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 Library
2013, 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.
TABLE OF CONTENTS
HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
AUTHORS CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
ACKNOWLEDGEMENTS
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Analysis 1.1. Comparison 1 Oxytocin versus no uterotonics, Outcome 1 PPH (clinically estimated blood loss > or = 500
mL). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Analysis 1.2. Comparison 1 Oxytocin versus no uterotonics, Outcome 2 Therapeutic uterotonics. . . . . . . .
Analysis 1.3. Comparison 1 Oxytocin versus no uterotonics, Outcome 3 Severe PPH (clinically estimated blood loss > or =
1000 mL). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Analysis 1.4. Comparison 1 Oxytocin versus no uterotonics, Outcome 4 Mean blood loss (mL). . . . . . . .
Analysis 1.5. Comparison 1 Oxytocin versus no uterotonics, Outcome 5 Maternal haemoglobin concentration (Hb) < 9
g/dL 24 to 48 hours postpartum. . . . . . . . . . . . . . . . . . . . . . . . . . . .
Analysis 1.6. Comparison 1 Oxytocin versus no uterotonics, Outcome 6 Blood transfusion. . . . . . . . . .
Analysis 1.7. Comparison 1 Oxytocin versus no uterotonics, Outcome 7 Third stage greater than 30 minutes. . . .
Analysis 1.8. Comparison 1 Oxytocin versus no uterotonics, Outcome 8 Mean length of third stage (minutes). . .
Analysis 1.9. Comparison 1 Oxytocin versus no uterotonics, Outcome 9 Manual removal of the placenta. . . . .
Analysis 1.12. Comparison 1 Oxytocin versus no uterotonics, Outcome 12 Nausea between delivery of the baby and
discharge from the labour ward. . . . . . . . . . . . . . . . . . . . . . . . . . . .
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. . . . . . . . . . . . . . . . .
blood loss > or = 500 mL); active v. expectant management. . . . . . . . . . . . . . . . . . .
blood loss > or = 500 mL); IM v. IV oxytocin.
. . . . . . . . . . . . . . . . . . . . . .
blood loss > 500 mL); oxytocin dose < 10 IU v. 10 IU. . . . . . . . . . . . . . . . . . . . .
Analysis 2.5. Comparison 2 Oxytocin versus no uterotonics--subgroup analyses, Outcome 5 Therapeutic uterotonics;
randomised v. quasi-randomised trials. . . . . . . . . . . . . . . . . . . . . . . . . .
Analysis 2.6. Comparison 2 Oxytocin versus no uterotonics--subgroup analyses, Outcome 6 Therapeutic uterotonics; active
v. expectant management.
. . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Analysis 2.7. Comparison 2 Oxytocin versus no uterotonics--subgroup analyses, Outcome 7 Therapeutic uterotonics; IM v.
IV oxytocin. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Analysis 2.8. Comparison 2 Oxytocin versus no uterotonics--subgroup analyses, Outcome 8 Therapeutic uterotonics;
oxytocin dose < 10 IU v. 10 IU. . . . . . . . . . . . . . . . . . . . . . . . . . . .
Analysis 3.1. Comparison 3 Oxytocin versus ergot alkaloids, Outcome 1 PPH (clinically estimated blood loss > or = 500
mL). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Analysis 3.2. Comparison 3 Oxytocin versus ergot alkaloids, Outcome 2 Therapeutic uterotonics. . . . . . . .
Analysis 3.3. Comparison 3 Oxytocin versus ergot alkaloids, Outcome 3 Severe PPH (clinically estimated blood loss > or =
1000 mL). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Analysis 3.4. Comparison 3 Oxytocin versus ergot alkaloids, Outcome 4 Mean blood loss (mL). . . . . . . .
Analysis 3.6. Comparison 3 Oxytocin versus ergot alkaloids, Outcome 6 Blood transfusion. . . . . . . . . .
Analysis 3.8. Comparison 3 Oxytocin versus ergot alkaloids, Outcome 8 Mean length of third stage (minutes). . .
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Analysis 3.9. Comparison 3 Oxytocin versus ergot alkaloids, Outcome 9 Manual removal of the placenta. . . . .
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. . . . . . . . . . . . . . . . . . . .
Analysis 3.11. Comparison 3 Oxytocin versus ergot alkaloids, Outcome 11 Vomiting between delivery of the baby and
Analysis 3.12. Comparison 3 Oxytocin versus ergot alkaloids, Outcome 12 Nausea between delivery of the baby and
Analysis 3.13. Comparison 3 Oxytocin versus ergot alkaloids, Outcome 13 Headaches between delivery of the baby and
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. . . . . . . . . . . . . . . . .
blood loss > or = 500 mL); active v. expectant management. . . . . . . . . . . . . . . . . . .
blood loss > or = 500 mL); IM v. IV oxytocin.
. . . . . . . . . . . . . . . . . . . . . .
blood loss > 500 mL); oxytocin dose < 10 IU v. 10 IU. . . . . . . . . . . . . . . . . . . . .
Analysis 4.5. Comparison 4 Oxytocin versus ergot alkaloids--subgroup analyses, Outcome 5 Therapeutic uterotonics;
randomised v. quasi-randomised trials. . . . . . . . . . . . . . . . . . . . . . . . . .
Analysis 4.6. Comparison 4 Oxytocin versus ergot alkaloids--subgroup analyses, Outcome 6 Therapeutic uterotonics; active
v. expectant management.
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Analysis 4.7. Comparison 4 Oxytocin versus ergot alkaloids--subgroup analyses, Outcome 7 Therapeutic uterotonics; IM v.
IV oxytocin. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Analysis 4.8. Comparison 4 Oxytocin versus ergot alkaloids--subgroup analyses, Outcome 8 Therapeutic uterotonics;
oxytocin dose < 10 IU v. 10 IU. . . . . . . . . . . . . . . . . . . . . . . . . . . .
Analysis 5.1. Comparison 5 Oxytocin + ergometrine versus ergot alkaloids, Outcome 1 PPH (clinically estimated blood
loss > or = 500 mL). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Analysis 5.3. Comparison 5 Oxytocin + ergometrine versus ergot alkaloids, Outcome 3 Severe PPH (clinically estimated
blood loss > or = 1000 mL). . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Analysis 5.4. Comparison 5 Oxytocin + ergometrine versus ergot alkaloids, Outcome 4 Mean blood loss (mL). . .
Analysis 5.6. Comparison 5 Oxytocin + ergometrine versus ergot alkaloids, Outcome 6 Blood transfusion. . . . .
Analysis 5.8. Comparison 5 Oxytocin + ergometrine versus ergot alkaloids, Outcome 8 Mean length of the third stage
(minutes). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Analysis 5.9. Comparison 5 Oxytocin + ergometrine versus ergot alkaloids, Outcome 9 Manual removal of the placenta.
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. . . . . . . . . . . . .
estimated blood loss > or = 500 mL); active v. expectant management. . . . . . . . . . . . . . .
estimated blood loss > or = 500 mL); IM v. IV oxytocin. . . . . . . . . . . . . . . . . . . .
APPENDICES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
FEEDBACK . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
WHATS NEW . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
HISTORY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
DIFFERENCES BETWEEN PROTOCOL AND REVIEW . . . . . . . . . . . . . . . . . . . . .
INDEX TERMS
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[Intervention Review]
Prophylactic oxytocin for the third stage of labour to prevent

postpartum haemorrhage
Gina Westhoff1 , Amanda M Cotter2,3 , Jorge E Tolosa3,4
1 Stanford University and University of California-San Francisco, Stanford, CA, USA. 2 Department of Obstetrics and Gynaecology,
University of Limerick, Limerick, Ireland. 3 Global Network for Perinatal and Reproductive Health, Portland, OR, USA. 4 Department
of 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. ginaw@stanford.edu. ginawesthoff@gmail.com.
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.
ABSTRACT
Background
Active management of the third stage of labour has been shown to reduce the risk of postpartum haemorrhage (PPH) greater than 1000
mL. 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 to
the third stage of labour.
Search methods
We searched the Cochrane Pregnancy and Childbirth Groups Trials Register (31 May 2013).
Selection criteria
Randomised or quasi-randomised controlled trials including pregnant women anticipating a vaginal delivery where prophylactic
oxytocin was given during management of the third stage of labour. The primary outcomes were blood loss > 500 mL and the use of
therapeutic 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% confidence
interval (CI) 0.38 to 0.74; six trials, 4203 women; T = 0.11, I = 78%) and the need for therapeutic uterotonics (RR 0.56; 95%
CI 0.36 to 0.87, four trials, 3174 women; T = 0.10, I = 58%). The benefit of prophylactic oxytocin to prevent PPH greater than
500 mL was seen in all subgroups. Decreased use of therapeutic uterotonics was only seen in the following subgroups: randomised
trials with low risk of bias (RR 0.58; 95% CI 0.36 to 0.92; three trials, 3122 women; T = 0.11, I = 69%); trials that performed
active management of the third stage (RR 0.39; 95% CI 0.26 to 0.58; one trial, 1901 women; heterogeneity not applicable); trials that
delivered oxytocin as an IV bolus (RR 0.57; 95% CI 0.39 to 0.82; one trial, 1000 women; heterogeneity not applicable); and in trials
that gave oxytocin at a dose of 10 IU (RR 0.48; 95% CI 0.33 to 0.68; two trials, 2901 women; T = 0.02, I = 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; five
trials, 2226 women; T = 0.00, I = 0%). The benefit of oxytocin over ergot alkaloids to prevent PPH greater than 500 mL only
persisted in the subgroups of quasi-randomised trials (RR 0.71, 95% CI 0.53 to 0.96; three trials, 1402 women; T = 0.00, I = 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; T
= 0.00, I = 0%). Use of prophylactic oxytocin was associated with fewer side effects compared with use of ergot alkaloids; including
decreased nausea between delivery of the baby and discharge from the labour ward (RR 0.18; 95% CI 0.06 to 0.53; three trials, 1091
women; T = 0.41, I = 41%) and vomiting between delivery of the baby and discharge from the labour ward (RR 0.07; 95% CI 0.02
to 0.25; three trials, 1091 women; T = 0.45, I = 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 than
500 mL (RR 0.90; 95% CI 0.34 to 2.41; five trials, 2891 women; T = 0.89, I = 80%). The use of oxytocin and ergometrine was
associated 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 between
treatment arms.
Authors conclusions
Prophylactic oxytocin at any dose decreases both PPH greater than 500 mL and the need for therapeutic uterotonics compared to
placebo alone. Taking into account the subgroup analyses from both primary outcomes, to achieve maximal benefit providers may opt
to implement a practice of giving prophylactic oxytocin as part of the active management of the third stage of labour at a dose of 10
IU 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 prevent
PPH 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 this
benefit did not persist when only randomised trials with low risk of methodologic bias were analysed. Based on this, there is limited
high-quality evidence supporting a benefit of prophylactic oxytocin over ergot alkaloids. However, the use of prophylactic oxytocin
was associated with fewer side effects, specifically nausea and vomiting, making oxytocin the more desirable option for routine use to
prevent PPH.
There is no evidence of benefit when adding oxytocin to ergometrine compared to ergot alkaloids alone, and there may even be increased
harm as one study showed evidence that using the combination was associated with increased mean blood loss compared to ergot
alkaloids alone.
Importantly, there is no evidence to suggest that prophylactic oxytocin increases the risk of retained placenta when compared to placebo
or ergot alkaloids.
More placebo-controlled, randomised, and double-blinded trials are needed to improve the quality of data used to evaluate the effective
dose, timing, and route of administration of prophylactic oxytocin to prevent PPH. In addition, more trials are needed especially, but
not only, in low- and middle-income countries to evaluate these interventions in the birth centres that shoulder the majority of the
burden of PPH in order to improve maternal morbidity and mortality worldwide.
PLAIN LANGUAGE SUMMARY

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 to
occur once the placenta is removed. The degree of blood loss during this stage depends, among other factors, on how quickly the uterine
muscle contracts and the placenta separates from the uterine wall. Postpartum haemorrhage is a major problem, particularly where
there is poor nutrition and lack of access to treatment. This review of 20 trials (involving 10,806 women) found that the routine use
of 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 when
they were used together. More research is needed, especially in low- and middle-income countries, on the best method to implement
this intervention in the third stage for women in all countries, on the dose to use, and the best route for administration (intramuscular
or intravenous).
BACKGROUND
The most reliable estimates of global maternal mortality report
between 250,000 and 300,000 deaths from childbirth annually
(Lozano 2011). The majority of these deaths are due to complications of the third stage of labour, and most commonly are from
postpartum haemorrhage (PPH) (AbouZahr 2003). Nearly all maternal 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, may
contribute to death in the presence of severe PPH. Many more
women survive and suffer serious illness as a result, not only from
the effects of acute anaemia but also from the interventions which
a severe haemorrhage may necessitate (such as general anaesthesia,
manual removal of the placenta, blood transfusion, and hysterectomy).
The degree of blood loss associated with placental separation and
delivery depends on how quickly the placenta separates from
the uterine wall and how effectively the uterine muscle contracts
around the placental bed (where the placenta is attached to the
wall of the uterus) and the uterine blood vessels, in addition to
how quickly the uterus expels the placenta through the birth canal.
Techniques to prevent PPH can target any of these points in placental delivery. A recent review determined that active management of the third stage of labour prevents severe PPH, defined
as 1000 mL, when compared to expectant management (Begley
2011). Active management includes administration of a uterotonic, early cord clamping, and controlled cord traction until delivery of the placenta.
Uterotonic drugs increase the tone of the uterine muscles and were
initially introduced for the treatment of PPH. Moir 1932 showed
that ergometrine was the active principle on which the known
uterotonic effect of ergot had depended. Reviewing its use in obstetric practice by the early 1950s, his opinion was that Few drugs
have become so firmly established in so short a time and few drugs
can be so completely indispensable as ergometrine is now (Moir

