induction of labour

11/29/2015 www.medscape.com/viewarticle/754479_print

http://www.medscape.com/viewarticle/754479_print 1/24

www.medscape.com

ASystematicReview

AbstractandIntroductionAbstract

Background:Ratesoflabourinductionareincreasing.Weconductedthissystematicreviewtoassesstheevidencesupportinguseofeachmethodoflabourinduction.Methods:Welistedmethodsoflabourinductionthenreviewedtheevidencesupportingeach.WesearchedMEDLINEandtheCochraneLibrarybetween1980andNovember2010usingmultipletermsandcombinations,includinglabor,induced/orinductionoflabor,prostaglandinorprostaglandins,misoprostol,Cytotec,16,16,dimethylprostaglandinE2orE2,dinoprostonePrepidil,Cervidil,Dinoprost,Carboprostorhemabateprostin,oxytocin,misoprostol,membranesweepingormembranestripping,amniotomy,ballooncatheterorFoleycatheter,hygroscopicdilators,laminaria,dilapan,salineinjection,nipplestimulation,intercourse,acupuncture,castoroil,herbs.Weperformedabestevidencereviewoftheliteraturesupportingeachmethod.Weidentified2048abstractsandreviewed283fulltextarticles.Wepreferentiallyincludedhighqualitysystematicreviewsorlargerandomisedtrials.Wherenosuchstudiesexisted,weincludedthebestevidenceavailablefromsmallerrandomisedorquasirandomisedtrials.Results:Weincluded46fulltextarticles.Weassignedaqualityratingtoeachincludedarticleandastrengthofevidenceratingtoeachbodyofliterature.ProstaglandinE2(PGE2)andvaginalmisoprostolweremoreeffectivethanoxytocininbringingaboutvaginaldeliverywithin24hoursbutwereassociatedwithmoreuterinehyperstimulation.MechanicalmethodsreduceduterinehyperstimulationcomparedwithPGE2andmisoprostol,butincreasedmaternalandneonatalinfectiousmorbiditycomparedwithothermethods.Membranesweepingreducedposttermgestations.Mostincludedstudiesweretoosmalltoevaluateriskforrareadverseoutcomes.Conclusions:Researchisneededtodeterminebenefitsandharmsofmanyinductionmethods.

BackgroundTheincidenceoflabourinductionhasincreasedoverthelastdecade.[1]Labourinductionmaybeindicatedbymedicalorobstetricalcomplicationsofpregnancyormayberequestedorchosenfornonmedicalorsocialreasons.Whenawomanandhercareproviderdecidethatlaborinductionisdesired,theymustnextchooseamethodofinduction.Severalfactorsmayinfluencethechoiceofmethodforinductionoflabourincludingcervicalandmembranestatus,parity,andpatientandproviderpreference.Inthispaperwereviewtheevidenceforeffectivenessofpharmacologic,mechanical,investigational,andcomplementaryandalternativemedicinemeansofthirdtrimesterlabourinduction.Wealsoaddresspossibleharmsofeachmethod.

Weconductedthisreviewtosummarizethebestevidenceavailableforpregnantwomenrequiringinductionoflaborinthethirdtrimesterofpregnancywithalivefetus.Wecomparedeachmethodwithplaceboandwithothermethodsoflaborinduction.TheoutcomesofthisreviewweretheclinicallyimportantbenefitsandharmsoflaborinductionspecifiedbytheCochraneCollaboration'sPregnancyandChildbirthGroupintheirgenericprotocolforinductionoflabour.[2]

MethodsWeconductedacomprehensiveliteraturesearchoftheEnglishlanguageliteratureusingMedlineandtheCochraneDatabaseofSystematicReviews.ThesearchcoveredtheperiodfromJanuary1980toNovember2010.Weusedcombinationsofthefollowingsearchterms"labor,induced/orinductionoflaborprostaglandinorprostaglandins,misoprostolCytotec16,16,dimethylprostaglandinE2orE2dinoprostonePrepidilCervidil:DinoprostCarboprostorhemabateprostin,oxytocin,misoprostol,prostaglandins,membranesweepingormembranestripping,amniotomy,ballooncatheterorFoleycatheter,hygroscopicdilators,laminaria,dilapan,salineinjection,nipplestimulation,intercourse,acupuncture,castoroil,herbs".Titles

MethodsofInductionofLabour

EllenLMozurkewichJulieLChilimigrasDeborahRBermanUmaCPerniVivianCRomeroValerieJKingKristieLKeetonBMCPregnancyChildbirth.201111(84)



andabstractswerereviewedforpossibleexclusionbytworeviewers(KKorEMandJC).Ifbothreviewersexcludedacitation,weeliminatedthatpublicationfromfurtherreview.Ifatleastonereviewerfeltthecitationmightbeincludedoriftherewasinsufficientinformationtomakeadeterminationfromthetitleandabstract,weobtainedthefullarticleforreview.Weidentifiedadditionalarticlesforconsiderationofinclusionthroughcrosschecksofrelevantbibliographies.Referencelistswerecreatedandfulltextarticleswereretrievedforfurtherconsiderationforinclusion.

Inaccordancewithpublishedguidelinesfora"bestevidence"review,[35]thisstudyincludedhighqualitysystematicreviewsandrandomisedcontrolledtrialsinahierarchicalfashion.Ifahighqualitysystematicreviewwasavailable,onlyrandomisedcontrolledtrials(RCT)publishedafterthesearchdateforthesystematicreviewwereincluded,exceptintheinstanceinwhichwefoundaRCTthathadnotbeenidentifiedbythesystematicreview'ssearchoraRCTthathadbeenidentifiedbythesystematicreview'ssearchbutwhichwasawaitingclassification.Inaddition,weincludedstudieswithatleastoneothercomparisongroup(control,placebooranothermethod)forwomenundergoinginductionoflabourattermwithalivefetus.Weexcludedsystematicreviewsdealingexclusivelywithsubgroupsofparticipants,suchasnulliparasorwomenwithprelabourruptureofmembranesorwithonlyaparticulardoseorformulationofthemethodunderstudy(i.e.lowdoseorsustainedreleasepreparations).Weexcludeddoserangingstudies,comparisonsoftwodifferentformulationsofthesamemethodandstudiesinwhichsubjectsinoneormoretreatmentarmreceivedseveraldifferentmethodsoflabourinduction.Wedidnotexcludestudiesinwhichsubjectsreceivedoxytocinaugmentationaftercervicalripening.

Iffiveormorerandomisedcontrolledtrialsinvolvingamethodofinductionwerepublishedsubsequenttothesearchdateofthemostrecentincludedsystematicrevieworwere"awaitingclassification"inthesystematicreview,weconductedmetaanalysesoftheprimaryoutcomesreportedinthesestudies.Twoauthors,VRandUPextracteddataindependently.Differenceswereresolvedbyathirdreviewer(EM)aftercarefulreviewofeachmanuscript.ThenewdatawereaddedtothedataonthecomparisonavailableintheCochranereview.Wecomputedriskratiosand95%confidenceintervalsforthemainoutcomemeasuresreportedinthesesubsequentstudiesusingComprehensiveMetaAnalysis,Version2,Englewood,NJ.WeusedthefixedeffectsmethodfortheseanalysesinordertomatchthemeasuresofeffectreportedbytheincludedCochranereviews.

Wearrangedthemethodsoflabourinductionaccordingtotypesincludingpharmacologicmethods,nonpharmacologicmethods,complementaryandalternativemedicinemethods,andinvestigationalmethods.However,forcomparisonsofmethodswitheachother,wefollowedtheprespecifiedhierarchyusedfortheseriesofinductionoflabourCochraneReviewsandarrangedlabourinductionmethodsinthatspecificorder.[2]Ineachsubsectionofthispaper,wecompareeachmethodwiththosemethodspriortoitonthislist.(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



(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.Inordertobeincludedinthisreview,trialshadtoreportononeormoreoftheoutcomesofinterestspecifiedbytheCochraneCollaborationinductionoflabourgenericprotocol.[2]TheCochranegenericprotocolidentifiedthemostclinicallyimportantbenefitsandharmsoflaborinductionastheoutcomesofinterest.Theseincludedthefollowingfiveprimaryoutcomeswhichwerefelttobeofmostclinicalimportance:vaginaldeliverynotachievedwithin24hours(orperiodspecifiedbyauthors),uterinehyperstimulationwithfetalheartrate(FHR)changes,caesareansection,seriousneonatalmorbidityorperinataldeath(e.g.seizures,birthasphyxiadefinedbytrialists,neonatalencephalopathy,disabilityinchildhood),seriousmaternalmorbidityordeath(e.g.uterinerupture,admissiontointensivecareunit,septicaemia).[2]

Secondaryoutcomesincludedunfavourableorunchangedcervixafter12or24hours,needforoxytocinaugmentation,uterinehyperstimulationwithoutFHRchanges,uterinerupture,epiduralanalgesia,instrumentalvaginaldelivery,meconiumstainedamnioticfluid,Apgarscorelessthansevenatfiveminutes,neonatalintensivecareadmission,neonatalencephalopathy,perinataldeath,disabilityinchildhood,maternalsideeffectsincludingnausea,vomitinganddiarrhea.Othersecondaryoutcomesincludedpostpartumhemorrhage,seriousmaternalcomplications,maternalinfectionsincludingchorioamnionitisandendometritis,andneonatalinfectionsincludingmeningitis,pneumonia,andsepsis.Maternalsatisfactiondatawereincludedwhenavailable.Foreachofthemethodsofinduction,wereportedthesignificantmeasuresofeffect(oddsratiosorriskratios)onouroutcomesofinterestfromtheincludedsystematicreviewsandRCTs.

Duetothelargenumberofmethods,comparisonsandoutcomes,wedidnotincludediscussionofsubgroupanalyses.However,becauseoftheimportanceofcervicalstatusasadeterminantoffailureofinductionoflabortoachievevaginalbirth,wereportedontheeffectofinductionmethodsoncaesareandeliveriesforthesubgroupwithunfavorablecervices,whereavailableintheCochranereviews.

