CochraneDatabaseofSystematicReviews Treatment for primary postpartum haemorrhage (Review) MousaHA,BlumJ,AbouElSenounG,ShakurH,AlfirevicZ MousaHA,BlumJ,AbouElSenounG,ShakurH,AlfirevicZ. Treatmentforprimarypostpartumhaemorrhage. CochraneDatabaseofSystematicReviews2014,Issue2.Art.No.:CD003249. DOI:10.1002/14651858.CD003249.pub3. www.cochranelibrary.com Treatmentforprimarypostpartumhaemorrhage(Review) Copyright©2014TheCochraneCollaboration.PublishedbyJohnWiley&Sons,Ltd. TABLE OF CONTENTS HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 PLAINLANGUAGESUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6 METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6 RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10 Figure1. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11 Figure2. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12 DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16 AUTHORS’CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17 ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18 REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19 CHARACTERISTICSOFSTUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26 DATAANDANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44 Analysis 1.1. Comparison 1 Misoprostol (any route)versus placebo or no additional treatment given to women simultaneouslytreatedwithconventionaluterotonics,Outcome1Maternaldeath. . . . . . . . . . . 55 Analysis 1.2. Comparison 1 Misoprostol (any route)versus placebo or no additional treatment given to women simultaneouslytreatedwithconventionaluterotonics,Outcome2Seriousmaternalmorbidity. . . . . . . 56 Analysis 1.3. Comparison 1 Misoprostol (any route)versus placebo or no additional treatment given to women simultaneouslytreatedwithconventionaluterotonics,Outcome3Admissiontointensivecareunit. . . . . 57 Analysis 1.4. Comparison 1 Misoprostol (any route)versus placebo or no additional treatment given to women simultaneouslytreatedwithconventionaluterotonics,Outcome4Hysterectomy. . . . . . . . . . . 58 Analysis 1.5. Comparison 1 Misoprostol (any route)versus placebo or no additional treatment given to women simultaneouslytreatedwithconventionaluterotonics,Outcome5Averagebloodlossafterenrolmentinmillilitres. 59 Analysis 1.6. Comparison 1 Misoprostol (any route)versus placebo or no additional treatment given to women simultaneouslytreatedwithconventionaluterotonics,Outcome6Bloodloss500mLormoreafterenrolment. 60 Analysis 1.7. Comparison 1 Misoprostol (any route)versus placebo or no additional treatment given to women simultaneouslytreatedwithconventionaluterotonics,Outcome7Bloodtransfusion. . . . . . . . . . 61 Analysis 1.8. Comparison 1 Misoprostol (any route)versus placebo or no additional treatment given to women simultaneouslytreatedwithconventionaluterotonics,Outcome8Bloodloss1000mLormoreafterenrolment. 62 Analysis 1.9. Comparison 1 Misoprostol (any route)versus placebo or no additional treatment given to women simultaneouslytreatedwithconventionaluterotonics,Outcome9Additionaluterotonics. . . . . . . . 63 Analysis1.10. Comparison 1Misoprostol (any route)versusplaceboor noadditional treatmentgiventowomen simultaneouslytreatedwithconventionaluterotonics,Outcome10Manualremovaloftheplacentaafterenrolment. 64 Analysis1.11. Comparison 1Misoprostol (any route)versusplaceboor noadditional treatmentgiventowomen simultaneouslytreatedwithconventionaluterotonics,Outcome11Uterinetamponadeafterenrolment. . . 65 Analysis1.12. Comparison 1Misoprostol (any route)versusplaceboor noadditional treatmentgiventowomen simultaneouslytreatedwithconventional uterotonics,Outcome12Arteryligation(uterineand/orhypogastric arteries)afterenrolment. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 66 Analysis1.13. Comparison 1Misoprostol (any route)versusplaceboor noadditional treatmentgiventowomen simultaneouslytreatedwithconventionaluterotonics,Outcome13Arterialembolisationafterenrolment. . . 67 Analysis1.14. Comparison 1Misoprostol (any route)versusplaceboor noadditional treatmentgiventowomen simultaneouslytreatedwithconventionaluterotonics,Outcome14Uterinecompressionstitchafterenrolment. 68 Analysis1.15. Comparison 1Misoprostol (any route)versusplaceboor noadditional treatmentgiventowomen simultaneouslytreatedwithconventionaluterotonics,Outcome15Evacuationofretainedproductofconception. 69 Analysis1.16. Comparison 1Misoprostol (any route)versusplaceboor noadditional treatmentgiventowomen simultaneouslytreatedwithconventionaluterotonics,Outcome16Anysurgicalco-interventions(uterinetamponade, arteryligations,arterialembolisation)excludinghysterectomyafterenrolment. . . . . . . . . . . . 70 Analysis1.17. Comparison 1Misoprostol (any route)versusplaceboor noadditional treatmentgiventowomen simultaneouslytreatedwithconventionaluterotonics,Outcome17Nausea. . . . . . . . . . . . . 