1955). Ergometrine (ergonovine in the United States) became
popular for routine management in the early 1950s. Oxytocin is a
naturally occurring uterotonic, which Du Vigneaud et al synthesised and reported in 1953 (Du Vigneaud 1953). Embrey 1963
reported advantages of combining this with ergometrine (as Syntometrine - oxytocin five international units (IU) plus ergometrine
0.5 mg). In order to prevent blood loss, these uterotonics and,
more recently, prostaglandins are also being used for prophylactic
third-stage management. One commonly given uterotonic is oxytocin, and recently it was shown that there was no difference in
preventing PPH if you administer the oxytocin with the anterior
shoulder or after delivery of the placenta (Soltani 2010).
While few would dispute the contribution of uterotonic drugs
in the treatment of PPH, their role in routine prophylaxis is less
clear. This review considers the prophylactic role of one of these
uterotonics, oxytocin, in the third stage of labour. Other relevant
published reviews are by Begley 2011, which compares active with
expectant third-stage management (where active management involves the package of interconnected interventions of prophylactic uterotonics, early cutting and clamping of the umbilical cord,
and controlled cord traction); Tunalp 2012 and McDonald 2004,
which both consider the role of different prophylactic uterotonics
(prostaglandins, and ergometrine-oxytocin compared with oxytocin, respectively) in third-stage management; and Carroli 2001,
which looks at the role of umbilical vein injection for the treatment
of retained placenta. Subsequent third-stage management reviews
will consider the role of prophylactic uterotonics more generally,
and of prophylactic ergot alkaloids in particular. As these interventions are very inter-related, some aspects of the role of oxytocin
may be found in these other reviews (e.g. Begley 2011; McDonald
2004; Soltani 2010; Tunalp 2012).
Any research related to PPH must also recognise the limitations of
the data collected due to the lack of a formal definition of PPH and
an easy, objective technique to accurately measure blood loss after

delivery. For example, although PPH is generally defined as blood
loss 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 likely
to underestimate the actual volume of blood lost by 34% to 50%
(Newton 1961a) and as a result, there is significant variability in
the estimated incidence of PPH, from 5% to 18% in one country (
AbouZahr 2003; DoH 2004; Gilbert 1987; Hall 1985; Prendiville
1988a). Using the outcome of measured blood loss, therefore, has
significant limitations and potential for bias. Due to the fact that
blood measurement is so variable, more objective measures, such
as the need for therapeutic uterotonics, should also be evaluated
as a primary outcome to minimise measurement bias related to
estimating PPH from blood loss.
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 prophylactic
prostaglandins or ergot alkaloids and uterotonics given through
the umbilical vein, for the treatment of blood loss or retained
placenta, will be the subject of other reviews and were not included
here (Liabsuetrakul 2007; Mori 2012; Tunalp 2012). Similarly,
endogenous oxytocin (nipple stimulation) is not included in this
review.
OBJECTIVES
The objective of this review is to examine the effect of prophylactic
oxytocin at any dose given in the third stage of labour, defined as
that period from birth of the baby until delivery of the placenta,
on outcomes such as maternal blood loss, the need for therapeutic
uterotonics, the length of the third stage of labour, and other
adverse maternal events. The objectives of this review will consider
the following comparisons:
1. oxytocin versus no uterotonics;
2. oxytocin versus ergot alkaloids;
Types of outcome measures
Primary outcomes
Postpartum haemorrhage (PPH) (reported estimates of

blood loss greater than or equal to 500 mL)
Use of additional therapeutic uterotonics
Secondary outcomes
All randomised or quasi-randomised controlled trials comparing

prophylactic oxytocin with another uterotonic or placebo for the
management of the third stage of labour were considered for inclusion.
Severe PPH (clinically estimated blood loss greater than or

equal 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
Types of participants
Search methods for identification of studies
All trials including pregnant women anticipating a vaginal delivery were considered. Studies where participants received the prophylactic uterotonic after delivery of the placenta were excluded.
Electronic searches
3. oxytocin plus ergometrine versus ergot alkaloids.
METHODS
Criteria for considering studies for this review
Types of studies
We searched the Cochrane Pregnancy and Childbirth Groups Trials Register by contacting the Trials Search Co-ordinator (31 May
2013).
The Cochrane Pregnancy and Childbirth Groups Trials Register
is maintained by the Trials Search Co-ordinator and contains trials
identified from:
1. monthly searches of the Cochrane Central Register of
Controlled 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 and
Embase, the list of handsearched journals and conference proceedings, and the list of journals reviewed via the current awareness service can be found in the Specialized Register section
within the editorial information about the Cochrane Pregnancy
and Childbirth Group.
Trials identified through the searching activities described above
are each assigned to a review topic (or topics). The Trials Search
Co-ordinator searches the register for each review using the topic
list rather than keywords.
We did not apply any language restrictions.
Data collection and analysis

For the methods used when assessing the trials identified in the
previous version of this review, see Appendix 1.
Selection of studies
Two review authors independently assessed for inclusion all the
potential studies we identified as a result of the search strategy. We
resolved any disagreement through discussion or, if required, by
consulting the third author.
Data extraction and management

We designed a form to extract data. For eligible studies, two review
authors extracted the data using the agreed form. We resolved
discrepancies through discussion or, if required, by consulting a
third 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, we
attempted to contact the authors of the original reports to provide
further details.
Assessment of risk of bias in included studies
Two review authors independently assessed risk of bias for each

study using the criteria outlined in the Cochrane Handbook for
Systematic Reviews of Interventions (Higgins 2011). They resolved
any 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 generate

the allocation sequence in sufficient detail to allow an assessment
of whether it should produce comparable groups.
We assessed the method as:
low risk of bias (any truly random process, e.g. random
number table; computer random number generator);
high risk of bias (any non-random process, e.g. odd or even
date 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 conceal

the allocation sequence and determined whether intervention allocation could have been foreseen in advance of, or during recruitment, 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 nonopaque envelopes, alternation; date of birth);
(3) Blinding (checking for possible performance bias)
We described for each included study the methods used, if any, to

blind study participants and personnel from knowledge of which
intervention a participant received. We considered that studies
were at low risk of bias if they were blinded, or if we judged that the
lack of blinding could not have affected the results. We assessed
blinding separately for different outcomes or classes of outcomes.
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 or

class of outcomes, the completeness of data including attrition
and exclusions from the analysis. We stated whether attrition and
exclusions were reported, the numbers included in the analysis at
each stage (compared with the total randomised participants), reasons for attrition or exclusion where reported, and whether missing data were balanced across groups or were related to outcomes.
Where sufficient information was reported, or could be supplied
by the trial authors, we re-included missing data in the analyses
which we undertake. We assessed methods as:
low risk of bias (e.g. no missing outcome data; missing
outcome data balanced across groups;
high risk of bias (e.g. numbers or reasons for missing data
imbalanced across groups; as treated analysis done with
substantial departure of intervention received from that assigned
at randomisation);
(5) Selective reporting bias
We described for each included study how we investigated the

possibility of selective outcome reporting bias and what we found.
low risk of bias (where it is clear that all of the studys prespecified outcomes and all expected outcomes of interest to the
review have been reported);
high risk of bias (where not all the studys pre-specified
outcomes have been reported; one or more reported primary
outcomes were not pre-specified; outcomes of interest are
reported incompletely and so cannot be used; study fails to
include results of a key outcome that would have been expected
to have been reported);
Measures of treatment effect
Dichotomous data
For dichotomous data, we presented results as summary risk ratio

with 95% confidence intervals.
Continuous data
For continuous data, we used the mean difference if outcomes are

measured in the same way between trials. We planned to use the
standardised mean difference to combine trials that measure the
same outcome, but used different methods.
Unit of analysis issues

There were no cluster-randomised or cross-over trials included in
this review. No additional unit of analysis issues were encountered.
Dealing with missing data

For included studies, we noted levels of attrition. We explored the
impact of including studies with high levels of missing data in the
overall assessment of treatment effect by using sensitivity analysis.
For all outcomes, we carried out analyses, as far as possible, on
an intention-to-treat basis, i.e. we attempted to include all participants randomised to each group in the analyses, and all participants were analysed in the group to which they were allocated, regardless of whether or not they received the allocated intervention.
The denominator for each outcome in each trial was the number
randomised minus any participants whose outcomes are known
to be missing.
(6) Other sources of bias
We described for each included study any important concerns we

have about other possible sources of bias.
We assessed whether each study was free of other problems that
could put it at risk of bias:
low risk of other bias;
high risk of other bias;
unclear whether there is risk of other bias.
Assessment of heterogeneity
We assessed statistical heterogeneity in each meta-analysis using
the T, I and Chi statistics. We regarded heterogeneity as substantial if the T was greater than zero and either an I was greater
than 40% or there was a low P value (less than 0.10) in the Chi
test for heterogeneity.
Assessment of reporting biases

(7) Overall risk of bias
We made explicit judgements about whether studies are at high risk

of bias, according to the criteria given in the Cochrane Handbook
(Higgins 2011). With reference to (1) to (6) above, we assessed
the likely magnitude and direction of the bias and whether we
considered it likely to impact on the findings. We explored the
impact of the level of bias through undertaking sensitivity analyses
- see Sensitivity analysis.
If there had been 10 or more studies in the meta-analysis, we

planned to investigate reporting biases (such as publication bias)
using funnel plots. We would have assessed funnel plot asymmetry visually, and used formal tests for funnel plot asymmetry. For
continuous outcomes, we would have used the test proposed by
Egger 1997, and for dichotomous outcomes, the test proposed by
Harbord 2006. If asymmetry was detected in any of these tests or
was suggested by a visual assessment, we would have performed
exploratory analyses to investigate it.
Data synthesis
We carried out statistical analysis using the Review Manager software (RevMan 2012). We used fixed-effect meta-analysis for combining data where it was reasonable to assume that studies were
estimating the same underlying treatment effect: i.e. where trials
were examining the same intervention, and the trials populations
and methods were judged sufficiently similar. If there was clinical
heterogeneity sufficient to expect that the underlying treatment effects differed between trials, or if substantial statistical heterogeneity was detected, we used random-effects meta-analysis to produce
an overall summary, if an average treatment effect across trials was
considered clinically meaningful. The random-effects summary
was treated as the average range of possible treatment effects and
we discussed the clinical implications of treatment effects differing
between trials. If the average treatment effect was not clinically
meaningful, we did not combine trials.
If we used random-effects analyses, the results were presented as
the average treatment effect with its 95% confidence interval, and
the estimates of T and I.
Subgroup analysis and investigation of heterogeneity

If we identified substantial heterogeneity, random-effects I greater
than 40%, we investigated it using subgroup analyses and sensitivity analyses. We considered whether an overall summary was
meaningful, and if it was, used random-effects analysis to produce
it.
We carried out the following subgroup analyses.
1. Extent of selection bias: randomised trials with low risk of
bias versus quasi-randomised trials with high risk of bias.
2. Management of the third stage: active versus expectant
management. Active management was defined as using at least
two of the following components: early cord clamping,
controlled cord traction, and uterine massage. Expectant
management involves allowing the natural physiologic process to
promote separation of the placenta.
3. Route of administration of oxytocin; IV versus IM. When
given intravenously, oxytocin was given as a bolus in all trials and
not as a diluted infusion.
4. Dose of administration of oxytocin; less than 10 IU versus
10 IU.
We assessed subgroup differences by interaction tests available
within RevMan (RevMan 2012). We planned to report the results
of any subgroup differences quoting the 2 statistic and p-value,
and the interaction test I value.
RESULTS
Description of studies
See Characteristics of included studies; Characteristics of excluded
studies.
Fifty-seven trials were identified as being potentially eligible for this
review. Thirty-six of these trials were excluded, see Characteristics
of excluded studies. Altogether, 20 trials were included involving
10,806 women, see Characteristics of included studies for details.
One trial, Fugo 1958, met the criteria for inclusion but no data
from this trial were used because the protocol called for manual
removal of the placenta at 10 minutes after delivery of the infant
and we felt that the methodology of this trial had high risk of bias
and was not translatable into clinical practice.
Of the remaining trials, four trials evaluated oxytocin versus
placebo only (Abdel-Aleem 2010; Jerbi 2007; Nordstrom 1997;
Pierre 1992), five trials evaluated oxytocin versus ergot alkaloids
only (Jago 2007; Moodie 1976; Orji 2008; Saito 2007; Sorbe
1978), three trials evaluated oxytocin plus ergometrine versus ergot alkaloids only (Barbaro 1961; Bonham 1963; Soiva 1964).
Eight trials had several treatment arms (Bader 2000; De
Groot 1996; Francis 1965; Ilancheran 1990; McGinty 1956;
Poeschmann 1991; Vaughan Williams1974). Bader 2000 had
three treatment arms, prophylactic oxytocin, acupuncture and
placebo; the acupuncture group was not included in this analysis. De Groot 1996, had three treatment arms prophylactic oxytocin, 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 this
analysis. Ilancheran 1990 included four arms: prophylactic oxytocin, ergometrine, ergometrine plus oxytocin and placebo and
all were included in this analysis. McGinty 1956 had four treatment arms, methergine, ergonovine, oxytocin or placebo and the
methergine and ergometrine arms were combined for this analysis.
Poeschmann 1991 had three treatment arms, oxytocin, sulprostone and placebo; the sulprostone arm was not included. Vaughan
Williams1974 included six arms: ergometrine with delivery of the
anterior shoulder, ergometrine with delivery of the baby, oxytocin
with delivery of the anterior shoulder, ergometrine plus oxytocin
with delivery of the anterior shoulder, diazepam in labour followed
by ergometrine plus oxytocin with delivery of the anterior shoulder, and placebo. For this trial, the two ergometrine arms were
combined for this analysis and the arm with diazepam was not
included.
Settings
Sensitivity analysis
Sensitivity analysis was performed to explore the effects of fixedeffect or random-effects analyses for primary outcomes with statistical heterogeneity, as described above.
This review includes trials from low-, middle-, and high-income

countries. All births were attended by midwives or physicians in
birth 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 2010

trial was conducted in Egypt and South Africa, Jerbi 2007 was
conducted in Tunisia, and Jago 2007 and Orji 2008 were conducted in Nigeria. The remainder of the trials were conducted
in 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), Sweden (Nordstrom 1997; Sorbe 1978), United Kingdom (Bonham
1963; Francis 1965; Vaughan Williams1974), and the United
States (McGinty 1956).
trials (Bader 2000; Ilancheran 1990; Jerbi 2007; Nordstrom

1997; Pierre 1992; Vaughan Williams1974). The dose also varied from 3 IU (Bader 2000) to 5 IU (De Groot 1996; Jerbi
2007; Pierre 1992; Poeschmann 1991) to 10 IU (Abdel-Aleem
2010; Nordstrom 1997; Vaughan Williams1974) to standard
dose (Ilancheran 1990). The non-oxytocin group was either
nothing (Abdel-Aleem 2010; Bader 2000; Ilancheran 1990; Jerbi
2007; Pierre 1992; Vaughan Williams1974) or a saline placebo
(Nordstrom 1997; Poeschmann 1991). In one trial (De Groot
1996), an oral placebo was given to allow blinding with a third
group given oral ergometrine.
Management of the third stage of labour
Oxytocin versus ergot alkaloids
In seven trials, the third stage was managed actively (at least two
of the components of active management described, or specified
as active) (Abdel-Aleem 2010; Francis 1965; Jerbi 2007; Orji
2008; Pierre 1992; Saito 2007; Vaughan Williams1974); four trials used expectant management (De Groot 1996; Nordstrom
1997; Poeschmann 1991; Sorbe 1978); seven trials did not mention management of the third stage (Bader 2000; Barbaro 1961;
Ilancheran 1990; Jago 2007; McGinty 1956; Moodie 1976; Soiva
1964) and one was mixed with components of both active or passive management used (Bonham 1963).
One trial, Fugo 1958, was conducted with expectant management
of the third stage until 10 minutes at which point manual extraction of the placenta was performed for teaching purposes. Given
this study had a high percentage of manual extractions, the was
felt to have high risk for bias and data from this trial were not
included.
In the nine trials that provided data for this analysis, the sample
size ranged from 10 to 1049 women. The oxytocin was given intramuscularly in two trials (De Groot 1996; Saito 2007), as an
IV bolus in six trials (Ilancheran 1990; Jago 2007; Moodie 1976;
Orji 2008; Sorbe 1978; Vaughan Williams1974) and both intramuscularly and intravenously in one trial (McGinty 1956). The
dose of oxytocin varied from 5 IU (De Groot 1996; Moodie 1976;
Saito 2007) to 10 IU (Jago 2007; McGinty 1956; Orji 2008; Sorbe
1978; Vaughan Williams1974). In the trial by Ilancheran 1990,
the only information given is that it was the standard dose. The ergot alkaloid arm was even more varied, ranging from slightly different preparations - ergometrine/ergonovine (De Groot 1996; Fugo
1958; Ilancheran 1990; Jago 2007; McGinty 1956; Moodie 1976;
Orji 2008; Sorbe 1978) and methergine (McGinty 1956; Saito
2007); 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), and
the standard dose in Ilancheran 1990; and different routes - all
IV except oral in De Groot 1996 and IM in Jago 2007 and Saito
2007. The trial by Fugo 1958 met criteria for inclusion, however,
did not provide any data due to concerns regarding significant
methodological bias.
Blood loss assessment

