytocinsignificantlyreducedchorioamnionitis(14studies,5514
women144/2720versus213/2795RR0.69,95%CI0.57to0.85NNT=40)howevertherewassignificantheterogeneity
amongtheincludedtrialsforthiscomparison,(I 2=65%,P=0.001)andtheauthors'analysisofthestudiesincludedinthis
comparisonusingtherandomeffectsmethodwasnotstatisticallysignificant.Likewise,NICUadmissionswerereducedby
oxytocincomparedtoplaceboorexpectantmanagement,(7studies,4387women,264/2196versus333/2191RR0.79,95%
CI0.68to0.92,NNT=32).However,therewassignificantbetweenstudyheterogeneityforthiscomparison(I 2=70%,P=
0.0003)andthisresultwasnolongerstatisticallysignificantwhentherandomeffectsmethodwasusedforanalysis.The
majorityofthestudiesincludedinthesecomparisonsrequiredrupturedmembranesforentry,likelyinfluencingthisresult.Data
wereinsufficienttoestablishconclusionsregardingneonatalandmaternalmortalityorseriousmorbidity. [16]
Threetrialsincluding260womenreportedthatoxytocinwasassociatedwithmorefailurestoachievevaginaldeliverywithin24
hoursthanvaginalPGE2(73/132versus40/128RR1.77,95%CI1.31to2.38NNH=5).Whencomparingoxytocinwith
vaginalPGE2,therewasnosignificantdifferenceintheratesofcaesareansection(26trials,4514women,274/2259versus
246/2255RR1.11,95%CI0.94to1.30).Theincidenceofuterinehyperstimulationwithfetalheartrate(FHR)changeswas
verylowandnotdifferentbetweengroups.Fewerwomenreceivingoxytocindevelopedchorioamnionitisthanthosereceiving
vaginalPGE2(4trials,2742women,54/1381versus81/1361RR0.66,95%CI0.47to0.92,NNT=50).Datawere
insufficienttodrawconclusionsregardingneonatalandmaternalmortalityormorbiditybasedonlimiteddata,therewereno
differencesbetweengroups. [16]
Twostudiesthatincluded258womencomparingoxytocinwithintracervicalPGE2foundthatoxytocinwasassociatedwith
morefailuretoachievevaginaldeliverieswithin24hours(63/125versus46/133RR1.47,95%CI1.10to1.96NNH=7).
OxytocinwasassociatedwithmorecaesareandeliveriesthanintracervicalPGE2(14studies,1331women,123/643versus
94/688RR1.37,95%CI1.08to1.74NNH=20).TherewasnosignificantdifferenceinuterinehyperstimulationwithFHR
changes.Therewerenotenoughdatatodevelopconclusionsregardingneonatalandmaternalmortality/morbidity. [16]
Therewereonlythreetrialswith291womenthatcomparedoxytocinwithPGF2.Nonereportedonthenumberofwomen
failingtodelivervaginallywithin24hours.TherewerenosignificantdifferencesinuterinehyperstimulationwithFHRchanges
(onetrial23women)orratesofcaesareandelivery(3trials280women).Therewerenocasesofseriousneonatalmorbidityor
perinataldeathsinthetwostudiesthatreportedthisoutcome. [16]
UnfavorableCervixSubgroupComparedwithplaceboorexpectantmanagement,therewasnodifferenceincaesarean
deliveriesamongparticipantswithunfavorablecervices(13trials,1366women).Similarly,therewasnodifferenceincaesarean
deliveriesamong1041womenin15trialswithunfavorablecerviceswhoreceivedoxytocinorvaginalPGE2.However,oxytocin
usewasmorelikelytoresultincaesareandeliverythanintracervicalPGE2(10trials,1003women,107/477versus79/526,RR
1.44,95%CI,1.12to1.86,NNH=16). [16]
RandomisedControlledTrialsPublishedAftertheSearchDateofSystematicReviewsOursearchidentifiedonestudy
including240womenthatcomparedoxytocinwithvaginalprostaglandinE2forprematureruptureofmembranesatterm. [17]In
thisstudy,oxytocinwasassociatedwithasignificantlyshortertimefrominductiontodelivery(3.4+/1.5versus9.6+/4.7
hoursp=0.02).Therewasnodifferenceintheriskofcaesareansection. [17]
Summary:OxytocinismoreeffectivethanexpectantmanagementorplacebobutlesseffectivethanvaginalandcervicalPGE2
inbringingaboutvaginaldeliverywithin24hours.OxytocinresultedinmorecaesareandeliveriesthancervicalPGE2.
Amniotomy
WeidentifiedoneCochranesystematicreviewofamniotomyforinductionoflabour. [18]Thisreviewincludedtwostudieswith
310totalparticipants.Oneincludedstudycomparedwomenreceivingamniotomywiththosereceivingeitheroxytocinaloneor
nointervention.Thisstudywasunderpoweredtodetectdifferencesinanyoutcomeofinterestandthereviewconcludedthat
nomeaningfulresultscouldbedrawnfromthesecomparisons.Thesecondincludedstudycomparedamniotomyalonetoa
singledoseofvaginalprostaglandinsforwomenwithafavourablecervixandfoundasignificantincreaseintheneedfor
oxytocinaugmentationintheamniotomyalonegroupcomparedwiththewomenreceivingPGE2(260women,57/130versus
20/130RR2.85,95%CI1.82to4.46NNH=3).Therewasnodifferenceincaesareandeliveries. [18]
SubgroupWithunfavorablecervixTherewerenostudiesthatincludedparticipantswithunfavorablecervices.
[18]
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SubgroupWithunfavorablecervixTherewerenostudiesthatincludedparticipantswithunfavorablecervices. [18]
Summary:ComparedwithvaginalPGE2,amniotomyincreasestheneedforoxytocinaugmentation.
OxytocinWithAmniotomy
OursearchidentifiedoneCochranesystematicreviewincluding17trialswith2566womencomparingIVoxytocinplus
amniotomywithothermethodsforinductionoflabour. [19]Thisreviewcomparedamniotomyplusoxytocin(invaryingdoses),
withplacebo,vaginalprostaglandinE2orF2,oramniotomyalone.Oxytocinplusamniotomyresultedinfewercasesof
meconiumstainedamnioticfluidthanplaceboornotreatment(onetrial,184participants,3/92versus13/92RR0.23,95%CI
0.07to0.78NNT=9).Therewerenoothersignificantdifferencesinouroutcomesofinterestforthiscomparison. [19]
Whencomparedwithvaginalprostaglandins,amniotomyplusIVoxytocinwasassociatedwithmorepostpartumhemorrhage(2
studies,160women,11/80versus2/80RR5.5,CI1.26to24.07NNH=9).OneRCTof100subjectsfoundthatmore
womenweredissatisfiedwithamniotomyandIVoxytocinthanvaginalprostaglandins,(26/50versus0/50RR53,CI3.32to
846.51NNH=1).Therewerenoothersignificantdifferencesbetweenoxytocinplusamniotomyandvaginalprostaglandins. [19]
Onestudywith30participantscomparedoxytocinplusamniotomywithcervicalprostaglandins.Thisstudywastoosmallto
detectanydifferencesinoutcomesofinterest.Likewise,onlytwostudieswith309totalparticipantscomparedoxytocinplus
amniotomywithoxytocinalone.Thesestudieswerealsounderpoweredtodetectdifferencesinanyoutcomeofinterest. [19]
Whencomparedwiththosewhoreceivedamniotomyalone,fewerwomenwhoreceivedamniotomyplusIVoxytocinwerenot
deliveredvaginallyat24hours(2studies,296participants,3/148versus24/148RR0.13,95%CI0.04to0.41NNT=8).
AmniotomyplusIVoxytocinalsoresultedinsignificantlyfewerinstrumentalvaginaldeliveriesthanamniotomyalone(2studies,
510participants,57/255versus88/255RR0.65,CI0.49to0.85NNT=995%CI6to20). [19]
UnfavorableCervixSubgroupThereviewincludedtwotrialswith106womenwhohadcervicesunfavorableforinductionof
labor.Therewasnodifferenceincaesareanbirthamongwomenallocatedtoamniotomyandoxytocinversusvaginal
prostaglandins.Therewerenoothertrialsincludingwomenwithcervicesunfavorableforinduction. [19]
Summary:Oxytocinplusamniotomyismoreeffectivethanamniotomyaloneinachievingvaginaldeliverywithin24hours.
