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  OriginalArticle Evaluation   of    effect   of    letrozole   prior   to   misoprostol   in   comparisonwith   misoprostolalone   insuccess   rate   of    induced   abortion T.Behroozi-Lak a, *,   S.Derakhshan-Aydenloo b ,F.   Broomand a a Reproductive   Health   Research   Center,   Department    of    Infertility,   Urmia   University   of    Medical   Sciences,   Urmia,   Iran b Urmia   University   of    Medical   Sciences,   Urmia,   Iran Introduction Abortion,   spontaneous   or   induced,   is   a   common   complication   of pregnancy.   The   World   Health   Organization   reported   that   annuallyabout   79   million   unintended   pregnancies   excluding   miscarriagesare   occurring   worldwide   [1].   And   annually,   about   46   millioninduced   abortions   occur   in   the   world   [2,3].   The   estimation   of    thetotal   number   of    abortions   is   quite   difficult,   especially   in   developingcountries,   and   it   is   usually   underreported   due   to   the   legalrestrictions   a   huge   number   of    the   inducted   abortions   areperformed   in   non-hygienic   situations.   The   abortion   might   loadan   undesirable   cost   to   the   families   and   health   care   system.   Seriouscomplications   such   as   maternal   death,   uterine   rupture,   and   sepsismay   occur   after   abortions   that   are   not   taken   place   under   medicalobservation   [4].   The   safety   of    the   procedure   has   a   dramaticimportance   in   order   to   achieve   a   non-life   threatening   result.Induced   abortion   can   be   performed   by   medical   and   surgicalmethods.   Medical   abortion   is   the   induction   of    early   abortion   byconsumption   of    special   of    medications   and   is   named   successful   if    itis   completed   without   the   need   of    any   surgical   intervention.   Also,the   medical   approach   is   a   safe   and   effective   alternative   to   surgicalmethods   with   a   high   level   of    patient   satisfaction   [5,6].Prostaglandins   and   their   analogs   are   widely   used   for   medicalinduced   abortion.   Misoprostol,   a   prostaglandin   E1   analog,   is   usedwidely   for   early   abortion   and   has   been   shown   to   be   a   betteralternative   to   other   prostaglandin   substances   due   to   feasibility,simple   and   easy   administration,   low   price,   stability   at   roomtemperature,   and   fewer   systemic   side-effects   [7,8].   Sublingual   andvaginal   are   two   common   routes   of    misoprostol   administrationwith   different   pharmacokinetics   and   effectiveness.   Sublingualmisoprostol   reaches   its   peak   concentration   in   a   short   time   andvaginal   route   has   less   adverse   effects   after   administration   [9].The  J   Gynecol   Obstet   Hum   Reprod   xxx   (2017)   xxx–xxx* Corresponding   author. E-mail   address:   (T.   Behroozi-Lak). A   R    T   I   C   L    E   I   N   F   O  Articlehistory: Received   30    July   2017 Receivedinrevisedform27October2017 Accepted   2   November   2017Available   online   xxx Keywords: LetrozoleMisoprostolAbortion A   B   S   T   R    A   C   T Background.   –   Abortion,spontaneousorinduced,isacommoncomplicationofpregnancyandexplorationofavailableandsaferegimensformedicalabortionindevelopingcountriesseemscrucial.  Aims.– Thepresentstudywasaimedtoassesstheeffectofletrozoleincombinationwithmisoprostolinwomeneligibleforlegaltherapeuticabortionwithgestationalage  14weeks. Materialsandmethods.– Thisclinicalrandomizedtrialwasconductedon78womenwhowerecandidateofmedicalabortionandeligibleforlegalabortionwithgestationalage  14weeksthatwererandomlydividedintotwogroupsofcaseandcontrols.Casegroupreceiveddailyoraldoseof10mgletrozoleforthreedaysfollowedbyvaginalmisoprostol.Incontrolgroupthepatientsreceivedonlyvaginalmisoprostol.Therateofcompleteabortion,induction-of-abortiontime,andside-effectswereassessed. Results.– Completeabortionwasobservedin30patients(76.9%)incasegroupand9(23.1%)caseswerefailed.Incontrolgrouptherewas16(41.03%)completeabortionsand23(58.97%)caseswerefailedtoabort.Patientswithgestationalageofbetween6and10weeksdidnotshowsignificantdifferenceinbothgroups( P  =0.134).Regardingpregnancyremnantsthereweresignificantdifferencesbetweentwogroups( P  =0.034).Thetimeformadmissiontodischargeincasegroupsweresignificantlyshorterthanthoseincontrolgroup( P  =0.001).Theindicationforcurettageincasegroupwassignificantlylessthancontrolgroup( P  =0.001). Conclusion.