71 Treatmentforprimarypostpartumhaemorrhage(Review) i Copyright©2014TheCochraneCollaboration.PublishedbyJohnWiley&Sons,Ltd. Analysis1.18. Comparison 1Misoprostol (any route)versusplaceboor noadditional treatmentgiventowomen simultaneouslytreatedwithconventionaluterotonics,Outcome18Vomiting. . . . . . . . . . . . 72 Analysis1.19. Comparison 1Misoprostol (any route)versusplaceboor noadditional treatmentgiventowomen simultaneouslytreatedwithconventionaluterotonics,Outcome19Diarrhoea. . . . . . . . . . . . 73 Analysis1.20. Comparison 1Misoprostol (any route)versusplaceboor noadditional treatmentgiventowomen simultaneouslytreatedwithconventionaluterotonics,Outcome20Maternalpyrexia38degreesormore. . . 74 Analysis1.21. Comparison 1Misoprostol (any route)versusplaceboor noadditional treatmentgiventowomen simultaneouslytreatedwithconventionaluterotonics,Outcome21Maternalpyrexia40degreesormore. . . 75 Analysis1.22. Comparison 1Misoprostol (any route)versusplaceboor noadditional treatmentgiventowomen simultaneouslytreatedwithconventionaluterotonics,Outcome22Headache. . . . . . . . . . . . 76 Analysis1.23. Comparison 1Misoprostol (any route)versusplaceboor noadditional treatmentgiventowomen simultaneouslytreatedwithconventionaluterotonics,Outcome23Shivering. . . . . . . . . . . . 77 Analysis1.24. Comparison 1Misoprostol (any route)versusplaceboor noadditional treatmentgiventowomen simultaneouslytreatedwithconventionaluterotonics,Outcome24Feelingfaintorfainting. . . . . . . . 78 Analysis1.25. Comparison 1Misoprostol (any route)versusplaceboor noadditional treatmentgiventowomen simultaneouslytreatedwithconventionaluterotonics,Outcome25Allergy. . . . . . . . . . . . . 79 Analysis2.1.Comparison2SublingualmisoprostolversusintravenousoxytocintherapyforprimaryPPHtreatmentamong womenwhohavenotreceivedanyconventionaluterotonictherapy,Outcome1Maternalmortality. . . . . 80 Analysis2.2.Comparison2SublingualmisoprostolversusintravenousoxytocintherapyforprimaryPPHtreatmentamong womenwhohavenotreceivedanyconventionaluterotonictherapy,Outcome2Seriousmaternalmorbidity. . 81 Analysis2.3.Comparison2SublingualmisoprostolversusintravenousoxytocintherapyforprimaryPPHtreatmentamong womenwhohavenotreceivedanyconventionaluterotonictherapy,Outcome3Admissiontointensivecare. . 82 Analysis2.4.Comparison2SublingualmisoprostolversusintravenousoxytocintherapyforprimaryPPHtreatmentamong womenwhohavenotreceivedanyconventionaluterotonictherapy,Outcome4Hysterectomy. . . . . . . 83 Analysis2.5.Comparison2SublingualmisoprostolversusintravenousoxytocintherapyforprimaryPPHtreatmentamong womenwhohavenotreceivedanyconventionaluterotonictherapy,Outcome5Bloodloss500mLormoreafter enrolment. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 84 Analysis2.6.Comparison2SublingualmisoprostolversusintravenousoxytocintherapyforprimaryPPHtreatmentamong womenwhohavenotreceivedanyconventionaluterotonictherapy,Outcome6Meanbloodlossafterenrolment. 85 Analysis2.7.Comparison2SublingualmisoprostolversusintravenousoxytocintherapyforprimaryPPHtreatmentamong womenwhohavenotreceivedanyconventionaluterotonictherapy,Outcome7Bloodloss1000mLormoreafter enrolment. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 86 Analysis2.8.Comparison2SublingualmisoprostolversusintravenousoxytocintherapyforprimaryPPHtreatmentamong womenwhohavenotreceivedanyconventionaluterotonictherapy,Outcome8Bloodtransfusionwithin24hours. 87 Analysis2.9.Comparison2SublingualmisoprostolversusintravenousoxytocintherapyforprimaryPPHtreatmentamong womenwhohavenotreceivedanyconventionaluterotonictherapy,Outcome9Durationfromrandomisationtill cessationofbleedingorsatisfactoryresponse. . . . . . . . . . . . . . . . . . . . . . . . 88 Analysis2.10.Comparison2SublingualmisoprostolversusintravenousoxytocintherapyforprimaryPPHtreatment amongwomenwhohavenotreceivedanyconventionaluterotonictherapy,Outcome10Additionaluterotonicsafter enrolment. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 89 Analysis2.11.Comparison2SublingualmisoprostolversusintravenousoxytocintherapyforprimaryPPHtreatment amongwomenwhohavenotreceivedany conventional uterotonic therapy,Outcome11Examination under anaesthesia. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 90 Analysis2.12.Comparison2SublingualmisoprostolversusintravenousoxytocintherapyforprimaryPPHtreatment amongwomenwhohavenotreceivedanyconventionaluterotonictherapy,Outcome12Uterinetamponadeafter enrolment. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 91 Analysis2.13.Comparison2SublingualmisoprostolversusintravenousoxytocintherapyforprimaryPPHtreatment amongwomenwhohavenotreceivedanyconventionaluterotonictherapy,Outcome13Bimanualcompression. 92 Analysis2.14.Comparison2SublingualmisoprostolversusintravenousoxytocintherapyforprimaryPPHtreatment amongwomenwhohavenotreceivedanyconventionaluterotonictherapy,Outcome14Arteryligation(uterine and/orhypogastricarteries)afterenrolment. . . . . . . . . . . . . . . . . . . . . . . . 