Oxytocinplusamniotomymaybeassociatedwithmorepostpartumhemorrhageandlessmaternalsatisfactionthanvaginal
prostaglandins.
VaginalMisoprostol
TheCochranereviewofvaginalmisoprostolforlabourinductionincluded121trials. [20]Therewerenosignificantdifferencein
vaginaldeliveriesnotachievedwith24hoursamongfivetrialswith769womenthatcomparedvaginalmisoprostolwith
placebo/notreatment.Likewise,infivetrialswith777women,therewerenosignificantdifferencesinhyperstimulationwith
FHRchanges.Comparedwithplacebo/notreatment,vaginalmisoprostolwasassociatedwithmorehyperstimulationwithout
FHRchanges(31/313versus10/481,6trials,794women,RR3.52,95%CI1.78to6.99,NNH=19)butwithlessmeconium
stainedamnioticfluid(6trials,814participants,27/326versus83/488,RR0.56,95%CI0.35to0.87,NNT=14)Vaginal
misoprostolreducedthenumberofparticipantswithacervixunfavorableorunchangedafter12to24hours(2studies107
women,4/56versus41/51,RR0.10,95%CI0.01to0.64,NNT=2).Therewasnodifferenceincaesareandeliveriesin10
trialsthatincluded1141women.
Twentytwotrialswith5,229participantscomparedvaginalmisoprostolwithothervaginalprostaglandinsfortheoutcomeof
vaginaldeliverieswithin24hours.Womenreceivingmisoprostolwerelesslikelytonotbedeliveredwithin24hours(22trials
5229participants,920/2550versus1179/2679,RR0.77,95%CI0.66to0.89,NNT=10)andwerelesslikelytorequire
oxytocinaugmentation(38trials,7022participants,1355/3465versus1794/3557,RR0.68,95%CI0.61to0.76,NNT=7).
Meconiumstainedamnioticfluidwasmorecommonamongsubjectsreceivingmisoprostol(18trials,3991women,246/1909
versus190/2082,RR1.35,95%CI1.13to1.61,NNH=32).MisoprostolincreaseduterinehyperstimulationwithoutFHR
changes(26trials4804women381/2311versus199/2493,RR1.99,95%CI1.41to2.79,NNH=13),although
hyperstimulationwithFHRchangesdidnotdiffer(31trials5830women).Vaginalmisoprostolreducedtheneedforoxytocin
augmentation(38trials,7022women,1355/3465versus1794/3557,RR0.68,95%CI0.61to0.76,NNT=7)andepidural
anesthesia(8trials,2141women,469/1063versus516/1078,RR0.9295%CI0.85to0.99,NNH=27).Caesareansection
rateswerenotsignificantlydifferent. [20]
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rateswerenotsignificantlydifferent. [20]
ComparedwithcervicalPGE2,vaginalmisoprostolreducedfailuretoachievevaginaldeliverywithin24hours(13trials,1627
women,253/814versus402/813,RR0.63,95%CI0.56to0.71,NNT=6).Oxytocinaugmentationwasrequiredlessoften
withmisoprostolbasedon20trialsincluding2316women,(411/1177versus727/1139,RR0.55,95%CI,0.48to0.64NNT=
4)andwomenreceivingmisoprostolwerelesslikelytohaveacervixunfavorableforinductionafter1224hours(1trial,155
women,38/76versus58/79,RR0.68,95%CI0.52to0.88,NNT=5).Womenreceivingmisoprostolwerelesslikelytorequire
epiduralanesthesia(2trials,321women,48/160versus75/161,RR0.64,95%CI0.48to0.86,NNT=6).Misoprostolresulted
inmoreuterinehyperstimulationwithFHRchanges(20trials,2224women,98/1129versus39/1095,RR2.32,95%CI1.64
to3.28,NNH=22)andwithoutFHRchanges(17trials2178women,194/1097versus96/1081,RR1.95,95%CI1.57to2.42,
NNH=12).Increasedratesofmeconiumstainedamnioticfluidwereobservedwithuseofmisoprostol(14trials2018women,
161/1015versus123/1003,RR1.29,95%CI1.04to1.59,NNH=29).Therewerenootherstatisticallysignificantdifferencesin
perinatalormaternaloutcomes. [20]
Comparedwithoxytocin,vaginalmisoprostolreducedthelikelihoodofparticipantsnotbeingdeliveredvaginallywithin24hours
(10trials,1397women,135/690versus226/707,RR0.6595%CI.47to0.90,NNT=9).Vaginalmisoprostolwasassociated
withincreaseduterinehyperstimulationwithFHRchanges(9trialswith1419women49/690versus28/729,RR1.87,95%CI
1.20to2.91,NNH=31)andwithoutFHRchanges(15trials2050women,218/1009versus102/1041,RR2.24,95%CI1.82
to2.77,NNH=9).Womenreceivingmisoprostolweremorelikelytoexperiencegastrointestinalsideeffectsthanthose
receivingoxytocin(4trials334women,15/170versus2/164,RR5.04,95%CI1.51to16.86,NNH=21)Caesareandeliveries
werelesslikelyamongwomenreceivingvaginalmisoprostol(25trials3074women,258/1527versus364/1547,RR0.7695%
CI0.60to0.96,NNT=18)aswereinstrumentalvaginaldeliveries(13trials,1639women,69/810versus96/829,RR0.74
95%CI0.56to0.99,NNT=34).InfantsborntowomenreceivingmisoprostolwerelesslikelytohaveApgarscore<7at5
minutesoflife(13trials,1906women,22/938versus41/968,RR0.56,95%CI0.34to0.92,NNT=54).Therewereno
differencesinothermaternalorfetaloutcomesofinterest. [20]
UnfavorableCervixSubgroupComparedwithplacebo,therewasnodifferenceincaesareandeliveriesforwomenreceiving
vaginalmisoprostol(7trials,862women).Therewasnodifferenceinthelikelihoodofcaesareandeliveriesamongwomen
receivingmisoprostolorwomenreceivingvaginalPGE2(28trials,5832women),cervicalPGE2(21trials,2499women)or
oxytocin(14trials,1598women). [20]
Summary:Vaginalmisoprostolismorelikelytoresultinvaginaldeliverywithin24hoursthanvaginalorcervicalPGE2or
oxytocinbutisassociatedwithincreaseduterinehyperstimulation.ComparedwithIVoxytocin,vaginalmisoprostolmayreduce
thelikelihoodofcaesareandelivery.
OralMisoprostol
TheCochranereviewoforalmisoprostolcomparedtoothermethodsoflabourinductionincluded56RCTswithatotalof
11,590participants. [21]Therewereseventrialswith669womenthatcomparedoralmisoprostoltoplacebo.Womenassigned
toreceiveoralmisoprostolweremorelikelytogivebirthvaginallywithin24hours(1trial,96women,3/47versus20/49RR
0.16,CI0.05to0.49NNT=3).Oralmisoprostolwasalsoassociatedwithlowercaesareansectionratesthanplacebo(six
trials,629women,31/312versus51/317RR0.61,95%CI0.41to0.93NNT=16).Fewerwomenreceivingoralmisoprostol
requiredoxytocinaugmentation(6trials,535subjects,63/266versus181/269RR0.35,95%CI0.28to0.44NNT=3). [21]
Tentrialswithatotalof3368womencomparedoralmisoprostolwithvaginalPGE2.Fewerwomenassignedtoreceiveoral
misoprostolrequiredcaesareandelivery(10trials,3368participants,340/1599versus467/1769RR0.87,95%CI0.77to0.98
NNT=30).Intwotrialsincluding930subjects,morewomenassignedtooralmisoprostolhadanunfavourablecervixafter24
hours(74/470versus51/460RR1.41,95%CI1.01to1.96NNH=22).Therewerenostatisticallysignificantdifferences
betweenthegroupsinanyoftheotheroutcomes,includinghyperstimulationwithandwithoutFHRchangesandthefrequency
ofmeconiumstainedamnioticfluid.Therewassignificantheterogeneity(P=0.002)amongstudiescomparingoralmisoprostol
andvaginalPGE2fortheoutcomeofuterinehyperstimulationwithoutFHRchanges,likelyrelatedtothedifferingdosesoforal
misoprostolusedintheincludedstudies. [21]
Fourtrialswith681womencomparedoralmisoprostoltointracervicalPGE2.Fewerwomenassignedtooralmisoprostolgroup
failedtodelivervaginallywithin24hours,althoughthisfindingwasofborderlinestatisticalsignificance(2trials,391
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participants,81/196versus100/195RR0.81,95%CI0.651.00NNT=11).Oralmisoprostolwasassociatedwithmore
uterinehyperstimulationwithFHRchanges(3trials,490women,12/245versus3/245RR3.57,95%CI1.11to11.54NNH=
32).TherewasatrendofborderlinesignificancetowardmorehyperstimulationwithoutFHRchangeswithoralmisoprostol(1
trial,190women,8/95versus0/95RR17.01,95%CI1.00to290.42).Therewerenodifferencesinanyotheroutcomeof
interest. [21]
Eighttrialsincluding1026womencomparedoralmisoprostolwithIVoxytocin.Meconiumstainingoftheamnioticfluidwas
seenmorefrequentlyinthemisoprostolgroup(6trials,916women,47/477versus24/439RR1.72,95%CI1.08to2.74
NNH=26),butoralmisoprostolwasnotassociatedwithanyotherdifferencesinadversefetal,neonatalormaternaloutcomes.