– A3-daycourseofletrozole(10mg/daily)followedbymisoprostolwasassociatedwithahighercompleteabortionandlowercurettageratesandreductionintimefromadmissiontodischargeinwomenwithgestationalage  14weekscomparedtomisoprostolalone.  C 2017ElsevierMassonSAS.Allrightsreserved. GModel JOGOH   118   1–5 Please   cite   this   article   in   press   as:   Behroozi-Lak   T,   et   al.   Evaluation   of    effect   of    letrozole   prior   to   misoprostol   in   comparison   withmisoprostol   alone   in   success   rate   of    induced   abortion.    J   Gynecol   Obstet   Hum   Reprod   (2017), j.jogoh.2017.11.002  Available   online   at ScienceDirect  C 2017   Elsevier   Masson   SAS.   All   rights   reserved.  range   of    reported   successes   rate   of    abortion   induction   withmisoprostol   is   quite   different   in   several   studies   (between   37%   and86%)   depending   on   the   regimen,   route   of    administration,   anddosage   used.   However,   in   combination   with   other   drugs   was   moreeffective   [10–12].Letrozole,   aromatase   inhibitors,   in   combinedwith   vaginal   misoprostol   shown   that   was   more   effective   thanmisoprostol   alone   with   lower,   but   not   significant   induction-of-abortion   time   in   termination   of    pregnancy   [13].   Letrozole   is   a   thirdgeneration   aromatase   inhibitor   and   its   action   is   suppressingestrogen   production   [14,15].Misoprostol   is   a   synthetic   prostaglandin   E1   analogue,   manu-factured   as   an   oral   preparation   available   as   200   m g   tablets   used   toprevent   and   treat   gastroduodenal   damage   induced   by   nonsteroidalanti-inflammatory   drugs   [16].   The   most   common   adverse   effects   of misoprostol   are   nausea,   vomiting,   diarrhea,   abdominal   pain,   chills,shivering,   and   fever,   all   of    which   are   dose-dependent   [17].Miso-prostol   taken   by   pregnant   women   increases   uterine   tone   andcontractions.The   success   rate   of    abortion   of    mifepristone   in   combinationwith   misoprostol   is   significant,   however,   this   medication   is   notavailable   in   our   country.   Therefore,   we   decided   to   study   effect   of letrozole   prior   to   misoprostol   in   success   rate   of    induced   abortion.In   this   study   patients   with   missed   abortion   were   included   andpatients   with   failure   pregnancy   and   incomplete   abortion   were   notincluded.The   aim   of    this   study   was   to   evaluate   effect   of    letrozole   prior   tomisoprostol   in   comparison   with   misoprostol   alone   in   success   rateof    induced   abortion   in   women   with   gestational   age   of       14   weeks. Patients   and   methods This   clinical   randomized   trial   study   was   conducted   on78   women   who   were   candidate   of    medical   abortion   and   eligiblefor   legal   abortion   with   gestational   age      14   weeks,   attendingMotahari   Hospital   in   Urmia,   Iran.The   inclusion   criteria   were:   good   general   health;   older   than   theage   of    legal   consent   (ie,   older   than   18   years);   the   gestational   age    14   weeks   as   confirmed   by   ultrasound   scanning   on   day   1   of    thestudy,   hemoglobin      10   g/L    and   diastolic   pressure   <   95   mmHg.The   exclusion   criteria   were:   history   or   evidence   of    adrenalpathology,   steroid-dependent,   cancer,   porphyria,   diastolic   pres-sure   over   95   mmHg,   bronchial   asthma,   arterial   hypertension,history   or   evidence   of    thromboembolism,   severe   or   recurrent   liverdisease,   breast   feeding,   anomaly   of    fetus,   regular   use   of    prescrip-tion   drugs   before   admission   to   the   study,   any   abnormal   values   inpretreatment   blood   tests,   namely   complete   blood   picture,   renaland   liver   function   tests.   Individuals   who   fulfilled   the   selectioncriteria   and   death   of    the   fetus   was   confirmed   by   two   separateultra-sonographies   and   were   willing   to   participate   gave   theirinformed   written   consent.The   study   was   approved   by   the   Institutional   Ethical   Committeeof    the   Urmia   University   of    Medical   Sciences,   Urmia,   Iran.   