induction of labour
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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)
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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
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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.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
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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
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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
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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.
PharmacologicMethodsIntravaginalProstaglandins(PGE2andPGF2a)
OursearchidentifiedoneCochranesystematicreviewofvaginalprostaglandinE2(PGE2)orF2(PGF2).[14]Withinthisreview,37studiescomparedPGE2withplacebo.Ofthese,twotrialswith384womenaddressedtheprimaryoutcomeofachievingvaginaldeliverywithin24hours.ThesestudiesdemonstratedthatPGE2reducedfailuretoachievevaginaldelivery
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within24hourscomparedwithplacebo(36/199versus183/185RelativeRisk[RR]0.19,95%ConfidenceInterval[CI]0.14to0.25NNT=2).However,therewassignificantbetweenstudyheterogeneityinthesetwoincludedstudies,(P
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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]
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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]
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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
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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
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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
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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
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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
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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
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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
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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]
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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]
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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
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alsofoundconsiderableimprecisionsurroundingbenefitsandharmsofmanyoftheincludedmethods.Numbersofincludedwomeninmostinductionrandomizedtrialsweretoosmalltoexcludedifferencesinrareadverseoutcomessuchasuterinerupture,amnioticfluidembolism,orperinatalasphyxia.Furtherresearchisnecessarytoidentifypotentialrisksandbenefitsofbothcommonlyusedandinvestigationalmethodsofinductionoflabour.
ConclusionCliniciansshouldusethebestavailableevidencetochoosemethodsoflabourinduction.Researchersandfundingagenciesshouldprioritizestudiesthatcanhelptodefinitivelyguidecareinthesesituations.Womenshouldbegiveninformationaboutwhatisknownandnotknownregardingmethodsofinductioninordertobeabletoparticipatefullyinmakingdecisionsaboutinductionoflabour.
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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.
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CochraneDatabaseofSystematicReviews2009,1.
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