[21]
Twentysixtrialswith5096participantscomparedoralwithvaginalmisoprostol.Theoralrouteofadministrationwasassociated
withmorefrequentuseofoxytocin(22trials,4557women,1301/2279versus1151/2278RR1.19,95%CI1.06to1.34NNH
=11),buttherewasnodifferenceinvaginaldeliverywithin24hours.Thereweresignificantlylowerratesofuterine
hyperstimulationwithoutFHRchangeswithoralregimens(9trials,1420women,85/698versus146/722RR0.58,95%CI
0.35to0.96NNT=12),buttherateofhyperstimulationwithFHRchangeswasnotdifferentbetweenthetwogroups.Fewer
babiesborntomotherswhoreceivedoralmisoprostolhadApgarscoreslessthan7atfiveminutesoflife(14trials,3270
women37/1638versus57/1632RR0.65,95%CI0.44to0.97NNT=82).Therewasnodifferenceincaesareandeliveriesin
25trialswith5096women. [21]
UnfavorableCervixSubgroupTherewerenostudiescomparingoralmisoprostolwithplacebo,vaginalPGE2,intracervical
PGE2,oroxytocinthatreportedoncaesareandeliveriesamongwomenwithunfavorablecervices.Amongwomenwith
unfavorablecerviceswhowererandomizedtoreceiveoralmisoprostolorvaginalmisoprostoltherewerenodifferencesin
caesareandeliveriesamongprimiparous(2studies,85participants)ormultiparous(1study,24participants)subjects. [21]
RandomisedControlledTrialsPublishedAftertheSearchDateofSystematicReviewsSubsequenttothesearchdateof
theCochranereview,weidentifiedonestudywith87participantsthatcomparedoralmisoprostolwithplacebo. [22]Thisstudy
foundoralmisoprostolsuperiortoplaceboinachievingdeliverywithin24hours(19/43versus6/44,P=0.024,NNT=4).An
additionalstudythatcomparedoralmisoprostolwithPGE2foundthatmorewomenreceivingmisoprostoldeliveredvaginally
within12hours,althoughvaginaldeliverieswithin24hoursdidnotdiffer. [23]Morewomenreceivingoralmisoprostolwere
satisfiedwiththeirinductionmethod. [23]
Summary:OralmisoprostolreducedcaesareansectionscomparedwithvaginalPGE2andplacebo.Comparedwithvaginal
misoprostol,oralmisoprostolisassociatedwithfewercontractileabnormalities,butmoreneedforoxytocinaugmentation.
BuccalorSublingualMisoprostol
Oursearchuncoveredthreesystematicreviewscomparingsublingualorbuccalmisoprostolwithothermethodsoflabour
induction. [2426]TheCochranereviewbyMuzonzini[24]andcolleaguesandthereviewbyBartuseviciusandcolleagues[25]both
includedthesamethreestudieswithatotalof507womenandreachedsimilarconclusions.Twoofthestudieswithatotalof
350womencomparedbuccalorsublingualmisoprostol(50g)tooralmisoprostol(50or100g)andonestudywith157
participantscomparedbuccalandvaginalmisoprostol.Neitherreviewfoundsignificantdifferencesinanyoutcomeofinterest.
[2425]
UnfavorableCervixSubgroupTheCochranereviewersdidnotconductanysubgroupanalysesaccordingtocervicalstatus.
[24]
Othersystematicreviews
In2008Souzaandcolleaguespublishedasystematicreviewofstudiescomparingsublingualorbuccalmisoprostolwithvaginal
misoprostolforinductionoflabour.Thisreviewincludedfivestudieswith740subjects. [26]Theauthorsfoundnosignificant
differencesintheratesofvaginaldeliverynotachievedwithin24hours,hyperstimulation,orcesareandeliveries.Therewere
morecasesofuterinetachysystole,definedasmorethanfivecontractionsin10minutesforatleast20minutes,among
womenassignedtosublingualmisoprostol(5trials,740women,42/368versus26/372OR1.70,95%CI1.02to2.83NNH=
24,95%CI10to771),althoughtherewassignificantheterogeneityamongstudiesincludedinthiscomparison(P=0.04). [26]
RandomisedControlledTrialsPublishedAftertheSearchDateofSystematicReviewsOursearchidentifiedtwo
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additionalstudiescarriedoutsubsequenttothesearchdatesofthesesystematicreviews.Oneofthesestudiescompared
sublingualmisoprostol50gwithamniotomyandoxytocinforinductionoflabouramong50womenattermwithfavourable
cervices. [27]Thisstudywasterminatedearlywhenaninterimanalysisrevealedthatsignificantlyfewerwomenallocatedto
sublingualmisoprostoldeliveredwithin24hours(15/22versus21/21RR0.68,95%CI0.51to0.91NNH=3).Therewereno
differencesinothermaternalorfetaloutcomes,althoughmaternalsatisfactionwassignificantlyhigherwithsublingual
misoprostol.Thesecondstudyincluded150womenandcompared50gmisoprosolbyoral,vaginal,orsublingualroutes. [28]
Thisstudyfoundthattheinductiontodeliveryintervalwassignificantlydecreasedamongwomenreceivingsublingual
misoprostolcomparedwiththevaginalandoralroutes(13.3hoursversus16.1hours[oral]versus15.1hours[vaginal]).Fewer
babiesborntomothersreceivingsublingualmisoprostolhadApgarscoreslessthansevenatoneminute(0/50versus6/100,P
=0.003,NNT=17). [28]
Summary:Comparedwithvaginalmisoprostol,administrationofmisoprostolbythebuccalorsublingualrouteincreasesuterine
tachysystole.