The   studywas   registered   with   the   trial   number   IR.UMSU.REC.1395.436The   participants   were   randomized   into   the   two   groups   of 39   patients   each   by   the   hospital   pharmacists   according   tocomputer-generated   random   numbers.   Until   the   completion   of the   study,   both   patients   and   the   clinicians   were   blinded   to   thegroup   assigned.Ultrasound   examination   was   performed   on   eligible   women   toconfirm   intrauterine   pregnancy   and   the   gestational   age.   After   adetailed   history   and   a   full   body   examination,   complete   bloodcount,   renal,   and   liver   function   were   checked.Women   in   case   group   were   given   10   mg   letrozole   orally   on   days1–3   followed   by   vaginal   misoprostol   each   12   hrs   for   3   times.   Incontrol   group,   the   patients   were   received   only   vaginal   misoprostolwith   the   same   method.   The   initial   dose   of    misoprostol   was   800   mgper   12   h   and   transvaginally.Until   abortion   was   occurred   within   3-dose   misoprostoladministration,   the   regimen   was   continued.   Where   abortion   wasnot   occurred   48   hours   after   termination   of    regimen   or   pregnancyremnant   after   abortion   was   more   than   15   mL,   or   hemorrhage   was   alot,   the   patient   was   undergone   curettage.   In   cases   with   pregnancyremnant   less   than   15   mL,   the   patients   with   the   same   remnantswere   discharged   and   then   these   patients   were   followed   byultrasonography   after   1   week.   If    pregnancy   remnant   persisted   incontrol   ultrasonography,   the   curettage   was   performed.   Indicationsfor   hospitalization   of    the   patients   were   severe   hemorrhage,   pain,anxiety   of    abortion   within   3-day   letrozole   therapy   and   no   abortionwith   only   letrozole   (for   vaginal   misoprostol   use).In   both   group   frequency   of    complete   abortion,   interval   forminduction   to   complete   exit   of    pregnancy   products,   frequency   of need   for   curettage,   consumed   misoprostol   and   side   effects   (nausea,vomiting,   diarrhea,   fatigue,   dizziness,   headache,   lower   abdominalpain,   fever,   rash,   and   chills   or   shivering)   were   assessed.In   case   group   patients,   in   each   step   of    letrozole   or   misoprostoladministration,   the   administration   of    the   medicine   was   stopped   if the   abortion   was   achieved.   In   other   patients   the   administrationwas   continued   until   achievement   of    abortion   based   on   the   studydesign.   Therefore,   the   total   administration   of    letrozole   andmisoprostol   was   not   the   same   in   patients.The   clinical   criteria   of    successful   abortion   included   lack   of severe   hemorrhage   and   hemodynamic   stability   of    patients   afterabortion   that   avoided   curettage.   The   sonographic   criteria   of successful   abortion   included   no   pregnancy   remnant   or   remnantsless   than   15   mL    in   transvaginal   ultrasonography,   provided   that   theremnants   were   cleared   in   one   week   follow   up. Statistical   analysis The   sample   size   was   calculated   as   78   subjects   using   thecomparison   of    proportion   formula   with   two-sided   log-rank   test, a =   0.05,   and   84%   of    power.   All   statistical   analyses   were   done   usingSPSS   version   20   (SPSS   Inc,   Chicago,   IL,   USA).   Descriptive   data   arereported   as   mean      standard   deviation,   or   number   (percent)   asappropriate.   Independent   sample   t-test,   Chi-square   test,   and   Kaplan-Meier   were   used   for   data   analysis.   The   level   of    significance   isconsidered   to   be   P    <   0.05. Results In   the   present   study   78   patients   were   randomized   into   twogroups   of    39   patients   each.   In   control   group   only   vaginalmisoprostol   and   in   case   group   letrozole   and   vaginal   misoprostolwere   assessed.   The   demographic   data   are   shown   in   Table   1.Therewere   no   significant   differences   in   age,   gravidity,   parity,   history   of miscarriages,   natural   delivery   and   C-section   and   history   of abortion   ( P    >   0.05).   