prophylactic oxytocin for the third stage of labour to prevent

Prophylactic oxytocin for the third stage of labour to prevent

postpartum haemorrhage (Review)

Westhoff G, Cotter AM, Tolosa JE

This is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library2013, Issue 10

http://www.thecochranelibrary.com

Prophylactic oxytocin for the third stage of labour to prevent postpartum haemorrhage (Review)

Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

http://www.thecochranelibrary.com

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

1HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .2PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .3BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .4OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .4METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .7RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

11DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .11AUTHORS’ CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .12ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .13REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .17CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . .40DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Analysis 1.1. Comparison 1 Oxytocin versus no uterotonics, Outcome 1 PPH (clinically estimated blood loss > or = 500mL). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45

Analysis 1.2. Comparison 1 Oxytocin versus no uterotonics, Outcome 2 Therapeutic uterotonics. . . . . . . . 46Analysis 1.3. Comparison 1 Oxytocin versus no uterotonics, Outcome 3 Severe PPH (clinically estimated blood loss > or =

1000 mL). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47Analysis 1.4. Comparison 1 Oxytocin versus no uterotonics, Outcome 4 Mean blood loss (mL). . . . . . . . 48Analysis 1.5. Comparison 1 Oxytocin versus no uterotonics, Outcome 5 Maternal haemoglobin concentration (Hb) < 9

g/dL 24 to 48 hours postpartum. . . . . . . . . . . . . . . . . . . . . . . . . . . . 49Analysis 1.6. Comparison 1 Oxytocin versus no uterotonics, Outcome 6 Blood transfusion. . . . . . . . . . 50Analysis 1.7. Comparison 1 Oxytocin versus no uterotonics, Outcome 7 Third stage greater than 30 minutes. . . . 50Analysis 1.8. Comparison 1 Oxytocin versus no uterotonics, Outcome 8 Mean length of third stage (minutes). . . 51Analysis 1.9. Comparison 1 Oxytocin versus no uterotonics, Outcome 9 Manual removal of the placenta. . . . . 52Analysis 1.12. Comparison 1 Oxytocin versus no uterotonics, Outcome 12 Nausea between delivery of the baby and

discharge from the labour ward. . . . . . . . . . . . . . . . . . . . . . . . . . . . 53Analysis 2.1. Comparison 2 Oxytocin versus no uterotonics--subgroup analyses, Outcome 1 PPH (clinically estimated

blood loss > or = 500 mL); randomised v. quasi-randomised trials. . . . . . . . . . . . . . . . . 54Analysis 2.2. Comparison 2 Oxytocin versus no uterotonics--subgroup analyses, Outcome 2 PPH (clinically estimated

blood loss > or = 500 mL); active v. expectant management. . . . . . . . . . . . . . . . . . . 55Analysis 2.3. Comparison 2 Oxytocin versus no uterotonics--subgroup analyses, Outcome 3 PPH (clinically estimated

blood loss > or = 500 mL); IM v. IV oxytocin. . . . . . . . . . . . . . . . . . . . . . . 56Analysis 2.4. Comparison 2 Oxytocin versus no uterotonics--subgroup analyses, Outcome 4 PPH (clinically estimated

blood loss > 500 mL); oxytocin dose < 10 IU v. 10 IU. . . . . . . . . . . . . . . . . . . . . 57Analysis 2.5. Comparison 2 Oxytocin versus no uterotonics--subgroup analyses, Outcome 5 Therapeutic uterotonics;

randomised v. quasi-randomised trials. . . . . . . . . . . . . . . . . . . . . . . . . . 58Analysis 2.6. Comparison 2 Oxytocin versus no uterotonics--subgroup analyses, Outcome 6 Therapeutic uterotonics; active

v. expectant management. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 59Analysis 2.7. Comparison 2 Oxytocin versus no uterotonics--subgroup analyses, Outcome 7 Therapeutic uterotonics; IM v.

IV oxytocin. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 60Analysis 2.8. Comparison 2 Oxytocin versus no uterotonics--subgroup analyses, Outcome 8 Therapeutic uterotonics;

oxytocin dose < 10 IU v. 10 IU. . . . . . . . . . . . . . . . . . . . . . . . . . . . 61Analysis 3.1. Comparison 3 Oxytocin versus ergot alkaloids, Outcome 1 PPH (clinically estimated blood loss > or = 500

mL). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 62Analysis 3.2. Comparison 3 Oxytocin versus ergot alkaloids, Outcome 2 Therapeutic uterotonics. . . . . . . . 63Analysis 3.3. Comparison 3 Oxytocin versus ergot alkaloids, Outcome 3 Severe PPH (clinically estimated blood loss > or =

1000 mL). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 64Analysis 3.4. Comparison 3 Oxytocin versus ergot alkaloids, Outcome 4 Mean blood loss (mL). . . . . . . . 65Analysis 3.6. Comparison 3 Oxytocin versus ergot alkaloids, Outcome 6 Blood transfusion. . . . . . . . . . 66Analysis 3.8. Comparison 3 Oxytocin versus ergot alkaloids, Outcome 8 Mean length of third stage (minutes). . . 66

iProphylactic oxytocin for the third stage of labour to prevent postpartum haemorrhage (Review)


Analysis 3.9. Comparison 3 Oxytocin versus ergot alkaloids, Outcome 9 Manual removal of the placenta. . . . . 67Analysis 3.10. Comparison 3 Oxytocin versus ergot alkaloids, Outcome 10 Diastolic blood pressure > 100 mm Hg between

delivery of the baby and discharge from the labour ward. . . . . . . . . . . . . . . . . . . . 68Analysis 3.11. Comparison 3 Oxytocin versus ergot alkaloids, Outcome 11 Vomiting between delivery of the baby and

discharge from the labour ward. . . . . . . . . . . . . . . . . . . . . . . . . . . . 69Analysis 3.12. Comparison 3 Oxytocin versus ergot alkaloids, Outcome 12 Nausea between delivery of the baby and

discharge from the labour ward. . . . . . . . . . . . . . . . . . . . . . . . . . . . 70Analysis 3.13. Comparison 3 Oxytocin versus ergot alkaloids, Outcome 13 Headaches between delivery of the baby and

discharge from the labour ward. . . . . . . . . . . . . . . . . . . . . . . . . . . . 71Analysis 4.1. Comparison 4 Oxytocin versus ergot alkaloids--subgroup analyses, Outcome 1 PPH (clinically estimated

blood loss > or = 500 mL); randomised v. quasi-randomised trials. . . . . . . . . . . . . . . . . 72Analysis 4.2. Comparison 4 Oxytocin versus ergot alkaloids--subgroup analyses, Outcome 2 PPH (clinically estimated

blood loss > or = 500 mL); active v. expectant management. . . . . . . . . . . . . . . . . . . 73Analysis 4.3. Comparison 4 Oxytocin versus ergot alkaloids--subgroup analyses, Outcome 3 PPH (clinically estimated

blood loss > or = 500 mL); IM v. IV oxytocin. . . . . . . . . . . . . . . . . . . . . . . 74Analysis 4.4. Comparison 4 Oxytocin versus ergot alkaloids--subgroup analyses, Outcome 4 PPH (clinically estimated

blood loss > 500 mL); oxytocin dose < 10 IU v. 10 IU. . . . . . . . . . . . . . . . . . . . . 75Analysis 4.5. Comparison 4 Oxytocin versus ergot alkaloids--subgroup analyses, Outcome 5 Therapeutic uterotonics;

randomised v. quasi-randomised trials. . . . . . . . . . . . . . . . . . . . . . . . . . 76Analysis 4.6. Comparison 4 Oxytocin versus ergot alkaloids--subgroup analyses, Outcome 6 Therapeutic uterotonics; active

v. expectant management. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 77Analysis 4.7. Comparison 4 Oxytocin versus ergot alkaloids--subgroup analyses, Outcome 7 Therapeutic uterotonics; IM v.

IV oxytocin. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 78Analysis 4.8. Comparison 4 Oxytocin versus ergot alkaloids--subgroup analyses, Outcome 8 Therapeutic uterotonics;

oxytocin dose < 10 IU v. 10 IU. . . . . . . . . . . . . . . . . . . . . . . . . . . . 79Analysis 5.1. Comparison 5 Oxytocin + ergometrine versus ergot alkaloids, Outcome 1 PPH (clinically estimated blood

loss > or = 500 mL). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 80Analysis 5.3. Comparison 5 Oxytocin + ergometrine versus ergot alkaloids, Outcome 3 Severe PPH (clinically estimated

blood loss > or = 1000 mL). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 81Analysis 5.4. Comparison 5 Oxytocin + ergometrine versus ergot alkaloids, Outcome 4 Mean blood loss (mL). . . 81Analysis 5.6. Comparison 5 Oxytocin + ergometrine versus ergot alkaloids, Outcome 6 Blood transfusion. . . . . 82Analysis 5.8. Comparison 5 Oxytocin + ergometrine versus ergot alkaloids, Outcome 8 Mean length of the third stage

(minutes). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 82Analysis 5.9. Comparison 5 Oxytocin + ergometrine versus ergot alkaloids, Outcome 9 Manual removal of the placenta. 83Analysis 6.1. Comparison 6 Oxytocin + ergometrine versus ergot alkaloids--subgroup analyses, Outcome 1 PPH (clinically

estimated blood loss > or = 500 mL); randomised v. quasi-randomised trials. . . . . . . . . . . . . 84Analysis 6.2. Comparison 6 Oxytocin + ergometrine versus ergot alkaloids--subgroup analyses, Outcome 2 PPH (clinically

estimated blood loss > or = 500 mL); active v. expectant management. . . . . . . . . . . . . . . 85Analysis 6.3. Comparison 6 Oxytocin + ergometrine versus ergot alkaloids--subgroup analyses, Outcome 3 PPH (clinically

estimated blood loss > or = 500 mL); IM v. IV oxytocin. . . . . . . . . . . . . . . . . . . . 8686APPENDICES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .88FEEDBACK . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .89WHAT’S NEW . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .89HISTORY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .89CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . .90DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .90DIFFERENCES BETWEEN PROTOCOL AND REVIEW . . . . . . . . . . . . . . . . . . . . .90INDEX TERMS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

iiProphylactic oxytocin for the third stage of labour to prevent postpartum haemorrhage (Review)


[Intervention Review]

Prophylactic oxytocin for the third stage of labour to preventpostpartum haemorrhage

Gina Westhoff1, Amanda M Cotter2,3, Jorge E Tolosa3,4

1Stanford University and University of California-San Francisco, Stanford, CA, USA. 2Department of Obstetrics and Gynaecology,University of Limerick, Limerick, Ireland. 3Global Network for Perinatal and Reproductive Health, Portland, OR, USA. 4Departmentof Obstetrics and Gynecology, Oregon Health and Science University, Portland, Oregon, USA

Contact address: Gina Westhoff, Stanford University and University of California-San Francisco, 300 Pasteur Dr. HH333, Stanford,CA, 94305-5317, USA. [email protected]. [email protected].

Editorial group: Cochrane Pregnancy and Childbirth Group.Publication status and date: New search for studies and content updated (conclusions changed), published in Issue 10, 2013.Review content assessed as up-to-date: 24 June 2013.

Citation: Westhoff G, Cotter AM, Tolosa JE. Prophylactic oxytocin for the third stage of labour to prevent postpartum haemorrhage.Cochrane Database of Systematic Reviews 2013, Issue 10. Art. No.: CD001808. DOI: 10.1002/14651858.CD001808.pub2.


A B S T R A C T

Background

Active management of the third stage of labour has been shown to reduce the risk of postpartum haemorrhage (PPH) greater than 1000mL. One aspect of the active management protocol is the administration of prophylactic uterotonics, however, the type of uterotonic,dose, and route of administration vary across the globe and may have an impact on maternal outcomes.

Objectives

To determine the effectiveness of prophylactic oxytocin at any dose to prevent PPH and other adverse maternal outcomes related tothe third stage of labour.

Search methods

We searched the Cochrane Pregnancy and Childbirth Group’s Trials Register (31 May 2013).

Selection criteria

Randomised or quasi-randomised controlled trials including pregnant women anticipating a vaginal delivery where prophylacticoxytocin was given during management of the third stage of labour. The primary outcomes were blood loss > 500 mL and the use oftherapeutic uterotonics.

Data collection and analysis

Two review authors independently assessed trials for inclusion, assessed trial quality and extracted data. Data were checked for accuracy.

Main results

This updated review included 20 trials (involving 10,806 women).

Prophylactic oxytocin versus placebo

Prophylactic oxytocin compared with placebo reduced the risk of PPH greater than 500 mL, (risk ratio (RR) 0.53; 95% confidenceinterval (CI) 0.38 to 0.74; six trials, 4203 women; T² = 0.11, I² = 78%) and the need for therapeutic uterotonics (RR 0.56; 95%

1Prophylactic oxytocin for the third stage of labour to prevent postpartum haemorrhage (Review)


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CI 0.36 to 0.87, four trials, 3174 women; T² = 0.10, I² = 58%). The benefit of prophylactic oxytocin to prevent PPH greater than500 mL was seen in all subgroups. Decreased use of therapeutic uterotonics was only seen in the following subgroups: randomisedtrials with low risk of bias (RR 0.58; 95% CI 0.36 to 0.92; three trials, 3122 women; T² = 0.11, I² = 69%); trials that performedactive management of the third stage (RR 0.39; 95% CI 0.26 to 0.58; one trial, 1901 women; heterogeneity not applicable); trials thatdelivered oxytocin as an IV bolus (RR 0.57; 95% CI 0.39 to 0.82; one trial, 1000 women; heterogeneity not applicable); and in trialsthat gave oxytocin at a dose of 10 IU (RR 0.48; 95% CI 0.33 to 0.68; two trials, 2901 women; T² = 0.02, I² = 27%).

Prophylactic oxytocin versus ergot alkaloids

Prophylactic oxytocin was superior to ergot alkaloids in preventing PPH greater than 500 mL (RR 0.76; 95% CI 0.61 to 0.94; fivetrials, 2226 women; T² = 0.00, I² = 0%). The benefit of oxytocin over ergot alkaloids to prevent PPH greater than 500 mL onlypersisted in the subgroups of quasi-randomised trials (RR 0.71, 95% CI 0.53 to 0.96; three trials, 1402 women; T² = 0.00, I² = 0%)and in trials that performed active management of the third stage of labour (RR 0.58; 95% CI 0.38 to 0.89; two trials, 943 women; T²= 0.00, I² = 0%). Use of prophylactic oxytocin was associated with fewer side effects compared with use of ergot alkaloids; includingdecreased nausea between delivery of the baby and discharge from the labour ward (RR 0.18; 95% CI 0.06 to 0.53; three trials, 1091women; T² = 0.41, I² = 41%) and vomiting between delivery of the baby and discharge from the labour ward (RR 0.07; 95% CI 0.02to 0.25; three trials, 1091 women; T² = 0.45, I² = 30%).

Prophylactic oxytocin + ergometrine versus ergot alkaloids

There was no benefit seen in the combination of oxytocin and ergometrine versus ergometrine alone in preventing PPH greater than500 mL (RR 0.90; 95% CI 0.34 to 2.41; five trials, 2891 women; T² = 0.89, I² = 80%). The use of oxytocin and ergometrine wasassociated with increased mean blood loss (MD 61.0 mL; 95% CI 6.00 to 116.00 mL; fixed-effect analysis; one trial, 34 women;heterogeneity not applicable).

In all three comparisons, there was no difference in mean length of the third stage or need for manual removal of the placenta betweentreatment arms.

Authors’ conclusions

Prophylactic oxytocin at any dose decreases both PPH greater than 500 mL and the need for therapeutic uterotonics compared toplacebo alone. Taking into account the subgroup analyses from both primary outcomes, to achieve maximal benefit providers may optto implement a practice of giving prophylactic oxytocin as part of the active management of the third stage of labour at a dose of 10IU given as an IV bolus. If IV delivery is not possible, IM delivery may be used as this route of delivery did show a benefit to preventPPH greater than 500 mL and there was a trend to decrease the need for therapeutic uterotonics, albeit not statistically significant.

Prophylactic oxytocin was superior to ergot alkaloids in preventing PPH greater than 500 mL; however, in subgroup analysis thisbenefit did not persist when only randomised trials with low risk of methodologic bias were analysed. Based on this, there is limitedhigh-quality evidence supporting a benefit of prophylactic oxytocin over ergot alkaloids. However, the use of prophylactic oxytocinwas associated with fewer side effects, specifically nausea and vomiting, making oxytocin the more desirable option for routine use toprevent PPH.

There is no evidence of benefit when adding oxytocin to ergometrine compared to ergot alkaloids alone, and there may even be increasedharm as one study showed evidence that using the combination was associated with increased mean blood loss compared to ergotalkaloids alone.

Importantly, there is no evidence to suggest that prophylactic oxytocin increases the risk of retained placenta when compared to placeboor ergot alkaloids.

More placebo-controlled, randomised, and double-blinded trials are needed to improve the quality of data used to evaluate the effectivedose, timing, and route of administration of prophylactic oxytocin to prevent PPH. In addition, more trials are needed especially, butnot only, in low- and middle-income countries to evaluate these interventions in the birth centres that shoulder the majority of theburden of PPH in order to improve maternal morbidity and mortality worldwide.

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

Prophylactic oxytocin for the third stage of labour



Prophylactic oxytocin at any dose used routinely after birth can reduce blood loss with fewer side effects than ergot alkaloids.

The third stage of labour is that period from birth of the baby until delivery of the placenta, however, complications can continue tooccur once the placenta is removed. The degree of blood loss during this stage depends, among other factors, on how quickly the uterinemuscle contracts and the placenta separates from the uterine wall. Postpartum haemorrhage is a major problem, particularly wherethere is poor nutrition and lack of access to treatment. This review of 20 trials (involving 10,806 women) found that the routine useof prophylactic oxytocin, a drug that helps the uterus contract, may reduce the amount of blood loss during the third stage of labour.Prophylactic oxytocin is better at preventing blood loss compared with ergot alkaloids, however, no further improvement is seen whenthey were used together. More research is needed, especially in low- and middle-income countries, on the best method to implementthis intervention in the third stage for women in all countries, on the dose to use, and the best route for administration (intramuscularor intravenous).

B A C K G R O U N D

The most reliable estimates of global maternal mortality reportbetween 250,000 and 300,000 deaths from childbirth annually(Lozano 2011). The majority of these deaths are due to compli-cations of the third stage of labour, and most commonly are frompostpartum haemorrhage (PPH) (AbouZahr 2003). Nearly all ma-ternal deaths (99%) occur in the developing world (Kwast 1991),where other factors, such as infection (especially HIV infection),poor nutritional status, and lack of easy access to treatment, maycontribute to death in the presence of severe PPH. Many morewomen survive and suffer serious illness as a result, not only fromthe effects of acute anaemia but also from the interventions whicha severe haemorrhage may necessitate (such as general anaesthesia,manual removal of the placenta, blood transfusion, and hysterec-tomy).

The degree of blood loss associated with placental separation anddelivery depends on how quickly the placenta separates fromthe uterine wall and how effectively the uterine muscle contractsaround the placental bed (where the placenta is attached to thewall of the uterus) and the uterine blood vessels, in addition tohow quickly the uterus expels the placenta through the birth canal.Techniques to prevent PPH can target any of these points in pla-cental delivery. A recent review determined that active manage-ment of the third stage of labour prevents severe PPH, definedas 1000 mL, when compared to expectant management (Begley2011). Active management includes administration of a utero-tonic, early cord clamping, and controlled cord traction until de-livery of the placenta.

Uterotonic drugs increase the tone of the uterine muscles and wereinitially introduced for the treatment of PPH. Moir 1932 showedthat ergometrine was the active principle on which the knownuterotonic effect of ergot had depended. Reviewing its use in ob-stetric practice by the early 1950s, his opinion was that “Few drugshave become so firmly established in so short a time and few drugs

can be so completely indispensable as ergometrine is now” (Moir1955). Ergometrine (ergonovine in the United States) becamepopular for routine management in the early 1950s. Oxytocin is anaturally occurring uterotonic, which Du Vigneaud et al synthe-sised and reported in 1953 (Du Vigneaud 1953). Embrey 1963reported advantages of combining this with ergometrine (as Syn-tometrine - oxytocin five international units (IU) plus ergometrine0.5 mg). In order to prevent blood loss, these uterotonics and,more recently, prostaglandins are also being used for prophylacticthird-stage management. One commonly given uterotonic is oxy-tocin, and recently it was shown that there was no difference inpreventing PPH if you administer the oxytocin with the anteriorshoulder or after delivery of the placenta (Soltani 2010).