93 Treatmentforprimarypostpartumhaemorrhage(Review) ii Copyright©2014TheCochraneCollaboration.PublishedbyJohnWiley&Sons,Ltd. Analysis2.15.Comparison2SublingualmisoprostolversusintravenousoxytocintherapyforprimaryPPHtreatment amongwomenwhohavenotreceivedanyconventionaluterotonictherapy,Outcome15Arterialembolisationafter enrolment. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 94 Analysis2.16.Comparison2SublingualmisoprostolversusintravenousoxytocintherapyforprimaryPPHtreatment amongwomenwhohavenotreceivedanyconventionaluterotonictherapy,Outcome16Uterinetamponadeafter enrolment. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 95 Analysis2.17.Comparison2SublingualmisoprostolversusintravenousoxytocintherapyforprimaryPPHtreatment amongwomenwhohavenotreceivedanyconventionaluterotonictherapy,Outcome17Unsatisfactoryresponseafter enrolmentafterenrolment. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 96 Analysis2.18.Comparison2SublingualmisoprostolversusintravenousoxytocintherapyforprimaryPPHtreatment amongwomenwhohavenotreceivedanyconventionaluterotonictherapy,Outcome18Uterinecompressionstitch afterenrolment. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 97 Analysis2.19.Comparison2SublingualmisoprostolversusintravenousoxytocintherapyforprimaryPPHtreatment amongwomenwhohavenotreceivedanyconventionaluterotonictherapy,Outcome19Anysurgicalco-interventions (uterinetamponade,arteryligations,arterialembolisation)excludinghysterectomyafterenrolment. . . . . 98 Analysis2.20.Comparison2SublingualmisoprostolversusintravenousoxytocintherapyforprimaryPPHtreatment amongwomenwhohavenotreceivedanyconventionaluterotonictherapy,Outcome20Nausea. . . . . . 99 Analysis2.21.Comparison2SublingualmisoprostolversusintravenousoxytocintherapyforprimaryPPHtreatment amongwomenwhohavenotreceivedanyconventionaluterotonictherapy,Outcome21Vomiting. . . . . 100 Analysis2.22.Comparison2SublingualmisoprostolversusintravenousoxytocintherapyforprimaryPPHtreatment amongwomenwhohavenotreceivedanyconventionaluterotonictherapy,Outcome22Diarrhoea. . . . . 101 Analysis2.23.Comparison2SublingualmisoprostolversusintravenousoxytocintherapyforprimaryPPHtreatment amongwomenwhohavenotreceivedanyconventionaluterotonictherapy,Outcome23Headache. . . . . 102 Analysis2.24.Comparison2SublingualmisoprostolversusintravenousoxytocintherapyforprimaryPPHtreatment amongwomenwhohavenotreceivedanyconventionaluterotonictherapy,Outcome24Shivering. . . . . 103 Analysis2.25.Comparison2SublingualmisoprostolversusintravenousoxytocintherapyforprimaryPPHtreatment amongwomenwhohavenotreceivedanyconventionaluterotonictherapy,Outcome25Feelingfaintorfainting. 104 Analysis2.26.Comparison2SublingualmisoprostolversusintravenousoxytocintherapyforprimaryPPHtreatment amongwomenwhohavenotreceivedanyconventionaluterotonictherapy,Outcome26Maternalpyrexia38degrees ormore. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 105 Analysis2.27.Comparison2SublingualmisoprostolversusintravenousoxytocintherapyforprimaryPPHtreatment amongwomenwhohavenotreceivedanyconventionaluterotonictherapy,Outcome27Maternalpyrexia40degrees ormore. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 106 Analysis2.28.Comparison2SublingualmisoprostolversusintravenousoxytocintherapyforprimaryPPHtreatment amongwomenwhohavenotreceivedanyconventionaluterotonictherapy,Outcome28Allergy. . . . . . 107 Analysis3.1.Comparison3RectalmisoprostolversuscombinationofergometrineandoxytocintherapyforprimaryPPH treatmentamongwomenwhohavenotreceivedanyconventionaluterotonictherapy,Outcome1Hysterectomy. 108 Analysis3.2.Comparison3Rectalmisoprostolversuscombination ofergometrineandoxytocintherapyforprimary PPHtreatmentamongwomenwhohavenotreceivedanyconventionaluterotonictherapy,Outcome2Persistent haemorrhage. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 109 Analysis3.3.Comparison3Rectalmisoprostolversuscombination ofergometrineandoxytocintherapyforprimary PPHtreatmentamongwomenwhohavenotreceivedanyconventionaluterotonictherapy,Outcome3Additional uterotonics. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 109 Analysis3.4.Comparison3Rectalmisoprostolversuscombination ofergometrineandoxytocintherapyforprimary PPHtreatmentamongwomenwhohavenotreceivedanyconventionaluterotonictherapy,Outcome4Surgicalco- interventions(excludinghysterectomy). . . . . . . . . . . . . . . . . . . . . . . . . . 110 Analysis4.1.Comparison4Estrogenversusplacebo/notreatmentamongwomenreceivingconventionaluterotonicsfor primaryPPH,Outcome1Hysterectomy. . . . . . . . . . . . . . . . . . . . . . . . . 111 Analysis4.2.Comparison4Estrogenversusplacebo/notreatmentamongwomenreceivingconventionaluterotonicsfor primaryPPH,Outcome2Meanbloodlosswithintwohours. . . . . . . . . . . . . . . . . . 111 Analysis4.3.Comparison4Estrogenversusplacebo/notreatmentamongwomenreceivingconventionaluterotonicsfor primaryPPH,Outcome3Meanbloodlossbetweentwoand24hours. . . . . . . . . . . . . . . 