Despite   randomized   sampling,   mean   valuesfor   gestational   age   based   on   ultrasonography   was   significantlydifferent   between   two   groups   ( P    <   0.05).Complete   abortion   was   observed   in   30   patients   (76.9%)   in   casegroup   and   9   (23.1%)   cases   were   failed.   In   control   group   there   was16   (41.03%)   complete   abortions   and   23   (58.97%)   cases   were   failedto   abort.   The   successful   rate   of    abortion   was   completely   different   incase   group   compared   to   control   group   ( P    =   0.001).   In   case   group58.97%   of    the   patients   received   only   letrozole   and   41.03%   of    thepatients   received   letrozole   and   misoprostol.   In   case   group   1   (2.6%),2   (5.1%),   2   (5.1%),   1   (2.6%)   and   33   (84/6%)   patients   received   15,   20,22.5,   25   and   30   mg   letrozole,   respectively.Regarding   the   administered   misoprostol   doses,   in   case   group   8(50%),   1   (6.2%)   and   7   (43.8%)   patients   received   800,   1600   and T.   Behroozi-Lak   et    al.    /     J    Gynecol   Obstet    Hum   Reprod    xxx   (2017)    xxx–xxx 2 GModel JOGOH   118   1–5 Please   cite   this   article   in   press   as:   Behroozi-Lak   T,   et   al.   Evaluation   of    effect   of    letrozole   prior   to   misoprostol   in   comparison   withmisoprostol   alone   in   success   rate   of    induced   abortion.    J   Gynecol   Obstet   Hum   Reprod   (2017), j.jogoh.2017.11.002  2400   mg   misoprostol,   respectively.   In   control   group   12   (30.8%),   6(15,4%)   and   21   (53.8%0   of    patients   received   800,   1600   and   2400   mgmisoprostol,   respectively.   Therefore,   there   were   no   significantdifferences   between   two   groups   in   dose   of    misoprostol   consump-tion   ( P    =   0.346).The   induction-to-abortion   time   following   misoprostol   admin-istration   in   both   case   and   controls   are   shown   in   Table   2.Theindication   for   curettage   case   group   was   significantly   lower   thancontrol   group   ( P    =   0.001)   (Table   3).In   case   group,   two   (22.2%),   four(44.4%)   and   three   (33.3%)   of    patients   were   undergone   curettagebecause   of    failed   abortion,   severe   hemorrhage   and   pregnancyremnant   >   15   mL,   respectively.   In   control   group,   4   (17.4%),   10(43.5%)   and   9   (39.1%)   of    patients   were   also   undergone   curettagebecause   of    failed   abortion,   severe   hemorrhage   and   pregnancyremnant,   respectively.   There   were   no   significant   differencesbetween   two   groups   in   terms   of    reason   for   curettage   ( P    =   0.932).Regarding   pregnancy,   remnants   there   were   significant   diffe-rences   between   two   groups   ( P    =   0.034)   (Table   3).In   case   group,   three   patients   were   ultrasonographicallyconfirmed   to   undergo   curettage   and   30   (90.9%)   of    patients   didnot   need   curettage.   In   control   group   9   (36%)   patients   wereundergone   curettage   and   16   (64%)   of    patients   did   not   needcurettage,   therefore,   there   was   significant   difference   between   twogroups   ( P    =   0.012).   The   time   form   admission   to   discharge   in   casegroups   were   significantly   shorter   than   those   in   control   group( P    =   0.000)   (Table   3).The   most   common   side   effects   in   both   groups   was   abdominalpain.   The   incidence   of    side   effects   was   comparable   for   the   twogroups   also   the   severity   of    side-effects   was   not   significantlydifferent   between   groups   ( P    >   0.05).   In   case   and   control   groups11   and   4   women   with   gestational   age   of    less   than   six   weeks,respectively,   showed   successful   abortion.   In   case   group   16   (69.6%)and   7   (30.4%)   patients   with   gestational   age   of    between   6   and10   weeks   showed   complete   and   failed   abortions,   respectively.   Incontrol   group,   11   (47.8%)   and   12   (52.2%)   patients   with   gestationalage   of    between   6   and   10   weeks   showed   complete   and   failedabortions,   respectively.   Patients   with   gestational   age   of    between6   and   10   weeks   did   not   show   significant   difference   in   both   groups(P   =   0.134).   