While few would dispute the contribution of uterotonic drugsin the treatment of PPH, their role in routine prophylaxis is lessclear. This review considers the prophylactic role of one of theseuterotonics, oxytocin, in the third stage of labour. Other relevantpublished reviews are by Begley 2011, which compares active withexpectant third-stage management (where active management in-volves the package of interconnected interventions of prophylac-tic uterotonics, early cutting and clamping of the umbilical cord,and controlled cord traction); Tunçalp 2012 and McDonald 2004,which both consider the role of different prophylactic uterotonics(prostaglandins, and ergometrine-oxytocin compared with oxy-tocin, respectively) in third-stage management; and Carroli 2001,which looks at the role of umbilical vein injection for the treatmentof retained placenta. Subsequent third-stage management reviewswill consider the role of prophylactic uterotonics more generally,and of prophylactic ergot alkaloids in particular. As these inter-ventions are very inter-related, some aspects of the role of oxytocinmay be found in these other reviews (e.g. Begley 2011; McDonald2004; Soltani 2010; Tunçalp 2012).

Any research related to PPH must also recognise the limitations ofthe data collected due to the lack of a formal definition of PPH and



an easy, objective technique to accurately measure blood loss afterdelivery. For example, although PPH is generally defined as bloodloss greater than 500 mL, alternative cut-off points of 600 mL (Beischer 1986) and 1000 mL (Burchell 1980) have been suggested.It has long been recognised that such clinical estimation is likelyto underestimate the actual volume of blood lost by 34% to 50%(Newton 1961a) and as a result, there is significant variability inthe estimated incidence of PPH, from 5% to 18% in one country (AbouZahr 2003; DoH 2004; Gilbert 1987; Hall 1985; Prendiville1988a). Using the outcome of measured blood loss, therefore, hassignificant limitations and potential for bias. Due to the fact thatblood measurement is so variable, more objective measures, suchas the need for therapeutic uterotonics, should also be evaluatedas a primary outcome to minimise measurement bias related toestimating PPH from blood loss.

O B J E C T I V E S

The objective of this review is to examine the effect of prophylacticoxytocin at any dose given in the third stage of labour, defined asthat period from birth of the baby until delivery of the placenta,on outcomes such as maternal blood loss, the need for therapeuticuterotonics, the length of the third stage of labour, and otheradverse maternal events. The objectives of this review will considerthe following comparisons:

1. oxytocin versus no uterotonics;

2. oxytocin versus ergot alkaloids;

3. oxytocin plus ergometrine versus ergot alkaloids.

M E T H O D S

Criteria for considering studies for this review

Types of studies

All randomised or quasi-randomised controlled trials comparingprophylactic oxytocin with another uterotonic or placebo for themanagement of the third stage of labour were considered for in-clusion.

Types of participants

All trials including pregnant women anticipating a vaginal deliv-ery were considered. Studies where participants received the pro-phylactic uterotonic after delivery of the placenta were excluded.

Types of interventions

The purpose of this review is to compare three interventions:1. use of prophylactic oxytocin at any dose for the third stage

of labour versus placebo;2. use of prophylactic oxytocin at any dose for the third stage

of labour versus ergot alkaloids;3. use of prophylactic oxytocin and ergometrine

(synometrine) versus ergot alkaloids.The current review concentrates on oxytocin given by injection,usually into a maternal vein or a muscle. When given intravenously,the oxytocin was given as a bolus injection. The role of prophylacticprostaglandins or ergot alkaloids and uterotonics given throughthe umbilical vein, for the treatment of blood loss or retainedplacenta, will be the subject of other reviews and were not includedhere (Liabsuetrakul 2007; Mori 2012; Tunçalp 2012). Similarly,endogenous oxytocin (nipple stimulation) is not included in thisreview.

Types of outcome measures

Primary outcomes

• Postpartum haemorrhage (PPH) (reported estimates ofblood loss greater than or equal to 500 mL)

• Use of additional therapeutic uterotonics

Secondary outcomes

• Severe PPH (clinically estimated blood loss greater than orequal to 1000 mL)

• Mean blood loss (mL)• Maternal haemoglobin concentration (Hb) less than 9 g/dL

24 to 48 hours postpartum• Blood transfusion• Third stage greater than 30 minutes• Mean length of third stage (minutes)• Manual removal of the placenta• Diastolic blood pressure greater than 100 mmHg between

delivery of baby and discharge from the labour ward• Vomiting between delivery of baby and discharge from the

labour ward• Nausea between delivery of baby and discharge from the

labour ward• Headache between delivery of baby and discharge from the

labour ward

Search methods for identification of studies

Electronic searches



We searched the Cochrane Pregnancy and Childbirth Group’s Tri-als Register by contacting the Trials Search Co-ordinator (31 May2013).The Cochrane Pregnancy and Childbirth Group’s 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 MEDLINE;3. weekly searches of Embase;4. handsearches of 30 journals and the proceedings of major

conferences;5. weekly current awareness alerts for a further 44 journals

plus monthly BioMed Central email alerts.Details 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 ‘Specialized Register’ sectionwithin the editorial information about the Cochrane Pregnancyand Childbirth Group.Trials 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 keywords.We did not apply any language restrictions.

Data collection and analysis

For the methods used when assessing the trials identified in theprevious version of this review, see Appendix 1.

Selection of studies

Two review authors independently assessed for inclusion all thepotential studies we identified as a result of the search strategy. Weresolved any disagreement through discussion or, if required, byconsulting the third author.

Data extraction and management

We designed a form to extract data. For eligible studies, two reviewauthors extracted the data using the agreed form. We resolveddiscrepancies through discussion or, if required, by consulting athird person. We entered the data into Review Manager software(RevMan 2012) and checked them for accuracy.When information regarding any of the above was unclear, weattempted to contact the authors of the original reports to providefurther details.

Assessment of risk of bias in included studies

Two review authors independently assessed risk of bias for eachstudy using the criteria outlined in the Cochrane Handbook forSystematic Reviews of Interventions (Higgins 2011). They resolvedany disagreement by discussion or by involving a third assessor.

(1) Sequence generation (checking for possible selection

bias)

We described for each included study the method used to generatethe allocation sequence in sufficient detail to allow an assessmentof whether it should produce comparable groups.We assessed the method as:

• low risk of bias (any truly random process, e.g. randomnumber table; computer random number generator);

• high risk of bias (any non-random process, e.g. odd or evendate of birth; hospital or clinic record number);

• unclear risk of bias.

(2) Allocation concealment (checking for possible selection

bias)

We described for each included study the method used to concealthe allocation sequence and determined whether intervention al-location could have been foreseen in advance of, or during recruit-ment, or changed after assignment.We assessed the methods as:

• low risk of bias (e.g. telephone or central randomisation;consecutively numbered sealed opaque envelopes);

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


(3) Blinding (checking for possible performance bias)

We described for each included study the methods used, if any, toblind study participants and personnel from knowledge of whichintervention a participant received. We considered that studieswere at low risk of bias if they were blinded, or if we judged that thelack of blinding could not have affected the results. We assessedblinding separately for different outcomes or classes of outcomes.We assessed the methods as:

• low, high or unclear risk of bias for participants;• low, high or unclear risk of bias for personnel;• low, high or unclear risk of bias for outcome assessors.

(4) Incomplete outcome data (checking for possible attrition

bias through withdrawals, dropouts, protocol deviations)

We described for each included study, and for each outcome orclass of outcomes, the completeness of data including attritionand exclusions from the analysis. We stated whether attrition andexclusions were reported, the numbers included in the analysis at



http://www.mrw.interscience.wiley.com/cochrane/clabout/articles/PREG/frame.html





each stage (compared with the total randomised participants), rea-sons for attrition or exclusion where reported, and whether miss-ing data were balanced across groups or were related to outcomes.Where sufficient information was reported, or could be suppliedby the trial authors, we re-included missing data in the analyseswhich we undertake. We assessed methods as:

• low risk of bias (e.g. no missing outcome data; missingoutcome data balanced across groups;

• high risk of bias (e.g. numbers or reasons for missing dataimbalanced across groups; “as treated” analysis done withsubstantial departure of intervention received from that assignedat randomisation);


(5) Selective reporting bias

We described for each included study how we investigated thepossibility of selective outcome reporting bias and what we found.We assessed the methods as:

• low risk of bias (where it is clear that all of the study’s pre-specified outcomes and all expected outcomes of interest to thereview have been reported);

• high risk of bias (where not all the study’s pre-specifiedoutcomes have been reported; one or more reported primaryoutcomes were not pre-specified; outcomes of interest arereported incompletely and so cannot be used; study fails toinclude results of a key outcome that would have been expectedto have been reported);


(6) Other sources of bias

We described for each included study any important concerns wehave about other possible sources of bias.We assessed whether each study was free of other problems thatcould put it at risk of bias:

• low risk of other bias;• high risk of other bias;• unclear whether there is risk of other bias.

(7) Overall risk of bias

We made explicit judgements about whether studies are at high riskof bias, according to the criteria given in the Cochrane Handbook(Higgins 2011). With reference to (1) to (6) above, we assessedthe likely magnitude and direction of the bias and whether weconsidered it likely to impact on the findings. We explored theimpact of the level of bias through undertaking sensitivity analyses- see Sensitivity analysis.

Measures of treatment effect

Dichotomous data

For dichotomous data, we presented results as summary risk ratiowith 95% confidence intervals.

Continuous data

For continuous data, we used the mean difference if outcomes aremeasured in the same way between trials. We planned to use thestandardised mean difference to combine trials that measure thesame outcome, but used different methods.

Unit of analysis issues

There were no cluster-randomised or cross-over trials included inthis review. No additional unit of analysis issues were encountered.

Dealing with missing data

For included studies, we noted levels of attrition. We explored theimpact of including studies with high levels of missing data in theoverall assessment of treatment effect by using sensitivity analysis.For all outcomes, we carried out analyses, as far as possible, onan intention-to-treat basis, i.e. we attempted to include all partic-ipants randomised to each group in the analyses, and all partici-pants were analysed in the group to which they were allocated, re-gardless of whether or not they received the allocated intervention.The denominator for each outcome in each trial was the numberrandomised minus any participants whose outcomes are knownto be missing.

Assessment of heterogeneity

We assessed statistical heterogeneity in each meta-analysis usingthe T², I² and Chi² statistics. We regarded heterogeneity as sub-stantial if the T² was greater than zero and either an I² was greaterthan 40% or there was a low P value (less than 0.10) in the Chi²test for heterogeneity.

Assessment of reporting biases

If there had been 10 or more studies in the meta-analysis, weplanned to investigate reporting biases (such as publication bias)using funnel plots. We would have assessed funnel plot asymme-try visually, and used formal tests for funnel plot asymmetry. Forcontinuous outcomes, we would have used the test proposed byEgger 1997, and for dichotomous outcomes, the test proposed byHarbord 2006. If asymmetry was detected in any of these tests orwas suggested by a visual assessment, we would have performedexploratory analyses to investigate it.



Data synthesis

We carried out statistical analysis using the Review Manager soft-ware (RevMan 2012). We used fixed-effect meta-analysis for com-bining data where it was reasonable to assume that studies wereestimating the same underlying treatment effect: i.e. where trialswere examining the same intervention, and the trials’ populationsand methods were judged sufficiently similar. If there was clinicalheterogeneity sufficient to expect that the underlying treatment ef-fects differed between trials, or if substantial statistical heterogene-ity was 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 treated as the average range of possible treatment effects andwe discussed the clinical implications of treatment effects differingbetween trials. If the average treatment effect was not clinicallymeaningful, we did not combine trials.If we used random-effects analyses, the results were presented asthe average treatment effect with its 95% confidence interval, andthe estimates of T² and I².

Subgroup analysis and investigation of heterogeneity

If we identified substantial heterogeneity, random-effects I² greaterthan 40%, we investigated it using subgroup analyses and sensi-tivity analyses. We considered whether an overall summary wasmeaningful, and if it was, used random-effects analysis to produceit.We carried out the following subgroup analyses.

1. Extent of selection bias: randomised trials with low risk ofbias versus quasi-randomised trials with high risk of bias.

2. Management of the third stage: active versus expectantmanagement. Active management was defined as using at leasttwo of the following components: early cord clamping,controlled cord traction, and uterine massage. Expectantmanagement involves allowing the natural physiologic process topromote separation of the placenta.

3. Route of administration of oxytocin; IV versus IM. Whengiven intravenously, oxytocin was given as a bolus in all trials andnot as a diluted infusion.

4. Dose of administration of oxytocin; less than 10 IU versus10 IU.We assessed subgroup differences by interaction tests availablewithin RevMan (RevMan 2012). We planned to report the resultsof any subgroup differences quoting the χ2 statistic and p-value,and the interaction test I² value.

Sensitivity analysis

Sensitivity analysis was performed to explore the effects of fixed-effect or random-effects analyses for primary outcomes with sta-tistical heterogeneity, as described above.

R E S U L T S

Description of studies

See Characteristics of included studies; Characteristics of excludedstudies.Fifty-seven trials were identified as being potentially eligible for thisreview. Thirty-six of these trials were excluded, see Characteristicsof excluded studies. Altogether, 20 trials were included involving10,806 women, see Characteristics of included studies for details.One trial, Fugo 1958, met the criteria for inclusion but no datafrom this trial were used because the protocol called for manualremoval of the placenta at 10 minutes after delivery of the infantand we felt that the methodology of this trial had high risk of biasand was not translatable into clinical practice.Of the remaining trials, four trials evaluated oxytocin versusplacebo only (Abdel-Aleem 2010; Jerbi 2007; Nordstrom 1997;Pierre 1992), five trials evaluated oxytocin versus ergot alkaloidsonly (Jago 2007; Moodie 1976; Orji 2008; Saito 2007; Sorbe1978), three trials evaluated oxytocin plus ergometrine versus er-got alkaloids only (Barbaro 1961; Bonham 1963; Soiva 1964).Eight trials had several treatment arms (Bader 2000; DeGroot 1996; Francis 1965; Ilancheran 1990; McGinty 1956;Poeschmann 1991; Vaughan Williams1974). Bader 2000 hadthree treatment arms, prophylactic oxytocin, acupuncture andplacebo; the acupuncture group was not included in this analy-sis. De Groot 1996, had three treatment arms prophylactic oxy-tocin, prophylactic ergometrine and placebo and all were included.Francis 1965 had three treatment arms, ergometrine plus oxytocin,ergometrine, and placebo; the placebo arm was not used in thisanalysis. Ilancheran 1990 included four arms: prophylactic oxy-tocin, ergometrine, ergometrine plus oxytocin and placebo andall were included in this analysis. McGinty 1956 had four treat-ment arms, methergine, ergonovine, oxytocin or placebo and themethergine and ergometrine arms were combined for this analysis.Poeschmann 1991 had three treatment arms, oxytocin, sulpros-tone and placebo; the sulprostone arm was not included. VaughanWilliams1974 included six arms: ergometrine with delivery of theanterior shoulder, ergometrine with delivery of the baby, oxytocinwith delivery of the anterior shoulder, ergometrine plus oxytocinwith delivery of the anterior shoulder, diazepam in labour followedby ergometrine plus oxytocin with delivery of the anterior shoul-der, and placebo. For this trial, the two ergometrine arms werecombined for this analysis and the arm with diazepam was notincluded.

Settings

This review includes trials from low-, middle-, and high-incomecountries. All births were attended by midwives or physicians inbirth centres or hospitals, and no trials included home births.Of the 20 included trials, only four trials included centres in



low- and middle-income countries only. The Abdel-Aleem 2010trial was conducted in Egypt and South Africa, Jerbi 2007 wasconducted in Tunisia, and Jago 2007 and Orji 2008 were con-ducted in Nigeria. The remainder of the trials were conductedin the following high-income countries: Finland (Soiva 1964),France (Pierre 1992), Germany (Bader 2000), Japan (Saito 2007),Nederlands (De Groot 1996; Poeschmann 1991), New Zealand(Barbaro 1961; Moodie 1976), Singapore (Ilancheran 1990), Swe-den (Nordstrom 1997; Sorbe 1978), United Kingdom (Bonham1963; Francis 1965; Vaughan Williams1974), and the UnitedStates (McGinty 1956).

Management of the third stage of labour

In seven trials, the third stage was managed actively (at least twoof the components of active management described, or specifiedas ’active’) (Abdel-Aleem 2010; Francis 1965; Jerbi 2007; Orji2008; Pierre 1992; Saito 2007; Vaughan Williams1974); four tri-als used ’expectant management’ (De Groot 1996; Nordstrom1997; Poeschmann 1991; Sorbe 1978); seven trials did not men-tion management of the third stage (Bader 2000; Barbaro 1961;Ilancheran 1990; Jago 2007; McGinty 1956; Moodie 1976; Soiva1964) and one was mixed with components of both active or pas-sive management used (Bonham 1963).One trial, Fugo 1958, was conducted with expectant managementof the third stage until 10 minutes at which point manual extrac-tion of the placenta was performed for teaching purposes. Giventhis study had a high percentage of manual extractions, the wasfelt to have high risk for bias and data from this trial were notincluded.

Blood loss assessment

The majority of the trials (n = 13) used some form of measurement,mainly by collecting and measuring blood plus weighing blood-soaked guaze. Measuring the decrease in haematocrit (Hct) wasdone in one trial, and for this trial total estimated blood loss (EBL)was not an outcome reported (Jerbi 2007). In one trial, the totalblood loss was only reported in 54% of participants, so it was notincluded in the analysis of postpartum haemorrhage (PPH) > 500,PPH > 1000 or mean blood loss (Moodie 1976). No description ofthe method of measurement was mentioned in the remaining fourtrials (Ilancheran 1990; Jago 2007; McGinty 1956; Soiva 1964).

Comparisons

Oxytocin versus no uterotonics

Of the nine trials included in this analysis, the sample sizeranged from 10 to almost 2000 women. The oxytocin wasgiven intramuscularly in three trials (Abdel-Aleem 2010; DeGroot 1996; Poeschmann 1991), and as an IV bolus in six

trials (Bader 2000; Ilancheran 1990; Jerbi 2007; Nordstrom1997; Pierre 1992; Vaughan Williams1974). The dose also var-ied from 3 IU (Bader 2000) to 5 IU (De Groot 1996; Jerbi2007; Pierre 1992; Poeschmann 1991) to 10 IU (Abdel-Aleem2010; Nordstrom 1997; Vaughan Williams1974) to “standarddose” (Ilancheran 1990). The non-oxytocin group was either’nothing’ (Abdel-Aleem 2010; Bader 2000; Ilancheran 1990; Jerbi2007; Pierre 1992; Vaughan Williams1974) or a saline placebo(Nordstrom 1997; Poeschmann 1991). In one trial (De Groot1996), an oral placebo was given to allow blinding with a thirdgroup given oral ergometrine.

Oxytocin versus ergot alkaloids

In the nine trials that provided data for this analysis, the samplesize ranged from 10 to 1049 women. The oxytocin was given in-tramuscularly in two trials (De Groot 1996; Saito 2007), as anIV bolus in six trials (Ilancheran 1990; Jago 2007; Moodie 1976;Orji 2008; Sorbe 1978; Vaughan Williams1974) and both intra-muscularly and intravenously in one trial (McGinty 1956). Thedose of oxytocin varied from 5 IU (De Groot 1996; Moodie 1976;Saito 2007) to 10 IU (Jago 2007; McGinty 1956; Orji 2008; Sorbe1978; Vaughan Williams1974). In the trial by Ilancheran 1990,the only information given is that it was the ’standard dose’. The er-got alkaloid arm was even more varied, ranging from slightly differ-ent preparations - ergometrine/ergonovine (De Groot 1996; Fugo1958; Ilancheran 1990; Jago 2007; McGinty 1956; Moodie 1976;Orji 2008; Sorbe 1978) and methergine (McGinty 1956; Saito2007); different doses - from 0.2 mg (McGinty 1956; Saito 2007;Sorbe 1978), to 0.25 mg (Orji 2008), 0.4 mg (De Groot 1996),0.5 mg (Jago 2007; Moodie 1976; Vaughan Williams1974), andthe ’standard dose’ in Ilancheran 1990; and different routes - allIV except oral in De Groot 1996 and IM in Jago 2007 and Saito2007. The trial by Fugo 1958 met criteria for inclusion, however,did not provide any data due to concerns regarding significantmethodological bias.

