cochrane databaseofsystematicreviewsresearchonline.lshtm.ac.uk/1592717/1/mousa_et_al-2014...analysis...

Cochrane Database of Systematic Reviews

Treatment for primary postpartum haemorrhage (Review)

Mousa HA Blum J Abou El Senoun G Shakur H Alfirevic Z

Mousa HA Blum J Abou El Senoun G Shakur H Alfirevic Z

Treatment for primary postpartum haemorrhage

Cochrane Database of Systematic Reviews 2014 Issue 2 Art No CD003249

DOI 10100214651858CD003249pub3

wwwcochranelibrarycom

Treatment for primary postpartumhaemorrhage (Review)

Copyright copy 2014 The Cochrane Collaboration Published by John Wiley amp Sons Ltd

T A B L E O F C O N T E N T S

1HEADER 1ABSTRACT 2PLAIN LANGUAGE SUMMARY 2BACKGROUND 6OBJECTIVES 6METHODS

10RESULTS Figure 1 11Figure 2 12

16DISCUSSION 17AUTHORSrsquo CONCLUSIONS 18ACKNOWLEDGEMENTS 19REFERENCES 26CHARACTERISTICS OF STUDIES 44DATA AND ANALYSES

Analysis 11 Comparison 1 Misoprostol (any route) versus placebo or no additional treatment given to womensimultaneously treated with conventional uterotonics Outcome 1 Maternal death 55

Analysis 12 Comparison 1 Misoprostol (any route) versus placebo or no additional treatment given to womensimultaneously treated with conventional uterotonics Outcome 2 Serious maternal morbidity 56

Analysis 13 Comparison 1 Misoprostol (any route) versus placebo or no additional treatment given to womensimultaneously treated with conventional uterotonics Outcome 3 Admission to intensive care unit 57

Analysis 14 Comparison 1 Misoprostol (any route) versus placebo or no additional treatment given to womensimultaneously treated with conventional uterotonics Outcome 4 Hysterectomy 58

Analysis 15 Comparison 1 Misoprostol (any route) versus placebo or no additional treatment given to womensimultaneously treated with conventional uterotonics Outcome 5 Average blood loss after enrolment in millilitres 59

Analysis 16 Comparison 1 Misoprostol (any route) versus placebo or no additional treatment given to womensimultaneously treated with conventional uterotonics Outcome 6 Blood loss 500 mL or more after enrolment 60

Analysis 17 Comparison 1 Misoprostol (any route) versus placebo or no additional treatment given to womensimultaneously treated with conventional uterotonics Outcome 7 Blood transfusion 61


Analysis 19 Comparison 1 Misoprostol (any route) versus placebo or no additional treatment given to womensimultaneously treated with conventional uterotonics Outcome 9 Additional uterotonics 63

Analysis 110 Comparison 1 Misoprostol (any route) versus placebo or no additional treatment given to womensimultaneously treated with conventional uterotonics Outcome 10 Manual removal of the placenta after enrolment 64

Analysis 111 Comparison 1 Misoprostol (any route) versus placebo or no additional treatment given to womensimultaneously treated with conventional uterotonics Outcome 11 Uterine tamponade after enrolment 65

Analysis 112 Comparison 1 Misoprostol (any route) versus placebo or no additional treatment given to womensimultaneously treated with conventional uterotonics Outcome 12 Artery ligation (uterine andor hypogastricarteries) after enrolment 66

Analysis 113 Comparison 1 Misoprostol (any route) versus placebo or no additional treatment given to womensimultaneously treated with conventional uterotonics Outcome 13 Arterial embolisation after enrolment 67

Analysis 114 Comparison 1 Misoprostol (any route) versus placebo or no additional treatment given to womensimultaneously treated with conventional uterotonics Outcome 14 Uterine compression stitch after enrolment 68

Analysis 115 Comparison 1 Misoprostol (any route) versus placebo or no additional treatment given to womensimultaneously treated with conventional uterotonics Outcome 15 Evacuation of retained product of conception 69

Analysis 116 Comparison 1 Misoprostol (any route) versus placebo or no additional treatment given to womensimultaneously treated with conventional uterotonics Outcome 16 Any surgical co-interventions (uterine tamponadeartery ligations arterial embolisation) excluding hysterectomy after enrolment 70

Analysis 117 Comparison 1 Misoprostol (any route) versus placebo or no additional treatment given to womensimultaneously treated with conventional uterotonics Outcome 17 Nausea 71

iTreatment for primary postpartum haemorrhage (Review)


Analysis 118 Comparison 1 Misoprostol (any route) versus placebo or no additional treatment given to womensimultaneously treated with conventional uterotonics Outcome 18 Vomiting 72

Analysis 119 Comparison 1 Misoprostol (any route) versus placebo or no additional treatment given to womensimultaneously treated with conventional uterotonics Outcome 19 Diarrhoea 73

Analysis 120 Comparison 1 Misoprostol (any route) versus placebo or no additional treatment given to womensimultaneously treated with conventional uterotonics Outcome 20 Maternal pyrexia 38 degrees or more 74


Analysis 122 Comparison 1 Misoprostol (any route) versus placebo or no additional treatment given to womensimultaneously treated with conventional uterotonics Outcome 22 Headache 76

Analysis 123 Comparison 1 Misoprostol (any route) versus placebo or no additional treatment given to womensimultaneously treated with conventional uterotonics Outcome 23 Shivering 77

Analysis 124 Comparison 1 Misoprostol (any route) versus placebo or no additional treatment given to womensimultaneously treated with conventional uterotonics Outcome 24 Feeling faint or fainting 78

Analysis 125 Comparison 1 Misoprostol (any route) versus placebo or no additional treatment given to womensimultaneously treated with conventional uterotonics Outcome 25 Allergy 79

Analysis 21 Comparison 2 Sublingual misoprostol versus intravenous oxytocin therapy for primary PPH treatment amongwomen who have not received any conventional uterotonic therapy Outcome 1 Maternal mortality 80

Analysis 22 Comparison 2 Sublingual misoprostol versus intravenous oxytocin therapy for primary PPH treatment amongwomen who have not received any conventional uterotonic therapy Outcome 2 Serious maternal morbidity 81

Analysis 23 Comparison 2 Sublingual misoprostol versus intravenous oxytocin therapy for primary PPH treatment amongwomen who have not received any conventional uterotonic therapy Outcome 3 Admission to intensive care 82

Analysis 24 Comparison 2 Sublingual misoprostol versus intravenous oxytocin therapy for primary PPH treatment amongwomen who have not received any conventional uterotonic therapy Outcome 4 Hysterectomy 83

Analysis 25 Comparison 2 Sublingual misoprostol versus intravenous oxytocin therapy for primary PPH treatment amongwomen who have not received any conventional uterotonic therapy Outcome 5 Blood loss 500 mL or more afterenrolment 84

Analysis 26 Comparison 2 Sublingual misoprostol versus intravenous oxytocin therapy for primary PPH treatment amongwomen who have not received any conventional uterotonic therapy Outcome 6 Mean blood loss after enrolment 85


Analysis 28 Comparison 2 Sublingual misoprostol versus intravenous oxytocin therapy for primary PPH treatment amongwomen who have not received any conventional uterotonic therapy Outcome 8 Blood transfusion within 24 hours 87

Analysis 29 Comparison 2 Sublingual misoprostol versus intravenous oxytocin therapy for primary PPH treatment amongwomen who have not received any conventional uterotonic therapy Outcome 9 Duration from randomisation tillcessation of bleeding or satisfactory response 88

Analysis 210 Comparison 2 Sublingual misoprostol versus intravenous oxytocin therapy for primary PPH treatmentamong women who have not received any conventional uterotonic therapy Outcome 10 Additional uterotonics afterenrolment 89

Analysis 211 Comparison 2 Sublingual misoprostol versus intravenous oxytocin therapy for primary PPH treatmentamong women who have not received any conventional uterotonic therapy Outcome 11 Examination underanaesthesia 90

Analysis 212 Comparison 2 Sublingual misoprostol versus intravenous oxytocin therapy for primary PPH treatmentamong women who have not received any conventional uterotonic therapy Outcome 12 Uterine tamponade afterenrolment 91

Analysis 213 Comparison 2 Sublingual misoprostol versus intravenous oxytocin therapy for primary PPH treatmentamong women who have not received any conventional uterotonic therapy Outcome 13 Bimanual compression 92

Analysis 214 Comparison 2 Sublingual misoprostol versus intravenous oxytocin therapy for primary PPH treatmentamong women who have not received any conventional uterotonic therapy Outcome 14 Artery ligation (uterineandor hypogastric arteries) after enrolment 93

iiTreatment for primary postpartum haemorrhage (Review)


Analysis 215 Comparison 2 Sublingual misoprostol versus intravenous oxytocin therapy for primary PPH treatmentamong women who have not received any conventional uterotonic therapy Outcome 15 Arterial embolisation afterenrolment 94


Analysis 217 Comparison 2 Sublingual misoprostol versus intravenous oxytocin therapy for primary PPH treatmentamong women who have not received any conventional uterotonic therapy Outcome 17 Unsatisfactory response afterenrolment after enrolment 96

Analysis 218 Comparison 2 Sublingual misoprostol versus intravenous oxytocin therapy for primary PPH treatmentamong women who have not received any conventional uterotonic therapy Outcome 18 Uterine compression stitchafter enrolment 97

Analysis 219 Comparison 2 Sublingual misoprostol versus intravenous oxytocin therapy for primary PPH treatmentamong women who have not received any conventional uterotonic therapy Outcome 19 Any surgical co-interventions(uterine tamponade artery ligations arterial embolisation) excluding hysterectomy after enrolment 98

Analysis 220 Comparison 2 Sublingual misoprostol versus intravenous oxytocin therapy for primary PPH treatmentamong women who have not received any conventional uterotonic therapy Outcome 20 Nausea 99

Analysis 221 Comparison 2 Sublingual misoprostol versus intravenous oxytocin therapy for primary PPH treatmentamong women who have not received any conventional uterotonic therapy Outcome 21 Vomiting 100

Analysis 222 Comparison 2 Sublingual misoprostol versus intravenous oxytocin therapy for primary PPH treatmentamong women who have not received any conventional uterotonic therapy Outcome 22 Diarrhoea 101

Analysis 223 Comparison 2 Sublingual misoprostol versus intravenous oxytocin therapy for primary PPH treatmentamong women who have not received any conventional uterotonic therapy Outcome 23 Headache 102

Analysis 224 Comparison 2 Sublingual misoprostol versus intravenous oxytocin therapy for primary PPH treatmentamong women who have not received any conventional uterotonic therapy Outcome 24 Shivering 103

Analysis 225 Comparison 2 Sublingual misoprostol versus intravenous oxytocin therapy for primary PPH treatmentamong women who have not received any conventional uterotonic therapy Outcome 25 Feeling faint or fainting 104

Analysis 226 Comparison 2 Sublingual misoprostol versus intravenous oxytocin therapy for primary PPH treatmentamong women who have not received any conventional uterotonic therapy Outcome 26 Maternal pyrexia 38 degreesor more 105


Analysis 228 Comparison 2 Sublingual misoprostol versus intravenous oxytocin therapy for primary PPH treatmentamong women who have not received any conventional uterotonic therapy Outcome 28 Allergy 107

Analysis 31 Comparison 3 Rectal misoprostol versus combination of ergometrine and oxytocin therapy for primary PPHtreatment among women who have not received any conventional uterotonic therapy Outcome 1 Hysterectomy 108

Analysis 32 Comparison 3 Rectal misoprostol versus combination of ergometrine and oxytocin therapy for primaryPPH treatment among women who have not received any conventional uterotonic therapy Outcome 2 Persistenthaemorrhage 109

Analysis 33 Comparison 3 Rectal misoprostol versus combination of ergometrine and oxytocin therapy for primaryPPH treatment among women who have not received any conventional uterotonic therapy Outcome 3 Additionaluterotonics 109

Analysis 34 Comparison 3 Rectal misoprostol versus combination of ergometrine and oxytocin therapy for primaryPPH treatment among women who have not received any conventional uterotonic therapy Outcome 4 Surgical co-interventions (excluding hysterectomy) 110

Analysis 41 Comparison 4 Estrogen versus placebono treatment among women receiving conventional uterotonics forprimary PPH Outcome 1 Hysterectomy 111

Analysis 42 Comparison 4 Estrogen versus placebono treatment among women receiving conventional uterotonics forprimary PPH Outcome 2 Mean blood loss within two hours 111

Analysis 43 Comparison 4 Estrogen versus placebono treatment among women receiving conventional uterotonics forprimary PPH Outcome 3 Mean blood loss between two and 24 hours 112

iiiTreatment for primary postpartum haemorrhage (Review)


Analysis 51 Comparison 5 Tranexamic acid versus placebono treatment among women receiving conventional uterotonicsfor primary PPH Outcome 1 Maternal mortality 112

Analysis 52 Comparison 5 Tranexamic acid versus placebono treatment among women receiving conventional uterotonicsfor primary PPH Outcome 2 Serious maternal morbidity (renal failure respiratory failure cardiac arrest multipleorgan failure) 113

Analysis 53 Comparison 5 Tranexamic acid versus placebono treatment among women receiving conventional uterotonicsfor primary PPH Outcome 3 Admission to intensive care unit 113

Analysis 54 Comparison 5 Tranexamic acid versus placebono treatment among women receiving conventional uterotonicsfor primary PPH Outcome 4 Hysterectomy 114

Analysis 55 Comparison 5 Tranexamic acid versus placebono treatment among women receiving conventional uterotonicsfor primary PPH Outcome 5 Blood loss 500 mL or more after enrolment 114


Analysis 57 Comparison 5 Tranexamic acid versus placebono treatment among women receiving conventional uterotonicsfor primary PPH Outcome 7 Total mean blood loss after enrolment 115

Analysis 58 Comparison 5 Tranexamic acid versus placebono treatment among women receiving conventional uterotonicsfor primary PPH Outcome 8 Blood transfusion within 24 hours 116

Analysis 59 Comparison 5 Tranexamic acid versus placebono treatment among women receiving conventional uterotonicsfor primary PPH Outcome 9 Additional uterotonics after enrolment 116

Analysis 510 Comparison 5 Tranexamic acid versus placebono treatment among women receiving conventionaluterotonics for primary PPH Outcome 10 Unsatisfactory response after enrolment 117

Analysis 511 Comparison 5 Tranexamic acid versus placebono treatment among women receiving conventionaluterotonics for primary PPH Outcome 11 Uterine compression stitch after enrolment 117

Analysis 512 Comparison 5 Tranexamic acid versus placebono treatment among women receiving conventional uterotonicsfor primary PPH Outcome 12 Interventions to control bleeding for secondary postpartum haemorrhage 118

Analysis 513 Comparison 5 Tranexamic acid versus placebono treatment among women receiving conventionaluterotonics for primary PPH Outcome 13 Examination under anaesthesia 119

Analysis 514 Comparison 5 Tranexamic acid versus placebono treatment among women receiving conventionaluterotonics for primary PPH Outcome 14 Uterine tamponade after enrolment 119

Analysis 515 Comparison 5 Tranexamic acid versus placebono treatment among women receiving conventionaluterotonics for primary PPH Outcome 15 Artery ligation (uterine andor hypogastric arteries) after enrolment 120

Analysis 516 Comparison 5 Tranexamic acid versus placebono treatment among women receiving conventionaluterotonics for primary PPH Outcome 16 Arterial embolisation after enrolment 120

Analysis 517 Comparison 5 Tranexamic acid versus placebono treatment among women receiving conventionaluterotonics for primary PPH Outcome 17 Headache 121

Analysis 518 Comparison 5 Tranexamic acid versus placebono treatment among women receiving conventionaluterotonics for primary PPH Outcome 18 Nausea 121

Analysis 519 Comparison 5 Tranexamic acid versus placebono treatment among women receiving conventionaluterotonics for primary PPH Outcome 19 Maternal pyrexia 38 degrees or more 122


Analysis 521 Comparison 5 Tranexamic acid versus placebono treatment among women receiving conventionaluterotonics for primary PPH Outcome 21 Deep vein thrombosis 123

Analysis 522 Comparison 5 Tranexamic acid versus placebono treatment among women receiving conventionaluterotonics for primary PPH Outcome 22 Seizures 123

Analysis 523 Comparison 5 Tranexamic acid versus placebono treatment among women receiving conventionaluterotonics for primary PPH Outcome 23 Dizziness 124

Analysis 524 Comparison 5 Tranexamic acid versus placebono treatment among women receiving conventionaluterotonics for primary PPH Outcome 24 Phosphenes 124

Analysis 525 Comparison 5 Tranexamic acid versus placebono treatment among women receiving conventionaluterotonics for primary PPH Outcome 25 Secondary postpartum haemorrhage 125

Analysis 526 Comparison 5 Tranexamic acid versus placebono treatment among women receiving conventionaluterotonics for primary PPH Outcome 26 Surgical evacuation for secondary postpartum haemorrhage 125

ivTreatment for primary postpartum haemorrhage (Review)


Analysis 527 Comparison 5 Tranexamic acid versus placebono treatment among women receiving conventionaluterotonics for primary PPH Outcome 27 Intravenous iron therapy in the puerperium 126

Analysis 528 Comparison 5 Tranexamic acid versus placebono treatment among women receiving conventionaluterotonics for primary PPH Outcome 28 Hospital re-admission for secondary postpartum haemorrhage 126

Analysis 529 Comparison 5 Tranexamic acid versus placebono treatment among women receiving conventionaluterotonics for primary PPH Outcome 29 Postnatal depression at day 42 postpartum 127

Analysis 61 Comparison 6 Lower uterine segment compression versus conventional treatment Outcome 1 Maternalmortality 127

Analysis 62 Comparison 6 Lower uterine segment compression versus conventional treatment Outcome 2 Seriousmaternal morbidity 128

Analysis 63 Comparison 6 Lower uterine segment compression versus conventional treatment Outcome 3Hysterectomy 128

Analysis 64 Comparison 6 Lower uterine segment compression versus conventional treatment Outcome 4 Blood loss 500mL or more after enrolment 129

Analysis 65 Comparison 6 Lower uterine segment compression versus conventional treatment Outcome 5 Blood loss1000 mL or more after enrolment 130

Analysis 66 Comparison 6 Lower uterine segment compression versus conventional treatment Outcome 6 Average bloodloss after enrolment 130

Analysis 67 Comparison 6 Lower uterine segment compression versus conventional treatment Outcome 7 Bloodtransfusion 131

Analysis 68 Comparison 6 Lower uterine segment compression versus conventional treatment Outcome 8 Other surgicalinterventions to control bleeding (other than hysterectomy) 131

Analysis 69 Comparison 6 Lower uterine segment compression versus conventional treatment Outcome 9 Unsatisfactoryresponse after enrolment 132

132WHATrsquoS NEW 133HISTORY 133CONTRIBUTIONS OF AUTHORS 133DECLARATIONS OF INTEREST 133SOURCES OF SUPPORT 134DIFFERENCES BETWEEN PROTOCOL AND REVIEW 134INDEX TERMS

vTreatment for primary postpartum haemorrhage (Review)


[Intervention Review]


Hatem A Mousa1 Jennifer Blum2 Ghada Abou El Senoun3 Haleema Shakur4 Zarko Alfirevic5

1University Department of Obstetrics and Gynaecology Fetal and Maternal Medicine Unit Leicester Royal Infirmary Leicester UK2Gynuity Health Projects New York USA 3Department of Obstetrics and Gynaecology Queenrsquos Medical Centre Nottingham Uni-versity Hospital Nottingham UK 4Clinical Trials Unit London School of Hygiene amp Tropical Medicine London UK 5Departmentof Womenrsquos and Childrenrsquos Health The University of Liverpool Liverpool UK

Contact address Hatem A Mousa University Department of Obstetrics and Gynaecology Fetal and Maternal Medicine Unit LeicesterRoyal Infirmary Infirmary Square Leicester LE1 5WW UK mousa339hotmailcom

Editorial group Cochrane Pregnancy and Childbirth GroupPublication status and date New search for studies and content updated (conclusions changed) published in Issue 2 2014Review content assessed as up-to-date 31 August 2013

Citation Mousa HA Blum J Abou El Senoun G Shakur H Alfirevic Z Treatment for primary postpartum haemorrhage CochraneDatabase of Systematic Reviews 2014 Issue 2 Art No CD003249 DOI 10100214651858CD003249pub3


A B S T R A C T

Background

Primary postpartum haemorrhage (PPH) is one of the top five causes of maternal mortality in both developed and developing countries

Objectives

To assess the effectiveness and safety of any intervention used for the treatment of primary PPH

Search methods

We searched the Cochrane Pregnancy and Childbirth Grouprsquos Trials Register (31 August 2013)

Selection criteria

Randomised controlled trials comparing any interventions for the treatment of primary PPH

Data collection and analysis

We assessed studies for eligibility and quality and extracted data independently We contacted authors of the included studies to requestmore information

Main results

Ten randomised clinical trials (RCTs) with a total of 4052 participants fulfilled our inclusion criteria and were included in this review

Four RCTs (1881 participants) compared misoprostol with placebo given in addition to conventional uterotonics Adjunctive use ofmisoprostol (in the dose of 600 to 1000 mcg) with simultaneous administration of additional uterotonics did not provide additionalbenefit for our primary outcomes including maternal mortality (risk ratio (RR) 616 95 confidence interval (CI) 075 to 5085)serious maternal morbidity (RR 034 95 CI 001 to 831) admission to intensive care (RR 079 95 CI 030 to 211) or hysterectomy(RR 093 95 CI 016 to 541)

Two RCTs (1787 participants) compared 800 mcg sublingual misoprostol versus oxytocin infusion as primary PPH treatment onetrial included women who had received prophylactic uterotonics and the other did not Primary outcomes did not differ between the

1Treatment for primary postpartum haemorrhage (Review)


two groups although women given sublingual misoprostol were more likely to have additional blood loss of at least 1000 mL (RR265 95 CI 104 to 675) Misoprostol was associated with a significant increase in vomiting and shivering

Two trials attempted to test the effectiveness of estrogen and tranexamic acid respectively but were too small for any meaningfulcomparisons of pre-specified outcomes

One study compared lower segment compression but was too small to assess impact on primary outcomes

We did not identify any trials evaluating surgical techniques or radiological interventions for women with primary PPH unresponsiveto uterotonics andor haemostatics

Authorsrsquo conclusions

Clinical trials included in the current review were not adequately powered to assess impact on the primary outcome measures Comparedwith misoprostol oxytocin infusion is more effective and causes fewer side effects when used as first-line therapy for the treatment ofprimary PPH When used after prophylactic uterotonics misoprostol and oxytocin infusion worked similarly The review suggests thatamong women who received oxytocin for the treatment of primary PPH adjunctive use of misoprostol confers no added benefit

The role of tranexamic acid and compression methods requires further evaluation Furthermore future studies should focus on thebest way to treat women who fail to respond to uterotonic therapy

P L A I N L A N G U A G E S U M M A R Y

Treatment for excessive bleeding after childbirth

After a woman gives birth womb muscles contract clamping down on the blood vessels and helping to limit bleeding when the placentahas detached If the muscles do not contract strongly enough very heavy bleeding (postpartum haemorrhage) can occur which can belife threatening These situations are common in resource-poor countries and maternal mortality is about 100 times higher than inresource-rich countries It is a very serious problem that requires effective treatments that might avoid the use of surgery to remove thewomb (hysterectomy) This is often the last treatment option and leaves the woman unable to have more children In most settingswomen are given a drug at the time of birth (before excessive bleeding occurs) to reduce the likelihood of excessive blood loss Howeverdespite this intervention some women bleed excessively and this review looked to see what interventions might be used to reduce theamount of blood lost by these women Treatment options include drugs to increase muscles contractions (such as oxytocin ergometrineand prostaglandins like misoprostol) drugs to help with blood clotting (haemostatic drugs such as tranexamic acid and recombinantactivated factor VII) surgical techniques (such as tying off or blocking of the uterine artery) and radiological interventions (to assist inblocking the main artery to the womb by using gel foams)

The review identified 10 randomised controlled trials involving 4052 women Seven of these trials looked at a drug called misoprostolwhich is a prostaglandin and so works by increasing muscle contractions Overall the trials suggest that misoprostol does not work aswell as oxytocin infusion and it has more side effects However oxytocin needs to be kept in a refrigerator and so in settings whererefrigeration and infusions are not readily available misoprostol can be used

Other clinical trials looked into using other types of drugs or squeezing the main artery that supplies blood to the woman The numberof women included in these studies was too small for any useful conclusions regarding their effectiveness and safety

B A C K G R O U N D

Nearly half a million women die annually across the world fromcauses related to pregnancy and childbirth (Khan 2006 WHO2010) Approximately one-quarter of these deaths are caused by

complications of the third stage of labour that is excessive bleed-ing within the first 24 hours after delivery also known as primarypostpartum haemorrhage (PPH) (Abou Zahr 1991) In the devel-oping world PPH remains the leading cause of maternal death



accounting for one-third of maternal deaths in Asia and Africa(Khan 2006 WHO 2010) In the United Kingdom (UK) the riskof death from obstetrical haemorrhage is about one in 100000deliveries (Cantwell 2011)

Physiology

The uterus is composed of a unique interlacing network of musclefibres known as rsquomyometriumrsquo The blood vessels that supply theplacental bed pass through this latticework of uterine muscle (Baskett 2000) Myometrial contraction is the main driving forcefor both placental separation and haemostasis through constrictionof these blood vessels This blood-saving mechanism is known asthe rsquophysiological suturesrsquo or rsquoliving ligaturesrsquo (Baskett 2000) Thephysiological increase in clotting factors during labour helps tocontrol blood loss after separation of the placentaActive management of the third stage of labour has been standardpractice in many parts of the world for many years (Prendiville1989) It is suggested that prophylactic administration of a utero-tonic will help to reduce blood loss and blood transfusion af-ter delivery (Begley 2011) The role of early cord clamping andcontrolled cord traction in the reduction of bleeding is less clearalthough it was once thought important to deliver the placentaquickly after uterotonic drug administration to prevent it frombeing retained (McDonald 2013) delayed cord clamping is nowfavouredBlood loss up to 500 mL at delivery is regarded as rsquophysiologicalrsquoIt is part of the normal mechanism that brings the motherrsquos bloodparameters to their normal non-pregnant levels and a healthypregnant woman can cope with it with no difficulty (Gyte 1992Ripley 1999)

Definition

Traditionally primary PPH is defined as bleeding from the genitaltract of 500 mL or more in the first 24 hours following delivery ofthe baby (Cunningham 1993 Abou Zahr 1991) Alternative cut-off levels of 600 mL (Beischer 1986) 1000 mL (Burchell 1980)1500 mL (Mousa 2002) with a substantial fall in haematocritor the need for blood transfusion (ACOG 1998 Combs 1991)have also been used Unfortunately underestimation of blood lossfollowing delivery is a common problem as visually (clinically)assessed bleeding underestimates measured blood loss by an av-erage of 100 to 150 mL (Pritchard 1962 Sloan 2010 Stafford2008) Several methods have been proposed for measuring bloodloss objectively but they are used mainly for research purposes(Sloan 2010) In addition women delivering by caesarean sectionlose more blood on average than women who have vaginal birththerefore 1000 mL is commonly used as a cutoff for significantblood loss after caesarean section Overall a trend towards increas-

ing the rate of primary PPH has been seen in developed countries(Knight 2009)

Causes and risk factors

Several factors influence PPH rates including whether blood lossis measured how the third stage of labour is managed (eg theprovision of uterotonic uterine massage controlled cord trac-tion) obstetrical interventions carried out at the time of deliv-ery (eg episiotomy mode of delivery) and characteristics of thestudy population (Begley 2011 Carroli 2008) Lack of efficientuterine contraction (uterine atony) is the most common cause ofprimary PPH Other aetiological factors include retained parts ofthe placenta and vaginal or cervical tears Uterine rupture clottingdisorders and uterine inversion are extremely rare but often verydramatic causes of heavy bleeding Several investigators have at-tempted to identify factors that may pre-dispose women to exces-sive blood loss after delivery Examples of risk factors include firstpregnancy (Gilbert 1987 Hall 1985) maternal obesity (Aisaka1988) a large baby (Stones 1993) twin pregnancy (Combs 1991Suzuki 2012) prolonged or augmented labour (Gilbert 1987)chorioamnionitis pre-eclampsia maternal anaemia and antepar-tum haemorrhage (Wetta 2013) High multiparity does not ap-pear to be a risk factor in high- or low-income countries even aftercontrol for maternal age (Drife 1997 Stones 1993 Tsu 1993)Despite the identification of potential risk factors primary PPHoften occurs unpredictably in low-risk women (Mousa 2008)

Complications

The most important consequences of severe PPH include deathhypovolaemic shock disseminated intravascular coagulopathy re-nal failure hepatic failure and adult respiratory distress syndrome(Bonnar 2000) In low-income countries poor nutritional statuslack of easy access to treatment and inadequate intensive care andblood bank facilities are additional contributing factors that leadto high morbidity and mortality rates in these countries (Khan2006 WHO 2010) As no definition of PPH has been universallyaccepted the exact incidence of serious complications is difficultto ascertain (Knight 2009)

Management of primary PPH

Treatment for primary PPH requires a multidisciplinary approachAfter exclusion of lower genital tract tears in most cases bleedingis due to uterine atony Uterotonics that increase the efficiency ofuterine contraction including ergometrine and oxytocin were in-troduced as first-line therapy for atonic PPH in the 19th centuryWomen who continue to bleed require further assessment and in-terventions to control bleeding These interventions may includeadditional uterotonics haemostatic drugs surgical interventions



radiological embolisation andor compression devices (Abou ElSenoun 2011)

A Uterotonics

Ergometrine

John Stearns (Stearns 1822) was the first to emphasise the use ofergots for PPH Earlier he wrote describing ergotrsquos action ldquoIt ex-pedites lingering parturition The pains induced by it are pe-culiarly forcing In most cases you will be surprised with thesuddenness of its operationrdquo (Stearns 1808) Moir 1932 noticedthat administration of aqueous ergot extract by mouth is associ-ated with dramatic and vigorous uterine contractions which weredescribed as the rsquoJohn Stearns effectrsquo In 1935 Dudley and Moirwere able to isolate the pure crystallised substance from the water-soluble extract of ergot that was responsible for the rsquoJohn Stearnseffectrsquo and they called it rsquoergometrinersquo (Dudley 1935) The iso-lation of a new water-soluble extract of ergot was announced al-most simultaneously from three other centres in America (Davis1935) the UK (Thompson 1935) and Switzerland (Stoll 1935)It turned out to be the same substance The Americans called theirpreparation ergonovine and the Swiss used the name ergobasineAlthough the use of oxytocin is usually free of adverse effects theuse of ergometrine may be associated with nausea vomiting andhypertension (ACOG 1998)

Oxytocin

In 1953 Vincent Du Vigneaud (Du Vigneaud 1953) identifiedthe structure of oxytocin and was able to synthesise the hormoneBy the 1980s several randomised controlled trials and their meta-analyses confirmed the effectiveness of active management of thethird stage in reducing PPH (Begley 2011) Oxytocin and er-gometrine have traditionally formed essential components of first-line therapy in the management of primary PPH Ergometrine(and the mixed drug combination of oxytocin and ergometrine)is contraindicated in women with a history of hypertension heartdisease pre-eclampsia or eclampsiaCarbetocin is a long-acting synthetic oxytocin analogue that canbe administered as a single dose either intravenously or intramus-cularly it produces a similar uterotonic effect as oxytocin Intra-venously administered carbetocin has a half-life of 40 minutes(four to 10 times longer than oxytocin) Uterine activity persistsfor 120 minutes and 60 minutes following intramuscular and in-travenous injection respectively (Hunter 1992) In Europe thisdrug is licenced only for prevention of uterine atony after cae-sarean section Carbetocin is as effective but more expensive thanoxytocin (Su 2007) It may have unpleasant side effects includ-ing headaches tremor hypotension flushing nausea abdominalpain pruritus and a feeling of warmth (Rath 2009)

Prostaglandins

By the 1970s the prostaglandin F2 alpha series was discoveredby Sune Bergstrom among others (Bergstrom 1962) The 15-methyl analogue of prostaglandin F2 alpha has been reported tohave a high success rate if used alone (88) or in combinationwith other uterotonic agents (95) (Oleen 1990) Prostaglandinadministration could be associated with unpleasant side effectsincluding vomiting diarrhoea hypertension and fever (Oleen1990)Misoprostol a methyl ester synthetic analogue of naturalprostaglandin E1 is a thermo-stable inexpensive drug that can beused for prevention and treatment of PPH It can be administeredorally sublingually buccally vaginally or rectally A Cochrane sys-tematic review of randomised trials of misoprostol versus injectableuterotonics in management of the third stage of labour suggeststhat the drug is less effective than injectable uterotonics in the pre-vention of severe PPH (blood loss ge 1000 mL) and has more ad-verse effects including nausea vomiting and diarrhoea (Hofmeyr2008 Tunccedilalp 2012)In most cases uterotonic drugs will control postpartum bleedingbut if they do not surgical intervention must be considered