In   case   group,   3   (60%)   and   2   (40%)   patients   withgestational   age   of    more   than   10   weeks   showed   complete   and   failedabortions,   respectively.   In   control   group,   1   (8.3%)   and   11   (91.7%)patients   with   gestational   age   of    more   than   10   weeks   showedcomplete   and   failed   abortions,   respectively   and   a   significantdifference   was   observed   between   two   groups   ( P    =   0.022).   Table   4shows   frequency   of    complete   expulsion   and   no   expulsion   of    fetus,and   severe   vaginal   hemorrhage   with   letrozole   alone   and   letrozolewith   misoprostol   in   both   groups.It   should   be   noted   that   since   half    the   patients   showed   successfulabortion   with   letrozole   only,   the   misoprostol   administration   wasnot   performed   for   them   in   case   group. Discussion The   present   study   is   aimed   to   assess   letrozole   as   a   synergisticagent   in   combination   with   misoprostol   compared   with   misopros-tol   alone   for   medical   abortion.   Our   results   demonstrated   an   earliercomplete   abortion   rate   of    57.1%   in   women   requesting   medical  Table   1 Comparison   of    demographic   data   of    the   patients   in   both   groups.Group   Case   Control   P  -valueMax.   Min.   Mean   SD   Max.   Min.   Mean   SDAge   44   year   19   year   29.56   year   6.09   year   44   year   19   year   28.31   year   0.381Gravidity   7   1   2.46   1.48   6   1   2.46   1.21   0.638Parity   6   1.03   6   1.03   1.16   0.932Gestational   age(ultrasonography)13   week   5   week   7   week   +   6   day   +   2   week   +1   day   14   week   +   2   day   5   week   9   week   +   1   day   +   2   week   +   3day   0.008Abortion   number   6   0   3   0   0.371  Table   2 The   interval   from   misoprostol   administration   to   abortion   in   hour.The   interval   from   administration   to   abortion   (hr)   Total <   12   12–24   24–36   36–48   48–60   60–72   <   72 Group CaseNumber   8   1   1   1   2   1   0   14Percent   57.1   7.1   7.1   7.1   14.3   7.1   0   100ControlNumber   9   8   11   3   3   0   1   35Percent   25.7   22.9   31.4   8.6   8.6   0   2.9   100  Table   3 Frequency   of    curettage   in   both   groups,   frequency   of    pregnancy   remnants   in   bothgroups   following   administration   of    misoprostol,   The   interval   of    hospitalization   of patients   in   both   groups.Groups   Case   Control   P  -valueNumbers   Percent   Numbers   Percent Curettage Yes   9   23.1   23   59.0   0.001No   30   76.9   16   41.0Total   39   100.0   39   100.0 Pregnancy   remnants <   15   CC   11   84.6   8   47.1   0.034 > 15   CC   2   15.4   9   52.9Total   13   100.0   17   100.0 The   interval   of    hospitalization <   3   days   12   50.0   5   12.8   0.0013–6   days   12   50.0   34   87.2Total   24   100.0   39   100.0  Table   4 Frequency   of    abortion,   no   abortion   and   severe   vaginal   hemorrhage   in   twogroups.Group   Status   Type   of    effect   Number   (%)Case   Abortion   with   letrozole   Complete   abortion   15   (38.46)Remnants   <   15   CC   5   (12.82)Remnants      15   CC   0   (0)Abortion   with   letrozole   andmisoprostolComplete   abortion   5   (12.82)Remnants   <   15   CC   6   (15.38)15   CC      remnants   2   (5.13)No   abortion   2   (5.13)Severe   vaginal   hemorrhage   4   (10.26)Control   Abortion   with   misoprostol   Complete   abortion   8   (20.51)Remnants   <   15   CC   8   (20.51)15   CC      remnants   9   (23.08)No   abortion   4   (10.26)Severe   vaginal   hemorrhage   10   (25.64) T.   Behroozi-Lak   et    al.    /     J    Gynecol   Obstet    Hum   Reprod    xxx   (2017)    xxx–xxx   3 GModel JOGOH   118   1–5 Please   cite   this   article   in   press   as:   Behroozi-Lak   T,   et   al.   Evaluation   of    effect   of    letrozole   prior   to   misoprostol   in   comparison   withmisoprostol   alone   in   success   rate   of    induced   abortion.    J   Gynecol   Obstet   Hum   Reprod   (2017), j.jogoh.2017.11.002  abortion   with   the   regimen   of    letrozole   and   misoprostol   comparedto   25.7%   in   women   with   the   regimen   of    misoprostol   alone.Others   reported   56.3%   of    complete   abortion   after   firstadministration   of    800   mg   of    misoprostol   vaginally,   and   92.4%after   administration   of    the   second   dose   (1600   mg)   [18].   