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

  • Conclusions changed
  • Review
  • Intervention

Authors

  • Gina Westhoff,

    Corresponding author
    1. Stanford University and University of California-San Francisco, Stanford, CA, USA
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  • Amanda M Cotter,

    1. University of Limerick, Department of Obstetrics and Gynaecology, Limerick, Ireland
    2. Global Network for Perinatal and Reproductive Health, Portland, OR, USA
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  • Jorge E Tolosa

    1. Global Network for Perinatal and Reproductive Health, Portland, OR, USA
    2. Oregon Health and Science University, Department of Obstetrics and Gynecology, Portland, Oregon, USA
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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 Group's 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; T² = 0.11, I² = 78%) and the need for therapeutic uterotonics (RR 0.56; 95% CI 0.36 to 0.87, four trials, 3174 women; T² = 0.10, I² = 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; T² = 0.11, I² = 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; T² = 0.02, I² = 27%).

Prophylactic oxytocin versus ergot alkaloids

Prophylactic oxytocin was superior to ergot alkaloids in preventing PPH greater than 500 mL (RR 0.76; 95% CI 0.61 to 0.94; five trials, 2226 women; T² = 0.00, I² = 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; T² = 0.00, I² = 0%) and in trials that performed active management of the third stage of labour (RR 0.58; 95% CI 0.38 to 0.89; two trials, 943 women; T² = 0.00, I² = 0%). Use of prophylactic oxytocin was associated with fewer side effects compared with use of ergot alkaloids; 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; T² = 0.41, I² = 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; T² = 0.45, I² = 30%).

Prophylactic oxytocin + ergometrine versus ergot alkaloids

There was no benefit seen in the combination of oxytocin and ergometrine versus ergometrine alone in preventing PPH greater than 500 mL (RR 0.90; 95% CI 0.34 to 2.41; five trials, 2891 women; T² = 0.89, I² = 80%). The use of oxytocin and ergometrine 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.

Zusammenfassung

Prophylaktische Oxytocin-Gabe in der Nachgeburtsphase zur Vermeidung einer postpartalen Blutung

Hintergrund

Für das aktive Management der Nachgeburtsphase wurde gezeigt, dass sie das Risiko einer postpartalen Blutung (PPH) von mehr als 1000 ml reduziert. Eine der Interventionen des aktiven Managements ist die Verabreichung von prophylaktischen Uterotonika, jedoch variieren die Art des Uterotonikums, die Dosierung und die Verabreichungsform weltweit und haben möglicherweise einen Einfluss auf maternale Endpunkte.

Ziele

Bestimmung der Alltagswirksamkeit einer prophylaktischen Oxytocin-Gabe jeglicher Dosierung, um PPH und andere schwerwiegende maternale Endpunkte im Zusammenhang mit der Nachgeburtsphase zu verhindern.

Literatursuche

Wir suchten im Cochrane Pregnancy and Childbirth Group's Trials Register (31. Mai 2013).

Auswahlkriterien

Randomisierte oder quasi-randomisierte kontrollierte Studien, welche schwangere Frauen mit erwarteter vaginaler Geburt einbezogen, denen während der Nachgeburtsphase prophylaktisch Oxytocin gegeben wurde. Die primären Endpunkte waren Blutverlust von mehr als 500 ml und der Gebrauch von therapeutischen Uterotonika.

Datenerhebung und -analyse

Zwei Review-Autoren beurteilten unabhängig voneinander klinische Studien hinsichtlich der Einschlusskriterien, bewerteten die Studienqualität und extrahierten Daten. Die Daten wurden auf Genauigkeit überprüft.

Wesentliche Ergebnisse

Dieser aktualisierte Review beinhaltet 20 Studien (mit 10.806 Frauen).