Twoauthors(EMandJC)assignedqualityscorestoeachincludedfulltextarticlebasedontheScottishIntercollegiateGuidelinesNetwork(SIGN)qualityassessmentinstruments.Thesequalityassessmentinstrumentsaredesignedtoassesstheinternalvalidityofeachstudy,andthedegreetowhichthestudies'performanceminimizedbias.[6]TheScottishIntercollegiateGuidelinesNetworkpublishesmethodologychecklistsforcriticalappraisalofbothrandomisedcontrolledtrialsandforsystematicreviews.[6]

Wesystematicallyreviewedbenefitsandharmsofeachinductionmethodandcalculatednumberneededtotreat(NNT)andnumberneededtoharm(NNH)foreachsignificantcomparisonamongmethods.Forcomparisonsincludingonlyonetrial,weusedthe"treatasonetrial"methodofcalculatingtheNNT.[7]Whenmorethanonetrialwasincludedinthecomparison,wecalculatedNNTfrompooledoddsratiosandriskratiosreportedintheincludedmetaanalysesusingtheVisualRx,version2thismethodislesspronetobiasthanthe"treatasonetrial"methodofNNTcalculation.[89]ForthepurposeofNNTcalculationsfrompooledestimates,weusedriskratiosoroddsratioswherereportedforadverseoutcomesandoddsratiostocalculatedNNTfrompositiveoutcomes.[9]Whenoddsratioswerenotavailableinthesourcestudies,wecalculatedthemfrom



availabledatausingComprehensiveMetaAnalysis,Version2,Englewood,NJ.NNTestimateswereroundeduptothenextwholenumberwhereasNNHestimateswereroundeddowntothenearestwholenumber.[710]

Foreachmethodofinduction,twoauthors(EMandKK)assignedalevelofevidencebasedonthe"GRADE"(GradingofRecommendationsAssessment,DevelopmentandEvaluation)system.[11]Inthissystem,theoverallstrengthofevidenceisassignednotonlybasedonstudydesignandconduct,butalsoonfactorssuchastheconsistencyandprecisionoftheresultsandthelikelihoodofpublicationbias.OverallstrengthofevidenceisclassifiedintheGRADEsystemashigh,intermediate,loworverylow.Thelevelsofevidencewereassignedinthefollowingmanner.Ifthepreponderanceofevidencesupportingaparticularmethodoflaborinductionfortheoutcomesofinterestisstrongenoughthatfurtherresearchwouldbeunlikelytochangethereviewers'confidenceintheestimateofeffect,theevidencequalitywasassessedashigh.[11]Iffurtherresearchwouldbelikelytohaveanimportantimpactonconfidenceintheestimate,theevidencequalitywasassessedasmoderate.[11]

Iffurtherresearchwouldbeverylikelytohaveanimportantimpactintheestimateofeffect,thequalityofevidencewasassessedaslow,andiftheestimateofeffectisveryuncertain,theevidencewasassessedasverylow.[11]

Thesesameauthors(EMandKK)alsoassignedabalanceofbenefitsandharmsandagradeofrecommendationaccordingtoGRADEsystemguidelines.[11,12]Foreachclinicalinterventionunderstudy,thebalanceofbenefitsandharmsisassessed,andagradeofrecommendationisclassifiedasstrongorweak.Thissystematicreviewdoesnothavea"standalone"studyprotocol.Inreportingoutcomesfromincludedstudy,wefollowedPRISMAguidelines.[13]

Thisisasystematicreviewofpreviouslypublisheddataandassuchdoesnotrequireethicsapproval.

ResultsWereviewed2048abstracts,ofwhich283fulltextarticleswereexaminedforfurtherconsiderationforinclusionandfromwhich46studieswereincluded.Thus,weincludedatotalof46studiesinthissystematicreview.[1459]Includedstudiesarelistedin.TheflowofabstractsandarticlesthroughthereviewprocessisoutlinedinFigure1.Asummaryoftheoverallqualityofevidenceandstrengthofrecommendationforeachinterventionispresentedin.

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 Medium

Bricker[18] 2009 Amniotomy SR,MA January2007 High

Howarth[19] 2009 Intravenousoxytocinplusamniotomy SR,MA September2009 High

Hofmeyr[20] 2010 Vaginalmisoprostol SR,MA April2010 High

Alfirevic[21] 2008 Oralmisoprostol SR,MA May2008 High

Gaffaney[22] 2009 Oralmisoprostol RCT High

Nagpal[23] 2009 Oralmisoprostol RCT High

Muzonzini[24] 2009 Buccalmisoprostol SR,MA December2003 High

Bartusevicius[25] 2005 Buccalmisoprostol SR 2004 High

Souza[26] 2008 Buccalmisoprostol SR February2008 High

Lo[27] 2006 Buccalmisoprostol RCT High

Elhassan[28] 2007 Buccalmisoprostol RCT High



Boulvain[29] 2010 Mechanicalmethods SR,MA April2001 High

Heinemann[30] 2005 Mechanicalmethods SR,MA November2005 High

Vaknin[31] 2010 Mechanicalmethods SR,MA April2008 High

MoraesFilho[32] 2010 Mechanicalmethods RCT High

Boulvain[33] 2009 Membranesweeping SR,MA July2009 High

Kaul[34] 2004 Membranesweeping RCT High

Kashanian[35] 2006 Membranesweeping RCT High

DeMiranda[36] 2006 Membranesweeping RCT High

Hill[37] 2008 Membranesweeping RCT High

Yildirim[38] 2010 Membranesweeping RCT High

Hamdan[39] 2009 Membranesweeping RCT High

Kelly[40] 2009 Castoroil SR,MA August2009 High

Smith[41] 2009 Acupuncture SR,MA January2008 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 Low

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

Abbreviations:SRSystematicReviewMAMetaanalysisRCTRandomisedcontrolledtrial

Table3.Summary:QualityofEvidenceandGradesofRecommendation11,12

Method Qualityofevidence BalanceofBenefits/Harms GradeofRecommendation

VaginalPGE2 Moderate Tradeoffs Strong

CervicalPGE2 Moderate Netbenefits Strong



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



Figure1.

FlowDiagram.

PharmacologicMethodsIntravaginalProstaglandins(PGE2andPGF2a)

OursearchidentifiedoneCochranesystematicreviewofvaginalprostaglandinE2(PGE2)orF2(PGF2).[14]Withinthisreview,37studiescomparedPGE2withplacebo.Ofthese,twotrialswith384womenaddressedtheprimaryoutcomeofachievingvaginaldeliverywithin24hours.ThesestudiesdemonstratedthatPGE2reducedfailuretoachievevaginaldelivery



within24hourscomparedwithplacebo(36/199versus183/185RelativeRisk[RR]0.19,95%ConfidenceInterval[CI]0.14to0.25NNT=2).However,therewassignificantbetweenstudyheterogeneityinthesetwoincludedstudies,(P



trialsincluding6620womenfoundasmallbutstatisticallysignificantincreasedrateofcaesareandeliveryforwomenintheoxytocingroup(339/3267versus301/3353RR1.17,95%CI1.01to1.35NNH=66).TherewasnosignificantdifferenceinuterinehyperstimulationwithorwithoutFHRchanges.Useofoxytocinsignificantlyreducedchorioamnionitis(14studies,5514women144/2720versus213/2795RR0.69,95%CI0.57to0.85NNT=40)howevertherewassignificantheterogeneityamongtheincludedtrialsforthiscomparison,(I2=65%,P=0.001)andtheauthors'analysisofthestudiesincludedinthiscomparisonusingtherandomeffectsmethodwasnotstatisticallysignificant.Likewise,NICUadmissionswerereducedbyoxytocincomparedtoplaceboorexpectantmanagement,(7studies,4387women,264/2196versus333/2191RR0.79,95%CI0.68to0.92,NNT=32).However,therewassignificantbetweenstudyheterogeneityforthiscomparison(I2=70%,P=0.0003)andthisresultwasnolongerstatisticallysignificantwhentherandomeffectsmethodwasusedforanalysis.Themajorityofthestudiesincludedinthesecomparisonsrequiredrupturedmembranesforentry,likelyinfluencingthisresult.Datawereinsufficienttoestablishconclusionsregardingneonatalandmaternalmortalityorseriousmorbidity.[16]

Threetrialsincluding260womenreportedthatoxytocinwasassociatedwithmorefailurestoachievevaginaldeliverywithin24hoursthanvaginalPGE2(73/132versus40/128RR1.77,95%CI1.31to2.38NNH=5).WhencomparingoxytocinwithvaginalPGE2,therewasnosignificantdifferenceintheratesofcaesareansection(26trials,4514women,274/2259versus246/2255RR1.11,95%CI0.94to1.30).Theincidenceofuterinehyperstimulationwithfetalheartrate(FHR)changeswasverylowandnotdifferentbetweengroups.FewerwomenreceivingoxytocindevelopedchorioamnionitisthanthosereceivingvaginalPGE2(4trials,2742women,54/1381versus81/1361RR0.66,95%CI0.47to0.92,NNT=50).Datawereinsufficienttodrawconclusionsregardingneonatalandmaternalmortalityormorbiditybasedonlimiteddata,therewerenodifferencesbetweengroups.[16]

Twostudiesthatincluded258womencomparingoxytocinwithintracervicalPGE2foundthatoxytocinwasassociatedwithmorefailuretoachievevaginaldeliverieswithin24hours(63/125versus46/133RR1.47,95%CI1.10to1.96NNH=7).OxytocinwasassociatedwithmorecaesareandeliveriesthanintracervicalPGE2(14studies,1331women,123/643versus94/688RR1.37,95%CI1.08to1.74NNH=20).TherewasnosignificantdifferenceinuterinehyperstimulationwithFHRchanges.Therewerenotenoughdatatodevelopconclusionsregardingneonatalandmaternalmortality/morbidity.[16]

Therewereonlythreetrialswith291womenthatcomparedoxytocinwithPGF2.Nonereportedonthenumberofwomenfailingtodelivervaginallywithin24hours.TherewerenosignificantdifferencesinuterinehyperstimulationwithFHRchanges(onetrial23women)orratesofcaesareandelivery(3trials280women).Therewerenocasesofseriousneonatalmorbidityorperinataldeathsinthetwostudiesthatreportedthisoutcome.[16]

UnfavorableCervixSubgroupComparedwithplaceboorexpectantmanagement,therewasnodifferenceincaesareandeliveriesamongparticipantswithunfavorablecervices(13trials,1366women).Similarly,therewasnodifferenceincaesareandeliveriesamong1041womenin15trialswithunfavorablecerviceswhoreceivedoxytocinorvaginalPGE2.However,oxytocinusewasmorelikelytoresultincaesareandeliverythanintracervicalPGE2(10trials,1003women,107/477versus79/526,RR1.44,95%CI,1.12to1.86,NNH=16).[16]

RandomisedControlledTrialsPublishedAftertheSearchDateofSystematicReviewsOursearchidentifiedonestudyincluding240womenthatcomparedoxytocinwithvaginalprostaglandinE2forprematureruptureofmembranesatterm.[17]Inthisstudy,oxytocinwasassociatedwithasignificantlyshortertimefrominductiontodelivery(3.4+/1.5versus9.6+/4.7hoursp=0.02).Therewasnodifferenceintheriskofcaesareansection.[17]

Summary:OxytocinismoreeffectivethanexpectantmanagementorplacebobutlesseffectivethanvaginalandcervicalPGE2inbringingaboutvaginaldeliverywithin24hours.OxytocinresultedinmorecaesareandeliveriesthancervicalPGE2.

