(2014) Treatment for primary postpartum haemorrhage. Cochrane Dat

141 Pages·2017·1.63 MB·English

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
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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
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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.