Oxytocin plus ergometrine versus ergot alkaloids

In the six trials included in this analysis, the sample size rangedfrom 10 to 1120 women. The ergometrine-oxytocin was gener-ally given intramuscularly, although in one trial it was given intra-venously (Ilancheran 1990). The dose was standard, one ampoulecontaining oxytocin 5 IU and ergometrine 0.5 mg. The ergot al-kaloid arm was more varied, ranging from slightly different prepa-rations - ergometrine (Bonham 1963; Francis 1965; Ilancheran1990), ergometrine maleate (Barbaro 1961), and methergine(Soiva 1964); different doses - from 0.12 mg (Soiva 1964), to 0.5mg (Bonham 1963; Francis 1965; Vaughan Williams1974), 0.10mg (Barbaro 1961), and the ’standard dose’ in Ilancheran 1990;and different routes - IV bolus in Ilancheran 1990, Soiva 1964,Vaughan Williams1974 and IM in Bonham 1963 and Francis1965, and both in Barbaro 1961.



Risk of bias in included studies

In trials evaluating different interventions in the third stage oflabour, PPH is often the primary outcome. Assessment of PPH isprone to bias if the staff making the assessments are not blind to theintervention. In this review, all outcome assessments were blindedin five trials. Because of the inherent bias in the remaining 15 trialsthat either had no blinding or unclear description of the blindingprocess, we changed the primary outcomes to include the use oftherapeutic uterotonics, which do not rely on the measurement ofblood loss.


For this update, four trials (Abdel-Aleem 2010; Bader 2000;Jerbi 2007; Vaughan Williams1974) are added for a total of 10trials included in this comparison (De Groot 1996; Ilancheran1990; McGinty 1956; Nordstrom 1997; Pierre 1992; Poeschmann1991), but McGinty 1956 provides no usable data for this part ofthe review. Random sequence generation was considered adequatein four trials, high risk in two trials, and was not clearly describedin four trials. Allocation concealment was considered adequate infive trials that used sealed envelopes, opaque containers, or iden-tical numbered envelopes or boxes containing trial medications.Bader 2000 excluded 7% of women after randomisation on var-ious secondary exclusion grounds: one in the control group andseven in the oxytocin group. Poeschmann 1991 was stopped earlyafter two years of enrolment due to organisational issues and atthat time they had enrolled 77 out of 150 patients.


For this update, five trials (Jago 2007; Moodie 1976; Orji 2008;Saito 2007; Vaughan Williams1974) are added for a total of ninetrials included in this comparison (De Groot 1996; Ilancheran1990; McGinty 1956; Sorbe 1978). Random sequence generationwas considered adequate in three trials, high risk in three trials,and was not clearly described in four trials. Allocation conceal-ment was considered adequate in four trials that used sealed en-velopes, opaque containers, or identical numbered envelopes orboxes containing trial medications. Moodie 1976 excluded 46%of women from the “blood loss” outcome and as a result that datawere not included in this analysis; data were only used for analysisof nausea and vomiting outcomes.


For this update, one trial (Vaughan Williams1974) was added tothis comparison for a total of six trials included in this comparison(Barbaro 1961; Bonham 1963; Francis 1965; Ilancheran 1990;Soiva 1964). Random sequence generation was considered highrisk in three trials and was not clearly described in three trials.Allocation concealment was not clearly described in all six trials.

Effects of interventions

The results are based on 20 trials.


Primary outcomes

Over 4000 women were included from nine trials for this com-parison.There was significant statistical heterogeneity for both primaryoutcomes: PPH greater than 500 mL and the need for therapeu-tic uterotonics so a random-effects analysis was used. Prophylacticoxytocin compared with placebo reduced the risk of PPH greaterthan 500 mL (average risk ratio (RR) 0.53; 95% confidence in-terval (CI) 0.38 to 0.74; six trials, 4203 women; random-effects,T² = 0.11, I² = 78%, Analysis 1.1) and the need for therapeuticuterotonics (average RR 0.56; 95% CI 0.36 to 0.87, four trials,3174 women; random-effects; T² = 0.10, I² = 58%, Analysis 1.2).The benefit of prophylactic oxytocin to prevent PPH greater than500 mL was seen in all subgroups; randomised and quasi-ran-domised controlled trials, trials with active and expectant man-agement of the third stage of labour, trials that used either IV orIM delivery, and in trials that used doses of oxytocin less than 10IU or 10 IU. The decreased use of therapeutic uterotonics wasonly seen in the following subgroups: randomised trials with lowrisk of bias (average RR 0.58; 95% CI 0.36 to 0.92; three trials,3122 women; random-effects; T² = 0.11, I² = 69%, Analysis 2.5),trials that performed active management of the third stage (RR0.39; 95% CI 0.26 to 0.58; one trial, 1901 women; random-ef-fects; heterogeneity not applicable, Analysis 2.6), trials that deliv-ered oxytocin intravenously (RR 0.57; 95% CI 0.39 to 0.82; onetrial, 1000 women; random-effects; heterogeneity not applicable,Analysis 2.7), and in trials that gave oxytocin at a dose of 10 IU(average RR 0.48; 95% CI 0.33 to 0.68; two trials, 2901 women;random-effects; T² = 0.02, I² = 27%, Analysis 2.8). There was noevidence of a difference between subgroups as indicated by thesubgroup interaction test.

Secondary outcomes

The following secondary outcomes were also improved with theuse of prophylactic oxytocin when compared with placebo: se-vere PPH, as defined by EBL greater than 1000 mL (average RR0.62; 95% CI 0.44 to 0.87; five trials, 4162 women; random-effects; T² = 0.00, I² = 0%, Analysis 1.3) and mean blood loss(mean difference (MD) -99.46 mL; 95% CI -181.97 to -16.95mL; five trials, 1402 women; random-effects; T² = 6691.5, I² =85%, Analysis 1.4). Between the two groups, there was no signifi-cant difference in maternal haemoglobin concentration less than 9g/dL (Analysis 1.5), the need for blood transfusion (Analysis 1.6),third stage length greater than 30 minutes (Analysis 1.7), mean



length of the third stage (Analysis 1.8), manual removal of theplacenta (Analysis 1.9), or nausea between delivery and discharge(Analysis 1.12). There were no available data to analyse the follow-ing outcomes: diastolic blood pressure greater than 100 mmHg,vomiting or headaches between delivery of the baby and dischargefrom the hospital.


Primary outcomes

Over 3000 women were included from nine trials for this com-parison.There was significant statistical heterogeneity for both primaryoutcomes: PPH greater than 500 mL and the need for therapeu-tic uterotonics so a random-effects analysis was used. Prophylacticoxytocin was superior to ergot alkaloids in preventing PPH greaterthan 500 mL (average RR 0.76; 95% CI 0.61 to 0.94; five trials,2226 women; random-effects; T² = 0.00, I² = 0%, Analysis 3.1).The benefit of oxytocin over ergot alkaloids to prevent PPH > 500mL only persisted in the subgroups of quasi-randomised trials (RR0.71, 95% CI 0.53 to 0.96; three trials, 1402 women; random-ef-fects; T² = 0.00, I² = 0%, Analysis 4.1) and in trials that performedactive management of the third stage of labour (RR 0.58; 95% CI0.38 to 0.89; two trials, 943 women; random-effects; T² = 0.00,I² = 0%, Analysis 4.2).There was no benefit of using prophylacticoxytocin over ergot alkaloids to prevent PPH greater than 500 mLwhen the following subgroups were analysed: trials that used onlyIV or IM delivery (Analysis 4.7) and trials that used oxytocin at adose of less than 10 IU or 10 IU (Analysis 4.8).There was a trend towards a benefit of prophylactic oxytocin overergot alkaloids to decrease the need for therapeutic uterotonics,but that benefit was not significant (average RR 0.70; 95% CI0.38 to 1.29; three trials,1167 women; random-effects; T² = 0.18,I² = 62%, Analysis 3.2). Subgroup analyses did show a significantbenefit of prophylactic oxytocin over ergot alkaloids to prevent theneed for therapeutic uterotonics in quasi-randomised trials (RR0.42, 95% CI 0.19 to 0.91; one trial, 343 women, Analysis 4.5) ortrials that used prophylactic oxytocin as part of active managementof the third stage of labour (RR 0.54, 95% CI 0.34 to 0.85; twotrials, 943 women; random-effects; T² = 0.00, I² = 0%, Analysis4.6). No benefit was seen when trials that used only IV or onlyIM delivery (Analysis 4.7) or in trials that used doses of oxytocinless than 10 IU or 10 IU (Analysis 4.8) were analysed separately.

Secondary outcomes

Use of prophylactic oxytocin was associated with fewer side effectscompared with use of ergot alkaloids; including decreased nauseabetween delivery of the baby and discharge from the labour ward(average RR 0.18; 95% CI 0.06 to 0.53; three trials, 1091 women;random-effects; T² = 0.41, I² = 41%, Analysis 3.12) and vomiting

(average RR 0.07; 95% CI 0.02 to 0.25; three trials, 1091 women;random-effects; T² = 0.45, I² = 30%, Analysis 3.11). There wasno significant difference in severe PPH greater than 1000 mL(Analysis 3.3), mean blood loss (Analysis 3.4), the need for bloodtransfusion (Analysis 3.6), mean length of the third stage, manualremoval of the placenta (Analysis 3.9), diastolic blood pressuregreater than 100 mmHg (Analysis 3.10), or headaches betweendelivery of the baby and discharge from the hospital (Analysis3.11). There were no available data to analyse the following out-comes: maternal haemoglobin concentration less than 9 g/dL orthird stage length greater than 30 minutes.


Primary outcomes

Over 2800 women were included from six trials for this compar-ison.There was significant statistical heterogeneity for both primaryoutcomes: PPH greater than 500 mL and the need for therapeuticuterotonics so a random-effects analysis was used.There was no statistical benefit seen in the combination of oxytocinand ergometrine versus ergometrine alone to prevent PPH greaterthan 500 mL (average RR 0.90; 95% CI 0.34 to 2.41; five trials,2891 women; random-effects; T² = 0.89, I² = 80%, Analysis5.1). All trials included in this analysis were considered high-risk,quasi-randomised trials so a subgroup analysis of only low-riskrandomised trials was not performed. There was no benefit ofusing the combination of oxytocin and ergometrine seen whenthe following subgroups were analysed separately: trials that usedactive or expectant management (Analysis 6.2) or trials that usedonly IV or IM delivery (Analysis 6.3).There were no data from these trials to analyse second primaryoutcome, the need for therapeutic uterotonics.

Secondary outcomes

In one trial involving 34 women, the combination of oxytocinand ergometrine was associated with higher mean blood loss (MD61.0 mL; 95% CI 6.00 to 116.00 mL; test for heterogeneity notapplicable, Analysis 5.4); however, this trial did not have the ran-domisation or allocation concealment protocol clearly described.There was no significant difference in severe PPH greater than1000 mL (Analysis 5.3), the need for blood transfusion (Analysis5.6), mean length of the third stage (Analysis 5.8), or manual re-moval of the placenta (Analysis 5.8). There were no available datato analyse the following outcomes: maternal haemoglobin con-centration less than 9 g/dL third stage length greater than 30 min-utes, diastolic blood pressure greater than 100 mmHg, vomiting,nausea, or headaches between delivery of the baby and dischargefrom the hospital.



D I S C U S S I O N

This review compares the use of prophylactic oxytocin at any dosegiven during the third stage of labour to placebo and ergot alka-loids. Overall, the data show a benefit of using prophylactic oxy-tocin compared with placebo to reduce postpartum haemorrhage(PPH) greater than 500 mL and to reduce the need for therapeuticuterotonics. Given that this analysis included trials with unclearor high-risk random sequence generation and allocation conceal-ment, a subgroup analysis of only randomised trials with low risk ofmethodologic was performed. After analysing only these low-riskof bias randomised trials, the benefit in preventing PPH greaterthan 500 mL remains statistically significant and of a similar mag-nitude of all trials (all trials risk ratio (RR) 0.53, 95% confidenceinterval (CI) 0.38 to 0.74; low-risk randomised trials only RR0.61, 95% CI 0.48 to 0.77). The benefit of oxytocin to preventPPH greater than 500 mL was seen regardless of the managementof the third stage of labour, the route of delivery, or the dose ofoxytocin given. This data strongly support the use of prophylacticoxytocin over placebo during the third stage of labour to minimisePPH greater than 500 mL.

The majority of the trials included in this analysis were not blindedand therefore increased the risk of bias when using the subjectiveoutcome of measured blood loss. As a result, we modified the pri-mary outcomes to include the need for therapeutic uterotonics,which do not rely on absolute blood loss measurements but maymore objectively reflect severe blood loss. Prophylactic oxytocinversus placebo also decreased the need for therapeutic uteroton-ics, further supporting the clinical benefit of using prophylacticoxytocin during the third stage of labour to prevent PPH. Thisbenefit persisted when only randomised trials with low risk ofmethodologic bias were analysed (all trials RR 0.56, 95% CI 0.36to 0.87; low-risk trials RR 0.58, 95% CI 0.36 to 0.92). Basedon the subgroups analysed, the benefit of prophylactic oxytocinto decrease the need for therapeutic uterotonics is seen only intrials where oxytocin is given as part of the active managementof the third stage of labour and at a dose of 10 IU delivered asan IV bolus. This suggests that the maximum benefit of oxytocinmay be seen when used as one component of active managementof the third stage and that simply administering oxytocin alonemay not be adequate to prevent PPH. Further studies on the spe-cific aspects of active management of the third stage of labour areneeded to help answer the question of what component of activemanagement provides the most benefit. Regarding the delivery ofoxytocin, our subgroup analysis shows a benefit of decreasing theuse of therapeutic uterotonics only when oxytocin is given as anIV bolus. If IV delivery is not possible, IM delivery may be usedas this route of delivery did show a benefit to prevent PPH greaterthan 500 mL and there was a trend to decrease the use of therapeu-tic uterotonics, albeit not statistically significant. When lookingat the analysis of the IM subgroup in more detail, there are twosmall trials that used IM oxytocin and showed no benefit and one

large trial that did show a benefit when giving oxytocin IM. Thelarger trial, Abdel-Aleem 2010, had a more rigorous study designthan the others included in this analysis and did show a benefitof IM oxytocin to prevent the need for therapeutic uterotonics. Ifonly the Abdel-Aleem 2010 was included in the subgroup analysis,IM delivery would also have significantly decreased the need fortherapeutic uterotonics, so it is likely that either IV or IM deliveryof oxytocin provides clinical benefit.

Importantly, using prophylactic oxytocin in the third stage oflabour did not increase the need for manual removal of the pla-centa when compared to placebo. Using prophylactic oxytocin inthe third stage of labour offers a significant benefit of preventingPPH and the need for therapeutic uterotonics without increasingrisks of adverse events.

After inclusion of data from five new studies (Jago 2007; Moodie1976; Orji 2008; Saito 2007; Vaughan Williams1974), a new find-ing of this review is that prophylactic oxytocin is more efficaciousin preventing PPH greater than 500 mL than ergot alkaloids. Thisbenefit is not statistically significant when only the low-risk ran-domised trials are analysed separately (RR 0.82, 95% CI 0.58 to1.15, random-effects, T² = 0.0, I² = 0%). Of the nine trials in-cluded in this analysis, only three had adequate random sequencegeneration and only four had adequate allocation concealment,suggesting significant risk of bias in the analysis of all trials. Themore accurate analysis is that of only trials with low methodologicbias, as a result, there is no high-quality evidence to suggest asignificant benefit from using prophylactic oxytocin versus ergotalkaloids to prevent PPH greater than 500 mL. There is a trendtowards a benefit of prophylactic oxytocin compared to ergot al-kaloids to decrease the need for therapeutic uterotonics, but thiswas not statistically significant. However, even though there is notstrong evidence supporting the use of prophylactic oxytocin overergot alkaloids to prevent PPH greater than 500 mL or the needfor therapeutic uterotonics, there is also no evidence that ergotalkaloids are better to prevent PPH. In addition, prophylactic oxy-tocin is associated with fewer side effects, making the routine useof prophylactic oxytocin the preferred uterotonic to prevent PPHcompared with ergot alkaloids.

At this time, there is little evidence to support any additive benefitwhen using oxytocin plus ergometrine, and there is some limitedevidence from this review that the combination may increase meanblood loss when compared to ergot alkaloids alone. The trialsused for this analysis have high risk of methodologic bias and as aresult, there are very limited data to rigorously analyse these twotreatment groups for a clinical benefit.

A U T H O R S ’ C O N C L U S I O N S



Implications for practice

Before making major changes to practice based on the currentreview, further information from other reviews considering therole of active management (Begley 2011), the timing of delivery ofoxytocin (Soltani 2010), of prostaglandins (Tunçalp 2012), and ofergot alkaloids (McDonald 2004) needs to be taken into account.

Nevertheless, given the benefit of prophylactic oxytocin in terms ofreducing postpartum haemorrhage (PPH) and the need for ther-apeutic uterotonics when compared to using no uterotonic, thereappears to be a strong evidence in favour of using prophylacticoxytocin. Taking into account the data from both primary out-comes, in order to achieve maximal benefit providers may opt toimplement a practice of giving prophylactic oxytocin as part ofthe active management of the third stage of labour at a dose of10 IU given as an intravenous (IV) bolus. If IV delivery is notpossible, intramuscular (IM) delivery may be used as this routeof delivery did show a benefit to prevent PPH greater than 500mL and there was a trend to decrease the use of therapeutic utero-tonics, albeit not statistically significant. In addition, the use ofprophylactic oxytocin does not increase the risk of adverse events,specifically the need for manual removal of the placenta. This hasto be tempered, however, by the knowledge that a number of thetrials included have unclear or high risk of study bias and that thetranslation of this data to all international birth centres is limiteddue to the majority of studies taking place in developed countries.

Similarly, the balance of evidence does not support the prophy-lactic use of ergot alkaloids alone (when compared to either oxy-tocin alone, or to ergometrine-oxytocin). In addition, the use ofprophylactic oxytocin decreases the risk of maternal side effects,specifically nausea and vomiting, when compared to ergot alka-loids, making oxytocin the preferred option for routine manage-ment of the third stage of labour.

There is no benefit seen when using a combination of oxytocinand ergometrine versus ergot alkaloids alone.

Implications for research

Birth centres in low- and middle-income countries shoulder theburden of most of the complications arising from the managementof the third stage of labour, and there needs to be more studies inthese countries to increase the translatability of these data to thesehigh-risk centres. In order to improve outcomes worldwide, espe-cially where routine management of the third stage is expectant,there needs to be better evidence on which components of the ac-tive management of the third stage of labour contribute to preven-tion of PPH. A definition of PPH is urgently needed with use of anobjective measure and not the subjective evaluation by providers of

what constitutes PPH. The optimal dosing of oxytocin and routeof administration need to be determined in addition to dispellingconcerns of potential side effects. Delivery systems for oxytocinneed to be studied, especially in developing countries, such as theuse of BD-Uniject™ Prefillable Injection System (Franklin Lakes,NJ, USA) to deliver prophylactic oxytocin. Another aspect of themanagement of the third stage may affect the amount of blood lostis delayed cord clamping of the neonate. There is not sufficientevidence on the use of immediate/early or delayed cord clampingin order to improve neonatal outcomes. There is a need for a defi-nition of what is delayed cord clamping, on whether it is clinicallyuseful, and if so, at what gestational age. The lack of uniformityin clinical studies of the management of the third stage questionsthe strength of existing evidence, specifically in the lack of stan-dard definitions of various procedures (i.e. active management)and outcomes (i.e. PPH). It also makes it very difficult for trainingof healthcare personnel and for scaling up of these procedures andinterventions worldwide.

Once there is a consensus on the effective components of the activemanagement of the third stage of labour, there is a need to conductclinical studies to determine why active management of the thirdstage is not utilised consistently.

These trials should study outcomes which are of relevance to themajority of postpartum women such as fatigue, the ability to carefor their babies, and those more rare but serious complicationsassociated with severe morbidity, such as renal failure, transfusionof blood products, coagulopathy, intrauterine infections, hysterec-tomy, and the worst outcome, mortality.

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

Edgardo Abalos and Virginia Diaz for their contribution to assess-ing the reports from the updated search; completing the Charac-teristics of included and excluded studies tables for the new trials;and adding the new data to the analyses.

Amanda Ness for her contribution to the previous version of thisreview.

Clinical and consumer referees, and the staff at the editorial office.Thanks to the original review authors Prof Walter Prendiville,Diana Elbourne and Juliet Wood.

The National Institute for Health Research (NIHR) is the largestsingle funder of the Cochrane Pregnancy and Childbirth Group.The views and opinions expressed therein are those of the authorsand do not necessarily reflect those of the NIHR, NHS or theDepartment of Health.