Amniotomy

WeidentifiedoneCochranesystematicreviewofamniotomyforinductionoflabour.[18]Thisreviewincludedtwostudieswith310totalparticipants.Oneincludedstudycomparedwomenreceivingamniotomywiththosereceivingeitheroxytocinaloneornointervention.Thisstudywasunderpoweredtodetectdifferencesinanyoutcomeofinterestandthereviewconcludedthatnomeaningfulresultscouldbedrawnfromthesecomparisons.ThesecondincludedstudycomparedamniotomyalonetoasingledoseofvaginalprostaglandinsforwomenwithafavourablecervixandfoundasignificantincreaseintheneedforoxytocinaugmentationintheamniotomyalonegroupcomparedwiththewomenreceivingPGE2(260women,57/130versus20/130RR2.85,95%CI1.82to4.46NNH=3).Therewasnodifferenceincaesareandeliveries.[18]

SubgroupWithunfavorablecervixTherewerenostudiesthatincludedparticipantswithunfavorablecervices.[18]



SubgroupWithunfavorablecervixTherewerenostudiesthatincludedparticipantswithunfavorablecervices.[18]

Summary:ComparedwithvaginalPGE2,amniotomyincreasestheneedforoxytocinaugmentation.

OxytocinWithAmniotomy

OursearchidentifiedoneCochranesystematicreviewincluding17trialswith2566womencomparingIVoxytocinplusamniotomywithothermethodsforinductionoflabour.[19]Thisreviewcomparedamniotomyplusoxytocin(invaryingdoses),withplacebo,vaginalprostaglandinE2orF2,oramniotomyalone.Oxytocinplusamniotomyresultedinfewercasesofmeconiumstainedamnioticfluidthanplaceboornotreatment(onetrial,184participants,3/92versus13/92RR0.23,95%CI0.07to0.78NNT=9).Therewerenoothersignificantdifferencesinouroutcomesofinterestforthiscomparison.[19]

Whencomparedwithvaginalprostaglandins,amniotomyplusIVoxytocinwasassociatedwithmorepostpartumhemorrhage(2studies,160women,11/80versus2/80RR5.5,CI1.26to24.07NNH=9).OneRCTof100subjectsfoundthatmorewomenweredissatisfiedwithamniotomyandIVoxytocinthanvaginalprostaglandins,(26/50versus0/50RR53,CI3.32to846.51NNH=1).Therewerenoothersignificantdifferencesbetweenoxytocinplusamniotomyandvaginalprostaglandins.[19]

Onestudywith30participantscomparedoxytocinplusamniotomywithcervicalprostaglandins.Thisstudywastoosmalltodetectanydifferencesinoutcomesofinterest.Likewise,onlytwostudieswith309totalparticipantscomparedoxytocinplusamniotomywithoxytocinalone.Thesestudieswerealsounderpoweredtodetectdifferencesinanyoutcomeofinterest.[19]

Whencomparedwiththosewhoreceivedamniotomyalone,fewerwomenwhoreceivedamniotomyplusIVoxytocinwerenotdeliveredvaginallyat24hours(2studies,296participants,3/148versus24/148RR0.13,95%CI0.04to0.41NNT=8).AmniotomyplusIVoxytocinalsoresultedinsignificantlyfewerinstrumentalvaginaldeliveriesthanamniotomyalone(2studies,510participants,57/255versus88/255RR0.65,CI0.49to0.85NNT=995%CI6to20).[19]

UnfavorableCervixSubgroupThereviewincludedtwotrialswith106womenwhohadcervicesunfavorableforinductionoflabor.Therewasnodifferenceincaesareanbirthamongwomenallocatedtoamniotomyandoxytocinversusvaginalprostaglandins.Therewerenoothertrialsincludingwomenwithcervicesunfavorableforinduction.[19]

Summary:Oxytocinplusamniotomyismoreeffectivethanamniotomyaloneinachievingvaginaldeliverywithin24hours.Oxytocinplusamniotomymaybeassociatedwithmorepostpartumhemorrhageandlessmaternalsatisfactionthanvaginalprostaglandins.

VaginalMisoprostol

TheCochranereviewofvaginalmisoprostolforlabourinductionincluded121trials.[20]Therewerenosignificantdifferenceinvaginaldeliveriesnotachievedwith24hoursamongfivetrialswith769womenthatcomparedvaginalmisoprostolwithplacebo/notreatment.Likewise,infivetrialswith777women,therewerenosignificantdifferencesinhyperstimulationwithFHRchanges.Comparedwithplacebo/notreatment,vaginalmisoprostolwasassociatedwithmorehyperstimulationwithoutFHRchanges(31/313versus10/481,6trials,794women,RR3.52,95%CI1.78to6.99,NNH=19)butwithlessmeconiumstainedamnioticfluid(6trials,814participants,27/326versus83/488,RR0.56,95%CI0.35to0.87,NNT=14)Vaginalmisoprostolreducedthenumberofparticipantswithacervixunfavorableorunchangedafter12to24hours(2studies107women,4/56versus41/51,RR0.10,95%CI0.01to0.64,NNT=2).Therewasnodifferenceincaesareandeliveriesin10trialsthatincluded1141women.

Twentytwotrialswith5,229participantscomparedvaginalmisoprostolwithothervaginalprostaglandinsfortheoutcomeofvaginaldeliverieswithin24hours.Womenreceivingmisoprostolwerelesslikelytonotbedeliveredwithin24hours(22trials5229participants,920/2550versus1179/2679,RR0.77,95%CI0.66to0.89,NNT=10)andwerelesslikelytorequireoxytocinaugmentation(38trials,7022participants,1355/3465versus1794/3557,RR0.68,95%CI0.61to0.76,NNT=7).Meconiumstainedamnioticfluidwasmorecommonamongsubjectsreceivingmisoprostol(18trials,3991women,246/1909versus190/2082,RR1.35,95%CI1.13to1.61,NNH=32).MisoprostolincreaseduterinehyperstimulationwithoutFHRchanges(26trials4804women381/2311versus199/2493,RR1.99,95%CI1.41to2.79,NNH=13),althoughhyperstimulationwithFHRchangesdidnotdiffer(31trials5830women).Vaginalmisoprostolreducedtheneedforoxytocinaugmentation(38trials,7022women,1355/3465versus1794/3557,RR0.68,95%CI0.61to0.76,NNT=7)andepiduralanesthesia(8trials,2141women,469/1063versus516/1078,RR0.9295%CI0.85to0.99,NNH=27).Caesareansection

rateswerenotsignificantlydifferent.[20]



rateswerenotsignificantlydifferent.[20]

ComparedwithcervicalPGE2,vaginalmisoprostolreducedfailuretoachievevaginaldeliverywithin24hours(13trials,1627women,253/814versus402/813,RR0.63,95%CI0.56to0.71,NNT=6).Oxytocinaugmentationwasrequiredlessoftenwithmisoprostolbasedon20trialsincluding2316women,(411/1177versus727/1139,RR0.55,95%CI,0.48to0.64NNT=4)andwomenreceivingmisoprostolwerelesslikelytohaveacervixunfavorableforinductionafter1224hours(1trial,155women,38/76versus58/79,RR0.68,95%CI0.52to0.88,NNT=5).Womenreceivingmisoprostolwerelesslikelytorequireepiduralanesthesia(2trials,321women,48/160versus75/161,RR0.64,95%CI0.48to0.86,NNT=6).MisoprostolresultedinmoreuterinehyperstimulationwithFHRchanges(20trials,2224women,98/1129versus39/1095,RR2.32,95%CI1.64to3.28,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).Therewerenootherstatisticallysignificantdifferencesinperinatalormaternaloutcomes.[20]

Comparedwithoxytocin,vaginalmisoprostolreducedthelikelihoodofparticipantsnotbeingdeliveredvaginallywithin24hours(10trials,1397women,135/690versus226/707,RR0.6595%CI.47to0.90,NNT=9).VaginalmisoprostolwasassociatedwithincreaseduterinehyperstimulationwithFHRchanges(9trialswith1419women49/690versus28/729,RR1.87,95%CI1.20to2.91,NNH=31)andwithoutFHRchanges(15trials2050women,218/1009versus102/1041,RR2.24,95%CI1.82to2.77,NNH=9).Womenreceivingmisoprostolweremorelikelytoexperiencegastrointestinalsideeffectsthanthosereceivingoxytocin(4trials334women,15/170versus2/164,RR5.04,95%CI1.51to16.86,NNH=21)Caesareandeliverieswerelesslikelyamongwomenreceivingvaginalmisoprostol(25trials3074women,258/1527versus364/1547,RR0.7695%CI0.60to0.96,NNT=18)aswereinstrumentalvaginaldeliveries(13trials,1639women,69/810versus96/829,RR0.7495%CI0.56to0.99,NNT=34).InfantsborntowomenreceivingmisoprostolwerelesslikelytohaveApgarscore



participants,81/196versus100/195RR0.81,95%CI0.651.00NNT=11).OralmisoprostolwasassociatedwithmoreuterinehyperstimulationwithFHRchanges(3trials,490women,12/245versus3/245RR3.57,95%CI1.11to11.54NNH=32).TherewasatrendofborderlinesignificancetowardmorehyperstimulationwithoutFHRchangeswithoralmisoprostol(1trial,190women,8/95versus0/95RR17.01,95%CI1.00to290.42).Therewerenodifferencesinanyotheroutcomeofinterest.[21]

Eighttrialsincluding1026womencomparedoralmisoprostolwithIVoxytocin.Meconiumstainingoftheamnioticfluidwasseenmorefrequentlyinthemisoprostolgroup(6trials,916women,47/477versus24/439RR1.72,95%CI1.08to2.74NNH=26),butoralmisoprostolwasnotassociatedwithanyotherdifferencesinadversefetal,neonatalormaternaloutcomes.[21]