112 Treatmentforprimarypostpartumhaemorrhage(Review) iii Copyright©2014TheCochraneCollaboration.PublishedbyJohnWiley&Sons,Ltd. Analysis5.1.Comparison5Tranexamicacidversusplacebo/notreatmentamongwomenreceivingconventionaluterotonics forprimaryPPH,Outcome1Maternalmortality. . . . . . . . . . . . . . . . . . . . . . 112 Analysis5.2.Comparison5Tranexamicacidversusplacebo/notreatmentamongwomenreceivingconventionaluterotonics forprimaryPPH,Outcome2Seriousmaternalmorbidity(renalfailurerespiratoryfailure,cardiacarrest,multiple organfailure). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 113 Analysis5.3.Comparison5Tranexamicacidversusplacebo/notreatmentamongwomenreceivingconventionaluterotonics forprimaryPPH,Outcome3Admissiontointensivecareunit. . . . . . . . . . . . . . . . . . 113 Analysis5.4.Comparison5Tranexamicacidversusplacebo/notreatmentamongwomenreceivingconventionaluterotonics forprimaryPPH,Outcome4Hysterectomy. . . . . . . . . . . . . . . . . . . . . . . . 114 Analysis5.5.Comparison5Tranexamicacidversusplacebo/notreatmentamongwomenreceivingconventionaluterotonics forprimaryPPH,Outcome5Bloodloss500mLormoreafterenrolment. . . . . . . . . . . . . . 114 Analysis5.6.Comparison5Tranexamicacidversusplacebo/notreatmentamongwomenreceivingconventionaluterotonics forprimaryPPH,Outcome6Bloodloss1000mLormoreafterenrolment. . . . . . . . . . . . . 115 Analysis5.7.Comparison5Tranexamicacidversusplacebo/notreatmentamongwomenreceivingconventionaluterotonics forprimaryPPH,Outcome7Totalmeanbloodlossafterenrolment. . . . . . . . . . . . . . . 115 Analysis5.8.Comparison5Tranexamicacidversusplacebo/notreatmentamongwomenreceivingconventionaluterotonics forprimaryPPH,Outcome8Bloodtransfusionwithin24hours. . . . . . . . . . . . . . . . . 116 Analysis5.9.Comparison5Tranexamicacidversusplacebo/notreatmentamongwomenreceivingconventionaluterotonics forprimaryPPH,Outcome9Additionaluterotonicsafterenrolment. . . . . . . . . . . . . . . 116 Analysis5.10. Comparison 5Tranexamic acidversusplacebo/notreatmentamong womenreceiving conventional uterotonicsforprimaryPPH,Outcome10Unsatisfactoryresponseafterenrolment. . . . . . . . . . 117 Analysis5.11. Comparison 5Tranexamic acidversusplacebo/notreatmentamong womenreceiving conventional uterotonicsforprimaryPPH,Outcome11Uterinecompressionstitchafterenrolment. . . . . . . . . 117 Analysis5.12.Comparison5Tranexamicacidversusplacebo/notreatmentamongwomenreceivingconventionaluterotonics forprimaryPPH,Outcome12Interventionstocontrolbleedingforsecondarypostpartumhaemorrhage. . . 118 Analysis5.13. Comparison 5Tranexamic acidversusplacebo/notreatmentamong womenreceiving conventional uterotonicsforprimaryPPH,Outcome13Examinationunderanaesthesia. . . . . . . . . . . . . 119 Analysis5.14. Comparison 5Tranexamic acidversusplacebo/notreatmentamong womenreceiving conventional uterotonicsforprimaryPPH,Outcome14Uterinetamponadeafterenrolment. . . . . . . . . . . . 119 Analysis5.15. Comparison 5Tranexamic acidversusplacebo/notreatmentamong womenreceiving conventional uterotonicsforprimaryPPH,Outcome15Arteryligation(uterineand/orhypogastricarteries)afterenrolment. 120 Analysis5.16. Comparison 5Tranexamic acidversusplacebo/notreatmentamong womenreceiving conventional uterotonicsforprimaryPPH,Outcome16Arterialembolisationafterenrolment. . . . . . . . . . . 120 Analysis5.17. Comparison 5Tranexamic acidversusplacebo/notreatmentamong womenreceiving conventional uterotonicsforprimaryPPH,Outcome17Headache. . . . . . . . . . . . . . . . . . . . . 121 Analysis5.18. Comparison 5Tranexamic acidversusplacebo/notreatmentamong womenreceiving conventional uterotonicsforprimaryPPH,Outcome18Nausea. . . . . . . . . . . . . . . . . . . . . . 121 Analysis5.19. Comparison 5Tranexamic acidversusplacebo/notreatmentamong womenreceiving conventional uterotonicsforprimaryPPH,Outcome19Maternalpyrexia38degreesormore. . . . . . . . . . . 122 Analysis5.20. Comparison 5Tranexamic acidversusplacebo/notreatmentamong womenreceiving conventional uterotonicsforprimaryPPH,Outcome20Maternalpyrexia40degreesormore. . . . . . . . . . . 122 Analysis5.21. Comparison 5Tranexamic acidversusplacebo/notreatmentamong womenreceiving conventional uterotonicsforprimaryPPH,Outcome21Deepveinthrombosis. . . . . . . . . . . . . . . . 123 Analysis5.22. Comparison 5Tranexamic acidversusplacebo/notreatmentamong womenreceiving conventional uterotonicsforprimaryPPH,Outcome22Seizures. . . . . . . . . . . . . . . . . . . . . 123 Analysis5.23. Comparison 5Tranexamic acidversusplacebo/notreatmentamong womenreceiving conventional uterotonicsforprimaryPPH,Outcome23Dizziness. . . . . . . . . . . . . . . . . . . . . 124 Analysis5.24. Comparison 5Tranexamic acidversusplacebo/notreatmentamong womenreceiving conventional uterotonicsforprimaryPPH,Outcome24Phosphenes. . . . . . . . . . . . . . . . . . . . 124 Analysis5.25. Comparison 5Tranexamic acidversusplacebo/notreatmentamong womenreceiving conventional uterotonicsforprimaryPPH,Outcome25Secondarypostpartumhaemorrhage. . . . . . . . . . . . 