B Haemostatic drugs

Haemostatic drugs including tranexamic acid (As 1996) and re-combinant activated factor VII (rFVIIa) (Moscardo 2001) havebeen used for the treatment of intractable haemorrhage unrespon-sive to first- and second-line therapies Tranexamic acid is a sys-temic antifibrinolytic agent that is widely used in surgery to pre-vent clot breakdown (fibrinolysis) and therefore to reduce bloodloss It is a simple inexpensive drug that requires no training foradministration and can be used for prevention and treatment ofprimary PPH (As 1996 Ferrer 2009 Novikova 2010) It has ashort half-life of two hoursThe use of tranexamic acid may beassociated with side effects including nausea vomiting and diar-rhoea Other rare complications include hypotension thrombosisblurred vision renal cortical necrosis and retinal artery obstruc-tion (Novikova 2010 Peitsidis 2011)Recombinant activated factor VII (rFVIIa Novo Nordisk ASBagsvaerd Denmark) has also been successfully used for control-ling life-threatening PPH It reduces blood loss through enhance-ment of tissue factor-dependent coagulation It is effective in upto 80 of cases (Alfirevic 2007) but is quite expensive Adverseevents were observed in 25 of treated cases (Franchini 2010)Of note all adverse events were thrombotic including deep ve-nous thrombosis pulmonary embolism cerebral thrombosis andmyocardial infarction

C Surgical interventions

Porro (Porro 1876) was the first to describe caesarean hysterectomyto prevent death from uterine haemorrhage However the tech-nique is associated with major complications and sterility Active



attempts have been made to introduce other conservative measuresto avoid hysterectomy

Uterine tamponade

Uterine packing using several yards of wide gauze placed insidethe uterine cavity was one of the earliest methods introduced toachieve a tamponade effect to control primary PPH (Eastman1950) It fell out of favour in the 1950s as it was thought to concealhaemorrhage and cause infection (Eastman 1950) However thistechnique re-emerged in the 1980s and 1990s after these concernswere not confirmed (Maier 1993)Over the past decade active attempts have been made to intro-duce better alternatives for uterine packing through the use ofballoon tamponade including Foleyrsquos catheter (De Loor 1996)the Sengstaken-Blakemore tube (Chan 1997) the Rusch catheter(Johanson 2001) the Bakri balloon (Bakri 1999) and the condomcatheter (Akhter 2005) After exclusion of a genital tract lacera-tion these procedures can be considered for control of obstetri-cal haemorrhage secondary to uterine atony placenta accreta andplacenta praevia Overall the difference between them is relatedmainly to balloon volume and the presence or absence of a cav-ity for draining blood The overall success rate is around 80(Doumouchtsis 2007 Georgiou 2009) Close observation of uter-ine size and the general condition of the woman is mandatory assignificant bleeding may occur distal to the bulb (Alamia 1999)

Artery ligation and uterine compression sutures

Ligation of the uterine artery or its main supply (internal iliacartery) may be considered in selected cases (AbdRabbo 1994Jouppila 1995) However the latter may be technically difficultand is successful in less than 50 of cases (Clark 1985)Uterine compression sutures have recently been described (B-Lynch 1997 Cho 2000 Hayman 2002 Marasinghe 2011Ouahba 2007 Pereira 2005 Zheng 2011) B-Lynch was the firstto describe a suture that runs through the full thickness of bothuterine walls (anterior and posterior) (B-Lynch 1997) When tiedthe suture allows tight compression of the uterine walls and stopsthe bleeding (Mousa 2001) Single or multiple stitches may beinserted at the same time and according to the shape they may becalled brace suture (B-Lynch 1997) simple brace (Hayman 2002)or square sutures (Cho 2000) Although they are thought to be ef-fective in selected cases unexpected occlusion of the uterine cavitywith subsequent development of intrauterine synechiae (Poujade2011 Rathat 2011) or infection (pyometra) has been reported(Ochoa 2002) The choice of the type of surgical interventiondepends on several factors paramount of which is the experienceof the surgeon Other factors include parity and desire for futurechildren the extent of the haemorrhage and the general conditionof the woman (Cantwell 2011)

D Radiological embolisation

Selective radiological embolisation of the bleeding vessel may bea therapeutic option in centres where interventional radiologistsare available and the bleeding is not life threatening (Arulkumaran2007) In a systematic review Doumouchtsis and colleagues eval-uated the success rate of emergency embolisation for the control ofmajor PPH They reported a success rate of 91 (Doumouchtsis2007) The procedure has many advantages including minimalmorbidity and complication rates shorter hospital stay and preser-vation of fertility it can be carried out under local anaesthesiaand success can be verified The procedure is not free of compli-cations (Doumouchtsis 2007 Penninx 2010 Tseng 2011) Post-procedure fever is the most common complication and typicallyresolves within two to three days Other complications includefeet ischaemia bladder and rectal wall necrosis and sciatic nerveinjury (Doumouchtsis 2007) Late re-bleeding is a rare but seri-ous problem and repeated embolisation or hysterectomy may berequired The use of interventional radiological techniques is lim-ited by availability and few centres have a 24-hour trained skilledteam Unlike with other procedures an unstable patient has to bemoved to the angiography suite (Mousa 2002)

E Non-pneumatic antishock garment (NASG) and

aortic compression device

In the 1900s an inflatable pressure suit was developed by GeorgeCrile (Vahedi 1995) After several modifications it was used in theVietnam War for resuscitation of soldiers with traumatic injuries(Cutler 1971) In the 1970s the G-suit was modified into a half-suit which became known as MAST (military antishock trousers)or PASG (pneumatic antishock garment) From the 1970s the Na-tional Aeronautics and Space Administration (NASA) contributedto the development of a ldquonon-pneumatic versionrdquo of the antishockgarment This was originally used for children with haemophiliabut has since been developed into the garment known as the non-pneumatic antishock garment (NASG) (Haggerty 1996) TheNASG is a low-technology pressure device that decreases bloodloss restores vital signs and has the potential to reduce adverseoutcomes by helping women survive delays in receiving adequateemergency obstetrical care Use of this garment as a temporis-ing measure to stabilise women awaiting transfer to higher levelsof care began in 2002 (Hensleigh 2002) Use of NASG amongwomen with primary PPH in low-income countries was associatedwith significant reduction of measured blood loss severe maternalmorbidities and mortality and emergency hysterectomy (Miller2009 Ojengbede 2011)External aortic compression is an emergency manoeuvre proposedto reduce PPH and permit time for resuscitation and control ofbleeding This technique involves compression of the abdominalaorta using a strong metal spring that is cylindrical in shape andis fixed in place by a leather belt wrapped around the waist (



Soltan 2009) It is a cost-effective and easily applied manoeuvrethat allows satisfactory management of PPH (Soltan 2009)

Rationale for the review

The quest for fast effective and safe interventions in cases of majorprimary PPH is the focus of this review Other relevant publishedCochrane reviews are Begley 2011 which compares active withexpectant third-stage management Tunccedilalp 2012 Cotter 2001McDonald 2004 Su 2012 Liabsuetrakul 2007 and Oladapo2012b which consider the role of different prophylactic uteroton-ics in third-stage management Nardin 2011 which looks at therole of umbilical vein injection in the treatment of retained pla-centa Oladapo 2012a which evaluates advance community dis-tribution of misoprostol for preventing or treating PPH Novikova2010 which evaluates the place of tranexamic acid for preventingPPH and Alexander 2002 which is examining drug treatment forsecondary PPH The current review focuses primarily on atonicprimary PPH Management of haemorrhage due to laceration ofthe genital tract is outside the scope of this review

O B J E C T I V E S

To determine the effectiveness of any intervention used for thetreatment of primary postpartum haemorrhage

M E T H O D S

Criteria for considering studies for this review

Types of studies

All randomised controlled trials of treatment for primary postpar-tum haemorrhage (PPH)

Types of participants

Women after delivery following a pregnancy of at least 24 weeksrsquogestation with a diagnosis of primary PPH regardless of mode ofdelivery (vaginal or caesarean section) or other aspects of third-stage management Initially our protocol stipulated that only stud-ies in which primary PPH was defined as blood loss greater than500 mL would be included As it may be difficult to obtain anaccurate measurement of blood loss before recruitment we ex-panded our inclusion criteria to include trials in which PPH wasdefined in one of the following ways

bull women with blood loss of 500 mL or more andor

bull women with primary PPH requiring blood transfusion andor blood products andor

bull women with a clinical diagnosis of primary PPH (as definedby trialists)

Exclusion criteria

bull Women with PPH with gestational age less than 24 weeks

Types of interventions

Eligible interventions includedbull uterotonic agents that encourage uterine contractility (such

as oxytocin ergometrine carbetocin and prostaglandins)bull haemostatic agents that influence the clotting cascade

(tranexamic acid and recombinant activated factor VII)bull surgical interventions such as uterine packing or

intrauterine catheter insertion artery ligation uterinecompression sutures andor hysterectomy

bull interventional radiology (X-ray-guided embolisation)bull non-pneumatic antishock garment (NASG) and aortic

compression device andbull any other medical or surgical intervention

Main comparisons included the following interventionsbull Uterotonics versus control (no intervention) or placebobull One uterotonic agent versus other single or multiple

uterotonic drugsbull Haemostatic drugs versus other treatment or versus control

or placebobull Uterine packing or balloon tamponade (eg Foley

hydrostatic catheter) versus other treatment or versus control orplacebo

bull Uterine compression sutures (eg brace square) versusother treatment or versus control or placebo

bull Vessel ligation versus other treatment or versus control orplacebo

bull Hysterectomy versus other treatment or versus control orplacebo

bull Radiological embolisation versus other treatment or versuscontrol or placebo

bull Non-pneumatic antishock garment (NASG) and aorticcompression device versus other treatment or versus control orplacebo

bull Any other medical or surgical intervention used fortreatment of primary PPH versus other treatment or versuscontrol or placebo

Control group is defined as a group of participants randomly as-signed to not receiving the active medication or factor under studyand thereby serving as a comparison group for the interventionPlacebo group is defined as a group of women randomly assignedto receive a dummy treatment



Treatment for primary PPH requires a multidisciplinary approachAny measures andor drug therapy taken as part of the initial treat-ment is considered first-line therapy In most cases this includesresuscitation measures exclusion of genital tract laceration check-ing of the placenta and the use of uterotonics Women who con-tinue to bleed require further assessment and interventions to con-trol the bleeding commonly referred to as second-line therapyThis may include additional uterotonics haemostatic drugs sur-gical interventions radiological embolisation andor compressiondevices (Abou El Senoun 2011)

Types of outcome measures

Primary outcomes

bull Maternal mortalitybull Serious maternal morbidity (renal or respiratory failure

cardiac arrest or multiple-organ failure)bull Admission to intensive carebull Hysterectomy (provided it is not part of the intervention

under investigation)

Secondary outcomes

Outcome measures related to blood loss

bull Number of women with total blood loss 500 mL or moreafter enrolment


bull Mean blood loss (mL)bull Blood transfusionbull Duration from randomisation to cessation of bleeding or

obtaining satisfactory response (as determined by the trialist)bull Post-randomisation additional uterotonic used to control

bleedingbull Post-randomisation surgical intervention used to control

bleeding

Side effects

Side effects of therapy or intervention (such as headache vomitinginjuries) These will be related to the type of intervention underinvestigation

Other

bull Days in hospitalbull Iron therapy in the puerperiumbull Secondary PPH (vaginal bleeding after 24 hours to 42 days

following delivery)

bull Interventions to control secondary PPH (medical surgicalor both)

bull Hospital readmission and number of days in hospitalbull Failure to continue breastfeeding at discharge from hospital

and at 42 days of deliverybull Economic outcomesbull Maternal dissatisfaction with therapybull Quality of life including physiological activity and social

and emotional changes

Assessment of blood loss could vary between trials It is expectedthat measurement of blood and blood clots in jars and weighingof linen are likely to be more precise than clinical judgement Thelatter is known to underestimate blood loss (Pritchard 1962) Theway of reporting the amount of loss as rsquogreater thanrsquo or rsquogreaterthan or equal torsquo a certain cutoff level (eg greater than 500 mLor greater than or equal to 500 mL) may affect the total reportedamount of blood loss especially when this amount is estimated Itis expected that trials evaluating uterotonic or haemostatic drugsmay use other uterotonics to maintain contractions of the uterusafter randomisation Also it should be taken into considerationthat hysterectomy could be a method of intervention or co-inter-vention as well as an outcome measure

Search methods for identification of studies

Electronic searches

We searched the Cochrane Pregnancy and Childbirth Grouprsquos Tri-als Register by contacting the Trials Search Co-ordinator (31 Au-gust 2013)The Cochrane Pregnancy and Childbirth Grouprsquos Trials Registeris maintained by the Trials Search Co-ordinator and contains trialsidentified from

1 monthly searches of the Cochrane Central Register ofControlled Trials (CENTRAL)

2 weekly searches of MEDLINE3 weekly searches of Embase4 handsearches of 30 journals and the proceedings of major

conferences5 weekly current awareness alerts for a further 44 journals

plus monthly BioMed Central email alertsDetails of the search strategies for CENTRAL MEDLINE andEmbase the list of handsearched journals and conference pro-ceedings and the list of journals reviewed via the current aware-ness service can be found in the lsquoSpecialized Registerrsquo sectionwithin the editorial information about the Cochrane Pregnancyand Childbirth GroupTrials identified through the searching activities described aboveare each assigned to a review topic (or topics) The Trials SearchCo-ordinator searches the register for each review using the topiclist rather than keywordsnot



We did not apply any language restrictions


For methods used in assessing the trials identified in the previousversion of this review see Mousa 2007For this update (2014) we used the following methods whenassessing trials identified by the search

Selection of studies

Two review authors (HAM and GAES or HAM and HS) inde-pendently assessed for inclusion all potential studies identified as aresult of the search strategy We resolved any disagreement throughdiscussion and consultation with ZA

Data extraction and management

HAM designed a special data extraction form For eligible studiesat least two review authors (HAM and GAES or HAM and HS)extracted data using the agreed form We resolved any discrepan-cies through discussion and consultation with ZAHAM and GAES entered data into Review Manager software (RevMan 2012) and checked for accuracyWhen information regarding any of the above was unclear weattempted to contact authors of the original reports to providefurther detailsIn addition to the main outcomes we systematically extracted thefollowing data for each study

bull Trial entry criteria (specific inclusion and exclusion criteria)bull Exclusions and missing data after randomisationbull Mode of deliverybull Management of the third stage of labourbull Duration and technique of assessment of blood loss

Assessment of risk of bias in included studies

HAM and HS independently assessed risk of bias for each studyusing the criteria outlined in the Cochrane Handbook for SystematicReviews of Interventions (Higgins 2011) Any disagreement wasresolved by discussion with ZA

(1) Random sequence generation (checking for possible

selection bias)

We have described for each included study the method used togenerate the allocation sequence in sufficient detail to allow anassessment of whether it should produce comparable groupsWe have assessed the method as

bull low risk of bias (any truly random process eg randomnumber table computer random number generator)

bull high risk of bias (any non-random process eg odd or evendate of birth hospital or clinic record number) or

bull unclear risk of bias

(2) Allocation concealment (checking for possible selection

bias)

We have described for each included study in sufficient detail themethod used to conceal the allocation sequence and have deter-mined whether intervention allocation could have been foreseenin advance of or during recruitment or changed after assignmentWe have assessed the methods as

bull low risk of bias (eg telephone or central randomisationconsecutively numbered sealed opaque envelopes)

bull high risk of bias (open random allocation unsealed or non-opaque envelopes alternation date of birth) or


(31) Blinding of participants and personnel (checking for

possible performance bias)

We have described for each included study the methods used ifany to blind study participants and personnel from knowledge ofwhich intervention a participant received Studies were judged atlow risk of bias if they were blinded or if we judged that the lack ofblinding could not have affected the results Blinding was assessedseparately for different outcomes or classes of outcomesWe have assessed the methods as

bull low high or unclear risk of bias for participants andbull low high or unclear risk of bias for personnel

(32) Blinding of outcome assessment (checking for possible

detection bias)

We have described for each included study the methods used ifany to blind outcome assessors from knowledge of which inter-vention a participant received We assessed blinding separately fordifferent outcomes or classes of outcomesWe have assessed methods used to blind outcome assessment as

bull low high or unclear risk of bias

(4) Incomplete outcome data (checking for possible attrition

bias through withdrawals dropouts protocol deviations)

We have described for each included study and for each outcomeor class of outcomes the completeness of data including attritionand exclusions from the analysis We have stated whether attritionand exclusions were reported the numbers included in the anal-ysis at each stage (compared with the total of randomly assignedparticipants) reasons for attrition or exclusion where reported andwhether missing data were balanced across groups or were relatedto outcomes We have contacted authors regarding published data



and to request any missing outcome data that was included in ouranalysisWe have assessed methods as

bull low risk of bias (eg no missing outcome data missingoutcome data balanced across groups)

bull high risk of bias (eg numbers or reasons for missing dataimbalanced across groups lsquoas treatedrsquo analysis done withsubstantial departure of intervention received from that assignedat randomisation) or


(5) Selective reporting bias

We have described for each included study how we investigatedthe possibility of selective outcome reporting bias and what wehave foundWe have assessed the methods as

bull low risk of bias (when it was clear that all of the studyrsquos pre-specified outcomes and all expected outcomes of interest to thereview have been reported)

bull high risk of bias (when not all of the studyrsquos pre-specifiedoutcomes have been reported one or more reported primaryoutcomes were not pre-specified outcomes of interest werereported incompletely and so cannot be used study failed toinclude results of a key outcome that would have been expectedto have been reported) or


(6) Other sources of bias

We have described for each included study any important concernsthat we have about other possible sources of biasWe have assessed whether each study was free of other problemsthat could put it at risk of bias

bull Low risk of other biasbull High risk of other biasbull Unclear whether there is risk of other bias

(7) Overall risk of bias

We have made explicit judgements about whether studies are athigh risk of bias according to the criteria given in the CochraneHandbook for Systematic Reviews of Interventions (Higgins 2011)With reference to the items listed above we have assessed the likelymagnitude and direction of the bias and whether we consider itlikely to impact the findings

Measures of treatment effect

Dichotomous data

For dichotomous data we presented the results as summary riskratios with 95 confidence intervals

Continuous data

For continuous data we used the mean difference if outcomes weremeasured in the same way between trials We used the standardisedmean difference to combine trials that measured the same outcomebut used different methods

Unit of analysis issues

Cluster-randomised trials

No cluster-randomised trials were identified for inclusion In thefuture if eligible for inclusion we will include cluster-randomisedtrials in the analyses along with individually randomised trialsWe will adjust sample sizes using the methods described in theCochrane Handbook for Systematic Reviews of Interventions (Section1634) based on an estimate of the intracluster correlation coeffi-cient (ICC) derived from the trial (if possible) from a similar trialor from a study of a similar population If we use ICCs from othersources we will report this and will conduct sensitivity analyses toinvestigate the effect of variation in the ICC If we identify bothcluster-randomised trials and individually randomised trials weplan to synthesise the relevant information We will consider itreasonableto combine the results from both if little heterogeneity is evidentbetween the study designs and if interaction between the effect ofthe intervention and the choice of randomisation unit is consid-ered to be unlikelyWe will also acknowledge heterogeneity in the randomisation unitand will perform a (sensitivity or subgroup) analysis to investigatethe effects of therandomisation unit

Cross-over trials

We considered cross-over designs inappropriate for this reviewquestion

Dealing with missing data

For included studies levels of attrition were noted The impactof including studies with high levels of missing data in the overallassessment of treatment effect was explored by using sensitivityanalysisFor all outcomes analyses were carried out as far as possible onan intention-to-treat basis (ie we have included in the analyses allparticipants randomly assigned to each group) The denominatorfor each outcome in each trial was the number randomly assignedminus any participants whose outcomes are known to be missing



Assessment of heterogeneity

We assessed statistical heterogeneity in each meta-analysis usingTausup2 Isup2 and Chisup2 statistics We regarded heterogeneity as substan-tial if Isup2 was greater than 30 and either Tausup2 was greater thanzero or a low P value (less than 010) was obtained in the Chisup2 testfor heterogeneity

Assessment of reporting biases

We planned to assess reporting biases if 10 or more studies wereincluded in the meta-analysis In this update (2014) no meta-analysis included 10 or more studies In future updates if morestudies are included we will investigate reporting biases (such aspublication bias) using funnel plots We will visually assess funnelplot asymmetry

Data synthesis

We have carried out statistical analysis using the Review Managersoftware (RevMan 2012) We used fixed-effect meta-analysis forcombining data in cases where it is reasonable to assume that stud-ies are estimating the same underlying treatment effect that iswhen trials are examining the same intervention and the trialsrsquopopulations and methods are judged sufficiently similar If clinicalheterogeneity is sufficient to expect that underlying treatment ef-fects differ between trials or if substantial statistical heterogeneitywas detected we used random-effects meta-analysis to producean overall summary if an average treatment effect across trials wasconsidered clinically meaningful The random-effects summarywas to be treated as the average range of possible treatment effectsand we planned to discuss the clinical implications of treatmenteffects differing between trials If the average treatment effect wasnot clinically meaningful we did not combine trialsIf we used random-effects analyses results were presented as theaverage treatment effect with 95 confidence intervals and esti-mates of Tausup2 and Isup2

Subgroup analysis and investigation of heterogeneity

We have carried out subgroup analyses according to route of ad-ministration and dose of the drug used for misoprostol trials apriori irrespective of heterogeneityIn future updates with the addition of new trials if we identifysubstantial heterogeneity we plan to investigate it further usingthe following subgroup analyses

bull Mode of delivery (caesarean versus vaginal delivery)bull Setting (hospital versus community)

All primary outcome measures will be used in subgroup analysesWe plan to assess subgroup differences by using interaction testsavailable within RevMan (RevMan 2012) We will report the re-sults of subgroup analyses by quoting the Chisup2 statistic and P valueas well as the interaction test Isup2 value

In the presence of significant heterogeneity (Isup2 gt 30) we willuse random-effects

Sensitivity analysis

We planned to carry out sensitivity analyses to explore the effect ontrial quality as assessed by concealment of allocation high attritionrates or both with poor-quality studies excluded from the analysesto assess whether this made any difference to the overall resultPoor quality was defined as studies at high risk of bias for allocationconcealment andor incomplete outcome data

R E S U L T S

Description of studies

Included studies

Ten randomised clinical trials (RCTs) with a total of 4060 par-ticipants fulfilled our inclusion criteria and were included in thisreview

Uterotonic trials

Eight uterotonic studies were identified and considered for inclu-sion in this review Of these one was excluded (Takagi 1976) be-cause the trial included women with blood loss less than 500 mLand the trial report did not allow analysis based on treatment allo-cation (rsquointention to treatrsquo) Seven misoprostol trials were includedin the review Four placebo-controlled trials compared misopros-tol (at doses of 600 to 1000 mcg) versus placebo (1881 partici-pants) among women receiving conventional uterotonics for pri-mary postpartum haemorrhage (PPH) treatment (Hofmeyr 2004Walraven 2004 Widmer 2010 Zuberi 2008) The main objec-tive of these studies was to assess the effectiveness of the randomlyselected drug to result in fewer women having additional bloodloss of 500 mL of more Lokugamage 2001 (64 participants) com-pared rectally administered misoprostol (800 mcg) versus oxyto-cics (combined syntometrine and oxytocin infusion) for the treat-ment of primary PPH defined as blood loss greater than 500 mLThe main objective of the study was to assess the effectiveness ofthe randomly selected drug to stop PPH within 20 minutes TheBlum 2010 and Winikoff 2010 trials (1787 participants) com-pared sublingual misoprostol (800 mcg) versus oxytocin infusion(40 IU infusion) for the treatment of primary PPH among womenwho had a vaginal delivery with clinically diagnosed or measuredblood loss of 700 mL or more within the first hour of delivery Themain objective of these studies was to assess the effectiveness ofthe randomly selected drug to stop PPH within 20 minutes and



or to result in additional blood loss of at least 300 mL The latterwas restricted to women who had received prophylactic oxytocinduring the second or third stage of labour

Haemostatic trials

Ducloy-Bouthors 2011 (144 participants) evaluated the place ofintravenous tranexamic acid (loading dose 4 g intravenously overone hour then infusion of 1 ghour over six hours) among womenwith primary PPH defined as measured blood loss of more than800 mL following vaginal delivery All participants with PPH gt500 mL were managed according to French practice guidelinesbladder catheter manual removal of retained placenta genital tractexamination uterine exploration and oxytocin (30 U30 min)followed and if these procedures were inefficacious sulprostonewas administered (500 microg in one hour) with no procoagulanttreatment Patients with PPH gt 800 mL were included in thestudy Immediately after inclusion participants were randomlyassigned to receive tranexamic acid (tranexamic acid group) or noantifibrinolytic treatment (control group) The main objective ofthe study was to assess the effect of randomly assigned tranexamicacid administration on blood loss at 30 minutes two hours andsix hours of administration

Other drug therapy trials

Zhou 2006 (112 participants) assessed the additional benefit ofestrogen adjuvant therapy (4 mg estradiol benzoate injected in-tramuscularly) for the amount of blood loss at two and 24 hoursamong women with primary PPH 4 mg estradiol benzoate in-

jected intramuscularly with routine management when bleedingexceeded 500 mL versus routine management only for the controlgroup Routine management of the control group was describedas rsquouterine massage and uterotonics administrationrsquo and includedrsquo20 U cervical muscle injection to contract the uterus 20 U intra-venous drip to contract the uterusrsquo In case of the cervical musclesnot restoring injection or intravenous drip did not exceed 80 U

Surgical trials

Chantrapitak 2009 (64 participants) assessed the amount of bloodloss at two hours after randomly assigning women with primaryPPH (defined as blood loss 500 mL or more) to lower uterinesegment compression in addition to conventional therapy for pri-mary PPH versus conventional therapy aloneWe did not identify any trials related to uterine tamponade uterinecompression suturing techniques artery ligations or radiologicalinterventionsFor further details of included studies see table of Characteristicsof included studies

Excluded studies

For details of excluded studies see table of Characteristics ofexcluded studies

Risk of bias in included studies

Please see Figure 1 and Figure 2 for summary of risk of bias assess-ments

Figure 1 Risk of bias graph review authorsrsquo judgements about each risk of bias item presented as

percentages across all included studies



Figure 2 Risk of bias summary review authorsrsquo judgements about each risk of bias item for each included

study



The Lokugamage 2001 trial compared misoprostol (800 mcg rec-tal) versus syntometrine combined with oxytocin infusion fortreatment of PPH The authors described clearly the random gen-eration method and allocation concealment using consecutivelynumbered sealed opaque envelopes It was a single-blinded studyas obstetricians were aware of the type of drug given althoughwomen and midwives were not The trial authors indicated thatsingle blinding was used mainly for safety ldquoto prevent over-dosageand to know what had been given in case of need of additionaldrugsrdquo No description was provided of the method of measure-ment of blood loss or the management of the third stage of labourThe authors have been contacted to request more informationPost-randomisation withdrawal of one woman (132) was reportedin the misoprostol arm The trial was prone to assessment biasas physicians were aware of the treatment given Generalisationof the results (external validity) is somewhat limited because ef-fectiveness outcomes such as rsquotreatment failurersquo were susceptibleto biased ascertainment Furthermore the authors performed aninterim analysis after 12 months (30 recruited women) and itis unclear whether this information was shared with the clini-cians participating in the trial Therefore one cannot rule out thepossibility that postrandomisation management and outcome as-sessment were influenced by knowledge of interim results Thestudy was terminated after an interim analysis revealed an 80difference between the two treatment arms for the pre-specifiedoutcome measure (effectiveness at stopping PPH within 20 min-utes of trial drugsrsquo administration) Only three outcome measureswere adequately reported (hysterectomy persistent vaginal bleed-ing following randomisation medical and surgical co-interven-tions) Maternal death was not reported as an outcome Otherreported outcome measures included blood transfusion length ofinpatient stay and drug side effects However they were reportedas ldquoP value of significancerdquo with no numbers or percentages Nolong-term outcome data were presentedThe Walraven 2004 and Hofmeyr 2004 trials were double-blindedstudies that compared misoprostol (600 mcg in Walraven and1000 mcg in Hofmeyr delivered by multiple routes) versus placebowhen used as an adjunct to standard uterotonics for the treatmentof primary PPH However the authors of the former trial believedthat blinding may have been compromised by differences in thesize of the misoprostol tablets and the placebo Both trials used ac-tive management of the third stage of labour and measured bloodloss after administration of conventional oxytocics for primaryPPH treatment and the trial drug In Hofmeyr 2004 six of 244data sheets did not include pack numbers and could not be in-cluded in the analysis In the Walraven 2004 trial no withdrawalsafter enrolment were reported No long-term outcome data werepresentedThe Zuberi 2008 trial was a multi-centre double-blind randomisedcontrolled study that compared sublingual misoprostol (600 mcg)

versus placebo when used as an adjunct to standard uterotonicsfor the treatment of primary PPH Blinding and allocation con-cealment were adequate and participants were randomly assignedin blocks of 10 using a computer-generated random sequencePlacebo tablets were identical in shape colour weight feel andtaste to misoprostol tablets The study was powered to recruit900 participants however investigators managed to recruit only61 participants and reported results for 59 of them The primaryoutcome measure was measured blood loss of 500 mL or moreafter treatment Authors indicated that accurate use of the scalesfor assessment of blood loss proved difficult Therefore volume ofblood was not analysed instead measurement according to read-ing of the blood collection device was recorded and analysed Nolong-term outcome data were presentedThe Widmer 2010 trial was a multicentre double-blind ran-domised controlled study that compared sublingual misoprostol(600 mcg) versus placebo when used as an adjunct to standarduterotonics for the treatment of primary PPH Investigators usedcomputer-generated randomisation sequence in blocks of six andeight stratified by country Overall blinding and allocation con-cealment were adequate Placebo tablets were identical in shapecolour weight feel and taste to misoprostol tablets A total of1422 women were recruited to the study three women did notreceive interventions and five women were lost to follow-up at 90minutes as blood loss was not recorded The study was poweredto measure impact on blood loss Methods of blood collection andmeasurement varied between centres However trial authors in-dicated that some of the methods used had been previously eval-uated in the World Health Organization trial of misoprostol forthe prevention of PPH (Guumllmezoglu 2001) Both groups receivedstandard uterotonics for the treatment of primary PPH No long-term outcome data were presentedThe Blum 2010 and Winikoff 2010 trials were double-blind ran-domised controlled trials that compared sublingual misoprostol(800 mcg) versus oxytocin infusion (40 IU in one 1000 mL ofsaline over 15 minutes) Both described clearly their methods of al-location concealment and blinding and used similar inclusion andexclusion criteria Placebo tablets were identical in shape colourweight feel and taste to misoprostol tablets However the lattertrial included only participants for whom oxytocic drugs were notadministered during the second and third stages of labour Theyused cessation of active bleeding within 20 minutes after initialtreatment and additional blood loss of 300 mL or more as primaryend points and reported outcomes in 100 of cases No long-term outcome data were reportedThe Ducloy-Bouthors 2011 trial was an open-label randomisedcontrolled study It was liable to selection and performance biasPartial blinding was achieved as obstetricians midwives and par-ticipants were not aware of interventions used However anaes-



thetists were aware of the intervention and were responsible forrandomisation and administration of the trial drug It is unclearhow the allocated intervention was concealed as intravenous in-fusion would be visible to all Investigators recruited 152 partici-pants but one was excluded as it was found later that she did notfulfil the inclusion criteria Protocol violations were reported forseven women (five in the tranexamic acid group and two in thecontrol group) and the analysis reported on 144 participants (72participants in each group) The study was not powered to mea-sure any of our primary outcome measures Investigators reportedfew long-term outcome dataThe Zhou 2006 trial was a randomised controlled study in whichwomen were randomly assigned to conventional therapy versusestrogen adjuvant therapy in addition to conventional therapyNo description of methods of randomisation and blinding wasprovided The study was underpowered to measure any impacton primary outcome measures Investigators reported impact ofoutcome on blood loss and hysterectomy However the methodused for measurement of blood loss was not describedThe Chantrapitak 2009 trial was a randomised controlled study inwhich women were randomly assigned to lower uterine segmentcompression in addition to conventional therapy or conventionaltherapy only Authors were contacted to clarify randomisation andthey have indicated that it occurred through random generationusing opaque concealed envelopes However the study is prone toconcealment bias as clinicians were aware of interventions usedThe trial was underpowered to measure impact on primary out-come measures

Effects of interventions

Misoprostol (any route) versus placebo or no

additional treatment given to women simultaneously

treated with conventional uterotonics (four trials

comparison 1)

Sublingual misoprostol at a dose of 600 mcg was used by Zuberi2008 and Widmer 2010 (total of 1483 women) in additionto conventional uterotonics among women treated for primaryPPH A total dose of 600 mcg (200 mcg oral and 400 mcg sublin-gual) misoprostol was used simultaneously in Walraven 2004 (160participants) and Hofmeyr 2004 (238 participants) used 1000mcg misoprostol simultaneously (200 mcg oral 400 mcg sublin-gual and 400 mcg rectal)