Twentysixtrialswith5096participantscomparedoralwithvaginalmisoprostol.Theoralrouteofadministrationwasassociatedwithmorefrequentuseofoxytocin(22trials,4557women,1301/2279versus1151/2278RR1.19,95%CI1.06to1.34NNH=11),buttherewasnodifferenceinvaginaldeliverywithin24hours.ThereweresignificantlylowerratesofuterinehyperstimulationwithoutFHRchangeswithoralregimens(9trials,1420women,85/698versus146/722RR0.58,95%CI0.35to0.96NNT=12),buttherateofhyperstimulationwithFHRchangeswasnotdifferentbetweenthetwogroups.FewerbabiesborntomotherswhoreceivedoralmisoprostolhadApgarscoreslessthan7atfiveminutesoflife(14trials,3270women37/1638versus57/1632RR0.65,95%CI0.44to0.97NNT=82).Therewasnodifferenceincaesareandeliveriesin25trialswith5096women.[21]

UnfavorableCervixSubgroupTherewerenostudiescomparingoralmisoprostolwithplacebo,vaginalPGE2,intracervicalPGE2,oroxytocinthatreportedoncaesareandeliveriesamongwomenwithunfavorablecervices.Amongwomenwithunfavorablecerviceswhowererandomizedtoreceiveoralmisoprostolorvaginalmisoprostoltherewerenodifferencesincaesareandeliveriesamongprimiparous(2studies,85participants)ormultiparous(1study,24participants)subjects.[21]

RandomisedControlledTrialsPublishedAftertheSearchDateofSystematicReviewsSubsequenttothesearchdateoftheCochranereview,weidentifiedonestudywith87participantsthatcomparedoralmisoprostolwithplacebo.[22]Thisstudyfoundoralmisoprostolsuperiortoplaceboinachievingdeliverywithin24hours(19/43versus6/44,P=0.024,NNT=4).AnadditionalstudythatcomparedoralmisoprostolwithPGE2foundthatmorewomenreceivingmisoprostoldeliveredvaginallywithin12hours,althoughvaginaldeliverieswithin24hoursdidnotdiffer.[23]Morewomenreceivingoralmisoprostolweresatisfiedwiththeirinductionmethod.[23]

Summary:OralmisoprostolreducedcaesareansectionscomparedwithvaginalPGE2andplacebo.Comparedwithvaginalmisoprostol,oralmisoprostolisassociatedwithfewercontractileabnormalities,butmoreneedforoxytocinaugmentation.

BuccalorSublingualMisoprostol

Oursearchuncoveredthreesystematicreviewscomparingsublingualorbuccalmisoprostolwithothermethodsoflabourinduction.[2426]TheCochranereviewbyMuzonzini[24]andcolleaguesandthereviewbyBartuseviciusandcolleagues[25]bothincludedthesamethreestudieswithatotalof507womenandreachedsimilarconclusions.Twoofthestudieswithatotalof350womencomparedbuccalorsublingualmisoprostol(50g)tooralmisoprostol(50or100g)andonestudywith157participantscomparedbuccalandvaginalmisoprostol.Neitherreviewfoundsignificantdifferencesinanyoutcomeofinterest.[2425]

UnfavorableCervixSubgroupTheCochranereviewersdidnotconductanysubgroupanalysesaccordingtocervicalstatus.[24]

Othersystematicreviews

In2008Souzaandcolleaguespublishedasystematicreviewofstudiescomparingsublingualorbuccalmisoprostolwithvaginalmisoprostolforinductionoflabour.Thisreviewincludedfivestudieswith740subjects.[26]Theauthorsfoundnosignificantdifferencesintheratesofvaginaldeliverynotachievedwithin24hours,hyperstimulation,orcesareandeliveries.Thereweremorecasesofuterinetachysystole,definedasmorethanfivecontractionsin10minutesforatleast20minutes,amongwomenassignedtosublingualmisoprostol(5trials,740women,42/368versus26/372OR1.70,95%CI1.02to2.83NNH=24,95%CI10to771),althoughtherewassignificantheterogeneityamongstudiesincludedinthiscomparison(P=0.04).[26]

RandomisedControlledTrialsPublishedAftertheSearchDateofSystematicReviewsOursearchidentifiedtwo



additionalstudiescarriedoutsubsequenttothesearchdatesofthesesystematicreviews.Oneofthesestudiescomparedsublingualmisoprostol50gwithamniotomyandoxytocinforinductionoflabouramong50womenattermwithfavourablecervices.[27]Thisstudywasterminatedearlywhenaninterimanalysisrevealedthatsignificantlyfewerwomenallocatedtosublingualmisoprostoldeliveredwithin24hours(15/22versus21/21RR0.68,95%CI0.51to0.91NNH=3).Therewerenodifferencesinothermaternalorfetaloutcomes,althoughmaternalsatisfactionwassignificantlyhigherwithsublingualmisoprostol.Thesecondstudyincluded150womenandcompared50gmisoprosolbyoral,vaginal,orsublingualroutes.[28]

Thisstudyfoundthattheinductiontodeliveryintervalwassignificantlydecreasedamongwomenreceivingsublingualmisoprostolcomparedwiththevaginalandoralroutes(13.3hoursversus16.1hours[oral]versus15.1hours[vaginal]).FewerbabiesborntomothersreceivingsublingualmisoprostolhadApgarscoreslessthansevenatoneminute(0/50versus6/100,P=0.003,NNT=17).[28]

Summary:Comparedwithvaginalmisoprostol,administrationofmisoprostolbythebuccalorsublingualrouteincreasesuterinetachysystole.

MechanicalMethods

Oursearchidentifiedthreesystematicreviewsevaluatingmechanicalmethodsforinductionoflabour.TheCochranereviewstudiedmechanicalmethodsincludinglaminariatents,syntheticequivalentssuchasDilapan,Foleycatheters,andothertypesofballooncatheterforinductionoflabour.Itincluded45RCTsthatcomparedmechanicalmethodswithPGE2,misoprostol,oxytocin,andplacebo.Mosttrialshadsmallsamplesizes.[29]

Theauthorsdidnotfindanyadvantageofmechanicalmethodscomparedwithplaceboornotreatmentintheprespecifiedoutcomesofvaginaldeliverynotachievedwithin24hoursorcaesareandeliveries(1trial,48women).Therewasnodifferenceincaesareandeliveriesbetweenwomenreceivingmechanicalmethodsandwomenreceivingplaceboornotreatment(6studies,416participants).Therewasnodifferenceinanyotheroutcomeofinterest,includingchorioamnionitis(1trial,240participants)andendometritis(2trials,288participants).[29]

Moresubjectsallocatedtomechanicalmethodsfailedtodelivervaginallywithin24hoursthanthoseassignedtovaginalPGE2(1trial,109participants,43/59versus21/50,RR1.74,CI1.21to2.49NNH=3),andmorewomenallocatedtomechanicalmethodsrequiredoxytocinaugmentation(2trials,169women,30/89versus9/80,RR2.90,95%CI1.40to6.00,NNH=5),althoughthisfindingshouldbeinterpretedwithcaution,astherewassignificantheterogeneitybetweenthe2studiesincludedinthiscomparison(P=0.0008).MechanicalmethodswerelesslikelytoresultinuterinehyperstimulationwithFHRchangesin6trialswith484women,(0/246versus14/238,RR0.14,95%CI0.04to0.53,NNT=20)andwithoutFHRchangesin8trialswith580women(6/293vs28/287,RR0.26,95%CI0.13to0.54,NNT=14).TherewasnodifferenceincaesareandeliveriesbetweenmechanicalmethodsandvaginalPGE2(12trials,786women),butmechanicalmethodswereassociatedwithreducedneedforinstrumentalvaginaldeliveries(5trials,378women,36/192versus53/186,RR0.65,95%CI0.46to0.93,NNT=11).[29]

Morewomenassignedtomechanicalmethodsdidnotachievevaginaldeliverywithin24hoursthanthoseassignedtocervicalPGE2(1trial,100participants,34/50versus20/50RR1.70,CI1.15to2.50NNH=3),andmorewomenallocatedtomechanicalmethodsrequiredoxytocinaugmentation(1trial,185women,84/90versus63/95,RR1.41,95%CI1.21to1.64,NNH=3).However,therewasnodifferenceincaesareansectionsin12trialsthatincluded1614women.ComparedwithcervicalPGE2,mechanicalmethodswereassociatedwithlessendometritis(4trials,693participants,9/352versus34/341RR0.26,95%CI0.13to0.52,NNT=14).However,in3studieswith619womenthatcomparedmechanicalmethodstocervicalPGE2,thereweremoreneonatalinfectionsinbabiesborntomotherswhohadreceivedmechanicalmethodscomparedtocervicalPGE2(24/316versus9/303,RR2.4595%CI1.18,to5.07,NNH=24).[29]

Analysisoffourstudieswith198womencomparingmechanicalmethodswithoxytocinfoundthatmechanicalmethodsresultedinfewercaesareandeliveries(18/103versus30/95RR0.55,95%CI0.33to0.91NNT=8).TherewasnodifferenceinhyperstimulationwithoutFHRchanges,postpartumhemorrhage,orseriousmaternalmorbidityordeathin1trialwith60women.Nootheroutcomescouldbeevaluatedforthiscomparison.[29]

Fourstudiesincluding618womencomparedmechanicalmethodstovaginalmisoprostol.Therewerenostatisticaldifferencesinthelikelihoodofachievingvaginaldeliverywithin24hours(2studies,234women)orincaesareandeliveries(4studies,618women).TherewasreducedriskforuterinehyperstimulationwithFHRchangesseeninthreetrialsincluding434women



comparingmechanicalmethodstovaginalmisoprostol(8/226versus19/208RR0.41,CI0.20to0.87NNT=19).Therewerenodifferencesnotedininfectiousmorbidityorneonataloutcomes.[29]

UnfavorableCervixSubgroupTherewasnodifferenceincaesareandeliveriesamong396womenenrolledinfiverandomizedcontrolledtrialscomparingmechanicalmethodswithplaceboornotreatment,in10trialswith738womencomparingmechanicalmethodswithvaginalPGE2orin12trialswith1614womencomparingmechanicalmethodswithintracervicalPGE2.Therewasnodifferenceincesareansectionsinthreetrialswith482participantscomparingmechanicalmethodswithvaginalmisoprostol.Inthesubgroupofwomenwithunfavorablecervices,mechanicalmethodswerelesslikelytoresultincaesareandeliverythanoxytocin(3trials,178women,15/93versus27/85,RR0.50,95%CI,0.29to0.87,NNT=7).[29]