125 Analysis5.26. Comparison 5Tranexamic acidversusplacebo/notreatmentamong womenreceiving conventional uterotonicsforprimaryPPH,Outcome26Surgicalevacuationforsecondarypostpartumhaemorrhage. . . . 125 Treatmentforprimarypostpartumhaemorrhage(Review) iv Copyright©2014TheCochraneCollaboration.PublishedbyJohnWiley&Sons,Ltd. Analysis5.27. Comparison 5Tranexamic acidversusplacebo/notreatmentamong womenreceiving conventional uterotonicsforprimaryPPH,Outcome27Intravenousirontherapyinthepuerperium. . . . . . . . . 126 Analysis5.28. Comparison 5Tranexamic acidversusplacebo/notreatmentamong womenreceiving conventional uterotonicsforprimaryPPH,Outcome28Hospitalre-admissionforsecondarypostpartumhaemorrhage. . . 126 Analysis5.29. Comparison 5Tranexamic acidversusplacebo/notreatmentamong womenreceiving conventional uterotonicsforprimaryPPH,Outcome29Postnataldepressionatday42postpartum. . . . . . . . . 127 Analysis6.1.Comparison6Loweruterinesegmentcompressionversusconventionaltreatment,Outcome1Maternal mortality. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 127 Analysis6.2.Comparison6Loweruterinesegmentcompressionversusconventional treatment,Outcome2Serious maternalmorbidity. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 128 Analysis 6.3. Comparison 6 Lower uterine segment compression versus conventional treatment, Outcome 3 Hysterectomy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 128 Analysis6.4.Comparison6Loweruterinesegmentcompressionversusconventionaltreatment,Outcome4Bloodloss500 mLormoreafterenrolment. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 129 Analysis6.5.Comparison6Loweruterinesegmentcompressionversusconventionaltreatment,Outcome5Bloodloss 1000mLormoreafterenrolment. . . . . . . . . . . . . . . . . . . . . . . . . . . 130 Analysis6.6.Comparison6Loweruterinesegmentcompressionversusconventionaltreatment,Outcome6Averageblood lossafterenrolment. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 130 Analysis6.7.Comparison 6Loweruterinesegmentcompressionversusconventional treatment,Outcome7Blood transfusion. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 131 Analysis6.8.Comparison6Loweruterinesegmentcompressionversusconventionaltreatment,Outcome8Othersurgical interventionstocontrolbleeding(otherthanhysterectomy). . . . . . . . . . . . . . . . . . . 131 Analysis6.9.Comparison6Loweruterinesegmentcompressionversusconventionaltreatment,Outcome9Unsatisfactory responseafterenrolment. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 132 WHAT’SNEW . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 132 HISTORY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 133 CONTRIBUTIONSOFAUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 133 DECLARATIONSOFINTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 133 SOURCESOFSUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 133 DIFFERENCESBETWEENPROTOCOLANDREVIEW . . . . . . . . . . . . . . . . . . . . . 134 INDEXTERMS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 134 Treatmentforprimarypostpartumhaemorrhage(Review) v Copyright©2014TheCochraneCollaboration.PublishedbyJohnWiley&Sons,Ltd. [InterventionReview] Treatment for primary postpartum haemorrhage HatemAMousa1,JenniferBlum2,GhadaAbouElSenoun3,HaleemaShakur4,ZarkoAlfirevic5 1UniversityDepartmentofObstetricsandGynaecology,FetalandMaternalMedicineUnit,LeicesterRoyalInfirmary,Leicester,UK. 2GynuityHealthProjects,NewYork,USA.3DepartmentofObstetricsandGynaecology,Queen’sMedicalCentre,NottinghamUni- versityHospital,Nottingham,UK.4ClinicalTrialsUnit,LondonSchoolofHygiene&TropicalMedicine,London,UK.5Department ofWomen’sandChildren’sHealth,TheUniversityofLiverpool,Liverpool,UK Contactaddress:HatemAMousa,UniversityDepartmentofObstetricsandGynaecology,FetalandMaternalMedicineUnit,Leicester RoyalInfirmary,InfirmarySquare,Leicester,LE15WW,[email protected]. Editorialgroup:CochranePregnancyandChildbirthGroup. Publicationstatusanddate:Newsearchforstudiesandcontentupdated(conclusionschanged),publishedinIssue2,2014. Reviewcontentassessedasup-to-date: 31August2013. Citation: MousaHA,BlumJ,AbouElSenounG,ShakurH,AlfirevicZ.Treatmentforprimarypostpartumhaemorrhage.Cochrane DatabaseofSystematicReviews2014,Issue2.Art.No.:CD003249.DOI:10.1002/14651858.CD003249.pub3. Copyright©2014TheCochraneCollaboration.PublishedbyJohnWiley&Sons,Ltd. ABSTRACT Background Primarypostpartumhaemorrhage(PPH)isoneofthetopfivecausesofmaternalmortalityinbothdevelopedanddevelopingcountries. Objectives ToassesstheeffectivenessandsafetyofanyinterventionusedforthetreatmentofprimaryPPH. Searchmethods WesearchedtheCochranePregnancyandChildbirthGroup’sTrialsRegister(31August2013). Selectioncriteria RandomisedcontrolledtrialscomparinganyinterventionsforthetreatmentofprimaryPPH. Datacollectionandanalysis Weassessedstudiesforeligibilityandqualityandextracteddataindependently.Wecontactedauthorsoftheincludedstudiestorequest