Primary outcomes

Compared with placebo misoprostol conferred no additional ben-efit in terms of reduction in the rate of maternal mortality (risk ra-tio (RR) 616 95 confidence interval (CI) 075 to 5085 5930versus 0951 Analysis 11) and hysterectomy (average RR 09395 CI 016 to 541 random-effects Tausup2 = 083 Isup2 = 33 5930 versus 5951 Analysis 14) Only Widmer 2010 and Zuberi2008 reported serious maternal morbidity (RR 034 95 CI 001

to 831 0734 versus 1749 Analysis 12) and admission to theintensive care unit (RR 079 95 CI 030 to 211 7734 versus9749 Analysis 13)

Secondary outcomes

Compared with placebo misoprostol administered in addition toconventional uterotonics had no significant impact on blood lossof at least 500 mL (RR 089 95 CI 071 to 112 121930versus 138950 Analysis 16) blood loss of at least 1000 mL (RR088 95 CI 042 to 186 12930 versus 14950 Analysis 18)or blood transfusion (RR 095 95 CI 077 to 117 139928versus 150949 Analysis 17)

Side effects

Compared with placebo misoprostol intake by any route was as-sociated with a significant increase in vomiting (RR 184 95CI 116 to 295 Analysis 118) shivering (average RR 225 95CI 176 to 288 heterogeneity Tausup2 = 002 Chisup2 = 471 df = 3(P = 019) Isup2 = 36 Analysis 123) maternal pyrexia of at least38degC (RR 312 95 CI 266 to 367 Analysis 120) and mater-nal pyrexia of 40degC or more (RR 1358 95 CI 493 to 3744Analysis 121)

Misoprostol versus other uterotonics given to women

who have not received any conventional uterotonic

therapy (three trials comparisons 2 and 3)

Sublingual misoprostol (800 mcg) was compared with oxytocininfusion (40 IU) in two trials (Blum 2010 Winikoff 2010 1787women total) The latter was restricted to women who had receivedprophylactic oxytocin during the second or third stage of labourLokugamage 2001 compared rectal misoprostol (800 mcg) with acombination of oxytocin infusion and syntometrine (64 women)

Primary outcomes

In the Blum 2010 and Winikoff 2010 trials no significant differ-ences were noted between the two groups for any of the primaryoutcomes maternal mortality (RR 099 95 CI 006 to 1574Analysis 21) hysterectomy (RR 198 95 CI 036 to 1072 4895 versus 2892 Analysis 24) admission to intensive care unit(RR 033 95 CI 001 to 806 0895 versus 1892 Analysis 23)and serious maternal morbidity (RR 033 95 CI 001 to 8060895 versus 1892 Analysis 22)In Lokugamage 2001 the rate of hysterectomy did not differ be-tween the two groups (RR 033 95 CI 001 789 032 versus132 Analysis 31) However the authors did not report rates ofmaternal morbidity mortality or admission to the intensive careunit



Secondary outcome measures

Compared with oxytocin infusion sublingual misoprostol use wasassociated with a significant increase in the number of womenwho had blood loss of at least 1000 mL (RR 265 95 CI 104to 675 Analysis 27) and blood transfusion (RR 147 95 CI102 to 214 Analysis 28) However no significant differenceswere associated with blood loss of at least 500 mL (average RR151 95 CI 0114 to 200 heterogeneity Chisup2 = 854 df = 1(P = 0003) Isup2 = 88 Analysis 25) and postrandomisation useof additional uterotonics to control bleeding (average RR 13095 CI 057 to 294 random-effects Tausup2 = 030 Isup2 = 88Analysis 210 analysed using a random-effects model because ofsubstantial heterogeneity) No significant differences were notedbetween the two groups regarding the number of women whorequired examination under anaesthesia bimanual compressionor surgical intervention to control bleedingThe Lokugamage 2001 trial found that rectal misoprostol (800mcg) was more effective than combined oxytocin and syn-tometrine in decreasing the need for additional uterotonics (RR018 95 CI 004 076 Analysis 33) No significant differencesin any other pre-specified secondary outcomes were reported

Side effects

Sublingual misoprostol use in 800 mcg was consistently associatedwith significantly higher rates of prostaglandin-related side effectssuch as vomiting and shivering

Estrogen adjuvant therapy trials (one trial

comparison 4)

Estrogen therapy (4 mg estradiol benzoate injected intramuscu-larly) in addition to conventional PPH treatment was evaluated inone single-centre trial (Zhou 2006 112 women) 4 mg estradiolbenzoate was injected intramuscularly when routine managementwas ineffective and bleeding exceeded 500 mL versus routine man-agement only Management of the control group was describedas rsquouterine massage and uterotonics administrationrsquo and includedrsquo20 U cervical muscle injection to contract the uterus 20 U intra-venous drip to contract the uterus In case of the cervical musclesnot restoring injection or intravenous drip did not exceed 80 UWhere rate of blood loss exceeded 2000 mL hysterectomy wasperformedrsquo

Primary outcomes

Three women in the control group and no women in the estrogengroup required hysterectomy (RR 016 95 CI 001 to 311Analysis 41)

Secondary outcomes

We have included two additional measures to assess blood loss asauthors did not report any of our pre-specified secondary outcomemeasures The authors reported a significant reduction in bloodloss within two hours (-27490 mL mean difference (MD) 95CI -38472 to -16508 mL Analysis 42) and between two and24 hours from intervention (-5070 mL MD 95 CI -8307 to-1833 mL Analysis 43)

Tranexamic acid (one trial comparison 5)

Ducloy-Bouthors 2011 is the only placebo-controlled trial oftranexamic acid (144 women)

Primary outcomes

No maternal deaths were reported in the study population Nosignificant difference was noted between the two groups regardingserious maternal morbidity (RR 033 95 CI 001 to 805 072 versus 172 Analysis 52) admission to the intensive care unit(RR 060 95 CI 015 to 242 372 versus 572 Analysis 53)and hysterectomy (RR 033 95 CI 001 to 805 072 versus 172 Analysis 54)

Secondary outcomes

No significant differences were observed in any of the pre-specifiedsecondary outcome measures between women with primary PPHtreated with tranexamic acid and those given placebo

Side effects

Nausea was common with tranexamic acid administration (RR1100 95 CI 146 to 8299 Analysis 518) Three cases of deepvein thrombosis were reported in the study population (two in thetranexamic acid group and one in the control group RR 20095 CI 019 to 2157 Analysis 521)

Lower uterine segment compression versus no

compression (one trial comparison 6)

Chantrapitak 2009 compared lower uterine segment compressionversus no intervention (64 women)

Primary outcomes

No maternal death admission to the intensive care unit seri-ous maternal morbidity or hysterectomy was reported in the twogroups



Secondary outcomes

The number of women who had blood loss of at least 500 mLwas significantly lower among women who had lower segmentcompression (RR 013 95 CI 002 to 094 Analysis 64) How-ever no difference was observed between the two groups regard-ing mean blood loss (-10500 mL MD 95 CI -26200 to 52mL Analysis 66) rate of blood transfusion (RR 233 95 CI066 to 823 Analysis 67) number of women with blood loss ofat least 1000 mL (RR 020 95 CI 001 to 401 Analysis 65)and number who required surgical co-intervention to control thebleeding (no events in either group so not estimable) (Analysis68)

D I S C U S S I O N

Summary of main results

The current review evaluated 10 clinical trials that fulfilled our in-clusion criteria None was adequately powered to address our pri-mary outcome measures Seven uterotonics trials evaluated the useof misoprostol for the treatment of primary PPH Data from thisreview show that when misoprostol was compared with placebo(four clinical trials) intravenous oxytocin (two trials) or combinedoxytocin and ergometrine (one trial) no statistically significant dif-ferences were seen in clinically important outcomes including ma-ternal mortality serious maternal morbidity admission to inten-sive care and hysterectomy Secondary outcomes such as blood lossgreater than 1000 mL and use of additional uterotonics favouredintravenous oxytocin over misoprostol The review suggests thatconventional primary PPH treatment with intravenous oxytocinshould be recommended as the more effective treatmentThe occurrence of five maternal deaths in the group of studiescomparing misoprostol versus placebo is unexpected (5930 ver-sus 0930 RR 616 95 CI 075 to 5085) This promptedHofmeyr and colleagues to examine the frequency of maternaldeaths among 40000 participants in 46 clinical trials of misopros-tol used for the prevention or treatment of PPH (Hofmeyr 2009)Of 11 maternal deaths reported in five clinical trials eight occurredin women receiving misoprostol (odds ratio 249 95 CI 067to 813 Hofmeyr 2009) Subsequent trials comparing sublingualmisoprostol versus intravenous oxytocin for treatment of primaryPPH (Blum 2010 Winikoff 2010) have been more reassuringwith one maternal death reported in each group (1895 versus1895 RR 099 95 CI 006 to 1574) Furthermore anotherrecent randomised trial comparing misoprostol versus placebo forPPH prevention reported no maternal deaths (Mobeen 2011)Tranexamic acid has been used for the prevention of haemorrhagefor quite some time (CRASH-2 trial collaborators 2010 Ferrer2009 Novikova 2010 Peitsidis 2011) but Ducloy-Bouthors 2011

was the first published randomised trial that examined the use oftranexamic acid to treat primary PPH The study is underpow-ered to assess any impact on pre-specified primary outcome mea-sures The Zhou 2006 trial of estrogen adjuvant therapy was notbig enough to evaluate the impact on primary and secondary out-comes In the absence of any pharmacological studies to supportthis current approach it is sensible to avoid any estrogen therapyfor PPH especially as risk of deep vein thrombosis is increased inthe immediate postpartum periodChantrapitak 2009 described two new techniques to control bloodloss through transabdominal compression of the lower uterinesegment These techniques appear simple and safe do not requirespecial skills and have no major side effects Unfortunately theauthors did not specify which technique they used during the trialperiod Lower uterine segment compression was associated witha modest reduction in mean blood loss and blood loss of at least500 mL The method warrants further evaluation as it could be ofconsiderable benefit in the management of women who developprimary PPH following home birth and require hospital transferfor further managementWe focused on four parameters to evaluate the impact of PPHtreatments on postrandomisation blood loss (1) blood loss of atleast 500 mL (2) blood loss of at least 1000 mL (3) blood trans-fusion and (4) mean blood loss after enrolment In this regardmisoprostol provided no additional benefit when compared withplacebo when given to women simultaneously treated with con-ventional uterotonics Misoprostol was evaluated as an effectiveand easy to administer alternative to intravenous oxytocin as first-line therapy for the treatment of primary PPH in two other trials(Blum 2010 Winikoff 2010) Compared with 40 IU oxytocininfusion 800 mcg sublingual misoprostol was associated with asignificant increase in the number of women who had blood lossof at least 1000 mL (RR 265 95 CI 104 to 675) blood trans-fusion (RR 147 95 CI 102 to 214) and mean blood loss (mL)(MD 4486 95 CI 2650 6322) Therefore where availableoxytocin infusion should be recommended as first-line treatmentfor primary PPH Lack of significant differences in primary out-comes suggests that when oxytocin infusion is not available sub-lingual misoprostol may serve as a valid alternative for providersseeking a uterotonic therapy for their patients No significant dif-ference was reported between tranexamic acid and placebo in theDucloy-Bouthors 2011 study in terms of women who had bloodloss of at least 500 mL or at least 1000 mL This is consistentwith the results of two systematic reviews (Ferrer 2009 Novikova2010) that evaluated the use of tranexamic acid for the preventionof PPH

Agreements and disagreements with otherstudies or reviews

Several potential reasons may explain why misoprostol randomisedtrials have not confirmed optimistic preliminary results from ob-



servational studies (Abdel-Aleem 2001 Adekanmi 2001 OrsquoBrien1998 Oboro 2003) In previous reports blood loss was subjec-tively assessed but in the seven trials included in this review bloodloss was measured objectively This is particularly important aslack of blinding in previous studies may have affected the percep-tion of effectiveness The pharmacokinetics of misoprostol mayalso be a contributing factor Variation in the route and dose ofadministration may result in significant variation in plasma ther-apeutic levels of the drug Current evidence suggests that the oralroute provides the advantage of rapid onset of action althoughthe vaginal and rectal routes confer the advantage of prolongedactivity and greater bioavailability The sublingual route possessesboth of these advantages with a rapid onset of action prolongedactivity and greater bioavailability (Abdel-Aleem 2003 Andolina2003 Danielsson 1999 Hofmeyr 2005 Khan 2003 Tang 2002Zieman 1997)Misoprostol intake was associated with a significant increase inprostaglandin-mediated side effects including maternal pyrexia (atleast 38degC or at least 40degC) vomiting and shivering Side effectsappear to be dose dependent Maternal pyrexia in particular isvery rare when low-dose misoprostol is used for induction of labouror termination of pregnancy (Alfirevic 2006 Dodd 2010) Theseside effects appear to be associated with high doses of misoprostoland may impact the management of patients with major obstetricalhaemorrhage For instance blood transfusion forms an essentialpart of fluid resuscitation in women with major PPH and a rise inbody temperature following misoprostol use could be incorrectlylabelled as a ldquotransfusion reactionrdquo with subsequent stoppage oftransfusion having a major impact on the general condition of thepatient Similarly maternal pyrexia could mistakenly be labelledas ldquomaternal sepsisrdquo which may result in the commencement ofunnecessary intravenous antibiotic therapyThree cases of deep vein thrombosis were reported in theDucloy-Bouthors 2011 study two in the tranexamic acid groupand one in the control group (RR 200 95 CI 019 to 2157)It is difficult to draw any conclusion regarding safety and risk ofthromboembolic complications after tranexamic acid administra-tion It is noteworthy that several large studies did not observe anysignificant increase in the risk of thromboembolism (CRASH-2trial collaborators 2010 Peitsidis 2011)In this current update we have not included postrandomisa-tion haemoglobin level or disseminated intravascular coagulopa-thy (DIC) as an outcome of interest for several reasons First bloodand clotting factor transfusions form an essential part of any pri-mary PPH resuscitation protocol in women with massive obstetri-cal haemorrhage Therefore a corrected haemoglobin level andorclotting factors may simply confirm adequate resuscitation ratherthan effectiveness of the uterotonics or the intervention Secondpostdelivery haemoglobin level is directly related to pre-deliverylevels rather than the impact of intervention on blood loss Ideallyone should measure the drop in haemoglobin andor hematocritlevels before delivery and the first blood transfusion However as

primary PPH occurs unexpectedly often among low-risk womenpre-delivery haemoglobin andor hematocrit levels usually are notavailable The trials by Winikoff 2010 Blum 2010 and Zuberi2008 have set an example by checking haemoglobin concentrationfor all labouring women before birth and after administration ofthe trial drug However this will be very difficult to replicate inother large pragmatic trials Currently lack of agreement has beennoted between clinicians regarding the definition of DIC (Gando2006)Two excluded quasi-randomised trials from the same centre(Soltan 2009 Soltan 2010) evaluated the use of external aorticcompression devices in addition to conventional therapy in thetreatment of primary PPH Investigators observed less blood trans-fusion when this device was used (RR 055 95 CI 045 to 066)but the studies were too small to show an impact on other substan-tive outcomes Although the use of external aortic compressiondevices was associated with abdominal discomfort and numbnessand a tingling sensation the lack of any short- or long-term Is-chaemic manifestations was quite reassuring Currently interestin evaluating the non-pneumatic antishock garment (NASG) isgrowing especially in low-resource areas With brief training itappears that individuals without a medical background can use thisfirst-aid device Miller and colleagues examined the use of NASGin a pre-interventionintervention study involving 1442 partici-pants with hypovolaemic shock secondary to obstetrical haemor-rhage from any cause and an estimated blood loss of at least 750mL (Miller 2010) The NASG intervention was associated with asignificant reduction in measured blood loss maternal mortalitysevere morbidities and emergency hysterectomyThe question related to the management of women with majorprimary PPH who remain unresponsive to medical managementwith uterotonics andor tranexamic acid therapy remains largelyunanswered In the absence of randomised controlled trials clin-icians are left to make their own judgement on the best combina-tion of surgical radiological andor pharmaceutical interventionsto control bleeding Large double-blind multi-centre randomisedcontrolled trials are needed to evaluate the effects of surgical in-terventions andor radiological interventions on the primary out-come measures however the inability to obtain informed consentfrom critically ill patients may make it difficult to recruit partici-pants Clinicians should be encouraged to conduct such trials pro-vided that they are able to follow agreed procedures for gettingconsent from critically ill patients and to ensure that recruitmentdoes not interfere with standard clinical management

A U T H O R S rsquo C O N C L U S I O N S

Implications for practice

Primary PPH is a life-threatening condition and availability offirst-aid treatment (IV line parenteral fluids and uterotonics)



is crucial Current evidence suggests that intravenous oxytocinshould be used as first-line therapy for the treatment of primaryPPH due to uterine atony Evidence suggests that misoprostol isless effective than oxytocin and provides no additional uterotoniceffect when used simultaneously with conventional oxytocin treat-ment Efforts should be made to make injectable oxytocin avail-able for use at deliveries occurring outside of facilities When in-jectable oxytocin is not available misoprostol can be used

Variation in dose regimens between the seven different misopros-tol studies made it difficult for the review authors to draw clearconclusions regarding the most effective dose or route As first-line treatment the largest body of evidence available supports thesafety and effectiveness of an 800-mcg sublingual dose As an ad-junct treatment to standard oxytocin infusion various routes wereexamined but none proved to be beneficial so no regimen is sug-gested at this time In general the use of higher doses should bebalanced against the likelihood of a greater incidence of maternalside effects associated with misoprostol A system of ldquoadverse eventregistrationrdquo might be helpful in identifying and tracking seriousmaternal morbidity and mortality associated with the use of alluterotonics in clinical practice

Use of tranexamic acid in routine clinical practice is under in-vestigation The results of one ongoing trial the WOMAN trialshould be large enough to provide information on the effective-ness and safety of this drug for women with primary PPH (Shakur2010)

Lower segment compression is a simple and promising methodparticularly when unwell patients with major haemorrhage aretransferred between centres in low-resource settings where accessto blood services is limited Results from field studies of thesemethods will be included in a future review

We are unable to provide any guidance regarding the managementof women with primary PPH who fail to respond to uterotonicsandor haemostatic drug therapies However it is logical to con-sider conservative surgical techniques andor radiological inter-ventions in an effort to avoid hysterectomy The main challenge isto ensure that adequate clinical expertise is available at all times todetermine when the conservative approach should be abandonedin favour of hysterectomy in a timely fashion

Implications for research

High-quality studies with adequate power are urgently needed to

address our primary outcome measures Future interventions ad-dressing management of PPH at the community level would alsobe useful Studies seeking to identify appropriate uterotonic man-agement of primary PPH following home deliveries particularlyin developing countries are of particular interest

Currently no randomised data are available on the effectivenessof carbetocin a long-acting synthetic oxytocin analogue but re-cent reports suggest that it may be of benefit in the prevention ofprimary PPH (Su 2012) and therefore further research would bejustified

Three areas of research would be of particular interest for womenwith primary PPH unresponsive to uterotonics First further workis needed to identify the most effective tamponade procedures anduterine haemostatic suturing techniques in women with majorprimary PPH Second aortic compression devices and the non-pneumatic antishock garment should be tested further in patientswith major obstetrical haemorrhage Finally the benefits of inter-ventional radiology for women at increased risk of bleeding duringdelivery and for those who bleed following childbirth should becritically evaluated in randomised trials Ideally first-line utero-tonics and second-line surgical intervention trials should be con-ducted in both developed and developing countries

A C K N O W L E D G E M E N T S

We are very grateful for the corresponding authors and re-search teams of the following trials Blum 2010 Chantrapitak2009 Ducloy-Bouthors 2011 Hofmeyr 2004 Widmer 2010 andWinikoff 2010 who completed our data collection forms

As part of the pre-publication editorial process this review has beencommented on by three peers (an editor and two referees externalto the editorial team) a member of the Pregnancy and ChildbirthGrouprsquos international panel of consumers and the Grouprsquos Statis-tical Adviser

The National Institute for Health Research (NIHR) is the largestsingle funder of the Cochrane Pregnancy and Childbirth GroupThe views and opinions expressed therein are those of the reviewauthors and do not necessarily reflect those of the NIHR the NHSor the Department of Health



R E F E R E N C E S

References to studies included in this review

Blum 2010 published data onlylowast Blum J Winikoff B Raghavan S Dabash R RamadanMC Dilbaz B et al Treatment of post-partumhaemorrhage with sublingual misoprostol versus oxytocinin women receiving prophylactic oxytocin a double-blindrandomised non-inferiority trial Lancet 2010375(9710)217ndash23Blum J Winikoff B Raghavan S Dabash R RamadanMC Dilbaz B et al Treatment of postpartum hemorrhagewith sublingual misoprostol versus oxytocin results froma randomized noninferiority trial among women receivingprophylactic oxytocin International Journal of Gynecology amp

Obstetrics 2009107(Suppl 2)S22ndashS23Dao B Blum J Barrera G Cherine Ramadan M DabashR Darwish E et al Side effect profiles for misoprostoland oxytocin in the treatment of postpartum hemorrhageInternational Journal of Gynecology amp Obstetrics 2009107

(Suppl 2)S150

Chantrapitak 2009 published data only

Chantrapitak W Srijanteok K Puangsa-art S Lower uterinesegment compression for management of early postpartumhemorrhage after vaginal delivery at CharoenkrungPracharak Hospital Journal of the Medical Association of

Thailand 200992(5)600ndash5

Ducloy-Bouthors 2011 published data only

Ducloy-Bouthers A Broisin F Keita H Fontaine S DepretS Legoeff F et al Tranexamic acid reduces blood loss inpostpartum haemorrhage Critical Care 201014()(Suppl1)S124Ducloy-Bouthors AS Duhamel A Broisin F Keita HFontaine S Tranexamic acid reduces blood loss in post-partum haemorrhage by reducing hyperfibrinolysis British

Journal of Anaesthesia 2012108ii191Ducloy-Bouthors AS Duhamel A Tournoys A Prado-Dupont A Debize G Peneau E et al Post-partumhaemorrhage induced hyperfibrinolysis Thrombosis

Research 2013131(Suppl 1)S89ndash90lowast Ducloy-Bouthors AS Jude B Duhamel A Broisin FHuissoud C Keita-Meyer H et al High-dose tranexamicacid reduces blood loss in postpartum haemorrhage Critical

Care (London England) 201115(2)R117

Hofmeyr 2004 published data onlylowast Hofmeyr GJ Ferreira S Nikodem VC MangesiL Singata M Jafta Z et al Misoprostol for treatingpostpartum haemorrhage a randomized controlled trial[ISRCTN72263357] BMC Pregnancy and Childbirth

20044(1)16Maholwana B Hofmeyr GJ Nikodem C Ferreira S SingataM Mangesi L et al Misoprostol for treating postpartumhaemorrhage Presented at 21st Conference on Prioritiesin Perinatal Care in South Africa 2002 March 5ndash8 EasternCape South Africa

Lokugamage 2001 published data only

Lokugamage AU Moodley J Sullivan K Rodeck CHNiculescu L Tigere P The Durban primary postpartumhaemorrhage study Womenrsquos Health-into the newmillennium Proceedings of the 4th International ScientificMeeting of the Royal College of Obstetricians andGynaecologists 1999 October 3-6 Cape Town SouthAfrica 199977ndash8lowast Lokugamage AU Sullivan KR Niculescu I TigereP Onyangunga F El Refaey H et al A randomizedstudy comparing rectally administered misoprostol versussyntometrine combined with an oxytocin infusion forthe cessation of primary post partum hemorrhage Acta

Obstetricia et Gynecologica Scandinavica 200180(9)835ndash9

Walraven 2004 published data only

Walraven G Dampha Y Bittaye B Sowe M Hofmeyr JMisoprostol in the treatment of postpartum haemorrhagein addition to routine management a placebo randomisedcontrol trial BJOG an international journal of obstetrics and

gynaecology 20041111014ndash7

Widmer 2010 published data only

Villar J Misoprostol to treat postpartum hemorrhage(PPH) a randomized controlled trial (Argentina EgyptSouth Africa Thailand and Viet Nam) Current ControlledTrials (wwwcontrolled-trialscommrct) (accessed 21 March2006)lowast Widmer M Blum J Hofmeyr GJ Carroli G Abdel-Aleem H Lumbiganon P et al Misoprostol as an adjunctto standard uterotonics for treatment of post-partumhaemorrhage a multicentre double-blind randomised trialLancet 2010375(9728)1808ndash13

Winikoff 2010 published data only

Winikoff B Misoprostol for the treatment of postpartumhemorrhage ClinicalTrialsgov (httpclinicaltrialsgov)(accessed 20 February 2008)Winikoff B Dabash R Durocher J Darwish E NgocNTN Leon W et al Treatment of postpartum hemorrhagewith sublingual misoprostol versus oxytocin results froma randomized non-inferiority trial among women notexposed to oxytocin during labor International Journal of

Gynecology amp Obstetrics 2009107(Suppl 2)S59lowast Winikoff B Dabash R Durocher J Darwish E NguyenTN Leon W et al Treatment of post-partum haemorrhagewith sublingual misoprostol versus oxytocin in womennot exposed to oxytocin during labour a double-blindrandomised non-inferiority trial Lancet 2010375(9710)210ndash6

Zhou 2006 published data only

Zhou M Yang CY Zhao Y Li P Clinical value of adjuvanttherapy with estrogen for postpartum hemorrhage Journal

of Southern Medical University 200626(6)865ndash6

Zuberi 2008 published data only

Zuberi NF Durocher J Sikander R Baber N Blum JWalraven G Misoprostol in addition to routine treatment



of postpartum hemorrhage a hospital-based randomized-controlled trial in Karachi Pakistan BMC Pregnancy and

Childbirth 2008840

References to studies excluded from this review

Deneux-Tharaux 2010 published data only

Deneux-Tharaux C Dupont C Colin C Rabilloud MTouzet S Lansac J et al Multifaceted intervention todecrease the rate of severe postpartum haemorrhage thePITHAGORE6 cluster-randomised controlled trial BJOG

an international journal of obstetrics and gynaecology 2010117(10)1278ndash87

Khalil 2011 published data only

Khalil MI Al-Dohami H Aldahish MM A methodto improve the effectiveness of the Bakri balloon formanagement of postpartum haemorrhage at caesareanInternational Journal of Gynaecology and Obstetrics 2011115

(2)198ndash200

Khireddine 2012 published data only

Khireddine I Le C Dupont C Rudigoz R Bouvier-ColleM Deneux-Tharaux C Induction of labor and risk ofpostpartum hemorrhage in low risk parturient womenJournal of Maternal-Fetal and Neonatal Medicine 201225

(S2)101

Magwali 2012 published data only

Magwali TL Butrick E Mambo V El Ayadi A LippmanS Bergel E et al Non-pneumatic anti-shock garment(NASG) for obstetric hemorrhageHarare ZimbabweInternational Journal of Gynecology amp Obstetrics 2012119

(Suppl 3)S410

Soltan 2009 published data only

Soltan MH Faragallah MF Mosabah MH Al-AdawyAR External aortic compression device the first aid forpostpartum hemorrhage control Journal of Obstetrics and

Gynaecology Research 200935(3)453ndash8


Soltan MH Imam HH Zahran KA Atallah SM Assessingchanges in flow velocimetry and clinical outcome followinguse of an external aortic compression device in women withpostpartum hemorrhage International Journal of Gynecology

amp Obstetrics 2010110(3)257ndash61

Takagi 1976 published data only

Takagi S Yoshida T Togo Y Tochigi H Abe M Sakata H etal The effects of intramyometrial injection of prostaglandinF2alpha on severe post-partum hemorrhage Prostaglandins

197612(4)565ndash79

References to studies awaiting assessment

Lavigne-Lissalde 2013 published data only

Gris JC rhuFVIIa in post-partum hemorrhageClinicalTrialsgov (httpclinicaltrialsgov) (accessed 20February 2008)Lavigne-Lissalde G Aya G Mercier F Roger-ChristopheS Chauleur C Morau E et al rhuFVIIa in womenwith a refractory primary postpartum haemorrhage an

international multicenter randomised opened controlledtrial Thrombosis Research 2013131(Suppl 1)S74

References to ongoing studies

Collins 2013 published data only

Collins P Fibrinogen concentrate versus placebo fortreatment of postpartum haemorrhage A multicentreprospective double blind randomised control trialClinicalTrialsgov (httpclinicaltrialsgov) (accessed2013)

Miller 2008 published data only

Miller S Non-pneumatic anti-shock garment for obstetricalhemorrhage Zambia and Zimbabwe ClinicalTrialsgov(httpclinicaltrialsgov) (accessed 20 February 2008)

Mirzazada 2011 published data only

Mirzazada S Misoprostol for the treatment of postpartumhaemorrhage (PPH) following self-administrationof misoprostol prophylaxis in home deliveriesClinicalTrialsgov (accessed 21 May 2013)

Shakur 2010 published data only

Gulmezoglu M Alfirevic Z Elbourne D RobertsI Tranexamic acid for the treatment of postpartumhaemorrhage an international randomised double blindplacebo controlled trial (woman trial-Protocol NumberISRCTN76912190) International Journal of Gynecology amp

Obstetrics 2009107(Suppl 2)S500Shakur H Elbourne D Gulmezoglu M Alfirevic ZRonsmans C Allen E et al The WOMAN Trial (WorldMaternal Antifibrinolytic Trial) tranexamic acid for thetreatment of postpartum haemorrhage an internationalrandomised double blind placebo controlled trial Trials

20101140

Wikkelsoe 2012 published data only

Wikkelsoe AJ Afshari A Stensballe J Langhoff-Roos JAlbrechtsen C Ekelund K et al The FIB-PPH trialfibrinogen concentrate as initial treatment for postpartumhaemorrhage study protocol for a randomised controlledtrial Trials [Electronic Resource] 201213110

Additional references

Abdel-Aleem 2001

Abdel-Aleem H El-Nashar I Abdel-Aleem A Managementof severe postpartum hemorrhage with misoprostolInternational Journal of Gynecology amp Obstetrics 20017275ndash6

Abdel-Aleem 2003

Abdel-Aleem H Villar J Gulmezoglu AM Mostafa SAYoussef AA Shokry M et al The pharmacokinetics ofthe prostaglandin E1 analogue misoprostol in plasma andcolostrum after postpartum oral administration European

Journal of Obstetrics amp Gynecology and Reproductive Biology

200310825ndash8

AbdRabbo 1994

AbdRabbo SA Stepwise uterine devascularization anovel technique for the management of uncontrollable



postpartum hemorrhage with preservation of the uterusAmerican Journal of Obstetrics and Gynecology 1994171694ndash700

Abou El Senoun 2011

Abou El Senoun G Singh M Mousa HA Alfirevic ZUpdate on the new modalities on the prevention andmanagement of postpartum haemorrhage Fetal and

Maternal Medicine Review 201122(4)247ndash64

Abou Zahr 1991

Abou Zahr C Royston E Global Mortality Global FactbookGeneva World Health Organization 1991

ACOG 1998

ACOG Technical Bulletin American College ofObstetricians and Gynecologists educational bulletinPostpartum hemorrhage Number 243 International

Journal of Gynecology amp Obstetrics 199861(1)79ndash86

Adekanmi 2001

Adekanmi OA Purmessur S Edwards G BarringtonJW Intrauterine misoprostol for the treatment of severerecurrent atonic secondary postpartum haemorrhageBJOG an international journal of obstetrics and gynaecology

2001108541ndash2

Aisaka 1988

Aisaka K Ando S Kokuho K Tawada T Kaneda SYoshimatsu J et al Effects of obesity and weight gainduring pregnancy on obstetrical factors Acta Obstetrica et

Gynaecologica Japonica 1988631851ndash8

Akhter 2005

Akhter S Begum MR Kabir J Condom hydrostatictamponade for massive postpartum hemorrhageInternational Journal of Gynecology amp Obstetrics 200590134-5

Alamia 1999

Alamia V Jr Meyer BA Peripartum hemorrhage Obstetrics

and Gynecology Clinics of North America 199926(2)385ndash98

Alexander 2002

Alexander J Thomas P Sanghera J Treatments forsecondary postpartum haemorrhage Cochrane Database

of Systematic Reviews 2002 Issue 1 [DOI 10100214651858CD002867]

Alfirevic 2006

Alfirevic Z Weeks A Oral misoprostol for induction oflabour Cochrane Database of Systematic Reviews 2006 Issue2 [DOI 10100214651858CD001338pub2]

Alfirevic 2007

Alfirevic Z Elbourne D Pavord S Bolte A Van Geijn HMercier F et al Use of recombinant activated factorVII inprimary postpartum hemorrhage the Northern Europeanregistry 2000-2004 Obstetrics and Gynecology 2007110(6)1270ndash8

Andolina 2003

Andolina KL Tolosa JE Monzo JM Roberts NS Daly SOral misoprostol is rapidly absorbed in postpartum womenat term Journal of Maternal-Fetal amp Neonatal Medicine

200314229ndash32

Arulkumaran 2007

Arulkumaran S Walker JJ Watkinson AF NicholsonT Kessel D Patel J The Role of Emergency and Elective

Interventional Radiology in Postpartum Haemorrhage Good

Practice No 6 London RCOG 2007

As 1996

As AK Hagen P Webb JB Tranexamic acid in themanagement of postpartum haemorrhage British Journal of