Prophylaktische Oxytocin-Gabe versus Placebo

Die prophylaktische Oxytocin-Gabe verglichen mit Placebo reduzierte das Risiko einer PPH von mehr als 500 ml (Risiko-Verhältnis (RR) 0,53; 95% Konfidenzintervall (KI) 0,38 bis 0,74; sechs Studien, 4.203 Frauen; T² = 0,11; I²= 78%) und die Notwendigkeit eines therapeutischen Uterotonikums (RR 0,56; 95% KI 0,36 bis 0,87, vier Studien, 3.174 Frauen; T²= 0,10, I²= 58%). Der Nutzen einer prophylaktischen Oxytocin-Gabe zur Vermeidung einer PPH von mehr als 500 ml, wurde in allen Subgruppen beobachtet. Ein verminderter Gebrauch von therapeutischen Uterotonika wurde nur in den folgenden Subgruppen beobachtet: in randomisierten Studien mit geringem Risiko für Bias (RR 0,58; 95% KI 0,36 bis 0,92; drei Studien, 3.122 Frauen; T² = 0,11, I²= 69%); in Studien, in denen ein aktives Management der Nachgeburtsphase durchgeführt wurde (RR 0,39; 95% CI 0,26 bis 0,58; eine Studie, 1.901 Frauen; Heterogenitätsanalyse nicht anwendbar); in Studien, in welchen Oxytocin als i.v.-Bolus verabreicht wurde (RR 0,57; 95% CI 0,39 bis 0,82; eine Studie, 1.000 Frauen; Heterogenitätsanalyse nicht anwendbar); und in Studien, in welchen Oxytocin in einer Dosierung von 10 IU verabreicht wurde (RR 0,48; 95% CI 0,33 bis 0,68; zwei Studien, 2.901 Frauen; T²0,02; I²= 27%).

Prophylaktische Oxytocin-Gabe versus Mutterkornalkaloiden

Hinsichtlich der Vermeidung einer PPH von mehr als 500 ml war die prophylaktische Oxytocin-Gabe im Vergleich zu Mutterkornalkaloiden überlegen (RR 0,76; 95% KI 0,61 bis 0,94; fünf Studien, 2.226 Frauen; T²= 0,00, I²= 0%). Der Vorteil von Oxytocin gegenüber Mutterkornalkaloiden eine PPH von mehr als 500 ml zu vermeiden blieb nur in den Subgruppen von quasi-randomisierten Studien bestehen (RR 0,71, 95% KI bis 0,53 bis 0,96; drei Untersuchungen, 1.402 Frauen; T² = 0,00, I²= 0%) sowie in Studien, in denen eine aktive Nachgeburtsphase durchgeführt wurde (RR 0,58; 95% KI 0.38 bis 0,89; zwei Studien, 943 Frauen; T² = 0,00; I²= 0%). Der prophylaktische Gebrauch von Oxytocin war im Vergleich zum Gebrauch von Mutterkornalkaloiden mit weniger Nebenwirkungen assoziiert, einschließlich einer verminderten Übelkeit in der Zeit zwischen der Geburt des Kindes und der Verlegung aus dem Kreißsaal (RR 0,18; 95% KI 0,06 bis 0,53; drei Untersuchungen, 1.091 Frauen; T² = 0,41; I²= 41%),sowie vermindertes Erbrechen in der Zeit zwischen der Geburt des Kindes und der Verlegung aus dem Kreißsaal (RR 0,07; 95% KI 0,02 bis 0,25; drei Untersuchungen, 1.091 Frauen; T²= 0,45, I²= 30%).

Kombinierte prophylaktische Gabe von Oxytocin+Ergometrin versus Mutterkornalkaloiden

Für die Kombination aus Oxytocin und Ergometrin gegenüber der alleinigen Gabe von Ergometrin zur Vermeidung einer PPH von mehr als 500 ml konnte kein Nutzen festgestellt werden (RR 0,90; 95% KI 0,34 bis 2,41; fünf Studien, 2.891 Frauen; T²= 0,89; I²= 80%). Der Gebrauch von Oxytocin und Ergometrin wurde mit einem erhöhten durchschnittlichen Blutverlust assoziiert (MD 61.0 ml; 95% KI 6,00 bis 116,00 ml; Fixed-Effect Analyse, eine Studie, 34 Frauen; Heterogenitätsanalyse nicht anwendbar).