OtherSystematicReviewsOursearchidentifiedasecondsystematicreviewthatcomparedmechanicalmethodsoflabourinductionwithPGE2,misoprostol,hyaluronidaseorplacebo.[30]Thissystematicreview,whichincluded30randomised,controlledtrialswithatotalof4468participants,focusedontheoutcomesofmaternalandneonatalinfectiousmorbidity.Theauthorsdefinedmaternalinfectiousmorbidityasmaternaltemperaturegreaterthan38C,endometritisorchorioamnionitis.Theydefinedneonatalinfectiousmorbidityasfever,suspectedorprovensepsis,orneedforantibiotics.Controlswerethepooledgroupofwomenwhohadreceivedotherpharmacologicmethodsoflabourinduction.Comparedwithcontrols,womenundergoinglabourinductionwithmechanicalmethodsweremorelikelytoexperienceinfectiousmorbidity(30studies,4468participants,252/2220versus188/2248OR1.38,95%CI1.12to1.68NNH=36).Theauthorsreportednosignificantheterogeneityforthiscomparison.Similarly,infantsborntomothersundergoingmechanicalmethodsofinductionweremorelikelytoexperienceneonatalinfectiousmorbiditythaninfantsborntomothersundergoinginductionwithpharmacologicmethods(8trials,1775women,40/893versus18/882OR2.03,95%CI1.19to3.51NNH=50).Theauthorsreportedthattherewasnosignificantheterogeneityforthiscomparison.[30]

Athirdsystematicreviewcomparedmechanicalmethods(Foleycatheterballoon)withlocallyappliedprostaglandins(vaginalPGE2,cervicalPGE2andvaginalmisoprostol).[31]Thissystematicreviewincluded27randomizedcontrolledtrialsthatincluded3532participants.Whencomparedwithalllocallyappliedprostaglandins(LAPG)combined,therewerenodifferencesbetweenmechanicalmethodsandprostaglandinsincaesareandeliveries(27trial,3532participants),participantswithcervicesthatwereunfavorableorunchangedafter12to24hours(6trials,613participants),ripeningtodeliveryinterval(13trials,1270participants),vaginaldeliverieswithin12to24hours(13trials,1779women),maternalfevers(19trials,2421women),5minuteApgarscoreslessthan7(14trials,1661women),meconiumstaining(13trials1841women),oradmissionoftheneonatetoaNICU(12trials,1796women).WomenwhoreceivedLAPGwerelesslikelytorequireoxytocinaugmentationthanthosereceivingmechanicalmethods(16trials,1644participants,RR0.73,95%CI0.62to0.86,P=0.0002),butweremorelikelytoexperienceexcessiveuterineactivity,definedastachysystole,hypertonus,orhyperstimulationsyndrome(21trials,2661participants,244/1306versus147/1355,RR,2.3595%CI,1.41to3.90P=.001,NNHforlocallyappliedprostaglandinswhencomparedwithmechanicalmethods=7).Therewassignificantheterogeneitynotedfortheoutcomesofexcessiveuterineactivity,vaginaldeliverywithin1224hours,andforneedforoxytocinaugmentation.[31]

TheauthorsconductedsubgroupanalysescomparingmechanicalmethodswithvaginalPGE2,cervicalPGE2,andvaginalmisoprostol.TheyfoundthatmechanicalmethodswereassociatedwithalongerripeningtodeliveryintervalthancervicalPGE2(5trials,552subjects,weightedmeandifference[WMD]5.48hours,95%CI2.79to8.16,P



OursearchidentifiedoneCochranesystematicreviewof22trialswhichincluded2797subjectsthatcomparedmembranesweepingwithoxytocin,PGE2,ornotreatment.[33]Therewasnodifferenceinratesofcaesareandeliveries,seriousneonatalmorbidity,perinataldeath,seriousmaternalorneonatalinfectionswhencomparingmembranesweepingwithnotreatment.Apolicyofroutinemembranesweepingfrom37weeksonwardreducedthelikelihoodofgestationcontinuingtoboth41(6studies,937women,77/473versus129/464RR0.59,95%CI0.46to0.74NNT=9)and42(6studies,722women,12/365versus43/357RR0.28,95%CI0.15to0.50NNT=12)weeks'gestation.Membranesweepingwasassociatedwithreducedlikelihoodofnotbeinginlabourwithin48hours(fivestudies,726women,234/367versus298/359RR0.77,95%CI0.70to0.84NNT=6).Membranesweepingwasalsoassociatedwithreducedriskfornotbeingdeliveredwithinoneweek(9studies,1375women,320/695versus440/680RR0.71,95%CI0.65to0.78NNT=6).Membranesweepingwasassociatedwithmorevaginalbleeding(3trials,391women,35/200versus18/191RR1.75,95%CI1.08to2.83NNH=15)andmorematernaldiscomfort(2studies,320women,94/163versus32/157RR2.83,95%CI2.03to3.96NNH=3)comparedwithnotreatment.DatacomparingmembranesweepingwithPGE2andwithoxytocinwereinsufficienttodrawconclusionsofrelativeefficacy.[33]

UnfavorableCervixSubgroupTherewasnodifferenceincaesareansectionsamongwomenallocatedtomembranesweepingversusnotreatment(3trials,200women)norintwotrialswith252womencomparingmembranesweepingwithvaginalprostaglandinsnorinonetrialwith69womencomparingmembranesweepingwithoxytocin.[33]

RandomisedControlledTrialsPublishedAftertheSearchDateofSystematicReviewsorAwaitingClassificationAmongthestudiesawaitingclassificationintheCochranereviewwerefivehighqualityRCTs.[3438]Inaddition,weidentifiedoneadditionalhighqualityRCTthatwaspublishedaftertheCochranereview'ssearchdate.[39]Ofthese,fivestudieswith1700participantscomparedmembranesweepingwithnotreatmentorvaginalexamalone.[3539]Inametaanalysisthataddedourindependentlyextracteddatafromthetwostudies[36,37]thatevaluatingtheeffectofmembranesweepingonposttermgestationstothedatareportedintheCochranereview,membranesweepingsignificantlydecreasedthenumberofpregnanciesprogressingto42weeks'gestation(8studies,1874participants,102/902versus194/862,RR0.53,95%CI0.43to0.65,NNT=10).Therewasnosignificantheterogeneityforthiscomparison.ThustheadditionofthesetwonewtrialsdidnotaltertheconclusionreachedbytheCochranereview.

DeMirandafoundthatmembranesweepingsignificantlyreducedthetimefromrandomizationtodeliverybyoneday(3.50versus4.47days,meandifference0.97days95%CI0.60to1.35).[36]Inamorerecentstudyinvolving351women,Yildirimandcolleaguesfoundthatmembranesweepingsignificantlyincreasedthelikelihoodofspontaneouslaborby41weeks'gestation(162/179versus118/167,P=0.0001).[38]Bycontrast,Hamdanfoundthatmembranesweepingdidnotincreasetheproportionofwomenplanningtrialoflaborafterpriorcesareansection(TOLAC)whoenteredspontaneouslabor.[39]TheHillstudywasdesignedtotestwhethermembranesweepingincreasesprelabourruptureofmembranes,butfoundnooveralldifferenceinthisoutcome.[37]Onestudywith60participantscomparedmembranesweepingwithasingledoseofintracervicalPGE2.[34]UseofcervicalPGE2resultedinasignificantlyshorterinterventiontodeliveryintervalthandidmembranesweeping(26.23hoursversus19.15hours,P



Acupuncture

OursearchidentifiedaCochranesystematicreviewthatincluded3trialswith212womenthatfocusedonacupunctureforinductionoflabour.[41]Comparedwithstandardcare(oxytocin,prostaglandins,or"routinecare"),morewomenundergoingacupuncturedidnotrequiretheuseofotherinductionmethods(2trials,147women,49/73versus34/74RR1.45,95%CI1.08to1.95NNT=5).Nodifferenceswerefoundintimetodelivery,ratesofcaesareandelivery,instrumentalvaginaldelivery,orepiduralanesthesia.Fetalorneonataloutcomeswerenotestimable.[41]

UnfavorableCervixSubgroupTherewasnodataintheincludedtrialsconcerningtheeffectofacupunctureforlaborinductioninwomenwithunfavorablecervices.[41]

RandomisedControlledTrialsPublishedAftertheSearchDateofSystematicReviewsWeidentifiedthreefurthertrialswith684participants,threepublishedafterthesearchdateofthesystematicreview[4244]andonethatwasnotidentifiedbytheCochranesearch.[45]Thesestudiesdidnotrevealanydifferencesbetweenacupunctureandplaceboornotreatmentinanyoutcomeofinterest.

Summary:Theuseofacupunctureforinductionoflabourisinvestigationalnoadvantagesforthismethodhavebeendemonstrated.

BreastStimulation

Oursearchidentifiedonesystematicreviewthatcombinedsixstudieswith719subjectsthatevaluatedbreaststimulationforlabourinduction.[46]Therewerenodifferencesincesareandeliveries,meconiumstaining,oruterinehyperstimulationwhencomparingbreaststimulationwithnotreatment.Breaststimulationdecreasedthenumberofwomenwhowerenotinlabourwithin72hours(4studies,437women,136/217versus206/220RR0.67,95%CI0.60to0.74NNT=4).Breaststimulationwasassociatedwithlesspostpartumhemorrhage(2studies,300women,1/150versus9/150RR0.16,95%CI0.03to0.87NNT=20).Thereweremoreperinataldeathsamongpregnanciesassignedtobreaststimulationthantonotreatment,althoughthisdifferencewasnotstatisticallysignificant(3studies,337participants,3/167versus0/170RR8.17,95%CI0.45to147.8).Thisresultshouldbeinterpretedwithcaution,asallofthedeathsoccurredinasingletrialconductedamonghighriskwomeninadevelopingcountry.[46]

Twostudieswithatotalof99subjectscomparedbreaststimulationwithoxytocin.Therewerenodifferencesincaesareandeliveries.Inonetrialwith37women,morewomenassignedtobreaststimulationwerenotinlabourwithin72hourscomparedwiththosewhowereallocatedtotheoxytocingroup,althoughthisdifferencewasofborderlinestatisticalsignificance(10/17versus5/20RR2.35,95%CI1.00to5.54).Therewerenodifferencesinuterinehyperstimulationormeconiumstaining.Therewerethreeperinataldeathsinthebreaststimulationgroupversusoneintheoxytocingroup,anonsignificantdifference.Alldeathswerefromthesametrialconductedamonghighriskwomeninadevelopingworldsetting.[46]

UnfavorableCervixSubgroupTherewasnoinformationoncesareandeliveriesintheoneincludedtrialthatincludedwomenwithunfavorablecervices.[46]

Summary:Breaststimulationmayreducethenumberofwomennotinlabourwithin72hourscomparedtonotreatmentbutislesseffectivethanoxytocinforthisoutcome.Moreresearchisneededtoevaluatethesafetyofbreaststimulation.