R E F E R E N C E S

References to studies included in this review

Abdel-Aleem 2010 {published data only}

Abdel-Aleem H, Singata M, Abdel-Aleem M, MshweshweN, Williams X, Hofmeyr GJ. Uterine massage to reducepostpartum hemorrhage after vaginal delivery. InternationalJournal of Gynecology & Obstetrics 2010;111(1):32–6.

Bader 2000 {published data only}∗ Bader W, Ast S, Hatzmann W. The significance ofacupuncture in the third stage of labour. Deutsche Zeitschrift

fur Akupunktur 2000;43:264–8.Bader W, Ast S, Reinehr J, Hackmann J, Hatzmann W.Oxytocin versus Akupunktur in der Plazentarperiode - eineprospektiv randomisierte Studie [abstract]. Geburtshilfe und

Frauenheilkunde 2000;60 Suppl 1:S73.

Barbaro 1961 {published data only}

Barbaro CA, Smith GO. Clinical trial of SE505 - a newoxytocic mixture. Australian and New Zealand Journal ofObstetrics and Gynaecology 1961;1:147–50.

Bonham 1963 {published data only}

Bonham DG. Intramuscular oxytocics and cord traction inthird stage of labour. Brtish Medical Journal 1963;2:1620–3.

De Groot 1996 {published data only}

De Groot ANJA, Van Roosmalen J, Van Dongen PWJ,Borm GF. A placebo-controlled trial of oral ergometrineto reduce postpartum hemorrhage. Acta Obstetricia et

Gynecologica Scandinavica 1996;75:464–8.

Francis 1965 {published data only}

Francis HH, Miller JM, Porteous CR. Clinical trial of anoxytocin-ergometrine mixture. Australian & New Zealand

Journal of Obstetrics and Gynaecology 1965;5:47–51.

Fugo 1958 {published data only}

Fugo NW, Dieckmann WJ. A comparison of oxytocic drugsin the management of the placental stage. American Journal

of Obstetrics and Gynecology 1958;76:141–6.

Ilancheran 1990 {published data only}

Ilancheran A, Ratnam SS. Effect of oxytocics onprostaglandin levels in the third stage of labour. Gynecologic

and Obstetric Investigation 1990;29:177–80.

Jago 2007 {published data only}

Jago AA, Ezechi OC, Achinge GI, Okunlola MA. Effect ofoxytocics on the blood pressure of normotensive Nigerianparturients. Journal of Maternal-Fetal & Neonatal Medicine2007;20(9):703–5.

Jerbi 2007 {published data only}

Jerbi M, Hidar S, Elmoueddeb, Chaieb A, Khairi H.Oxytocin in the third stage of labor. International Journal ofGynecology & Obstetrics 2007;96(3):198–9.

McGinty 1956 {published data only}

McGinty LB. A study of the vasopressor effects of oxytocicswhen used intravenously in the third stage of labour.Western Journal of Surgery 1956;64:22–8.

Moodie 1976 {published data only}

Moodie JE, Moir DD. Ergometrine, oxytocin and extraduralanalgesia. British Journal of Anaesthesia 1976;48:571–4.

Nordstrom 1997 {published data only}

Nordstrom L, Fogelstam K, Fridman G, Larsson A,Rydhstroem H. Routine oxytocin in the third stage oflabour: a placebo controlled randomised trial. BritishJournal of Obstetrics and Gynaecology 1997;104:781–6.

Orji 2008 {published data only}

Orji E, Agwu F, Loto O, Olaleye O. A randomizedcomparative study of prophylactic oxytocin versusergometrine in the third stage of labor. International Journal

of Gynecology & Obstetrics 2008;101(2):129–32.

Pierre 1992 {published data only}

Pierre F, Mesnard L, Body G. For a systematic policy of ivoxytocin inducted placenta deliveries in a unit where a fairlyactive management of third stage of labour is yet applied:results of a controlled trial. European Journal of Obstetrics &

Gynecology and Reproductive Biology 1992;43:131–5.

Poeschmann 1991 {published data only}

Poeschmann RP, Doesburg WH, Eskes TKAB. Arandomized comparison of oxytocin, sulprostone andplacebo in the management of the third stage of labour.British Journal of Obstetrics and Gynaecology 1991;98:528–30.

Saito 2007 {published data only}

Saito K, Haruki A, Ishikawa H, Takahashi T, NagaseH, Koyama M, et al.Prospective study of intramuscularergometrine compared with intramuscular oxytocin forprevention of postpartum hemorrhage. Journal of Obstetrics

and Gynaecology Research 2007;33(3):254–8.

Soiva 1964 {published data only}

Soiva K, Koistinen O. Clinical experience with simultaneousintramuscular injection of oxytocin and methylergometrine.Annales Chirurgiae et Gynaecologiae 1964;53:173–86.

Sorbe 1978 {published data only}

Sorbe B. Active pharmacologic management of the thirdstage of labor. A comparison of oxytocin and ergometrine.Obstetrics & Gynecology 1978;52:694–7.

Vaughan Williams1974 {published data only}

Vaughan Williams CA, Johnson A, Ledward R. Acomparison of central venous pressure changes in thethird stage of labour following oxytocic drugs anddiazepam. Journal of Obstetrics and Gynaecology of the British

Commonwealth 1974;81:596–9.

References to studies excluded from this review

Boucher 2004 {published data only}

Boucher M, Nimrod C, Tawagi G. Carbetocin IM injectionvs oxytocin IV infusion for prevention of postpartumhemorrhage in women at risk following vaginal delivery.



American Journal of Obstetrics and Gynecology 2001;185(6

Pt 2):A494.∗ Boucher M, Nimrod CA, Tawagi GF, Meeker TA,Rennicks, White RE, et al.Comparison of carbetocin andoxytocin for the prevention of postpartum hemorrhagefollowing vaginal delivery:a double-blind randomized trial.Journal of Obstetrics & Gynaecology Canada: JOGC 2004;26

(5):481–8.

Dickinson 2009 {published data only}

Dickinson JE, Doherty DA. Optimization of third-stagemanagement after second-trimester medical pregnancytermination. American Journal of Obstetrics & Gynecology

2009;201(3):303.e1–7.

Docherty 1982 {published data only}

Docherty PW, Hooper M. Choice of an oxytocic agent forroutine use at delivery. Journal of Obstetrics and Gynaecology1981;2:60.

Dommisse 1980 {published data only}

Dommisse J. The routine use of oxytocic drugs in the thirdstage of labour [letter]. South African Medical Journal 1980;46:549.

Dumoulin 1981 {published data only}

Dumoulin JG. A reappraisal of the use of ergometrine.Journal of Obstetrics and Gynaecology 1981;1:178–81.

Friedman 1957 {published data only}

Friedman EA. Comparative clinical evaluation ofpostpartum oxytocics. Journal of Obstetrics and Gynecology

1957;73:1306–13.

Gerstenfeld 2001 {published data only}

Gerstenfeld T, Wing D. Rectal misoprostol versusintravenous oxytocin for the prevention of postpartumhemorrhage after vaginal delivery. American Journal of

Obstetrics and Gynecology 2001;185:878–82.

Hacker 1979 {published data only}

Hacker NF, Biggs JSG. Blood pressure changes when uterinestimulants are used after normal delivery. British Journal ofObstetrics Gynaecology 1979;86:633–6.

Hoffman 2006b {published data only}∗ Hoffman M, Castagnola D, Naqvi F. A randomized trialof active versus expectant management of the third stageof labor [abstract]. American Journal of Obstetrics andGynecology 2006;195(6 Suppl 1):S107.Hoffman M, Naqvi F, Sciscione A. A randomized trial ofactive versus expectant management of the third stage oflabor. American Journal of Obstetrics and Gynecology 2004;191(6 Suppl 1):S82..

Howard 1964 {published data only}

Howard WF, McFadden PR, Keettel WC. Oxytocic drugsin fourth stage of labor. JAMA 1964;189:411–3.

Huh 2000 {published data only}

Huh W, Chelmow D, Malone FD. A randomized,double-blinded, placebo controlled trial of oxytocin at thebeginning versus the end of the third stage of labor forprevention of postpartum hemorrhage. American Journal of

Obstetrics and Gynecology 2000;182(1 Pt 2):S130.

Irons 1994 {published data only}

Irons DW, Sriskandabalan P, Bullough CHW. A simplealternative to parenteral oxytocics for the third stage oflabor. International Journal of Gynecology & Obstetrics 1994;46:15–8.

Jackson 2001 {published data only}

Jackson KJ, Allbert J, Schemmer G, Elliot M, Humphrey A,Taylor J. A randomized controlled trial comparing oxytocinadministration before and after placental delivery in theprevention of postpartum hemorrhage. American Journal ofObstetrics and Gynecology 2001;185:873–7.

Khan 1997 {published data only}

Khan GQ, John IS, Chan T, Wani S, Doherty T. Controlledcord traction versus minimal intervention techniques indelivery of the placenta: a randomized controlled trial.American Journal of Obstetrics and Gynecology 1997;177(4):770–4.

Kundodyiwa 2001 {published data only}

Kundodyiwa T, Majoko F, Rusakaniko S. Misoprostolversus oxytocin in the third stage of labor. International

Journal of Gynecology & Obstetrics 2001;75:235–41.

Lokugamage 2001 {published data only}∗ Lokugamage A, Paine M, Bassaw-Balroop K, Sullivan K,El-Refaey H, Rodeck C. Active management of the thirdstage at caesarean section: a randomised controlled trial ofmisoprostol versus syntocinon. Australian and New ZealandJournal of Obstetrics & Gynaecology 2001;41(4):411–4.Lokugamage AU, Paine M, Bassau-Balroop H, El-Refaey K,Sullivan K, Rodek C. Active management of the third stageat caesarean section: misoprostol vs syntocinon. XVI FIGOWorld Congress of Obstetrics & Gynecology. 2000 Sept3–8; Washington DC, USA 2000; Book 2:54.

Muller 1996 {published data only}

Muller R, Beck G. Active management of the third stageof labour. 19th Swiss Congress of the Swiss Societyof Gynecology and Obstetrics; 1996 June; Interlaken,Switzerland. 1996.

Newton 1961 {published data only}

Newton M, Mosey LM, Egli GE, Gifford WB, Hull CT.Blood loss during and immediately after delivery. Obstetrics& Gynecology 1961;17:9–18.

Nieminen 1963 {published data only}

Nieminen U, Jarvinen PA. A comparative study of differentmedical treatments of the third stage of labour. AnnalesChirurgiae et Gynaecologiae Fenniae 1963;53:424–9.

Parsons 2004 {published data only}

Parsons S, Ntumy YM, Walley RL, Wilson JB, Crane JMG,Matthews K, et al.Rectal misoprostol vs intramuscularoxytocin in the routine management of the third stageof labour. 30th British Congress of Obstetrics andGynaecology; 2004 July 7-9; Glasgow, UK 2004;18. 2004.

Porter 1991 {published data only}

Porter KB, O’Brien WF, Collins MK, Givens P, Knuppel R,Bruskivage L. A randomized comparison of umbilical veinand intravenous oxytocin during the puerperium. Obstetrics

& Gynecology 1991;78:254–6.



Ramirez 2001 {published data only}

Ramirez O, Benito V, Jimenez R, Valido C, HernandezC, Garcia J. Third stage of labour: active or expectantmanagement? preliminary results. Journal of PerinatalMedicine 2001;Suppl 1(Pt 2):364.

Rouse 2011 {published data only}

Rouse D, Abramovici A, Szychowski J, Seals S, Andrews W,Hauth J, et al.Oxytocin dose-regimens to prevent uterineatony after vaginal delivery: does treatment efficacy vary byrisk status?. American Journal of Obstetrics and Gynecology

2011;204(1 Suppl):S50–S51.

Sariganont 1999 {published data only}

Sariganont J. Comparative study between syntocinon andmethergin in prevention of postpartum hemorrhage. ThaiJournal of Obstetrics and Gynaecology 1999;11(4):248.

Schaefer 2004 {published data only}

Schaefer A, Klein L, Wolfe P, Heindricks G, Downs L,Guinn D. Double blind rct of early versus traditionaloxytocin management in the third stage to prevent bloodloss. American Journal of Obstetrics and Gynecology 2004;191(6 Suppl 1):S69.

Schemmer 2001 {published data only}

Schemmer G. A randomized controlled trial comparingprophylactic administration of oxytocin before andafter placental delivery in the prevention of postpartumhemorrhage [abstract]. American Journal of Obstetrics andGynecology 2001;184(1):S20.

Soriano 1995 {published data only}

Soriano D, Dulitzki M, Schiff E, Barkai G, Seldman DS. Arandomized prospective trial of oxytocin plus ergometrin vsoxytocin alone for prevention of postpartum hemorrhage.American Journal of Obstetrics and Gynecology 1995;172:361.

Stanton 2012 {published data only}

Stanton CK, Newton S, Mullany LC, Cofie P, AgyemangCT, Adiibokah E, et al.Impact on postpartum hemorrhageof prophylactic administration of oxytocin 10 IU via Unijectby peripheral health care providers at home births: Designof a community-based cluster-randomized trial. BMC

Pregnancy and Childbirth 2012;12:42.

Stearn 1963 {published data only}

Stearn RH. Syntometrine in the management of the thirdstage of labour. Journal of Obstetrics and Gynaecology of the

British Commonwealth 1963;70:593–6.

Symes 1984 {published data only}

Symes JB. A study on the effect of ergometrine on serumprolactin levels following delivery. Journal of Obstetrics and

Gynaecology 1984;5:36–8. [: Record 2022]

Tessier 2000 {published data only}

Tessier JL, Davies GAL, Woodman MC, Lipson A. Maternalhemodynamics after oxytocin bolus versus infusion in thethird stage of labor. American Journal of Obstetrics andGynecology 2000;182(1 Pt 2):S128.

Thornton 1988 {published data only}

Thornton S, Davison JM, Baylis PH. Plasma oxytocinduring third stage of labour: comparison of natural andactive management. BMJ 1988;297:167–9.

Tita 2012 {published data only}

Tita ATN, Szychowski JM, Rouse DJ, Bean CM, ChapmanV, Nothern A, et al.Higher-dose oxytocin and hemorrhageafter vaginal delivery: A randomized controlled trial.Obstetrics and Gynecology 2012;119(2 Pt 1):293–300.

Vasegh 2005 {published data only}

Vasegh FR, Bahiraie A, Mahmoudi M, Salehi L. Comparisonof active and physiologic management of third stage oflabor. HAYAT: The Journal of Tehran Faculty of Nursing &Midwifery 2005;10(23):102.

Wetta 2011 {published data only}

Wetta L, Szychowski J, Seals S, Mancuso M, Hauth J, TitaA. Risk factors for uterine atony at vaginal delivery: acomprehensive evaluation. American Journal of Obstetrics

and Gynecology 2011;204(1 Suppl):S71–2.

Yuen 1995 {published data only}

Yuen PM, Chan NST, Yim SF, Chang AMZ. A randomiseddouble blind comparison of Syntometrine and Syntocinonin the management of the third stage of labour. British

Journal of Obstetrics and Gynaecology 1995;102:377–80.

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Beischer NA, Mackay EV. Obstetrics and the Newborn.Eastbourne: Bailliere Tindall, 1986.

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Burchell RC. Postpartum haemorrhage. In: Quilligan ESeditor(s). Current Therapy in Obstetrics and Gynaecology.Philadelphia: WB Saunders, 1980.

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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. Vol. 2, Oxford:Oxford University Press, 1989:1145–69.

∗ 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]

Abdel-Aleem 2010

Methods Randomised controlled trial.Women were randomly allocated to 1 of 3 groups by selecting the next number in acomputer-generated random number sequence. The allocated group was noted insideopaque sealed envelopes. Not blinded

Participants Pregnant woman who were expected to have a vaginal delivery at Women’s Health CenterAssiut, Egypt and the Department of Obstetrics and Gynecology, East London HospitalComplex, East London South Africa between September 1, 2006 and February 28, 2009.Women were excluded for medical complications as follows; hypertension, diabetes,previous cesarean section, abdominal wall not thin enough to allow adequate palpationof uterus after delivery

Interventions All interventions were given after delivery of the anterior shoulder or after delivery ofthe neonate1) 10 IU IM oxytocin.2) Sustained uterine massage shortly after delivery performed by the research midwives;massage was sustained for 30 minutes an involved manual stimulation of the wholesurface of the uterus3) Combined management with 10 IU IM oxytocin plus uterine massageIn all 3 groups active management was performed: the umbilical cord was clamped soonafter delivery of the neonate and the placenta was delivered by controlled cord tractionwhen the uterus became contracted. A plastic drape or a low profile plastic bedpan wasplaced under the mother’s buttocks after delivery of the neonate to collect the bloodlost within 30 minutes of delivery. For the group that did not initially receive oxytocin,injections of oxytocin were given if blood loss > 500 mL occurred during the 30-minutecollection timeComparison for review is groups 1 and 3 combined vs group 2.

Outcomes Blood loss > 300 mL, > 500 mL or > 1000 mL within 30 minutes of delivery, deliveryof the placenta within 30 minutes of neonate delivery, use of additional uterotonics orother procedures to manage haemorrhage, Hb level after 12-24 hours of < 8 g in 100mL or < 10 g in 100 mL (South Africa only), blood transfusion, MRP or placenta notdelivered in 30 minutes, maternal morbidity and adverse effects (nausea, vomiting, painor discomfort)

Notes

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selectionbias)

Low risk Women were randomly allocated to 1 of3 groups by selecting the next number ina computer-generated random number se-



Abdel-Aleem 2010 (Continued)

quence

Allocation concealment (selection bias) Low risk The allocated group was noted insideopaque sealed envelopes

Blinding (performance bias and detectionbias)All outcomes

Unclear risk No mention of blinding procedures.

Incomplete outcome data (attrition bias)All outcomes

Low risk Minimal loss.

Selective reporting (reporting bias) Unclear risk Unclear.

Other bias Unclear risk Unclear.

Bader 2000

Methods Quasi-randomised controlled trial.Women were randomly allocated. No further information is given aside from confirma-tion that the allocation was randomisedNot blinded.

Participants 180 women in the third stage of labour at the Gynaecological Clinic of the Universityof Witten/Herdecke, part of the Marienhospital WittenPrimary grounds for exclusion included complicated pregnancies requiring oxytocinstimulation during delivery, multiple pregnancies, weight over 100 kg, uterus myomato-sus, previous treatment with oxytocin and conditions tending to increased blood lossSecondary grounds were the need for surgical intervention (forceps or vacuum) in de-livery, unusually high levels of blood loss of unknown origin and placenta delivery timeslonger than 30 min after delivery

Interventions After delivery of the fetus, women were randomly assigned to receive;1) acupuncture: 2 needles (0.3 x 25 mm) applied 1.5 cm on either side of the navel(point Ni16);2) oxytocin: 3 units administered intravenously directly after delivery;3) control: no treatment.After the birth, waterproof bedding was laid down in order to measure blood loss. Thetime between delivery of the baby and delivery of the placenta was measured in minutes.After delivery of the placenta the waterproof bedding was removed and weighed (tomeasure blood loss). The Hb levels of each patient were measured on arrival in thedelivery room and on leaving the hospitalThe midwives involved were advised not to interfere postpartum with the uterus andumbilical cord--expectant managementComparison for review is group 2 vs group 3.

Outcomes Primary outcomes included blood loss and the length of the placental delivery period.The duration of the birth and the delivery period were also recorded



Bader 2000 (Continued)

Notes Only the oxytocin and control group data is used in the analysis

Risk of bias



Unclear risk Method of randomisation not describedother than “allocation was randomised”

Allocation concealment (selection bias) Unclear risk Not described.


High risk Not blinded.


High risk There were a total of 20 exclusions on var-ious secondary exclusion grounds: 1 in thecontrol group, 12 in the acupuncture groupand 7 in the oxytocin group, leaving a totalof 160 patients

Selective reporting (reporting bias) Low risk All outcomes reported.

Barbaro 1961

Methods Quasi-randomised controlled trial.No randomisation methodology described.Timing of randomisation not stated.Not blinded.

Participants Women admitted for delivery in 1 of 2 obstetric units in hospital in Melbourne, Australia.Over 28 weeks. No antepartum or labour complications

Interventions (1) IM SE505 (synthetic preparation-mixture of 5 units of syntocin and 0.5 mg er-gometrine maleate in 1 mL) given immediately after delivery of the baby (n = 300).(2) IV 0.5 mg ergometrine maleate given immediately after delivery of the baby + IM 0.5 mg ergometrine maleate after delivery of placenta (n = 300)No comment regarding other actions performed relating to active management of thethird stageBlood loss was carefully measured; allowances were made for contamination with liquoror urine and for blood contained within swabs and packs

Outcomes PPH (> 600 mL); average blood loss 266 vs 219 mL (SD not given); average durationof 3rd stage 16 vs 13 minutes (SD not given)

Notes



Barbaro 1961 (Continued)

Risk of bias



Unclear risk No randomisation method described.