In allen drei Vergleichen gab es keinen Unterschied zwischen den Behandlungsgruppen hinsichtlich der durchschnittlichen Dauer der Nachgeburtsphase oder der Notwendigkeit einer manuellen Plazentalösung.

Schlussfolgerungen der Autoren

Die prophylaktische Oxytocin-Gabe (unabhängig von der Dosierung) verringert sowohl eine PPH von mehr als 500 ml als auch den Gebrauch von therapeutischen Uterotonika im Vergleich zu Placebo. Um einen maximalen Nutzen zu erreichen, könnten sich Gesundheitsdienstleister auf der Basis der Subgruppenanalysen bzgl. der beiden primären Endpunkte dafür entscheiden, die routinemäßige prophylaktische Oxytocin-Gabe als Teil des aktiven Managements der Nachgeburtsphase in der Dosierung von 10 IU als i.v.-Bolus zu implementieren. Sofern eine i.v.-Gabe nicht möglich ist, könnte eine i.m.-Gabe genutzt werden, da für diesen Verabreichungsmodus sowohl ein Nutzen hinsichtlich der Vermeidung einer PPH von mehr als 500 ml, als auch eine Tendenz zum verringerten Gebrauch von therapeutischen Uterotonika gezeigt werden konnte, obwohl dies nicht statistisch signifikant war.

Die prophylaktische Gabe von Oxytocin zeigte sich der Gabe von Mutterkorn-alkaloiden zur Vorbeugung einer PPH von mehr als 500 ml überlegen; allerdings blieb dieser Vorteil in der Subgruppenanalyse nicht bestehen, wenn ausschließlich randomisierte Studien mit geringem Risiko für Bias analysiert wurden. Basierend auf diesen Ergebnissen gibt es kaum qualitativ hochwertige Evidenz, die einen Vorteil der prophylaktischen Oxytocin-Gabe gegenüber Mutterkornalkaloiden unterstützt. Jedoch war der Gebrauch von prophylaktischem Oxytocin mit weniger Nebenwirkungen, insbesondere Übelkeit und Erbrechen, verbunden, was Oxytocin zu einer geeigneteren Option für den Routinegebrauch macht, um einer PPH vorzubeugen.

Es gibt keine Evidenz für einen Nutzen der Kombination aus Oxytocin und Ergometrin im Vergleich zur alleinigen Gabe von Mutterkornalkaloiden. Es besteht sogar die Möglichkeit, dass der Schaden durch die Kombination erhöht werden kann, da eine Studie Evidenz aufzeigt, die die Gabe der Kombination verglichen mit Ergotalkaloiden alleine mit einem erhöhten durchschnittlichen Blutverlust assoziierte.

Wichtig ist, dass es keine Evidenz gibt, die darauf hinweist, dass ein erhöhtes Risiko einer Plazentaretention durch eine prophylaktische Oxytocin-Gabe im Vergleich zur Gabe von Placebo oder Ergotalkaloiden besteht.

Zur Verbesserung der Datenqualität werden mehr Placebo-kontrollierte, randomisierte und doppelblinde Studien benötigt, um die effektive Dosierung, den Zeitpunkt und die Verabreichungsform einer prophylaktischen Oxytocingabe zur Vermeidung einer PPH beurteilen zu können. Um die maternale Morbidität und Mortalität weltweit zu senken, werden vor allem, jedoch nicht ausschließlich, weitere Studien aus Ländern mit niedrigem und mittlerem Einkommen benötigt, um diese Interventionen in Geburtszentren zu evaluieren, welche die Hauptlast der PPH tragen.

Anmerkungen zur Übersetzung

N. Peterwerth, Koordination durch Cochrane Deutschland.

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).

Laienverständliche Zusammenfassung

Prophylaktische Oxytocin-Gabe in der Nachgeburtsphase

Prophylaktisches Oxytocin jeglicher Dosis, das routinemäßig nach der Geburt verabreicht wird, kann Blutverlust mit weniger Nebenwirkungen als Mutterkornalkaloide reduzieren.