Obstetrics and Gynaecology 1996103(12)1250ndash1

B-Lynch 1997

B-Lynch C Coker A Lawal AH Abu J Cowen MJ TheB-Lynch surgical technique for the control of massivepostpartum haemorrhage an alternative to hysterectomyFive cases reported British Journal of Obstetrics and

Gynaecology 1997104(3)372ndash5

Bakri 1999

Bakri YN Balloon device for control of obstetricalbleeding European Journal of Obstetrics amp Gynecology and

Reproductive Biology 199986S84

Baskett 2000

Baskett TF A flux of the reds evolution of activemanagement of the third stage of labour Journal of the Royal

Society of Medicine 200093489ndash93

Begley 2011

Begley CM Gyte GML Devane D McGuire W Weeks AActive versus expectant management for women in the thirdstage of labour Cochrane Database of Systematic Reviews

2011 Issue 11 [DOI 10100214651858CD007412]

Beischer 1986

Beischer NA Mackay EV Obstetrics and the NewbornEastbourne Bailliere Tindall 1986

Bergstrom 1962

Bergstrom S Ryhag ER Samuelson B Sjovall J Thestructure of prostaglandin E F1 F2 Acta Chemica

Scandinavica 196216501ndash2

Bonnar 2000

Bonnar J Massive obstetric haemorrhage Baillieres Best

Practice and Research in Clinical Obstetrics and Gynaecology

200014(1)1ndash18

Burchell 1980

Burchell RC Postpartum haemorrhage In Quilligan ESeditor(s) Current Therapy in Obstetrics and GynaecologyPhiladelphia WB Saunders 1980

Cantwell 2011

Cantwell R Clutton-Brock T Cooper G Dawson ADrife J Garrod D et al Saving Mothersrsquo Lives reviewingmaternal deaths to make motherhood safer 2006-2008The Eighth Report of the Confidential Enquiries intoMaternal Deaths in the United Kingdom BJOG an

international journal of obstetrics and gynaecology 2011118

(Suppl 1)1ndash203

Carroli 2008

Carroli G Cuesta C Abalos E Gulmezoglu AMEpidemiology of postpartum hemorrhage a systematic



review Best Practice and Research Clinical Obstetrics and


Chan 1997

Chan C Razvi K Tham KF Arulkumaran S The useof a Sengstaken-Blakemore tube to control post-partumhemorrhage International Journal of Gynaecology and

Obstetrics 199758251-2

Cho 2000

Cho JH Jun HS Lee CN Hemostatic suturing techniquefor uterine bleeding during cesarean delivery Obstetrics amp

Gynecology 200096(1)129ndash31

Clark 1985

Clark SL Phelan JP Yeh SY Bruce SR Paul RHHypogastric artery ligation for obstetric hemorrhageObstetrics amp Gynecology 198566(3)353ndash6

Combs 1991

Combs CA Murphy EL Laros RK Factors associated withpostpartum haemorrhage with vaginal birth Obstetrics amp

Gynecology 19917769ndash76

Cotter 2001

Cotter AM Ness A Tolosa JE Prophylactic oxytocin for thethird stage of labour Cochrane Database of Systematic Reviews

2001 Issue 4 [DOI 10100214651858CD001808]

CRASH-2 trial collaborators 2010

CRASH-2 trial collaborators Shakur H Roberts I BautistaR Caballero J Coats T et al Effects of tranexamic acid ondeath vascular occlusive events and blood transfusion intrauma patients with significant haemorrhage (CRASH-2)a randomised placebo-controlled trial Lancet 2010376

(9734)23ndash32

Cunningham 1993

Cunningham FG MacDonald PC Gant NF Leveno KJGilstrap LC Abnormalities of the third stage of laborWilliams Obstetrics 19th Edition Norwalk CT Appletonamp Lange 1993

Cutler 1971

Cutler BS Daggett WM Application of the ldquoG-suitrdquo to thecontrol of hemorrhage in massive trauma Annals of Surgery

1971173(4)511ndash4

Danielsson 1999

Danielsson KG Marions L Rodriguez A Spur BW WongPY Bygdeman M Comparison between oral and vaginaladministration of misoprostol on uterine contractilityObstetrics amp Gynecology 199993275ndash80

Davis 1935

Davis ME Adher FL Rogers G Kharasch MS Legault RRA new active principle in ergot and its effects on uterinemotility American Journal of Obstetrics and Gynecology

193529155ndash67

De Loor 1996

De Loor JA van Dam PA Foley catheters for uncontrollableobstetric or gynecologic hemorrhage Obstetrics amp

Gynecology 199688737-8

Dodd 2010

Dodd JM Crowther CA Misoprostol for inductionof labour to terminate pregnancy in the second orthird trimester for women with a fetal anomaly orafter intrauterine fetal death Cochrane Database of

Systematic Reviews 2010 Issue 4 [DOI 10100214651858CD004901pub2]

Doumouchtsis 2007

Doumouchtsis SK Papageorghiou AT ArulkumaranS Systematic review of conservative management ofpostpartum hemorrhage what to do when medicaltreatment fails Obstetrical and Gynecological Survey 200762(8)540ndash7

Drife 1997

Drife J Management of primary postpartum haemorrhageBritish Journal of Obstetrics and Gynaecology 1997104275ndash7

Du Vigneaud 1953

Du Vigneaud V Ressler C Swan JM Roberts CWKatsoyannis PG Gordon S The synthesis of an octapeptidewith the hormonal activity of oxytocin Journal of the

American Chemical Society 1953754879ndash80

Dudley 1935

Dudley HW Moir C The substance responsible for thetraditional clinical effect of ergot BMJ 1935i520ndash3

Eastman 1950

Eastman NJ Anomalies of the third stage of labor Williamrsquos

Obstetrics 10th Edition New York Appleton-Century-Crofts 1950917ndash9

Ferrer 2009

Ferrer P Roberts I Sydenham E Blackhall K Shakur HAnti-fibrinolytic agents in post partum haemorrhage asystematic review BMC Pregnancy Childbirth 200915(9)29

Franchini 2010

Franchini M Franchi M Bergamini V Montagnana MSalvagno GL Targher G et al The use of recombinantactivated FVII in postpartum haemorrhage Clinical

Obstetrics and Gynecology 201053219ndash27

Gando 2006

Gando S Iba T Eguchi Y Ohtomo Y Okamoto KKoseki K et al A multicenter prospective validation ofdisseminated intravascular coagulation diagnostic criteriafor critically ill patients comparing current criteria Critical

Care Medicine 200634(3)625ndash31

Georgiou 2009

Georgiou C Balloon tamponade in the management ofpostpartum haemorrhage a review BJOG an international

journal of obstetrics and gynaecology 2009116748ndash57

Gilbert 1987

Gilbert L Porter W Brown VA Postpartum haemorrhagea continuing problem British Journal of Obstetrics and

Gynaecology 19879467ndash71

Gyte 1992

Gyte G The significance of blood loss at delivery MIDIRS

Midwifery Digest 19922(1)88ndash92



Guumllmezoglu 2001

Guumllmezoglu AM Villar J Ngoc NT Piaggio G Carroli GAdetoro L et al WHO multicentre randomised trial ofmisoprostol in the management of the third stage of labourLancet 2001358(9283)689ndash95

Haggerty 1996

Haggerty J Antishock garment httpwwwstinasagovttospinoff199628 (accessed 20 February 2008)

Hall 1985

Hall MH Halliwell R Carr-Hill R Concomitant andrepeated happenings of complications of the third stage oflabour British Journal of Obstetrics and Gynaecology 198592732ndash8

Hayman 2002

Hayman RG Arulkumaran S Steer PJ Uterine compressionsutures surgical management of postpartum hemorrhageObstetrics amp Gynecology 200299(3)502ndash6

Hensleigh 2002

Hensleigh PA Anti-shock garment provides resuscitationand haemostasis for obstetric haemorrhage BJOG an


(12)1377ndash84

Higgins 2011

Higgins JPT Green S editors Cochrane Handbook forSystematic Reviews of Interventions Version 510 [updatedMarch 2011] The Cochrane Collaboration 2011Available from wwwcochrane-handbookorg

Hofmeyr 2005

Hofmeyr GJ Walraven G Gulmezoglu AM MaholwanaB Alfirevic Z Villar J Misoprostol to treat postpartumhaemorrhage a systematic review BJOG an international


Hofmeyr 2008

Hofmeyr GJ Guumllmezoglu AM Misoprostol for theprevention and treatment of postpartum haemorrhage Best

Practice amp Research Clinical Obstetrics amp Gynaecology 200822(6)1025ndash41

Hunter 1992

Hunter DJ Schulz P Wassenaar W Effect of carbetocin along acting oxytocin analogue in the postpartum uterusClinical Pharmacology and Therapeutics 19925260ndash7

Johanson 2001

Johanson R Kumar M Obhrai M Young P Managementof massive postpartum haemorrhage use of a hydrostaticballoon catheter to avoid laparotomy BJOG an


(4)420ndash2

Jouppila 1995

Jouppila P Postpartum haemorrhage Current Opinion in


Khan 2003

Khan RU El-Refaey H Pharmacokinetics and adverse-effect profile of rectally administered misoprostol in thethird stage of labour Obstetrics amp Gynecology 2003101968ndash74

Khan 2006

Khan KS Wojdyla D Say L Guumllmezoglu AM Van LookPF WHO analysis of causes of maternal death a systematicreview Lancet 2006367(9516)1066ndash74

Knight 2009

Knight M Callaghan WM Berg C Alexander SBouvier-Colle MH Ford JB et al Trends in postpartumhaemorrhage in high resource countries a review andrecommendations from the International PostpartumHaemorrhage Collaborative Group BMC Pregnancy

Childbirth 200927(9)55

Liabsuetrakul 2007

Liabsuetrakul T Choobun T Peeyananjarassri K IslamQM Prophylactic use of ergot alkaloids in the third stage oflabour Cochrane Database of Systematic Reviews 2007 Issue2 [DOI 10100214651858CD005456pub2]

Maier 1993

Maier RC Control of postpartum haemorrhage with uterinepacking American Journal of Obstetrics and Gynecology

1993169317ndash23

Marasinghe 2011

Marasinghe JP Condous G Seneviratne HR MarasingheU Modified anchored B-Lynch uterine compressionsuture for post partum bleeding with uterine atony Acta

Obstetricia et Gynecologica Scandinavica 201190280-3

McDonald 2004

McDonald SJ Abbott JM Higgins SP Prophylacticergometrine-oxytocin versus oxytocin for the third stage oflabour Cochrane Database of Systematic Reviews 2004 Issue1 [DOI 10100214651858CD000201]

McDonald 2013

McDonald SJ Middleton P Dowswell T Morris PS Effectof timing of umbilical cord clamping of term infants onmaternal and neonatal outcomes Cochrane Database

of Systematic Reviews 2013 Issue 7 [DOI 10100214651858CD004074pub3]

Miller 2009

Miller S Ojengbede O Turan JM Morhason-Bello IOMartin HB Nsima D A comparative study of the non-pneumatic anti-shock garment for the treatment of obstetrichemorrhage in Nigeria International Journal of Gynecology


Miller 2010

Miller S Fathalla MM Ojengbede OA Camlin C Mourad-Youssif M Morhason-Bello IO et al Obstetric hemorrhageand shock management using the low technology non-pneumatic anti-shock garment in Nigerian and Egyptiantertiary care facilities BMC Pregnancy Childbirth 20101810ndash64

Mobeen 2011

Mobeen N Durocher J Zuberi N Jahan N Blum J WasimS et al Administration of misoprostol by trained traditionalbirth attendants to prevent postpartum haemorrhage inhomebirths in Pakistan a randomised placebo-controlledtrial BJOG an international journal of obstetrics and

gynaecology 2011118353-61



Moir 1932

Moir JC The action of ergot preparations on the puerperaluterus BMJ 1935i520ndash3

Moscardo 2001

Moscardo F Perez F de la Rubia J Balerdi B LorenzoJI Senent ML et al Successful treatment of severeintra-abdominal bleeding associated with disseminatedintravascular coagulation using recombinant activated factorVII British Journal of Haematology 2001114174ndash6

Mousa 2001

Mousa HA Walkinshaw S Major postpartum haemorrhageCurrent Opinion in Obstetrics and Gynecology 200113(6)595ndash603

Mousa 2002

Mousa H Alfirevic Z Major postpartum hemorrhagesurvey of maternity units in the United Kingdom Acta


Mousa 2008

Mousa HA Cording V Alfirevic Z Risk factors andinterventions associated with major primary postpartumhemorrhage unresponsive to first-line conventional therapyActa Obstetricia et Gynecologica Scandinavica 200887(6)652ndash61

Nardin 2011

Nardin JM Weeks A Carroli G Umbilical vein injectionfor management of retained placenta Cochrane Database


Novikova 2010

Novikova N Hofmeyr GJ Tranexamic acid forpreventing postpartum haemorrhage Cochrane Database


OrsquoBrien 1998

OrsquoBrien P El-Refaey H Gordon A Geary M RodeckCH Rectally administered misoprostol for the treatmentof postpartum haemorrhage unresponsive to oxytocin andergometrine a descriptive study Obstetrics amp Gynecology

199892212ndash4

Oboro 2003

Oboro VO Tabowei TO Bosah JO Intrauterinemisoprostol for refractory postpartum haemorrhageInternational Journal of Gynecology amp Obstetrics 20038067ndash8

Ochoa 2002

Ochoa M Allaire AD Stitely ML Pyometria afterhemostatic square suture technique Obstetrics amp Gynecology

200299(3)506ndash9

Ojengbede 2011

Ojengbede OA Morhason-Bello IO Galadanci H MeyerC Nsima D Camlin C et al Assessing the role of thenon-pneumatic anti-shock garment in reducing mortalityfrom postpartum hemorrhage in Nigeria Gynecologic and

Obstetric Investigation 201171(1)66ndash72

Oladapo 2012a

Oladapo OT Fawole B Blum J Abalos E Advancemisoprostol distribution for preventing and treatingpostpartum haemorrhage Cochrane Database of

Systematic Reviews 2012 Issue 2 [DOI 10100214651858CD009336]

Oladapo 2012b

Oladapo OT Okusanya BO Abalos E Intramuscular versusintravenous prophylactic oxytocin for the third stage oflabour Cochrane Database of Systematic Reviews 2012 Issue2 [DOI 10100214651858CD009332]

Oleen 1990

Oleen MA Mariano JP Controlling refractory atonicpostpartum hemorrhage with hemabate sterile solutionAmerican Journal of Obstetrics and Gynecology 1990162(1)205ndash8

Ouahba 2007

Ouahba J Piketty M Huel C Azarian M Feraud O LutonD et al Uterine compression sutures for postpartumbleeding with uterine atony BJOG an international journal

of obstetrics and gynaecology 2007114(5)619ndash22

Peitsidis 2011

Peitsidis P Kadir RA Antifibrinolytic therapy withtranexamic acid in pregnancy and postpartum Expert

Opinion on Pharmacotherapy 201112(4)503ndash16

Penninx 2010

Penninx JP Pasmans HL Oei SG Arterial balloon occlusionof the internal iliac arteries for treatment of life-threateningmassive postpartum haemorrhage a series of 15 consecutivecases European Journal of Obstetrics amp Gynecology and

Reproductive Biology 2010148(2)131ndash4

Pereira 2005

Pereira A Nunes F Pedroso S Saraiva J Retto H MeirinhoM Compressive uterine sutures to treat postpartumbleeding secondary to uterine atony Obstetrics and


Porro 1876

Porro E Della amputazione utero-ovarica comecomplemento di taglio cesareo Milan 1876

Poujade 2011

Poujade O Grossetti A Mougel L Ceccaldi P Ducarme GLuton D Risk of synechiae following uterine compressionsutures in the management of major postpartumhaemorrhage BJOG an international journal of obstetrics

and gynaecology 2011118433-9

Prendiville 1989

Prendiville WJ Elbourne DR Care during the third stage oflabour In Chalmers I Enkin M Keirse MJNC editor(s)Effective care in pregnancy and childbirth Oxford OxfordUniversity Press 19891145-69

Pritchard 1962

Pritchard JA Baldwin RM Dickey JC Wiggins KMBlood volume changes in pregnancy and puerperium IIred blood cell loss and changes in apparent blood volumeduring and following vaginal delivery cesarean section and



cesarean section plus total hysterectomy American Journal

of Obstetrics and Gynecology 1962841271ndash82

Rath 2009

Rath W Prevention of postpartum haemorrhage with theoxytocin analogue carbetocin European Journal of Obstetrics

amp Gynecology and Reproductive Biology 2009147(1)15ndash20

Rathat 2011

Rathat G Do Trinh P Mercier G Reyftmann L DechanetC Boulot P et al Synechia after uterine compressionsutures Fertility and Sterility 201195(1)405ndash9

RevMan 2012 [Computer program]

The Nordic Cochrane Centre The Cochrane CollaborationReview Manager (RevMan) Version 52 CopenhagenThe Nordic Cochrane Centre The Cochrane Collaboration2012

Ripley 1999

Ripley DL Uterine emergencies Atony inversion andrupture Obstetrics and Gynecology Clinics of North America

199926(3)419ndash34

Sloan 2010

Sloan NL Durocher J Aldrich T Blum J Winikoff BWhat measured blood loss tells us about postpartumbleeding a systematic review BJOG an international

journal of obstetrics and gynaecology 2010117(7)788ndash800

Stafford 2008

Stafford I Dildy GA Clark SL Belfort MA Visuallyestimated and calculated blood loss in vaginal and cesareandelivery American Journal of Obstetrics and Gynecology

2008199(5)e511-e517

Stearns 1808

Stearns J Account of the pulvis parturiens a remedy forquickening childbirth Medical Repository of New York 180811308ndash9

Stearns 1822

Steans J Observations on the secale cornutum or ergotwith directions for its use in parturition Medical Research

1822590

Stoll 1935

Stoll A Burckhardt E Lrsquoergobasine nouvel alkaloidede lrsquoergot de seigle solubile dans lrsquoeau Bulletin of

Pharmaceutical Sciences 193542257ndash66

Stones 1993

Stones RW Paterson CM Saunders NSTG Risk factors formajor obstetric haemorrhage European Journal of Obstetrics

amp Gynecology and Reproductive Biology 19934815ndash8

Su 2007

Su LL Chong YS Samuel M Oxytocin agonists forpreventing postpartum haemorrhage Cochrane Database


Su 2012

Su LL Chong YS Samue lM Carbetocin for preventingpostpartum haemorrhage Cochrane Database of


Suzuki 2012

Suzuki S Hiraizumi Y Miyake H Risk factors forpostpartum hemorrhage requiring transfusion in cesareandeliveries for Japanese twins comparison with those forsingletons Archives of Gynecology and Obstetrics 2012286

(6)1363ndash7

Tang 2002

Tang OS Schweer H Seyberth HW Lee SW Ho PCPharmacokinetics of different routes of administration ofmisoprostol Human Reproduction 200217332ndash6

Thompson 1935

Thompson MR The active constituents of ergot Apharmacological and chemical study Journal of the American

Pharmaceutical Association 193524185ndash96

Tseng 2011

Tseng JJ Ho JY Wen MC Hwang JI Uterine necrosisassociated with acute suppurative myometritis afterangiographic selective embolization for refractorypostpartum hemorrhage American Journal of Obstetrics and

Gynecology 2011204(6)e4ndashe6

Tsu 1993

Tsu VD Postpartum haemorrhage in Zimbabwe a riskfactor analysis British Journal of Obstetrics and Gynaecology

1993100327ndash33

Tunccedilalp 2012

Tunccedilalp Ouml Hofmeyr GJ Guumllmezoglu AM Prostaglandinsfor preventing postpartum haemorrhage Cochrane Database


Vahedi 1995

Vahedi M Ayuyao A Parsa M Freeman H Pneumaticantishock garment-associated compartment syndrome inuninjured lower extremities Journal of Trauma 1995384

(4)616ndash8

Wetta 2013

Wetta LA Szychowski JM Seals S Mancuso MS BiggioJR Tita AT Risk factors for uterine atonypostpartumhemorrhage requiring treatment after vaginal deliveryAmerican Journal of Obstetrics and Gynecology 2013209(1)51e1ndash51e6

WHO 2010

WHO UNICEF UNFPA The World Bank World HealthOrganization (WHO) Press Trends in Maternal Mortality

1990 to 2008 Estimates Developed by WHO UNICEF

UNFPA and The World Bank Geneva WHO 2010

Zheng 2011

Zheng J Xiong X Ma Q Zhang X Li M A new uterinecompression suture for postpartum haemorrhage withatony BJOG an international journal of obstetrics and


Zieman 1997

Zieman M Fong SK Benowitz NL Banskter D DarneyPD Absorption kinetics of misoprostol with oral or vaginaladministration Obstetrics amp Gynecology 19979088ndash92



References to other published versions of this review

Hofmeyr 2009

Hofmeyr GJ Guumllmezoglu AM Novikova N Linder VFerreira S Piaggio G Misoprostol to prevent and treatpostpartum haemorrhage a systematic review and meta-analysis of maternal deaths and dose-related effects Bulletin

of the World Health Organization 200987(9)666ndash77

Mousa 2003

Mousa HA Alfirevic Z Treatment for primary postpartumhaemorrhage Cochrane Database of Systematic Reviews

2003 Issue 1 [DOI 10100214651858CD003249]

Mousa 2007

Mousa HA Alfirevic Z Treatment for primary postpartumhaemorrhage Cochrane Database of Systematic Reviews 2007Issue 1 [DOI 10100214651858CD003249pub2]

lowast Indicates the major publication for the study



C H A R A C T E R I S T I C S O F S T U D I E S

Characteristics of included studies [ordered by study ID]

Blum 2010

Methods Computer-generated random allocation sequence in blocks of 10 Sealed and numberedopaque boxes contained the treatment allocation and were opened in strict numericalsequence Participants received simultaneously either 40 IU oxytocin in a litre of intra-venous solution over 15 minutes or 800 mcg (4 tablets of 200 mcg) misoprostol placedunder the tongue for 20 minutes and a placebo for the other treatment (ie 4 placebopills or an ampoule of saline)

Participants 809 women diagnosed with PPH due to uterine atony were randomly assigned to receive800 mcg misoprostol or 40 IU intravenous oxytocin Diagnosis of PPH was based onneed for treatment as determined by clinical judgement or measured blood loss of 700mL in the first hour after delivery whichever occurred firstWomen were excluded if their PPH was suspected to have a cause other than uterineatony if oxytocin was not received during the third stage of labour or if delivery was bycaesarean section

Interventions Prophylactic oxytocin given during the third stage of labour plus 800 mcg misoprostolsublingually or 40 IU intravenous oxytocin after diagnosis of PPH due to uterine atony

Outcomes Primary outcome cessation of active bleeding within 20 minutes and additional bloodloss of 300 mL or more after treatmentSecondary outcomes total blood loss after treatment change in haemoglobin after treat-ment time to active bleeding cessation provision of any additional interventions andside effects

Notes

Risk of bias

Bias Authorsrsquo judgement Support for judgement

Random sequence generation (selectionbias)

Low risk Computer-generated random allocationsequence in blocks of 10

Allocation concealment (selection bias) Low risk Allocation sequence was not revealed un-til data collection and cleaning were com-pleted Periodic monitoring to ensure hos-pitals were following the numerical se-quence of the boxes

Blinding (performance bias and detectionbias)All outcomes

Low risk Participants received simultaneously either40 IU oxytocin in a litre of intravenoussolution over 15 minutes or 800 mcg (4tablets of 200 mcg) misoprostol placed un-der the tongue for 20 minutes and a placebo



Blum 2010 (Continued)

for the other treatment (ie 4 placebo pillsor an ampoule of saline) Periodic moni-toring of hospitals to ensure masking wassuccessful

Incomplete outcome data (attrition bias)All outcomes

Low risk 100 outcome data

Selective reporting (reporting bias) Low risk Prior registration of protocol

Other bias Unclear risk Outcome measure of additional blood lossof 300 mL or more after treatment mayhave included blood from episiotomy andother liquids collected during delivery

Chantrapitak 2009

Methods Randomly assigned

Participants Women 28 to 42 weeksrsquo gestational age pregnancy with vaginal delivery with PPHdefined as blood loss gt 500 mL (assessed by weighing soaking drapes and blood in bucket)

Interventions Conventional treatment plus lower uterine compression (either compression of lowersegment only or compression of lower segment with counteracting pressure from fundus)for 10 minutes versus conventional treatment alone for PPH Conventional treatmentis described as uterine massage oxytocin (10 to 20 units in 1000 mL of intravenoussolution 200 mLmin) intravenous ergometrine) placing cold pack on the uterus andurinary catheterisation

Outcomes Main outcome amount of blood loss in conventionally treated group versus experimentalgroup 2 hours after treatment

Notes

Risk of bias



Low risk Authors indicated random generation using opaque concealedenvelopes

Allocation concealment (selection bias) High risk Clinicians were aware of intervention used


High risk Both participants and clinicians were aware of intervention used



Chantrapitak 2009 (Continued)


Low risk Outcome data collected on all 64 randomly assigned women

Selective reporting (reporting bias) Unclear risk No prior publication of protocol or statistical analysis planagainst which to assess

Other bias Unclear risk Outcome measure of blood loss may have included blood andother liquids collected during delivery

Ducloy-Bouthors 2011

Methods Randomised open-label multi-centre trial Randomisation sequence was generated bya central computer and randomisation was balanced by centre

Participants Women with measured blood loss gt 800 mL following vaginal delivery were includedin the study All participants with PPH gt 500 mL were managed according to Frenchpractice guidelines bladder catheter manual removal of retained placenta genital tractexamination uterine exploration and oxytocin (30 U30 min) followed and if theseprocedures were inefficacious sulprostone was administered (500 microg in 1 hour) with noprocoagulant treatment Participants with PPH gt 800 mL were included in the studyImmediately after inclusion participants were randomly assigned to receive tranexamicacid (tranexamic acid group) or no antifibrinolytic treatment (control group)Exclusion criteria were age lt 18 years absence of informed consent caesarean sectionpresence of known haemostatic abnormalities before pregnancy and history of thrombosisor epilepsyAll women were managed according to French practice guidelines bladder cathetermanual removal of retained placenta genital tract examination uterine exploration andoxytocin (30 U30 min) followed and if these procedures were inefficacious sulpros-tone (an analogue of prostaglandin E2 was administered 500 mcg in 1 hour) with noprocoagulant treatment

Interventions Tranexamic acid of loading dose 4 grams intravenously over 1 hour then infusion of 1gh over 6 hours versus no antifibrinolytics

Outcomes Primary outcome was volume of blood loss between T1 and T4 (T1 = inclusion and T4= T1 + 6 hours)Secondary outcomes were

bull duration of bleeding andbull impact of tranexamic acid on PPH-related outcome

Decrease in haemoglobin concentration Transfusion of packed red blood cells at T4 and at day 42 Need for invasive procedures (uterine artery embolisation or ligature

hysterectomy) Late postpartum curettage General outcome (intensive care unit stay use of vasopressors dyspnoea

renal and multiple organ failure) Severe PPH defined according to Charbit et al as exhibiting 1 of the

following criteria peripartum decrease of haemoglobin gt 4 gdL with the last



Ducloy-Bouthors 2011 (Continued)

haemoglobin value before delivery considered as the reference transfusion of at least 4packed red blood cells invasive haemostatic intervention death

Notes

Risk of bias



Low risk Randomisation sequence was generated bya central computer and randomisation wasbalanced by centre

Allocation concealment (selection bias) Unclear risk Allocation is described as being concealedto outcome assessors Obstetricians mid-wives and participants were not aware of theintervention used However anaesthetistswere aware of the intervention and were re-sponsible for randomisation and adminis-tration of the trial drug It is unclear howthe allocated intervention was concealed asthe intravenous infusion would be visibleto all


High risk Open labelled


Low risk 152 women randomly assigned and dataon 151 women reported in intention-to-treat analysis

Selective reporting (reporting bias) High risk Public registration of protocol done nearly3 years after study completion Report pub-lished several years after end of trial

Other bias Unclear risk Outcome measure of blood loss may haveincluded blood and other liquids collectedduring delivery

Hofmeyr 2004

Methods Next in a series of treatment packs containing 5 tablets of independently preparedordered in computer-generated random sequence and numbered consecutively Packscontained either placebo or misoprostol 5 times 200 mcg

Participants 244 women with bleeding more than expected at least 10 minutes after delivery thoughtto be due to uterine atony and requiring additional uterotonic therapy



Hofmeyr 2004 (Continued)

Interventions Routine active management of the third stage of labour with oxytocin 10 units or syn-tometrine 1 ampoule soon after birth All participants were given all routine treatmentsfor PPH (intravenous infusion uterotonics etc) from a special rsquoPPH Trollyrsquo Trial tablets(misoprostol 200 mcg or placebo) were administered 1 orally 2 sublingually and 2 rec-tally

Outcomes Primary outcomesbull Measured blood loss 500 mL or more in first hour after enrolmentbull Mean measured blood loss in first hour after enrolmentbull Haemoglobin level day 1 after birth lt 6 gdL or blood transfusionbull Side effects (pyrexia 385 degrees Celsius or more moderate or severe shivering 1

hour after enrolment)Secondary outcomes

bull Blood loss 1000 mL or more in first hour after enrolmentbull Blood transfusionbull Haemoglobin level first day after birth lt 8 gdL or blood transfusionbull Additional uterotonic given after enrolmentbull Manual removal of the placentabull Evacuation of retained products of conceptionbull Hysterectomybull Maternal death

Notes 6244 data sheets did not have pack numbers completed and were excluded from theanalysis No abnormal outcomes were observed in any of the excluded group except 1case of shivering and 1 of blood transfusion No information given regarding allocationgroup Authors were contacted to clarify amount of blood loss before recruitment andthey have provided the following information

bull The trial was planned as a PPH treatment trial to assess the effect of misoprostolover and above routine treatment of PPH

bull Entry criteria were intended to identify women who had PPH requiringadditional treatment No blood loss criterion was included as clinically we diagnosePPH on the basis of ongoing abnormal bleeding irrespective of the volume lost so farThus all participants in the opinion of the attending clinician had abnormal bleedingrequiring treatment It is likely that in most cases this would have been more than 500mL but we do not have these data

bull 10 minutes was the minimum time after delivery but in most cases the time waslonger (in the 3 cases of maternal mortality enrolment ranged between 85 and 140minutes after delivery)

Risk of bias



Low risk Computer-generated random sequenceand numbered consecutively

Allocation concealment (selection bias) Low risk Adequate as participants were allocated asnext in a series of treatment packs contain-




ing 5 tablets of independently prepared trialdrug (misoprostol or placebo)


Low risk Treatment sequence was kept sealed andthe code was broken only after completeentry and checking of all trial data


Low risk 244 women were randomly assigned Packnumbers for 6 women were incompletelyfilled in on the data sheets Group allo-cation of these women was therefore un-known and they could not be included inthe analysis

Selective reporting (reporting bias) Unclear risk No prior public registration of protocol


Lokugamage 2001

Methods Random allocation by sealed sequentially numbered envelopes No blinding

Participants 64 women with primary PPH gt 500 mL in 2 centres Women with hypertension atrecruitment cardiac abnormalities ongoing severe asthma connective tissue disordershaemorrhage due to obvious genital tract trauma Any contraindications to prostaglandintherapy were excluded

Interventions Syntometrine + syntocinon intravenous infusion + 4 placebo tablets per rectum versus800 mcg (4 tablets) misoprostol per rectum + a placebo normal saline 2 mL intramuscularinjection + placebo crystalloid intravenous infusion

Outcomes Effectiveness to control PPH within 20 minutes of administration

Notes Single-blinded study as obstetricians were aware of the type of drug given and womenand midwives were blindedNo mention of (a) drugs used in the third stage (b) measurement of blood lossOutcome measures for the following factors were reported as P value only(a) DIC (b) blood transfusion (c) length of hospital stay (d) drug side effects

Risk of bias



Low risk Randomisation was performed by generat-ing random numbers via STATA a statis-tical software package



Lokugamage 2001 (Continued)

Allocation concealment (selection bias) Low risk Sealed sequentially numbered opaque en-velopes were used and they were openedin succession once a participant had beenrecruited


High risk Midwives were blinded to treatment al-though obstetricians and research doctorwere aware of the randomisation


Low risk 64 participants are presented in the finalresults 32 participants having been allo-cated to each arm of the study 1 participantwas recruited to the misoprostol arm butwas excluded from the analysis because thehaemorrhage was due to uterine rupture

Selective reporting (reporting bias) High risk Certain outcome data were reported as ldquoPrdquovalue of significance Therefore data can-not be entered in a meta-analysisNo attempt was made to measure bloodloss and it was not reported as an outcomemeasureNo prior public registration of protocol

Other bias High risk Original sample size calculation 142 par-ticipants needed to be recruited How-ever the first year interim analysis whichincluded 15 participants per study armshowed that misoprostol performed bestThe decision was made to terminate thestudy after recruitment of 64 participantsas the difference between the 2 treat-ment regimens reached statistical signifi-cance with power in excess of 80As the study is a single-blinded study theinterim results may have influenced clini-ciansrsquo management

Walraven 2004

Methods Next in a series of randomised treatment packs in opaque envelopes with 3 tablets ofmisoprostol 200 mcg or placebo

