Uses of Misoprostol in Obstetrics and Gynecology

UsesofMisoprostolinObstetricsandGynecologyRebeccaAllen,MD,MPHandBarbaraMO’Brien,MDDepartmentofObstetricsandGynecology,WomenandInfants’HospitalandWarrenAlpertMedicalSchoolofBrownUniversity,Providence,RIAbstractMisoprostolisasyntheticprostaglandinE1analoguethatisusedoff-labelforavarietyofindicationsinthepracticeofobstetricsandgynecology,includingmedicationabortion,medicalmanagementofmiscarriage,inductionoflabor,cervicalripeningbeforesurgicalprocedures,andthetreatmentofpostpartumhemorrhage.Duetoitswide-rangingapplicationsinreproductivehealth,misoprostolisontheWorldHealthOrganizationModelListofEssentialMedicines.Thisarticlebrieflyreviewsthevariedusesofmisoprostolinobstetricsandgynecology.Keywords:Misoprostol,Inducedabortion,Inductionoflabor,Postpartumhemorrhage,Cervicalripening,HysteroscopyMisoprostolisasyntheticprostaglandinE1analoguemarketedasanoralpreparationusedtopreventandtreatgastroduodenaldamageinducedbynonsteroidalanti-inflammatorydrugs(NSAIDs).However,misoprostolisusedoff-labelforavarietyofindicationsinthepracticeofobstetricsandgynecology,includingmedicationabortion,medicalmanagementofmiscarriage,inductionoflabor,cervicalripeningbeforesurgicalprocedures,andthetreatmentofpostpartumhemorrhage.Misoprostol’seffectsaredosedependentandincludecervicalsofteninganddilation,uterinecontractions,nausea,vomiting,diarrhea,fever,andchills.AlthoughmisoprostolisnotapprovedbytheUSFoodandDrugAdministration(FDA)fortheseindications,in2002,pregnancywasremovedfromthelabelasanabsolutecontraindicationtomisoprostoluse.Misoprostol’sadvantagesoverothersyntheticprostaglandinanaloguesareitslowcost,longshelflife,lackofneedforrefrigeration,andworldwideavailability(Figure1).PharmacokineticsRoutesofmisoprostoladministrationincludeoral,vaginal,sublingual,buccal,orrectal.Pharmacokineticsstudies(Figure2)comparingoralandvaginaladministrationhaveshownthatvaginalmisoprostolisassociatedwithslowerabsorption,lowerpeakplasmalevels,andslowerclearance,similartoanextended-releasepreparation.Vaginalmisoprostolisalsoassociatedwithagreateroverallexposuretothedrug(areaunderthecurve[AUC])andgreatereffectsonthecervixanduterus.Thereis,however,awidevariationintheabsorptionofmisoprostolthroughthevaginalepitheliumamongdifferentwomen.Thereisnoclinicallysignificantdifferencebetweenvaginalmisoprostolthatisadministereddryandvaginalmisoprostolmoistenedwithwater,saline,oraceticacid.Therectalrouteofadministrationshowsasimilarpatterntovaginaladministration,buthasalowerAUC,includingasignificantlylowermaximumpeakconcentration.ThesublingualrouteofadministrationhasanAUCsimilartovaginaladministration,butmorerapidabsorptionandhigherpeaklevelsthaneithervaginalororaladministration(Figure2).Thistranslatesintohigherratesofgastrointestinalsideeffects.Nevertheless,thesublingualroutealsocausesuterinecontractionsatarateequivalenttovaginaladministrationandhaslessvariationinabsorption.ThebuccalrouteofadministrationshowsalowerAUC,alowerpeakconcentration,andfewersideeffectsthansublingualadministration.Thebuccalroutehasapatternofabsorptionsimilartothevaginalroute,butproduceslowerserumlevelsoverall.Nonetheless,thebuccalandvaginalroutesofadministrationhavesimilareffectsonuterinetoneandactivity.Thebuccalrouteofadministrationisalsothoughttobetheleastvariableintermsofdrugexposureandpeaklevels.TheadministrationofNSAIDsforpainreliefdoesnotaltertheefficacyofmisoprostol.Therearenoknowndruginteractionswithmisoprostol.TeratogenicityMisoprostolisconsideredateratogen.Congenitaldefectsfollowingprenatalexposureinearlypregnancytomisoprostolincludeskulldefects,bladderexstrophy,arthrogryposis,cranialnervepalsies,facialmalformations,terminaltransverselimbdefects,andMoebiussequence.Thisconstellationofcongenitalmalformationsisthoughttobeduetoavasculardisruptionsecondarytouterinecontractionscausedbymisoprostol.Theincidenceoftheseabnormalitiesdoesnotappeartobehighwhenpopulationregistrieshavebeenstudied,especiallygiventhatexposuretomisoprostolisquitecommonamongsomepopulationsofpatients.Theabsoluteriskofcongenitalmalformationsafterprenatalexposuretomisoprostolisestimatedtobeapproximately1%.Pharmacokineticstudiesrevealthatmisoprostolisexcretedintobreastmilkwithdruglevelsthatriseandfallveryquickly.Levelsbecomeundetectablewithin5hoursofmaternalingestion.However,breastfeedingwomenshouldbeadvisedthatmisoprostolmaycauseinfantdiarrhea.MedicationAbortionIn2000,theFDAapprovedmedicationabortionusing600mgoforalmifepristone,aprogesteroneantagonist,with400µgoforalmisoprostol48hourslaterforpregnanciesupto49daysofgestation.However,thereisexcellentevidenceofefficacyupto63daysofgestationusingtheregimensof200mgofmifepristoneorallyfollowedbyhomeadministrationofeither800µgofbuccalmisoprostolin24to36hoursor800µgofvaginalmisoprostolin6to48hours.Womenthenreturn4to14dayslaterforaclinicalevaluationtodocumentcompleteabortion.Successratesfortheseregimensrangefrom95%to98%,withfailureduetoongoingpregnancyinapproximately1%.IntheUnitedStates,mostwomenundergoultrasoundforpregnancydatingandconfirmationofcompleteabortion.However,serialserumβ-