Die Nachgeburtsphase beschreibt den Zeitraum zwischen der Geburt des Kindes und des Ausstoßens der Plazenta. Komplikationen können jedoch auch nachdem die Plazenta entfernt wurde auftreten. Die Schwere des Blutverlustes während dieser Phase hängt unter anderen davon ab, wie schnell sich der Gebärmuttermuskel zusammenzieht und die Plazenta sich von der Gebärmutterwand löst. Postpartale Blutungen sind vor allem dort ein großes Problem, wo die Nahrungsmittelversorgung und der Zugang zu medizinischer Versorgung mangelhaft ist. Dieser Review von 20 Studien (mit 10.806 Frauen) stellt fest, dass die routinemäßige Verwendung von prophylaktischem Oxytocin, einem Medikament, das der Gebärmutter hilft sich zusammenzuziehen, die Menge des Blutverlustes während der Nachgeburtsphase verringern kann. Prophylaktisches Oxytocin verhindert Blutverlust besser als Mutterkornalkaloide, jedoch wird durch die Kombination von beiden keine weitere Verbesserung beobachtet. Weitere Forschung ist notwendig, um herauszufinden, wie diese Intervention in der Nachgeburtsphase für Frauen in allen Ländern, vor allem in Ländern mit geringem und mittlerem Einkommen, implementiert werden kann. Des weiteren ist mehr Forschung bezüglich der optimalen Dosis, und der besten Verabreichungsform (intramuskulär oder intravenös) nötig.

Anmerkungen zur Übersetzung

N. Peterwerth, Koordination durch Cochrane Deutschland.

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); Tunçalp 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; Tunçalp 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.

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;

  3. oxytocin plus ergometrine versus ergot alkaloids.

Methods

Criteria for considering studies for this review

Types of studies

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.

Types of participants

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.

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; Tunçalp 2012). Similarly, endogenous oxytocin (nipple stimulation) is not included in this review.

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
  • 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

Search methods for identification of studies

Electronic searches

We searched the Cochrane Pregnancy and Childbirth Group’s Trials Register by contacting the Trials Search Co-ordinator (31 May 2013).

The Cochrane Pregnancy and Childbirth Group’s 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 non-opaque envelopes, alternation; date of birth);

  • unclear risk of bias.

(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.

We assessed the methods as:

  • low, high or unclear risk of bias for participants;

  • low, high or unclear risk of bias for personnel;

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

(4) Incomplete outcome data (checking for possible attrition bias through withdrawals, dropouts, protocol deviations)

We described for each included study, and for each outcome 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);

  • unclear risk of bias.

(5) Selective reporting bias

We described for each included study how we investigated the possibility of selective outcome reporting bias and what we found.

We assessed the methods as:

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

  • high risk of bias (where not all the study’s 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);

  • unclear risk of bias.

(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.

(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.

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.

Assessment of heterogeneity

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

Assessment of reporting biases

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  T² and I².

Subgroup analysis and investigation of heterogeneity

If we identified substantial heterogeneity, random-effects I² 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 χ2 statistic and p-value, and the interaction test I² value.

Sensitivity analysis

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

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

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).

Management of the third stage of labour

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.

Blood loss assessment

The majority of the trials (n = 13) used some form of measurement, mainly by collecting and measuring blood plus weighing blood-soaked guaze. Measuring the decrease in haematocrit (Hct) 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 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.

Oxytocin versus ergot alkaloids

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.

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

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.

Oxytocin versus no uterotonics

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.

Oxytocin versus ergot alkaloids

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.

Oxytocin plus ergometrine versus ergot alkaloids

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.

Effects of interventions

The results are based on 20 trials.

Oxytocin versus no uterotonics

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, T² = 0.11, I² = 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; T² = 0.10, I² = 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; T² = 0.11, I² = 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; T² = 0.02, I² = 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; random-effects; T² = 0.00, I² = 0%, Analysis 1.3) and mean blood loss (mean difference (MD) -99.46 mL; 95% CI -181.97 to -16.95 mL; five trials, 1402 women; random-effects; T² = 6691.5, I² = 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.