Allocation concealment (selection bias) Unclear risk No concealment method described.




Low risk Adequate.



Bonham 1963

Methods Randomised controlled trial.Selection of drug was made by random numbers. Timing of randomisation not stated.Not blinded.

Participants All vaginal deliveries April 1961 to October 1962 in hospital in London, except: multiplepregnancies, previous PPH or manual removal, forceps and breech deliveries must bepost-randomisation exclusions but does not state how many were randomised), parity 4or more, induction or augmentation with syntocinon

Interventions (1) IM 0.5 mg ergometrine + 5 units synthetic oxytocin, given at crowning of the head(n = 391).(2) IM 0.5 mg ergometrine, given at crowning of the head (n = 416).[Third group of ergometrine + hyaluronidase not considered for this review.]Women were also selected in random 2-week groups to either controlled cord traction(n = 199 ergometrine + oxytocin vs 217 ergometrine alone) or maternal effort/fundalpressure (192 vs 199)--combination of both active and expectant management.No information about timing of cord clamping/cutting.Blood loss was estimated by adding to the measured quantity a figure for loss on linenand swabs used during the perineal repair

Outcomes Primary PPH (> 568 mL estimated by adding to measured quantity a figure for losson linen and swabs used for perineal repair); mean blood loss (154 vs 178 mL, SD notgiven); mean length of third stage (6.3 vs 6.2 minutes, SD not given); prolonged thirdstage (> 30 minutes); MRP

Notes



Bonham 1963 (Continued)

Risk of bias



Unclear risk Randomisation by numbers; procedure notdescribed in detail.



High risk Inadequate.


Low risk Attrition described; no loss of data.



De Groot 1996

Methods Randomised controlled trial.Hospital pharmacy supplied numbered boxes of tablets and ampoules according to com-puter-generated randomisation list. Informed consent asked in early labour. Assignedbefore delivery of baby’s head. Double-blind for oral ergometrine vs placebo and un-blinded for ergometrine and/or placebo vs oxytocin. Randomisation 1:2:2, oxytocin toergometrine to placebo. Multicentre

Participants 2 university hospitals, a midwifery school and independent midwives in and aroundNijmegen, Netherlands. Women expecting to deliver in one of these settings, and whodid not develop following exclusion criteria: refusal, cardiovascular disease/hypertension,multiple pregnancy, non-cephalic presentation, polyhydramnios, tocolysis 2 hours priorto delivery, anticoagulant therapy, stillbirth, APH, chemical induction or augmentation(oxytocin, prostaglandins), instrumental/operative delivery (some of these must havebeen post-randomisation exclusions), anaemia Hb < 6.8 mmol/L (timing not stated),previous third stage complications.4 of 371 women were assigned to the study erroneously (3 forceps, 1 augmentation)and were excluded post-randomisation. Otherwise eligible women wishing a naturalchildbirth refused to enter the trial (numbers not stated)

Interventions All 3 interventions given immediately after birth of baby:(1) IM 5 IU oxytocin;(2) oral 0.4 mg ergometrine;(3) oral placebo.Other third stage management expectant (although no information given about timingof cord clamping/cutting). When mother feels contractions or there are signs of separa-tion, maternal effort encouraged, adopting position to aid gravity. If necessary, flat hand



De Groot 1996 (Continued)

on abdomen to act as brace to aid pushing. Re-attempt if placenta does not deliver spon-taneously. If haemorrhage, administer extra oxytocics and/or controlled cord tractionBlood loss measured gravimetrically--fresh perineal pad under perineum to absorb bloodor fluid; gauzes and pads collected until 1 hour after delivery of placenta and weighed.100 g increase in weight considered equivalent to 100 mL bloodComparison for review is group 1 vs. group 2 and group 1 vs group 3

Outcomes Mean blood loss (mL); PPH (>= 500 mL); severe PPH (>= 1000 mL); length of thirdstage (11 (range 4-90), 15 (2-90), 14 (3-55) in oxytocin, ergometrine and placebo groupsrespectively. No information about whether mean or median, and SD not given); bloodpressure 15, 30, 45 and 60 minutes after delivery of placenta, in institutional deliveriesonly (oral ergometrine showed no significant elevation); use of further oxytocics; MRP;transfusion

Notes

Risk of bias



Low risk Numbered boxes of tablets and am-poules according to computer-generatedrandomisation list

Allocation concealment (selection bias) Low risk No difference could be detected betweenboxes.




Low risk Attrition minimal and described.

Selective reporting (reporting bias) Low risk All outcomes described.


Francis 1965

Methods Quasi-randomised controlled trial.’Ampoules used in rotation and participants were unselected’.Blinded.

Participants 2 maternity hospitals in Liverpool, UK. in 1961.All women expected to deliver except those in whom an abnormal third stage wasanticipated (previous PPH, instrumental or breech deliveries, twin pregnancies, APH,severe anaemia, IV oxytocin for induction or augmentation)



Francis 1965 (Continued)

Interventions (1) 1 mL IM ergometrine-oxytocin (5 IU oxytocin + 0.5 mg per 1 mL ergometrine) afterdelivery of baby and cord divided, AND 1 mL water after placental delivery (n = 171).(2) 0.5 mg IM ergometrine after delivery of baby and cord divided, AND 1 mL waterafter placental delivery (n = 183).(3) 1 mL IM water after delivery of baby and cord divided, AND 0.5 mg IM ergometrineafter placental delivery (n = 167).The collection of blood commenced with birth of the baby and continued for one hourafter delivery. Swabs were rung out manually. Blood loss was measured in a graduatedjugWhen signs of descent became apparent, the placenta delivered with uterine massageand cord traction--active management.Comparison in review is between groups 1 and 2.

Outcomes Blood loss (average 4.9, 6.4, 7.0 in groups 1, 2 and 3 respectively - no SD given); for thereview, loss of > 20 oz has been taken as PPH; retained placenta (> 20 minutes)

Notes

Risk of bias



High risk Treatments were rotated, no random se-quence generated.



Low risk Vials were blinded to personnel, partici-pants and outcome assessors


Low risk All outcomes reported.

Selective reporting (reporting bias) Low risk No attrition.


Fugo 1958

Methods Randomised controlled trial.Numbered identical drug packages administered in rotation. Number meaningless toobstetrician.Blinded.

Participants Women delivering in a hospital in Chicago, USA.No details given of inclusion/exclusion criteria, but description of study participantsshowed that half had labour over 8 hours, and 98% received some anaesthetic agent



Fugo 1958 (Continued)

Interventions All administered intravenously in 2 mL with anterior shoulder.(1) 2 IU oxytocin (natural oxytocin) n = 168.(2) 2 IU syntocinon (synthetic oxytocin) n = 156.(3) 4 mg ergonovine 149.(4) 80 mg U3772 (alpha, alpha diphenyl gamma dimethylamino N-methyl valeramide-HCl) n = 151.Blood lost when the placenta separated was collected in a basin containing 200 mL of4% sodium oxalate solution as an anticoagulant and was measured in a graduated jugExpectant management of the third stage with MRP at 10 minutes for teaching purposes.Comparison for review is groups 1 and 2 combined vs group 3.

Outcomes Method of placental delivery (high % of manual removals for teaching purposes if haem-orrhage or undelivered within 10 minutes); length of third stage (not significantly dif-ferent between groups but data only given for those delivered spontaneously, i.e. within10 minutes); blood loss with placenta; (1 hour postpartum (?) average blood loss 50.2vs 40.8 mL; no SDs given)

Notes Given the high number of manual placental removals for teaching purposes, the datafrom this trial were not used due to concern for methodologic bias and lack of clinicaltranslatability of this trial as MRP this early in the third stage is not standard of care

Risk of bias



Unclear risk Randomisation method not described.

Allocation concealment (selection bias) Low risk Identical packages were used.


Low risk Blinded.



Selective reporting (reporting bias) Low risk No significant attrition.




Ilancheran 1990

Methods Quasi-randomised controlled trial.’Consecutive participants divided equally into 4 subgroups, distribution being done ona random basis’

Participants Women in spontaneous labour between 38 and 42 weeks’ gestation with normal vertexdeliveries in hospital in Singapore. 17/20 were multigravid

Interventions Control group and 3 groups given IV uterotonic in ’standard’ doses with the delivery ofthe anterior shoulderA. No oxytocic in third stage.B. Oxytocin.C. Ergometrine-oxytocin.D. Ergometrine.Blood loss estimation technique not described.Other methods to manage third stage of labour not described.Comparisons for this review are: B vs A; B vs D; C vs D.

Outcomes Prostaglandin levels 5, 15b and 30 minutes after delivery (significant rise in all 4 groupsbut no differences between the groups); PPH

Notes

Risk of bias



High risk Women randomly assigned into groups; nocomputer sequence.

Allocation concealment (selection bias) Unclear risk Unclear.


Unclear risk Not described.



Selective reporting (reporting bias) Unclear risk Not described.

Jago 2007

Methods Randomised controlled trial.Randomisation was performed using a computer-generated table of random numbers,which were labelled on envelopes containing the drug (ergometrine or oxytocin)

Participants 510 consenting normotensive women with singleton pregnancies and no proteinuria ata Hospital in NigeriaExcluded those with history of hypertensive disorders of pregnancy, hypertension,



Jago 2007 (Continued)

chronic renal disease, endocrine disorders, vascular or cardiac disease, on anticoagulanttherapy, having epidural anaesthesia, with allergy to one of the drugs under study, andthose with intended instrumental/operative delivery

Interventions At delivery of the anterior shoulder:A. oxytocin 10 IU IV (n = 256).B. ergometrine 0.5 mg IM (n = 254).Management of the third stage of labour not otherwise describedTechnique for measurement of blood loss not described.

Outcomes Elevated blood pressure (> 140/90 mmHg).Estimated blood loss (mL).

Notes

Risk of bias



Low risk Computer-generated table of randomnumbers.

Allocation concealment (selection bias) Low risk Labelled envelopes containing the drug.




Low risk No loss to follow-up reported for the out-come included in the review

Selective reporting (reporting bias) Unclear risk No data.

Other bias Unclear risk No data.

Jerbi 2007

Methods Quasi randomised trial.Not stated. Authors say: “...women were randomly allocated to...”

Participants 130 women with singleton pregnancies at term who were expected to deliver vaginallyin a hospital in TunisiaExcluded: placenta previa, APH, non-cephalic presentation, history of PPH, intrauterinedeath, parity > 5, caesarean section, uterine fibroids, anticoagulant therapy

Interventions At the time of delivery of the anterior shoulder:A. oxytocin 5 IU IV (n = 65);B. no oxytocin (n = 65).



Jerbi 2007 (Continued)

Authors say that the comparison arms are active vs expectant management--active isdefined as receiving prophylactic oxytocin. The third stage of labour was managed in thesame way for all women: immediate cord clamping and cutting, controlled cord tractionand gentle fundal pressure

Outcomes Decrease in haematocrit, decrease in Hb concentration, duration of the third stage oflabour (min), MRP, maternal Hb concentration, postpartum anaemiaTotal blood loss was not an outcome.

Notes

Risk of bias



Unclear risk Not stated.

Allocation concealment (selection bias) Unclear risk Not stated. Authors only say: “...womenwere randomly allocated to...”




Low risk No loss to follow-up reported for the out-comes included in the review



McGinty 1956

Methods Quasi-randomised trial.’Cases picked at random’.Unblinded.

Participants All vaginally delivered under pudendal block and demerol/scopolamine, in hospital inUnited States of America

Interventions Drug given at birth of anterior shoulder:A. 1 mL normal saline intravenously (n = 50);B. 0.2 mg methergine intravenously (n = 50);C. 0.2 mg ergonovine intravenously (n = 50);D. oxytocin 5 IU each intravenously and intramuscularly (n = 50).Comparisons for this review:D vs A; D vs B and C.No information about other aspects of third stage management



McGinty 1956 (Continued)

Outcomes Diastolic and systolic blood pressure 5, 15 and 60 minutes after administration - althoughdata not provided for control group; estimated severe blood loss over 1000 mL mentionedfor 1 women in methergine series and 1 in control group (not included in data tables asunlikely to have been systematically recorded)

Notes

Risk of bias



Unclear risk “cases picked at random”. Randomisationtechnique not described

Allocation concealment (selection bias) Unclear risk Allocation concealment not described.


High risk Unblinded.


Unclear risk Unclear.


Moodie 1976

Methods Quasi-randomised trial.Not stated, authors say “...the allocation being at random...”.

Participants 148 women with instrumental deliveries (143 forceps, 5 vacuum) under epidural anaes-thesia in a Hospital in New ZelandExcluded multiple births and breech presentation.

Interventions At delivery of the anterior shoulder:A. oxytocin 5 IU IV (n = 70);B. ergometrine 0.5 mg IV (n = 78).No mention of other aspects of the management of the third stage of labour

Outcomes Blood loss (mL).Emetic sequelae (retching or vomiting and nausea).

Notes Blood loss was measured only in 54% of women (80/148), so this outcome was notincluded in this review

Risk of bias



Moodie 1976 (Continued)



Unclear risk Not stated.

Allocation concealment (selection bias) Unclear risk Not stated. Authors only say: “...the alloca-tion being at random...”




Low risk No (for nausea and vomiting). 46% ofwomen excluded from outcome “bloodloss”, thus this outcome was not includedin the review



Nordstrom 1997

Methods Double-blind randomised trial.2 sets of ampoules prepared and numbered according to computer-generated schedule.Contents unknown to women or caregivers

Participants Hospital in Sweden.Singleton cephalic vaginal deliveries.

Interventions 1 mL IV after delivery of baby of either;1) 10 IU oxytocin.2) Saline.Passive (expectant) management of the placenta.Blood loss was calculated by measuring collected blood and adding what was estimatedto have been absorbed by surgical cloths and tissues

Outcomes Blood loss; additional oxytocin (data tables give methylergometrine; clarification aboutother oxytocics sought from authors), Hb, blood transfusion; manual removal

Notes Additional oxytocin (data tables give methylergometrine; clarification about other oxy-tocics sought from authors)

Risk of bias




Nordstrom 1997 (Continued)


Low risk 2 sets of ampoules prepared and numberedaccording to computer-generated schedule

Allocation concealment (selection bias) Low risk No difference in appearance of ampoules.


Low risk Contents unknown to women or care-givers.


Low risk No significant attrition.


Orji 2008

Methods Randomised controlled trial.Eligible participants who gave informed consent were randomly allocated to either oxy-tocin or ergometrine group. Allocation was done by opening a sealed envelope from apack that had been arranged serially. Not blinded

Participants 600 consenting women in labour with no illnesses or added risk in the active phase at 2tertiary hospitals in NigeriaExcluded those with hypertensive disorders of pregnancy, packed cell volume < 30%,history of PPH, haemoglobinopathy, heart disease or caesarean section

Interventions At delivery of the anterior shoulder:A. oxytocin 10 IU IV (n = 297);B. ergometrine 0.25 mg IV (n = 303).In both groups the third stage of labour was managed activelyBlood loss was measured using a pre-weighed guaze that was weighed again after delivery

Outcomes Primary outcomes: PPH (> 500 mL), severe PPH (> 1000 mL).Secondary outcomes: retained placenta, need for blood transfusion, MRP, estimatedblood loss (mL, nausea, vomiting, headaches, elevated blood pressure, need for additionaloxytocics

Notes

Risk of bias



Low risk Randomly assigned to previously deter-mined sequence.

Allocation concealment (selection bias) Low risk “...sealed envelopes arranged serially...”.



Orji 2008 (Continued)




Low risk No (for the outcomes reported).



Pierre 1992

Methods Quasi-randomised trial.Leaflets marked from 1-1000 alternate allocation ’this made possible a control of selectionbias at entry by the authors as the order in the trial had the same chronology as the dateand time of entry in the labour ward’

Participants Women expecting to deliver vaginally in hospital in France. Only exclusions - breech,twins, APH, refusal

Interventions Active management of third stage with (n = 488) and without 5 IU IV oxytocin (n =488) with the anterior shoulderBlood loss was estimated by placing a large plastic sheet under the patient’s bottom fromdelivery of the infant until delivery of the placentaThird stage managed actively.

Outcomes Blood loss; length of third stage, MRP, maternal side effects

Notes

Risk of bias



High risk Envelopes labelled in sequence. selectionat entry into the hospital. no random se-quence

Allocation concealment (selection bias) Low risk Envelopes sealed and randomly labelled.







Poeschmann 1991

Methods Randomised trial.Hospital pharmacy supplied numbered boxes. Allocation of boxes was by order of entryto the labour ward. A nurse not working in the labour room prepared the injection

Participants April 1986 -88, 2 hospitals in Netherlands.Uncomplicated singleton term pregnancies in spontaneous labour with spontaneousvaginal deliveries and Hobel score of less than 10

Interventions After birth of baby:A. IM 5 IU oxytocin;B. 500 micrograms sulprostone;C. saline.Comparison in this review is A vs C.Cord was clamped within 1 min of birth; otherwise expectant management of the thirdstage was performedBlood loss was calculated by measuring the amount of blood and clots collected inthe bedpan and by weighing the bloodstained swabs and linen obtained during 1 hrpostpartum

Outcomes Blood loss; need for additional oxytocics; length of third stage

Notes 77 women were entered into the trial; 3 were excluded because of induction of labour(2) and vacuum extractin (1)

Risk of bias



Low risk A random treatment allocation list was pre-viously prepared.

Allocation concealment (selection bias) Low risk Adequate.


Low risk Nurse not working in labour room pre-pared the injection. injection type blindedto participant and personnel



Other bias High risk Trial stopped at 2 years due to organisa-tional issues.



Saito 2007

Methods Quasi random: “...women were allocated to a group in a temporal manner (...) selectedweekly or monthly, as determined by each hospital, in alternate shifts”

Participants 343 consenting women with low risk of PPH at 4 hospitals in JapanExcluded: contraindication for ergometrine, multiple pregnancies, non-cephalic presen-tation, uterine fibroids or deformity, placenta previa, history of PPH, parity > 4, previouscaesarean section, severe anaemia, preeclampsia, epidural anaesthesia, use of oxytocics,anticoagulation therapy, estimated baby weight < 2000 g or > 4000 g

Interventions Shortly after delivery of the baby:A. oxytocin 5 IU IM (n = 156);B. methylergometrine 0.2 mg IM (n = 187).Active management of the third stage of labour in both groups. immediate cord clampingand cutting, controlled cord tractionBlood loss was calculated objectively by measuring the amount of collected blood and bythe weighting of surgical sponges, clothes and drapes by experienced attending midwiveswho were not involved in the administration of prophylactic oxytocics

Outcomes Blood loss (mL), maternal blood pressure, nausea, vomiting, headache, chest pain, dys-pnoea, duration of the third stage (min), additional oxytocics, blood transfusion, MRP

Notes

Risk of bias



High risk Quasi random: “...women were allocated toa group in a temporal manner (...) selectedweekly or monthly, as determined by eachhospital, in alternate shifts.”

Allocation concealment (selection bias) High risk Inadequate. “...women were allocated to agroup in a temporal manner (...) selectedweekly or monthly, as determined by eachhospital, in alternate shifts.”




Low risk No loss to follow-up reported for the out-comes included in the review





Soiva 1964

Methods Quasi-randomised trial.Every third normal parturient.

Participants Hospital, Finland.Spontaneous, singleton, cephalic.

Interventions Immediately after birth of baby.No efforts to expel placenta during first contraction of third stage.IV methergine 0.12-0.2 mgIM ergometrine-oxytocin (IU oxytocin + 0.5 ergometrine).Not clear whether rest of third stage managed actively or expectantly

Outcomes Blood loss; duration of third stage, retained placenta, complications, MRP

Notes

Risk of bias



High risk “every third participant”. No random se-quence generation used

Allocation concealment (selection bias) Unclear risk No allocation concealment described.




Unclear risk Unclear.


Sorbe 1978

Methods Quasi-randomised trial.Alternate - odd and even numbers of mothers’ hospital records.Not blinded.

Participants Hospital in Sweden.

Interventions IV after delivery of anterior shoulder.0.2 mg ergometrine.10 IU oxytocin.Expectant management of the third stage was routine.Blood was collected in a specially designed bedpan which was placed under the buttocksof the women immediately after the delivery of the child. The measurement of the bloodloss during the 2 hour period was then performed with a graduated glass



Sorbe 1978 (Continued)

Outcomes Blood loss; MRP, placental separation time.

Notes

Risk of bias



High risk Randomisation by odd/even hospitalrecord numbers.