Intercourse

TheCochranereviewofintercourseforinductionoflabourincludedonestudywith28subjects.[47]Participantswereassignedtohaveintercoursenightlyforthreenightsversusnointercourse.TherewerenodifferencesindeliverywithinthreedaysorfiveminuteApgarlessthanseven.[47]

UnfavorableCervixSubgroupTherewasnoinformationoncervicalstatusorcesareandeliveriesintheoneincludedstudy.[47]

Summary:Thereisnotenoughevidencetoevaluatetheefficacyandsafetyofintercourseforinductionoflabour.

HomeopathicMethods

Oursearchidentifiedonesystematicreviewoftwostudieswith133participantsthatcomparedhomeopathicherbsforlabour

inductionwithplacebo.[48]OnlyoneofthestudiesincludedintheCochranereviewreportedontheprespecifiedclinical



inductionwithplacebo.[48]OnlyoneofthestudiesincludedintheCochranereviewreportedontheprespecifiedclinicaloutcomesofinterest.Thatstudyincluded40subjectsandreportednodifferenceinratesofvaginaldeliverynotachievedwith24hours,caesareandeliveries,operativevaginaldelivery,needforoxytocinaugmentationoflabour,orlengthoflabour.[48]

UnfavorableCervixSubgroupTherewasnoinformationintheincludedstudyoncervicalstatus.[48]

Summary:Thereisnotenoughevidencetoevaluatetherisksandbenefitsofhomeopathyforinductionoflabour.

HypnoticRelaxation

Weidentifiedonequasirandomisedstudyofhypnoticrelaxationforinductionoflabourinposttermpregnancies.[49]Fortywomenwereassignedtohypnoticrelaxationandanequalnumbertonointerventionbasedonalternatedaysoftheweek.Controlswerealsochosenbasedonthebaselinecharacteristicsofparity,gestationalage,andcervicalstatus.Therewerenodifferencesindeliverywithin24hoursortimetodelivery.Theauthorsdidnotreportanyotheroutcomes.[49]

UnfavorableCervixSubgroupTherewasnoinformationontheeffectofhypnoticrelaxationamongwomenwithunfavorablecervices.[49]

Summary:Comparedtonointervention,hypnoticrelaxationdidnotaffectlikelihoodofdeliverywithin24hours.Datawereinsufficienttoevaluateanyotheroutcome.

InvestigationalMethodsExtraamnioticProstaglandins

Extraamnioticplacementofprostaglandinshasbeenstudiedasacombinationofamechanicalmethod(Foleycatheter)withapharmacologicmethod(prostaglandins).[50]Theprostaglandinisintroducedintotheextraamnioticspaceviathecatheter.Oursearchidentifiedonesystematicreviewcomparingextraamnioticprostaglandinswithothermethodsforinductionoflabour.Thisreviewincluded12studieswhichcomparedextraamnioticPGE2orPGF2withextraamnioticplacebo,vaginalprostaglandins,intracervicalprostaglandins,IVoxytocin,vaginalmisoprostol,ormechanicalmethods.Becauseofthewidevarietyofcomparisons,withfewerthan200participantsineachoftheindividualcomparisons,evaluationofthismodalitycomparedtoothermethodswaslimited.ThreeRCTswith167womencomparedextraamnioticprostaglandinswithplacebo.Womenreceivingextraamnioticprostaglandinswerelesslikelytorequireoxytocinaugmentation(34/84versus66/83RR0.51,95%CI0.39to0.67NNT=3).ExtraamnioticPGE2reducedthelikelihoodofcervixunfavourableforinductionafter12to24hourscomparedwithFoleycatheteralone(1trial,187participants,27/90versus49/97RR0.59,95%CI0.410.86NNT=5).[50]

TheauthorsfoundthatwomenallocatedtoextraamnioticF2prostaglandinsweremorelikelytobenotvaginallydeliveredwithin24hoursthanwomenreceivingvaginalmisoprostol(1trial,152women,34/76versus14/76,RR2.4395%CI1.42to4.15NNH=3).WomenweremorelikelytobesatisfiedwithextraamnioticprostaglandinscomparedwithvaginalPGE2(1trial,62women,meandifference4.40,95%CI3.50to5.30).Evaluationofothermaternalandfetaloutcomeswaslimitedduetothesmallnumbersofincludedwomenandmanydifferenttypesofcomparison.[50]

UnfavorableCervixSubgroupTherewasnodifferenceincaesareandeliveriesamongwomenreceivingextraamnioticPGE2versusextraamnioticplacebo(2trials,60participants)norbetweenwomenreceivingextraamnioticPGF2andextraamnioticplacebo(1trial,25participants).TherewasnodifferenceincaesareansectionsbetweenwomenreceivingextraamnioticPGE2andvaginalPGE2(3trialswith142women),orbetweenwomenreceivingextraamnioticPGE2andintracervicalPGE2(1trial194women).Onetrialwith30participantswithunfavorablecervicesfoundnodifferenceincaesareandeliveriesbetweenwomenreceivingextraamnioticPGE2andoxytocin.Inonetrialwith77womentherewasnodifferenceincaesareansectionsbetweenwomenreceivinganintracervicalFoleycatheterandextraamnioticPGE2.TherewasnodataforcomparisonofvaginalororalmisoprostolwithextraamnioticPGE2amongwomenwithunfavorablecervices.[50]

Summary:Dataareinsufficienttorecommendextraamnioticprostaglandins.

IntravenousProstaglandins

Inthe1970sand1980s,IVprostaglandinswereinvestigatedasapotentialoptionforinductionoflabour.[51]Oursearch



identifiedonesystematicreviewcomparingIVprostaglandins(PGE2orIVPGF2)withoxytocin.ThisCochranereviewincludedthirteentrials,withatotalof1165women,whichwerecarriedoutbetween1970and1987.ComparedwithIVoxytocin,theuseofIVprostaglandinwasassociatedwithhigherratesofuterinehyperstimulationbothwithFHRchanges(5trials,390women,9/199versus0/191RR6.76,95%CI1.23to37.11,NNH=notestimable)andwithoutFHRchanges(5trials318women,17/159versus4/159RR4.25,95%CI1.48to12.24,NNH=13).However,therewasnodifferenceincaesareandeliveries.Maternalsideeffects,definedasgastrointestinalsymptoms,fever,andthrombophlebitisweremorecommonintheIVprostaglandingroup(8trials,940women,87/474versus22/466RR3.75,95%CI2.46to5.70,NNH=8).Therewerefourperinataldeathsamong491womenwhoreceivedIVprostaglandinscomparedtonoperinataldeathsamong483womenwhoreceivedIVoxytocin.Thisdifferencewasnotstatisticallysignificant.TherewerenodifferencesinNICUadmissionsandApgarscores.Therewasnodifferenceinvaginaldeliverieswithin24hours.[51]

UnfavorableCervixSubgroupIn1trialwith100primiparousparticipants,therewasnodifferenceincaesareansectionamongwomenreceivingIVprostaglandinsandwomenreceivingIVoxytocin.[51]

Summary:Intravenousprostaglandinshavenoadvantagesandincreasematernalsideeffectscomparedtoothermethodsofinduction.Thismethodofinductionoflabourhasnotenteredintogeneraluseandisofhistoricalinterestonly.

OralProstaglandins(ExcludingMisoprostol)

OursearchidentifiedoneCochranesystematicreviewcomparingoralPGE2withothermethodsofinductionoflabour.[52]Thisreviewincluded19studieswith2588women.IncludedstudiescomparedoralPGE2withplacebo,cervicalorvaginalPGE2,ororalorIVoxytocin,withorwithoutamniotomy.Therewasnodifferenceinthenumberofparticipantswhoachievedvaginaldeliverywithin24hoursbetweenwomenreceivingoralPGE2andcontrolswhoreceivedIVoxytocin.OralPGE2wasassociatedwithfewercaesareandeliveriesthanplacebo(3studies,195women,14/105versus20/90RR0.54,95%CI0.29to0.98NNT=10).TherewasnodifferenceincaesareandeliverybetweensubjectsinducedwithoralPGE2andothermethodsofinduction.OralPGE2wasassociatedwithincreasedvomitingcomparedtoIVoxytocin(3studies,305women,25/150versus4/155RR5.56,95%CI2.15to14.38NNH=9).MorewomenallocatedtooralPGE2experienceddiarrhea(2studies,236women,6/114versus0/122RR8.13,95%CI1.03to63.93NNH=notestimable)comparedwithIVoxytocin.Therewerenosignificantdifferencesinothermaternalorfetaloutcomesinanyoftheothercomparisongroups.[52]

UnfavorableCervixSubgroupAmongwomenwithunfavorablecervices,oralPGE2wasassociatedwithfewercaesareandeliveriesthanplacebo(3studies,195women,14/105versus20/90RR0.54,95%CI0.29to0.98NNT=10).Therewasnodifferencebetweencaesareandeliveriesamongwomenreceivingoralprostaglandinsandthosereceivingvaginalprostaglandins(2trials,63women),cervicalprostaglandins(1trial,50participants),oroxytocin(3trials,171women).[52]

Summary:OralprostaglandinsareassociatedwithincreasedmaternalvomitinganddiarrheacomparedwithIVoxytocin.

Mifepristone

Oursearchuncoveredonesystematicreviewofmifepristoneforinductionoflabourcombining10trialsincluding1108women.[53]Theauthorsfoundthatmifepristonewassuperiortoplaceboinachievingafavourablecervicalscoreorinitiatinglabourwithin48hours(4studies,293women,75/152versus27/171RR2.41,95%CI1.70to3.42,NNT=4).Comparedtoplacebo,mifepristonereducedtheriskforcaesareansection(9trials,1043women,163/661versus113/382RR0.74,95%CI0.60to0.92NNT=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),butdidnotadverselyaffectneonataloutcomes.[53]

ThereviewersincludedonestudycomparingmifepristonetooxytocinforinductionoflaboramongwomenwithPROMatterm.Thatstudyfoundthatcomparedwithoxytocin,mifepristonedecreasedtheproportionofwomenwhoweredeliveredvaginallywithin24hours(1study,65participants,17/33versus25/32,RR0.66,95%CI0.45to0.96,NNH=3).MifepristonewasassociatedwithincreasedFHRtracingabnormalities(9/33versus2/32,RR4.46,95%CI1.02to18.66,NNH=4)andneonatalICUadmissions(11/33versus3/32,RR3.56,95%CI1.09to11.58,NNH=4).[53]

UnfavorableCervixSubgroupAmongwomenwithunfavorablecervices,mifepristonereducedthelikelihoodofcaesareansectioncomparedwithplacebo(8trials,919participants,153/599versus96/320,RR0.7795%CI0.61to0.96,NNT=15).[53]



Summary:Theuseofmifepristoneforlabourinductioniscurrentlyinvestigational.