The majority of the trials (n = 13) used some form of measurement,
mainly by collecting and measuring blood plus weighing bloodsoaked guaze. Measuring the decrease in haematocrit (Hct) was
done in one trial, and for this trial total estimated blood loss (EBL)
was not an outcome reported (Jerbi 2007). In one trial, the total
blood loss was only reported in 54% of participants, so it was not
included in the analysis of postpartum haemorrhage (PPH) > 500,
PPH > 1000 or mean blood loss (Moodie 1976). No description of
the method of measurement was mentioned in the remaining four
trials (Ilancheran 1990; Jago 2007; McGinty 1956; Soiva 1964).
Comparisons
Oxytocin versus no uterotonics
Of the nine trials included in this analysis, the sample size

ranged from 10 to almost 2000 women. The oxytocin was
given intramuscularly in three trials (Abdel-Aleem 2010; De
Groot 1996; Poeschmann 1991), and as an IV bolus in six
Oxytocin plus ergometrine versus ergot alkaloids
In the six trials included in this analysis, the sample size ranged
from 10 to 1120 women. The ergometrine-oxytocin was generally given intramuscularly, although in one trial it was given intravenously (Ilancheran 1990). The dose was standard, one ampoule
containing oxytocin 5 IU and ergometrine 0.5 mg. The ergot alkaloid arm was more varied, ranging from slightly different preparations - ergometrine (Bonham 1963; Francis 1965; Ilancheran
1990), ergometrine maleate (Barbaro 1961), and methergine
(Soiva 1964); different doses - from 0.12 mg (Soiva 1964), to 0.5
mg (Bonham 1963; Francis 1965; Vaughan Williams1974), 0.10
mg (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 Francis
1965, and both in Barbaro 1961.
Risk of bias in included studies
Effects of interventions
In trials evaluating different interventions in the third stage of

labour, PPH is often the primary outcome. Assessment of PPH is
prone to bias if the staff making the assessments are not blind to the
intervention. In this review, all outcome assessments were blinded
in five trials. Because of the inherent bias in the remaining 15 trials
that either had no blinding or unclear description of the blinding
process, we changed the primary outcomes to include the use of
therapeutic uterotonics, which do not rely on the measurement of
blood loss.
The results are based on 20 trials.

For this update, four trials (Abdel-Aleem 2010; Bader 2000;
Jerbi 2007; Vaughan Williams1974) are added for a total of 10
trials included in this comparison (De Groot 1996; Ilancheran
1990; McGinty 1956; Nordstrom 1997; Pierre 1992; Poeschmann
1991), but McGinty 1956 provides no usable data for this part of
the review. Random sequence generation was considered adequate
in four trials, high risk in two trials, and was not clearly described
in four trials. Allocation concealment was considered adequate in
five trials that used sealed envelopes, opaque containers, or identical numbered envelopes or boxes containing trial medications.
Bader 2000 excluded 7% of women after randomisation on various secondary exclusion grounds: one in the control group and
seven in the oxytocin group. Poeschmann 1991 was stopped early
after two years of enrolment due to organisational issues and at
that 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 nine
trials included in this comparison (De Groot 1996; Ilancheran
1990; McGinty 1956; Sorbe 1978). Random sequence generation
was considered adequate in three trials, high risk in three trials,
and was not clearly described in four trials. Allocation concealment was considered adequate in four trials that used sealed envelopes, opaque containers, or identical numbered envelopes or
boxes containing trial medications. Moodie 1976 excluded 46%
of women from the blood loss outcome and as a result that data
were not included in this analysis; data were only used for analysis
of nausea and vomiting outcomes.

For this update, one trial (Vaughan Williams1974) was added to
this 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 high
risk in three trials and was not clearly described in three trials.
Allocation concealment was not clearly described in all six trials.
Primary outcomes
Over 4000 women were included from nine trials for this comparison.
There was significant statistical heterogeneity for both primary
outcomes: PPH greater than 500 mL and the need for therapeutic uterotonics so a random-effects analysis was used. Prophylactic
oxytocin compared with placebo reduced the risk of PPH greater
than 500 mL (average risk ratio (RR) 0.53; 95% confidence interval (CI) 0.38 to 0.74; six trials, 4203 women; random-effects,
T = 0.11, I = 78%, Analysis 1.1) and the need for therapeutic
uterotonics (average RR 0.56; 95% CI 0.36 to 0.87, four trials,
3174 women; random-effects; T = 0.10, I = 58%, Analysis 1.2).
The benefit of prophylactic oxytocin to prevent PPH greater than
500 mL was seen in all subgroups; randomised and quasi-randomised controlled trials, trials with active and expectant management of the third stage of labour, trials that used either IV or
IM delivery, and in trials that used doses of oxytocin less than 10
IU or 10 IU. The decreased use of therapeutic uterotonics was
only seen in the following subgroups: randomised trials with low
risk of bias (average RR 0.58; 95% CI 0.36 to 0.92; three trials,
3122 women; random-effects; T = 0.11, I = 69%, Analysis 2.5),
trials that performed active management of the third stage (RR
0.39; 95% CI 0.26 to 0.58; one trial, 1901 women; random-effects; heterogeneity not applicable, Analysis 2.6), trials that delivered oxytocin intravenously (RR 0.57; 95% CI 0.39 to 0.82; one
trial, 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; T = 0.02, I = 27%, Analysis 2.8). There was no
evidence of a difference between subgroups as indicated by the
subgroup interaction test.
Secondary outcomes
The following secondary outcomes were also improved with the

use of prophylactic oxytocin when compared with placebo: severe PPH, as defined by EBL greater than 1000 mL (average RR
0.62; 95% CI 0.44 to 0.87; five trials, 4162 women; randomeffects; T = 0.00, I = 0%, Analysis 1.3) and mean blood loss
(mean difference (MD) -99.46 mL; 95% CI -181.97 to -16.95
mL; five trials, 1402 women; random-effects; T = 6691.5, I =
85%, Analysis 1.4). Between the two groups, there was no significant difference in maternal haemoglobin concentration less than 9
g/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 the

placenta (Analysis 1.9), or nausea between delivery and discharge
(Analysis 1.12). There were no available data to analyse the following outcomes: diastolic blood pressure greater than 100 mmHg,
vomiting or headaches between delivery of the baby and discharge
from the hospital.
Primary outcomes
Over 3000 women were included from nine trials for this comparison.
outcomes: PPH greater than 500 mL and the need for therapeutic uterotonics so a random-effects analysis was used. Prophylactic
oxytocin was superior to ergot alkaloids in preventing PPH greater
than 500 mL (average RR 0.76; 95% CI 0.61 to 0.94; five trials,
2226 women; random-effects; T = 0.00, I = 0%, Analysis 3.1).
The benefit of oxytocin over ergot alkaloids to prevent PPH > 500
mL only persisted in the subgroups of quasi-randomised trials (RR
0.71, 95% CI 0.53 to 0.96; three trials, 1402 women; random-effects; T = 0.00, I = 0%, Analysis 4.1) 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; random-effects; T = 0.00,
I = 0%, Analysis 4.2).There was no benefit of using prophylactic
oxytocin over ergot alkaloids to prevent PPH greater than 500 mL
when the following subgroups were analysed: trials that used only
IV or IM delivery (Analysis 4.7) and trials that used oxytocin at a
dose of less than 10 IU or 10 IU (Analysis 4.8).
There was a trend towards a benefit of prophylactic oxytocin over
ergot alkaloids to decrease the need for therapeutic uterotonics,
but that benefit was not significant (average RR 0.70; 95% CI
0.38 to 1.29; three trials,1167 women; random-effects; T = 0.18,
I = 62%, Analysis 3.2). Subgroup analyses did show a significant
benefit of prophylactic oxytocin over ergot alkaloids to prevent the
need for therapeutic uterotonics in quasi-randomised trials (RR
0.42, 95% CI 0.19 to 0.91; one trial, 343 women, Analysis 4.5) or
trials that used prophylactic oxytocin as part of active management
of the third stage of labour (RR 0.54, 95% CI 0.34 to 0.85; two
trials, 943 women; random-effects; T = 0.00, I = 0%, Analysis
4.6). No benefit was seen when trials that used only IV or only
IM delivery (Analysis 4.7) or in trials that used doses of oxytocin
less than 10 IU or 10 IU (Analysis 4.8) were analysed separately.
Secondary outcomes
Use of prophylactic oxytocin was associated with fewer side effects

compared with use of ergot alkaloids; including decreased nausea
between 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; T = 0.41, I = 41%, Analysis 3.12) and vomiting
(average RR 0.07; 95% CI 0.02 to 0.25; three trials, 1091 women;

random-effects; T = 0.45, I = 30%, Analysis 3.11). There was
no significant difference in severe PPH greater than 1000 mL
(Analysis 3.3), mean blood loss (Analysis 3.4), the need for blood
transfusion (Analysis 3.6), mean length of the third stage, manual
removal of the placenta (Analysis 3.9), diastolic blood pressure
greater than 100 mmHg (Analysis 3.10), or headaches between
delivery of the baby and discharge from the hospital (Analysis
3.11). There were no available data to analyse the following outcomes: maternal haemoglobin concentration less than 9 g/dL or
third stage length greater than 30 minutes.
Primary outcomes
Over 2800 women were included from six trials for this comparison.
outcomes: PPH greater than 500 mL and the need for therapeutic
uterotonics so a random-effects analysis was used.
There was no statistical benefit seen in the combination of oxytocin
and ergometrine versus ergometrine alone to prevent PPH greater
than 500 mL (average RR 0.90; 95% CI 0.34 to 2.41; five trials,
2891 women; random-effects; T = 0.89, I = 80%, Analysis
5.1). All trials included in this analysis were considered high-risk,
quasi-randomised trials so a subgroup analysis of only low-risk
randomised trials was not performed. There was no benefit of
using the combination of oxytocin and ergometrine seen when
the following subgroups were analysed separately: trials that used
active or expectant management (Analysis 6.2) or trials that used
only IV or IM delivery (Analysis 6.3).
There were no data from these trials to analyse second primary
outcome, the need for therapeutic uterotonics.
Secondary outcomes
In one trial involving 34 women, the combination of oxytocin

and ergometrine was associated with higher mean blood loss (MD
61.0 mL; 95% CI 6.00 to 116.00 mL; test for heterogeneity not
applicable, Analysis 5.4); however, this trial did not have the randomisation or allocation concealment protocol clearly described.
There was no significant difference in severe PPH greater than
1000 mL (Analysis 5.3), the need for blood transfusion (Analysis
5.6), mean length of the third stage (Analysis 5.8), or manual removal of the placenta (Analysis 5.8). There were no available data
to analyse the following outcomes: maternal haemoglobin concentration less than 9 g/dL third stage length greater than 30 minutes, diastolic blood pressure greater than 100 mmHg, vomiting,
nausea, or headaches between delivery of the baby and discharge
from the hospital.
10
DISCUSSION
This review compares the use of prophylactic oxytocin at any dose
given during the third stage of labour to placebo and ergot alkaloids. Overall, the data show a benefit of using prophylactic oxytocin compared with placebo to reduce postpartum haemorrhage
(PPH) greater than 500 mL and to reduce the need for therapeutic
uterotonics. Given that this analysis included trials with unclear
or high-risk random sequence generation and allocation concealment, a subgroup analysis of only randomised trials with low risk of
methodologic was performed. After analysing only these low-risk
of bias randomised trials, the benefit in preventing PPH greater
than 500 mL remains statistically significant and of a similar magnitude of all trials (all trials risk ratio (RR) 0.53, 95% confidence
interval (CI) 0.38 to 0.74; low-risk randomised trials only RR
0.61, 95% CI 0.48 to 0.77). The benefit of oxytocin to prevent
PPH greater than 500 mL was seen regardless of the management
of the third stage of labour, the route of delivery, or the dose of
oxytocin given. This data strongly support the use of prophylactic
oxytocin over placebo during the third stage of labour to minimise
PPH greater than 500 mL.
The majority of the trials included in this analysis were not blinded
and therefore increased the risk of bias when using the subjective
outcome of measured blood loss. As a result, we modified the primary outcomes to include the need for therapeutic uterotonics,
which do not rely on absolute blood loss measurements but may
more objectively reflect severe blood loss. Prophylactic oxytocin
versus placebo also decreased the need for therapeutic uterotonics, further supporting the clinical benefit of using prophylactic
oxytocin during the third stage of labour to prevent PPH. This
benefit persisted when only randomised trials with low risk of
methodologic bias were analysed (all trials RR 0.56, 95% CI 0.36
to 0.87; low-risk trials RR 0.58, 95% CI 0.36 to 0.92). Based
on the subgroups analysed, the benefit of prophylactic oxytocin
to decrease the need for therapeutic uterotonics is seen only in
trials where oxytocin is given as part of the active management
of the third stage of labour and at a dose of 10 IU delivered as
an IV bolus. This suggests that the maximum benefit of oxytocin
may be seen when used as one component of active management
of the third stage and that simply administering oxytocin alone
may not be adequate to prevent PPH. Further studies on the specific aspects of active management of the third stage of labour are
needed to help answer the question of what component of active
management provides the most benefit. Regarding the delivery of
oxytocin, our subgroup analysis shows a benefit of decreasing the
use of therapeutic uterotonics only when oxytocin is 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 prevent PPH greater
than 500 mL and there was a trend to decrease the use of therapeutic uterotonics, albeit not statistically significant. When looking
at the analysis of the IM subgroup in more detail, there are two
small trials that used IM oxytocin and showed no benefit and one
large trial that did show a benefit when giving oxytocin IM. The
larger trial, Abdel-Aleem 2010, had a more rigorous study design
than the others included in this analysis and did show a benefit
of IM oxytocin to prevent the need for therapeutic uterotonics. If
only the Abdel-Aleem 2010 was included in the subgroup analysis,
IM delivery would also have significantly decreased the need for
therapeutic uterotonics, so it is likely that either IV or IM delivery
of oxytocin provides clinical benefit.
Importantly, using prophylactic oxytocin in the third stage of
labour did not increase the need for manual removal of the placenta when compared to placebo. Using prophylactic oxytocin in
the third stage of labour offers a significant benefit of preventing
PPH and the need for therapeutic uterotonics without increasing
risks of adverse events.
After inclusion of data from five new studies (Jago 2007; Moodie
1976; Orji 2008; Saito 2007; Vaughan Williams1974), a new finding of this review is that prophylactic oxytocin is more efficacious
in preventing PPH greater than 500 mL than ergot alkaloids. This
benefit is not statistically significant when only the low-risk randomised trials are analysed separately (RR 0.82, 95% CI 0.58 to
1.15, random-effects, T = 0.0, I = 0%). Of the nine trials included in this analysis, only three had adequate random sequence
generation and only four had adequate allocation concealment,
suggesting significant risk of bias in the analysis of all trials. The
more accurate analysis is that of only trials with low methodologic
bias, as a result, there is no high-quality evidence to suggest a
significant benefit from using prophylactic oxytocin versus ergot
alkaloids to prevent PPH greater than 500 mL. There is a trend
towards a benefit of prophylactic oxytocin compared to ergot alkaloids to decrease the need for therapeutic uterotonics, but this
was not statistically significant. However, even though there is not
strong evidence supporting the use of prophylactic oxytocin over
ergot alkaloids to prevent PPH greater than 500 mL or the need
for therapeutic uterotonics, there is also no evidence that ergot
alkaloids are better to prevent PPH. In addition, prophylactic oxytocin is associated with fewer side effects, making the routine use
of prophylactic oxytocin the preferred uterotonic to prevent PPH
compared with ergot alkaloids.
At this time, there is little evidence to support any additive benefit
when using oxytocin plus ergometrine, and there is some limited
evidence from this review that the combination may increase mean
blood loss when compared to ergot alkaloids alone. The trials
used for this analysis have high risk of methodologic bias and as a
result, there are very limited data to rigorously analyse these two
treatment groups for a clinical benefit.
AUTHORS CONCLUSIONS
11
Implications for practice