MechanicalMethods
Oursearchidentifiedthreesystematicreviewsevaluatingmechanicalmethodsforinductionoflabour.TheCochranereview
studiedmechanicalmethodsincludinglaminariatents,syntheticequivalentssuchasDilapan,Foleycatheters,andothertypes
ofballooncatheterforinductionoflabour.Itincluded45RCTsthatcomparedmechanicalmethodswithPGE2,misoprostol,
oxytocin,andplacebo.Mosttrialshadsmallsamplesizes. [29]
Theauthorsdidnotfindanyadvantageofmechanicalmethodscomparedwithplaceboornotreatmentintheprespecified
outcomesofvaginaldeliverynotachievedwithin24hoursorcaesareandeliveries(1trial,48women).Therewasnodifference
incaesareandeliveriesbetweenwomenreceivingmechanicalmethodsandwomenreceivingplaceboornotreatment(6
studies,416participants).Therewasnodifferenceinanyotheroutcomeofinterest,includingchorioamnionitis(1trial,240
participants)andendometritis(2trials,288participants). [29]
Moresubjectsallocatedtomechanicalmethodsfailedtodelivervaginallywithin24hoursthanthoseassignedtovaginalPGE2
(1trial,109participants,43/59versus21/50,RR1.74,CI1.21to2.49NNH=3),andmorewomenallocatedtomechanical
methodsrequiredoxytocinaugmentation(2trials,169women,30/89versus9/80,RR2.90,95%CI1.40to6.00,NNH=5),
althoughthisfindingshouldbeinterpretedwithcaution,astherewassignificantheterogeneitybetweenthe2studiesincluded
inthiscomparison(P=0.0008).MechanicalmethodswerelesslikelytoresultinuterinehyperstimulationwithFHRchangesin
6trialswith484women,(0/246versus14/238,RR0.14,95%CI0.04to0.53,NNT=20)andwithoutFHRchangesin8trials
with580women(6/293vs28/287,RR0.26,95%CI0.13to0.54,NNT=14).Therewasnodifferenceincaesareandeliveries
betweenmechanicalmethodsandvaginalPGE2(12trials,786women),butmechanicalmethodswereassociatedwith
reducedneedforinstrumentalvaginaldeliveries(5trials,378women,36/192versus53/186,RR0.65,95%CI0.46to0.93,
NNT=11). [29]
Morewomenassignedtomechanicalmethodsdidnotachievevaginaldeliverywithin24hoursthanthoseassignedtocervical
PGE2(1trial,100participants,34/50versus20/50RR1.70,CI1.15to2.50NNH=3),andmorewomenallocatedto
mechanicalmethodsrequiredoxytocinaugmentation(1trial,185women,84/90versus63/95,RR1.41,95%CI1.21to1.64,
NNH=3).However,therewasnodifferenceincaesareansectionsin12trialsthatincluded1614women.Comparedwith
cervicalPGE2,mechanicalmethodswereassociatedwithlessendometritis(4trials,693participants,9/352versus34/341RR
0.26,95%CI0.13to0.52,NNT=14).However,in3studieswith619womenthatcomparedmechanicalmethodstocervical
PGE2,thereweremoreneonatalinfectionsinbabiesborntomotherswhohadreceivedmechanicalmethodscomparedto
cervicalPGE2(24/316versus9/303,RR2.4595%CI1.18,to5.07,NNH=24). [29]
Analysisoffourstudieswith198womencomparingmechanicalmethodswithoxytocinfoundthatmechanicalmethodsresulted
infewercaesareandeliveries(18/103versus30/95RR0.55,95%CI0.33to0.91NNT=8).Therewasnodifferencein
hyperstimulationwithoutFHRchanges,postpartumhemorrhage,orseriousmaternalmorbidityordeathin1trialwith60
women.Nootheroutcomescouldbeevaluatedforthiscomparison. [29]
Fourstudiesincluding618womencomparedmechanicalmethodstovaginalmisoprostol.Therewerenostatisticaldifferences
inthelikelihoodofachievingvaginaldeliverywithin24hours(2studies,234women)orincaesareandeliveries(4studies,618
women).TherewasreducedriskforuterinehyperstimulationwithFHRchangesseeninthreetrialsincluding434women
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comparingmechanicalmethodstovaginalmisoprostol(8/226versus19/208RR0.41,CI0.20to0.87NNT=19).Therewere
nodifferencesnotedininfectiousmorbidityorneonataloutcomes. [29]
UnfavorableCervixSubgroupTherewasnodifferenceincaesareandeliveriesamong396womenenrolledinfive
randomizedcontrolledtrialscomparingmechanicalmethodswithplaceboornotreatment,in10trialswith738women
comparingmechanicalmethodswithvaginalPGE2orin12trialswith1614womencomparingmechanicalmethodswith
intracervicalPGE2.Therewasnodifferenceincesareansectionsinthreetrialswith482participantscomparingmechanical
methodswithvaginalmisoprostol.Inthesubgroupofwomenwithunfavorablecervices,mechanicalmethodswerelesslikelyto
resultincaesareandeliverythanoxytocin(3trials,178women,15/93versus27/85,RR0.50,95%CI,0.29to0.87,NNT=7).
[29]
OtherSystematicReviewsOursearchidentifiedasecondsystematicreviewthatcomparedmechanicalmethodsoflabour
inductionwithPGE2,misoprostol,hyaluronidaseorplacebo. [30]Thissystematicreview,whichincluded30randomised,
controlledtrialswithatotalof4468participants,focusedontheoutcomesofmaternalandneonatalinfectiousmorbidity.The
authorsdefinedmaternalinfectiousmorbidityasmaternaltemperaturegreaterthan38C,endometritisorchorioamnionitis.
Theydefinedneonatalinfectiousmorbidityasfever,suspectedorprovensepsis,orneedforantibiotics.Controlswerethe
pooledgroupofwomenwhohadreceivedotherpharmacologicmethodsoflabourinduction.Comparedwithcontrols,women
undergoinglabourinductionwithmechanicalmethodsweremorelikelytoexperienceinfectiousmorbidity(30studies,4468
participants,252/2220versus188/2248OR1.38,95%CI1.12to1.68NNH=36).Theauthorsreportednosignificant
heterogeneityforthiscomparison.Similarly,infantsborntomothersundergoingmechanicalmethodsofinductionweremore
likelytoexperienceneonatalinfectiousmorbiditythaninfantsborntomothersundergoinginductionwithpharmacologic
methods(8trials,1775women,40/893versus18/882OR2.03,95%CI1.19to3.51NNH=50).Theauthorsreportedthat
therewasnosignificantheterogeneityforthiscomparison. [30]
Athirdsystematicreviewcomparedmechanicalmethods(Foleycatheterballoon)withlocallyappliedprostaglandins(vaginal
PGE2,cervicalPGE2andvaginalmisoprostol). [31]Thissystematicreviewincluded27randomizedcontrolledtrialsthat
included3532participants.Whencomparedwithalllocallyappliedprostaglandins(LAPG)combined,therewerenodifferences
betweenmechanicalmethodsandprostaglandinsincaesareandeliveries(27trial,3532participants),participantswithcervices
thatwereunfavorableorunchangedafter12to24hours(6trials,613participants),ripeningtodeliveryinterval(13trials,1270
participants),vaginaldeliverieswithin12to24hours(13trials,1779women),maternalfevers(19trials,2421women),5
minuteApgarscoreslessthan7(14trials,1661women),meconiumstaining(13trials1841women),oradmissionofthe
neonatetoaNICU(12trials,1796women).WomenwhoreceivedLAPGwerelesslikelytorequireoxytocinaugmentationthan
thosereceivingmechanicalmethods(16trials,1644participants,RR0.73,95%CI0.62to0.86,P=0.0002),butweremore
likelytoexperienceexcessiveuterineactivity,definedastachysystole,hypertonus,orhyperstimulationsyndrome(21trials,
2661participants,244/1306versus147/1355,RR,2.3595%CI,1.41to3.90P=.001,NNHforlocallyappliedprostaglandins
whencomparedwithmechanicalmethods=7).Therewassignificantheterogeneitynotedfortheoutcomesofexcessive
uterineactivity,vaginaldeliverywithin1224hours,andforneedforoxytocinaugmentation. [31]
TheauthorsconductedsubgroupanalysescomparingmechanicalmethodswithvaginalPGE2,cervicalPGE2,andvaginal
misoprostol.Theyfoundthatmechanicalmethodswereassociatedwithalongerripeningtodeliveryintervalthancervical
PGE2(5trials,552subjects,weightedmeandifference[WMD]5.48hours,95%CI2.79to8.16,P<0.0001)andvaginal
PGE2(2trials,118subjects,WMD,4.55hours,95%CI,0.33to8.77P=.03).CervicalPGE2wasassociatedwithahigher
riskforcaesareandeliveriesthanmechanicalmethodsinseventrialswith896women(OR1.27,95%CI1.01to1.59,P=
0.04).VaginalmisoprostolwasassociatedwithincreasedriskforexcessiveuterineactivitycomparedwithFoleyballoonin13
trialswith1847participants,RR3.41,95%CI,1.97to5.90P=0.0001). [31]
RandomisedControlledTrialsPublishedAftertheSearchDateofSystematicReviewsWeincludedoneadditionaltrial
thatwaspublishedsubsequenttothesearchdateofthethirdsystematicreview. [32]Thistrialrandomlyassigned240womento
receivevaginalmisoprostol25goraFoleycatheterforlaborinduction.ThisstudyfoundthattheFoleycatheterwas
associatedwithalongerinductiontovaginaldeliveryintervalthanthevaginalmisoprostol(20.2hoursversus17.3hours,P=
0.016).Therewerenosignificantdifferencesinotheroutcomesofinterest. [32]
Summary:MechanicalmethodsarelesslikelytoresultinuterinehyperstimulationthanPGE2orvaginalmisoprostol,butmay
beassociatedwithincreasedmaternalandneonatalinfectiousmorbidity.