moreinformation. Mainresults Tenrandomisedclinicaltrials(RCTs)withatotalof4052participantsfulfilledourinclusioncriteriaandwereincludedinthisreview. FourRCTs(1881participants)comparedmisoprostolwithplacebogiveninadditiontoconventionaluterotonics.Adjunctiveuseof misoprostol(inthedoseof600to1000mcg)withsimultaneousadministrationofadditionaluterotonicsdidnotprovideadditional benefitforourprimaryoutcomesincludingmaternalmortality(riskratio(RR)6.16,95%confidenceinterval(CI)0.75to50.85), seriousmaternalmorbidity(RR0.34,95%CI0.01to8.31),admissiontointensivecare(RR0.79,95%CI0.30to2.11)orhysterectomy (RR0.93,95%CI0.16to5.41). TwoRCTs(1787participants)compared800mcgsublingual misoprostolversusoxytocininfusionasprimaryPPHtreatment;one trialincludedwomenwhohadreceivedprophylacticuterotonics,andtheotherdidnot.Primaryoutcomesdidnotdifferbetweenthe Treatmentforprimarypostpartumhaemorrhage(Review) 1 Copyright©2014TheCochraneCollaboration.PublishedbyJohnWiley&Sons,Ltd. twogroups,althoughwomengivensublingual misoprostol weremorelikelytohaveadditional bloodlossofatleast1000mL(RR 2.65,95%CI1.04to6.75).Misoprostolwasassociatedwithasignificantincreaseinvomitingandshivering. Two trials attempted to test theeffectivenessof estrogen and tranexamic acid, respectively,but were too small for any meaningful comparisonsofpre-specifiedoutcomes. Onestudycomparedlowersegmentcompressionbutwastoosmalltoassessimpactonprimaryoutcomes. WedidnotidentifyanytrialsevaluatingsurgicaltechniquesorradiologicalinterventionsforwomenwithprimaryPPHunresponsive touterotonicsand/orhaemostatics. Authors’conclusions Clinicaltrialsincludedinthecurrentreviewwerenotadequatelypoweredtoassessimpactontheprimaryoutcomemeasures.Compared withmisoprostol,oxytocininfusionismoreeffectiveandcausesfewersideeffectswhenusedasfirst-linetherapyforthetreatmentof primaryPPH.Whenusedafterprophylacticuterotonics,misoprostolandoxytocininfusionworkedsimilarly.Thereviewsuggeststhat amongwomenwhoreceivedoxytocinforthetreatmentofprimaryPPH,adjunctiveuseofmisoprostolconfersnoaddedbenefit. Theroleoftranexamicacidandcompressionmethodsrequiresfurtherevaluation.Furthermore,futurestudiesshouldfocusonthe bestwaytotreatwomenwhofailtorespondtouterotonictherapy. PLAIN LANGUAGE SUMMARY Treatmentforexcessivebleedingafterchildbirth Afterawomangivesbirth,wombmusclescontract,clampingdownonthebloodvesselsandhelpingtolimitbleedingwhentheplacenta hasdetached.Ifthemusclesdonotcontractstronglyenough,veryheavybleeding(postpartumhaemorrhage)canoccur,whichcanbe lifethreatening.Thesesituationsarecommoninresource-poorcountries,andmaternalmortalityisabout100timeshigherthanin resource-richcountries.Itisaveryseriousproblemthatrequireseffectivetreatmentsthatmightavoidtheuseofsurgerytoremovethe womb(hysterectomy).Thisisoftenthelasttreatmentoptionandleavesthewomanunabletohavemorechildren.Inmostsettings, womenaregivenadrugatthetimeofbirth(beforeexcessivebleedingoccurs)toreducethelikelihoodofexcessivebloodloss.However, despitethisintervention,somewomenbleedexcessively,andthisreviewlookedtoseewhatinterventionsmightbeusedtoreducethe amountofbloodlostbythesewomen.Treatmentoptionsincludedrugstoincreasemusclescontractions(suchasoxytocin,ergometrine andprostaglandinslikemisoprostol),drugstohelpwithbloodclotting(haemostaticdrugssuchastranexamicacidandrecombinant activatedfactorVII),surgicaltechniques(suchastyingofforblockingoftheuterineartery)andradiologicalinterventions(toassistin blockingthemainarterytothewombbyusinggelfoams). Thereviewidentified10randomisedcontrolledtrialsinvolving4052women.Sevenofthesetrialslookedatadrugcalledmisoprostol, whichisaprostaglandinandsoworksbyincreasingmusclecontractions.Overall,thetrialssuggestthatmisoprostoldoesnotworkas wellasoxytocininfusion,andithasmoresideeffects.However,oxytocinneedstobekeptinarefrigerator,andsoinsettingswhere refrigerationandinfusionsarenotreadilyavailable,misoprostolcanbeused. Otherclinicaltrialslookedintousingothertypesofdrugsorsqueezingthemainarterythatsuppliesbloodtothewoman.Thenumber ofwomenincludedinthesestudieswastoosmallforanyusefulconclusionsregardingtheireffectivenessandsafety. BACKGROUND complicationsofthethirdstageoflabour,thatis,excessivebleed- ingwithinthefirst24hoursafterdelivery,alsoknownasprimary Nearlyhalfamillionwomendieannuallyacrosstheworldfrom postpartumhaemorrhage(PPH)(AbouZahr1991).Inthedevel- causes relatedto pregnancy and childbirth (Khan 2006; WHO opingworld,PPHremainstheleadingcauseofmaternaldeath, 2010).Approximatelyone-quarterofthesedeathsarecausedby Treatmentforprimarypostpartumhaemorrhage(Review) 2 Copyright©2014TheCochraneCollaboration.PublishedbyJohnWiley&Sons,Ltd. accounting for one-third of maternal deaths in Asia and Africa ingtherateofprimaryPPHhasbeenseenindevelopedcountries (Khan2006;WHO2010).IntheUnitedKingdom(UK),therisk (Knight2009). of death fromobstetrical haemorrhage isabout one in100,000 