Allocation concealment (selection bias) Unclear risk No allocation concealment described.





Vaughan Williams1974

Methods Quasi-randomised trial.“Patients were randomly assigned to one of six treatment groups.” No information aboutblinding or allocation concealment described

Participants 51 women in labour at the Royal Sussex County Hospital, Brighton, who required anIV infusion. Inclusion criteria was no known antenatal complications and expectationto have a spontaneous vaginal delivery. Patients with complications during labour wereexcluded. Informed consent was obtained

Interventions Women were randomly assigned to 1 of 6 treatment groups:1) no treatment, control;2) 0.5 mg ergometrine IV with delivery of the anterior shoulder;3) 0.5 mg ergometrine IV with delivery of the baby;4) 10 IU oxytocin IV with delivery of the anterior shoulder;5) ergometrine 0.5 mg plus 5 IU oxytocin IM with delivery of the anterior shoulder;6) 10 mg diazepam IM in the late first stage of labour followed by ergometrine 0.5 mgplus 5 IU oxytocin IM with delivery of the anterior shoulderPlacenta was delivered actively by controlled cord traction.Blood loss was measured by collection in a kidney dish placed below the perineum afterdelivery of the infantComparisons for this review are group 1 vs. 4, groups 2 and 3 vs. group 4, and groups5 and 6 vs group 2 and 3

Outcomes Primary outcomes were mean CVP and blood loss.



Vaughan Williams1974 (Continued)

Notes

Risk of bias



Unclear risk Randomisation not described.

Allocation concealment (selection bias) Unclear risk Allocation concealment not described.


High risk No blinding.




APH: antepartum haemorrhageCVP: central venous pressureHb: haemoglobinhr: hourIM: intramuscularIU: international unitsIV: intravenousmin: minuteMRP: manual removal of placentaPPH: postpartum haemorrhageSD: standard deviationvs: versus

Characteristics of excluded studies [ordered by study ID]

Study Reason for exclusion

Boucher 2004 Comparison of intramuscular carbetocin to a 2-hour IV oxytocin infusion administered after delivery of theplacenta

Dickinson 2009 Comparison of oxytocin, misoprostol and no additional medication for the third-stage management after secondtrimester medical termination

Docherty 1982 Oxytocin versus ergometrine-oxytocin (subject of separate review)



(Continued)

Dommisse 1980 No randomisation of treatment groups.

Dumoulin 1981 Oxytocin (different doses) versus ergometrine-oxytocin (subject of separate review)

Friedman 1957 Likely to be considerable bias after entry to study as 27% of the 1221 were ’deleted from the study’ as inadequateobservations were obtained. No other reasons given, and no indication of whether these women were missingin similar proportions from the 5 intervention groups

Gerstenfeld 2001 Comparison of oxytocin with misoprostol (subject of separate review)

Hacker 1979 No randomisation of treatment groups.

Hoffman 2006b Comparison of oxytocin within the context of active vs expectant management (subject of a separate review)

Howard 1964 Oxytocin, methergine or placebo given after delivery of the placenta

Huh 2000 Excluded as only different timing of administration.

Irons 1994 Comparison of nipple stimulation to ergometrine-oxytocin which is not a subject of this review

Jackson 2001 Comparison of oxytocin administered before and after placental delivery so the only difference is timing ofadministration

Khan 1997 Comparison of prophylactic oxytocin within context of active management vs oxytocin after placental deliverywithin context of expectant management (subject of separate review by Prendiville et al: Active versus expectantmanagement of third stage of labour - see Prendiville 2000).

Kundodyiwa 2001 Comparison of oxytocin with misoprostol (subject of separate review)

Lokugamage 2001 Comparison of oxytocin to misoprostol (subject of separate review) and at caesarean section

Muller 1996 5 IU IV oxytocin with crowning of head and Brandt-Andrews vs expectant. Abstract only, in French andGerman. No clinical data available from authors

Newton 1961 Oxytocin or placebo given after delivery of the placenta.

Nieminen 1963 No randomisation of treatment groups.

Parsons 2004 Comparison of oxytocin with misoprostol (subject of separate review)

Porter 1991 Only difference is different route of administration.

Ramirez 2001 Inadequate information available about randomisation and available only as abstract

Rouse 2011 Comparison between different doses of oxytocin without placebo or alternate uterotonic

Sariganont 1999 No randomisation of treatment groups.



(Continued)

Schaefer 2004 Excluded as only difference is timing of administration.

Schemmer 2001 Comparison of oxytocin administered before and after placental delivery so the only difference is timing ofadministration

Soriano 1995 Compares oxytocin with oxytocin plus ergometrine (subject of separate review)

Stanton 2012 Manuscript published is of study protocol only, data planned to be analysed in 2013

Stearn 1963 Allocation was to 2 different consultants, 1 of whom gave all patients ergometrine-oxytocin, and the other togive ’normal’ cases ergometrine with hyalase and abnormal given IV ergometrine

Symes 1984 Compares oxytocin with oxytocin plus ergometrine (subject of separate review)

Tessier 2000 Excluded as only different routes of administration.

Thornton 1988 Strong likelihood of post-entry bias as alternate allocation used for 65, but 40 were withdrawn 40 as did notmeet inclusion criteria, leaving 10 and 15 in trial comparing oxytocin vs no oxytocin within active management.Primary outcome plasma oxytocin concentration

Tita 2012 Comparison between different doses of oxytocin without placebo or alternate uterotonic

Vasegh 2005 Comparison of active vs expectant management of the third stage of labour (subject of a separate review). Studydesign information not available

Wetta 2011 Comparison between different doses of oxytocin without placebo or alternate uterotonic

Yuen 1995 Oxytocin vs ergometrine-oxytocin (subject of separate review)

IU: international unitIV: intravenousvs: versus



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

Comparison 1. Oxytocin versus no uterotonics

Outcome or subgroup titleNo. of

studies

No. of

participants Statistical method Effect size

1 PPH (clinically estimated bloodloss > or = 500 mL)

6 4203 Risk Ratio (M-H, Random, 95% CI) 0.53 [0.38, 0.74]

2 Therapeutic uterotonics 4 3174 Risk Ratio (M-H, Random, 95% CI) 0.56 [0.36, 0.87]

3 Severe PPH (clinically estimatedblood loss > or = 1000 mL)


4 Mean blood loss (mL) 5 1402 Mean Difference (IV, Random, 95% CI) -99.46 [-181.97, -16.95]

5 Maternal haemoglobinconcentration (Hb) < 9 g/dL24 to 48 hours postpartum


6 Blood transfusion 3 3120 Risk Ratio (M-H, Random, 95% CI) 0.89 [0.44, 1.78]

7 Third stage greater than 30minutes

1 1947 Risk Ratio (M-H, Fixed, 95% CI) 2.55 [0.88, 7.44]

8 Mean length of third stage(minutes)

3 294 Mean Difference (IV, Random, 95% CI) -3.61 [-9.06, 1.83]

9 Manual removal of the placenta 6 4320 Risk Ratio (M-H, Random, 95% CI) 1.26 [0.88, 1.81]

10 Diastolic blood pressure >100mm Hg between delivery of thebaby and discharge from thelabour ward


11 Vomiting between delivery ofthe baby and discharge fromthe labour ward


12 Nausea between delivery of thebaby and discharge from thelabour ward


13 Headace between delivery ofthe baby and discharge fromthe labour ward


Comparison 2. Oxytocin versus no uterotonics--subgroup analyses


studies

No. of


1 PPH (clinically estimated bloodloss > or = 500 mL); randomisedv. quasi-randomised trials


1.1 Randomised trials only(low risk of bias)




1.2 Quasi-randomised trials(high risk of bias)


2 PPH (clinically estimated bloodloss > or = 500 mL); active v.expectant management


2.1 Active management 2 2920 Risk Ratio (M-H, Random, 95% CI) 0.39 [0.22, 0.72]2.2 Expectant management 3 1273 Risk Ratio (M-H, Random, 95% CI) 0.64 [0.49, 0.84]

3 PPH (clinically estimated bloodloss > or = 500 mL); IM v. IVoxytocin


3.1 IV oxytocin 3 1980 Risk Ratio (M-H, Random, 95% CI) 0.41 [0.21, 0.79]3.2 IM oxytocin 3 2223 Risk Ratio (M-H, Random, 95% CI) 0.65 [0.47, 0.89]

4 PPH (clinically estimated bloodloss > 500 mL); oxytocin dose< 10 IU v. 10 IU

5 4193 Odds Ratio (M-H, Random, 95% CI) 0.44 [0.30, 0.64]

4.1 Oxytocin dose < 10 IU 3 1243 Odds Ratio (M-H, Random, 95% CI) 0.42 [0.17, 1.01]4.2 Oxytocin dose 10 IU 2 2950 Odds Ratio (M-H, Random, 95% CI) 0.47 [0.38, 0.59]

5 Therapeutic uterotonics;randomised v.quasi-randomised trials


5.1 Randomised trials (lowrisk of bias)


5.2 Quasi-randomised trials(high-risk of bias)


6 Therapeutic uterotonics; activev. expectant management



7 Therapeutic uterotonics; IM v.IV oxytocin


7.1 IV oxytocin 1 1000 Risk Ratio (M-H, Random, 95% CI) 0.57 [0.39, 0.82]7.2 IM oxytocin 3 2174 Risk Ratio (M-H, Random, 95% CI) 0.56 [0.24, 1.27]

8 Therapeutic uterotonics;oxytocin dose < 10 IU v. 10 IU


8.1 Oxytocin dose < 10 IU 2 273 Risk Ratio (M-H, Random, 95% CI) 0.77 [0.23, 2.56]8.2 Oxytocin dose 10 IU 2 2901 Risk Ratio (M-H, Random, 95% CI) 0.48 [0.33, 0.68]

Comparison 3. Oxytocin versus ergot alkaloids


studies

No. of




2 Therapeutic uterotonics 3 1167 Risk Ratio (M-H, Random, 95% CI) 0.70 [0.38, 1.29]



4 Mean blood loss (mL) 6 2748 Mean Difference (IV, Random, 95% CI) -12.49 [-37.66, 12.68]





6 Blood transfusion 2 567 Risk Ratio (M-H, Random, 95% CI) 3.74 [0.34, 40.64]7 Third stage > 30 minutes 0 0 Risk Ratio (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]

8 Mean length of third stage(minutes)

3 1992 Mean Difference (IV, Random, 95% CI) -0.43 [-0.89, 0.04]


10 Diastolic blood pressure > 100mm Hg between delivery of thebaby and discharge from thelabour ward






13 Headaches between delivery ofthe baby and discharge fromthe labour ward


Comparison 4. Oxytocin versus ergot alkaloids--subgroup analyses


studies

No. of













3.1 IM oxytocin 2 567 Risk Ratio (M-H, Random, 95% CI) 0.71 [0.44, 1.13]3.2 IV oxytocin 3 1659 Risk Ratio (M-H, Random, 95% CI) 0.78 [0.57, 1.07]

4 PPH (clinically estimated bloodloss > 500 mL); oxytocin dose< 10 IU v. 10 IU





5 Therapeutic uterotonics;randomised v.quasi-randomised trials






6 Therapeutic uterotonics; activev. expectant management



7 Therapeutic uterotonics; IM v.IV oxytocin



8 Therapeutic uterotonics;oxytocin dose < 10 IU v. 10 IU



Comparison 5. Oxytocin + ergometrine versus ergot alkaloids


studies

No. of




2 Therapeutic uterotonics 0 0 Risk Ratio (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]



4 Mean blood loss (mL) 1 34 Mean Difference (IV, Fixed, 95% CI) 61.0 [6.00, 116.00]



6 Blood transfusion 1 1120 Risk Ratio (M-H, Fixed, 95% CI) 0.71 [0.23, 2.24]7 Third stage > 30 minutes 0 0 Risk Ratio (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]

8 Mean length of the third stage(minutes)

1 372 Mean Difference (IV, Fixed, 95% CI) 0.0 [0.0, 0.0]


10 Diastolic blood pressure >100mm Hg between delivery of thebaby and discharge from thelabour ward








13 Headaches between delivery ofthe baby and discharge fromthe labour ward


Comparison 6. Oxytocin + ergometrine versus ergot alkaloids--subgroup analyses


studies

No. of
















Analysis 1.1. Comparison 1 Oxytocin versus no uterotonics, Outcome 1 PPH (clinically estimated blood

loss > or = 500 mL).

Review: Prophylactic oxytocin for the third stage of labour to prevent postpartum haemorrhage

Comparison: 1 Oxytocin versus no uterotonics

Outcome: 1 PPH (clinically estimated blood loss > or = 500 mL)

Study or subgroup Oxytocin Control Risk Ratio Weight Risk Ratio

n/N n/N

M-H,Random,95%

CI

M-H,Random,95%

CI

Abdel-Aleem 2010 68/1291 65/659 22.0 % 0.53 [ 0.39, 0.74 ]

De Groot 1996 25/78 55/143 20.4 % 0.83 [ 0.57, 1.22 ]

Ilancheran 1990 0/5 0/5 Not estimable

Nordstrom 1997 104/513 175/487 25.1 % 0.56 [ 0.46, 0.70 ]

Pierre 1992 37/488 126/482 21.5 % 0.29 [ 0.21, 0.41 ]

Poeschmann 1991 7/28 10/24 10.9 % 0.60 [ 0.27, 1.33 ]

Total (95% CI) 2403 1800 100.0 % 0.53 [ 0.38, 0.74 ]

Total events: 241 (Oxytocin), 431 (Control)

Heterogeneity: Tau2 = 0.11; Chi2 = 17.91, df = 4 (P = 0.001); I2 =78%

Test for overall effect: Z = 3.74 (P = 0.00019)

Test for subgroup differences: Not applicable

0.1 0.2 0.5 1 2 5 10

Favours Oxytocin Favours Control



Analysis 1.2. Comparison 1 Oxytocin versus no uterotonics, Outcome 2 Therapeutic uterotonics.



Outcome: 2 Therapeutic uterotonics


n/N n/N

M-H,Random,95%

CI

M-H,Random,95%

CI

Abdel-Aleem 2010 41/1260 53/641 35.2 % 0.39 [ 0.26, 0.58 ]

De Groot 1996 14/78 26/143 26.2 % 0.99 [ 0.55, 1.78 ]

Nordstrom 1997 40/513 67/487 36.5 % 0.57 [ 0.39, 0.82 ]

Poeschmann 1991 0/28 2/24 2.1 % 0.17 [ 0.01, 3.42 ]

Total (95% CI) 1879 1295 100.0 % 0.56 [ 0.36, 0.87 ]





0.001 0.01 0.1 1 10 100 1000




Analysis 1.3. Comparison 1 Oxytocin versus no uterotonics, Outcome 3 Severe PPH (clinically estimated

blood loss > or = 1000 mL).



Outcome: 3 Severe PPH (clinically estimated blood loss > or = 1000 mL)


n/N n/N

M-H,Random,95%

CI

M-H,Random,95%

CI

Abdel-Aleem 2010 4/1260 4/659 5.9 % 0.52 [ 0.13, 2.08 ]

De Groot 1996 7/78 16/143 15.9 % 0.80 [ 0.34, 1.87 ]

Nordstrom 1997 32/513 43/487 58.4 % 0.71 [ 0.45, 1.10 ]

Pierre 1992 7/488 21/482 15.8 % 0.33 [ 0.14, 0.77 ]

Poeschmann 1991 2/28 3/24 3.9 % 0.57 [ 0.10, 3.14 ]

Total (95% CI) 2367 1795 100.0 % 0.62 [ 0.44, 0.87 ]


Heterogeneity: Tau2 = 0.0; Chi2 = 2.93, df = 4 (P = 0.57); I2 =0.0%



0.1 0.2 0.5 1 2 5 10




Analysis 1.4. Comparison 1 Oxytocin versus no uterotonics, Outcome 4 Mean blood loss (mL).



Outcome: 4 Mean blood loss (mL)

Study or subgroup Oxytocin ControlMean

Difference WeightMean

Difference

N Mean(SD) N Mean(SD) IV,Random,95% CI IV,Random,95% CI

Bader 2000 53 229.79 (143.66) 59 226.89 (148.7) 23.8 % 2.90 [ -51.28, 57.08 ]

De Groot 1996 78 499 (454) 143 520 (419) 16.8 % -21.00 [ -142.93, 100.93 ]

Nordstrom 1997 513 409 (3.45) 487 527 (412) 25.2 % -118.00 [ -154.59, -81.41 ]

Poeschmann 1991 28 374 (279) 24 548 (376) 11.5 % -174.00 [ -356.51, 8.51 ]

Vaughan Williams1974 7 99 (72) 10 305 (60) 22.7 % -206.00 [ -271.02, -140.98 ]

Total (95% CI) 679 723 100.0 % -99.46 [ -181.97, -16.95 ]




-1000 -500 0 500 1000




Analysis 1.5. Comparison 1 Oxytocin versus no uterotonics, Outcome 5 Maternal haemoglobin

concentration (Hb) < 9 g/dL 24 to 48 hours postpartum.



Outcome: 5 Maternal haemoglobin concentration (Hb) < 9 g/dL 24 to 48 hours postpartum


n/N n/N

M-H,Random,95%

CI

M-H,Random,95%

CI

Abdel-Aleem 2010 86/382 52/190 71.0 % 0.82 [ 0.61, 1.11 ]

Jerbi 2007 8/65 10/65 8.4 % 0.80 [ 0.34, 1.90 ]

Nordstrom 1997 20/485 30/458 20.6 % 0.63 [ 0.36, 1.09 ]

Total (95% CI) 932 713 100.0 % 0.78 [ 0.60, 1.00 ]





0.1 0.2 0.5 1 2 5 10




Analysis 1.6. Comparison 1 Oxytocin versus no uterotonics, Outcome 6 Blood transfusion.



Outcome: 6 Blood transfusion


n/N n/N

M-H,Random,95%

CI

M-H,Random,95%

CI

Abdel-Aleem 2010 8/1257 7/642 47.4 % 0.58 [ 0.21, 1.60 ]

De Groot 1996 2/78 3/143 15.5 % 1.22 [ 0.21, 7.16 ]

Nordstrom 1997 7/513 5/487 37.1 % 1.33 [ 0.42, 4.16 ]

Total (95% CI) 1848 1272 100.0 % 0.89 [ 0.44, 1.78 ]





0.1 0.2 0.5 1 2 5 10


Analysis 1.7. Comparison 1 Oxytocin versus no uterotonics, Outcome 7 Third stage greater than 30

minutes.



Outcome: 7 Third stage greater than 30 minutes


n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI

Abdel-Aleem 2010 20/1289 4/658 100.0 % 2.55 [ 0.88, 7.44 ]

Total (95% CI) 1289 658 100.0 % 2.55 [ 0.88, 7.44 ]


Heterogeneity: not applicable



0.01 0.1 1 10 100




Analysis 1.8. Comparison 1 Oxytocin versus no uterotonics, Outcome 8 Mean length of third stage

(minutes).



Outcome: 8 Mean length of third stage (minutes)

Study or subgroup Oxytocin ControlMean


Difference


Bader 2000 53 11.85 (6.46) 59 12.46 (6.69) 33.8 % -0.61 [ -3.05, 1.83 ]

Jerbi 2007 65 2.5 (4.3) 65 10.6 (5) 35.2 % -8.10 [ -9.70, -6.50 ]

Poeschmann 1991 28 9.9 (7.4) 24 11.7 (6.4) 31.0 % -1.80 [ -5.55, 1.95 ]

Total (95% CI) 146 148 100.0 % -3.61 [ -9.06, 1.83 ]

Heterogeneity: Tau2 = 21.22; Chi2 = 29.27, df = 2 (P<0.00001); I2 =93%



-10 -5 0 5 10




Analysis 1.9. Comparison 1 Oxytocin versus no uterotonics, Outcome 9 Manual removal of the placenta.



Outcome: 9 Manual removal of the placenta


n/N n/N

M-H,Random,95%

CI

M-H,Random,95%

CI

Abdel-Aleem 2010 24/1289 6/658 16.2 % 2.04 [ 0.84, 4.97 ]

De Groot 1996 1/78 0/143 1.3 % 5.47 [ 0.23, 132.66 ]

Jerbi 2007 1/65 1/65 1.7 % 1.00 [ 0.06, 15.65 ]

Nordstrom 1997 18/513 11/487 23.5 % 1.55 [ 0.74, 3.26 ]

Pierre 1992 32/488 32/482 57.3 % 0.99 [ 0.62, 1.59 ]

Poeschmann 1991 0/28 0/24 Not estimable

Total (95% CI) 2461 1859 100.0 % 1.26 [ 0.88, 1.81 ]





0.001 0.01 0.1 1 10 100 1000




Analysis 1.12. Comparison 1 Oxytocin versus no uterotonics, Outcome 12 Nausea between delivery of the

baby and discharge from the labour ward.