About82.9%   of    complete   abortion   within   24   h   after   vaginal   administra-tion   of    misoprostol   (800   mcg)   has   been   reported   [19].   Also,   the   rateof    complete   abortion   between   68%   and   81%   has   been   reported   byothers   using   misoprostol   alone   [20–23].The   rate   of    completeabortion   in   the   present   study   was   76.9%   in   women   who   receivedletrozole   and   misoprostol   alone,   which   was   higher   than   otherreports.   The   variations   between   findings   may   explain   by   differentdoses   and   gestational   age   in   studied   women.The   use   of    letrozole   in   combination   with   vaginal   misoprostolhas   been   assessed   by   others   and   different   results   have   beenreported.   In   one   study   following   administration   of    letrozole   (10   mgfor   three   days)   in   combination   with   a   single   dose   of    vaginalmisoprostol   (800   mg),   complete   abortion   rate   was   observed   in86.9%   in   pregnancies   up   to   week   7   of    gestation   [24].Othersreported   that   in   a   7-day   course   of    letrozole   followed   by   vaginalmisoprostol   a   complete   abortion   rate   about   of    95%   was   observed[25].   The   regimen   of    vaginal   misoprostol   (800   mg)   followingpretreatment   with   mifepristone   (200   mg)   and   three   days   of letrozole   (10   mg/daily)   with   complete   abortion   rate   of    98%   hasalso   been   reported   [26].In   the   present   study   there   was   no   serious   adverse   eventfollowing   administration   of    letrozole.The   results   of    the   present   study   demonstrated   that   completeabortion   rate   was   76.9%   with   misoprostol   after   pretreatment   withthree   days   of    letrozole   (10   mg)   which   was   consistent   with   otherstudies   [24–27].These   variations   may   be   explained   by   differences   in   gestationalage   in   studied   women,   duration   of    letrozole,   and   different   doses   of administration.   However,   like   previous   studies   letrozole   incombination   with   misoprostol   was   more   effective   than   misopros-tol   alone.The   regimen   used   in   the   present   study   was   well   tolerated   withno   major   adverse   events   or   specific   side-effects   and   the   compara-ble   to   those   in   other   group.   Our   study   was   in   agreement   with   otherstudies   that   showed   similar   side-effects   between   letrozole   andvaginal   routes   of    misoprostol   [28–31].The   differences   betweenfindings   can   be   a   reason   to   perform   more   randomized   trial   for   useof    the   regimen   with   letrozole   and   misoprostol.In   our   study,   induction-to-abortion   time   in   case   group   wassignificantly   shorter   than   the   control   group.   In   other   study,   themedian   of    9.7   h   in   letrozole   group   compared   to   10.9   in   the   controlgroup   has   been   reported   [29].Other   study   reported   a   lower   medianof    induction-to-abortion   in   letrozole   group   compared   to   controlgroup.   Other   reports   showed   the   median   of    5.1   h,   7.5   h,   8.2   h,   and8.7   h,   after   combination   of    letrozole   misoprostol   administration[24–26,31].It   should   be   taken   into   consideration   that   decision   forcurettage   in   order   to   achieve   abortion,   is   dependent   on   rate   of hemorrhage,   clinical   conditions   and   surgeon’s   preferences.   Nospecific   volume   is   reported   for   the   remnants,   therefore,   we   decidedto   consider   15   mL    or   more   in   our   study   design   as   a   limit   forperforming   curettage. Conclusion Our   results   showed   that   a   3-day   course   of    letrozole(10   mg/daily)   followed   by   misoprostol   was   associated   with   ahigher   complete   abortion   and   lower   curettage   rates   and   reductionin   time   from   admission   to   discharge   in   women   with   gestational   age    14   weeks   compared   to   misoprostol   alone.   However,   furtherstudies   using   different   doses   and   longer   duration   may   bewarranted. Disclosure   of    interest The   authors   declare   that   they   have   no   competing   interest. 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