MembraneSweeping
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OursearchidentifiedoneCochranesystematicreviewof22trialswhichincluded2797subjectsthatcomparedmembrane
sweepingwithoxytocin,PGE2,ornotreatment. [33]Therewasnodifferenceinratesofcaesareandeliveries,seriousneonatal
morbidity,perinataldeath,seriousmaternalorneonatalinfectionswhencomparingmembranesweepingwithnotreatment.A
policyofroutinemembranesweepingfrom37weeksonwardreducedthelikelihoodofgestationcontinuingtoboth41(6
studies,937women,77/473versus129/464RR0.59,95%CI0.46to0.74NNT=9)and42(6studies,722women,12/365
versus43/357RR0.28,95%CI0.15to0.50NNT=12)weeks'gestation.Membranesweepingwasassociatedwithreduced
likelihoodofnotbeinginlabourwithin48hours(fivestudies,726women,234/367versus298/359RR0.77,95%CI0.70to
0.84NNT=6).Membranesweepingwasalsoassociatedwithreducedriskfornotbeingdeliveredwithinoneweek(9studies,
1375women,320/695versus440/680RR0.71,95%CI0.65to0.78NNT=6).Membranesweepingwasassociatedwith
morevaginalbleeding(3trials,391women,35/200versus18/191RR1.75,95%CI1.08to2.83NNH=15)andmore
maternaldiscomfort(2studies,320women,94/163versus32/157RR2.83,95%CI2.03to3.96NNH=3)comparedwithno
treatment.DatacomparingmembranesweepingwithPGE2andwithoxytocinwereinsufficienttodrawconclusionsofrelative
efficacy. [33]
UnfavorableCervixSubgroupTherewasnodifferenceincaesareansectionsamongwomenallocatedtomembrane
sweepingversusnotreatment(3trials,200women)norintwotrialswith252womencomparingmembranesweepingwith
vaginalprostaglandinsnorinonetrialwith69womencomparingmembranesweepingwithoxytocin. [33]
RandomisedControlledTrialsPublishedAftertheSearchDateofSystematicReviewsorAwaitingClassification
AmongthestudiesawaitingclassificationintheCochranereviewwerefivehighqualityRCTs. [3438]Inaddition,weidentified
oneadditionalhighqualityRCTthatwaspublishedaftertheCochranereview'ssearchdate. [39]Ofthese,fivestudieswith1700
participantscomparedmembranesweepingwithnotreatmentorvaginalexamalone. [3539]Inametaanalysisthataddedour
independentlyextracteddatafromthetwostudies[36,37]thatevaluatingtheeffectofmembranesweepingonpostterm
gestationstothedatareportedintheCochranereview,membranesweepingsignificantlydecreasedthenumberofpregnancies
progressingto42weeks'gestation(8studies,1874participants,102/902versus194/862,RR0.53,95%CI0.43to0.65,NNT
=10).Therewasnosignificantheterogeneityforthiscomparison.Thustheadditionofthesetwonewtrialsdidnotalterthe
conclusionreachedbytheCochranereview.
DeMirandafoundthatmembranesweepingsignificantlyreducedthetimefromrandomizationtodeliverybyoneday(3.50
versus4.47days,meandifference0.97days95%CI0.60to1.35). [36]Inamorerecentstudyinvolving351women,Yildirim
andcolleaguesfoundthatmembranesweepingsignificantlyincreasedthelikelihoodofspontaneouslaborby41weeks'
gestation(162/179versus118/167,P=0.0001). [38]Bycontrast,Hamdanfoundthatmembranesweepingdidnotincreasethe
proportionofwomenplanningtrialoflaborafterpriorcesareansection(TOLAC)whoenteredspontaneouslabor. [39]TheHill
studywasdesignedtotestwhethermembranesweepingincreasesprelabourruptureofmembranes,butfoundnooverall
differenceinthisoutcome. [37]Onestudywith60participantscomparedmembranesweepingwithasingledoseofintracervical
PGE2. [34]UseofcervicalPGE2resultedinasignificantlyshorterinterventiontodeliveryintervalthandidmembranesweeping
(26.23hoursversus19.15hours,P<0.01). [34]
Summary:Membranesweepingreducestheriskofposttermgestation.
ComplementaryandAlternativeMedicineMethods
CastorOil
Oursearchidentifiedonesystematicreviewoftheefficacyofcastoroilforinductionoflabour. [40]TheauthorsofthisCochrane
reviewidentifiedonlyonestudywith100subjectscomparingcastoroilwithnotreatment.Thetrialwasjudgedtobeofpoor
methodologicqualityduetomethodsofallocation.Therewerenoobserveddifferencesinratesofcaesareandelivery,
meconiumstainedfluid,orApgarlessthan7atfiveminutes.Morewomenreceivingcastoroilreportedexperiencingnausea
(52/52versus0/48RR97.08,95%CI6.16to150.34NNH=1). [40]
UnfavorableCervixSubgroupInonetrialwith100women,therewasnodifferenceincaesareandeliveriesbetweenwomen
whoreceivedcastoroilornotreatment. [40]
Summary:Comparedwithnotreatment,castoroilisassociatedwithincreasedmaternalsideeffects.
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Acupuncture
OursearchidentifiedaCochranesystematicreviewthatincluded3trialswith212womenthatfocusedonacupuncturefor
inductionoflabour. [41]Comparedwithstandardcare(oxytocin,prostaglandins,or"routinecare"),morewomenundergoing
acupuncturedidnotrequiretheuseofotherinductionmethods(2trials,147women,49/73versus34/74RR1.45,95%CI
1.08to1.95NNT=5).Nodifferenceswerefoundintimetodelivery,ratesofcaesareandelivery,instrumentalvaginaldelivery,
orepiduralanesthesia.Fetalorneonataloutcomeswerenotestimable. [41]
UnfavorableCervixSubgroupTherewasnodataintheincludedtrialsconcerningtheeffectofacupunctureforlabor
inductioninwomenwithunfavorablecervices. [41]
RandomisedControlledTrialsPublishedAftertheSearchDateofSystematicReviewsWeidentifiedthreefurthertrials
with684participants,threepublishedafterthesearchdateofthesystematicreview[4244]andonethatwasnotidentifiedby
theCochranesearch. [45]Thesestudiesdidnotrevealanydifferencesbetweenacupunctureandplaceboornotreatmentinany
outcomeofinterest.
Summary:Theuseofacupunctureforinductionoflabourisinvestigationalnoadvantagesforthismethodhavebeen
demonstrated.
BreastStimulation
Oursearchidentifiedonesystematicreviewthatcombinedsixstudieswith719subjectsthatevaluatedbreaststimulationfor
labourinduction. [46]Therewerenodifferencesincesareandeliveries,meconiumstaining,oruterinehyperstimulationwhen
comparingbreaststimulationwithnotreatment.Breaststimulationdecreasedthenumberofwomenwhowerenotinlabour
within72hours(4studies,437women,136/217versus206/220RR0.67,95%CI0.60to0.74NNT=4).Breaststimulation
wasassociatedwithlesspostpartumhemorrhage(2studies,300women,1/150versus9/150RR0.16,95%CI0.03to0.87
NNT=20).Thereweremoreperinataldeathsamongpregnanciesassignedtobreaststimulationthantonotreatment,
althoughthisdifferencewasnotstatisticallysignificant(3studies,337participants,3/167versus0/170RR8.17,95%CI0.45
to147.8).Thisresultshouldbeinterpretedwithcaution,asallofthedeathsoccurredinasingletrialconductedamonghigh
riskwomeninadevelopingcountry. [46]
Twostudieswithatotalof99subjectscomparedbreaststimulationwithoxytocin.Therewerenodifferencesincaesarean
deliveries.Inonetrialwith37women,morewomenassignedtobreaststimulationwerenotinlabourwithin72hours
comparedwiththosewhowereallocatedtotheoxytocingroup,althoughthisdifferencewasofborderlinestatisticalsignificance
(10/17versus5/20RR2.35,95%CI1.00to5.54).Therewerenodifferencesinuterinehyperstimulationormeconium
staining.Therewerethreeperinataldeathsinthebreaststimulationgroupversusoneintheoxytocingroup,anonsignificant
difference.Alldeathswerefromthesametrialconductedamonghighriskwomeninadevelopingworldsetting. [46]
UnfavorableCervixSubgroupTherewasnoinformationoncesareandeliveriesintheoneincludedtrialthatincludedwomen
withunfavorablecervices. [46]
Summary:Breaststimulationmayreducethenumberofwomennotinlabourwithin72hourscomparedtonotreatmentbutis
lesseffectivethanoxytocinforthisoutcome.Moreresearchisneededtoevaluatethesafetyofbreaststimulation.