Oestrogens

OursearchuncoveredonesystematicreviewofoestrogenswithorwithoutamniotomyforinductionoflabourthatincludedsevenRCTsandatotalof465women.[54]Fivestudiesincluding306subjectscomparedoestrogenwithplacebo.Therewerenodifferencesinratesofcaesareandeliveries,operativevaginaldeliveriesoruterinehyperstimulationwithorwithoutFHRchangesbetweengroups.Therewerenodifferencesbetweenoestrogensandvaginalprostaglandinsincaesareandeliveries,uterinehyperstimulationwithorwithoutFHRchanges,orepiduralanalgesia(1trial,60women).Therewerenodifferencesbetweenoestrogensandcervicalprostaglandinsincesareandeliveriesorinstrumentalvaginaldeliveries(2trials,151women).TherewasnodifferencebetweenoestrogensandcervicalprostaglandinsinseriousmaternalcomplicationsorNICUadmissionsin1trialwith85women.Therewerenodifferencesbetweenoestrogensandoxytocinincaesareandeliveriesoroperativevaginaldeliveriesinonetrialincluding66women.[54]

UnfavorableCervixSubgroupInthreetrialsincluding162women,therewasnodifferenceincaesareansectionsbetweenwomenreceivingoestrogensandplacebo.Therewasnodifferenceincaesareandeliveriesbetweenwomenreceivingoestrogensandvaginalprostaglandins(1trial,60women),cervicalprostaglandins(onetrial,66women),extraamnioticprostaglandins(onetrial,30women),oroxytocin(onetrial,66women).[54]

Summary:Theuseofoestrogensforinductionoflabouriscurrentlyinvestigational.

Corticosteroids

InaCochranereview,Kavanaghandcolleaguesidentifiedeightstudiesexaminingtheuseofcorticosteroidsforlabourinduction.[55]Sevenofthesedidnotmeettheauthors'inclusioncriteria.Theoneincludedtrialhad66womenandevaluatedposttermpregnancieswhichwererandomlyassignedtoreceivetwodexamethasoneinjections(12and24hourspriortooxytocininfusion)ornotreatmentpriortooxytocin.Therewerenodifferencesincaesareandeliveries,uterinehyperstimulationwithorwithoutFHRchanges,Apgarlessthan7atfiveminutesormaternalfevers.[55]

UnfavorableCervixSubgroupTherewasnoinformationabouttheefficacyofcorticosteroidsforinductionoflaboramongwomenwithunfavorablecervices.[55]

Summary:Theuseofcorticosteroidsforinductionoflabouriscurrentlyinvestigational.

Relaxin

OursearchidentifiedoneCochranereviewthatcombinedfourstudiesincluding267womenwhousedrelaxinforinductionoflabour.[56]Comparedwithplaceboornotreatment,relaxinreducedthenumberofparticipantswithunfavourablecervicesafter24hours(3studies,173women,21/96versus37/75RR0.45,95%CI0.28to0.72NNT=4),buttheneedforoxytocinaugmentationwasnotreduced(3trials,196women,65/121versus53/75RR0.83,95%CI0.65to1.06).Therewerenodifferencesintheratesofcesareandelivery,operativevaginaldeliveries,oruterinehyperstimulationwithoutFHRchanges.Therewereinsufficientdatatoevaluateperinataldeathormorbidity.[56]

UnfavorableCervixSubgroupInthreetrialswith207women,therewasnodifferenceincaesareandeliveriesinwomenallocatedtoreceiverelaxincomparedwithplacebo.[56]

Summary:Theuseofrelaxinforinductionoflabouriscurrentlyinvestigational.

Hyaluronidase

WeidentifiedoneCochranesystematicreviewthatincludedoneRCTwith168women.[57]Womenwererandomlyassignedtoundergointracervicalhyaluronidaseorplaceboinjections.Womenreceivinghyaluronidaseinjectionsweresignificantlylesslikelytorequirecesareansection(15/83versus42/85RR0.37,95%CI0.22to0.61NNT=4)andwerelesslikelytorequireoxytocinaugmentation(8/83versus40/85RR0.20,95%CI0.10to0.41NNT=3).Fewerwomenallocatedtohyaluronidasehadacervixunfavorable/unchangedafter24hours50/83versus83/85,RR0.62,95%CI0.52to0.74,NNT=3),Noadverseeffectswerereported.[57]



UnfavorableCervixSubgroupThisincludedsystematicreviewdidnotreportanysubgroupanalysesaccordingtocervicalstatus.[57]

Summary:Theuseofhyaluronidaseforinductionoflabouriscurrentlyinvestigational.

IsosorbideMononitrate

Oursearchidentifiedtworandomisedcontrolledtrialswithatotalof502participantscomparingisosorbidemononitrate,anitricoxidedonor,withplacebo[58]orPGE2.[59]TheHabibtrialcomparedisosorbidemononititetabletswithapyridoxineplaceboafterreceivingthetrialmedication,subjectsreceivedPGE2oroxytocinaccordingtohospitalprotocol.Comparedwithplacebo,isosorbidemononitratereducedthenumberofwomenwhorequiredtreatmentwithPGE2(32of51versus46of51,P=0.002).However,isosorbidemononitrateincreasedtheneedforoxytocinaugmentation(48of51versus27of51,P=0.0001).Morewomenwhoreceivedplaceboexperienceduterinetachysystole.Comparedwithplacebo,isosorbidemononitratesignificantlyshortenedtheadmissiontodeliveryinterval(102women,13.45+/6.63versus20.12+/8.19P=0.0001).Therewasnodifferenceinvaginaldeliveriesorcesareansectionsbetweenthegroups.[58]ThePRIMstudycomparedisosorbidemononitratetoPGE2.[59]ComparedwithPGE2,isosorbidemononitritesignificantlylengthenedthetimefromtreatmenttodelivery(398participants,39,712.0hoursversus26.9+.12.5hours,meandifference12.8hours,95%CI15.2hours10.4hours,P



alsofoundconsiderableimprecisionsurroundingbenefitsandharmsofmanyoftheincludedmethods.Numbersofincludedwomeninmostinductionrandomizedtrialsweretoosmalltoexcludedifferencesinrareadverseoutcomessuchasuterinerupture,amnioticfluidembolism,orperinatalasphyxia.Furtherresearchisnecessarytoidentifypotentialrisksandbenefitsofbothcommonlyusedandinvestigationalmethodsofinductionoflabour.

ConclusionCliniciansshouldusethebestavailableevidencetochoosemethodsoflabourinduction.Researchersandfundingagenciesshouldprioritizestudiesthatcanhelptodefinitivelyguidecareinthesesituations.Womenshouldbegiveninformationaboutwhatisknownandnotknownregardingmethodsofinductioninordertobeabletoparticipatefullyinmakingdecisionsaboutinductionoflabour.

References

1. CaugheyAB,SundaramV,KaimalAJ,ChengYW,GiengerA,LittleSE,LeeJF,WongL,ShafferBL,TranSH,etal:Maternalandneonataloutcomesofelectiveinductionoflabor.[Review][168refs].EvidenceReport/TechnologyAssessment2009,176:1257.

2. HofmeyrGJ,AlfirevicZ,KellyAJ,KavanaghJ,ThomasJ,NeilsonJP,DowswellT:Methodsforcervicalripeningandlabourinductioninlatepregnancy:genericprotocol[Protocol].CochraneDatabaseofSystematicReviews2009,4.

3. ClinicalEvidenceGlossary:HelpingYoutoPracticeEvidenceBasedMedicine.[http://clinicalevidence.bmj.com/ceweb/resources/glossary.jsp#B].

4. CreatingaFrameworkfor"BestEvidence"ApproachesinSystematicReviews,EvidencebasedPracticeCenterSystematicReviewProtocol.[http://www.ahrq.gov/clinic/tp/bestevtp.htm].

5. RubinsteinSM,vanTulderM:Abestevidencereviewofdiagnosticproceduresforneckandlowbackpain.BestPractice&ResearchClinicalRheumatology2008,22(3):471482.

6. Criticalappraisal:notesandchecklists.[http://www.sign.ac.uk/methodology/checklists.html].

7. NumberNeededtoTreat(NNT).[http://www.cebm.net/?o=1044].

8. CatesC:Simpson'sparadoxandcalculationofnumberneededtotreatfrommetaanalysis.BMCMedicalResearchMathodology2002,2:1.

9. VisualRx,Version2.[http://www.nntonline.net/visualrx/v2].

10. EBMTools:Glossary.[http://clinicalevidence.bmj.com/ceweb/resources/glossary.jsp].

11. BrozekJL,AklEA,AlonsoCoelloP,LangD,JaeschkeR,WilliamsJW,PhillipsB,LelgemannM,LethabyA,BousquetJ,etal:Gradingqualityofevidenceandstrengthofrecommendationsinclinicalpracticeguidelines.Part1of3.AnoverviewoftheGRADEapproachandgradingqualityofevidenceaboutinterventions.Allergy2009,64(5):669677.

12. Gradingqualityofevidenceandstrengthofrecommendations.BMJ2004,328(7454):1490.

13. MoherD:Preferredreportingitemsforsystematicreviewsandmetaanalyses:thePRISMAstatement.Journalofclinicalepidemiology2009,62(10):10061012.

14. KellyAJ,MalikS,SmithL,KavanaghJ,ThomasJ:Vaginalprostaglandin(PGE2andPGF2a)forinductionoflabouratterm.CochraneDatabaseofSystematicReviews2010,2.

15. BoulvainM,KellyAJ,IrionO:Intracervicalprostaglandinsforinductionoflabour[SystematicReview].CochraneDatabaseofSystematicReviews2009,3.

16. AlfirevicZ,KellyAJ,DowswellT:Intravenousoxytocinaloneforcervicalripeningandinductionoflabour[Systematic



Review].CochraneDatabaseofSystematicReviews2010,2:2.

17. KuntC,KanatPektasM,GungorANC,KurtRK,OzatM,GulermanC,GungorT,MollamahmutogluL:RandomizedTrialofVaginalProstaglandinE2VersusOxytocinforLaborInductioninTermPrematureRuptureofMembranes.TaiwaneseJournalofObstetricsandGynecology2010,49(1):5761.