Participants 160 women who delivered vaginally with measured postpartum blood loss of 500 mLor more within 1 hour of delivery and inadequate uterine contraction thought to be thepossible factor Exclusion criteria included women who delivered by caesarean sectionif blood loss was less than 500 mL in first hour following vaginal delivery if gestational



Walraven 2004 (Continued)

age was less than 28 weeks or if inadequate uterine contraction was not thought to bethe causative factor for PPH

Interventions Routine active management of third stage of labour with oxytocin 10 IU or syntometrine1 ampoule (5 mL) All participants had standard management of PPH (rubbing theuterus commencing intravenous infusion administering oxytocics delivering the pla-centa if undelivered and emptying the bladder)Trial tablets (misoprostol 200 mcg or placebo) were administered 1 orally and 2 sublin-gually

Outcomes Primary outcome additional blood loss after enrolmentSecondary outcomes frequency and severity of side effects additional blood loss of 500mL or more after enrolment clinical complications (blood transfusion hysterectomy)and haemoglobin level at 12 to 24 hours after delivery

Notes Blinding may have been compromised by non-identical placebos

Risk of bias



Low risk Next in a series of randomised treatmentpacks in opaque envelopes containingmisoprostol 3 200 Ag or placebo tablets

Allocation concealment (selection bias) Low risk The randomisation code was broken onlyafter entry and checking of data An in-dependent data monitor reviewed the datacollected from the first 80 women and rec-ommended that the study continue untilcomplete recruitment


Unclear risk Although this is a double-blind trial the au-thors indicated that the tablets were similarin size and colour but not in shape Effortsto obtain identical placebo tablets were un-successful Although no account indicatedthat the midwife caught sight of the tabletthis is not a sufficient guarantee of adequateblinding


Low risk No withdrawals after enrolment were re-ported and all outcomes were analysed ac-cording to the allocated study group

Selective reporting (reporting bias) Unclear risk No prior publication of protocol





Widmer 2010

Methods A computer-generated randomisation sequence derived centrally in United States andstratified by country Within the strata women were individually allocated by blockrandomisation (varying blocks of 6 and 8)

Participants 1422 women with clinically diagnosed PPH that was suspected to be due to uterine atonyand they needed additional uterotonics Participants were enrolled from hospitals inArgentina Egypt South Africa Thailand and Vietnam Women were not eligible for thetrial if delivery was by caesarean section misoprostol could not be given sublingually anysevere allergic or bleeding disorders (eg haemophilia) were recorded temperature washigher than 38middot5degC delivery was defined as a miscarriage according to local gestationalage limits or the placenta was not delivered

Interventions 600 microg misoprostol sublingually (3 tablets of 200 microg) or matching placebo in additionto standard care for PPH according to local protocol

Outcomes Primary outcome blood loss ge 500 mL within 60 minutes after randomisationSecondary outcomes need for blood transfusion haemoglobin concentration of less than80 gL within 24 hours postpartum or need for blood transfusion median blood loss at60 minutes and 90 minutes after randomisation blood loss of 500 mL or more within 90minutes after randomisation blood loss of 1000 mL or more within 60 minutes and 90minutes after randomisation need for any additional uterotonic maternal death severemorbidity (hysterectomy or admission to a maternal intensive care unit) side effects(shivering pyrexia diarrhoea vomiting or nausea) within 60 minutes and 90 minutesafter randomisation and need for any other interventions

Notes

Risk of bias



Low risk Computer-generated randomisation se-quence derived centrally and stratified bycountry Within the strata women wereindividually allocated by block randomisa-tion (varying blocks of 6 and 8)

Allocation concealment (selection bias) Low risk Randomisation code was not shown to anyparticipating trial centre or member of thestudy team until the trial was closed Toconceal allocation treatment boxes weresealed and numbered sequentially accord-



Widmer 2010 (Continued)

ing to the randomisation sequence andwere distributed in the order that womenwere judged to be eligible and were enrolledin the study


Low risk Treatment boxes were identical in appear-ance for both groups and placebo tabletswere identical to misoprostol tablets inshape colour weight feel and taste


Low risk All randomly assigned participants in-cluded in analysis



Winikoff 2010

Methods Computer-generated random allocation sequence in blocks of 10 and concealed fromstudy staff who enrolled and were allocated Sealed and opaque packets were administeredto participants in the order that they were diagnosed and providers and women weremasked to treatment assignment

Participants 978 women with PPH where administration of oxytocic drugs during the second (eg induction or augmentation) and third stages of labour (active management) was notroutine practice Diagnosis of PPH could occur at any time and at any amount ofblood loss however the protocol instructed providers to begin treatment immediatelyif measured blood loss exceeded 700 mLWomen who had a known allergy to prostaglandin had received any uterotonic drug inlabour or had a caesarean section or delivered outside the study site or whose postpartumbleeding was not suspected to be due to atonic uterus were excluded from the study

Interventions Either 1 ampoule of 40 IU oxytocin or 4 tablets of 200 mcg misoprostol and matchingplacebo (either 1 ampoule of saline solution or 4 placebo tablets resembling misoprostol) which were administered simultaneously Oxytocin or saline solution was administeredin a litre of intravenous solution over 15 minutes and misoprostol or placebo tabletswere placed under the tongue for 20 minutes

Outcomes Primary outcomes were the proportion of women who ceased active bleeding within 20minutes after study treatment alone and those who lost 300 mL or more of blood aftertreatmentSecondary outcomes were total blood loss after treatment change in haemoglobin con-centration after treatment time to active bleeding cessation and any other additionalinterventions All outcomes were assessed from the time of initial treatment



Winikoff 2010 (Continued)

Notes

Risk of bias




Allocation concealment (selection bias) Low risk Randomisation codes were maintainedcentrally and were concealed from studystaff who enrolled and allocated


Low risk Sealed and opaque packets were adminis-tered to participants in the order in whichthey were diagnosed Every packet con-tained 1 active treatment (either 1 am-poule of 40 IU oxytocin or 4 tablets of200 microg misoprostol) and matching placebo(either 1 ampoule of saline solution or4 placebo tablets resembling misoprostol) Note Only visual matching of placebotablets to active Matching of taste not de-scribed


Low risk Outcomes reported on all randomly as-signed participants



Zhou 2006

Methods Randomised

Participants 112 puerperants with PPH due to uterine atony who received routine management foruterine atony Exclusions were as follows younger than 18 years of age any pre-existingheart condition high blood pressure for which they had received medication in theprevious 2 years any pre-existing blood condition whether from birth or contractedlater in life such as haemophilia history of suffering from or exhibiting symptoms ofprogressive hepatitis or endocrinosis having undergone traditional caesarean havingundergone general anaesthetic in case of placenta previa or if the cervical muscles hadundergone surgery52 assigned to test group 60 to control group



Zhou 2006 (Continued)

Interventions 4 mg estradiol benzoate injected intramuscularly with routine management when bleed-ing exceeded 500 mL versus routine management only for the control group Routinemanagement of the control group was described as rsquouterine massage and uterotonicsadministrationrsquo and included rsquo20 U cervical muscle injection to contract the uterus 20U intravenous drip to contract the uterus In case of the cervical muscles not restoringinjection or intravenous drip did not exceed 80 U Where rate of blood loss exceeded2000 ml hysterectomy was performedrsquo

Outcomes Rate of blood loss at 2 hours and 2 to 24 hours and any reported instances of hysterectomyup to 24 hours

Notes

Risk of bias



Unclear risk Not described

Allocation concealment (selection bias) Unclear risk Not described




High risk Authors reported data only for blood loss and hysterectomy

Selective reporting (reporting bias) High risk Authors reported data only for blood loss and hysterectomyNo prior public registration of protocol

Other bias High risk Unclear how blood loss was measuredNo sample size calculation We were unable to identify manage-ment before randomisation

Zuberi 2008

Methods Sample was randomly assigned in blocks of 10 stratified by site using a computer-generated random sequence Eligible women were randomly assigned to next studyenvelope Each study envelope contained 3 tablets of misoprostol (200 mcg times 3) ormatching placebo

Participants 61 participants from a planned sample of 900 women with PPH (defined as measuredblood loss of 500 mL) had been reached Women with cesarean section gestational ageless than 28 weeks at time of delivery or not consenting were excluded from the study



Zuberi 2008 (Continued)

Interventions 600 mcg of misoprostol or matching placebo taken sublingually in addition to standardtreatment for PPHStandard treatment was management of the third stage of labour with standard utero-tonics controlled cord traction after delivery of baby and gentle uterine massage afterdelivery of the placenta At delivery of the anterior shoulder of the baby 1 of 2 uterotonicregimens was administered intravenous 10 IU of oxytocin or 5 IU of oxytocin plus 04mg of ergometrine given intramuscularly or intravenously

Outcomes Primary endpoint was measured blood loss ge 500 mL after PPH treatmentSecondary outcomes included change in haemoglobin side effects need for additionalinterventions including blood transfusion additional uterotonics balloon tamponadeand hysterectomy and mean blood loss

Notes Only 61 participants of a planned sample of 900 recruited

Risk of bias



Low risk Sample was randomly assigned in blocksof 10 stratified by site using a computer-generated random sequence

Allocation concealment (selection bias) Low risk Randomisation code was concealed untilall data were entered and cleaned


Low risk Use of the next randomised study envelopeeach contained 3 tablets of either miso-prostol (200 mcg times 3) or matching placebo(matching not described)


Unclear risk Main outcome data presented for 59 of the61 randomly assigned participants

Selective reporting (reporting bias) Low risk Prior public registration of protocol

Other bias High risk Failure to recruit sufficient participants tomeet sample size and power requirementsof the studyBias in outcome measurement Blood losswas collected on used gauze pieces and padsthat were counted and placed in a plas-tic bag The plastic bag was then weighedhowever accurate use of the scales proveddifficult these results could not be verifiedand were excluded

DIC disseminated intravascular coagulopathies



EACD external aortic compression deviceIU international unitsmin minutesPPH postpartum haemorrhage

Characteristics of excluded studies [ordered by study ID]

Study Reason for exclusion

Deneux-Tharaux 2010 A multifaceted intervention aimed at increasing the translation into practice of a protocol for early man-agement of PPH

Khalil 2011 The current study was carried out to evaluate the effectiveness of a new technique for keeping the Bakriballoon in place among women with major primary PPH All participants had a Bakri balloon insertedwith the same technique but they were randomly assigned to (a) Bakri balloon and a stitch to keep it inplace or (b) Bakri balloon without a stitch The current intervention of using ldquoa stitchrdquo was not direct forthe treatment of primary PPH

Khireddine 2012 This study was excluded as it was a non-randomised population-base case-controlled study that examinedthe association between induction of labour and postpartum haemorrhage according to its indications andmethods in low-risk parturient women

Magwali 2012 This study was a non-randomised study that compared blood loss and mortality in participants with severeobstetrical haemorrhage who received standard care in phase 1 (0ctober 2007 to October 2008) versusstandard of care plus non-pneumatic antishock garment (NASG) in phase 2 (October 2008 to October2009) at 2 referral hospitals in Harare

Soltan 2009 This study was excluded as it was a quasi-randomisation trial 300 participants with blood loss of 500mL from a non-contracted uterus associated with signs of circulatory compromise (eg tachycardia andor moderate to severe hypotension) were allocated in an alternative fashion to external aortic compressiondevices (EACDs) as a first intervention line simultaneously with conventional management versus con-ventional management alone Main outcome measures were maternal mortality surgical operation (eghysterectomy) and quantity of uterotonic drugs and blood transfusion units used Time in minutes requiredfor cessation of uterine bleeding and side effects of EACD in relation to duration of use were recordedPeriod of follow-up was not defined Authors presented data for only 240 women (120 participants in eacharm) Reasons for exclusion of 60 participants were unclear

Soltan 2010 This study was excluded as it was a quasi-randomisation trial 120 women with blood loss of 500 mLfrom a non-contracted uterus associated with signs of circulatory compromise (eg tachycardia andormoderate to severe hypotension) were allocated in an alternative fashion EACD as a first intervention linesimultaneously with conventional management versus conventional management alone Exclusion criteriaincluded women undergoing a caesarean delivery known lower limb ischaemia deep venous thrombosisand peripheral neuritis or other neurological respiratory hepatic renal or intestinal disorders Aims of thestudy were to monitor femoral artery blood flow by Doppler velocimetry in women treated for PPH withand without the adjunct of the EACD and to assess possible adverse effects of the aortic compression deviceAuthors did not provide enough information regarding obstetrical outcome measures



(Continued)

Takagi 1976 The study consists of 2 parts The first part was a retrospective analysis of data obtained before the clinicaltrial The clinical trial compared the effects of prostaglandin F2 alpha and ergot derivatives on the amount ofblood loss in women who suffered PPH as blood loss gt 400 mL in primiparas and gt 300 mL in multiparas13 women were randomly assigned to receive ergot derivatives and 46 women received prostaglandin F2alpha by 1 of the following routes (1) gluteal intramuscular (2) intravenous infusion (3) transabdominalintramyometrial or (4) transvaginal intramyometrial Method of randomisation was not reported We wereunable to extract data according to allocated groups to perform an rsquointention-to-treatrsquo analysis

PPH postpartum haemorrhage

Characteristics of studies awaiting assessment [ordered by study ID]

Lavigne-Lissalde 2013

Methods Block randomisation according to site

Participants Women with severe postpartum haemorrhage

Interventions Standard care plus recombinant activated factor VII (rhuVIIa) versus standard care only

Outcomes Impact on use of second-line therapy

Notes Not enough information in abstract for appraisal

Characteristics of ongoing studies [ordered by study ID]

Collins 2013

Trial name or title Fibrinogen concentrate to treat postpartum haemorrhage - OBS2 Study

Methods A multicentre prospective double blind randomised control trial

Participants Women experiencing major postpartum haemorrhage (PPH) About 1050 women will be recruited into theobservational phase of the study so that 60 can be randomised to receive fibrinogen concentrate or placebo

Interventions Fibrinogen concentrate (RiaStapreg) versus placeboThe woman will receive a bolus infusion of either fibrinogen concentrate or placebo plus standard treatmentThe dose of fibrinogen concentrate or placebo to be infused will be calculated based on the womanrsquos idealbody weight for height and the measured FIBTEM A5 with the aim of increasing the FIBTEM A5 to 23 mm

Outcomes Primary endpoints The total number of allogeneic blood products transfused after study medication untildischarge The total number of allogeneic blood products transfused will be compared between the two arms



Collins 2013 (Continued)

Starting date May 2013

Contact information Dr P Collins Reader in Haematology Dept of Haematology School of Medicine Cardiff University HeathPark Cardiff CF14 4XNTel 02920744144E-mail petercollinswalesnhsuk

Notes Estimated end September 2014

Miller 2008

Trial name or title Non-pneumatic anti-shock garment for obstetrical haemorrhage Zambia and Zimbabwe (NASG)

Methods Cluster-randomised controlled trial

Participants Approximately 2340 women who are pregnant or postpartum and experiencing obstetrical haemorrhage with2 of the following 3 blood loss gt 500 mL (at SHF 1000 mL at RH) SBP lt 100 mm Hg pulse gt 100 bpm

Interventions Half of the study clinics will use the non-pneumatic antishock garment on participants before transportingthem to the referral hospital for intervention

Outcomes Frequency of mortalities and frequency of severe morbidities combined as extreme adverse outcomes

Starting date October 2007

Contact information suellenmillergmailcom

Notes Estimated end May 2012

Mirzazada 2011

Trial name or title Misoprostol for the treatment of postpartum haemorrhage (PPH) following self-administration of misoprostolprophylaxis in home deliveries

Methods Randomised double-blind placebo-controlled trial

Participants Women with clinical diagnosis of postpartum haemorrhage following home birth in 4 districts in BadakshanProvince in Afghanistan All women enrolled in the study will receive 600 mcg misoprostol to be self-administered as prophylaxis for PPH after delivery of the baby and before delivery of the placenta

Interventions Misoprostol 800 mcg administered sublingually versus placebo

Outcomes Proportion of women who experience a drop in haemoglobin concentration greater than 2 gdL from beforedelivery to after delivery Outcomes will be compared between the 2 treatment arms

Starting date July 2012



Mirzazada 2011 (Continued)

Contact information dabbasgynuityorg

Notes

Shakur 2010

Trial name or title Tranexamic acid for the treatment of postpartum haemorrhage an international randomised double blindplacebo controlled trial (the WOMAN trial)


Participants 15000 women with clinician-diagnosed postpartum haemorrhage

Interventions Tranexamic acid versus placebo

Outcomes Proportion of women who die or undergo hysterectomy The primary cause of death will be described


Contact information thewomantriallshtmacuk

Notes Estimated end February 2015

Wikkelsoe 2012

Trial name or title FIB-PPH trial fibrinogen concentrate as initial treatment for postpartum haemorrhage study protocol for arandomised controlled trial


Participants 245 women with 1 of the following (1) following vaginal delivery with estimated blood loss exceeding 500mL and intended manual removal of the placenta (2) estimated blood loss exceeding 1000 mL and intendedmanual exploration of the uterus due to continuous bleeding after the birth of the placenta (3) followingcaesarean section with estimated perioperative blood loss exceeding 1000 mL

Interventions Fibrinogen versus placebo

Outcomes Need for blood transfusion

Starting date June 2011

Contact information wikkelsoegmailcom

Notes



D A T A A N D A N A L Y S E S

Comparison 1 Misoprostol (any route) versus placebo or no additional treatment given to women simultaneously

treated with conventional uterotonics

Outcome or subgroup titleNo of

studies

No of

participants Statistical method Effect size

1 Maternal death 4 1881 Risk Ratio (M-H Fixed 95 CI) 616 [075 5085]

11 Misoprotol 600 mcgsublingual versus placebo notreatment

2 1483 Risk Ratio (M-H Fixed 95 CI) 508 [024 10573]

12 Misoprotol 200 mcgoral400 mcg sublingual versusplacebo no treatment


13 Misoprotol 200 mcgoral400 mcg sublingual400mcg rectal versus placebo notreatment


2 Serious maternal morbidity 2 1483 Risk Ratio (M-H Fixed 95 CI) 034 [001 831]



22 Misoprostol 200 mcgoral400 mcg sublingual versusplacebo no treatment


23 Misoprostol 200 mcgoral400 mcg sublingual400mcg rectal versus placebo notreatment


3 Admission to intensive care unit 2 1483 Risk Ratio (M-H Fixed 95 CI) 079 [030 211]







4 Hysterectomy 4 1881 Risk Ratio (M-H Random 95 CI) 093 [016 541]


2 1483 Risk Ratio (M-H Random 95 CI) 068 [011 405]







5 Average blood loss afterenrolment in millilitres

4 1880 Mean Difference (IV Fixed 95 CI) -387 [-2363 1588]


2 1483 Mean Difference (IV Fixed 95 CI) 118 [-2161 2398]





6 Blood loss 500 mL or more afterenrolment








7 Blood transfusion 4 1877 Risk Ratio (M-H Fixed 95 CI) 095 [077 117]







8 Blood loss 1000 mL or moreafter enrolment










9 Additional uterotonics 4 1866 Risk Ratio (M-H Fixed 95 CI) 096 [084 108]







10 Manual removal of the placentaafter enrolment








11 Uterine tamponade afterenrolment








12 Artery ligation (uterine andorhypogastric arteries) afterenrolment








13 Arterial embolisation afterenrolment










14 Uterine compression stitchafter enrolment








15 Evacuation of retained productof conception








16 Any surgical co-interventions(uterine tamponade arteryligations arterial embolisation)excluding hysterectomy afterenrolment








17 Nausea 3 1643 Risk Ratio (M-H Fixed 95 CI) 118 [084 167]









18 Vomiting 2 1483 Risk Ratio (M-H Fixed 95 CI) 184 [116 295]







19 Diarrhoea 2 1483 Risk Ratio (M-H Fixed 95 CI) 122 [037 398]







20 Maternal pyrexia 38 degrees ormore


















22 Headache 3 1643 Risk Ratio (M-H Fixed 95 CI) 122 [097 153]







23 Shivering 4 1877 Risk Ratio (M-H Random 95 CI) 225 [176 288]



232 Misoprotol 200 mcgoral 400 mcg sublingual versusplacebo no treatment




24 Feeling faint or fainting 1 61 Risk Ratio (M-H Fixed 95 CI) 037 [002 866]







25 Allergy 1 61 Risk Ratio (M-H Fixed 95 CI) 00 [00 00]









Comparison 2 Sublingual misoprostol versus intravenous oxytocin therapy for primary PPH treatment among

women who have not received any conventional uterotonic therapy


studies

No of


1 Maternal mortality 2 1787 Risk Ratio (M-H Fixed 95 CI) 099 [006 1574]

11 800 mcg misoprostolversus 40 IU oxytocin





3 Admission to intensive care 2 1787 Risk Ratio (M-H Fixed 95 CI) 033 [001 806]



4 Hysterectomy 2 1787 Risk Ratio (M-H Fixed 95 CI) 198 [036 1072]







6 Mean blood loss after enrolment 2 1787 Mean Difference (IV Fixed 95 CI) 4486 [2650 6322]


2 1787 Mean Difference (IV Fixed 95 CI) 4486 [2650 6322]





8 Blood transfusion within 24hours




9 Duration from randomisationtill cessation of bleeding orsatisfactory response




10 Additional uterotonics afterenrolment




11 Examination under anaesthesia 2 1787 Risk Ratio (M-H Random 95 CI) 127 [087 187]





121 600 mcg 2 1483 Risk Ratio (M-H Fixed 95 CI) 032 [007 140]122 800 mcg 0 0 Risk Ratio (M-H Fixed 95 CI) 00 [00 00]

13 Bimanual compression 2 1787 Risk Ratio (M-H Fixed 95 CI) 106 [096 118]

















17 Unsatisfactory response afterenrolment after enrolment

2 1787 Risk Difference (M-H Random 95 CI) 003 [-002 008]























24 Shivering 2 1787 Risk Ratio (M-H Fixed 95 CI) 270 [228 319]



















Comparison 3 Rectal misoprostol versus combination of ergometrine and oxytocin therapy for primary PPH

treatment among women who have not received any conventional uterotonic therapy


studies

No of


1 Hysterectomy 1 64 Risk Ratio (M-H Fixed 95 CI) 033 [001 789]11 800 mcg 1 64 Risk Ratio (M-H Fixed 95 CI) 033 [001 789]

2 Persistent haemorrhage 1 64 Risk Ratio (M-H Fixed 95 CI) 018 [004 076]3 Additional uterotonics 1 64 Risk Ratio (M-H Fixed 95 CI) 018 [004 076]

4 Surgical co-interventions(excluding hysterectomy)


Comparison 4 Estrogen versus placebono treatment among women receiving conventional uterotonics for

primary PPH


studies

No of



2 Mean blood loss within twohours

1 112 Mean Difference (IV Fixed 95 CI) -2749 [-38472 -16508]

3 Mean blood loss between twoand 24 hours




Comparison 5 Tranexamic acid versus placebono treatment among women receiving conventional uterotonics

for primary PPH


studies

No of



2 Serious maternal morbidity(renal failure respiratory failurecardiac arrest multiple organfailure)


3 Admission to intensive care unit 1 144 Risk Ratio (M-H Fixed 95 CI) 06 [015 242]4 Hysterectomy 1 144 Risk Ratio (M-H Fixed 95 CI) 033 [001 805]





7 Total mean blood loss afterenrolment






10 Unsatisfactory response afterenrolment




12 Interventions to controlbleeding for secondarypostpartum haemorrhage


121 Medical interventionsto control bleeding (newsubgroup)


122 Surgical evacuation 1 144 Risk Ratio (M-H Fixed 95 CI) 05 [005 539]13 Examination under anaesthesia 1 144 Risk Ratio (M-H Fixed 95 CI) 10 [097 103]







17 Headache 1 144 Risk Ratio (M-H Fixed 95 CI) 00 [00 00]18 Nausea 1 144 Risk Ratio (M-H Fixed 95 CI) 110 [146 8299]





21 Deep vein thrombosis 1 144 Risk Ratio (M-H Fixed 95 CI) 20 [019 2157]22 Seizures 1 144 Risk Ratio (M-H Fixed 95 CI) 00 [00 00]



23 Dizziness 1 144 Risk Ratio (M-H Fixed 95 CI) 133 [031 575]24 Phosphenes 1 144 Risk Ratio (M-H Fixed 95 CI) 40 [088 1819]

25 Secondary postpartumhaemorrhage


26 Surgical evacuation forsecondary postpartumhaemorrhage


27 Intravenous iron therapy in thepuerperium


28 Hospital re-admissionfor secondary postpartumhaemorrhage


29 Postnatal depression at day 42postpartum


Comparison 6 Lower uterine segment compression versus conventional treatment


studies

No of


1 Maternal mortality 1 64 Risk Ratio (M-H Fixed 95 CI) 00 [00 00]2 Serious maternal morbidity 1 64 Risk Ratio (M-H Fixed 95 CI) 00 [00 00]3 Hysterectomy 1 64 Risk Ratio (M-H Fixed 95 CI) 00 [00 00]





6 Average blood loss afterenrolment

1 64 Mean Difference (IV Fixed 95 CI) -10300 [-260005200]


8 Other surgical interventions tocontrol bleeding (other thanhysterectomy)






Analysis 11 Comparison 1 Misoprostol (any route) versus placebo or no additional treatment given to

women simultaneously treated with conventional uterotonics Outcome 1 Maternal death

Review Treatment for primary postpartum haemorrhage

Comparison 1 Misoprostol (any route) versus placebo or no additional treatment given to women simultaneously treated with conventional uterotonics

Outcome 1 Maternal death

Study or subgroup Misoprostol Placebo Risk Ratio Weight Risk Ratio

nN nN M-HFixed95 CI M-HFixed95 CI

1 Misoprotol 600 mcg sublingual versus placebo no treatment

Zuberi 2008 029 032 Not estimable

Widmer 2010 2705 0717 502 508 [ 024 10573 ]

Subtotal (95 CI) 734 749 502 508 [ 024 10573 ]

Total events 2 (Misoprostol) 0 (Placebo)

Heterogeneity not applicable

Test for overall effect Z = 105 (P = 029)

2 Misoprotol 200 mcg oral400 mcg sublingual versus placebo no treatment

Walraven 2004 079 081 Not estimable

Subtotal (95 CI) 79 81 Not estimable



Test for overall effect not applicable

3 Misoprotol 200 mcg oral400 mcg sublingual400 mcg rectal versus placebo no treatment

Hofmeyr 2004 3117 0121 498 724 [ 038 13860 ]

Subtotal (95 CI) 117 121 498 724 [ 038 13860 ]




Total (95 CI) 930 951 1000 616 [ 075 5085 ]


Heterogeneity Chi2 = 003 df = 1 (P = 087) I2 =00


Test for subgroup differences Chi2 = 003 df = 1 (P = 087) I2 =00

0001 001 01 1 10 100 1000

Favours misoprostol Favours control




women simultaneously treated with conventional uterotonics Outcome 2 Serious maternal morbidity



Outcome 2 Serious maternal morbidity

Study or subgroupMisoprostol

any route Placebo Risk Ratio Weight Risk Ratio



Widmer 2010 0705 1717 1000 034 [ 001 831 ]


Subtotal (95 CI) 734 749 1000 034 [ 001 831 ]

Total events 0 (Misoprostol any route) 1 (Placebo)



2 Misoprostol 200 mcg oral400 mcg sublingual versus placebo no treatment





3 Misoprostol 200 mcg oral400 mcg sublingual400 mcg rectal versus placebo no treatment





Total (95 CI) 734 749 1000 034 [ 001 831 ]




Test for subgroup differences Not applicable

001 01 1 10 100





women simultaneously treated with conventional uterotonics Outcome 3 Admission to intensive care unit



Outcome 3 Admission to intensive care unit

Study or subgroup

Sublingualmisorpros-

tol Placebo Risk Ratio Weight Risk Ratio



Widmer 2010 7705 9717 1000 079 [ 030 211 ]


Subtotal (95 CI) 734 749 1000 079 [ 030 211 ]

Total events 7 (Sublingual misorprostol) 9 (Placebo)













Total (95 CI) 734 749 1000 079 [ 030 211 ]





001 01 1 10 100





women simultaneously treated with conventional uterotonics Outcome 4 Hysterectomy



Outcome 4 Hysterectomy


nN nN

M-HRandom95

CI

M-HRandom95

CI


Widmer 2010 2705 3717 487 068 [ 011 405 ]


Subtotal (95 CI) 734 749 487 068 [ 011 405 ]





Walraven 2004 079 281 252 021 [ 001 420 ]

Subtotal (95 CI) 79 81 252 020 [ 001 420 ]





Hofmeyr 2004 3117 0121 261 724 [ 038 13860 ]

Subtotal (95 CI) 117 121 261 724 [ 038 13860 ]




Total (95 CI) 930 951 1000 093 [ 016 541 ]


Heterogeneity Tau2 = 083 Chi2 = 298 df = 2 (P = 023) I2 =33



0001 001 01 1 10 100 1000





women simultaneously treated with conventional uterotonics Outcome 5 Average blood loss after enrolment

in millilitres



Outcome 5 Average blood loss after enrolment in millilitres

Study or subgroup Misoprostol PlaceboMean

Difference WeightMean

Difference

N Mean(SD) N Mean(SD) IVFixed95 CI IVFixed95 CI


Widmer 2010 705 250 (223) 717 248 (229) 707 200 [ -2149 2549 ]

Zuberi 2008 29 175 (168) 32 187 (207) 44 -1200 [ -10625 8225 ]

Subtotal (95 CI) 734 749 751 118 [ -2161 2398 ]




Walraven 2004 79 325 (264) 81 410 (397) 36 -8500 [ -18923 1923 ]

Subtotal (95 CI) 79 81 36 -8500 [ -18923 1923 ]




Hofmeyr 2004 117 168 (163) 120 176 (173) 213 -800 [ -5078 3478 ]

Subtotal (95 CI) 117 120 213 -800 [ -5078 3478 ]



Total (95 CI) 930 950 1000 -387 [ -2363 1588 ]




-1000 -500 0 500 1000





women simultaneously treated with conventional uterotonics Outcome 6 Blood loss 500 mL or more after

enrolment



Outcome 6 Blood loss 500 mL or more after enrolment




Zuberi 2008 229 432 28 055 [ 011 279 ]

Widmer 2010 100705 100717 726 102 [ 079 131 ]

Subtotal (95 CI) 734 749 754 100 [ 078 129 ]





Walraven 2004 1379 2381 166 058 [ 032 106 ]

Subtotal (95 CI) 79 81 166 058 [ 032 106 ]





Hofmeyr 2004 6117 11120 80 056 [ 021 146 ]

Subtotal (95 CI) 117 120 80 056 [ 021 146 ]




Total (95 CI) 930 950 1000 089 [ 071 112 ]





005 02 1 5 20





women simultaneously treated with conventional uterotonics Outcome 7 Blood transfusion



Outcome 7 Blood transfusion




Zuberi 2008 529 632 38 092 [ 031 269 ]

Widmer 2010 103705 117717 782 090 [ 070 114 ]

Subtotal (95 CI) 734 749 821 090 [ 071 114 ]





Walraven 2004 1279 1281 80 103 [ 049 214 ]

Subtotal (95 CI) 79 81 80 103 [ 049 214 ]





Hofmeyr 2004 19115 15119 99 131 [ 070 245 ]

Subtotal (95 CI) 115 119 99 131 [ 070 245 ]




Total (95 CI) 928 949 1000 095 [ 077 117 ]





01 02 05 1 2 5 10






enrolment








Widmer 2010 9705 9717 622 102 [ 041 255 ]

Subtotal (95 CI) 734 749 622 102 [ 041 255 ]





Walraven 2004 279 581 344 041 [ 008 205 ]

Subtotal (95 CI) 79 81 344 041 [ 008 205 ]





Hofmeyr 2004 1117 0120 34 308 [ 013 7476 ]

Subtotal (95 CI) 117 120 34 308 [ 013 7476 ]




Total (95 CI) 930 950 1000 088 [ 042 186 ]





001 01 1 10 100





women simultaneously treated with conventional uterotonics Outcome 9 Additional uterotonics



Outcome 9 Additional uterotonics




Zuberi 2008 2929 3232 103 100 [ 094 106 ]

Widmer 2010 188705 203717 671 094 [ 080 112 ]

Subtotal (95 CI) 734 749 774 095 [ 082 110 ]





Walraven 2004 379 581 16 062 [ 015 249 ]

Subtotal (95 CI) 79 81 16 062 [ 015 249 ]





Hofmeyr 2004 63111 63112 209 101 [ 080 127 ]

Subtotal (95 CI) 111 112 209 101 [ 080 127 ]




Total (95 CI) 924 942 1000 096 [ 084 108 ]





01 02 05 1 2 5 10





women simultaneously treated with conventional uterotonics Outcome 10 Manual removal of the placenta

after enrolment



Outcome 10 Manual removal of the placenta after enrolment


nN nN

M-HRandom95

CI

M-HRandom95

CI


Widmer 2010 29705 42717 925 070 [ 044 111 ]

Zuberi 2008 229 432 75 055 [ 011 279 ]

Subtotal (95 CI) 734 749 1000 069 [ 044 108 ]














Total (95 CI) 734 749 1000 069 [ 044 108 ]