Intercourse
TheCochranereviewofintercourseforinductionoflabourincludedonestudywith28subjects. [47]Participantswereassigned
tohaveintercoursenightlyforthreenightsversusnointercourse.Therewerenodifferencesindeliverywithinthreedaysorfive
minuteApgarlessthanseven. [47]
UnfavorableCervixSubgroupTherewasnoinformationoncervicalstatusorcesareandeliveriesintheoneincludedstudy.
[47]
Summary:Thereisnotenoughevidencetoevaluatetheefficacyandsafetyofintercourseforinductionoflabour.
HomeopathicMethods
Oursearchidentifiedonesystematicreviewoftwostudieswith133participantsthatcomparedhomeopathicherbsforlabour
inductionwithplacebo. [48]OnlyoneofthestudiesincludedintheCochranereviewreportedontheprespecifiedclinical
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inductionwithplacebo. [48]OnlyoneofthestudiesincludedintheCochranereviewreportedontheprespecifiedclinical
outcomesofinterest.Thatstudyincluded40subjectsandreportednodifferenceinratesofvaginaldeliverynotachievedwith
24hours,caesareandeliveries,operativevaginaldelivery,needforoxytocinaugmentationoflabour,orlengthoflabour. [48]
UnfavorableCervixSubgroupTherewasnoinformationintheincludedstudyoncervicalstatus. [48]
Summary:Thereisnotenoughevidencetoevaluatetherisksandbenefitsofhomeopathyforinductionoflabour.
HypnoticRelaxation
Weidentifiedonequasirandomisedstudyofhypnoticrelaxationforinductionoflabourinposttermpregnancies. [49]Forty
womenwereassignedtohypnoticrelaxationandanequalnumbertonointerventionbasedonalternatedaysoftheweek.
Controlswerealsochosenbasedonthebaselinecharacteristicsofparity,gestationalage,andcervicalstatus.Therewereno
differencesindeliverywithin24hoursortimetodelivery.Theauthorsdidnotreportanyotheroutcomes. [49]
UnfavorableCervixSubgroupTherewasnoinformationontheeffectofhypnoticrelaxationamongwomenwithunfavorable
cervices. [49]
Summary:Comparedtonointervention,hypnoticrelaxationdidnotaffectlikelihoodofdeliverywithin24hours.Datawere
insufficienttoevaluateanyotheroutcome.
InvestigationalMethods
ExtraamnioticProstaglandins
Extraamnioticplacementofprostaglandinshasbeenstudiedasacombinationofamechanicalmethod(Foleycatheter)witha
pharmacologicmethod(prostaglandins). [50]Theprostaglandinisintroducedintotheextraamnioticspaceviathecatheter.Our
searchidentifiedonesystematicreviewcomparingextraamnioticprostaglandinswithothermethodsforinductionoflabour.
Thisreviewincluded12studieswhichcomparedextraamnioticPGE2orPGF2withextraamnioticplacebo,vaginal
prostaglandins,intracervicalprostaglandins,IVoxytocin,vaginalmisoprostol,ormechanicalmethods.Becauseofthewide
varietyofcomparisons,withfewerthan200participantsineachoftheindividualcomparisons,evaluationofthismodality
comparedtoothermethodswaslimited.ThreeRCTswith167womencomparedextraamnioticprostaglandinswithplacebo.
Womenreceivingextraamnioticprostaglandinswerelesslikelytorequireoxytocinaugmentation(34/84versus66/83RR0.51,
95%CI0.39to0.67NNT=3).ExtraamnioticPGE2reducedthelikelihoodofcervixunfavourableforinductionafter12to24
hourscomparedwithFoleycatheteralone(1trial,187participants,27/90versus49/97RR0.59,95%CI0.410.86NNT=5).
[50]
TheauthorsfoundthatwomenallocatedtoextraamnioticF2prostaglandinsweremorelikelytobenotvaginallydelivered
within24hoursthanwomenreceivingvaginalmisoprostol(1trial,152women,34/76versus14/76,RR2.4395%CI1.42to
4.15NNH=3).WomenweremorelikelytobesatisfiedwithextraamnioticprostaglandinscomparedwithvaginalPGE2(1
trial,62women,meandifference4.40,95%CI3.50to5.30).Evaluationofothermaternalandfetaloutcomeswaslimiteddue
tothesmallnumbersofincludedwomenandmanydifferenttypesofcomparison. [50]
UnfavorableCervixSubgroupTherewasnodifferenceincaesareandeliveriesamongwomenreceivingextraamnioticPGE2
versusextraamnioticplacebo(2trials,60participants)norbetweenwomenreceivingextraamnioticPGF2andextraamniotic
placebo(1trial,25participants).Therewasnodifferenceincaesareansectionsbetweenwomenreceivingextraamniotic
PGE2andvaginalPGE2(3trialswith142women),orbetweenwomenreceivingextraamnioticPGE2andintracervicalPGE2
(1trial194women).Onetrialwith30participantswithunfavorablecervicesfoundnodifferenceincaesareandeliveries
betweenwomenreceivingextraamnioticPGE2andoxytocin.Inonetrialwith77womentherewasnodifferenceincaesarean
sectionsbetweenwomenreceivinganintracervicalFoleycatheterandextraamnioticPGE2.Therewasnodataforcomparison
ofvaginalororalmisoprostolwithextraamnioticPGE2amongwomenwithunfavorablecervices. [50]
Summary:Dataareinsufficienttorecommendextraamnioticprostaglandins.
IntravenousProstaglandins
Inthe1970sand1980s,IVprostaglandinswereinvestigatedasapotentialoptionforinductionoflabour. [51]Oursearch
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identifiedonesystematicreviewcomparingIVprostaglandins(PGE 2orIVPGF2)withoxytocin.ThisCochranereview
includedthirteentrials,withatotalof1165women,whichwerecarriedoutbetween1970and1987.ComparedwithIV
oxytocin,theuseofIVprostaglandinwasassociatedwithhigherratesofuterinehyperstimulationbothwithFHRchanges(5
trials,390women,9/199versus0/191RR6.76,95%CI1.23to37.11,NNH=notestimable)andwithoutFHRchanges(5
trials318women,17/159versus4/159RR4.25,95%CI1.48to12.24,NNH=13).However,therewasnodifferencein
caesareandeliveries.Maternalsideeffects,definedasgastrointestinalsymptoms,fever,andthrombophlebitisweremore
commonintheIVprostaglandingroup(8trials,940women,87/474versus22/466RR3.75,95%CI2.46to5.70,NNH=8).
Therewerefourperinataldeathsamong491womenwhoreceivedIVprostaglandinscomparedtonoperinataldeathsamong
483womenwhoreceivedIVoxytocin.Thisdifferencewasnotstatisticallysignificant.TherewerenodifferencesinNICU
admissionsandApgarscores.Therewasnodifferenceinvaginaldeliverieswithin24hours. [51]
UnfavorableCervixSubgroupIn1trialwith100primiparousparticipants,therewasnodifferenceincaesareansection
amongwomenreceivingIVprostaglandinsandwomenreceivingIVoxytocin. [51]
Summary:Intravenousprostaglandinshavenoadvantagesandincreasematernalsideeffectscomparedtoothermethodsof
induction.Thismethodofinductionoflabourhasnotenteredintogeneraluseandisofhistoricalinterestonly.