deliveries(Cantwell2011). Causesandriskfactors SeveralfactorsinfluencePPHrates,includingwhetherbloodloss Physiology is measured, how thethirdstage of labour ismanaged (e.g. the provision of uterotonic, uterine massage, controlled cord trac- Theuterusiscomposedofauniqueinterlacingnetworkofmuscle tion), obstetrical interventions carried out at the time of deliv- fibresknownas’myometrium’.Thebloodvesselsthatsupplythe ery(e.g.episiotomy,modeofdelivery)andcharacteristicsofthe placental bed pass through this latticework of uterine muscle ( study population(Begley2011;Carroli2008).Lackofefficient Baskett2000).Myometrialcontractionisthemaindrivingforce uterinecontraction(uterineatony)isthemostcommoncauseof forbothplacentalseparationandhaemostasisthroughconstriction primaryPPH.Otheraetiologicalfactorsincluderetainedpartsof ofthesebloodvessels.Thisblood-savingmechanismisknownas theplacentaandvaginalorcervicaltears.Uterinerupture,clotting the’physiologicalsutures’or’livingligatures’(Baskett2000).The disordersanduterineinversionareextremelyrarebutoftenvery physiological increase in clotting factors during labour helps to dramaticcausesofheavybleeding.Severalinvestigatorshaveat- controlbloodlossafterseparationoftheplacenta. temptedtoidentifyfactorsthatmaypre-disposewomentoexces- Activemanagementofthethirdstageoflabourhasbeenstandard sivebloodlossafterdelivery.Examplesofriskfactorsincludefirst practice in many parts of the world for many years(Prendiville pregnancy (Gilbert 1987; Hall 1985), maternal obesity (Aisaka 1989).Itissuggestedthatprophylacticadministrationofautero- 1988),alargebaby(Stones1993),twinpregnancy(Combs1991; tonic will help to reduce blood loss and blood transfusion af- Suzuki 2012), prolonged or augmented labour (Gilbert 1987), terdelivery(Begley2011).Theroleof earlycordclampingand chorioamnionitis,pre-eclampsia,maternalanaemiaandantepar- controlledcordtractioninthereductionofbleedingislessclear; tumhaemorrhage(Wetta2013).Highmultiparity doesnotap- although itwas once thoughtimportant to deliverthe placenta peartobeariskfactorinhigh-orlow-incomecountries,evenafter quickly afteruterotonic drugadministration, topreventitfrom control for maternal age (Drife 1997; Stones 1993; Tsu 1993). beingretained(McDonald2013),delayedcordclampingisnow Despitetheidentificationofpotentialriskfactors,primaryPPH favoured. oftenoccursunpredictablyinlow-riskwomen(Mousa2008). Bloodlossupto500mLatdeliveryisregardedas’physiological’. Itispartofthenormalmechanismthatbringsthemother’sblood parameters to their normal non-pregnant levels, and a healthy Complications pregnantwomancancopewithitwithnodifficulty(Gyte1992; Ripley1999). ThemostimportantconsequencesofseverePPHincludedeath, hypovolaemicshock,disseminatedintravascularcoagulopathy,re- nalfailure,hepaticfailureandadultrespiratorydistresssyndrome (Bonnar2000).Inlow-incomecountries,poornutritionalstatus, Definition lackofeasyaccesstotreatmentandinadequateintensivecareand bloodbankfacilitiesareadditionalcontributingfactorsthatlead Traditionally,primaryPPHisdefinedasbleedingfromthegenital to high morbidity and mortality rates in these countries (Khan tractof500mLormoreinthefirst24hoursfollowingdeliveryof 2006;WHO2010).AsnodefinitionofPPHhasbeenuniversally thebaby(Cunningham1993,AbouZahr1991).Alternativecut- accepted,theexactincidenceofseriouscomplicationsisdifficult offlevelsof600mL(Beischer1986),1000mL(Burchell1980), toascertain(Knight2009). 1500 mL (Mousa 2002), with a substantial fall in haematocrit ortheneedforbloodtransfusion(ACOG1998;Combs1991), havealsobeenused.Unfortunately,underestimationofbloodloss ManagementofprimaryPPH following delivery is a common problem, as visually (clinically) assessed bleeding underestimates measured blood lossby an av- TreatmentforprimaryPPHrequiresamultidisciplinaryapproach. erage of 100 to 150 mL (Pritchard 1962; Sloan 2010; Stafford Afterexclusionoflowergenitaltracttears,inmostcases,bleeding 2008).Severalmethodshavebeenproposedformeasuringblood isduetouterineatony.Uterotonicsthatincreasetheefficiencyof loss objectively, but they are used mainly for research purposes uterinecontraction,includingergometrineandoxytocin,werein- (Sloan2010).Inaddition,womendeliveringbycaesareansection troducedasfirst-linetherapyforatonicPPHinthe19thcentury. losemorebloodonaveragethanwomenwhohavevaginalbirth; Womenwhocontinuetobleedrequirefurtherassessmentandin- therefore,1000mLiscommonlyusedasacutoffforsignificant terventionstocontrolbleeding.Theseinterventionsmayinclude bloodlossaftercaesareansection.Overall,atrendtowardsincreas- additionaluterotonics,haemostaticdrugs,surgicalinterventions, Treatmentforprimarypostpartumhaemorrhage(Review) 3 Copyright©2014TheCochraneCollaboration.PublishedbyJohnWiley&Sons,Ltd. radiological embolisation and/or compression devices (Abou El Prostaglandins Senoun2011). By the 1970s, the prostaglandin F2 alpha series was discovered by Sune Bergstrom, among