Oxytocin versus ergot alkaloids

Primary outcomes

Over 3000 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 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; T² = 0.00, I² = 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; T² = 0.00, I² = 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; T² = 0.00, I² = 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; T² = 0.18, I² = 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; T² = 0.00, I² = 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; T² = 0.41, I² = 41%, Analysis 3.12) and vomiting (average RR 0.07; 95% CI 0.02 to 0.25; three trials, 1091 women; random-effects; T² = 0.45, I² = 30%, Analysis 3.11). There 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.

Oxytocin plus ergometrine versus ergot alkaloids

Primary outcomes

Over 2800 women were included from six 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.

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; T² = 0.89, I² = 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.

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, T² = 0.0, I² = 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

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 (Tunçalp 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.

Data and analyses

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Comparison 1. Oxytocin versus no uterotonics
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 PPH (clinically estimated blood loss > or = 500 mL)64203Risk Ratio (M-H, Random, 95% CI)0.53 [0.38, 0.74]
2 Therapeutic uterotonics43174Risk Ratio (M-H, Random, 95% CI)0.56 [0.36, 0.87]
3 Severe PPH (clinically estimated blood loss > or = 1000 mL)54162Risk Ratio (M-H, Random, 95% CI)0.62 [0.44, 0.87]
4 Mean blood loss (mL)51402Mean Difference (IV, Random, 95% CI)-99.46 [-181.97, -16.95]
5 Maternal haemoglobin concentration (Hb) < 9 g/dL 24 to 48 hours postpartum31645Risk Ratio (M-H, Random, 95% CI)0.78 [0.60, 1.00]
6 Blood transfusion33120Risk Ratio (M-H, Random, 95% CI)0.89 [0.44, 1.78]
7 Third stage greater than 30 minutes11947Risk Ratio (M-H, Fixed, 95% CI)2.55 [0.88, 7.44]
8 Mean length of third stage (minutes)3294Mean Difference (IV, Random, 95% CI)-3.61 [-9.06, 1.83]
9 Manual removal of the placenta64320Risk Ratio (M-H, Random, 95% CI)1.26 [0.88, 1.81]
10 Diastolic blood pressure >100 mm Hg between delivery of the baby and discharge from the labour ward00Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
11 Vomiting between delivery of the baby and discharge from the labour ward00Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
12 Nausea between delivery of the baby and discharge from the labour ward152Risk Ratio (M-H, Fixed, 95% CI)0.29 [0.01, 6.74]
13 Headace between delivery of the baby and discharge from the labour ward00Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
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.