Outcome: 12 Nausea between delivery of the baby and discharge from the labour ward



Poeschmann 1991 0/28 1/24 100.0 % 0.29 [ 0.01, 6.74 ]

Total (95% CI) 28 24 100.0 % 0.29 [ 0.01, 6.74 ]





0.01 0.1 1 10 100




Analysis 2.1. Comparison 2 Oxytocin versus no uterotonics--subgroup analyses, Outcome 1 PPH (clinically

estimated blood loss > or = 500 mL); randomised v. quasi-randomised trials.


Comparison: 2 Oxytocin versus no uterotonics–subgroup analyses

Outcome: 1 PPH (clinically estimated blood loss > or = 500 mL); randomised v. quasi-randomised trials


n/N n/N

M-H,Random,95%

CI

M-H,Random,95%

CI

1 Randomised trials only (low risk of bias)

Abdel-Aleem 2010 68/1291 65/659 22.0 % 0.53 [ 0.39, 0.74 ]

De Groot 1996 25/78 55/143 20.4 % 0.83 [ 0.57, 1.22 ]

Nordstrom 1997 104/513 175/487 25.1 % 0.56 [ 0.46, 0.70 ]

Subtotal (95% CI) 1882 1289 67.6 % 0.61 [ 0.48, 0.77 ]




2 Quasi-randomised trials (high risk of bias)


Pierre 1992 37/488 126/482 21.5 % 0.29 [ 0.21, 0.41 ]

Poeschmann 1991 7/28 10/24 10.9 % 0.60 [ 0.27, 1.33 ]

Subtotal (95% CI) 521 511 32.4 % 0.38 [ 0.19, 0.76 ]




Total (95% CI) 2403 1800 100.0 % 0.53 [ 0.38, 0.74 ]




Test for subgroup differences: Chi2 = 1.59, df = 1 (P = 0.21), I2 =37%

0.1 0.2 0.5 1 2 5 10





estimated blood loss > or = 500 mL); active v. expectant management.



Outcome: 2 PPH (clinically estimated blood loss > or = 500 mL); active v. expectant management


n/N n/N

M-H,Random,95%

CI

M-H,Random,95%

CI

1 Active management

Abdel-Aleem 2010 68/1291 65/659 22.0 % 0.53 [ 0.39, 0.74 ]

Pierre 1992 37/488 126/482 21.5 % 0.29 [ 0.21, 0.41 ]

Subtotal (95% CI) 1779 1141 43.6 % 0.39 [ 0.22, 0.72 ]




2 Expectant management

De Groot 1996 25/78 55/143 20.4 % 0.83 [ 0.57, 1.22 ]

Nordstrom 1997 104/513 175/487 25.1 % 0.56 [ 0.46, 0.70 ]

Poeschmann 1991 7/28 10/24 10.9 % 0.60 [ 0.27, 1.33 ]

Subtotal (95% CI) 619 654 56.4 % 0.64 [ 0.49, 0.84 ]




Total (95% CI) 2398 1795 100.0 % 0.53 [ 0.38, 0.74 ]





0.1 0.2 0.5 1 2 5 10





estimated blood loss > or = 500 mL); IM v. IV oxytocin.



Outcome: 3 PPH (clinically estimated blood loss > or = 500 mL); IM v. IV oxytocin


n/N n/N

M-H,Random,95%

CI

M-H,Random,95%

CI

1 IV oxytocin


Nordstrom 1997 104/513 175/487 25.1 % 0.56 [ 0.46, 0.70 ]

Pierre 1992 37/488 126/482 21.5 % 0.29 [ 0.21, 0.41 ]

Subtotal (95% CI) 1006 974 46.7 % 0.41 [ 0.21, 0.79 ]




2 IM oxytocin

Abdel-Aleem 2010 68/1291 65/659 22.0 % 0.53 [ 0.39, 0.74 ]

De Groot 1996 25/78 55/143 20.4 % 0.83 [ 0.57, 1.22 ]

Poeschmann 1991 7/28 10/24 10.9 % 0.60 [ 0.27, 1.33 ]

Subtotal (95% CI) 1397 826 53.3 % 0.65 [ 0.47, 0.89 ]




Total (95% CI) 2403 1800 100.0 % 0.53 [ 0.38, 0.74 ]





0.1 0.2 0.5 1 2 5 10





estimated blood loss > 500 mL); oxytocin dose < 10 IU v. 10 IU.



Outcome: 4 PPH (clinically estimated blood loss > 500 mL); oxytocin dose < 10 IU v. 10 IU

Study or subgroup Oxytocin Control Odds Ratio Weight Odds Ratio

n/N n/N

M-H,Random,95%

CI

M-H,Random,95%

CI

1 Oxytocin dose < 10 IU

De Groot 1996 25/78 55/143 18.0 % 0.75 [ 0.42, 1.35 ]

Pierre 1992 37/488 126/482 23.3 % 0.23 [ 0.16, 0.34 ]

Poeschmann 1991 7/28 10/24 7.8 % 0.47 [ 0.14, 1.52 ]

Subtotal (95% CI) 594 649 49.1 % 0.42 [ 0.17, 1.01 ]




2 Oxytocin dose 10 IU

Abdel-Aleem 2010 68/1291 65/659 24.5 % 0.51 [ 0.36, 0.72 ]

Nordstrom 1997 104/513 175/487 26.4 % 0.45 [ 0.34, 0.60 ]

Subtotal (95% CI) 1804 1146 50.9 % 0.47 [ 0.38, 0.59 ]



Test for overall effect: Z = 6.61 (P < 0.00001)

Total (95% CI) 2398 1795 100.0 % 0.44 [ 0.30, 0.64 ]




Test for subgroup differences: Chi2 = 0.07, df = 1 (P = 0.80), I2 =0.0%

0.01 0.1 1 10 100




Analysis 2.5. Comparison 2 Oxytocin versus no uterotonics--subgroup analyses, Outcome 5 Therapeutic

uterotonics; randomised v. quasi-randomised trials.



Outcome: 5 Therapeutic uterotonics; randomised v. quasi-randomised trials


n/N n/N

M-H,Random,95%

CI

M-H,Random,95%

CI

1 Randomised trials (low risk of bias)

Abdel-Aleem 2010 41/1260 53/641 35.2 % 0.39 [ 0.26, 0.58 ]

De Groot 1996 14/78 26/143 26.2 % 0.99 [ 0.55, 1.78 ]

Nordstrom 1997 40/513 67/487 36.5 % 0.57 [ 0.39, 0.82 ]

Subtotal (95% CI) 1851 1271 97.9 % 0.58 [ 0.36, 0.92 ]




2 Quasi-randomised trials (high-risk of bias)

Poeschmann 1991 0/28 2/24 2.1 % 0.17 [ 0.01, 3.42 ]

Subtotal (95% CI) 28 24 2.1 % 0.17 [ 0.01, 3.42 ]




Total (95% CI) 1879 1295 100.0 % 0.56 [ 0.36, 0.87 ]





0.001 0.01 0.1 1 10 100 1000





uterotonics; active v. expectant management.



Outcome: 6 Therapeutic uterotonics; active v. expectant management


n/N n/N

M-H,Random,95%

CI

M-H,Random,95%

CI

1 Active management

Abdel-Aleem 2010 41/1260 53/641 35.2 % 0.39 [ 0.26, 0.58 ]

Subtotal (95% CI) 1260 641 35.2 % 0.39 [ 0.26, 0.58 ]



Test for overall effect: Z = 4.61 (P < 0.00001)


De Groot 1996 14/78 26/143 26.2 % 0.99 [ 0.55, 1.78 ]

Nordstrom 1997 40/513 67/487 36.5 % 0.57 [ 0.39, 0.82 ]

Poeschmann 1991 0/28 2/24 2.1 % 0.17 [ 0.01, 3.42 ]

Subtotal (95% CI) 619 654 64.8 % 0.68 [ 0.41, 1.12 ]




Total (95% CI) 1879 1295 100.0 % 0.56 [ 0.36, 0.87 ]





0.001 0.01 0.1 1 10 100 1000





uterotonics; IM v. IV oxytocin.



Outcome: 7 Therapeutic uterotonics; IM v. IV oxytocin


n/N n/N

M-H,Random,95%

CI

M-H,Random,95%

CI

1 IV oxytocin

Nordstrom 1997 40/513 67/487 36.5 % 0.57 [ 0.39, 0.82 ]

Subtotal (95% CI) 513 487 36.5 % 0.57 [ 0.39, 0.82 ]




2 IM oxytocin

Abdel-Aleem 2010 41/1260 53/641 35.2 % 0.39 [ 0.26, 0.58 ]

De Groot 1996 14/78 26/143 26.2 % 0.99 [ 0.55, 1.78 ]

Poeschmann 1991 0/28 2/24 2.1 % 0.17 [ 0.01, 3.42 ]

Subtotal (95% CI) 1366 808 63.5 % 0.56 [ 0.24, 1.27 ]




Total (95% CI) 1879 1295 100.0 % 0.56 [ 0.36, 0.87 ]





0.001 0.01 0.1 1 10 100 1000





uterotonics; oxytocin dose < 10 IU v. 10 IU.



Outcome: 8 Therapeutic uterotonics; oxytocin dose < 10 IU v. 10 IU


n/N n/N

M-H,Random,95%

CI

M-H,Random,95%

CI


De Groot 1996 14/78 26/143 26.2 % 0.99 [ 0.55, 1.78 ]

Poeschmann 1991 0/28 2/24 2.1 % 0.17 [ 0.01, 3.42 ]

Subtotal (95% CI) 106 167 28.3 % 0.77 [ 0.23, 2.56 ]





Abdel-Aleem 2010 41/1260 53/641 35.2 % 0.39 [ 0.26, 0.58 ]

Nordstrom 1997 40/513 67/487 36.5 % 0.57 [ 0.39, 0.82 ]

Subtotal (95% CI) 1773 1128 71.7 % 0.48 [ 0.33, 0.68 ]




Total (95% CI) 1879 1295 100.0 % 0.56 [ 0.36, 0.87 ]





0.01 0.1 1 10 100




Analysis 3.1. Comparison 3 Oxytocin versus ergot alkaloids, Outcome 1 PPH (clinically estimated blood

loss > or = 500 mL).


Comparison: 3 Oxytocin versus ergot alkaloids


Study or subgroup Oxytocin Ergot Alkaloids Risk Ratio Weight Risk Ratio

n/N n/N

M-H,Random,95%

CI

M-H,Random,95%

CI

De Groot 1996 25/78 54/146 33.1 % 0.87 [ 0.59, 1.28 ]

Ilancheran 1990 0/5 1/5 0.6 % 0.33 [ 0.02, 6.65 ]

Orji 2008 12/297 18/303 9.7 % 0.68 [ 0.33, 1.39 ]

Saito 2007 17/156 38/187 17.5 % 0.54 [ 0.32, 0.91 ]

Sorbe 1978 48/506 63/543 39.1 % 0.82 [ 0.57, 1.17 ]

Total (95% CI) 1042 1184 100.0 % 0.76 [ 0.61, 0.94 ]

Total events: 102 (Oxytocin), 174 (Ergot Alkaloids)




0.001 0.01 0.1 1 10 100 1000

Favours Oxytocin Favours Ergots



Analysis 3.2. Comparison 3 Oxytocin versus ergot alkaloids, Outcome 2 Therapeutic uterotonics.



Outcome: 2 Therapeutic uterotonics


n/N n/N

M-H,Random,95%

CI

M-H,Random,95%

CI

De Groot 1996 14/78 21/146 34.5 % 1.25 [ 0.67, 2.31 ]

Orji 2008 18/297 30/303 36.8 % 0.61 [ 0.35, 1.07 ]

Saito 2007 8/156 23/187 28.7 % 0.42 [ 0.19, 0.91 ]

Total (95% CI) 531 636 100.0 % 0.70 [ 0.38, 1.29 ]





0.1 0.2 0.5 1 2 5 10




Analysis 3.3. Comparison 3 Oxytocin versus ergot alkaloids, Outcome 3 Severe PPH (clinically estimated

blood loss > or = 1000 mL).





n/N n/N

M-H,Random,95%

CI

M-H,Random,95%

CI

De Groot 1996 7/78 12/146 38.0 % 1.09 [ 0.45, 2.66 ]

Saito 2007 3/156 1/187 5.9 % 3.60 [ 0.38, 34.23 ]

Sorbe 1978 13/506 15/543 56.1 % 0.93 [ 0.45, 1.94 ]

Total (95% CI) 740 876 100.0 % 1.07 [ 0.62, 1.85 ]





0.1 0.2 0.5 1 2 5 10




Analysis 3.4. Comparison 3 Oxytocin versus ergot alkaloids, Outcome 4 Mean blood loss (mL).




Study or subgroup Oxytocin Ergot AlkaloidsMean


Difference


De Groot 1996 78 499 (454) 146 476 (340) 4.1 % 23.00 [ -91.86, 137.86 ]

Jago 2007 256 171.9 (81.6) 254 150.2 (63.6) 25.8 % 21.70 [ 9.01, 34.39 ]

Orji 2008 297 245.7 (95.4) 303 246.6 (77.6) 25.5 % -0.90 [ -14.83, 13.03 ]

Saito 2007 156 288.2 (209.9) 187 354.4 (209.3) 14.8 % -66.20 [ -110.75, -21.65 ]

Sorbe 1978 506 273 (247) 543 306 (271) 19.3 % -33.00 [ -64.35, -1.65 ]

Vaughan Williams1974 7 99 (72) 15 124 (60) 10.5 % -25.00 [ -86.37, 36.37 ]

Total (95% CI) 1300 1448 100.0 % -12.49 [ -37.66, 12.68 ]




-1000 -500 0 500 1000




Analysis 3.6. Comparison 3 Oxytocin versus ergot alkaloids, Outcome 6 Blood transfusion.





n/N n/N

M-H,Random,95%

CI

M-H,Random,95%

CI

De Groot 1996 2/78 1/146 100.0 % 3.74 [ 0.34, 40.64 ]

Saito 2007 0/156 0/187 Not estimable

Total (95% CI) 234 333 100.0 % 3.74 [ 0.34, 40.64 ]





0.001 0.01 0.1 1 10 100 1000


Analysis 3.8. Comparison 3 Oxytocin versus ergot alkaloids, Outcome 8 Mean length of third stage

(minutes).



Outcome: 8 Mean length of third stage (minutes)

Study or subgroup Oxytocin Ergot AlkaloidsMean


Difference


Orji 2008 297 5.88 (1.26) 303 6.46 (2.01) 50.8 % -0.58 [ -0.85, -0.31 ]

Saito 2007 156 5.4 (3) 187 5.3 (2.9) 29.0 % 0.10 [ -0.53, 0.73 ]

Sorbe 1978 506 9.5 (7.1) 543 10.3 (6.9) 20.2 % -0.80 [ -1.65, 0.05 ]

Total (95% CI) 959 1033 100.0 % -0.43 [ -0.89, 0.04 ]




-10 -5 0 5 10




Analysis 3.9. Comparison 3 Oxytocin versus ergot alkaloids, Outcome 9 Manual removal of the placenta.





n/N n/N

M-H,Random,95%

CI

M-H,Random,95%

CI

De Groot 1996 1/78 2/146 7.4 % 0.94 [ 0.09, 10.16 ]

Saito 2007 4/156 2/187 13.4 % 2.40 [ 0.45, 12.92 ]

Sorbe 1978 10/506 32/543 39.4 % 0.34 [ 0.17, 0.68 ]

Orji 2008 12/297 21/303 39.8 % 0.58 [ 0.29, 1.16 ]

Total (95% CI) 1037 1179 100.0 % 0.59 [ 0.29, 1.17 ]





0.001 0.01 0.1 1 10 100 1000




Analysis 3.10. Comparison 3 Oxytocin versus ergot alkaloids, Outcome 10 Diastolic blood pressure > 100

mm Hg between delivery of the baby and discharge from the labour ward.



Outcome: 10 Diastolic blood pressure > 100 mm Hg between delivery of the baby and discharge from the labour ward


n/N n/N

M-H,Random,95%

CI

M-H,Random,95%

CI

Jago 2007 0/256 0/254 Not estimable

McGinty 1956 4/50 15/100 100.0 % 0.53 [ 0.19, 1.52 ]

Total (95% CI) 306 354 100.0 % 0.53 [ 0.19, 1.52 ]





0.1 0.2 0.5 1 2 5 10




Analysis 3.11. Comparison 3 Oxytocin versus ergot alkaloids, Outcome 11 Vomiting between delivery of

the baby and discharge from the labour ward.



Outcome: 11 Vomiting between delivery of the baby and discharge from the labour ward


n/N n/N

M-H,Random,95%

CI

M-H,Random,95%

CI

Moodie 1976 0/70 31/78 17.9 % 0.02 [ 0.00, 0.28 ]

Orji 2008 12/297 132/303 82.1 % 0.09 [ 0.05, 0.16 ]

Saito 2007 0/156 0/187 Not estimable

Total (95% CI) 523 568 100.0 % 0.07 [ 0.02, 0.25 ]





0.01 0.1 1 10 100




Analysis 3.12. Comparison 3 Oxytocin versus ergot alkaloids, Outcome 12 Nausea between delivery of the

baby and discharge from the labour ward.



Outcome: 12 Nausea between delivery of the baby and discharge from the labour ward


n/N n/N

M-H,Random,95%

CI

M-H,Random,95%

CI

Moodie 1976 0/70 4/78 11.5 % 0.12 [ 0.01, 2.26 ]

Orji 2008 15/297 132/303 62.4 % 0.12 [ 0.07, 0.19 ]

Saito 2007 2/156 4/187 26.1 % 0.60 [ 0.11, 3.23 ]

Total (95% CI) 523 568 100.0 % 0.18 [ 0.06, 0.53 ]





0.01 0.1 1 10 100




Analysis 3.13. Comparison 3 Oxytocin versus ergot alkaloids, Outcome 13 Headaches between delivery of

the baby and discharge from the labour ward.



Outcome: 13 Headaches between delivery of the baby and discharge from the labour ward


n/N n/N

M-H,Random,95%

CI

M-H,Random,95%

CI

Orji 2008 0/297 54/303 48.9 % 0.01 [ 0.00, 0.15 ]

Saito 2007 1/156 2/187 51.1 % 0.60 [ 0.05, 6.55 ]

Total (95% CI) 453 490 100.0 % 0.08 [ 0.00, 9.46 ]





0.01 0.1 1 10 100




Analysis 4.1. Comparison 4 Oxytocin versus ergot alkaloids--subgroup analyses, Outcome 1 PPH (clinically

estimated blood loss > or = 500 mL); randomised v. quasi-randomised trials.


Comparison: 4 Oxytocin versus ergot alkaloids–subgroup analyses



n/N n/N

M-H,Random,95%

CI

M-H,Random,95%

CI


De Groot 1996 25/78 54/146 33.1 % 0.87 [ 0.59, 1.28 ]

Orji 2008 12/297 18/303 9.7 % 0.68 [ 0.33, 1.39 ]

Subtotal (95% CI) 375 449 42.8 % 0.82 [ 0.58, 1.15 ]





Ilancheran 1990 0/5 1/5 0.6 % 0.33 [ 0.02, 6.65 ]

Saito 2007 17/156 38/187 17.5 % 0.54 [ 0.32, 0.91 ]

Sorbe 1978 48/506 63/543 39.1 % 0.82 [ 0.57, 1.17 ]

Subtotal (95% CI) 667 735 57.2 % 0.71 [ 0.53, 0.96 ]




Total (95% CI) 1042 1184 100.0 % 0.76 [ 0.61, 0.94 ]





0.001 0.01 0.1 1 10 100 1000





estimated blood loss > or = 500 mL); active v. expectant management.





n/N n/N

M-H,Random,95%

CI

M-H,Random,95%

CI

1 Active management

Orji 2008 12/297 18/303 9.8 % 0.68 [ 0.33, 1.39 ]

Saito 2007 17/156 38/187 17.6 % 0.54 [ 0.32, 0.91 ]

Subtotal (95% CI) 453 490 27.4 % 0.58 [ 0.38, 0.89 ]





De Groot 1996 25/78 54/146 33.3 % 0.87 [ 0.59, 1.28 ]

Sorbe 1978 48/506 63/543 39.3 % 0.82 [ 0.57, 1.17 ]

Subtotal (95% CI) 584 689 72.6 % 0.84 [ 0.65, 1.09 ]




Total (95% CI) 1037 1179 100.0 % 0.76 [ 0.61, 0.95 ]





0.001 0.01 0.1 1 10 100 1000





estimated blood loss > or = 500 mL); IM v. IV oxytocin.





n/N n/N

M-H,Random,95%

CI

M-H,Random,95%

CI

1 IM oxytocin

De Groot 1996 25/78 54/146 33.1 % 0.87 [ 0.59, 1.28 ]

Saito 2007 17/156 38/187 17.5 % 0.54 [ 0.32, 0.91 ]

Subtotal (95% CI) 234 333 50.6 % 0.71 [ 0.44, 1.13 ]




2 IV oxytocin

Ilancheran 1990 0/5 1/5 0.6 % 0.33 [ 0.02, 6.65 ]

Orji 2008 12/297 18/303 9.7 % 0.68 [ 0.33, 1.39 ]

Sorbe 1978 48/506 63/543 39.1 % 0.82 [ 0.57, 1.17 ]

Subtotal (95% CI) 808 851 49.4 % 0.78 [ 0.57, 1.07 ]




Total (95% CI) 1042 1184 100.0 % 0.76 [ 0.61, 0.94 ]





0.001 0.01 0.1 1 10 100 1000





estimated blood loss > 500 mL); oxytocin dose < 10 IU v. 10 IU.