0001 001 01 1 10 100 1000





women simultaneously treated with conventional uterotonics Outcome 11 Uterine tamponade after

enrolment



Outcome 11 Uterine tamponade after enrolment


nN nN

M-HRandom95

CI

M-HRandom95

CI


Widmer 2010 0705 0717 Not estimable

Zuberi 2008 229 732 1000 032 [ 007 140 ]

Subtotal (95 CI) 734 749 1000 032 [ 007 140 ]














Total (95 CI) 734 749 1000 032 [ 007 140 ]





0001 001 01 1 10 100 1000





women simultaneously treated with conventional uterotonics Outcome 12 Artery ligation (uterine andor

hypogastric arteries) after enrolment



Outcome 12 Artery ligation (uterine andor hypogastric arteries) after enrolment


nN nN

M-HRandom95

CI

M-HRandom95

CI


Widmer 2010 2705 2717 1000 102 [ 014 720 ]


Subtotal (95 CI) 734 749 1000 102 [ 014 720 ]














Total (95 CI) 734 749 1000 102 [ 014 720 ]





0001 001 01 1 10 100 1000





women simultaneously treated with conventional uterotonics Outcome 13 Arterial embolisation after

enrolment



Outcome 13 Arterial embolisation after enrolment


nN nN

M-HRandom95

CI

M-HRandom95

CI


















Total (95 CI) 734 749 Not estimable




Test for subgroup differences Chi2 = 00 df = -1 (P = 00) I2 =00

0001 001 01 1 10 100 1000





women simultaneously treated with conventional uterotonics Outcome 14 Uterine compression stitch after

enrolment



Outcome 14 Uterine compression stitch after enrolment


nN nN

M-HRandom95

CI

M-HRandom95

CI























0001 001 01 1 10 100 1000





women simultaneously treated with conventional uterotonics Outcome 15 Evacuation of retained product of

conception



Outcome 15 Evacuation of retained product of conception














Hofmeyr 2004 2117 0121 1000 517 [ 025 10655 ]

Subtotal (95 CI) 117 121 1000 517 [ 025 10655 ]




Total (95 CI) 117 121 1000 517 [ 025 10655 ]





0001 001 01 1 10 100 1000





women simultaneously treated with conventional uterotonics Outcome 16 Any surgical co-interventions

(uterine tamponade artery ligations arterial embolisation) excluding hysterectomy after enrolment



Outcome 16 Any surgical co-interventions (uterine tamponade artery ligations arterial embolisation) excluding hysterectomy after enrolment


nN nN

M-HRandom95

CI

M-HRandom95

CI


Widmer 2010 2705 2717 367 102 [ 014 720 ]

Zuberi 2008 229 732 633 032 [ 007 140 ]

Subtotal (95 CI) 734 749 1000 048 [ 015 158 ]














Total (95 CI) 734 749 1000 048 [ 015 158 ]





0001 001 01 1 10 100 1000





women simultaneously treated with conventional uterotonics Outcome 17 Nausea



Outcome 17 Nausea

Study or subgroup

Sublingualmisopros-




Widmer 2010 60705 49717 877 125 [ 087 179 ]

Zuberi 2008 229 232 34 110 [ 017 734 ]

Subtotal (95 CI) 734 749 911 124 [ 087 177 ]

Total events 62 (Sublingual misoprostol) 51 (Placebo)




Walraven 2004 379 581 89 062 [ 015 249 ]

Subtotal (95 CI) 79 81 89 062 [ 015 249 ]









Total (95 CI) 813 830 1000 118 [ 084 167 ]





001 01 1 10 100





women simultaneously treated with conventional uterotonics Outcome 18 Vomiting



Outcome 18 Vomiting

Study or subgroup

Sublingualmisopros-




Widmer 2010 45705 25717 963 183 [ 114 295 ]

Zuberi 2008 229 132 37 221 [ 021 2308 ]

Subtotal (95 CI) 734 749 1000 184 [ 116 295 ]














Total (95 CI) 734 749 1000 184 [ 116 295 ]





001 01 1 10 100





women simultaneously treated with conventional uterotonics Outcome 19 Diarrhoea



Outcome 19 Diarrhoea

Study or subgroup

Sublingualmisopros-




Widmer 2010 6705 5717 1000 122 [ 037 398 ]


Subtotal (95 CI) 734 749 1000 122 [ 037 398 ]














Total (95 CI) 734 749 1000 122 [ 037 398 ]





001 01 1 10 100





women simultaneously treated with conventional uterotonics Outcome 20 Maternal pyrexia 38 degrees or

more



Outcome 20 Maternal pyrexia 38 degrees or more

Study or subgroup

Sublingualmisopros-




Widmer 2010 406705 137717 962 301 [ 256 355 ]

Zuberi 2008 1529 332 20 552 [ 178 1713 ]

Subtotal (95 CI) 734 749 983 307 [ 261 360 ]



Test for overall effect Z = 1358 (P lt 000001)


Walraven 2004 479 081 03 923 [ 050 16857 ]

Subtotal (95 CI) 79 81 03 923 [ 050 16857 ]





Hofmeyr 2004 11114 2118 14 569 [ 129 2512 ]

Subtotal (95 CI) 114 118 14 569 [ 129 2512 ]




Total (95 CI) 927 948 1000 312 [ 266 367 ]





001 01 1 10 100






more




Study or subgroup

Sublingualmisopros-




Widmer 2010 48705 3717 755 1627 [ 509 5200 ]

Zuberi 2008 129 032 121 330 [ 014 7795 ]

Subtotal (95 CI) 734 749 875 1448 [ 491 4272 ]










Hofmeyr 2004 3114 0118 125 724 [ 038 13868 ]

Subtotal (95 CI) 114 118 125 724 [ 038 13868 ]




Total (95 CI) 848 867 1000 1358 [ 493 3744 ]





001 01 1 10 100





women simultaneously treated with conventional uterotonics Outcome 22 Headache



Outcome 22 Headache

Study or subgroup

Sublingualmisopros-




Widmer 2010 125705 101717 898 126 [ 099 160 ]

Zuberi 2008 229 032 04 550 [ 027 11001 ]

Subtotal (95 CI) 734 749 903 128 [ 101 162 ]





Walraven 2004 779 1181 97 065 [ 027 160 ]

Subtotal (95 CI) 79 81 97 065 [ 027 160 ]









Total (95 CI) 813 830 1000 122 [ 097 153 ]





001 01 1 10 100





women simultaneously treated with conventional uterotonics Outcome 23 Shivering



Outcome 23 Shivering

Study or subgroup

Sublingualmisopros-


nN nN

M-HRandom95

CI

M-HRandom95

CI


Widmer 2010 514705 252717 593 207 [ 186 231 ]

Zuberi 2008 1529 232 30 828 [ 207 3313 ]

Subtotal (95 CI) 734 749 623 347 [ 093 1301 ]




2 Misoprotol 200 mcg oral 400 mcg sublingual versus placebo no treatment

Walraven 2004 2379 881 94 295 [ 140 619 ]

Subtotal (95 CI) 79 81 94 295 [ 140 619 ]





Hofmeyr 2004 63116 30118 283 214 [ 150 304 ]

Subtotal (95 CI) 116 118 283 214 [ 150 304 ]




Total (95 CI) 929 948 1000 225 [ 176 288 ]





001 01 1 10 100





women simultaneously treated with conventional uterotonics Outcome 24 Feeling faint or fainting



Outcome 24 Feeling faint or fainting

Study or subgroup

Sublingualmisopros-




Zuberi 2008 029 132 1000 037 [ 002 866 ]

Subtotal (95 CI) 29 32 1000 037 [ 002 866 ]














Total (95 CI) 29 32 1000 037 [ 002 866 ]





001 01 1 10 100





women simultaneously treated with conventional uterotonics Outcome 25 Allergy



Outcome 25 Allergy

Study or subgroup

Sublingualmisopros-
























001 01 1 10 100




Analysis 21 Comparison 2 Sublingual misoprostol versus intravenous oxytocin therapy for primary PPH

treatment among women who have not received any conventional uterotonic therapy Outcome 1 Maternal

mortality


Comparison 2 Sublingual misoprostol versus intravenous oxytocin therapy for primary PPH treatment among women who have not received any conventional uterotonic

therapy

Outcome 1 Maternal mortality

Study or subgroup

sublingualmisopros-

tol IV oxytocin Risk Ratio Weight Risk Ratio


1 800 mcg misoprostol versus 40 IU oxytocin

Blum 2010 1407 1402 1000 099 [ 006 1574 ]

Winikoff 2010 0488 0490 Not estimable

Total (95 CI) 895 892 1000 099 [ 006 1574 ]

Total events 1 (sublingual misoprostol) 1 (IV oxytocin)




001 01 1 10 100

Favours misoprostol Favours oxytocin




treatment among women who have not received any conventional uterotonic therapy Outcome 2 Serious

maternal morbidity



therapy


Study or subgroup

sublingualmisopros-




Blum 2010 0407 1402 1000 033 [ 001 806 ]


Total (95 CI) 895 892 1000 033 [ 001 806 ]





001 01 1 10 100





treatment among women who have not received any conventional uterotonic therapy Outcome 3 Admission

to intensive care



therapy

Outcome 3 Admission to intensive care

Study or subgroup

sublingualmisopros-




Blum 2010 0407 1402 1000 033 [ 001 806 ]


Total (95 CI) 895 892 1000 033 [ 001 806 ]





001 01 1 10 100





treatment among women who have not received any conventional uterotonic therapy Outcome 4

Hysterectomy



therapy


Study or subgroup

sublingualmisopros-




Blum 2010 4407 2402 1000 198 [ 036 1072 ]


Total (95 CI) 895 892 1000 198 [ 036 1072 ]





001 01 1 10 100





treatment among women who have not received any conventional uterotonic therapy Outcome 5 Blood loss

500 mL or more after enrolment



therapy


Study or subgroup

sublingualmisopros-


nN nN

M-HRandom95

CI

M-HRandom95

CI


Blum 2010 58407 53402 521 108 [ 076 153 ]

Winikoff 2010 53488 20490 479 266 [ 162 438 ]

Total (95 CI) 895 892 1000 166 [ 069 404 ]





001 01 1 10 100





treatment among women who have not received any conventional uterotonic therapy Outcome 6 Mean blood

loss after enrolment



therapy

Outcome 6 Mean blood loss after enrolment

Study or subgroup

sublingualmisopros-

tol IV oxytocinMean


Difference



Blum 2010 407 279 (251) 402 252 (205) 338 2700 [ -456 5856 ]

Winikoff 2010 488 244 (186) 490 190 (174) 662 5400 [ 3142 7658 ]

Total (95 CI) 895 892 1000 4486 [ 2650 6322 ]




-100 -50 0 50 100









therapy


Study or subgroup

sublingualmisopros-




Blum 2010 11407 3402 502 362 [ 102 1288 ]

Winikoff 2010 5488 3490 498 167 [ 040 696 ]

Total (95 CI) 895 892 1000 265 [ 104 675 ]





001 01 1 10 100





treatment among women who have not received any conventional uterotonic therapy Outcome 8 Blood

transfusion within 24 hours



therapy

Outcome 8 Blood transfusion within 24 hours

Study or subgroup

sublingualmisopros-




Blum 2010 24407 18402 411 132 [ 073 239 ]

Winikoff 2010 41488 26490 589 158 [ 098 255 ]

Total (95 CI) 895 892 1000 147 [ 102 214 ]





001 01 1 10 100





treatment among women who have not received any conventional uterotonic therapy Outcome 9 Duration

from randomisation till cessation of bleeding or satisfactory response



therapy

Outcome 9 Duration from randomisation till cessation of bleeding or satisfactory response

Study or subgroup

sublingualmisopros-

tol IV oxytocinMean


Difference



Blum 2010 407 193 (15) 402 191 (146) 280 020 [ -184 224 ]

Winikoff 2010 488 134 (82) 490 134 (118) 720 00 [ -127 127 ]

Total (95 CI) 895 892 1000 006 [ -102 114 ]




-100 -50 0 50 100





treatment among women who have not received any conventional uterotonic therapy Outcome 10 Additional

uterotonics after enrolment



therapy

Outcome 10 Additional uterotonics after enrolment

Study or subgroup

sublingualmisopros-


nN nN

M-HRandom95

CI

M-HRandom95

CI


Blum 2010 40407 46402 502 086 [ 058 128 ]

Winikoff 2010 61488 31490 498 198 [ 131 299 ]

Total (95 CI) 895 892 1000 130 [ 057 294 ]





001 01 1 10 100






Examination under anaesthesia



therapy

Outcome 11 Examination under anaesthesia

Study or subgroup

sublingualmisopros-


nN nN

M-HRandom95

CI

M-HRandom95

CI


Blum 2010 37407 22402 350 166 [ 100 276 ]

Winikoff 2010 99488 90490 650 110 [ 085 143 ]

Total (95 CI) 895 892 1000 127 [ 087 187 ]





001 01 1 10 100





treatment among women who have not received any conventional uterotonic therapy Outcome 12 Uterine

tamponade after enrolment



therapy


Study or subgroup

sublingualmisopros-



1 600 mcg


Zuberi 2008 229 732 1000 032 [ 007 140 ]

Subtotal (95 CI) 734 749 1000 032 [ 007 140 ]




2 800 mcg





Total (95 CI) 734 749 1000 032 [ 007 140 ]





001 01 1 10 100





treatment among women who have not received any conventional uterotonic therapy Outcome 13 Bimanual

compression



therapy

Outcome 13 Bimanual compression

Study or subgroup

sublingualmisopros-




Blum 2010 39407 31402 99 124 [ 079 195 ]

Winikoff 2010 294488 283490 901 104 [ 094 116 ]

Total (95 CI) 895 892 1000 106 [ 096 118 ]





001 01 1 10 100





treatment among women who have not received any conventional uterotonic therapy Outcome 14 Artery

ligation (uterine andor hypogastric arteries) after enrolment



therapy


Study or subgroup

sublingualmisopros-




Blum 2010 0407 0402 Not estimable







001 01 1 10 100





treatment among women who have not received any conventional uterotonic therapy Outcome 15 Arterial

embolisation after enrolment



therapy


Study or subgroup

sublingualmisopros-











001 01 1 10 100









therapy


Study or subgroup

sublingualmisopros-











001 01 1 10 100






Unsatisfactory response after enrolment after enrolment



therapy

Outcome 17 Unsatisfactory response after enrolment after enrolment

Study or subgroup

sublingualmisopros-

tol IV oxytocinRisk

Difference WeightRisk

Difference

nN nN

M-HRandom95

CI

M-HRandom95

CI


Blum 2010 44407 42402 461 000 [ -004 005 ]

Winikoff 2010 48488 22490 539 005 [ 002 009 ]

Total (95 CI) 895 892 1000 003 [ -002 008 ]





-1 -05 0 05 1






compression stitch after enrolment



therapy


Study or subgroup

sublingualmisopros-











001 01 1 10 100





treatment among women who have not received any conventional uterotonic therapy Outcome 19 Any

surgical co-interventions (uterine tamponade artery ligations arterial embolisation) excluding hysterectomy

after enrolment



therapy


Study or subgroup

sublingualmisopros-




Blum 2010 0407 1402 1000 033 [ 001 806 ]


Total (95 CI) 895 892 1000 033 [ 001 806 ]





001 01 1 10 100





treatment among women who have not received any conventional uterotonic therapy Outcome 20 Nausea



therapy

Outcome 20 Nausea

Study or subgroup

sublingualmisopros-




Blum 2010 59407 69402 629 084 [ 061 116 ]

Winikoff 2010 49488 41490 371 120 [ 081 178 ]

Total (95 CI) 895 892 1000 098 [ 076 125 ]





001 01 1 10 100





treatment among women who have not received any conventional uterotonic therapy Outcome 21 Vomiting



therapy

Outcome 21 Vomiting

Study or subgroup

sublingualmisopros-




Blum 2010 19407 10402 590 188 [ 088 399 ]

Winikoff 2010 24488 7490 410 344 [ 150 792 ]

Total (95 CI) 895 892 1000 252 [ 145 438 ]





001 01 1 10 100





treatment among women who have not received any conventional uterotonic therapy Outcome 22 Diarrhoea



therapy


Study or subgroup

sublingualmisopros-




Blum 2010 5407 3402 602 165 [ 040 684 ]

Winikoff 2010 2488 2490 398 100 [ 014 710 ]

Total (95 CI) 895 892 1000 139 [ 044 436 ]





001 01 1 10 100





treatment among women who have not received any conventional uterotonic therapy Outcome 23 Headache



therapy

Outcome 23 Headache

Study or subgroup

sublingualmisopros-




Blum 2010 0407 1402 431 033 [ 001 806 ]

Winikoff 2010 3488 2490 569 151 [ 025 897 ]

Total (95 CI) 895 892 1000 100 [ 023 438 ]





001 01 1 10 100





treatment among women who have not received any conventional uterotonic therapy Outcome 24 Shivering



therapy


Study or subgroup

sublingualmisopros-




Blum 2010 152407 59402 420 254 [ 195 332 ]

Winikoff 2010 229488 82490 580 280 [ 225 349 ]

Total (95 CI) 895 892 1000 270 [ 228 319 ]





001 01 1 10 100





treatment among women who have not received any conventional uterotonic therapy Outcome 25 Feeling

faint or fainting



therapy


Study or subgroup

sublingualmisopros-




Blum 2010 60407 59402 937 100 [ 072 140 ]

Winikoff 2010 4488 4490 63 100 [ 025 399 ]

Total (95 CI) 895 892 1000 100 [ 073 139 ]





001 01 1 10 100






pyrexia 38 degrees or more



therapy


Study or subgroup

sublingualmisopros-

tol IV oxytocinRisk


Difference

nN nN

M-HRandom95

CI

M-HRandom95

CI


Blum 2010 88407 59402 499 007 [ 002 012 ]

Winikoff 2010 217488 27490 501 039 [ 034 044 ]

Total (95 CI) 895 892 1000 023 [ -008 054 ]


Heterogeneity Tau2 = 005 Chi2 = 7647 df = 1 (Plt000001) I2 =99



-1 -05 0 05 1









therapy


Study or subgroup

sublingualmisopros-


nN nN

M-HRandom95

CI

M-HRandom95

CI


Blum 2010 5407 1402 526 494 [ 058 4208 ]

Winikoff 2010 66488 0490 474 13354 [ 829 215128 ]

Total (95 CI) 895 892 1000 2354 [ 050 110442 ]





001 01 1 10 100





treatment among women who have not received any conventional uterotonic therapy Outcome 28 Allergy



therapy

Outcome 28 Allergy

Study or subgroup

sublingualmisopros-




Blum 2010 1407 0402 252 296 [ 012 7252 ]

Winikoff 2010 0488 1490 748 033 [ 001 820 ]

Total (95 CI) 895 892 1000 100 [ 014 709 ]





001 01 1 10 100




Analysis 31 Comparison 3 Rectal misoprostol versus combination of ergometrine and oxytocin therapy for

primary PPH treatment among women who have not received any conventional uterotonic therapy Outcome

1 Hysterectomy


Comparison 3 Rectal misoprostol versus combination of ergometrine and oxytocin therapy for primary PPH treatment among women who have not received any

conventional uterotonic therapy


Study or subgroup Misoprostol Oxytocinergometrine Risk Ratio Weight Risk Ratio


1 800 mcg

Lokugamage 2001 032 132 1000 033 [ 001 789 ]

Total (95 CI) 32 32 1000 033 [ 001 789 ]

Total events 0 (Misoprostol) 1 (Oxytocinergometrine)




001 01 1 10 100

Favours misoprostol ergometrine and oxytocin





2 Persistent haemorrhage




Outcome 2 Persistent haemorrhage



Lokugamage 2001 232 1132 1000 018 [ 004 076 ]

Total (95 CI) 32 32 1000 018 [ 004 076 ]





001 01 1 10 100




3 Additional uterotonics







Lokugamage 2001 232 1132 1000 018 [ 004 076 ]

Total (95 CI) 32 32 1000 018 [ 004 076 ]





001 01 1 10 100






4 Surgical co-interventions (excluding hysterectomy)




Outcome 4 Surgical co-interventions (excluding hysterectomy)



Lokugamage 2001 232 232 1000 100 [ 015 667 ]

Total (95 CI) 32 32 1000 100 [ 015 667 ]





01 02 05 1 2 5 10




Analysis 41 Comparison 4 Estrogen versus placebono treatment among women receiving conventional

uterotonics for primary PPH Outcome 1 Hysterectomy


Comparison 4 Estrogen versus placebono treatment among women receiving conventional uterotonics for primary PPH


Study or subgroup Estrogen control Risk Ratio Weight Risk Ratio


Zhou 2006 052 360 1000 016 [ 001 311 ]

Total (95 CI) 52 60 1000 016 [ 001 311 ]

Total events 0 (Estrogen) 3 (control)




001 01 1 10 100

Favours estrogen Favours control


uterotonics for primary PPH Outcome 2 Mean blood loss within two hours



Outcome 2 Mean blood loss within two hours

Study or subgroup Estrogen controlMean


Difference


Zhou 2006 52 5896 (2264) 60 8645 (3595) 1000 -27490 [ -38472 -16508 ]

Total (95 CI) 52 60 1000 -27490 [ -38472 -16508 ]




-500 -250 0 250 500





uterotonics for primary PPH Outcome 3 Mean blood loss between two and 24 hours



Outcome 3 Mean blood loss between two and 24 hours



Difference


Zhou 2006 52 1108 (762) 60 1615 (983) 1000 -5070 [ -8307 -1833 ]

Total (95 CI) 52 60 1000 -5070 [ -8307 -1833 ]




-100 -50 0 50 100


Analysis 51 Comparison 5 Tranexamic acid versus placebono treatment among women receiving

conventional uterotonics for primary PPH Outcome 1 Maternal mortality


Comparison 5 Tranexamic acid versus placebono treatment among women receiving conventional uterotonics for primary PPH


Study or subgroup Tranexamic acid Placebo Risk Ratio Weight Risk Ratio


Ducloy-Bouthors 2011 072 072 Not estimable


Total events 0 (Tranexamic acid) 0 (Placebo)




001 01 1 10 100

Favours Tranexamic acid Favours placebo




conventional uterotonics for primary PPH Outcome 2 Serious maternal morbidity (renal failure respiratory

failure cardiac arrest multiple organ failure)



Outcome 2 Serious maternal morbidity (renal failure respiratory failure cardiac arrest multiple organ failure)



Ducloy-Bouthors 2011 072 172 1000 033 [ 001 805 ]

Total (95 CI) 72 72 1000 033 [ 001 805 ]





001 01 1 10 100



conventional uterotonics for primary PPH Outcome 3 Admission to intensive care unit






Ducloy-Bouthors 2011 372 572 1000 060 [ 015 242 ]

Total (95 CI) 72 72 1000 060 [ 015 242 ]





001 01 1 10 100





conventional uterotonics for primary PPH Outcome 4 Hysterectomy






Ducloy-Bouthors 2011 072 172 1000 033 [ 001 805 ]

Total (95 CI) 72 72 1000 033 [ 001 805 ]





001 01 1 10 100



conventional uterotonics for primary PPH Outcome 5 Blood loss 500 mL or more after enrolment






Ducloy-Bouthors 2011 7272 7272 1000 100 [ 097 103 ]

Total (95 CI) 72 72 1000 100 [ 097 103 ]





001 01 1 10 100











Ducloy-Bouthors 2011 1772 1572 1000 113 [ 061 209 ]

Total (95 CI) 72 72 1000 113 [ 061 209 ]





001 01 1 10 100



conventional uterotonics for primary PPH Outcome 7 Total mean blood loss after enrolment



Outcome 7 Total mean blood loss after enrolment

Study or subgroup Tranexamic acid PlaceboMean


Difference


Ducloy-Bouthors 2011 72 1319 (409) 72 1410 (510) 1000 -9100 [ -24200 6000 ]

Total (95 CI) 72 72 1000 -9100 [ -24200 6000 ]




-100 -50 0 50 100





conventional uterotonics for primary PPH Outcome 8 Blood transfusion within 24 hours






Ducloy-Bouthors 2011 772 1272 1000 058 [ 024 140 ]

Total (95 CI) 72 72 1000 058 [ 024 140 ]





001 01 1 10 100



conventional uterotonics for primary PPH Outcome 9 Additional uterotonics after enrolment






Ducloy-Bouthors 2011 3672 3472 1000 106 [ 076 148 ]

Total (95 CI) 72 72 1000 106 [ 076 148 ]





001 01 1 10 100





conventional uterotonics for primary PPH Outcome 10 Unsatisfactory response after enrolment



Outcome 10 Unsatisfactory response after enrolment



Ducloy-Bouthors 2011 6772 5772 1000 118 [ 103 134 ]

Total (95 CI) 72 72 1000 118 [ 103 134 ]





001 01 1 10 100



conventional uterotonics for primary PPH Outcome 11 Uterine compression stitch after enrolment






Ducloy-Bouthors 2011 072 272 1000 020 [ 001 409 ]

Total (95 CI) 72 72 1000 020 [ 001 409 ]





001 01 1 10 100





conventional uterotonics for primary PPH Outcome 12 Interventions to control bleeding for secondary

postpartum haemorrhage



Outcome 12 Interventions to control bleeding for secondary postpartum haemorrhage



1 Medical interventions to control bleeding (new subgroup)

Ducloy-Bouthors 2011 172 172 333 100 [ 006 1568 ]

Subtotal (95 CI) 72 72 333 100 [ 006 1568 ]




2 Surgical evacuation

Ducloy-Bouthors 2011 172 272 667 050 [ 005 539 ]

Subtotal (95 CI) 72 72 667 050 [ 005 539 ]




Total (95 CI) 144 144 1000 067 [ 011 393 ]





001 01 1 10 100





conventional uterotonics for primary PPH Outcome 13 Examination under anaesthesia






Ducloy-Bouthors 2011 7272 7272 1000 100 [ 097 103 ]

Total (95 CI) 72 72 1000 100 [ 097 103 ]





001 01 1 10 100



conventional uterotonics for primary PPH Outcome 14 Uterine tamponade after enrolment












001 01 1 10 100





conventional uterotonics for primary PPH Outcome 15 Artery ligation (uterine andor hypogastric arteries)

after enrolment






Ducloy-Bouthors 2011 072 172 1000 033 [ 001 805 ]

Total (95 CI) 72 72 1000 033 [ 001 805 ]





001 01 1 10 100



conventional uterotonics for primary PPH Outcome 16 Arterial embolisation after enrolment






Ducloy-Bouthors 2011 472 572 1000 080 [ 022 286 ]

Total (95 CI) 72 72 1000 080 [ 022 286 ]





001 01 1 10 100





conventional uterotonics for primary PPH Outcome 17 Headache



Outcome 17 Headache









001 01 1 10 100



conventional uterotonics for primary PPH Outcome 18 Nausea



Outcome 18 Nausea



Ducloy-Bouthors 2011 1172 172 1000 1100 [ 146 8299 ]

Total (95 CI) 72 72 1000 1100 [ 146 8299 ]





001 01 1 10 100





conventional uterotonics for primary PPH Outcome 19 Maternal pyrexia 38 degrees or more






Ducloy-Bouthors 2011 1272 1172 1000 109 [ 052 231 ]

Total (95 CI) 72 72 1000 109 [ 052 231 ]





001 01 1 10 100















001 01 1 10 100





conventional uterotonics for primary PPH Outcome 21 Deep vein thrombosis



Outcome 21 Deep vein thrombosis



Ducloy-Bouthors 2011 272 172 1000 200 [ 019 2157 ]

Total (95 CI) 72 72 1000 200 [ 019 2157 ]





001 01 1 10 100



conventional uterotonics for primary PPH Outcome 22 Seizures



Outcome 22 Seizures









001 01 1 10 100





conventional uterotonics for primary PPH Outcome 23 Dizziness



Outcome 23 Dizziness



Ducloy-Bouthors 2011 472 372 1000 133 [ 031 575 ]

Total (95 CI) 72 72 1000 133 [ 031 575 ]





001 01 1 10 100



conventional uterotonics for primary PPH Outcome 24 Phosphenes



Outcome 24 Phosphenes



Ducloy-Bouthors 2011 872 272 1000 400 [ 088 1819 ]

Total (95 CI) 72 72 1000 400 [ 088 1819 ]





001 01 1 10 100





conventional uterotonics for primary PPH Outcome 25 Secondary postpartum haemorrhage



Outcome 25 Secondary postpartum haemorrhage



Ducloy-Bouthors 2011 172 172 1000 100 [ 006 1568 ]

Total (95 CI) 72 72 1000 100 [ 006 1568 ]





001 01 1 10 100



conventional uterotonics for primary PPH Outcome 26 Surgical evacuation for secondary postpartum

haemorrhage



Outcome 26 Surgical evacuation for secondary postpartum haemorrhage



Ducloy-Bouthors 2011 172 272 1000 050 [ 005 539 ]

Total (95 CI) 72 72 1000 050 [ 005 539 ]





001 01 1 10 100





conventional uterotonics for primary PPH Outcome 27 Intravenous iron therapy in the puerperium



Outcome 27 Intravenous iron therapy in the puerperium



Ducloy-Bouthors 2011 2452 1856 1000 144 [ 089 232 ]

Total (95 CI) 52 56 1000 144 [ 089 232 ]





001 01 1 10 100



conventional uterotonics for primary PPH Outcome 28 Hospital re-admission for secondary postpartum

haemorrhage



Outcome 28 Hospital re-admission for secondary postpartum haemorrhage



Ducloy-Bouthors 2011 172 272 1000 050 [ 005 539 ]

Total (95 CI) 72 72 1000 050 [ 005 539 ]





001 01 1 10 100





conventional uterotonics for primary PPH Outcome 29 Postnatal depression at day 42 postpartum



Outcome 29 Postnatal depression at day 42 postpartum



Ducloy-Bouthors 2011 072 172 1000 033 [ 001 805 ]

Total (95 CI) 72 72 1000 033 [ 001 805 ]





001 01 1 10 100


Analysis 61 Comparison 6 Lower uterine segment compression versus conventional treatment Outcome

1 Maternal mortality




Study or subgroup

Lowersegment

compression No intervention Risk Ratio Weight Risk Ratio


Chantrapitak 2009 032 032 Not estimable


Total events 0 (Lower segment compression) 0 (No intervention)




001 01 1 10 100

Favours compression Favours no compression




2 Serious maternal morbidity




Study or subgroup

Lowersegment









001 01 1 10 100



3 Hysterectomy




Study or subgroup

Lowersegment









001 01 1 10 100





4 Blood loss 500 mL or more after enrolment




Study or subgroup

Lowersegment



Chantrapitak 2009 132 832 1000 013 [ 002 094 ]

Total (95 CI) 32 32 1000 013 [ 002 094 ]





001 01 1 10 100









Study or subgroup

Lowersegment



Chantrapitak 2009 032 232 1000 020 [ 001 401 ]

Total (95 CI) 32 32 1000 020 [ 001 401 ]





001 01 1 10 100



6 Average blood loss after enrolment



Outcome 6 Average blood loss after enrolment

Study or subgroup

Lowersegment

compression No interventionMean


Difference


Chantrapitak 2009 32 120 (211) 32 225 (401) 1000 -10500 [ -26200 5200 ]

Total (95 CI) 32 32 1000 -10500 [ -26200 5200 ]




-100 -50 0 50 100





7 Blood transfusion




Study or subgroup

Lowersegment



Chantrapitak 2009 732 332 1000 233 [ 066 823 ]

Total (95 CI) 32 32 1000 233 [ 066 823 ]





001 01 1 10 100



8 Other surgical interventions to control bleeding (other than hysterectomy)



Outcome 8 Other surgical interventions to control bleeding (other than hysterectomy)

Study or subgroup

Lowersegment









001 01 1 10 100





9 Unsatisfactory response after enrolment




Study or subgroup

Lowersegment



Chantrapitak 2009 232 232 1000 100 [ 015 667 ]

Total (95 CI) 32 32 1000 100 [ 015 667 ]





001 01 1 10 100


W H A T rsquo S N E W

Last assessed as up-to-date 31 August 2013

Date Event Description

31 August 2013 New search has been performed Search updated (31 August 2013) Seven new studies in-corporated into review (Blum 2010 Chantrapitak 2009Ducloy-Bouthors 2011 Widmer 2010 Winikoff 2010Zhou 2006 Zuberi 2008) One study awaiting classi-fication (Lavigne-Lissalde 2013) and five studies ongo-ing (Collins 2013 Miller 2008 Mirzazada 2011 Shakur2010 Wikkelsoe 2012) Methods updated



(Continued)

31 August 2013 New citation required and conclusions have changed Additional data from new studies now suggest that in com-parison with oxytocin women given sublingual misopros-tol are more likely to have greater blood lossFor other outcomes the conclusions remain the samemisoprostol in comparison with placebo has no impacton maternal mortality maternal morbidity hysterectomyand admission to intensive care sublingual misoprostolin comparison with oxytocin increases the likelihood ofadverse effects such as vomiting and shivering

H I S T O R Y

Protocol first published Issue 3 2001

Review first published Issue 1 2003


8 May 2008 Amended Converted to new review format

14 November 2006 New citation required and conclusions have changed Substantive amendment

C O N T R I B U T I O N S O F A U T H O R S

Hatem Mousa assessed trial eligibility extracted the data and co-wrote the review