OralProstaglandins(ExcludingMisoprostol)
OursearchidentifiedoneCochranesystematicreviewcomparingoralPGE2withothermethodsofinductionoflabour. [52]This
reviewincluded19studieswith2588women.IncludedstudiescomparedoralPGE2withplacebo,cervicalorvaginalPGE2,or
oralorIVoxytocin,withorwithoutamniotomy.Therewasnodifferenceinthenumberofparticipantswhoachievedvaginal
deliverywithin24hoursbetweenwomenreceivingoralPGE2andcontrolswhoreceivedIVoxytocin.OralPGE2was
associatedwithfewercaesareandeliveriesthanplacebo(3studies,195women,14/105versus20/90RR0.54,95%CI0.29to
0.98NNT=10).TherewasnodifferenceincaesareandeliverybetweensubjectsinducedwithoralPGE2andothermethods
ofinduction.OralPGE2wasassociatedwithincreasedvomitingcomparedtoIVoxytocin(3studies,305women,25/150
versus4/155RR5.56,95%CI2.15to14.38NNH=9).MorewomenallocatedtooralPGE2experienceddiarrhea(2studies,
236women,6/114versus0/122RR8.13,95%CI1.03to63.93NNH=notestimable)comparedwithIVoxytocin.There
werenosignificantdifferencesinothermaternalorfetaloutcomesinanyoftheothercomparisongroups. [52]
UnfavorableCervixSubgroupAmongwomenwithunfavorablecervices,oralPGE2wasassociatedwithfewercaesarean
deliveriesthanplacebo(3studies,195women,14/105versus20/90RR0.54,95%CI0.29to0.98NNT=10).Therewasno
differencebetweencaesareandeliveriesamongwomenreceivingoralprostaglandinsandthosereceivingvaginal
prostaglandins(2trials,63women),cervicalprostaglandins(1trial,50participants),oroxytocin(3trials,171women). [52]
Summary:OralprostaglandinsareassociatedwithincreasedmaternalvomitinganddiarrheacomparedwithIVoxytocin.
Mifepristone
Oursearchuncoveredonesystematicreviewofmifepristoneforinductionoflabourcombining10trialsincluding1108women.
[53]Theauthorsfoundthatmifepristonewassuperiortoplaceboinachievingafavourablecervicalscoreorinitiatinglabour
within48hours(4studies,293women,75/152versus27/171RR2.41,95%CI1.70to3.42,NNT=4).Comparedtoplacebo,
mifepristonereducedtheriskforcaesareansection(9trials,1043women,163/661versus113/382RR0.74,95%CI0.60to
0.92NNT=14),butincreasedtheriskforinstrumentalvaginaldelivery(7trials,814women,139/540versus47/274RR1.43,
95%CI1.04to1.96NNH=14).Comparedtoplacebo,mifepristoneincreasedthelikelihoodofFHRabnormalities(5trials,
721women,101/493versus35/228RR1.60,95%CI1.12to2.29NNH=11),butdidnotadverselyaffectneonatal
outcomes. [53]
ThereviewersincludedonestudycomparingmifepristonetooxytocinforinductionoflaboramongwomenwithPROMatterm.
Thatstudyfoundthatcomparedwithoxytocin,mifepristonedecreasedtheproportionofwomenwhoweredeliveredvaginally
within24hours(1study,65participants,17/33versus25/32,RR0.66,95%CI0.45to0.96,NNH=3).Mifepristonewas
associatedwithincreasedFHRtracingabnormalities(9/33versus2/32,RR4.46,95%CI1.02to18.66,NNH=4)andneonatal
ICUadmissions(11/33versus3/32,RR3.56,95%CI1.09to11.58,NNH=4). [53]
UnfavorableCervixSubgroupAmongwomenwithunfavorablecervices,mifepristonereducedthelikelihoodofcaesarean
sectioncomparedwithplacebo(8trials,919participants,153/599versus96/320,RR0.7795%CI0.61to0.96,NNT=15). [53]
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Summary:Theuseofmifepristoneforlabourinductioniscurrentlyinvestigational.
Oestrogens
Oursearchuncoveredonesystematicreviewofoestrogenswithorwithoutamniotomyforinductionoflabourthatincluded
sevenRCTsandatotalof465women. [54]Fivestudiesincluding306subjectscomparedoestrogenwithplacebo.Therewere
nodifferencesinratesofcaesareandeliveries,operativevaginaldeliveriesoruterinehyperstimulationwithorwithoutFHR
changesbetweengroups.Therewerenodifferencesbetweenoestrogensandvaginalprostaglandinsincaesareandeliveries,
uterinehyperstimulationwithorwithoutFHRchanges,orepiduralanalgesia(1trial,60women).Therewerenodifferences
betweenoestrogensandcervicalprostaglandinsincesareandeliveriesorinstrumentalvaginaldeliveries(2trials,151women).
TherewasnodifferencebetweenoestrogensandcervicalprostaglandinsinseriousmaternalcomplicationsorNICUadmissions
in1trialwith85women.Therewerenodifferencesbetweenoestrogensandoxytocinincaesareandeliveriesoroperative
vaginaldeliveriesinonetrialincluding66women. [54]
UnfavorableCervixSubgroupInthreetrialsincluding162women,therewasnodifferenceincaesareansectionsbetween
womenreceivingoestrogensandplacebo.Therewasnodifferenceincaesareandeliveriesbetweenwomenreceiving
oestrogensandvaginalprostaglandins(1trial,60women),cervicalprostaglandins(onetrial,66women),extraamniotic
prostaglandins(onetrial,30women),oroxytocin(onetrial,66women). [54]
Summary:Theuseofoestrogensforinductionoflabouriscurrentlyinvestigational.
Corticosteroids
InaCochranereview,Kavanaghandcolleaguesidentifiedeightstudiesexaminingtheuseofcorticosteroidsforlabour
induction. [55]Sevenofthesedidnotmeettheauthors'inclusioncriteria.Theoneincludedtrialhad66womenandevaluated
posttermpregnancieswhichwererandomlyassignedtoreceivetwodexamethasoneinjections(12and24hourspriorto
oxytocininfusion)ornotreatmentpriortooxytocin.Therewerenodifferencesincaesareandeliveries,uterinehyperstimulation
withorwithoutFHRchanges,Apgarlessthan7atfiveminutesormaternalfevers. [55]
UnfavorableCervixSubgroupTherewasnoinformationabouttheefficacyofcorticosteroidsforinductionoflaboramong
womenwithunfavorablecervices. [55]
Summary:Theuseofcorticosteroidsforinductionoflabouriscurrentlyinvestigational.
Relaxin
OursearchidentifiedoneCochranereviewthatcombinedfourstudiesincluding267womenwhousedrelaxinforinductionof
labour. [56]Comparedwithplaceboornotreatment,relaxinreducedthenumberofparticipantswithunfavourablecervicesafter
24hours(3studies,173women,21/96versus37/75RR0.45,95%CI0.28to0.72NNT=4),buttheneedforoxytocin
augmentationwasnotreduced(3trials,196women,65/121versus53/75RR0.83,95%CI0.65to1.06).Therewereno
differencesintheratesofcesareandelivery,operativevaginaldeliveries,oruterinehyperstimulationwithoutFHRchanges.
Therewereinsufficientdatatoevaluateperinataldeathormorbidity. [56]
UnfavorableCervixSubgroupInthreetrialswith207women,therewasnodifferenceincaesareandeliveriesinwomen
allocatedtoreceiverelaxincomparedwithplacebo. [56]
Summary:Theuseofrelaxinforinductionoflabouriscurrentlyinvestigational.
Hyaluronidase
WeidentifiedoneCochranesystematicreviewthatincludedoneRCTwith168women. [57]Womenwererandomlyassignedto
undergointracervicalhyaluronidaseorplaceboinjections.Womenreceivinghyaluronidaseinjectionsweresignificantlylesslikely
torequirecesareansection(15/83versus42/85RR0.37,95%CI0.22to0.61NNT=4)andwerelesslikelytorequire
oxytocinaugmentation(8/83versus40/85RR0.20,95%CI0.10to0.41NNT=3).Fewerwomenallocatedtohyaluronidase
hadacervixunfavorable/unchangedafter24hours50/83versus83/85,RR0.62,95%CI0.52to0.74,NNT=3),Noadverse
effectswerereported. [57]
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UnfavorableCervixSubgroupThisincludedsystematicreviewdidnotreportanysubgroupanalysesaccordingtocervical
status. [57]
Summary:Theuseofhyaluronidaseforinductionoflabouriscurrentlyinvestigational.