18. BrickerL,LuckasM:Amniotomyaloneforinductionoflabour.CochraneDatabaseofSystematicReviews2009,1.

19. HowarthG,BothaDJ:Amniotomyplusintravenousoxytocinforinductionoflabour.CochraneDatabaseofSystematicReviews2009,1.

20. HofmeyrJG,GulmezogluMA,PileggiC:Vaginalmisoprostolforcervicalripeningandinductionoflabour.CochraneDatabaseofSystematicReviews2010,10.

21. AlfirevicZ,WeeksA:Oralmisoprostolforinductionoflabour.CochraneDatabaseofSystematicReviews2009,1.

22. GaffaneyCAL,SaulL,RumneyP,MorrisonE,ThomasS,NageotteM,WingD:Outpatientoralmisoprostolforprolongedpregnancies:apilotinvestigation.AmericanJournalofPerinatology2009,26(9):673677.

23. NagpalM,RaghunandanC,SailiA:OralmisoprostolversusintracervicalprostaglandinE2gelforactivemanagementofprematureruptureofmembranesatterm.Internationaljournalofgynecologyandobstetrics2009,106(1):2326.

24. MuzonziniG,HofmeyrGJ:Buccalorsublingualmisoprostolforcervicalripeningandinductionoflabour.CochraneDatabaseofSystematicReviews2009,1.

25. BartuseviciusA,BarcaiteE,NadisauskieneR:Oral,vaginalandsublingualmisoprostolforinductionoflabor.IntJGynaecolObstet2005,91(1):29.

26. SouzaASR,AmorimMMR,FeitosaFEL:Comparisonofsublingualversusvaginalmisoprostolfortheinductionoflabour:asystematicreview.BJOG:AnInternationalJournalofObstetrics&Gynaecology2008,115(11):13401349.

27. LoTK,LauWL,WongKS,TangLC:Sublingualmisoprostolcomparedtoartificialruptureofmembranesplusoxytocininfusionforlabourinductioninnulliparouswomenwithafavourablecervixatterm.HongKongMedJ2006,12(5):345350.

28. ElhassanEM,NasrAM,AdamI:Sublingualcomparedwithoralandvaginalmisoprostolforlaborinduction.IntJGynaecolObstet2007,97(2):153154.

29. BoulvainM,KellyAJ,LohseC,StanCM,IrionO:Mechanicalmethodsforinductionoflabour.CochraneDatabaseofSystematicReviews2010,10.

30. HeinemannJ,GillenG,SanchezRamosL,KaunitzAM:Domechanicalmethodsofcervicalripeningincreaseinfectiousmorbidity?Asystematicreview.AmericanJournalofObstetrics&Gynecology2008,199(2):177187,discussion187178.

31. VakninZ,KurzweilY,ShermanD:Foleycatheterballoonvslocallyappliedprostaglandinsforcervicalripeningandlaborinduction:asystematicreviewandmetaanalysis.Americanjournalofobstetricsandgynecology2010,203(5):418429.

32. MoraesFilhoOB,AlbuquerqueR,CecattiJ:ArandomizedcontrolledtrialcomparingvaginalmisoprostolversusFoleycatheterplusoxytocinforlaborinduction.ActaObstetriciaetGynecologicaScandinavica2010,89(8):10451052.

33. BoulvainM,StanCM,IrionO:Membranesweepingforinductionoflabour.CochraneDatabaseofSystematicReviews2009,1.

34. KaulV,AggarwalN,RayP:Membranestrippingversussingledoseintracervicalprostaglandingeladministrationforcervicalripening.IntJGynaecolObstet2004,86(3):388389.



35. KashanianM,AkbarianA,BaradaranH,SamieeMM:Effectofmembranesweepingattermpregnancyondurationofpregnancyandlaborinduction:arandomizedtrial.GynecolObstetInvest2006,62(1):4144.

36. deMirandaE,vanderBomJG,BonselGJ,BlekerOP,RosendaalFR:Membranesweepingandpreventionofposttermpregnancyinlowriskpregnancies:arandomisedcontrolledtrial.Bjog2006,113(4):402408.

37. HillM,McWilliamsG,GarciaSurD,ChenB,MunroeM,HoeldtkeN:Theeffectofmembranesweepingonprelaborruptureofmembranes:arandomizedcontrolledtrial.Obstetricsandgynecology2008,111(6):13131319.

38. YildirimG,GngrdkK,KaradaOI,AslanH,TurhanE,CeylanY:Membranesweepingtoinducelaborinlowriskpatientsattermpregnancy:arandomisedcontrolledtrial.JournalofMaternalFetal&NeonatalMedicine2010,23(7):681687.

39. HamdanM,SidhuK,SabirN,OmarS,TanP:Serialmembranesweepingatterminplannedvaginalbirthaftercesarean:arandomizedcontrolledtrial.Obstetricsandgynecology2009,114(4):745751.

40. KellyAJ,KavanaghJ,ThomasJ:Castoroil,bathand/orenemaforcervicalprimingandinductionoflabour.CochraneDatabaseofSystematicReviews2009,1.

41. SmithCA,CrowtherCA:Acupunctureforinductionoflabour.CochraneDatabaseofSystematicReviews2009,1.

42. SmithCA,CrowtherCA,CollinsCT,CoyleME:Acupuncturetoinducelabor:arandomizedcontrolledtrial.Obstetrics&Gynecology2008,112(5):10671074.

43. AsherG,CoeytauxR,ChenW,ReillyA,LohY,HarperT:Acupuncturetoinitiatelabor(Acumoms2):arandomized,shamcontrolledclinicaltrial.JournalofMaternalFetal&NeonatalMedicine2009,22(10):843848.

44. ModlockJ,NielsenBB,UldbjergN:Acupuncturefortheinductionoflabour:adoubleblindrandomisedcontrolledstudy.BJOG:aninternationaljournalofobstetricsandgynaecology2010,117(10):12551261.

45. SelmerOlsenT,LydersenS,MrkvedS:Doesacupunctureusedinnulliparouswomenreducetimefromprelabourruptureofmembranesattermtoactivephaseoflabour?Arandomisedcontrolledtrial.ActaObstetriciaetGynecologicaScandinavica2007,86(12):14471452.

46. KavanaghJ,KellyAJ,ThomasJ:Breaststimulationforcervicalripeningandinductionoflabour.CochraneDatabaseofSystematicReviews2009,1.

47. KavanaghJ,KellyAJ,ThomasJ:Sexualintercourseforcervicalripeningandinductionoflabour.CochraneDatabaseofSystematicReviews2009,1.

48. SmithCA:Homoeopathyforinductionoflabour.CochraneDatabaseofSystematicReviews2010,3.

49. OmerH,SirkovitzA:Failureofhypnoticrelaxationinthetreatmentofposttermpregnancies.PsychosomMed1987,49(6):606609.

50. HuttonEK,MozurkewichEL:Extraamnioticprostaglandinforinductionoflabour.CochraneDatabaseofSystematicReviews2009,1.

51. LuckasM,BrickerL:Intravenousprostaglandinforinductionoflabour.CochraneDatabaseofSystematicReviews2010,4.

52. FrenchL:OralprostaglandinE2forinductionoflabour.CochraneDatabaseofSystematicReviews2009,1.

53. HapangamaD,NeilsonJP:Mifepristoneforinductionoflabour.[updateofCochraneDatabaseSystRev.2000(4):CD002865PMID:11034779].CochraneDatabaseofSystematicReviews2009,3:CD002865.

54. ThomasJ,KellyAJ,KavanaghJ:Oestrogensaloneorwithamniotomyforcervicalripeningorinductionoflabour.



ListofAbbreviationsTheabbreviationsusedinthismanuscriptinclude:CI:confidenceintervalFHR:fetalheartrateIV:intravenousMA:metaanalysisNNH:numberneededtoharmNNT:numberneededtotreatPGE2:ProstaglandinE2PGF2:ProstaglandinF2RCT:randomisedcontrolledtrialRR:riskratioSR:systematicreviewWMD:weightedmeandifference.

AcknowledgementsandFundingThisprojectwasfinanciallysupportedbyChildbirthConnectionthroughagrantfromtheNewHampshireCharitableFoundation.

Authors'contributionsKKandJCperformedtheliteraturesearchesrequiredforthisreviewandreviewedallabstracts.EMandJCperformedanupdatedsearchoftheliteratureandabstractreviewwhenitbecamenecessaryduringmanuscriptpreparation.EMandKKreviewedallfulltextarticles.EMandJCperformedallassessmentsofstudyquality.EM,KK,DB,VR,UP,andVKwroteandeditedthemanuscript.KKandVKparticipatedintheformulationofthemethodsofthisreviewandEMandKKassignedtheevidencegrades.Allauthorsreadandapprovedthefinalmanuscript.

CompetinginterestsDrs.Mozurkewich,Romero,Berman,andPerni,arecoinvestigatorsonanongoingmulticentre,industrysponsoredrandomizedcontrolledtrialcomparingthemisoprostolvaginalinsertwiththedinoprostonevaginalinsert.

BMCPregnancyChildbirth.201111(84)2011BioMedCentral,Ltd.

ThiswebsiteusescookiestodeliveritsservicesasdescribedinourCookiePolicy.Byusingthiswebsite,youagreetotheuseofcookies.close

CochraneDatabaseofSystematicReviews2009,1.

55. KavanaghJ,KellyAJ,ThomasJ:Corticosteroidsforcervicalripeningandinductionoflabour.CochraneDatabaseofSystematicReviews2009,1.

56. KellyAJ,KavanaghJ,ThomasJ:Relaxinforcervicalripeningandinductionoflabour.CochraneDatabaseofSystematicReviews2009,1.

57. KavanaghJ,KellyAJ,ThomasJ:Hyaluronidaseforcervicalripeningandinductionoflabour.CochraneDatabaseofSystematicReviews2009,1.

58. HabibSM,EmamSS,SaberAS:Outpatientcervicalripeningwithnitricoxidedonorisosorbidemononitratepriortoinductionoflabor.InternationalJournalofGynaecology&Obstetrics2008,101(1):5761.

59. OsmanI,MacKenzieF,NorrieJ,MurrayHM,GreerIA,NormanJE:The"PRIM"study:arandomizedcomparisonofprostaglandinE2gelwiththenitricoxidedonorisosorbidemononitrateforcervicalripeningbeforetheinductionoflaboratterm.AmJObstetGynecol2006,194(4):10121021.

induction of labour

Documents