Jennifer Blum provided data of published trials and co-wrote the review

Ghada Abou El Senoun assessed trial eligibility entered data and co-wrote the review

Haleema Shakur assessed trial eligibility and co-wrote the review

Zarko Alfirevic verified trial eligibility extracted data and co-wrote the review

D E C L A R A T I O N S O F I N T E R E S T

Haleema Shakur and Zarko Alfirevic are investigators in the currently ongoing WOMAN trial Jennifer Blum was a principal investigatorin the Blum 2010 Winikoff 2010 Widmer 2010 and Zuberi 2008 trials Hatem Mousa has received financial support from NovoNordisk to investigate recombinant activated factor VII (rFVIIa) as a potential treatment for massive postpartum haemorrhage



S O U R C E S O F S U P P O R T

Internal sources

bull The University of Liverpool UK

External sources

bull No sources of support supplied

D I F F E R E N C E S B E T W E E N P R O T O C O L A N D R E V I E W

Methods updated

I N D E X T E R M S

Medical Subject Headings (MeSH)

Administration Rectal Ergonovine [administration amp dosage] Hysterectomy Maternal Mortality Misoprostol [administration ampdosage] Oxytocics [administration amp dosage] Oxytocin [administration amp dosage] Postpartum Hemorrhage [drug therapy surgerylowasttherapy] Randomized Controlled Trials as Topic

MeSH check words

Female Humans Pregnancy



T A B L E O F C O N T E N T S

1HEADER 1ABSTRACT 2PLAIN LANGUAGE SUMMARY 2BACKGROUND 6OBJECTIVES 6METHODS

10RESULTS Figure 1 11Figure 2 12

16DISCUSSION 17AUTHORSrsquo CONCLUSIONS 18ACKNOWLEDGEMENTS 19REFERENCES 26CHARACTERISTICS OF STUDIES 44DATA AND ANALYSES

Analysis 11 Comparison 1 Misoprostol (any route) versus placebo or no additional treatment given to womensimultaneously treated with conventional uterotonics Outcome 1 Maternal death 55

Analysis 12 Comparison 1 Misoprostol (any route) versus placebo or no additional treatment given to womensimultaneously treated with conventional uterotonics Outcome 2 Serious maternal morbidity 56

Analysis 13 Comparison 1 Misoprostol (any route) versus placebo or no additional treatment given to womensimultaneously treated with conventional uterotonics Outcome 3 Admission to intensive care unit 57

Analysis 14 Comparison 1 Misoprostol (any route) versus placebo or no additional treatment given to womensimultaneously treated with conventional uterotonics Outcome 4 Hysterectomy 58

Analysis 15 Comparison 1 Misoprostol (any route) versus placebo or no additional treatment given to womensimultaneously treated with conventional uterotonics Outcome 5 Average blood loss after enrolment in millilitres 59


Analysis 17 Comparison 1 Misoprostol (any route) versus placebo or no additional treatment given to womensimultaneously treated with conventional uterotonics Outcome 7 Blood transfusion 61


Analysis 19 Comparison 1 Misoprostol (any route) versus placebo or no additional treatment given to womensimultaneously treated with conventional uterotonics Outcome 9 Additional uterotonics 63

Analysis 110 Comparison 1 Misoprostol (any route) versus placebo or no additional treatment given to womensimultaneously treated with conventional uterotonics Outcome 10 Manual removal of the placenta after enrolment 64

Analysis 111 Comparison 1 Misoprostol (any route) versus placebo or no additional treatment given to womensimultaneously treated with conventional uterotonics Outcome 11 Uterine tamponade after enrolment 65

Analysis 112 Comparison 1 Misoprostol (any route) versus placebo or no additional treatment given to womensimultaneously treated with conventional uterotonics Outcome 12 Artery ligation (uterine andor hypogastricarteries) after enrolment 66

Analysis 113 Comparison 1 Misoprostol (any route) versus placebo or no additional treatment given to womensimultaneously treated with conventional uterotonics Outcome 13 Arterial embolisation after enrolment 67

Analysis 114 Comparison 1 Misoprostol (any route) versus placebo or no additional treatment given to womensimultaneously treated with conventional uterotonics Outcome 14 Uterine compression stitch after enrolment 68

Analysis 115 Comparison 1 Misoprostol (any route) versus placebo or no additional treatment given to womensimultaneously treated with conventional uterotonics Outcome 15 Evacuation of retained product of conception 69

Analysis 116 Comparison 1 Misoprostol (any route) versus placebo or no additional treatment given to womensimultaneously treated with conventional uterotonics Outcome 16 Any surgical co-interventions (uterine tamponadeartery ligations arterial embolisation) excluding hysterectomy after enrolment 70

Analysis 117 Comparison 1 Misoprostol (any route) versus placebo or no additional treatment given to womensimultaneously treated with conventional uterotonics Outcome 17 Nausea 71

iTreatment for primary postpartum haemorrhage (Review)




































































































A B S T R A C T

Background


Objectives


Search methods


Selection criteria




Main results


















B A C K G R O U N D






Physiology


Definition





Complications







A Uterotonics

Ergometrine


Oxytocin


Prostaglandins


B Haemostatic drugs







Uterine tamponade














O B J E C T I V E S


M E T H O D S


Types of studies







Exclusion criteria
























Primary outcomes




Secondary outcomes







bleeding

Side effects


Other


following delivery)







Electronic searches



















selection bias)






bias)










detection bias)























Dichotomous data


Continuous data





Cross-over trials










Data synthesis









R E S U L T S


Included studies


Uterotonic trials





Haemostatic trials





Surgical trials


Excluded studies









study












comparison 1)


Primary outcomes



Secondary outcomes


Side effects






Primary outcomes






Side effects



comparison 4)


Primary outcomes


Secondary outcomes




Primary outcomes


Secondary outcomes


Side effects





Primary outcomes




Secondary outcomes


D I S C U S S I O N































R E F E R E N C E S




(Suppl 2)S150






























Childbirth 2008840







(2)198ndash200



(S2)101



(Suppl 3)S410









197612(4)565ndash79















20101140




Abdel-Aleem 2001


Abdel-Aleem 2003



200310825ndash8

AbdRabbo 1994





Abou El Senoun 2011



Abou Zahr 1991


ACOG 1998



Adekanmi 2001


2001108541ndash2

Aisaka 1988



Akhter 2005


Alamia 1999



Alexander 2002



Alfirevic 2006


Alfirevic 2007


Andolina 2003


200314229ndash32

Arulkumaran 2007




As 1996



B-Lynch 1997



Bakri 1999



Baskett 2000



Begley 2011


2011 Issue 11 [DOI 10100214651858CD007412]

Beischer 1986


Bergstrom 1962



Bonnar 2000



200014(1)1ndash18

Burchell 1980


Cantwell 2011



(Suppl 1)1ndash203

Carroli 2008






Chan 1997



Cho 2000



Clark 1985


Combs 1991



Cotter 2001


2001 Issue 4 [DOI 10100214651858CD001808]



(9734)23ndash32

Cunningham 1993


Cutler 1971


1971173(4)511ndash4

Danielsson 1999


Davis 1935


193529155ndash67

De Loor 1996



Dodd 2010



Doumouchtsis 2007


Drife 1997


Du Vigneaud 1953



Dudley 1935


Eastman 1950



Ferrer 2009


Franchini 2010



Gando 2006



Georgiou 2009



Gilbert 1987



Gyte 1992





Guumllmezoglu 2001


Haggerty 1996


Hall 1985


Hayman 2002


Hensleigh 2002



(12)1377ndash84

Higgins 2011


Hofmeyr 2005



Hofmeyr 2008



Hunter 1992


Johanson 2001



(4)420ndash2

Jouppila 1995



Khan 2003


Khan 2006


Knight 2009



Liabsuetrakul 2007


Maier 1993


1993169317ndash23

Marasinghe 2011



McDonald 2004


McDonald 2013



Miller 2009



Miller 2010


Mobeen 2011





Moir 1932


Moscardo 2001


Mousa 2001


Mousa 2002



Mousa 2008


Nardin 2011



Novikova 2010



OrsquoBrien 1998


199892212ndash4

Oboro 2003


Ochoa 2002


200299(3)506ndash9

Ojengbede 2011



Oladapo 2012a



Oladapo 2012b


Oleen 1990


Ouahba 2007



Peitsidis 2011



Penninx 2010



Pereira 2005



Porro 1876


Poujade 2011



Prendiville 1989


Pritchard 1962






Rath 2009



Rathat 2011




Ripley 1999


199926(3)419ndash34

Sloan 2010



Stafford 2008


2008199(5)e511-e517

Stearns 1808


Stearns 1822


1822590

Stoll 1935



Stones 1993



Su 2007



Su 2012



Suzuki 2012


(6)1363ndash7

Tang 2002


Thompson 1935



Tseng 2011



Tsu 1993


1993100327ndash33

Tunccedilalp 2012



Vahedi 1995


(4)616ndash8

Wetta 2013


WHO 2010




Zheng 2011



Zieman 1997





Hofmeyr 2009



Mousa 2003


2003 Issue 1 [DOI 10100214651858CD003249]

Mousa 2007







Blum 2010





Notes

Risk of bias















Chantrapitak 2009





Notes

Risk of bias




























Notes

Risk of bias











Hofmeyr 2004














Risk of bias















Lokugamage 2001






Risk of bias














Walraven 2004










Risk of bias














Widmer 2010





Notes

Risk of bias















Winikoff 2010








Notes

Risk of bias











Zhou 2006

Methods Randomised







Notes

Risk of bias











Zuberi 2008









Risk of bias

























(Continued)











Collins 2013












Miller 2008









Mirzazada 2011











Notes

Shakur 2010









Wikkelsoe 2012








Notes







studies

No of












































































































































































































studies

No of










































































































studies

No of







primary PPH


studies

No of










for primary PPH


studies

No of




















































studies

No of

























Widmer 2010 2705 0717 502 508 [ 024 10573 ]

Subtotal (95 CI) 734 749 502 508 [ 024 10573 ]











Hofmeyr 2004 3117 0121 498 724 [ 038 13860 ]

Subtotal (95 CI) 117 121 498 724 [ 038 13860 ]




Total (95 CI) 930 951 1000 616 [ 075 5085 ]





0001 001 01 1 10 100 1000













Widmer 2010 0705 1717 1000 034 [ 001 831 ]


Subtotal (95 CI) 734 749 1000 034 [ 001 831 ]














Total (95 CI) 734 749 1000 034 [ 001 831 ]





001 01 1 10 100









Study or subgroup





Widmer 2010 7705 9717 1000 079 [ 030 211 ]


Subtotal (95 CI) 734 749 1000 079 [ 030 211 ]














Total (95 CI) 734 749 1000 079 [ 030 211 ]





001 01 1 10 100










nN nN

M-HRandom95

CI

M-HRandom95

CI


Widmer 2010 2705 3717 487 068 [ 011 405 ]


Subtotal (95 CI) 734 749 487 068 [ 011 405 ]





Walraven 2004 079 281 252 021 [ 001 420 ]

Subtotal (95 CI) 79 81 252 020 [ 001 420 ]





Hofmeyr 2004 3117 0121 261 724 [ 038 13860 ]

Subtotal (95 CI) 117 121 261 724 [ 038 13860 ]




Total (95 CI) 930 951 1000 093 [ 016 541 ]





0001 001 01 1 10 100 1000






in millilitres






Difference



Widmer 2010 705 250 (223) 717 248 (229) 707 200 [ -2149 2549 ]

Zuberi 2008 29 175 (168) 32 187 (207) 44 -1200 [ -10625 8225 ]

Subtotal (95 CI) 734 749 751 118 [ -2161 2398 ]




Walraven 2004 79 325 (264) 81 410 (397) 36 -8500 [ -18923 1923 ]

Subtotal (95 CI) 79 81 36 -8500 [ -18923 1923 ]




Hofmeyr 2004 117 168 (163) 120 176 (173) 213 -800 [ -5078 3478 ]

Subtotal (95 CI) 117 120 213 -800 [ -5078 3478 ]



Total (95 CI) 930 950 1000 -387 [ -2363 1588 ]




-1000 -500 0 500 1000






enrolment







Zuberi 2008 229 432 28 055 [ 011 279 ]

Widmer 2010 100705 100717 726 102 [ 079 131 ]

Subtotal (95 CI) 734 749 754 100 [ 078 129 ]





Walraven 2004 1379 2381 166 058 [ 032 106 ]

Subtotal (95 CI) 79 81 166 058 [ 032 106 ]





Hofmeyr 2004 6117 11120 80 056 [ 021 146 ]

Subtotal (95 CI) 117 120 80 056 [ 021 146 ]




Total (95 CI) 930 950 1000 089 [ 071 112 ]





005 02 1 5 20












Zuberi 2008 529 632 38 092 [ 031 269 ]

Widmer 2010 103705 117717 782 090 [ 070 114 ]

Subtotal (95 CI) 734 749 821 090 [ 071 114 ]





Walraven 2004 1279 1281 80 103 [ 049 214 ]

Subtotal (95 CI) 79 81 80 103 [ 049 214 ]





Hofmeyr 2004 19115 15119 99 131 [ 070 245 ]

Subtotal (95 CI) 115 119 99 131 [ 070 245 ]




Total (95 CI) 928 949 1000 095 [ 077 117 ]





01 02 05 1 2 5 10






enrolment








Widmer 2010 9705 9717 622 102 [ 041 255 ]

Subtotal (95 CI) 734 749 622 102 [ 041 255 ]





Walraven 2004 279 581 344 041 [ 008 205 ]

Subtotal (95 CI) 79 81 344 041 [ 008 205 ]





Hofmeyr 2004 1117 0120 34 308 [ 013 7476 ]

Subtotal (95 CI) 117 120 34 308 [ 013 7476 ]




Total (95 CI) 930 950 1000 088 [ 042 186 ]





001 01 1 10 100












Zuberi 2008 2929 3232 103 100 [ 094 106 ]

Widmer 2010 188705 203717 671 094 [ 080 112 ]

Subtotal (95 CI) 734 749 774 095 [ 082 110 ]





Walraven 2004 379 581 16 062 [ 015 249 ]

Subtotal (95 CI) 79 81 16 062 [ 015 249 ]





Hofmeyr 2004 63111 63112 209 101 [ 080 127 ]

Subtotal (95 CI) 111 112 209 101 [ 080 127 ]




Total (95 CI) 924 942 1000 096 [ 084 108 ]





01 02 05 1 2 5 10






after enrolment





nN nN

M-HRandom95

CI

M-HRandom95

CI


Widmer 2010 29705 42717 925 070 [ 044 111 ]

Zuberi 2008 229 432 75 055 [ 011 279 ]

Subtotal (95 CI) 734 749 1000 069 [ 044 108 ]














Total (95 CI) 734 749 1000 069 [ 044 108 ]





0001 001 01 1 10 100 1000






enrolment





nN nN

M-HRandom95

CI

M-HRandom95

CI



Zuberi 2008 229 732 1000 032 [ 007 140 ]

Subtotal (95 CI) 734 749 1000 032 [ 007 140 ]














Total (95 CI) 734 749 1000 032 [ 007 140 ]





0001 001 01 1 10 100 1000











nN nN

M-HRandom95

CI

M-HRandom95

CI


Widmer 2010 2705 2717 1000 102 [ 014 720 ]


Subtotal (95 CI) 734 749 1000 102 [ 014 720 ]














Total (95 CI) 734 749 1000 102 [ 014 720 ]





0001 001 01 1 10 100 1000






enrolment





nN nN

M-HRandom95

CI

M-HRandom95

CI























0001 001 01 1 10 100 1000






enrolment





nN nN

M-HRandom95

CI

M-HRandom95

CI























0001 001 01 1 10 100 1000






conception

















Hofmeyr 2004 2117 0121 1000 517 [ 025 10655 ]

Subtotal (95 CI) 117 121 1000 517 [ 025 10655 ]




Total (95 CI) 117 121 1000 517 [ 025 10655 ]





0001 001 01 1 10 100 1000











nN nN

M-HRandom95

CI

M-HRandom95

CI


Widmer 2010 2705 2717 367 102 [ 014 720 ]

Zuberi 2008 229 732 633 032 [ 007 140 ]

Subtotal (95 CI) 734 749 1000 048 [ 015 158 ]














Total (95 CI) 734 749 1000 048 [ 015 158 ]





0001 001 01 1 10 100 1000








Outcome 17 Nausea

Study or subgroup

Sublingualmisopros-




Widmer 2010 60705 49717 877 125 [ 087 179 ]

Zuberi 2008 229 232 34 110 [ 017 734 ]

Subtotal (95 CI) 734 749 911 124 [ 087 177 ]





Walraven 2004 379 581 89 062 [ 015 249 ]

Subtotal (95 CI) 79 81 89 062 [ 015 249 ]









Total (95 CI) 813 830 1000 118 [ 084 167 ]





001 01 1 10 100








Outcome 18 Vomiting

Study or subgroup

Sublingualmisopros-




Widmer 2010 45705 25717 963 183 [ 114 295 ]

Zuberi 2008 229 132 37 221 [ 021 2308 ]

Subtotal (95 CI) 734 749 1000 184 [ 116 295 ]














Total (95 CI) 734 749 1000 184 [ 116 295 ]





001 01 1 10 100









Study or subgroup

Sublingualmisopros-




Widmer 2010 6705 5717 1000 122 [ 037 398 ]


Subtotal (95 CI) 734 749 1000 122 [ 037 398 ]














Total (95 CI) 734 749 1000 122 [ 037 398 ]





001 01 1 10 100






more




Study or subgroup

Sublingualmisopros-




Widmer 2010 406705 137717 962 301 [ 256 355 ]

Zuberi 2008 1529 332 20 552 [ 178 1713 ]

Subtotal (95 CI) 734 749 983 307 [ 261 360 ]





Walraven 2004 479 081 03 923 [ 050 16857 ]

Subtotal (95 CI) 79 81 03 923 [ 050 16857 ]





Hofmeyr 2004 11114 2118 14 569 [ 129 2512 ]

Subtotal (95 CI) 114 118 14 569 [ 129 2512 ]




Total (95 CI) 927 948 1000 312 [ 266 367 ]





001 01 1 10 100






more




Study or subgroup

Sublingualmisopros-




Widmer 2010 48705 3717 755 1627 [ 509 5200 ]

Zuberi 2008 129 032 121 330 [ 014 7795 ]

Subtotal (95 CI) 734 749 875 1448 [ 491 4272 ]










Hofmeyr 2004 3114 0118 125 724 [ 038 13868 ]

Subtotal (95 CI) 114 118 125 724 [ 038 13868 ]




Total (95 CI) 848 867 1000 1358 [ 493 3744 ]





001 01 1 10 100








Outcome 22 Headache

Study or subgroup

Sublingualmisopros-




Widmer 2010 125705 101717 898 126 [ 099 160 ]

Zuberi 2008 229 032 04 550 [ 027 11001 ]

Subtotal (95 CI) 734 749 903 128 [ 101 162 ]





Walraven 2004 779 1181 97 065 [ 027 160 ]

Subtotal (95 CI) 79 81 97 065 [ 027 160 ]









Total (95 CI) 813 830 1000 122 [ 097 153 ]





001 01 1 10 100









Study or subgroup

Sublingualmisopros-


nN nN

M-HRandom95

CI

M-HRandom95

CI


Widmer 2010 514705 252717 593 207 [ 186 231 ]

Zuberi 2008 1529 232 30 828 [ 207 3313 ]

Subtotal (95 CI) 734 749 623 347 [ 093 1301 ]





Walraven 2004 2379 881 94 295 [ 140 619 ]

Subtotal (95 CI) 79 81 94 295 [ 140 619 ]





Hofmeyr 2004 63116 30118 283 214 [ 150 304 ]

Subtotal (95 CI) 116 118 283 214 [ 150 304 ]




Total (95 CI) 929 948 1000 225 [ 176 288 ]





001 01 1 10 100









Study or subgroup

Sublingualmisopros-




Zuberi 2008 029 132 1000 037 [ 002 866 ]

Subtotal (95 CI) 29 32 1000 037 [ 002 866 ]














Total (95 CI) 29 32 1000 037 [ 002 866 ]





001 01 1 10 100








Outcome 25 Allergy

Study or subgroup

Sublingualmisopros-
























001 01 1 10 100






mortality



therapy


Study or subgroup

sublingualmisopros-




Blum 2010 1407 1402 1000 099 [ 006 1574 ]


Total (95 CI) 895 892 1000 099 [ 006 1574 ]





001 01 1 10 100






maternal morbidity



therapy


Study or subgroup

sublingualmisopros-




Blum 2010 0407 1402 1000 033 [ 001 806 ]


Total (95 CI) 895 892 1000 033 [ 001 806 ]





001 01 1 10 100






to intensive care



therapy


Study or subgroup

sublingualmisopros-




Blum 2010 0407 1402 1000 033 [ 001 806 ]


Total (95 CI) 895 892 1000 033 [ 001 806 ]





001 01 1 10 100






Hysterectomy



therapy


Study or subgroup

sublingualmisopros-




Blum 2010 4407 2402 1000 198 [ 036 1072 ]


Total (95 CI) 895 892 1000 198 [ 036 1072 ]





001 01 1 10 100









therapy


Study or subgroup

sublingualmisopros-


nN nN

M-HRandom95

CI

M-HRandom95

CI


Blum 2010 58407 53402 521 108 [ 076 153 ]

Winikoff 2010 53488 20490 479 266 [ 162 438 ]

Total (95 CI) 895 892 1000 166 [ 069 404 ]





001 01 1 10 100









therapy


Study or subgroup

sublingualmisopros-

tol IV oxytocinMean


Difference



Blum 2010 407 279 (251) 402 252 (205) 338 2700 [ -456 5856 ]

Winikoff 2010 488 244 (186) 490 190 (174) 662 5400 [ 3142 7658 ]

Total (95 CI) 895 892 1000 4486 [ 2650 6322 ]




-100 -50 0 50 100









therapy


Study or subgroup

sublingualmisopros-




Blum 2010 11407 3402 502 362 [ 102 1288 ]

Winikoff 2010 5488 3490 498 167 [ 040 696 ]

Total (95 CI) 895 892 1000 265 [ 104 675 ]





001 01 1 10 100









therapy


Study or subgroup

sublingualmisopros-




Blum 2010 24407 18402 411 132 [ 073 239 ]

Winikoff 2010 41488 26490 589 158 [ 098 255 ]

Total (95 CI) 895 892 1000 147 [ 102 214 ]





001 01 1 10 100









therapy


Study or subgroup

sublingualmisopros-

tol IV oxytocinMean


Difference



Blum 2010 407 193 (15) 402 191 (146) 280 020 [ -184 224 ]

Winikoff 2010 488 134 (82) 490 134 (118) 720 00 [ -127 127 ]

Total (95 CI) 895 892 1000 006 [ -102 114 ]




-100 -50 0 50 100









therapy


Study or subgroup

sublingualmisopros-


nN nN

M-HRandom95

CI

M-HRandom95

CI


Blum 2010 40407 46402 502 086 [ 058 128 ]

Winikoff 2010 61488 31490 498 198 [ 131 299 ]

Total (95 CI) 895 892 1000 130 [ 057 294 ]





001 01 1 10 100









therapy


Study or subgroup

sublingualmisopros-


nN nN

M-HRandom95

CI

M-HRandom95

CI


Blum 2010 37407 22402 350 166 [ 100 276 ]

Winikoff 2010 99488 90490 650 110 [ 085 143 ]

Total (95 CI) 895 892 1000 127 [ 087 187 ]





001 01 1 10 100









therapy


Study or subgroup

sublingualmisopros-



1 600 mcg


Zuberi 2008 229 732 1000 032 [ 007 140 ]

Subtotal (95 CI) 734 749 1000 032 [ 007 140 ]




2 800 mcg





Total (95 CI) 734 749 1000 032 [ 007 140 ]





001 01 1 10 100






compression



therapy


Study or subgroup

sublingualmisopros-




Blum 2010 39407 31402 99 124 [ 079 195 ]

Winikoff 2010 294488 283490 901 104 [ 094 116 ]

Total (95 CI) 895 892 1000 106 [ 096 118 ]





001 01 1 10 100









therapy


Study or subgroup

sublingualmisopros-











001 01 1 10 100









therapy


Study or subgroup

sublingualmisopros-











001 01 1 10 100









therapy


Study or subgroup

sublingualmisopros-











001 01 1 10 100









therapy


Study or subgroup

sublingualmisopros-

tol IV oxytocinRisk


Difference

nN nN

M-HRandom95

CI

M-HRandom95

CI


Blum 2010 44407 42402 461 000 [ -004 005 ]

Winikoff 2010 48488 22490 539 005 [ 002 009 ]

Total (95 CI) 895 892 1000 003 [ -002 008 ]





-1 -05 0 05 1









therapy


Study or subgroup

sublingualmisopros-











001 01 1 10 100







after enrolment



therapy


Study or subgroup

sublingualmisopros-




Blum 2010 0407 1402 1000 033 [ 001 806 ]


Total (95 CI) 895 892 1000 033 [ 001 806 ]





001 01 1 10 100








therapy

Outcome 20 Nausea

Study or subgroup

sublingualmisopros-




Blum 2010 59407 69402 629 084 [ 061 116 ]

Winikoff 2010 49488 41490 371 120 [ 081 178 ]

Total (95 CI) 895 892 1000 098 [ 076 125 ]





001 01 1 10 100








therapy

Outcome 21 Vomiting

Study or subgroup

sublingualmisopros-




Blum 2010 19407 10402 590 188 [ 088 399 ]

Winikoff 2010 24488 7490 410 344 [ 150 792 ]

Total (95 CI) 895 892 1000 252 [ 145 438 ]





001 01 1 10 100








therapy


Study or subgroup

sublingualmisopros-




Blum 2010 5407 3402 602 165 [ 040 684 ]

Winikoff 2010 2488 2490 398 100 [ 014 710 ]

Total (95 CI) 895 892 1000 139 [ 044 436 ]





001 01 1 10 100








therapy

Outcome 23 Headache

Study or subgroup

sublingualmisopros-




Blum 2010 0407 1402 431 033 [ 001 806 ]

Winikoff 2010 3488 2490 569 151 [ 025 897 ]

Total (95 CI) 895 892 1000 100 [ 023 438 ]





001 01 1 10 100








therapy


Study or subgroup

sublingualmisopros-




Blum 2010 152407 59402 420 254 [ 195 332 ]

Winikoff 2010 229488 82490 580 280 [ 225 349 ]

Total (95 CI) 895 892 1000 270 [ 228 319 ]





001 01 1 10 100






faint or fainting



therapy


Study or subgroup

sublingualmisopros-




Blum 2010 60407 59402 937 100 [ 072 140 ]

Winikoff 2010 4488 4490 63 100 [ 025 399 ]

Total (95 CI) 895 892 1000 100 [ 073 139 ]





001 01 1 10 100









therapy


Study or subgroup

sublingualmisopros-

tol IV oxytocinRisk


Difference

nN nN

M-HRandom95

CI

M-HRandom95

CI


Blum 2010 88407 59402 499 007 [ 002 012 ]

Winikoff 2010 217488 27490 501 039 [ 034 044 ]

Total (95 CI) 895 892 1000 023 [ -008 054 ]





-1 -05 0 05 1









therapy


Study or subgroup

sublingualmisopros-


nN nN

M-HRandom95

CI

M-HRandom95

CI


Blum 2010 5407 1402 526 494 [ 058 4208 ]

Winikoff 2010 66488 0490 474 13354 [ 829 215128 ]

Total (95 CI) 895 892 1000 2354 [ 050 110442 ]





001 01 1 10 100








therapy

Outcome 28 Allergy

Study or subgroup

sublingualmisopros-




Blum 2010 1407 0402 252 296 [ 012 7252 ]

Winikoff 2010 0488 1490 748 033 [ 001 820 ]

Total (95 CI) 895 892 1000 100 [ 014 709 ]





001 01 1 10 100






1 Hysterectomy







1 800 mcg

Lokugamage 2001 032 132 1000 033 [ 001 789 ]

Total (95 CI) 32 32 1000 033 [ 001 789 ]





001 01 1 10 100













Lokugamage 2001 232 1132 1000 018 [ 004 076 ]

Total (95 CI) 32 32 1000 018 [ 004 076 ]





001 01 1 10 100











Lokugamage 2001 232 1132 1000 018 [ 004 076 ]

Total (95 CI) 32 32 1000 018 [ 004 076 ]





001 01 1 10 100













Lokugamage 2001 232 232 1000 100 [ 015 667 ]

Total (95 CI) 32 32 1000 100 [ 015 667 ]





01 02 05 1 2 5 10











Zhou 2006 052 360 1000 016 [ 001 311 ]

Total (95 CI) 52 60 1000 016 [ 001 311 ]





001 01 1 10 100









Difference


Zhou 2006 52 5896 (2264) 60 8645 (3595) 1000 -27490 [ -38472 -16508 ]

Total (95 CI) 52 60 1000 -27490 [ -38472 -16508 ]




-500 -250 0 250 500











Difference


Zhou 2006 52 1108 (762) 60 1615 (983) 1000 -5070 [ -8307 -1833 ]

Total (95 CI) 52 60 1000 -5070 [ -8307 -1833 ]




-100 -50 0 50 100















001 01 1 10 100












Ducloy-Bouthors 2011 072 172 1000 033 [ 001 805 ]

Total (95 CI) 72 72 1000 033 [ 001 805 ]





001 01 1 10 100









Ducloy-Bouthors 2011 372 572 1000 060 [ 015 242 ]

Total (95 CI) 72 72 1000 060 [ 015 242 ]





001 01 1 10 100











Ducloy-Bouthors 2011 072 172 1000 033 [ 001 805 ]

Total (95 CI) 72 72 1000 033 [ 001 805 ]





001 01 1 10 100









Ducloy-Bouthors 2011 7272 7272 1000 100 [ 097 103 ]

Total (95 CI) 72 72 1000 100 [ 097 103 ]





001 01 1 10 100











Ducloy-Bouthors 2011 1772 1572 1000 113 [ 061 209 ]

Total (95 CI) 72 72 1000 113 [ 061 209 ]





001 01 1 10 100









Difference


Ducloy-Bouthors 2011 72 1319 (409) 72 1410 (510) 1000 -9100 [ -24200 6000 ]

Total (95 CI) 72 72 1000 -9100 [ -24200 6000 ]




-100 -50 0 50 100











Ducloy-Bouthors 2011 772 1272 1000 058 [ 024 140 ]

Total (95 CI) 72 72 1000 058 [ 024 140 ]





001 01 1 10 100









Ducloy-Bouthors 2011 3672 3472 1000 106 [ 076 148 ]

Total (95 CI) 72 72 1000 106 [ 076 148 ]





001 01 1 10 100











Ducloy-Bouthors 2011 6772 5772 1000 118 [ 103 134 ]

Total (95 CI) 72 72 1000 118 [ 103 134 ]





001 01 1 10 100









Ducloy-Bouthors 2011 072 272 1000 020 [ 001 409 ]

Total (95 CI) 72 72 1000 020 [ 001 409 ]





001 01 1 10 100













Ducloy-Bouthors 2011 172 172 333 100 [ 006 1568 ]

Subtotal (95 CI) 72 72 333 100 [ 006 1568 ]





Ducloy-Bouthors 2011 172 272 667 050 [ 005 539 ]

Subtotal (95 CI) 72 72 667 050 [ 005 539 ]




Total (95 CI) 144 144 1000 067 [ 011 393 ]





001 01 1 10 100











Ducloy-Bouthors 2011 7272 7272 1000 100 [ 097 103 ]

Total (95 CI) 72 72 1000 100 [ 097 103 ]





001 01 1 10 100















001 01 1 10 100






after enrolment






Ducloy-Bouthors 2011 072 172 1000 033 [ 001 805 ]

Total (95 CI) 72 72 1000 033 [ 001 805 ]





001 01 1 10 100









Ducloy-Bouthors 2011 472 572 1000 080 [ 022 286 ]

Total (95 CI) 72 72 1000 080 [ 022 286 ]





001 01 1 10 100








Outcome 17 Headache









001 01 1 10 100






Outcome 18 Nausea



Ducloy-Bouthors 2011 1172 172 1000 1100 [ 146 8299 ]

Total (95 CI) 72 72 1000 1100 [ 146 8299 ]





001 01 1 10 100











Ducloy-Bouthors 2011 1272 1172 1000 109 [ 052 231 ]

Total (95 CI) 72 72 1000 109 [ 052 231 ]





001 01 1 10 100















001 01 1 10 100











Ducloy-Bouthors 2011 272 172 1000 200 [ 019 2157 ]

Total (95 CI) 72 72 1000 200 [ 019 2157 ]





001 01 1 10 100






Outcome 22 Seizures









001 01 1 10 100











Ducloy-Bouthors 2011 472 372 1000 133 [ 031 575 ]

Total (95 CI) 72 72 1000 133 [ 031 575 ]





001 01 1 10 100









Ducloy-Bouthors 2011 872 272 1000 400 [ 088 1819 ]

Total (95 CI) 72 72 1000 400 [ 088 1819 ]





001 01 1 10 100











Ducloy-Bouthors 2011 172 172 1000 100 [ 006 1568 ]