Before making major changes to practice based on the current
review, further information from other reviews considering the
role of active management (Begley 2011), the timing of delivery of
oxytocin (Soltani 2010), of prostaglandins (Tunalp 2012), and of
ergot alkaloids (McDonald 2004) needs to be taken into account.
Nevertheless, given the benefit of prophylactic oxytocin in terms of
reducing postpartum haemorrhage (PPH) and the need for therapeutic uterotonics when compared to using no uterotonic, there
appears to be a strong evidence in favour of using prophylactic
oxytocin. Taking into account the data from both primary outcomes, in order to achieve maximal benefit providers may opt to
implement a practice of giving prophylactic oxytocin as part of
the active management of the third stage of labour at a dose of
10 IU given as an intravenous (IV) bolus. If IV delivery is not
possible, intramuscular (IM) delivery may be used as this route
of delivery did show a benefit to prevent PPH greater than 500
mL and there was a trend to decrease the use of therapeutic uterotonics, albeit not statistically significant. In addition, the use of
prophylactic oxytocin does not increase the risk of adverse events,
specifically the need for manual removal of the placenta. This has
to be tempered, however, by the knowledge that a number of the
trials included have unclear or high risk of study bias and that the
translation of this data to all international birth centres is limited
due to the majority of studies taking place in developed countries.
Similarly, the balance of evidence does not support the prophylactic use of ergot alkaloids alone (when compared to either oxytocin alone, or to ergometrine-oxytocin). In addition, the use of
prophylactic oxytocin decreases the risk of maternal side effects,
specifically nausea and vomiting, when compared to ergot alkaloids, making oxytocin the preferred option for routine management of the third stage of labour.
There is no benefit seen when using a combination of oxytocin
and ergometrine versus ergot alkaloids alone.
Implications for research

Birth centres in low- and middle-income countries shoulder the
burden of most of the complications arising from the management
of the third stage of labour, and there needs to be more studies in
these countries to increase the translatability of these data to these
high-risk centres. In order to improve outcomes worldwide, especially where routine management of the third stage is expectant,
there needs to be better evidence on which components of the active management of the third stage of labour contribute to prevention of PPH. A definition of PPH is urgently needed with use of an
objective measure and not the subjective evaluation by providers of
what constitutes PPH. The optimal dosing of oxytocin and route

of administration need to be determined in addition to dispelling
concerns of potential side effects. Delivery systems for oxytocin
need to be studied, especially in developing countries, such as the
use of BD-Uniject Prefillable Injection System (Franklin Lakes,
NJ, USA) to deliver prophylactic oxytocin. Another aspect of the
management of the third stage may affect the amount of blood lost
is delayed cord clamping of the neonate. There is not sufficient
evidence on the use of immediate/early or delayed cord clamping
in order to improve neonatal outcomes. There is a need for a definition of what is delayed cord clamping, on whether it is clinically
useful, and if so, at what gestational age. The lack of uniformity
in clinical studies of the management of the third stage questions
the strength of existing evidence, specifically in the lack of standard definitions of various procedures (i.e. active management)
and outcomes (i.e. PPH). It also makes it very difficult for training
of healthcare personnel and for scaling up of these procedures and
interventions worldwide.
Once there is a consensus on the effective components of the active
management of the third stage of labour, there is a need to conduct
clinical studies to determine why active management of the third
stage is not utilised consistently.
These trials should study outcomes which are of relevance to the
majority of postpartum women such as fatigue, the ability to care
for their babies, and those more rare but serious complications
associated with severe morbidity, such as renal failure, transfusion
of blood products, coagulopathy, intrauterine infections, hysterectomy, and the worst outcome, mortality.
ACKNOWLEDGEMENTS
Edgardo Abalos and Virginia Diaz for their contribution to assessing the reports from the updated search; completing the Characteristics 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 this
review.
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 largest
single funder of the Cochrane Pregnancy and Childbirth Group.
The views and opinions expressed therein are those of the authors
and do not necessarily reflect those of the NIHR, NHS or the
Department of Health.
12
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17
CHARACTERISTICS OF STUDIES
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 a
computer-generated random number sequence. The allocated group was noted inside
opaque sealed envelopes. Not blinded
Participants
Pregnant woman who were expected to have a vaginal delivery at Womens Health Center
Assiut, Egypt and the Department of Obstetrics and Gynecology, East London Hospital
Complex, 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 palpation
of uterus after delivery
Interventions
All interventions were given after delivery of the anterior shoulder or after delivery of
the neonate
1) 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 whole
surface of the uterus
3) Combined management with 10 IU IM oxytocin plus uterine massage
In all 3 groups active management was performed: the umbilical cord was clamped soon
after delivery of the neonate and the placenta was delivered by controlled cord traction
when the uterus became contracted. A plastic drape or a low profile plastic bedpan was
placed under the mothers buttocks after delivery of the neonate to collect the blood
lost 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-minute
collection time
Comparison 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, delivery
of the placenta within 30 minutes of neonate delivery, use of additional uterotonics or
other procedures to manage haemorrhage, Hb level after 12-24 hours of < 8 g in 100
mL or < 10 g in 100 mL (South Africa only), blood transfusion, MRP or placenta not
delivered in 30 minutes, maternal morbidity and adverse effects (nausea, vomiting, pain
or discomfort)
Notes
Risk of bias
Bias
Authors judgement
Random sequence generation (selection Low risk

bias)
Support for judgement

Women were randomly allocated to 1 of
3 groups by selecting the next number in
a computer-generated random number se-
18
Abdel-Aleem 2010
(Continued)
quence
Allocation concealment (selection bias)
Low risk
The allocated group was noted inside

opaque sealed envelopes
Blinding (performance bias and detection Unclear risk

bias)
All outcomes
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 confirmation that the allocation was randomised
Not blinded.
Participants
180 women in the third stage of labour at the Gynaecological Clinic of the University
of Witten/Herdecke, part of the Marienhospital Witten
Primary grounds for exclusion included complicated pregnancies requiring oxytocin
stimulation during delivery, multiple pregnancies, weight over 100 kg, uterus myomatosus, previous treatment with oxytocin and conditions tending to increased blood loss
Secondary grounds were the need for surgical intervention (forceps or vacuum) in delivery, unusually high levels of blood loss of unknown origin and placenta delivery times
longer 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. The
time 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 (to
measure blood loss). The Hb levels of each patient were measured on arrival in the
delivery room and on leaving the hospital
The midwives involved were advised not to interfere postpartum with the uterus and
umbilical cord--expectant management
Comparison 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
19
Bader 2000
(Continued)
Notes
Only the oxytocin and control group data is used in the analysis
Risk of bias
Bias
Authors judgement
Random sequence generation (selection Unclear risk

bias)
Method of randomisation not described

other than allocation was randomised
Not described.
Unclear risk
Blinding (performance bias and detection High risk

bias)
All outcomes
Not blinded.

All outcomes
High risk
There were a total of 20 exclusions on various secondary exclusion grounds: 1 in the

control group, 12 in the acupuncture group
and 7 in the oxytocin group, leaving a total
of 160 patients
Low risk
All outcomes reported.
Barbaro 1961
Methods

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 ergometrine 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 the
third stage
Blood loss was carefully measured; allowances were made for contamination with liquor
or urine and for blood contained within swabs and packs
Outcomes
PPH (> 600 mL); average blood loss 266 vs 219 mL (SD not given); average duration
of 3rd stage 16 vs 13 minutes (SD not given)
Notes
20
Barbaro 1961
(Continued)
Risk of bias
Bias
Authors judgement

bias)
No randomisation method described.
No concealment method described.
Unclear risk

bias)
All outcomes
Not blinded.

All outcomes
Low risk
Adequate.
Low risk
Other bias
Unclear risk
Unclear.
Bonham 1963
Methods

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: multiple
pregnancies, previous PPH or manual removal, forceps and breech deliveries must be
post-randomisation exclusions but does not state how many were randomised), parity 4
or 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/fundal
pressure (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 linen
and swabs used during the perineal repair
Outcomes
Primary PPH (> 568 mL estimated by adding to measured quantity a figure for loss
on linen and swabs used for perineal repair); mean blood loss (154 vs 178 mL, SD not
given); mean length of third stage (6.3 vs 6.2 minutes, SD not given); prolonged third
stage (> 30 minutes); MRP
Notes
21
Bonham 1963
(Continued)
Risk of bias
Bias
Authors judgement

bias)
Randomisation by numbers; procedure not

described in detail.
Not described.
Unclear risk

bias)
All outcomes
Inadequate.

All outcomes
Low risk
Attrition described; no loss of data.
Low risk
Other bias
Unclear risk
Unclear.
De Groot 1996
Methods

Hospital pharmacy supplied numbered boxes of tablets and ampoules according to computer-generated randomisation list. Informed consent asked in early labour. Assigned
before delivery of babys head. Double-blind for oral ergometrine vs placebo and unblinded for ergometrine and/or placebo vs oxytocin. Randomisation 1:2:2, oxytocin to
ergometrine to placebo. Multicentre
Participants
2 university hospitals, a midwifery school and independent midwives in and around

Nijmegen, Netherlands. Women expecting to deliver in one of these settings, and who
did not develop following exclusion criteria: refusal, cardiovascular disease/hypertension,
multiple pregnancy, non-cephalic presentation, polyhydramnios, tocolysis 2 hours prior
to delivery, anticoagulant therapy, stillbirth, APH, chemical induction or augmentation
(oxytocin, prostaglandins), instrumental/operative delivery (some of these must have
been 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 natural
childbirth 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 timing
of cord clamping/cutting). When mother feels contractions or there are signs of separation, maternal effort encouraged, adopting position to aid gravity. If necessary, flat hand
22
De Groot 1996
(Continued)
on abdomen to act as brace to aid pushing. Re-attempt if placenta does not deliver spontaneously. If haemorrhage, administer extra oxytocics and/or controlled cord traction
Blood loss measured gravimetrically--fresh perineal pad under perineum to absorb blood
or fluid; gauzes and pads collected until 1 hour after delivery of placenta and weighed.
100 g increase in weight considered equivalent to 100 mL blood
Comparison 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 third
stage (11 (range 4-90), 15 (2-90), 14 (3-55) in oxytocin, ergometrine and placebo groups
respectively. No information about whether mean or median, and SD not given); blood
pressure 15, 30, 45 and 60 minutes after delivery of placenta, in institutional deliveries
only (oral ergometrine showed no significant elevation); use of further oxytocics; MRP;
transfusion
Notes
Risk of bias
Bias
Authors judgement

bias)
Numbered boxes of tablets and ampoules according to computer-generated

randomisation list
No difference could be detected between

boxes.
Low risk

bias)
All outcomes
Not blinded.

All outcomes
Low risk
Attrition minimal and described.
Low risk
All outcomes described.
Other bias
Unclear risk
Unclear.
Francis 1965
Methods

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 was
anticipated (previous PPH, instrumental or breech deliveries, twin pregnancies, APH,
severe anaemia, IV oxytocin for induction or augmentation)
23
Francis 1965
(Continued)
Interventions
(1) 1 mL IM ergometrine-oxytocin (5 IU oxytocin + 0.5 mg per 1 mL ergometrine) after

delivery 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 water
after placental delivery (n = 183).
(3) 1 mL IM water after delivery of baby and cord divided, AND 0.5 mg IM ergometrine
after placental delivery (n = 167).
The collection of blood commenced with birth of the baby and continued for one hour
after delivery. Swabs were rung out manually. Blood loss was measured in a graduated
jug
When signs of descent became apparent, the placenta delivered with uterine massage
and 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 the
review, loss of > 20 oz has been taken as PPH; retained placenta (> 20 minutes)
Notes
Risk of bias
Bias
Authors judgement
Random sequence generation (selection High risk

bias)
Treatments were rotated, no random sequence generated.
Not described.
Unclear risk
Blinding (performance bias and detection Low risk

bias)
All outcomes
Vials were blinded to personnel, participants and outcome assessors

All outcomes
Low risk
Low risk
No attrition.
Other bias
Unclear risk
Unclear.
Fugo 1958
Methods

Numbered identical drug packages administered in rotation. Number meaningless to
obstetrician.
Blinded.
Participants
Women delivering in a hospital in Chicago, USA.

No details given of inclusion/exclusion criteria, but description of study participants
showed that half had labour over 8 hours, and 98% received some anaesthetic agent
24
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 valeramideHCl) n = 151.
Blood lost when the placenta separated was collected in a basin containing 200 mL of
4% sodium oxalate solution as an anticoagulant and was measured in a graduated jug
Expectant 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 haemorrhage or undelivered within 10 minutes); length of third stage (not significantly different between groups but data only given for those delivered spontaneously, i.e. within
10 minutes); blood loss with placenta; (1 hour postpartum (?) average blood loss 50.2
vs 40.8 mL; no SDs given)
Notes
Given the high number of manual placental removals for teaching purposes, the data
from this trial were not used due to concern for methodologic bias and lack of clinical
translatability of this trial as MRP this early in the third stage is not standard of care
Risk of bias
Bias
Authors judgement

bias)
Randomisation method not described.
Identical packages were used.
Low risk

bias)
All outcomes
Blinded.

All outcomes
Low risk
Low risk
No significant attrition.
Other bias
Unclear risk
Unclear.
25
Ilancheran 1990
Methods

Consecutive participants divided equally into 4 subgroups, distribution being done on
a random basis
Participants
Women in spontaneous labour between 38 and 42 weeks gestation with normal vertex
deliveries in hospital in Singapore. 17/20 were multigravid
Interventions
Control group and 3 groups given IV uterotonic in standard doses with the delivery of
the anterior shoulder
A. 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 groups
but no differences between the groups); PPH
Notes
Risk of bias
Bias
Authors judgement

bias)
Women randomly assigned into groups; no

computer sequence.
Unclear.
Unclear risk
Blinding (performance bias and detection Unclear risk

bias)
All outcomes
Not described.

All outcomes
Unclear risk
Not described.
Unclear risk
Not described.
Jago 2007
Methods

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 at

a Hospital in Nigeria
Excluded those with history of hypertensive disorders of pregnancy, hypertension,
26
Jago 2007
(Continued)
chronic renal disease, endocrine disorders, vascular or cardiac disease, on anticoagulant

therapy, having epidural anaesthesia, with allergy to one of the drugs under study, and
those 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 described
Technique for measurement of blood loss not described.
Outcomes
Elevated blood pressure (> 140/90 mmHg).