IsosorbideMononitrate
Oursearchidentifiedtworandomisedcontrolledtrialswithatotalof502participantscomparingisosorbidemononitrate,anitric
oxidedonor,withplacebo[58]orPGE2. [59]TheHabibtrialcomparedisosorbidemononititetabletswithapyridoxineplacebo
afterreceivingthetrialmedication,subjectsreceivedPGE2oroxytocinaccordingtohospitalprotocol.Comparedwithplacebo,
isosorbidemononitratereducedthenumberofwomenwhorequiredtreatmentwithPGE2(32of51versus46of51,P=
0.002).However,isosorbidemononitrateincreasedtheneedforoxytocinaugmentation(48of51versus27of51,P=0.0001).
Morewomenwhoreceivedplaceboexperienceduterinetachysystole.Comparedwithplacebo,isosorbidemononitrate
significantlyshortenedtheadmissiontodeliveryinterval(102women,13.45+/6.63versus20.12+/8.19P=0.0001).
Therewasnodifferenceinvaginaldeliveriesorcesareansectionsbetweenthegroups. [58]ThePRIMstudycompared
isosorbidemononitratetoPGE2. [59]ComparedwithPGE2,isosorbidemononitritesignificantlylengthenedthetimefrom
treatmenttodelivery(398participants,39,712.0hoursversus26.9+.12.5hours,meandifference12.8hours,95%CI
15.2hours10.4hours,P<0.0001).Therewasnodifferenceinspontaneousvaginaldeliveries,operativevaginaldeliveries,
orcesareansections. [59]
UnfavorableCervixSubgroupBoththeOsmanandHabibtrialsrequiredthequalifyingwomentohavecervicesunfavorable
forinduction. [5859]
Summary:Theuseofisosorbidemononitriteforinductionoflabouriscurrentlyinvestigational.
Discussion
Ourbestevidencereviewoftheliteraturesuggeststhatmanycommonlyrecommendedmethodsforinductionoflabourhave
importanttradeoffsbetweenbenefitsandharms.Comparedwithplacebo,useofvaginalandcervicalprostaglandinE2was
consistentlyassociatedwithreducedlikelihoodoffailuretodelivervaginallywithin24hoursbutincreasedriskfor
hyperstimulationwithandwithoutFHRchanges.Vaginalmisoprostolreducedfailuretoachievevaginaldeliverywithin24hours
comparedwithvaginalandcervicalPGE2,butincreaseduterinecontractileabnormalities.Likewise,vaginalmisoprostol
reducedcaesareandeliveriescomparedwithIVoxytocin,butincreaseduterinehyperstimulation.Mechanicalmethodsfor
inductionoflabourwereassociatedwithreducedratesofuterinehyperstimulationcomparedwithvaginalPGE2andvaginal
misoprostol,butwerealsoassociatedwithincreasedriskformaternalandneonatalinfectiouscomplicationsintheoneincluded
systematicreviewthatcomparedmechanicalmethodswithallothermethodspooled.Intravenousoxytocinwithandwithout
amniotomydidnotappeartohavesignificantbenefitscomparedwithvaginalPGE2.
Ofthenonpharmacologicmethods,membranesweepingappearedtohavethestrongestevidencebase.Itwassuccessfulin
reducingposttermgestationswithoutincreasingclinicallyimportantharms.Thereisnotenoughevidenceofbenefit/safetyto
recommendtheothernonpharmacologicmethodsofbreaststimulationandsexualintercourse.
Ourreviewincludedevaluationofseveralinvestigationalmethodsofinductionoflabour,ofwhichhyaluronidaseappearsthe
mostpromising.Inonesmalltrial,hyaluronidasereducedtheneedforoxytocinaugmentationandforcaesareandelivery.
Thesefindingsneedtobeconfirmedinlarge,appropriatelypoweredrandomisedcontrolledtrials.
OurreviewmayhavebeenlimitedbyrestrictingoursearchtotheEnglishlanguageliteratureandbypublicationbias.Because
weusedtheCochranehierarchy,wecomparedeachmethodoflabourinductiononlywithmethodsabovethemonthe
Cochranehierarchylist.Thismayhavelimitedthetotalnumberofcomparisonsmade.Likewise,theincludedstudiescontained
heterogeneouspopulationsofwomenwithbothintactandrupturedmembranesandcervicesfavourableandunfavourablefor
induction.Thelargenumberofmethodsofinductionconsideredinourreviewprecludedsubgroupanalysesaccordingto
membranestatus.Likewise,wewerenotabletoconsidervariationinpharmacologicpreparationanddosingofthedifferent
compoundsunderstudy.Inourreviewofmethodsofinductionoflaborinthesettingofunfavorablecervix,wedidnotidentifya
clearbestchoiceforinductionoflaborinthissetting.
Despitethelargeamountofevidencethatwewereabletobringtobearonseveralcommonmethodsoflabourinduction,we
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alsofoundconsiderableimprecisionsurroundingbenefitsandharmsofmanyoftheincludedmethods.Numbersofincluded
womeninmostinductionrandomizedtrialsweretoosmalltoexcludedifferencesinrareadverseoutcomessuchasuterine
rupture,amnioticfluidembolism,orperinatalasphyxia.Furtherresearchisnecessarytoidentifypotentialrisksandbenefitsof
bothcommonlyusedandinvestigationalmethodsofinductionoflabour.
Conclusion
Cliniciansshouldusethebestavailableevidencetochoosemethodsoflabourinduction.Researchersandfundingagencies
shouldprioritizestudiesthatcanhelptodefinitivelyguidecareinthesesituations.Womenshouldbegiveninformationabout
whatisknownandnotknownregardingmethodsofinductioninordertobeabletoparticipatefullyinmakingdecisionsabout
inductionoflabour.
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ListofAbbreviations
Theabbreviationsusedinthismanuscriptinclude:CI:confidenceintervalFHR:fetalheartrateIV:intravenousMA:meta
analysisNNH:numberneededtoharmNNT:numberneededtotreatPGE2:ProstaglandinE2PGF2:ProstaglandinF2
RCT:randomisedcontrolledtrialRR:riskratioSR:systematicreviewWMD:weightedmeandifference.
AcknowledgementsandFunding
ThisprojectwasfinanciallysupportedbyChildbirthConnectionthroughagrantfromtheNewHampshireCharitable
Foundation.
Authors'contributions
KKandJCperformedtheliteraturesearchesrequiredforthisreviewandreviewedallabstracts.EMandJCperformedan
updatedsearchoftheliteratureandabstractreviewwhenitbecamenecessaryduringmanuscriptpreparation.EMandKK
reviewedallfulltextarticles.EMandJCperformedallassessmentsofstudyquality.EM,KK,DB,VR,UP,andVKwroteand
editedthemanuscript.KKandVKparticipatedintheformulationofthemethodsofthisreviewandEMandKKassignedthe
evidencegrades.Allauthorsreadandapprovedthefinalmanuscript.
Competinginterests
Drs.Mozurkewich,Romero,Berman,andPerni,arecoinvestigatorsonanongoingmulticentre,industrysponsored
randomizedcontrolledtrialcomparingthemisoprostolvaginalinsertwiththedinoprostonevaginalinsert.
BMCPregnancyChildbirth.201111(84)2011BioMedCentral,Ltd.
ThiswebsiteusescookiestodeliveritsservicesasdescribedinourCookiePolicy.Byusingthiswebsite,youagreetotheuseof
cookies.
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Induction of Labour

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11/29/2015

2009 Intravenousoxytocinplusamniotomy SR,MA

Bartusevicius[25] 2005 Buccalmisoprostol

MoraesFilho[32] 2010 Mechanicalmethods

SelmerOlsen[45] 2007 Acupuncture

Qualityofevidence BalanceofBenefits/Harms GradeofRecommendation

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