Total (95 CI) 72 72 1000 100 [ 006 1568 ]





001 01 1 10 100




haemorrhage






Ducloy-Bouthors 2011 172 272 1000 050 [ 005 539 ]

Total (95 CI) 72 72 1000 050 [ 005 539 ]





001 01 1 10 100











Ducloy-Bouthors 2011 2452 1856 1000 144 [ 089 232 ]

Total (95 CI) 52 56 1000 144 [ 089 232 ]





001 01 1 10 100




haemorrhage






Ducloy-Bouthors 2011 172 272 1000 050 [ 005 539 ]

Total (95 CI) 72 72 1000 050 [ 005 539 ]





001 01 1 10 100











Ducloy-Bouthors 2011 072 172 1000 033 [ 001 805 ]

Total (95 CI) 72 72 1000 033 [ 001 805 ]





001 01 1 10 100







Study or subgroup

Lowersegment









001 01 1 10 100









Study or subgroup

Lowersegment









001 01 1 10 100



3 Hysterectomy




Study or subgroup

Lowersegment









001 01 1 10 100









Study or subgroup

Lowersegment



Chantrapitak 2009 132 832 1000 013 [ 002 094 ]

Total (95 CI) 32 32 1000 013 [ 002 094 ]





001 01 1 10 100









Study or subgroup

Lowersegment



Chantrapitak 2009 032 232 1000 020 [ 001 401 ]

Total (95 CI) 32 32 1000 020 [ 001 401 ]





001 01 1 10 100







Study or subgroup

Lowersegment



Difference


Chantrapitak 2009 32 120 (211) 32 225 (401) 1000 -10500 [ -26200 5200 ]

Total (95 CI) 32 32 1000 -10500 [ -26200 5200 ]




-100 -50 0 50 100





7 Blood transfusion




Study or subgroup

Lowersegment



Chantrapitak 2009 732 332 1000 233 [ 066 823 ]

Total (95 CI) 32 32 1000 233 [ 066 823 ]





001 01 1 10 100







Study or subgroup

Lowersegment









001 01 1 10 100









Study or subgroup

Lowersegment



Chantrapitak 2009 232 232 1000 100 [ 015 667 ]

Total (95 CI) 32 32 1000 100 [ 015 667 ]





001 01 1 10 100








(Continued)


H I S T O R Y

















Internal sources


External sources



Methods updated

I N D E X T E R M S



MeSH check words






































































































A B S T R A C T

Background


Objectives


Search methods


Selection criteria




Main results


















B A C K G R O U N D






Physiology


Definition





Complications







A Uterotonics

Ergometrine


Oxytocin


Prostaglandins


B Haemostatic drugs







Uterine tamponade














O B J E C T I V E S


M E T H O D S


Types of studies







Exclusion criteria
























Primary outcomes




Secondary outcomes







bleeding

Side effects


Other


following delivery)







Electronic searches



















selection bias)






bias)










detection bias)























Dichotomous data


Continuous data





Cross-over trials










Data synthesis









R E S U L T S


Included studies


Uterotonic trials





Haemostatic trials





Surgical trials


Excluded studies









study












comparison 1)


Primary outcomes



Secondary outcomes


Side effects






Primary outcomes






Side effects



comparison 4)


Primary outcomes


Secondary outcomes




Primary outcomes


Secondary outcomes


Side effects





Primary outcomes




Secondary outcomes


D I S C U S S I O N































R E F E R E N C E S




(Suppl 2)S150






























Childbirth 2008840







(2)198ndash200



(S2)101



(Suppl 3)S410









197612(4)565ndash79















20101140




Abdel-Aleem 2001


Abdel-Aleem 2003



200310825ndash8

AbdRabbo 1994





Abou El Senoun 2011



Abou Zahr 1991


ACOG 1998



Adekanmi 2001


2001108541ndash2

Aisaka 1988



Akhter 2005


Alamia 1999



Alexander 2002



Alfirevic 2006


Alfirevic 2007


Andolina 2003


200314229ndash32

Arulkumaran 2007




As 1996



B-Lynch 1997



Bakri 1999



Baskett 2000



Begley 2011


2011 Issue 11 [DOI 10100214651858CD007412]

Beischer 1986


Bergstrom 1962



Bonnar 2000



200014(1)1ndash18

Burchell 1980


Cantwell 2011



(Suppl 1)1ndash203

Carroli 2008






Chan 1997



Cho 2000



Clark 1985


Combs 1991



Cotter 2001


2001 Issue 4 [DOI 10100214651858CD001808]



(9734)23ndash32

Cunningham 1993


Cutler 1971


1971173(4)511ndash4

Danielsson 1999


Davis 1935


193529155ndash67

De Loor 1996



Dodd 2010



Doumouchtsis 2007


Drife 1997


Du Vigneaud 1953



Dudley 1935


Eastman 1950



Ferrer 2009


Franchini 2010



Gando 2006



Georgiou 2009



Gilbert 1987



Gyte 1992





Guumllmezoglu 2001


Haggerty 1996


Hall 1985


Hayman 2002


Hensleigh 2002



(12)1377ndash84

Higgins 2011


Hofmeyr 2005



Hofmeyr 2008



Hunter 1992


Johanson 2001



(4)420ndash2

Jouppila 1995



Khan 2003


Khan 2006


Knight 2009



Liabsuetrakul 2007


Maier 1993


1993169317ndash23

Marasinghe 2011



McDonald 2004


McDonald 2013



Miller 2009



Miller 2010


Mobeen 2011





Moir 1932


Moscardo 2001


Mousa 2001


Mousa 2002



Mousa 2008


Nardin 2011



Novikova 2010



OrsquoBrien 1998


199892212ndash4

Oboro 2003


Ochoa 2002


200299(3)506ndash9

Ojengbede 2011



Oladapo 2012a



Oladapo 2012b


Oleen 1990


Ouahba 2007



Peitsidis 2011



Penninx 2010



Pereira 2005



Porro 1876


Poujade 2011



Prendiville 1989


Pritchard 1962






Rath 2009



Rathat 2011




Ripley 1999


199926(3)419ndash34

Sloan 2010



Stafford 2008


2008199(5)e511-e517

Stearns 1808


Stearns 1822


1822590

Stoll 1935



Stones 1993



Su 2007



Su 2012



Suzuki 2012


(6)1363ndash7

Tang 2002


Thompson 1935



Tseng 2011



Tsu 1993


1993100327ndash33

Tunccedilalp 2012



Vahedi 1995


(4)616ndash8

Wetta 2013


WHO 2010




Zheng 2011



Zieman 1997





Hofmeyr 2009



Mousa 2003


2003 Issue 1 [DOI 10100214651858CD003249]

Mousa 2007







Blum 2010





Notes

Risk of bias















Chantrapitak 2009





Notes

Risk of bias




























Notes

Risk of bias











Hofmeyr 2004














Risk of bias















Lokugamage 2001






Risk of bias














Walraven 2004










Risk of bias














Widmer 2010





Notes

Risk of bias















Winikoff 2010








Notes

Risk of bias











Zhou 2006

Methods Randomised







Notes

Risk of bias











Zuberi 2008









Risk of bias

























(Continued)











Collins 2013












Miller 2008









Mirzazada 2011











Notes

Shakur 2010









Wikkelsoe 2012








Notes







studies

No of












































































































































































































studies

No of










































































































studies

No of







primary PPH


studies

No of










for primary PPH


studies

No of




















































studies

No of

























Widmer 2010 2705 0717 502 508 [ 024 10573 ]

Subtotal (95 CI) 734 749 502 508 [ 024 10573 ]











Hofmeyr 2004 3117 0121 498 724 [ 038 13860 ]

Subtotal (95 CI) 117 121 498 724 [ 038 13860 ]




Total (95 CI) 930 951 1000 616 [ 075 5085 ]





0001 001 01 1 10 100 1000













Widmer 2010 0705 1717 1000 034 [ 001 831 ]


Subtotal (95 CI) 734 749 1000 034 [ 001 831 ]














Total (95 CI) 734 749 1000 034 [ 001 831 ]





001 01 1 10 100









Study or subgroup





Widmer 2010 7705 9717 1000 079 [ 030 211 ]


Subtotal (95 CI) 734 749 1000 079 [ 030 211 ]














Total (95 CI) 734 749 1000 079 [ 030 211 ]





001 01 1 10 100










nN nN

M-HRandom95

CI

M-HRandom95

CI


Widmer 2010 2705 3717 487 068 [ 011 405 ]


Subtotal (95 CI) 734 749 487 068 [ 011 405 ]





Walraven 2004 079 281 252 021 [ 001 420 ]

Subtotal (95 CI) 79 81 252 020 [ 001 420 ]





Hofmeyr 2004 3117 0121 261 724 [ 038 13860 ]

Subtotal (95 CI) 117 121 261 724 [ 038 13860 ]




Total (95 CI) 930 951 1000 093 [ 016 541 ]





0001 001 01 1 10 100 1000






in millilitres






Difference



Widmer 2010 705 250 (223) 717 248 (229) 707 200 [ -2149 2549 ]

Zuberi 2008 29 175 (168) 32 187 (207) 44 -1200 [ -10625 8225 ]

Subtotal (95 CI) 734 749 751 118 [ -2161 2398 ]




Walraven 2004 79 325 (264) 81 410 (397) 36 -8500 [ -18923 1923 ]

Subtotal (95 CI) 79 81 36 -8500 [ -18923 1923 ]




Hofmeyr 2004 117 168 (163) 120 176 (173) 213 -800 [ -5078 3478 ]

Subtotal (95 CI) 117 120 213 -800 [ -5078 3478 ]



Total (95 CI) 930 950 1000 -387 [ -2363 1588 ]




-1000 -500 0 500 1000






enrolment







Zuberi 2008 229 432 28 055 [ 011 279 ]

Widmer 2010 100705 100717 726 102 [ 079 131 ]

Subtotal (95 CI) 734 749 754 100 [ 078 129 ]





Walraven 2004 1379 2381 166 058 [ 032 106 ]

Subtotal (95 CI) 79 81 166 058 [ 032 106 ]





Hofmeyr 2004 6117 11120 80 056 [ 021 146 ]

Subtotal (95 CI) 117 120 80 056 [ 021 146 ]




Total (95 CI) 930 950 1000 089 [ 071 112 ]





005 02 1 5 20












Zuberi 2008 529 632 38 092 [ 031 269 ]

Widmer 2010 103705 117717 782 090 [ 070 114 ]

Subtotal (95 CI) 734 749 821 090 [ 071 114 ]





Walraven 2004 1279 1281 80 103 [ 049 214 ]

Subtotal (95 CI) 79 81 80 103 [ 049 214 ]





Hofmeyr 2004 19115 15119 99 131 [ 070 245 ]

Subtotal (95 CI) 115 119 99 131 [ 070 245 ]




Total (95 CI) 928 949 1000 095 [ 077 117 ]





01 02 05 1 2 5 10






enrolment








Widmer 2010 9705 9717 622 102 [ 041 255 ]

Subtotal (95 CI) 734 749 622 102 [ 041 255 ]





Walraven 2004 279 581 344 041 [ 008 205 ]

Subtotal (95 CI) 79 81 344 041 [ 008 205 ]





Hofmeyr 2004 1117 0120 34 308 [ 013 7476 ]

Subtotal (95 CI) 117 120 34 308 [ 013 7476 ]




Total (95 CI) 930 950 1000 088 [ 042 186 ]





001 01 1 10 100












Zuberi 2008 2929 3232 103 100 [ 094 106 ]

Widmer 2010 188705 203717 671 094 [ 080 112 ]

Subtotal (95 CI) 734 749 774 095 [ 082 110 ]





Walraven 2004 379 581 16 062 [ 015 249 ]

Subtotal (95 CI) 79 81 16 062 [ 015 249 ]





Hofmeyr 2004 63111 63112 209 101 [ 080 127 ]

Subtotal (95 CI) 111 112 209 101 [ 080 127 ]




Total (95 CI) 924 942 1000 096 [ 084 108 ]





01 02 05 1 2 5 10






after enrolment





nN nN

M-HRandom95

CI

M-HRandom95

CI


Widmer 2010 29705 42717 925 070 [ 044 111 ]

Zuberi 2008 229 432 75 055 [ 011 279 ]

Subtotal (95 CI) 734 749 1000 069 [ 044 108 ]














Total (95 CI) 734 749 1000 069 [ 044 108 ]





0001 001 01 1 10 100 1000






enrolment





nN nN

M-HRandom95

CI

M-HRandom95

CI



Zuberi 2008 229 732 1000 032 [ 007 140 ]

Subtotal (95 CI) 734 749 1000 032 [ 007 140 ]














Total (95 CI) 734 749 1000 032 [ 007 140 ]





0001 001 01 1 10 100 1000











nN nN

M-HRandom95

CI

M-HRandom95

CI


Widmer 2010 2705 2717 1000 102 [ 014 720 ]


Subtotal (95 CI) 734 749 1000 102 [ 014 720 ]














Total (95 CI) 734 749 1000 102 [ 014 720 ]





0001 001 01 1 10 100 1000






enrolment





nN nN

M-HRandom95

CI

M-HRandom95

CI























0001 001 01 1 10 100 1000






enrolment





nN nN

M-HRandom95

CI

M-HRandom95

CI























0001 001 01 1 10 100 1000






conception

















Hofmeyr 2004 2117 0121 1000 517 [ 025 10655 ]

Subtotal (95 CI) 117 121 1000 517 [ 025 10655 ]




Total (95 CI) 117 121 1000 517 [ 025 10655 ]





0001 001 01 1 10 100 1000











nN nN

M-HRandom95

CI

M-HRandom95

CI


Widmer 2010 2705 2717 367 102 [ 014 720 ]

Zuberi 2008 229 732 633 032 [ 007 140 ]

Subtotal (95 CI) 734 749 1000 048 [ 015 158 ]














Total (95 CI) 734 749 1000 048 [ 015 158 ]





0001 001 01 1 10 100 1000








Outcome 17 Nausea

Study or subgroup

Sublingualmisopros-




Widmer 2010 60705 49717 877 125 [ 087 179 ]

Zuberi 2008 229 232 34 110 [ 017 734 ]

Subtotal (95 CI) 734 749 911 124 [ 087 177 ]





Walraven 2004 379 581 89 062 [ 015 249 ]

Subtotal (95 CI) 79 81 89 062 [ 015 249 ]









Total (95 CI) 813 830 1000 118 [ 084 167 ]





001 01 1 10 100








Outcome 18 Vomiting

Study or subgroup

Sublingualmisopros-




Widmer 2010 45705 25717 963 183 [ 114 295 ]

Zuberi 2008 229 132 37 221 [ 021 2308 ]

Subtotal (95 CI) 734 749 1000 184 [ 116 295 ]














Total (95 CI) 734 749 1000 184 [ 116 295 ]





001 01 1 10 100









Study or subgroup

Sublingualmisopros-




Widmer 2010 6705 5717 1000 122 [ 037 398 ]


Subtotal (95 CI) 734 749 1000 122 [ 037 398 ]














Total (95 CI) 734 749 1000 122 [ 037 398 ]





001 01 1 10 100






more




Study or subgroup

Sublingualmisopros-




Widmer 2010 406705 137717 962 301 [ 256 355 ]

Zuberi 2008 1529 332 20 552 [ 178 1713 ]

Subtotal (95 CI) 734 749 983 307 [ 261 360 ]





Walraven 2004 479 081 03 923 [ 050 16857 ]

Subtotal (95 CI) 79 81 03 923 [ 050 16857 ]





Hofmeyr 2004 11114 2118 14 569 [ 129 2512 ]

Subtotal (95 CI) 114 118 14 569 [ 129 2512 ]




Total (95 CI) 927 948 1000 312 [ 266 367 ]





001 01 1 10 100






more




Study or subgroup

Sublingualmisopros-




Widmer 2010 48705 3717 755 1627 [ 509 5200 ]

Zuberi 2008 129 032 121 330 [ 014 7795 ]

Subtotal (95 CI) 734 749 875 1448 [ 491 4272 ]










Hofmeyr 2004 3114 0118 125 724 [ 038 13868 ]

Subtotal (95 CI) 114 118 125 724 [ 038 13868 ]




Total (95 CI) 848 867 1000 1358 [ 493 3744 ]





001 01 1 10 100








Outcome 22 Headache

Study or subgroup

Sublingualmisopros-




Widmer 2010 125705 101717 898 126 [ 099 160 ]

Zuberi 2008 229 032 04 550 [ 027 11001 ]

Subtotal (95 CI) 734 749 903 128 [ 101 162 ]





Walraven 2004 779 1181 97 065 [ 027 160 ]

Subtotal (95 CI) 79 81 97 065 [ 027 160 ]









Total (95 CI) 813 830 1000 122 [ 097 153 ]





001 01 1 10 100









Study or subgroup

Sublingualmisopros-


nN nN

M-HRandom95

CI

M-HRandom95

CI


Widmer 2010 514705 252717 593 207 [ 186 231 ]

Zuberi 2008 1529 232 30 828 [ 207 3313 ]

Subtotal (95 CI) 734 749 623 347 [ 093 1301 ]





Walraven 2004 2379 881 94 295 [ 140 619 ]

Subtotal (95 CI) 79 81 94 295 [ 140 619 ]





Hofmeyr 2004 63116 30118 283 214 [ 150 304 ]

Subtotal (95 CI) 116 118 283 214 [ 150 304 ]




Total (95 CI) 929 948 1000 225 [ 176 288 ]





001 01 1 10 100









Study or subgroup

Sublingualmisopros-




Zuberi 2008 029 132 1000 037 [ 002 866 ]

Subtotal (95 CI) 29 32 1000 037 [ 002 866 ]














Total (95 CI) 29 32 1000 037 [ 002 866 ]





001 01 1 10 100








Outcome 25 Allergy

Study or subgroup

Sublingualmisopros-
























001 01 1 10 100






mortality



therapy


Study or subgroup

sublingualmisopros-




Blum 2010 1407 1402 1000 099 [ 006 1574 ]


Total (95 CI) 895 892 1000 099 [ 006 1574 ]





001 01 1 10 100






maternal morbidity



therapy


Study or subgroup

sublingualmisopros-




Blum 2010 0407 1402 1000 033 [ 001 806 ]


Total (95 CI) 895 892 1000 033 [ 001 806 ]





001 01 1 10 100






to intensive care



therapy


Study or subgroup

sublingualmisopros-




Blum 2010 0407 1402 1000 033 [ 001 806 ]


Total (95 CI) 895 892 1000 033 [ 001 806 ]





001 01 1 10 100






Hysterectomy



therapy


Study or subgroup

sublingualmisopros-




Blum 2010 4407 2402 1000 198 [ 036 1072 ]


Total (95 CI) 895 892 1000 198 [ 036 1072 ]





001 01 1 10 100









therapy


Study or subgroup

sublingualmisopros-


nN nN

M-HRandom95

CI

M-HRandom95

CI


Blum 2010 58407 53402 521 108 [ 076 153 ]

Winikoff 2010 53488 20490 479 266 [ 162 438 ]

Total (95 CI) 895 892 1000 166 [ 069 404 ]





001 01 1 10 100









therapy


Study or subgroup

sublingualmisopros-

tol IV oxytocinMean


Difference



Blum 2010 407 279 (251) 402 252 (205) 338 2700 [ -456 5856 ]

Winikoff 2010 488 244 (186) 490 190 (174) 662 5400 [ 3142 7658 ]

Total (95 CI) 895 892 1000 4486 [ 2650 6322 ]




-100 -50 0 50 100









therapy


Study or subgroup

sublingualmisopros-




Blum 2010 11407 3402 502 362 [ 102 1288 ]

Winikoff 2010 5488 3490 498 167 [ 040 696 ]

Total (95 CI) 895 892 1000 265 [ 104 675 ]





001 01 1 10 100









therapy


Study or subgroup

sublingualmisopros-




Blum 2010 24407 18402 411 132 [ 073 239 ]

Winikoff 2010 41488 26490 589 158 [ 098 255 ]

Total (95 CI) 895 892 1000 147 [ 102 214 ]





001 01 1 10 100









therapy


Study or subgroup

sublingualmisopros-

tol IV oxytocinMean


Difference



Blum 2010 407 193 (15) 402 191 (146) 280 020 [ -184 224 ]

Winikoff 2010 488 134 (82) 490 134 (118) 720 00 [ -127 127 ]

Total (95 CI) 895 892 1000 006 [ -102 114 ]




-100 -50 0 50 100









therapy


Study or subgroup

sublingualmisopros-


nN nN

M-HRandom95

CI

M-HRandom95

CI


Blum 2010 40407 46402 502 086 [ 058 128 ]

Winikoff 2010 61488 31490 498 198 [ 131 299 ]

Total (95 CI) 895 892 1000 130 [ 057 294 ]





001 01 1 10 100









therapy


Study or subgroup

sublingualmisopros-


nN nN

M-HRandom95

CI

M-HRandom95

CI


Blum 2010 37407 22402 350 166 [ 100 276 ]

Winikoff 2010 99488 90490 650 110 [ 085 143 ]

Total (95 CI) 895 892 1000 127 [ 087 187 ]





001 01 1 10 100









therapy


Study or subgroup

sublingualmisopros-



1 600 mcg


Zuberi 2008 229 732 1000 032 [ 007 140 ]

Subtotal (95 CI) 734 749 1000 032 [ 007 140 ]




2 800 mcg





Total (95 CI) 734 749 1000 032 [ 007 140 ]





001 01 1 10 100






compression



therapy


Study or subgroup

sublingualmisopros-




Blum 2010 39407 31402 99 124 [ 079 195 ]

Winikoff 2010 294488 283490 901 104 [ 094 116 ]

Total (95 CI) 895 892 1000 106 [ 096 118 ]





001 01 1 10 100









therapy


Study or subgroup

sublingualmisopros-











001 01 1 10 100









therapy


Study or subgroup

sublingualmisopros-











001 01 1 10 100









therapy


Study or subgroup

sublingualmisopros-











001 01 1 10 100









therapy


Study or subgroup

sublingualmisopros-

tol IV oxytocinRisk


Difference

nN nN

M-HRandom95

CI

M-HRandom95

CI


Blum 2010 44407 42402 461 000 [ -004 005 ]

Winikoff 2010 48488 22490 539 005 [ 002 009 ]

Total (95 CI) 895 892 1000 003 [ -002 008 ]





-1 -05 0 05 1









therapy


Study or subgroup

sublingualmisopros-











001 01 1 10 100







after enrolment



therapy


Study or subgroup

sublingualmisopros-




Blum 2010 0407 1402 1000 033 [ 001 806 ]


Total (95 CI) 895 892 1000 033 [ 001 806 ]





001 01 1 10 100








therapy

Outcome 20 Nausea

Study or subgroup

sublingualmisopros-




Blum 2010 59407 69402 629 084 [ 061 116 ]

Winikoff 2010 49488 41490 371 120 [ 081 178 ]

Total (95 CI) 895 892 1000 098 [ 076 125 ]





001 01 1 10 100








therapy

Outcome 21 Vomiting

Study or subgroup

sublingualmisopros-




Blum 2010 19407 10402 590 188 [ 088 399 ]

Winikoff 2010 24488 7490 410 344 [ 150 792 ]

Total (95 CI) 895 892 1000 252 [ 145 438 ]





001 01 1 10 100








therapy


Study or subgroup

sublingualmisopros-




Blum 2010 5407 3402 602 165 [ 040 684 ]

Winikoff 2010 2488 2490 398 100 [ 014 710 ]

Total (95 CI) 895 892 1000 139 [ 044 436 ]





001 01 1 10 100








therapy

Outcome 23 Headache

Study or subgroup

sublingualmisopros-




Blum 2010 0407 1402 431 033 [ 001 806 ]

Winikoff 2010 3488 2490 569 151 [ 025 897 ]

Total (95 CI) 895 892 1000 100 [ 023 438 ]





001 01 1 10 100








therapy


Study or subgroup

sublingualmisopros-




Blum 2010 152407 59402 420 254 [ 195 332 ]

Winikoff 2010 229488 82490 580 280 [ 225 349 ]

Total (95 CI) 895 892 1000 270 [ 228 319 ]





001 01 1 10 100






faint or fainting



therapy


Study or subgroup

sublingualmisopros-




Blum 2010 60407 59402 937 100 [ 072 140 ]

Winikoff 2010 4488 4490 63 100 [ 025 399 ]

Total (95 CI) 895 892 1000 100 [ 073 139 ]





001 01 1 10 100









therapy


Study or subgroup

sublingualmisopros-

tol IV oxytocinRisk


Difference

nN nN

M-HRandom95

CI

M-HRandom95

CI


Blum 2010 88407 59402 499 007 [ 002 012 ]

Winikoff 2010 217488 27490 501 039 [ 034 044 ]

Total (95 CI) 895 892 1000 023 [ -008 054 ]





-1 -05 0 05 1









therapy


Study or subgroup

sublingualmisopros-


nN nN

M-HRandom95

CI

M-HRandom95

CI


Blum 2010 5407 1402 526 494 [ 058 4208 ]

Winikoff 2010 66488 0490 474 13354 [ 829 215128 ]

Total (95 CI) 895 892 1000 2354 [ 050 110442 ]





001 01 1 10 100








therapy

Outcome 28 Allergy

Study or subgroup

sublingualmisopros-




Blum 2010 1407 0402 252 296 [ 012 7252 ]

Winikoff 2010 0488 1490 748 033 [ 001 820 ]

Total (95 CI) 895 892 1000 100 [ 014 709 ]





001 01 1 10 100






1 Hysterectomy







1 800 mcg

Lokugamage 2001 032 132 1000 033 [ 001 789 ]

Total (95 CI) 32 32 1000 033 [ 001 789 ]





001 01 1 10 100













Lokugamage 2001 232 1132 1000 018 [ 004 076 ]

Total (95 CI) 32 32 1000 018 [ 004 076 ]





001 01 1 10 100











Lokugamage 2001 232 1132 1000 018 [ 004 076 ]

Total (95 CI) 32 32 1000 018 [ 004 076 ]





001 01 1 10 100













Lokugamage 2001 232 232 1000 100 [ 015 667 ]

Total (95 CI) 32 32 1000 100 [ 015 667 ]





01 02 05 1 2 5 10











Zhou 2006 052 360 1000 016 [ 001 311 ]

Total (95 CI) 52 60 1000 016 [ 001 311 ]





001 01 1 10 100









Difference


Zhou 2006 52 5896 (2264) 60 8645 (3595) 1000 -27490 [ -38472 -16508 ]

Total (95 CI) 52 60 1000 -27490 [ -38472 -16508 ]




-500 -250 0 250 500











Difference


Zhou 2006 52 1108 (762) 60 1615 (983) 1000 -5070 [ -8307 -1833 ]

Total (95 CI) 52 60 1000 -5070 [ -8307 -1833 ]




-100 -50 0 50 100















001 01 1 10 100












Ducloy-Bouthors 2011 072 172 1000 033 [ 001 805 ]

Total (95 CI) 72 72 1000 033 [ 001 805 ]





001 01 1 10 100









Ducloy-Bouthors 2011 372 572 1000 060 [ 015 242 ]

Total (95 CI) 72 72 1000 060 [ 015 242 ]





001 01 1 10 100











Ducloy-Bouthors 2011 072 172 1000 033 [ 001 805 ]

Total (95 CI) 72 72 1000 033 [ 001 805 ]





001 01 1 10 100









Ducloy-Bouthors 2011 7272 7272 1000 100 [ 097 103 ]

Total (95 CI) 72 72 1000 100 [ 097 103 ]





001 01 1 10 100











Ducloy-Bouthors 2011 1772 1572 1000 113 [ 061 209 ]

Total (95 CI) 72 72 1000 113 [ 061 209 ]





001 01 1 10 100









Difference


Ducloy-Bouthors 2011 72 1319 (409) 72 1410 (510) 1000 -9100 [ -24200 6000 ]

Total (95 CI) 72 72 1000 -9100 [ -24200 6000 ]




-100 -50 0 50 100











Ducloy-Bouthors 2011 772 1272 1000 058 [ 024 140 ]

Total (95 CI) 72 72 1000 058 [ 024 140 ]





001 01 1 10 100









Ducloy-Bouthors 2011 3672 3472 1000 106 [ 076 148 ]

Total (95 CI) 72 72 1000 106 [ 076 148 ]





001 01 1 10 100











Ducloy-Bouthors 2011 6772 5772 1000 118 [ 103 134 ]

Total (95 CI) 72 72 1000 118 [ 103 134 ]





001 01 1 10 100









Ducloy-Bouthors 2011 072 272 1000 020 [ 001 409 ]

Total (95 CI) 72 72 1000 020 [ 001 409 ]





001 01 1 10 100













Ducloy-Bouthors 2011 172 172 333 100 [ 006 1568 ]

Subtotal (95 CI) 72 72 333 100 [ 006 1568 ]





Ducloy-Bouthors 2011 172 272 667 050 [ 005 539 ]

Subtotal (95 CI) 72 72 667 050 [ 005 539 ]




Total (95 CI) 144 144 1000 067 [ 011 393 ]





001 01 1 10 100











Ducloy-Bouthors 2011 7272 7272 1000 100 [ 097 103 ]

Total (95 CI) 72 72 1000 100 [ 097 103 ]





001 01 1 10 100















001 01 1 10 100






after enrolment






Ducloy-Bouthors 2011 072 172 1000 033 [ 001 805 ]

Total (95 CI) 72 72 1000 033 [ 001 805 ]





001 01 1 10 100









Ducloy-Bouthors 2011 472 572 1000 080 [ 022 286 ]

Total (95 CI) 72 72 1000 080 [ 022 286 ]





001 01 1 10 100








Outcome 17 Headache









001 01 1 10 100






Outcome 18 Nausea



Ducloy-Bouthors 2011 1172 172 1000 1100 [ 146 8299 ]

Total (95 CI) 72 72 1000 1100 [ 146 8299 ]





001 01 1 10 100











Ducloy-Bouthors 2011 1272 1172 1000 109 [ 052 231 ]

Total (95 CI) 72 72 1000 109 [ 052 231 ]





001 01 1 10 100















001 01 1 10 100











Ducloy-Bouthors 2011 272 172 1000 200 [ 019 2157 ]

Total (95 CI) 72 72 1000 200 [ 019 2157 ]





001 01 1 10 100






Outcome 22 Seizures









001 01 1 10 100











Ducloy-Bouthors 2011 472 372 1000 133 [ 031 575 ]

Total (95 CI) 72 72 1000 133 [ 031 575 ]





001 01 1 10 100









Ducloy-Bouthors 2011 872 272 1000 400 [ 088 1819 ]

Total (95 CI) 72 72 1000 400 [ 088 1819 ]





001 01 1 10 100











Ducloy-Bouthors 2011 172 172 1000 100 [ 006 1568 ]

Total (95 CI) 72 72 1000 100 [ 006 1568 ]





001 01 1 10 100




haemorrhage






Ducloy-Bouthors 2011 172 272 1000 050 [ 005 539 ]

Total (95 CI) 72 72 1000 050 [ 005 539 ]





001 01 1 10 100











Ducloy-Bouthors 2011 2452 1856 1000 144 [ 089 232 ]

Total (95 CI) 52 56 1000 144 [ 089 232 ]





001 01 1 10 100




haemorrhage






Ducloy-Bouthors 2011 172 272 1000 050 [ 005 539 ]

Total (95 CI) 72 72 1000 050 [ 005 539 ]





001 01 1 10 100











Ducloy-Bouthors 2011 072 172 1000 033 [ 001 805 ]

Total (95 CI) 72 72 1000 033 [ 001 805 ]





001 01 1 10 100







Study or subgroup

Lowersegment









001 01 1 10 100









Study or subgroup

Lowersegment









001 01 1 10 100



3 Hysterectomy




Study or subgroup

Lowersegment









001 01 1 10 100









Study or subgroup

Lowersegment



Chantrapitak 2009 132 832 1000 013 [ 002 094 ]

Total (95 CI) 32 32 1000 013 [ 002 094 ]





001 01 1 10 100









Study or subgroup

Lowersegment



Chantrapitak 2009 032 232 1000 020 [ 001 401 ]

Total (95 CI) 32 32 1000 020 [ 001 401 ]





001 01 1 10 100







Study or subgroup

Lowersegment



Difference


Chantrapitak 2009 32 120 (211) 32 225 (401) 1000 -10500 [ -26200 5200 ]

Total (95 CI) 32 32 1000 -10500 [ -26200 5200 ]




-100 -50 0 50 100





7 Blood transfusion




Study or subgroup

Lowersegment



Chantrapitak 2009 732 332 1000 233 [ 066 823 ]

Total (95 CI) 32 32 1000 233 [ 066 823 ]





001 01 1 10 100







Study or subgroup

Lowersegment









001 01 1 10 100









Study or subgroup

Lowersegment



Chantrapitak 2009 232 232 1000 100 [ 015 667 ]

Total (95 CI) 32 32 1000 100 [ 015 667 ]





001 01 1 10 100








(Continued)


H I S T O R Y

















Internal sources


External sources



Methods updated

I N D E X T E R M S



MeSH check words




cochrane databaseofsystematicreviewsresearchonline.lshtm.ac.uk/1592717/1/mousa_et_al-2014...analysis...

Documents