Estimated blood loss (mL).
Notes
Risk of bias
Bias
Authors judgement

bias)
Computer-generated table of random

numbers.
Labelled envelopes containing the drug.
Low risk

bias)
All outcomes
Not blinded.

All outcomes
Low risk
No loss to follow-up reported for the outcome included in the review
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 vaginally
in a hospital in Tunisia
Excluded: placenta previa, APH, non-cephalic presentation, history of PPH, intrauterine
death, 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).
27
Jerbi 2007
(Continued)
Authors say that the comparison arms are active vs expectant management--active is
defined as receiving prophylactic oxytocin. The third stage of labour was managed in the
same way for all women: immediate cord clamping and cutting, controlled cord traction
and gentle fundal pressure
Outcomes
Decrease in haematocrit, decrease in Hb concentration, duration of the third stage of

labour (min), MRP, maternal Hb concentration, postpartum anaemia
Total blood loss was not an outcome.
Notes
Risk of bias
Bias
Authors judgement

bias)
Not stated.
Not stated. Authors only say: ...women

were randomly allocated to...
Unclear risk

bias)
All outcomes
Not blinded.

All outcomes
Low risk
No loss to follow-up reported for the outcomes included in the review
Unclear risk
No data.
Other bias
Unclear risk
No data.
McGinty 1956
Methods
Quasi-randomised trial.
Cases picked at random.
Unblinded.
Participants
All vaginally delivered under pudendal block and demerol/scopolamine, in hospital in

United 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
28
McGinty 1956
(Continued)
Outcomes
Diastolic and systolic blood pressure 5, 15 and 60 minutes after administration - although
data not provided for control group; estimated severe blood loss over 1000 mL mentioned
for 1 women in methergine series and 1 in control group (not included in data tables as
unlikely to have been systematically recorded)
Notes
Risk of bias
Bias
Authors judgement

bias)
cases picked at random. Randomisation

technique not described
Allocation concealment not described.
Unclear risk

bias)
All outcomes
Unblinded.

All outcomes
Unclear risk
Unclear.
Unclear risk
Unclear.
Moodie 1976
Methods
Not stated, authors say ...the allocation being at random....
Participants
148 women with instrumental deliveries (143 forceps, 5 vacuum) under epidural anaesthesia in a Hospital in New Zeland
Excluded multiple births and breech presentation.
Interventions

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 not
included in this review
Risk of bias
29
Moodie 1976
(Continued)
Bias
Authors judgement

bias)
Not stated.
Not stated. Authors only say: ...the allocation being at random...
Unclear risk

bias)
All outcomes
Not blinded.

All outcomes
Low risk
No (for nausea and vomiting). 46% of

women excluded from outcome blood
loss, thus this outcome was not included
in the review
Unclear risk
No data.
Other bias
Unclear risk
No data.
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 estimated
to have been absorbed by surgical cloths and tissues
Outcomes
Blood loss; additional oxytocin (data tables give methylergometrine; clarification about
other oxytocics sought from authors), Hb, blood transfusion; manual removal
Notes
Additional oxytocin (data tables give methylergometrine; clarification about other oxytocics sought from authors)
Risk of bias
Bias
Authors judgement
30
Nordstrom 1997
(Continued)

bias)
2 sets of ampoules prepared and numbered

according to computer-generated schedule
Low risk
No difference in appearance of ampoules.

bias)
All outcomes
Contents unknown to women or caregivers.

All outcomes
Low risk
No significant attrition.
Low risk
Orji 2008
Methods

Eligible participants who gave informed consent were randomly allocated to either oxytocin or ergometrine group. Allocation was done by opening a sealed envelope from a
pack that had been arranged serially. Not blinded
Participants
600 consenting women in labour with no illnesses or added risk in the active phase at 2
tertiary hospitals in Nigeria
Excluded those with hypertensive disorders of pregnancy, packed cell volume < 30%,
history of PPH, haemoglobinopathy, heart disease or caesarean section
Interventions

B. ergometrine 0.25 mg IV (n = 303).
In both groups the third stage of labour was managed actively
Blood 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, estimated
blood loss (mL, nausea, vomiting, headaches, elevated blood pressure, need for additional
oxytocics
Notes
Risk of bias
Bias
Authors judgement

bias)
Randomly assigned to previously determined sequence.
...sealed envelopes arranged serially....
Low risk
31
Orji 2008
(Continued)

bias)
All outcomes
Not blinded.

All outcomes
Low risk
No (for the outcomes reported).
Unclear risk
No data.
Other bias
Unclear risk
No data.
Pierre 1992
Methods
Leaflets marked from 1-1000 alternate allocation this made possible a control of selection
bias at entry by the authors as the order in the trial had the same chronology as the date
and 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 shoulder
Blood loss was estimated by placing a large plastic sheet under the patients bottom from
delivery of the infant until delivery of the placenta
Third stage managed actively.
Outcomes
Blood loss; length of third stage, MRP, maternal side effects
Notes
Risk of bias
Bias
Authors judgement

bias)
Envelopes labelled in sequence. selection

at entry into the hospital. no random sequence
Envelopes sealed and randomly labelled.
Low risk

bias)
All outcomes
Not blinded.

All outcomes
Low risk
32
Poeschmann 1991
Methods
Randomised trial.
Hospital pharmacy supplied numbered boxes. Allocation of boxes was by order of entry
to 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 spontaneous
vaginal 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 third
stage was performed
Blood loss was calculated by measuring the amount of blood and clots collected in
the bedpan and by weighing the bloodstained swabs and linen obtained during 1 hr
postpartum
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
Bias
Authors judgement

bias)
A random treatment allocation list was previously prepared.
Adequate.
Low risk

bias)
All outcomes
Nurse not working in labour room prepared the injection. injection type blinded
to participant and personnel

All outcomes
Low risk
Other bias
High risk
Trial stopped at 2 years due to organisational issues.
33
Saito 2007
Methods
Quasi random: ...women were allocated to a group in a temporal manner (...) selected
weekly or monthly, as determined by each hospital, in alternate shifts
Participants
343 consenting women with low risk of PPH at 4 hospitals in Japan

Excluded: contraindication for ergometrine, multiple pregnancies, non-cephalic presentation, uterine fibroids or deformity, placenta previa, history of PPH, parity > 4, previous
caesarean 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 clamping
and cutting, controlled cord traction
Blood loss was calculated objectively by measuring the amount of collected blood and by
the weighting of surgical sponges, clothes and drapes by experienced attending midwives
who were not involved in the administration of prophylactic oxytocics
Outcomes
Blood loss (mL), maternal blood pressure, nausea, vomiting, headache, chest pain, dyspnoea, duration of the third stage (min), additional oxytocics, blood transfusion, MRP
Notes
Risk of bias
Bias
Authors judgement

bias)
Quasi random: ...women were allocated to

a group in a temporal manner (...) selected
weekly or monthly, as determined by each
hospital, in alternate shifts.
Inadequate. ...women were allocated to a

group in a temporal manner (...) selected
weekly or monthly, as determined by each
hospital, in alternate shifts.
High risk

bias)
All outcomes
Not blinded.

All outcomes
Low risk
No loss to follow-up reported for the outcomes included in the review
Unclear risk
No data.
Other bias
Unclear risk
No data.
34
Soiva 1964
Methods
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 mg
IM 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
Bias
Authors judgement

bias)
every third participant. No random sequence generation used
No allocation concealment described.
Unclear risk

bias)
All outcomes
Not blinded.

All outcomes
Unclear risk
Unclear.
Unclear risk
Unclear.
Sorbe 1978
Methods
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 buttocks
of the women immediately after the delivery of the child. The measurement of the blood
loss during the 2 hour period was then performed with a graduated glass
35
Sorbe 1978
(Continued)
Outcomes
Blood loss; MRP, placental separation time.
Notes
Risk of bias
Bias
Authors judgement

bias)
Randomisation by odd/even hospital

record numbers.
No allocation concealment described.
Unclear risk

bias)
All outcomes
Not blinded.

All outcomes
Not described.
Unclear risk
Vaughan Williams1974
Methods
Patients were randomly assigned to one of six treatment groups. No information about
blinding or allocation concealment described
Participants
51 women in labour at the Royal Sussex County Hospital, Brighton, who required an
IV infusion. Inclusion criteria was no known antenatal complications and expectation
to have a spontaneous vaginal delivery. Patients with complications during labour were
excluded. 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 mg
plus 5 IU oxytocin IM with delivery of the anterior shoulder
Placenta was delivered actively by controlled cord traction.
Blood loss was measured by collection in a kidney dish placed below the perineum after
delivery of the infant
Comparisons for this review are group 1 vs. 4, groups 2 and 3 vs. group 4, and groups
5 and 6 vs group 2 and 3
Outcomes
Primary outcomes were mean CVP and blood loss.
36
(Continued)
Notes
Risk of bias
Bias
Authors judgement

bias)
Randomisation not described.
Allocation concealment not described.
Unclear risk

bias)
All outcomes
No blinding.

All outcomes
Low risk
Unclear risk
Unclear.
APH: antepartum haemorrhage

CVP: central venous pressure
Hb: haemoglobin
hr: hour
IM: intramuscular
IU: international units
IV: intravenous
min: minute
MRP: manual removal of placenta
PPH: postpartum haemorrhage
SD: standard deviation
vs: 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 the
placenta
Dickinson 2009
Comparison of oxytocin, misoprostol and no additional medication for the third-stage management after second
trimester medical termination
Docherty 1982
Oxytocin versus ergometrine-oxytocin (subject of separate review)
37
(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 inadequate
observations were obtained. No other reasons given, and no indication of whether these women were missing
in similar proportions from the 5 intervention groups
Gerstenfeld 2001
Comparison of oxytocin with misoprostol (subject of separate review)
Hacker 1979
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 of
administration
Khan 1997
Comparison of prophylactic oxytocin within context of active management vs oxytocin after placental delivery
within context of expectant management (subject of separate review by Prendiville et al: Active versus expectant
management of third stage of labour - see Prendiville 2000).
Kundodyiwa 2001
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 and
German. No clinical data available from authors
Newton 1961
Oxytocin or placebo given after delivery of the placenta.
Nieminen 1963
Parsons 2004
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
38
(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 of
administration
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 to
give 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 not
meet inclusion criteria, leaving 10 and 15 in trial comparing oxytocin vs no oxytocin within active management.
Primary outcome plasma oxytocin concentration
Tita 2012
Vasegh 2005
Comparison of active vs expectant management of the third stage of labour (subject of a separate review). Study
design information not available
Wetta 2011
Yuen 1995
Oxytocin vs ergometrine-oxytocin (subject of separate review)
IU: international unit

IV: intravenous
vs: versus
39
DATA AND ANALYSES
Comparison 1. Oxytocin versus no uterotonics
No. of
studies
No. of
participants
1 PPH (clinically estimated blood

loss > or = 500 mL)
2 Therapeutic uterotonics
3 Severe PPH (clinically estimated
blood loss > or = 1000 mL)
4 Mean blood loss (mL)
4203
Risk Ratio (M-H, Random, 95% CI)
0.53 [0.38, 0.74]
4
5
3174
4162

0.56 [0.36, 0.87]

0.62 [0.44, 0.87]
1402
Mean Difference (IV, Random, 95% CI)
5 Maternal haemoglobin
concentration (Hb) < 9 g/dL
6 Blood transfusion
7 Third stage greater than 30
minutes
8 Mean length of third stage
(minutes)
9 Manual removal of the placenta
10 Diastolic blood pressure >100
mm Hg between delivery of the
baby and discharge from the
labour ward
11 Vomiting between delivery of
the baby and discharge from
the labour ward
12 Nausea between delivery of the
labour ward
13 Headace between delivery of
the labour ward
1645
-99.46 [-181.97, 16.95]

0.78 [0.60, 1.00]
3
1
3120
1947

Risk Ratio (M-H, Fixed, 95% CI)
0.89 [0.44, 1.78]

2.55 [0.88, 7.44]
294
-3.61 [-9.06, 1.83]
6
0
4320
0

1.26 [0.88, 1.81]

0.0 [0.0, 0.0]
0.0 [0.0, 0.0]
52
0.29 [0.01, 6.74]
0.0 [0.0, 0.0]
Outcome or subgroup title
Statistical method
Effect size
Comparison 2. Oxytocin versus no uterotonics--subgroup analyses

loss > or = 500 mL); randomised
v. quasi-randomised trials
1.1 Randomised trials only
(low risk of bias)
No. of
studies
No. of
participants
4203
0.53 [0.38, 0.74]
3171
0.61 [0.48, 0.77]
Statistical method
Effect size
40
1.2 Quasi-randomised trials

(high risk of bias)
loss > or = 500 mL); active v.
expectant management
2.1 Active management
2.2 Expectant management
loss > or = 500 mL); IM v. IV
oxytocin
3.1 IV oxytocin
3.2 IM oxytocin
loss > 500 mL); oxytocin dose
< 10 IU v. 10 IU
4.1 Oxytocin dose < 10 IU
4.2 Oxytocin dose 10 IU
5 Therapeutic uterotonics;
randomised v.
quasi-randomised trials
5.1 Randomised trials (low
risk of bias)
(high-risk of bias)
6 Therapeutic uterotonics; active
v. expectant management
7 Therapeutic uterotonics; IM v.
IV oxytocin
7.1 IV oxytocin
7.2 IM oxytocin
oxytocin dose < 10 IU v. 10 IU
1032
0.38 [0.19, 0.76]
4193
0.53 [0.38, 0.74]
2
3
6
2920
1273
4203

0.39 [0.22, 0.72]

0.64 [0.49, 0.84]
0.53 [0.38, 0.74]
3
3
5
1980
2223
4193

Odds Ratio (M-H, Random, 95% CI)
0.41 [0.21, 0.79]

0.65 [0.47, 0.89]
0.44 [0.30, 0.64]
3
2
4
1243
2950
3174

0.42 [0.17, 1.01]

0.47 [0.38, 0.59]
0.56 [0.36, 0.87]
3122
0.58 [0.36, 0.92]
52
0.17 [0.01, 3.42]
3174
0.56 [0.36, 0.87]
1
3
4
1901
1273
3174

0.39 [0.26, 0.58]

0.68 [0.41, 1.12]
0.56 [0.36, 0.87]
1
3
4
1000
2174
3174

0.57 [0.39, 0.82]

0.56 [0.24, 1.27]
0.56 [0.36, 0.87]
2
2
273
2901

0.77 [0.23, 2.56]

0.48 [0.33, 0.68]
Comparison 3. Oxytocin versus ergot alkaloids

loss > or = 500 mL)
No. of
studies
No. of
participants
2226
0.76 [0.61, 0.94]
3
3
1167
1616

0.70 [0.38, 1.29]

1.07 [0.62, 1.85]
2748
-12.49 [-37.66, 12.