Outcome: 4 PPH (clinically estimated blood loss > 500 mL); oxytocin dose < 10 IU v. 10 IU


n/N n/N

M-H,Random,95%

CI

M-H,Random,95%

CI


De Groot 1996 25/78 54/146 33.3 % 0.87 [ 0.59, 1.28 ]

Saito 2007 17/156 38/187 17.6 % 0.54 [ 0.32, 0.91 ]

Subtotal (95% CI) 234 333 50.9 % 0.71 [ 0.44, 1.13 ]





Orji 2008 12/297 18/303 9.8 % 0.68 [ 0.33, 1.39 ]

Sorbe 1978 48/506 63/543 39.3 % 0.82 [ 0.57, 1.17 ]

Subtotal (95% CI) 803 846 49.1 % 0.79 [ 0.57, 1.08 ]




Total (95% CI) 1037 1179 100.0 % 0.76 [ 0.61, 0.95 ]





0.01 0.1 1 10 100




Analysis 4.5. Comparison 4 Oxytocin versus ergot alkaloids--subgroup analyses, Outcome 5 Therapeutic

uterotonics; randomised v. quasi-randomised trials.



Outcome: 5 Therapeutic uterotonics; randomised v. quasi-randomised trials


n/N n/N

M-H,Random,95%

CI

M-H,Random,95%

CI


De Groot 1996 14/78 21/146 34.5 % 1.25 [ 0.67, 2.31 ]

Orji 2008 18/297 30/303 36.8 % 0.61 [ 0.35, 1.07 ]

Subtotal (95% CI) 375 449 71.3 % 0.86 [ 0.43, 1.74 ]





Saito 2007 8/156 23/187 28.7 % 0.42 [ 0.19, 0.91 ]

Subtotal (95% CI) 156 187 28.7 % 0.42 [ 0.19, 0.91 ]




Total (95% CI) 531 636 100.0 % 0.70 [ 0.38, 1.29 ]





0.1 0.2 0.5 1 2 5 10





uterotonics; active v. expectant management.



Outcome: 6 Therapeutic uterotonics; active v. expectant management


n/N n/N

M-H,Random,95%

CI

M-H,Random,95%

CI

1 Active management

Orji 2008 18/297 30/303 36.8 % 0.61 [ 0.35, 1.07 ]

Saito 2007 8/156 23/187 28.7 % 0.42 [ 0.19, 0.91 ]

Subtotal (95% CI) 453 490 65.5 % 0.54 [ 0.34, 0.85 ]





De Groot 1996 14/78 21/146 34.5 % 1.25 [ 0.67, 2.31 ]

Subtotal (95% CI) 78 146 34.5 % 1.25 [ 0.67, 2.31 ]




Total (95% CI) 531 636 100.0 % 0.70 [ 0.38, 1.29 ]





0.1 0.2 0.5 1 2 5 10





uterotonics; IM v. IV oxytocin.



Outcome: 7 Therapeutic uterotonics; IM v. IV oxytocin


n/N n/N

M-H,Random,95%

CI

M-H,Random,95%

CI

1 IM oxytocin

De Groot 1996 14/78 21/146 34.5 % 1.25 [ 0.67, 2.31 ]

Saito 2007 8/156 23/187 28.7 % 0.42 [ 0.19, 0.91 ]

Subtotal (95% CI) 234 333 63.2 % 0.74 [ 0.25, 2.19 ]




2 IV oxytocin

Orji 2008 18/297 30/303 36.8 % 0.61 [ 0.35, 1.07 ]

Subtotal (95% CI) 297 303 36.8 % 0.61 [ 0.35, 1.07 ]




Total (95% CI) 531 636 100.0 % 0.70 [ 0.38, 1.29 ]





0.1 0.2 0.5 1 2 5 10





uterotonics; oxytocin dose < 10 IU v. 10 IU.



Outcome: 8 Therapeutic uterotonics; oxytocin dose < 10 IU v. 10 IU


n/N n/N

M-H,Random,95%

CI

M-H,Random,95%

CI


De Groot 1996 14/78 21/146 34.5 % 1.25 [ 0.67, 2.31 ]

Saito 2007 8/156 23/187 28.7 % 0.42 [ 0.19, 0.91 ]

Subtotal (95% CI) 234 333 63.2 % 0.74 [ 0.25, 2.19 ]





Orji 2008 18/297 30/303 36.8 % 0.61 [ 0.35, 1.07 ]

Subtotal (95% CI) 297 303 36.8 % 0.61 [ 0.35, 1.07 ]




Total (95% CI) 531 636 100.0 % 0.70 [ 0.38, 1.29 ]





0.01 0.1 1 10 100




Analysis 5.1. Comparison 5 Oxytocin + ergometrine versus ergot alkaloids, Outcome 1 PPH (clinically

estimated blood loss > or = 500 mL).


Comparison: 5 Oxytocin + ergometrine versus ergot alkaloids


Study or subgroup Syntometrine Ergot Alkaloids Risk Ratio Weight Risk Ratio

n/N n/N

M-H,Random,95%

CI

M-H,Random,95%

CI

Barbaro 1961 39/300 10/300 24.9 % 3.90 [ 1.98, 7.67 ]

Bonham 1963 5/391 13/416 21.7 % 0.41 [ 0.15, 1.14 ]

Francis 1965 4/171 9/183 20.3 % 0.48 [ 0.15, 1.52 ]

Ilancheran 1990 0/5 1/5 7.8 % 0.33 [ 0.02, 6.65 ]

Soiva 1964 18/560 19/560 25.3 % 0.95 [ 0.50, 1.79 ]

Total (95% CI) 1427 1464 100.0 % 0.90 [ 0.34, 2.41 ]

Total events: 66 (Syntometrine), 52 (Ergot Alkaloids)




0.001 0.01 0.1 1 10 100 1000

Favours Syntometrine Favours Ergots



Analysis 5.3. Comparison 5 Oxytocin + ergometrine versus ergot alkaloids, Outcome 3 Severe PPH

(clinically estimated blood loss > or = 1000 mL).






Soiva 1964 5/560 3/560 100.0 % 1.67 [ 0.40, 6.94 ]

Total (95% CI) 560 560 100.0 % 1.67 [ 0.40, 6.94 ]





0.1 0.2 0.5 1 2 5 10


Analysis 5.4. Comparison 5 Oxytocin + ergometrine versus ergot alkaloids, Outcome 4 Mean blood loss

(mL).




Study or subgroup Synometrine Ergot alkaloidsMean


Difference

N Mean(SD) N Mean(SD) IV,Fixed,95% CI IV,Fixed,95% CI

Vaughan Williams1974 19 185 (102) 15 124 (60) 100.0 % 61.00 [ 6.00, 116.00 ]

Total (95% CI) 19 15 100.0 % 61.00 [ 6.00, 116.00 ]




-100 -50 0 50 100

Favours Synometrine Favours Ergots



Analysis 5.6. Comparison 5 Oxytocin + ergometrine versus ergot alkaloids, Outcome 6 Blood transfusion.






Soiva 1964 5/560 7/560 100.0 % 0.71 [ 0.23, 2.24 ]

Total (95% CI) 560 560 100.0 % 0.71 [ 0.23, 2.24 ]





0.1 0.2 0.5 1 2 5 10


Analysis 5.8. Comparison 5 Oxytocin + ergometrine versus ergot alkaloids, Outcome 8 Mean length of the

third stage (minutes).



Outcome: 8 Mean length of the third stage (minutes)

Study or subgroup Experimental ControlMean


Difference

N Mean(SD) N Mean(SD) IV,Fixed,95% CI IV,Fixed,95% CI

Barbaro 1961 199 16 (0) 173 13 (0) Not estimable

Total (95% CI) 199 173 Not estimable


Test for overall effect: not applicable


-100 -50 0 50 100

Favours Synometrine Favours Ergots



Analysis 5.9. Comparison 5 Oxytocin + ergometrine versus ergot alkaloids, Outcome 9 Manual removal of

the placenta.





n/N n/N

M-H,Random,95%

CI

M-H,Random,95%

CI

Bonham 1963 5/391 5/416 38.4 % 1.06 [ 0.31, 3.65 ]

Soiva 1964 8/560 8/560 61.6 % 1.00 [ 0.38, 2.65 ]

Total (95% CI) 951 976 100.0 % 1.02 [ 0.48, 2.20 ]





0.1 0.2 0.5 1 2 5 10




Analysis 6.1. Comparison 6 Oxytocin + ergometrine versus ergot alkaloids--subgroup analyses, Outcome 1

PPH (clinically estimated blood loss > or = 500 mL); randomised v. quasi-randomised trials.


Comparison: 6 Oxytocin + ergometrine versus ergot alkaloids–subgroup analyses



n/N n/N

M-H,Random,95%

CI

M-H,Random,95%

CI


Subtotal (95% CI) 0 0 Not estimable



Test for overall effect: not applicable


Barbaro 1961 39/300 10/300 24.9 % 3.90 [ 1.98, 7.67 ]

Bonham 1963 5/391 13/416 21.7 % 0.41 [ 0.15, 1.14 ]

Francis 1965 4/171 9/183 20.3 % 0.48 [ 0.15, 1.52 ]

Ilancheran 1990 0/5 1/5 7.8 % 0.33 [ 0.02, 6.65 ]

Soiva 1964 18/560 19/560 25.3 % 0.95 [ 0.50, 1.79 ]

Subtotal (95% CI) 1427 1464 100.0 % 0.90 [ 0.34, 2.41 ]




Total (95% CI) 1427 1464 100.0 % 0.90 [ 0.34, 2.41 ]





0.001 0.01 0.1 1 10 100 1000





PPH (clinically estimated blood loss > or = 500 mL); active v. expectant management.





n/N n/N

M-H,Random,95%

CI

M-H,Random,95%

CI

1 Active management

Francis 1965 4/171 9/183 24.2 % 0.48 [ 0.15, 1.52 ]

Subtotal (95% CI) 171 183 24.2 % 0.48 [ 0.15, 1.52 ]





Soiva 1964 18/560 19/560 75.8 % 0.95 [ 0.50, 1.79 ]

Subtotal (95% CI) 560 560 75.8 % 0.95 [ 0.50, 1.79 ]




Total (95% CI) 731 743 100.0 % 0.80 [ 0.45, 1.43 ]





0.001 0.01 0.1 1 10 100 1000





PPH (clinically estimated blood loss > or = 500 mL); IM v. IV oxytocin.





n/N n/N

M-H,Random,95%

CI

M-H,Random,95%

CI

1 IM oxytocin

Barbaro 1961 39/300 10/300 24.9 % 3.90 [ 1.98, 7.67 ]

Bonham 1963 5/391 13/416 21.7 % 0.41 [ 0.15, 1.14 ]

Francis 1965 4/171 9/183 20.3 % 0.48 [ 0.15, 1.52 ]

Soiva 1964 18/560 19/560 25.3 % 0.95 [ 0.50, 1.79 ]

Subtotal (95% CI) 1422 1459 92.2 % 0.98 [ 0.34, 2.78 ]




2 IV oxytocin

Ilancheran 1990 0/5 1/5 7.8 % 0.33 [ 0.02, 6.65 ]

Subtotal (95% CI) 5 5 7.8 % 0.33 [ 0.02, 6.65 ]




Total (95% CI) 1427 1464 100.0 % 0.90 [ 0.34, 2.41 ]





0.001 0.01 0.1 1 10 100 1000




A P P E N D I C E S

Appendix 1. Methods used to assess trials included in previous versions of this review

For the first publication, two review authors checked the titles and abstracts identified from the search. Two of the review authorsobtained the full text of all studies of possible relevance for independent assessment. The methodological quality of the studies wasassessed with particular concentration on allocation concealment, ranked using the Cochrane approach of adequate, uncertain orinadequate. Two review authors performed the data extraction. Trial authors were contacted for clarification where relevant. Analysiswas by intention-to-treat.For this update the following methods were used.

Selection of studies

We assessed for inclusion all potential studies we identified as a result of the search strategy. We resolved any disagreement throughdiscussion.

Assessment of methodological quality of included studies

We assessed the validity of each study using the criteria outlined in the Cochrane Reviewers’ Handbook (Alderson 2004).

(1) Selection bias (randomisation and allocation concealment)

We planned to assign a quality score for each trial, using the following criteria:(A) adequate concealment of allocation, such as telephone randomisation, consecutively numbered sealed opaque envelopes;(B) unclear whether adequate concealment of allocation; such as list or table used, sealed envelopes, or study does not report anyconcealment approach;(C) inadequate concealment of allocation, such as open list of random number tables, use of case record numbers, dates of birth ordays of the week.

(2) Performance bias (blinding of participants, researchers and outcome assessment)

We planned to assess blinding using the following criteria:(A) blinding of participants (yes/no/unclear);(B) blinding of caregiver (yes/no/unclear);(C) blinding of outcome assessment (yes/no/unclear).

(3) Attrition bias (loss of participants, e.g. withdrawals, dropouts, protocol deviations)

We planned to assess completeness to follow-up using the following criteria:(A) less than 5% loss of participants;(B) 5% to 10% loss of participants;(C) more than 10% and less than 20% loss of participants;(D) more than 20% loss of participants.

Data extraction and management

We planned for all three review authors to extract the data and to resolve discrepancies through discussion. We planned to use theReview Manager software (RevMan 2003) to double-enter the data.



Measures of treatment effect

We planned to carry out statistical analysis using the Review Manager software (RevMan 2003) and would have used a fixed-effectmeta-analysis for combining data if trials were sufficiently similar.For dichotomous data: we planned to present results as summary relative risk with 95% confidence intervals.For continuous data: we planned to use the weighted mean difference if outcomes were measured in the same way between trials. Weplanned to use the standardised mean difference to combine trials that measured the same outcome, but used different methods. Ifthere was evidence of skewness this would have been reported.We planned to analyse data on an intention-to-treat basis. Therefore, all participants with available data would have been included inthe analysis in the group to which they were allocated, regardless of whether or not they received the allocated intervention. If in theoriginal reports participants were not analysed in the group to which they were randomised, and there was sufficient information inthe trial report, we would have attempted to restore them to the correct group.

Assessment of heterogeneity

Tests of heterogeneity between trials would have been applied if appropriate using the I² statistic. If we identified high levels ofheterogeneity among the trials, (exceeding 50%), we would have explored it by prespecified subgroup analysis and have performedsensitivity analysis. A random-effects meta-analysis would have been used as an overall summary if considered appropriate.Three comparisons would have been considered:(a) oxytocin versus no uterotonics;(b) oxytocin versus ergot alkaloids;(c) oxytocin plus ergometrine versus ergot alkaloids.Subgroup analyses were planned based on extent of control for selection bias, on whether the oxytocin is administered within thecontext of active or expectant management of the third stage of labour, and on the timing of administration. Further subgroup analysesmay consider the effects of different doses or different routes of administration if appropriate data become available.Results are presented as relative risk ratios for dichotomous data, and weighted mean difference for continuous data, both with 95%confidence intervals using a fixed-effect model. If sufficient heterogeneity existed, sensitivity analyses would have be performed.

F E E D B A C K

Pastrana, March 2007

Summary

It is important to take care that the conclusions are based on pre-specified objectives, as sometimes the study is done and then theobjectives decided afterwards.In this review, there is no discussion of the way different studies determined blood loss, and the limitations of these methods. Thisis especially true for Pierre 1992. Also, the results should take into account Hoffman 2004, comparing oxytocin with expectantmanagement. In this study, although the mean change in hematocrit was significantly less in the oxytocin group, there was no differencein the incidence of postpartum haemorrhage.(Summary of comment from Jose Luis Pastrana, March 2007)

Reply

6 July 2011We agree that there are a lot of limitations to this review, specifically that in the studies included there are differences in the method ofdelivery of pitocin, definition of the active management of the third stage, and determining accurate blood loss after delivery. However,this review incorporates the only randomised controlled trials that attempt to address this important topic. We agree that a formalizedmethod for determining blood loss is needed as that will further advance our ability to perform useful research in this field.Please see our conclusion section for a more thorough discussion of these topics.



Contributors

Feedback: Jose Luis PastranaResponse: Gina Westhoff

W H A T ’ S N E W

Last assessed as up-to-date: 24 June 2013.

Date Event Description

24 June 2013 New citation required and conclusions have changed There is now evidence to show that prophylactic oxytocin isassociated with fewer side effects than ergot alkaloidsA new author has joined the review team and is now theguarantor for the review

31 May 2013 New search has been performed Search updated. Six new trials have been included (Abdel-Aleem 2010; Jago 2007; Jerbi 2007; Moodie 1976; Orji2008; Saito 2007) and eight trials excluded (Dickinson2009; Dommisse 1980; Rouse 2011; Sariganont 1999;Stanton 2012; Tita 2012; Wetta 2011; Vasegh 2005). Wealso identified one additional report identified for an alreadyexcluded trial (Hoffman 2006a).This updated reviews is now comprised of 20 included stud-ies (involving 10,806 women)

H I S T O R Y

Protocol first published: Issue 4, 1999

Review first published: Issue 4, 2001

Date Event Description

6 July 2011 Feedback has been incorporated The authors have responded to feedback from Pastrana (March 2007) - seeFeedback 1.

1 October 2009 Amended Search updated. Ten reports added to Studies awaiting classification

20 September 2008 Amended Converted to new review format.

1 March 2007 Feedback has been incorporated Feedback added from Pastrana, March 2007.

1 December 2004 New search has been performed Search updated. We identified 16 new studies; however, none fulfilled theinclusion criteria



C O N T R I B U T I O N S O F A U T H O R S

For the 2013 update, Gina Westhoff, Amanda Cotter, and Jorge Tolosa reread the review and its objectives and edited the results anddiscussion based on the updated data.

D E C L A R A T I O N S O F I N T E R E S T

None known.

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

In order to reduce subjectivity in our primary analysis, we have added the use of therapeutic uterotonics as a primary outcome and havemoved severe postpartum haemorrhage to a secondary outcome. The use of therapeutic uterotonics is an outcome that is dichotomousand does not rely on the highly subjective techniques that are used to measure total blood loss and may more objectively reflect severeblood loss. We feel that by making this change, we have increased the strength of the observations made by this review.

In addition, we have added an additional subgroup analysis based on the dose of oxytocin. We feel that this analysis may help toanswer an important clinical question regarding the dose of prophylactic oxytocin that is the most beneficial in order to improve thetranslatability of this analysis into clinical practice. Subgroup analysis based on the timing of the oxytocin has been removed.

Given that included trials did not report on neonatal data and the effect on neonatal outcomes was not an objective of this study, thesesecondary outcomes were removed.

For the 2013 update, our threshold for ’substantial’ heterogeneity was increased from I² greater than 30% to greater than 40%.

I N D E X T E R M SMedical Subject Headings (MeSH)

Ergonovine [administration & dosage]; Ergot Alkaloids [administration & dosage]; Labor Stage, Third [∗drug effects]; Maternal Mor-tality; Oxytocics [∗administration & dosage]; Oxytocin [∗administration & dosage]; Postpartum Hemorrhage [mortality; ∗prevention& control]; Randomized Controlled Trials as Topic

MeSH check words

Female; Humans; Pregnancy



prophylactic oxytocin for the third stage of labour to prevent

Documents

iv oxytocin

prophylactic oxytocin

analyses analysis

subgroup analyses

therapeutic uterotonics

estimatedblood loss

estimated blood loss

severe pph