others (Bergstrom 1962). The 15- methylanalogueofprostaglandinF2alphahasbeenreportedto A.Uterotonics havea highsuccess rate if usedalone (88%) or in combination withotheruterotonicagents(95%)(Oleen1990).Prostaglandin administration could be associated with unpleasant side effects, Ergometrine including vomiting, diarrhoea, hypertension and fever (Oleen JohnStearns(Stearns1822)wasthefirsttoemphasisetheuseof 1990). ergotsforPPH.Earlier,hewrotedescribingergot’saction:“Itex- Misoprostol, a methyl ester synthetic analogue of natural pediteslingering parturition ... The pains induced by it are pe- prostaglandinE1,isathermo-stable,inexpensivedrugthatcanbe culiarly forcing ... In most cases you will be surprised with the usedforpreventionandtreatmentofPPH.Itcanbeadministered suddennessofitsoperation”(Stearns1808).Moir 1932noticed orally,sublingually,buccally,vaginallyorrectally.ACochranesys- thatadministrationofaqueousergotextractbymouthisassoci- tematicreviewofrandomisedtrialsofmisoprostolversusinjectable atedwithdramaticandvigorousuterinecontractions,whichwere uterotonicsinmanagementofthethirdstageoflaboursuggests describedasthe’JohnStearnseffect’.In1935,DudleyandMoir thatthedrugislesseffectivethaninjectableuterotonicsinthepre- wereabletoisolatethepurecrystallisedsubstancefromthewater- ventionofseverePPH(bloodloss≥1000mL)andhasmoread- solubleextractofergotthatwasresponsibleforthe’JohnStearns verseeffects,includingnausea,vomitinganddiarrhoea(Hofmeyr effect’,andtheycalledit’ergometrine’(Dudley1935).Theiso- 2008;Tunçalp2012). lationofanewwater-solubleextractofergotwasannouncedal- Inmostcases,uterotonicdrugswillcontrolpostpartumbleeding, mostsimultaneouslyfromthreeothercentres:inAmerica(Davis butiftheydonot,surgicalinterventionmustbeconsidered. 1935),theUK(Thompson1935)andSwitzerland(Stoll1935). Itturnedouttobethesamesubstance.TheAmericanscalledtheir B.Haemostaticdrugs preparationergonovine,andtheSwissusedthenameergobasine. Haemostaticdrugs,includingtranexamicacid(As1996)andre- Althoughtheuseofoxytocinisusuallyfreeofadverseeffects,the combinantactivatedfactorVII(rFVIIa)(Moscardo2001),have useofergometrinemaybeassociatedwithnausea,vomitingand beenusedforthetreatmentofintractablehaemorrhageunrespon- hypertension(ACOG1998). sivetofirst-andsecond-linetherapies.Tranexamicacidisasys- temicantifibrinolyticagentthatiswidelyusedinsurgerytopre- ventclotbreakdown(fibrinolysis)andthereforetoreduceblood Oxytocin loss.Itisasimple,inexpensivedrugthatrequiresnotrainingfor In1953, VincentDuVigneaud(DuVigneaud 1953)identified administrationandcanbeusedforpreventionandtreatmentof thestructureofoxytocinandwasabletosynthesisethehormone. primary PPH (As 1996; Ferrer 2009; Novikova 2010). It has a Bythe1980s,severalrandomisedcontrolledtrialsandtheirmeta- short half-life of two hours.The use of tranexamic acid may be analysesconfirmedtheeffectivenessofactivemanagementofthe associatedwithsideeffects,includingnausea,vomitinganddiar- third stage in reducing PPH (Begley 2011). Oxytocin and er- rhoea.Otherrarecomplicationsincludehypotension,thrombosis, gometrinehavetraditionallyformedessentialcomponentsoffirst- blurredvision, renalcorticalnecrosisandretinalarteryobstruc- line therapy in the management of primary PPH. Ergometrine tion(Novikova2010;Peitsidis2011). (andthemixeddrugcombination ofoxytocinandergometrine) Recombinant activated factor VII (rFVIIa; Novo Nordisk A/S, iscontraindicatedinwomenwithahistoryofhypertension,heart Bagsvaerd,Denmark)hasalsobeensuccessfullyusedforcontrol- disease,pre-eclampsiaoreclampsia. linglife-threateningPPH.Itreducesbloodlossthroughenhance- Carbetocinisalong-actingsyntheticoxytocinanaloguethatcan mentoftissuefactor-dependentcoagulation.Itiseffectiveinup beadministeredasasingledoseeitherintravenouslyorintramus- to80%ofcases(Alfirevic2007)butisquiteexpensive.Adverse cularly;itproducesasimilaruterotoniceffectasoxytocin.Intra- eventswereobservedin2.5%oftreatedcases(Franchini2010). venously administered carbetocin has a half-life of 40 minutes Ofnote,alladverseeventswerethrombotic, including deepve- (fourto10timeslongerthanoxytocin).Uterineactivitypersists nousthrombosis,pulmonaryembolism,cerebralthrombosisand for120minutesand60minutesfollowingintramuscularandin- myocardialinfarction. travenousinjection,respectively(Hunter1992).InEurope,this drug is licenced only for prevention of uterine atony after cae- sareansection.Carbetocinisaseffective,butmoreexpensive,than C.Surgicalinterventions oxytocin(Su2007).Itmayhaveunpleasantsideeffects,includ- Porro(Porro1876)wasthefirsttodescribecaesareanhysterectomy ingheadaches,tremor,hypotension,flushing,nausea,abdominal topreventdeathfromuterinehaemorrhage.However,thetech- pain,pruritusandafeelingofwarmth(Rath2009). niqueisassociatedwithmajorcomplicationsandsterility.Active Treatmentforprimarypostpartumhaemorrhage(Review) 4 Copyright©2014TheCochraneCollaboration.PublishedbyJohnWiley&Sons,Ltd.