68]
Statistical method
Effect size
41
6 Blood transfusion
7 Third stage > 30 minutes
8 Mean length of third stage
(minutes)
10 Diastolic blood pressure > 100
labour ward
the labour ward
labour ward
13 Headaches between delivery of
the labour ward
0.0 [0.0, 0.0]
2
0
3
567
0
1992

3.74 [0.34, 40.64]

0.0 [0.0, 0.0]
-0.43 [-0.89, 0.04]
4
2
2216
660

0.59 [0.29, 1.17]

0.53 [0.19, 1.52]
1091
0.07 [0.02, 0.25]
1091
0.18 [0.06, 0.53]
943
0.08 [6.49, 9.46]
Comparison 4. Oxytocin versus ergot alkaloids--subgroup analyses

risk of bias)
(high risk of bias)
oxytocin
3.1 IM oxytocin
3.2 IV oxytocin
loss > 500 mL); oxytocin dose
< 10 IU v. 10 IU
No. of
studies
No. of
participants
2226
0.76 [0.61, 0.94]
824
0.82 [0.58, 1.15]
1402
0.71 [0.53, 0.96]
2216
0.76 [0.61, 0.95]
2
2
5
943
1273
2226

0.58 [0.38, 0.89]

0.84 [0.65, 1.09]
0.76 [0.61, 0.94]
2
3
4
567
1659
2216

0.71 [0.44, 1.13]

0.78 [0.57, 1.07]
0.76 [0.61, 0.95]
2
2
567
1649

0.71 [0.44, 1.13]

0.79 [0.57, 1.08]
Statistical method
Effect size
42
randomised v.
quasi-randomised trials
risk of bias)
(high risk of bias)
6 Therapeutic uterotonics; active
v. expectant management
7 Therapeutic uterotonics; IM v.
IV oxytocin
7.1 IM oxytocin
7.2 IV oxytocin
oxytocin dose < 10 IU v. 10 IU
1167
0.70 [0.38, 1.29]
824
0.86 [0.43, 1.74]
343
0.42 [0.19, 0.91]
1167
0.70 [0.38, 1.29]
2
1
3
943
224
1167

0.54 [0.34, 0.85]

1.25 [0.67, 2.31]
0.70 [0.38, 1.29]
2
1
3
567
600
1167

0.74 [0.25, 2.19]

0.61 [0.35, 1.07]
0.70 [0.38, 1.29]
2
1
567
600

0.74 [0.25, 2.19]

0.61 [0.35, 1.07]
Comparison 5. Oxytocin + ergometrine versus ergot alkaloids

loss > or = 500 mL)
6 Blood transfusion
7 Third stage > 30 minutes
8 Mean length of the third stage
(minutes)
10 Diastolic blood pressure >100
labour ward
the labour ward
labour ward
No. of
studies
No. of
participants
2891
0.90 [0.34, 2.41]
0
1
0
1120

0.0 [0.0, 0.0]

1.67 [0.40, 6.94]
1
0
34
0
Mean Difference (IV, Fixed, 95% CI)

61.0 [6.00, 116.00]

0.0 [0.0, 0.0]
1
0
1
1120
0
372

Mean Difference (IV, Fixed, 95% CI)
0.71 [0.23, 2.24]

0.0 [0.0, 0.0]
0.0 [0.0, 0.0]
2
0
1927
0

1.02 [0.48, 2.20]

0.0 [0.0, 0.0]
0.0 [0.0, 0.0]
0.0 [0.0, 0.0]
Statistical method
Effect size
43
13 Headaches between delivery of

the labour ward
0.0 [0.0, 0.0]
Comparison 6. Oxytocin + ergometrine versus ergot alkaloids--subgroup analyses

risk of bias)
(high risk of bias)
oxytocin
3.1 IM oxytocin
3.2 IV oxytocin
No. of
studies
No. of
participants
2891
0.90 [0.34, 2.41]
0.0 [0.0, 0.0]
2891
0.90 [0.34, 2.41]
1474
0.80 [0.45, 1.43]
1
1
5
354
1120
2891

0.48 [0.15, 1.52]

0.95 [0.50, 1.79]
0.90 [0.34, 2.41]
4
1
2881
10

0.98 [0.34, 2.78]

0.33 [0.02, 6.65]
Statistical method
Effect size
44
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
MH,Random,95%
CI
Weight
Risk Ratio
MH,Random,95%
CI
n/N
n/N
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
104/513
175/487
25.1 %
0.56 [ 0.46, 0.70 ]
37/488
126/482
21.5 %
0.29 [ 0.21, 0.41 ]
7/28
10/24
10.9 %
0.60 [ 0.27, 1.33 ]
2403
1800
100.0 %
0.53 [ 0.38, 0.74 ]
Abdel-Aleem 2010
Nordstrom 1997
Pierre 1992
Poeschmann 1991
Total (95% CI)
Not estimable
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
Favours Oxytocin
10
Favours Control
45
Analysis 1.2. Comparison 1 Oxytocin versus no uterotonics, Outcome 2 Therapeutic uterotonics.

Review:

Outcome: 2 Therapeutic uterotonics
Study or subgroup
Oxytocin
Control
Risk Ratio
MH,Random,95%
CI
Weight
Risk Ratio
MH,Random,95%
CI
n/N
n/N
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 ]
0/28
2/24
2.1 %
0.17 [ 0.01, 3.42 ]
1879
1295
100.0 %
0.56 [ 0.36, 0.87 ]
Abdel-Aleem 2010
Poeschmann 1991
Total (95% CI)

0.001 0.01 0.1

Favours Oxytocin
10 100 1000
Favours Control
46
Analysis 1.3. Comparison 1 Oxytocin versus no uterotonics, Outcome 3 Severe PPH (clinically estimated
blood loss > or = 1000 mL).
Review:

Outcome: 3 Severe PPH (clinically estimated blood loss > or = 1000 mL)
Study or subgroup
Abdel-Aleem 2010
De Groot 1996
Nordstrom 1997
Pierre 1992
Poeschmann 1991
Total (95% CI)
Oxytocin
Control
Risk Ratio
MH,Random,95%
CI
Weight
Risk Ratio
MH,Random,95%
CI
n/N
n/N
4/1260
4/659
5.9 %
0.52 [ 0.13, 2.08 ]
7/78
16/143
15.9 %
0.80 [ 0.34, 1.87 ]
32/513
43/487
58.4 %
0.71 [ 0.45, 1.10 ]
7/488
21/482
15.8 %
0.33 [ 0.14, 0.77 ]
2/28
3/24
3.9 %
0.57 [ 0.10, 3.14 ]
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
Favours Oxytocin
10
Favours Control
47
Analysis 1.4. Comparison 1 Oxytocin versus no uterotonics, Outcome 4 Mean blood loss (mL).
Review:

Outcome: 4 Mean blood loss (mL)
Study or subgroup
Oxytocin
N
Mean
Difference
Control
Mean(SD)
Mean(SD)
Weight
Mean
Difference
23.8 %
2.90 [ -51.28, 57.08 ]
IV,Random,95% CI
IV,Random,95% CI
Bader 2000
53 229.79 (143.66)
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 ]
99 (72)
10
305 (60)
22.7 %
-206.00 [ -271.02, -140.98 ]
Total (95% CI)
679
59 226.89 (148.7)
100.0 % -99.46 [ -181.97, -16.95 ]
723

-1000
-500
Favours Oxytocin
500
1000
Favours Control
48
Analysis 1.5. Comparison 1 Oxytocin versus no uterotonics, Outcome 5 Maternal haemoglobin

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

Outcome: 5 Maternal haemoglobin concentration (Hb) < 9 g/dL 24 to 48 hours postpartum
Study or subgroup
Oxytocin
Control
Risk Ratio
MH,Random,95%
CI
Weight
Risk Ratio
MH,Random,95%
CI
n/N
n/N
86/382
52/190
71.0 %
0.82 [ 0.61, 1.11 ]
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 ]
Abdel-Aleem 2010
Jerbi 2007

0.1 0.2
0.5
Favours Oxytocin
10
Favours Control
49
Analysis 1.6. Comparison 1 Oxytocin versus no uterotonics, Outcome 6 Blood transfusion.

Review:

Outcome: 6 Blood transfusion
Study or subgroup
Oxytocin
Control
Risk Ratio
MH,Random,95%
CI
Weight
Risk Ratio
MH,Random,95%
CI
n/N
n/N
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 ]
Abdel-Aleem 2010

0.1 0.2
0.5
Favours Oxytocin
10
Favours Control
Analysis 1.7. Comparison 1 Oxytocin versus no uterotonics, Outcome 7 Third stage greater than 30
minutes.
Review:

Outcome: 7 Third stage greater than 30 minutes
Study or subgroup
Abdel-Aleem 2010
Total (95% CI)
Oxytocin
Control
n/N
n/N
Risk Ratio
Weight
20/1289
4/658
100.0 %
2.55 [ 0.88, 7.44 ]
1289
658
100.0 %
2.55 [ 0.88, 7.44 ]
M-H,Fixed,95% CI
Risk Ratio
M-H,Fixed,95% CI

Heterogeneity: not applicable
0.01
0.1
Favours Oxytocin
10
100
Favours Control
50
Analysis 1.8. Comparison 1 Oxytocin versus no uterotonics, Outcome 8 Mean length of third stage
(minutes).
Review:

Outcome: 8 Mean length of third stage (minutes)
Study or subgroup
Oxytocin
Mean
Difference
Control
Weight
Mean
Difference
Mean(SD)
Mean(SD)
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 ]
100.0 %
-3.61 [ -9.06, 1.83 ]
Total (95% CI)
146
IV,Random,95% CI
IV,Random,95% CI
148
Heterogeneity: Tau2 = 21.22; Chi2 = 29.27, df = 2 (P<0.00001); I2 =93%

-10
-5
Favours Oxytocin
10
Favours Control
51
Analysis 1.9. Comparison 1 Oxytocin versus no uterotonics, Outcome 9 Manual removal of the placenta.
Review:

Outcome: 9 Manual removal of the placenta
Study or subgroup
Oxytocin
Control
Risk Ratio
MH,Random,95%
CI
Weight
Risk Ratio
MH,Random,95%
CI
n/N
n/N
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 ]
0/28
0/24
2461
1859
Abdel-Aleem 2010
Poeschmann 1991
Total (95% CI)
Not estimable
100.0 %
1.26 [ 0.88, 1.81 ]

0.001 0.01 0.1

Favours Oxytocin
10 100 1000
Favours Control
52
Analysis 1.12. Comparison 1 Oxytocin versus no uterotonics, Outcome 12 Nausea between delivery of the
baby and discharge from the labour ward.
Review:

Outcome: 12 Nausea between delivery of the baby and discharge from the labour ward
Study or subgroup
Poeschmann 1991
Oxytocin
Control
n/N
n/N
0/28
1/24
100.0 %
0.29 [ 0.01, 6.74 ]
28
24
100.0 %
0.29 [ 0.01, 6.74 ]
Total (95% CI)
Risk Ratio
Weight
M-H,Fixed,95% CI
Risk Ratio
M-H,Fixed,95% CI

0.01
0.1
Favours Oxytocin
10
100
Favours Control
53
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.
Review:
Comparison: 2 Oxytocin versus no uterotonicssubgroup analyses

Outcome: 1 PPH (clinically estimated blood loss > or = 500 mL); randomised v. quasi-randomised trials
Study or subgroup
Oxytocin
Control
n/N
n/N
Risk Ratio
MH,Random,95%
CI
Weight
Risk Ratio
MH,Random,95%
CI
1 Randomised trials only (low risk of bias)

Abdel-Aleem 2010
De Groot 1996
Nordstrom 1997
Subtotal (95% CI)
68/1291
65/659
22.0 %
0.53 [ 0.39, 0.74 ]
25/78
55/143
20.4 %
0.83 [ 0.57, 1.22 ]
104/513
175/487
25.1 %
0.56 [ 0.46, 0.70 ]
1882
1289
67.6 %
0.61 [ 0.48, 0.77 ]

2 Quasi-randomised trials (high risk of bias)
Ilancheran 1990
0/5
0/5
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 ]
100.0 %
0.53 [ 0.38, 0.74 ]
Pierre 1992
Not estimable

Total (95% CI)
2403
1800

Test for subgroup differences: Chi2 = 1.59, df = 1 (P = 0.21), I2 =37%
0.1 0.2
0.5
Favours Oxytocin
10
Favours Control
54
estimated blood loss > or = 500 mL); active v. expectant management.
Review:

Outcome: 2 PPH (clinically estimated blood loss > or = 500 mL); active v. expectant management
Study or subgroup
Oxytocin
Control
Risk Ratio
MH,Random,95%
CI
Weight
Risk Ratio
MH,Random,95%
CI
n/N
n/N
68/1291
65/659
22.0 %
0.53 [ 0.39, 0.74 ]
37/488
126/482
21.5 %
0.29 [ 0.21, 0.41 ]
1779
1141
43.6 %
0.39 [ 0.22, 0.72 ]
1 Active management
Abdel-Aleem 2010
Pierre 1992
Subtotal (95% CI)

2 Expectant management
25/78
55/143
20.4 %
0.83 [ 0.57, 1.22 ]
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 ]
100.0 %
0.53 [ 0.38, 0.74 ]
De Groot 1996
Nordstrom 1997

Total (95% CI)
2398
1795

0.1 0.2
0.5
Favours Oxytocin
10
Favours Control
55
estimated blood loss > or = 500 mL); IM v. IV oxytocin.
Review:

Outcome: 3 PPH (clinically estimated blood loss > or = 500 mL); IM v. IV oxytocin
Study or subgroup
Oxytocin
Control
Risk Ratio
MH,Random,95%
CI
Weight
Risk Ratio
MH,Random,95%
CI
n/N
n/N
0/5
0/5
104/513
175/487
25.1 %
0.56 [ 0.46, 0.70 ]
37/488
126/482
21.5 %
0.29 [ 0.21, 0.41 ]
1006
974
46.7 %
0.41 [ 0.21, 0.79 ]
1 IV oxytocin
Ilancheran 1990
Nordstrom 1997
Pierre 1992
Subtotal (95% CI)
Not estimable

2 IM oxytocin
Abdel-Aleem 2010
De Groot 1996
Poeschmann 1991
Subtotal (95% CI)
68/1291
65/659
22.0 %
0.53 [ 0.39, 0.74 ]
25/78
55/143
20.4 %
0.83 [ 0.57, 1.22 ]
7/28
10/24
10.9 %
0.60 [ 0.27, 1.33 ]
1397
826
53.3 %
0.65 [ 0.47, 0.89 ]
100.0 %
0.53 [ 0.38, 0.74 ]

Total (95% CI)
2403
1800

0.1 0.2
0.5
Favours Oxytocin
10
Favours Control
56
estimated blood loss > 500 mL); oxytocin dose < 10 IU v. 10 IU.
Review:

Outcome: 4 PPH (clinically estimated blood loss > 500 mL); oxytocin dose < 10 IU v. 10 IU
Study or subgroup
Oxytocin
Control
Odds Ratio
MH,Random,95%
CI
Weight
Odds Ratio
MH,Random,95%
CI
n/N
n/N
25/78
55/143
18.0 %
0.75 [ 0.42, 1.35 ]
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 ]
1 Oxytocin dose < 10 IU

De Groot 1996
Pierre 1992

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 ]
1804
1146
50.9 %
0.47 [ 0.38, 0.59 ]
100.0 %
0.44 [ 0.30, 0.64 ]
Subtotal (95% CI)

Test for overall effect: Z = 6.61 (P < 0.00001)
Total (95% CI)
2398
1795

Test for subgroup differences: Chi2 = 0.07, df = 1 (P = 0.80), I2 =0.0%
0.01
0.1
Favours Oxytocin
10
100
Favours Control
57
Analysis 2.5. Comparison 2 Oxytocin versus no uterotonics--subgroup analyses, Outcome 5 Therapeutic

uterotonics; randomised v. quasi-randomised trials.
Review:

Outcome: 5 Therapeutic uterotonics; randomised v. quasi-randomised trials
Study or subgroup
Oxytocin
Control
Risk Ratio
MH,Random,95%
CI
Weight
Risk Ratio
MH,Random,95%
CI
n/N
n/N
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 ]
1851
1271
97.9 %
0.58 [ 0.36, 0.92 ]
1 Randomised trials (low risk of bias)

Abdel-Aleem 2010
Subtotal (95% CI)

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 ]
1879
1295
100.0 %
0.56 [ 0.36, 0.87 ]

Total (95% CI)

0.001 0.01 0.1

Favours Oxytocin
10 100 1000
Favours Control
58

uterotonics; active v. expectant management.
Review:

Outcome: 6 Therapeutic uterotonics; active v. expectant management
Study or subgroup
Oxytocin
Control
Risk Ratio
MH,Random,95%
CI
Weight
Risk Ratio
MH,Random,95%
CI
n/N
n/N
41/1260
53/641
35.2 %
0.39 [ 0.26, 0.58 ]
1260
641
35.2 %
0.39 [ 0.26, 0.58 ]
1 Active management
Abdel-Aleem 2010
Subtotal (95% CI)

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 ]
100.0 %
0.56 [ 0.36, 0.87 ]

Total (95% CI)
1879
1295

0.001 0.01 0.1

Favours Oxytocin
10 100 1000
Favours Control
59

uterotonics; IM v. IV oxytocin.
Review:

Outcome: 7 Therapeutic uterotonics; IM v. IV oxytocin
Study or subgroup
Oxytocin
Control
Risk Ratio
MH,Random,95%
CI
Weight
Risk Ratio
MH,Random,95%
CI
n/N
n/N
40/513
67/487
36.5 %
0.57 [ 0.39, 0.82 ]
513
487
36.5 %
0.57 [ 0.39, 0.82 ]
41/1260
53/641
35.2 %
0.39 [ 0.26, 0.58 ]
14/78
26/143
26.2 %
0.99 [ 0.55, 1.78 ]
0/28
2/24
2.1 %
0.17 [ 0.01, 3.42 ]
1366
808
63.5 %
0.56 [ 0.24, 1.27 ]
100.0 %
0.56 [ 0.36, 0.87 ]
1 IV oxytocin
Nordstrom 1997
Subtotal (95% CI)

2 IM oxytocin
Abdel-Aleem 2010
De Groot 1996
Poeschmann 1991
Subtotal (95% CI)

Total (95% CI)
1879
1295

0.001 0.01 0.1

Favours Oxytocin
10 100 1000
Favours Control
60

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

Outcome: 8 Therapeutic uterotonics; oxytocin dose < 10 IU v. 10 IU
Study or subgroup
Oxytocin
Control
Risk Ratio
MH,Random,95%
CI
Weight
Risk Ratio
MH,Random,95%
CI
n/N
n/N
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 ]

De Groot 1996

Abdel-Aleem 2010
Nordstrom 1997
Subtotal (95% CI)
41/1260
53/641
35.2 %
0.39 [ 0.26, 0.58 ]
40/513
67/487
36.5 %
0.57 [ 0.39, 0.82 ]
1773
1128
71.7 %
0.48 [ 0.33, 0.68 ]
100.0 %
0.56 [ 0.36, 0.87 ]

Total (95% CI)
1879
1295

0.01
0.1
Favours Oxytocin
10
100
Favours Control
61
Analysis 3.1. Comparison 3 Oxytocin versus ergot alkaloids, Outcome 1 PPH (clinically estimated blood
loss > or = 500 mL).
Review:
Comparison: 3 Oxytocin versus ergot alkaloids

Study or subgroup
Oxytocin
n/N
n/N
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 ]
1042
1184
100.0 %
0.76 [ 0.61, 0.94 ]
Total (95% CI)
Ergot Alkaloids
Risk Ratio
MH,Random,95%
CI
Weight
Risk Ratio
MH,Random,95%
CI
Total events: 102 (Oxytocin), 174 (Ergot Alkaloids)

0.001 0.01 0.1

Favours Oxytocin
10 100 1000
Favours Ergots
62
Analysis 3.2. Comparison 3 Oxytocin versus ergot alkaloids, Outcome 2 Therapeutic uterotonics.
Review:

Outcome: 2 Therapeutic uterotonics
Study or subgroup
Oxytocin
n/N
n/N
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 ]
531
636
100.0 %
0.70 [ 0.38, 1.29 ]
Total (95% CI)
Ergot Alkaloids
Risk Ratio
MH,Random,95%
CI
Weight
Risk Ratio
MH,Random,95%
CI

0.1 0.2
0.5
Favours Oxytocin
10
Favours Ergots
63
Analysis 3.3. Comparison 3 Oxytocin versus ergot alkaloids, Outcome 3 Severe PPH (clinically estimated
blood loss > or = 1000 mL).
Review:

Study or subgroup
Oxytocin
n/N
n/N
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 ]
740
876
100.0 %
1.07 [ 0.62, 1.85 ]
Total (95% CI)
Ergot Alkaloids
Risk Ratio
MH,Random,95%
CI
Weight
Risk Ratio
MH,Random,95%
CI

0.1 0.2
0.5
Favours Oxytocin
10
Favours Ergots
64
Analysis 3.4. Comparison 3 Oxytocin versus ergot alkaloids, Outcome 4 Mean blood loss (mL).
Review:

Study or subgroup
Oxytocin
Mean
Difference
Ergot Alkaloids
Weight
Mean
Difference
Mean(SD)
Mean(SD)
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 ]
99 (72)
15
124 (60)
10.5 %
-25.00 [ -86.37, 36.37 ]
De Groot 1996
Total (95% CI)
1300
IV,Random,95% CI
IV,Random,95% CI
1448
100.0 % -12.49 [ -37.66, 12.68 ]

-1000
-500
Favours Oxytocin
500
1000
Favours Ergots
65
Analysis 3.6. Comparison 3 Oxytocin versus ergot alkaloids, Outcome 6 Blood transfusion.
Review:

Study or subgroup
Oxytocin
n/N
n/N
De Groot 1996
2/78
1/146
0/156
0/187
234
333
Saito 2007
Total (95% CI)
Ergot Alkaloids
Risk Ratio
MH,Random,95%
CI
Weight
100.0 %
Risk Ratio
MH,Random,95%
CI
3.74 [ 0.34, 40.64 ]
Not estimable
100.0 %
3.74 [ 0.34, 40.64 ]

0.001 0.01 0.1
Favours Oxytocin
10 100 1000
Favours Ergots
Analysis 3.8. Comparison 3 Oxytocin versus ergot alkaloids, Outcome 8 Mean length of third stage
(minutes).
Review:

Outcome: 8 Mean length of third stage (minutes)
Study or subgroup
Oxytocin
Mean
Difference
Ergot Alkaloids
Weight
Mean
Difference
Mean(SD)
Mean(SD)
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 ]
100.0 %
-0.43 [ -0.89, 0.04 ]
Total (95% CI)
959
IV,Random,95% CI
IV,Random,95% CI
1033

-10
-5
Favours Oxytocin
10
Favours Ergots
66
Analysis 3.9. Comparison 3 Oxytocin versus ergot alkaloids, Outcome 9 Manual removal of the placenta.
Review:

Study or subgroup
Oxytocin
n/N
n/N
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 ]
1037
1179
100.0 %
0.59 [ 0.29, 1.17 ]
Total (95% CI)
Ergot Alkaloids
Risk Ratio
MH,Random,95%
CI
Weight
Risk Ratio
MH,Random,95%
CI

0.001 0.01 0.1

Favours Oxytocin
10 100 1000
Favours Ergots
67
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.
Review:

Outcome: 10 Diastolic blood pressure > 100 mm Hg between delivery of the baby and discharge from the labour ward
Study or subgroup
Oxytocin
Ergot Alkaloids
Risk Ratio
MH,Random,95%
CI
Weight
Risk Ratio
MH,Random,95%
CI
n/N
n/N
0/256
0/254
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 ]
Jago 2007
Not estimable

0.1 0.2
0.5
Favours Oxytocin
10
Favours Ergots
68
Analysis 3.11. Comparison 3 Oxytocin versus ergot alkaloids, Outcome 11 Vomiting between delivery of
the baby and discharge from the labour ward.
Review:

Outcome: 11 Vomiting between delivery of the baby and discharge from the labour ward
Study or subgroup
Oxytocin
Ergot Alkaloids
Risk Ratio
MH,Random,95%
CI
Weight
Risk Ratio
MH,Random,95%
CI
n/N
n/N
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
523
568
Moodie 1976
Total (95% CI)
Not estimable
100.0 %
0.07 [ 0.02, 0.25 ]

0.01
0.1
Favours Oxytocin
10
100
Favours Ergots
69
Analysis 3.12. Comparison 3 Oxytocin versus ergot alkaloids, Outcome 12 Nausea between delivery of the
baby and discharge from the labour ward.
Review:

Outcome: 12 Nausea between delivery of the baby and discharge from the labour ward
Study or subgroup
Oxytocin
Ergot Alkaloids
Risk Ratio
MH,Random,95%
CI
Weight
Risk Ratio
MH,Random,95%
CI
n/N
n/N
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 ]
523
568
100.0 %
0.18 [ 0.06, 0.53 ]
Moodie 1976
Total (95% CI)

0.01
0.1
Favours Oxytocin
10
100
Favours Ergots
70
Analysis 3.13. Comparison 3 Oxytocin versus ergot alkaloids, Outcome 13 Headaches between delivery of
the baby and discharge from the labour ward.
Review:

Outcome: 13 Headaches between delivery of the baby and discharge from the labour ward
Study or subgroup
Oxytocin
Ergot Alkaloids
Risk Ratio
MH,Random,95%
CI
Weight
Risk Ratio
MH,Random,95%
CI
n/N
n/N
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 ]
453
490
100.0 %
0.08 [ 0.00, 9.46 ]
Total (95% CI)

0.01
0.1
Favours Oxytocin
10
100
Favours Ergots
71
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.
Review:
Comparison: 4 Oxytocin versus ergot alkaloidssubgroup analyses

Study or subgroup
Oxytocin
Ergot Alkaloids
Risk Ratio
MH,Random,95%
CI
Weight
Risk Ratio
MH,Random,95%
CI
n/N
n/N
25/78
54/146
33.1 %
0.87 [ 0.59, 1.28 ]
12/297
18/303
9.7 %
0.68 [ 0.33, 1.39 ]
375
449
42.8 %
0.82 [ 0.58, 1.15 ]

De Groot 1996
Orji 2008
Subtotal (95% CI)

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 ]
667
735
57.2 %
0.71 [ 0.53, 0.96 ]
100.0 %
0.76 [ 0.61, 0.94 ]
Ilancheran 1990
Subtotal (95% CI)

Total (95% CI)
1042
1184

0.001 0.01 0.1

Favours Oxytocin
10 100 1000
Favours Ergots
72
estimated blood loss > or = 500 mL); active v. expectant management.
Review:

Study or subgroup
Oxytocin
Ergot Alkaloids
Risk Ratio
MH,Random,95%
CI
Weight
Risk Ratio
MH,Random,95%
CI
n/N
n/N
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 ]
453
490
27.4 %
0.58 [ 0.38, 0.89 ]
1 Active management
Subtotal (95% CI)

De Groot 1996
Sorbe 1978
Subtotal (95% CI)
25/78
54/146
33.3 %
0.87 [ 0.59, 1.28 ]
48/506
63/543
39.3 %
0.82 [ 0.57, 1.17 ]
584
689
72.6 %
0.84 [ 0.65, 1.09 ]
100.0 %
0.76 [ 0.61, 0.95 ]

Total (95% CI)
1037
1179

0.001 0.01 0.1

Favours Oxytocin
10 100 1000
Favours Ergots
73
estimated blood loss > or = 500 mL); IM v. IV oxytocin.
Review:

Study or subgroup
Oxytocin
Ergot Alkaloids
Risk Ratio
MH,Random,95%
CI
Weight
Risk Ratio
MH,Random,95%
CI
n/N
n/N
25/78
54/146
33.1 %
0.87 [ 0.59, 1.28 ]
17/156
38/187
17.5 %
0.54 [ 0.32, 0.91 ]
234
333
50.6 %
0.71 [ 0.44, 1.13 ]
1 IM oxytocin
De Groot 1996
Saito 2007
Subtotal (95% CI)

2 IV oxytocin
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 ]
808
851
49.4 %
0.78 [ 0.57, 1.07 ]
100.0 %
0.76 [ 0.61, 0.94 ]
Ilancheran 1990
Subtotal (95% CI)

Total (95% CI)
1042
1184

0.001 0.01 0.1

Favours Oxytocin
10 100 1000
Favours Ergots
74
estimated blood loss > 500 mL); oxytocin dose < 10 IU v. 10 IU.
Review:

Outcome: 4 PPH (clinically estimated blood loss > 500 mL); oxytocin dose < 10 IU v. 10 IU
Study or subgroup
Oxytocin
Ergot Alkaloids
Risk Ratio
MH,Random,95%
CI
Weight
Risk Ratio
MH,Random,95%
CI
n/N
n/N
25/78
54/146
33.3 %
0.87 [ 0.59, 1.28 ]
17/156
38/187
17.6 %
0.54 [ 0.32, 0.91 ]
234
333
50.9 %
0.71 [ 0.44, 1.13 ]

De Groot 1996
Saito 2007
Subtotal (95% CI)

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 ]
803
846
49.1 %
0.79 [ 0.57, 1.08 ]
100.0 %
0.76 [ 0.61, 0.95 ]
Subtotal (95% CI)

Total (95% CI)
1037
1179

0.01
0.1
Favours Oxytocin
10
100
Favours Ergots
75
Analysis 4.5. Comparison 4 Oxytocin versus ergot alkaloids--subgroup analyses, Outcome 5 Therapeutic
uterotonics; randomised v. quasi-randomised trials.
Review:

Outcome: 5 Therapeutic uterotonics; randomised v. quasi-randomised trials
Study or subgroup
Oxytocin
Ergot Alkaloids
Risk Ratio
MH,Random,95%
CI
Weight
Risk Ratio
MH,Random,95%
CI
n/N
n/N
14/78
21/146
34.5 %
1.25 [ 0.67, 2.31 ]
18/297
30/303
36.8 %
0.61 [ 0.35, 1.07 ]
375
449
71.3 %
0.86 [ 0.43, 1.74 ]

De Groot 1996
Orji 2008
Subtotal (95% CI)

Saito 2007
Subtotal (95% CI)
8/156
23/187
28.7 %
0.42 [ 0.19, 0.91 ]
156
187
28.7 %
0.42 [ 0.19, 0.91 ]
636
100.0 %
0.70 [ 0.38, 1.29 ]

Total (95% CI)
531

0.1 0.2
0.5
Favours Oxytocin
10
Favours Ergots
76
uterotonics; active v. expectant management.
Review:

Outcome: 6 Therapeutic uterotonics; active v. expectant management
Study or subgroup
Oxytocin
Ergot Alkaloids
Risk Ratio
MH,Random,95%
CI
Weight
Risk Ratio
MH,Random,95%
CI
n/N
n/N
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 ]
453
490
65.5 %
0.54 [ 0.34, 0.85 ]
1 Active management
Subtotal (95% CI)

De Groot 1996
Subtotal (95% CI)
14/78
21/146
34.5 %
1.25 [ 0.67, 2.31 ]
78
146
34.5 %
1.25 [ 0.67, 2.31 ]
636
100.0 %
0.70 [ 0.38, 1.29 ]

Total (95% CI)
531

0.1 0.2
0.5
Favours Oxytocin
10
Favours Ergots
77
uterotonics; IM v. IV oxytocin.
Review:

Outcome: 7 Therapeutic uterotonics; IM v. IV oxytocin
Study or subgroup
Oxytocin
Ergot Alkaloids
Risk Ratio
MH,Random,95%
CI
Weight
Risk Ratio
MH,Random,95%
CI
n/N
n/N
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 ]
234
333
63.2 %
0.74 [ 0.25, 2.19 ]
1 IM oxytocin
Subtotal (95% CI)

2 IV oxytocin
Orji 2008
Subtotal (95% CI)
18/297
30/303
36.8 %
0.61 [ 0.35, 1.07 ]
297
303
36.8 %
0.61 [ 0.35, 1.07 ]
636
100.0 %
0.70 [ 0.38, 1.29 ]

Total (95% CI)
531

0.1 0.2
0.5
Favours Oxytocin
10
Favours Ergots
78
uterotonics; oxytocin dose < 10 IU v. 10 IU.
Review:

Outcome: 8 Therapeutic uterotonics; oxytocin dose < 10 IU v. 10 IU
Study or subgroup
Oxytocin
Ergot Alkaloids
Risk Ratio
MH,Random,95%
CI
Weight
Risk Ratio
MH,Random,95%
CI
n/N
n/N
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 ]
234
333
63.2 %
0.74 [ 0.25, 2.19 ]
Subtotal (95% CI)

Orji 2008
Subtotal (95% CI)
18/297
30/303
36.8 %
0.61 [ 0.35, 1.07 ]
297
303
36.8 %
0.61 [ 0.35, 1.07 ]
636
100.0 %
0.70 [ 0.38, 1.29 ]

Total (95% CI)
531

0.01
0.1
Favours Oxytocin
10
100
Favours Ergots
79
Analysis 5.1. Comparison 5 Oxytocin + ergometrine versus ergot alkaloids, Outcome 1 PPH (clinically
estimated blood loss > or = 500 mL).
Review:
Comparison: 5 Oxytocin + ergometrine versus ergot alkaloids

Study or subgroup
Syntometrine
Ergot Alkaloids
Risk Ratio
MH,Random,95%
CI
Weight
Risk Ratio
MH,Random,95%
CI
n/N
n/N
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 ]
0/5
1/5
7.8 %
0.33 [ 0.02, 6.65 ]
18/560
19/560
25.3 %
0.95 [ 0.50, 1.79 ]
1427
1464
100.0 %
0.90 [ 0.34, 2.41 ]
Ilancheran 1990
Soiva 1964
Total (95% CI)
Total events: 66 (Syntometrine), 52 (Ergot Alkaloids)

0.001 0.01 0.1

Favours Syntometrine
10 100 1000
Favours Ergots
80
Analysis 5.3. Comparison 5 Oxytocin + ergometrine versus ergot alkaloids, Outcome 3 Severe PPH
(clinically estimated blood loss > or = 1000 mL).
Review:

Study or subgroup
Syntometrine
Ergot Alkaloids
n/N
n/N
5/560
3/560
100.0 %
1.67 [ 0.40, 6.94 ]
560
560
100.0 %
1.67 [ 0.40, 6.94 ]
Soiva 1964
Total (95% CI)
Risk Ratio
Weight
M-H,Fixed,95% CI
Risk Ratio
M-H,Fixed,95% CI

0.1 0.2
0.5
10
Favours Ergots
Analysis 5.4. Comparison 5 Oxytocin + ergometrine versus ergot alkaloids, Outcome 4 Mean blood loss
(mL).
Review:

Study or subgroup
Synometrine
Total (95% CI)
Mean
Difference
Ergot alkaloids
Mean(SD)
Mean(SD)
19
185 (102)
15
124 (60)
19
Weight
Mean
Difference
100.0 %
61.00 [ 6.00, 116.00 ]
IV,Fixed,95% CI
IV,Fixed,95% CI
15
100.0 % 61.00 [ 6.00, 116.00 ]

-100
-50
Favours Synometrine
50
100
Favours Ergots
81
Analysis 5.6. Comparison 5 Oxytocin + ergometrine versus ergot alkaloids, Outcome 6 Blood transfusion.
Review:

Study or subgroup
Syntometrine
Ergot Alkaloids
n/N
n/N
5/560
7/560
100.0 %
0.71 [ 0.23, 2.24 ]
560
560
100.0 %
0.71 [ 0.23, 2.24 ]
Soiva 1964
Total (95% CI)
Risk Ratio
Weight
Risk Ratio
M-H,Fixed,95% CI
M-H,Fixed,95% CI

0.1 0.2
0.5
10
Favours Ergots
Analysis 5.8. Comparison 5 Oxytocin + ergometrine versus ergot alkaloids, Outcome 8 Mean length of the
third stage (minutes).
Review:

Outcome: 8 Mean length of the third stage (minutes)
Study or subgroup
Experimental
Mean
Difference
Control
Mean(SD)
Mean(SD)
Barbaro 1961
199
16 (0)
173
13 (0)
Total (95% CI)
199
Weight
IV,Fixed,95% CI
Mean
Difference
IV,Fixed,95% CI
Not estimable
Not estimable
173

Test for overall effect: not applicable
-100
-50
Favours Synometrine
50
100
Favours Ergots
82
Analysis 5.9. Comparison 5 Oxytocin + ergometrine versus ergot alkaloids, Outcome 9 Manual removal of
the placenta.
Review:

Study or subgroup
Syntometrine
Ergot Alkaloids
Risk Ratio
MH,Random,95%
CI
Weight
Risk Ratio
MH,Random,95%
CI
n/N
n/N
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 ]
951
976
100.0 %
1.02 [ 0.48, 2.20 ]
Total (95% CI)

0.1 0.2
0.5
10
Favours Ergots
83
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.
Review:
Comparison: 6 Oxytocin + ergometrine versus ergot alkaloidssubgroup analyses

Study or subgroup
Syntometrine
Ergot Alkaloids
n/N
n/N
Risk Ratio
MH,Random,95%
CI
Weight
Risk Ratio
MH,Random,95%
CI
Subtotal (95% CI)
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 ]
0/5
1/5
7.8 %
0.33 [ 0.02, 6.65 ]
18/560
19/560
25.3 %
0.95 [ 0.50, 1.79 ]
1427
1464
100.0 %
0.90 [ 0.34, 2.41 ]
100.0 %
0.90 [ 0.34, 2.41 ]
Ilancheran 1990
Soiva 1964
Subtotal (95% CI)

Total (95% CI)
1427
1464

0.001 0.01 0.1

10 100 1000
Favours Ergots
84
PPH (clinically estimated blood loss > or = 500 mL); active v. expectant management.
Review:

Study or subgroup
Syntometrine
Ergot Alkaloids
Risk Ratio
MH,Random,95%
CI
Weight
Risk Ratio
MH,Random,95%
CI
n/N
n/N
4/171
9/183
24.2 %
0.48 [ 0.15, 1.52 ]
171
183
24.2 %
0.48 [ 0.15, 1.52 ]
18/560
19/560
75.8 %
0.95 [ 0.50, 1.79 ]
560
560
75.8 %
0.95 [ 0.50, 1.79 ]
743
100.0 %
0.80 [ 0.45, 1.43 ]
1 Active management
Francis 1965
Subtotal (95% CI)

Soiva 1964
Subtotal (95% CI)

Total (95% CI)
731

0.001 0.01 0.1

10 100 1000
Favours Ergots
85
PPH (clinically estimated blood loss > or = 500 mL); IM v. IV oxytocin.
Review:

Study or subgroup
Syntometrine
Ergot Alkaloids
Risk Ratio
MH,Random,95%
CI
Weight
Risk Ratio
MH,Random,95%
CI
n/N
n/N
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 ]
18/560
19/560
25.3 %
0.95 [ 0.50, 1.79 ]
1422
1459
92.2 %
0.98 [ 0.34, 2.78 ]
1 IM oxytocin
Soiva 1964
Subtotal (95% CI)

2 IV oxytocin
Ilancheran 1990
Subtotal (95% CI)
0/5
1/5
7.8 %
0.33 [ 0.02, 6.65 ]
7.8 %
0.33 [ 0.02, 6.65 ]
1464
100.0 %
0.90 [ 0.34, 2.41 ]

Total (95% CI)
1427

0.001 0.01 0.1

10 100 1000
Favours Ergots
86
APPENDICES
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 authors
obtained the full text of all studies of possible relevance for independent assessment. The methodological quality of the studies was
assessed with particular concentration on allocation concealment, ranked using the Cochrane approach of adequate, uncertain or
inadequate. Two review authors performed the data extraction. Trial authors were contacted for clarification where relevant. Analysis
was 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 through
discussion.
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 any
concealment approach;
(C) inadequate concealment of allocation, such as open list of random number tables, use of case record numbers, dates of birth or
days 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 the
Review Manager software (RevMan 2003) to double-enter the data.
87
Measures of treatment effect

We planned to carry out statistical analysis using the Review Manager software (RevMan 2003) and would have used a fixed-effect
meta-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. We
planned to use the standardised mean difference to combine trials that measured the same outcome, but used different methods. If
there 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 in
the analysis in the group to which they were allocated, regardless of whether or not they received the allocated intervention. If in the
original reports participants were not analysed in the group to which they were randomised, and there was sufficient information in
the 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 I statistic. If we identified high levels of
heterogeneity among the trials, (exceeding 50%), we would have explored it by prespecified subgroup analysis and have performed
sensitivity 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 the
context of active or expectant management of the third stage of labour, and on the timing of administration. Further subgroup analyses
may 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.
FEEDBACK
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 the
objectives decided afterwards.
In this review, there is no discussion of the way different studies determined blood loss, and the limitations of these methods. This
is especially true for Pierre 1992. Also, the results should take into account Hoffman 2004, comparing oxytocin with expectant
management. In this study, although the mean change in hematocrit was significantly less in the oxytocin group, there was no difference
in the incidence of postpartum haemorrhage.
(Summary of comment from Jose Luis Pastrana, March 2007)
Reply
6 July 2011
We agree that there are a lot of limitations to this review, specifically that in the studies included there are differences in the method of
delivery 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 formalized
method 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.
88
Contributors
Feedback: Jose Luis Pastrana
Response: Gina Westhoff
WHATS NEW
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 is

associated with fewer side effects than ergot alkaloids
A new author has joined the review team and is now the
guarantor for the review
31 May 2013
New search has been performed
Search updated. Six new trials have been included (AbdelAleem 2010; Jago 2007; Jerbi 2007; Moodie 1976; Orji
2008; Saito 2007) and eight trials excluded (Dickinson
2009; Dommisse 1980; Rouse 2011; Sariganont 1999;
Stanton 2012; Tita 2012; Wetta 2011; Vasegh 2005). We
also identified one additional report identified for an already
excluded trial (Hoffman 2006a).
This updated reviews is now comprised of 20 included studies (involving 10,806 women)
HISTORY
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) - see
Feedback 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 the

inclusion criteria
89
CONTRIBUTIONS OF AUTHORS
For the 2013 update, Gina Westhoff, Amanda Cotter, and Jorge Tolosa reread the review and its objectives and edited the results and
discussion based on the updated data.
DECLARATIONS OF INTEREST
None known.
DIFFERENCES BETWEEN PROTOCOL AND REVIEW

In order to reduce subjectivity in our primary analysis, we have added the use of therapeutic uterotonics as a primary outcome and have
moved severe postpartum haemorrhage to a secondary outcome. The use of therapeutic uterotonics is an outcome that is dichotomous
and does not rely on the highly subjective techniques that are used to measure total blood loss and may more objectively reflect severe
blood 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 to
answer an important clinical question regarding the dose of prophylactic oxytocin that is the most beneficial in order to improve the
translatability 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, these
secondary outcomes were removed.
For the 2013 update, our threshold for substantial heterogeneity was increased from I greater than 30% to greater than 40%.
INDEX TERMS
Medical Subject Headings (MeSH)
Ergonovine [administration & dosage]; Ergot Alkaloids [administration & dosage]; Labor Stage, Third [ drug effects]; Maternal Mortality; Oxytocics [ administration & dosage]; Oxytocin [ administration & dosage]; Postpartum Hemorrhage [mortality; prevention
& control]; Randomized Controlled Trials as Topic
MeSH check words

Female; Humans; Pregnancy
90

Prophylactic Oxytocin For The Third Stage of Labour To Prevent

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Prophylactic oxytocin for the third stage of labour to prevent

postpartum haemorrhage (Review)

Prophylactic oxytocin for the third stage of labour to prevent

PLAIN LANGUAGE SUMMARY

can be so completely indispensable as ergometrine is now (Moir

an easy, objective technique to accurately measure blood loss after

Types of outcome measures

Postpartum haemorrhage (PPH) (reported estimates of

All randomised or quasi-randomised controlled trials comparing

Severe PPH (clinically estimated blood loss greater than or

Search methods for identification of studies

3. oxytocin plus ergometrine versus ergot alkaloids.

Criteria for considering studies for this review

Data collection and analysis

Data extraction and management

Assessment of risk of bias in included studies

Two review authors independently assessed risk of bias for each

(1) Sequence generation (checking for possible selection

We described for each included study the method used to generate

(2) Allocation concealment (checking for possible selection

We described for each included study the method used to conceal

(3) Blinding (checking for possible performance bias)

We described for each included study the methods used, if any, to

(4) Incomplete outcome data (checking for possible attrition

We described for each included study, and for each outcome or

(5) Selective reporting bias

We described for each included study how we investigated the

Measures of treatment effect

For dichotomous data, we presented results as summary risk ratio

For continuous data, we used the mean difference if outcomes are

Unit of analysis issues

Dealing with missing data

(6) Other sources of bias

We described for each included study any important concerns we

Assessment of reporting biases

We made explicit judgements about whether studies are at high risk

If there had been 10 or more studies in the meta-analysis, we

Subgroup analysis and investigation of heterogeneity

This review includes trials from low-, middle-, and high-income

low- and middle-income countries only. The Abdel-Aleem 2010

trials (Bader 2000; Ilancheran 1990; Jerbi 2007; Nordstrom

Management of the third stage of labour

Oxytocin versus ergot alkaloids

Blood loss assessment

Oxytocin versus no uterotonics

Of the nine trials included in this analysis, the sample size

Oxytocin plus ergometrine versus ergot alkaloids

Risk of bias in included studies

In trials evaluating different interventions in the third stage of

The results are based on 20 trials.

Oxytocin versus no uterotonics

Oxytocin versus ergot alkaloids

Oxytocin plus ergometrine versus ergot alkaloids

Oxytocin versus no uterotonics

The following secondary outcomes were also improved with the

length of the third stage (Analysis 1.8), manual removal of the

Use of prophylactic oxytocin was associated with fewer side effects

(average RR 0.07; 95% CI 0.02 to 0.25; three trials, 1091 women;

Oxytocin plus ergometrine versus ergot alkaloids

In one trial involving 34 women, the combination of oxytocin

Implications for practice

Implications for research

what constitutes PPH. The optimal dosing of oxytocin and route