Comparison 2. Oxytocin versus no uterotonics--subgroup analyses
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 PPH (clinically estimated blood loss > or = 500 mL); randomised v. quasi-randomised trials64203Risk Ratio (M-H, Random, 95% CI)0.53 [0.38, 0.74]
1.1 Randomised trials only (low risk of bias)33171Risk Ratio (M-H, Random, 95% CI)0.61 [0.48, 0.77]
1.2 Quasi-randomised trials (high risk of bias)31032Risk Ratio (M-H, Random, 95% CI)0.38 [0.19, 0.76]
2 PPH (clinically estimated blood loss > or = 500 mL); active v. expectant management54193Risk Ratio (M-H, Random, 95% CI)0.53 [0.38, 0.74]
2.1 Active management22920Risk Ratio (M-H, Random, 95% CI)0.39 [0.22, 0.72]
2.2 Expectant management31273Risk Ratio (M-H, Random, 95% CI)0.64 [0.49, 0.84]
3 PPH (clinically estimated blood loss > or = 500 mL); IM v. IV oxytocin64203Risk Ratio (M-H, Random, 95% CI)0.53 [0.38, 0.74]
3.1 IV oxytocin31980Risk Ratio (M-H, Random, 95% CI)0.41 [0.21, 0.79]
3.2 IM oxytocin32223Risk Ratio (M-H, Random, 95% CI)0.65 [0.47, 0.89]
4 PPH (clinically estimated blood loss > 500 mL); oxytocin dose < 10 IU v. 10 IU54193Odds Ratio (M-H, Random, 95% CI)0.44 [0.30, 0.64]
4.1 Oxytocin dose < 10 IU31243Odds Ratio (M-H, Random, 95% CI)0.42 [0.17, 1.01]
4.2 Oxytocin dose 10 IU22950Odds Ratio (M-H, Random, 95% CI)0.47 [0.38, 0.59]
5 Therapeutic uterotonics; randomised v. quasi-randomised trials43174Risk Ratio (M-H, Random, 95% CI)0.56 [0.36, 0.87]
5.1 Randomised trials (low risk of bias)33122Risk Ratio (M-H, Random, 95% CI)0.58 [0.36, 0.92]
5.2 Quasi-randomised trials (high-risk of bias)152Risk Ratio (M-H, Random, 95% CI)0.17 [0.01, 3.42]
6 Therapeutic uterotonics; active v. expectant management43174Risk Ratio (M-H, Random, 95% CI)0.56 [0.36, 0.87]
6.1 Active management11901Risk Ratio (M-H, Random, 95% CI)0.39 [0.26, 0.58]
6.2 Expectant management31273Risk Ratio (M-H, Random, 95% CI)0.68 [0.41, 1.12]
7 Therapeutic uterotonics; IM v. IV oxytocin43174Risk Ratio (M-H, Random, 95% CI)0.56 [0.36, 0.87]
7.1 IV oxytocin11000Risk Ratio (M-H, Random, 95% CI)0.57 [0.39, 0.82]
7.2 IM oxytocin32174Risk Ratio (M-H, Random, 95% CI)0.56 [0.24, 1.27]
8 Therapeutic uterotonics; oxytocin dose < 10 IU v. 10 IU43174Risk Ratio (M-H, Random, 95% CI)0.56 [0.36, 0.87]
8.1 Oxytocin dose < 10 IU2273Risk Ratio (M-H, Random, 95% CI)0.77 [0.23, 2.56]
8.2 Oxytocin dose 10 IU22901Risk Ratio (M-H, Random, 95% CI)0.48 [0.33, 0.68]
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.

Analysis 2.2.

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

Analysis 2.3.

Comparison 2 Oxytocin versus no uterotonics--subgroup analyses, Outcome 3 PPH (clinically estimated blood loss > or = 500 mL); IM v. IV oxytocin.

Analysis 2.4.

Comparison 2 Oxytocin versus no uterotonics--subgroup analyses, Outcome 4 PPH (clinically estimated blood loss > 500 mL); oxytocin dose < 10 IU v. 10 IU.

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.

Comparison 3. Oxytocin versus ergot alkaloids
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 PPH (clinically estimated blood loss > or = 500 mL)52226Risk Ratio (M-H, Random, 95% CI)0.76 [0.61, 0.94]
2 Therapeutic uterotonics31167Risk Ratio (M-H, Random, 95% CI)0.70 [0.38, 1.29]
3 Severe PPH (clinically estimated blood loss > or = 1000 mL)31616Risk Ratio (M-H, Random, 95% CI)1.07 [0.62, 1.85]
4 Mean blood loss (mL)62748Mean Difference (IV, Random, 95% CI)-12.49 [-37.66, 12.68]
5 Maternal haemoglobin concentration (Hb) < 9 g/dL 24 to 48 hours postpartum00Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
6 Blood transfusion2567Risk Ratio (M-H, Random, 95% CI)3.74 [0.34, 40.64]
7 Third stage > 30 minutes00Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
8 Mean length of third stage (minutes)31992Mean Difference (IV, Random, 95% CI)-0.43 [-0.89, 0.04]
9 Manual removal of the placenta42216Risk Ratio (M-H, Random, 95% CI)0.59 [0.29, 1.17]
10 Diastolic blood pressure > 100 mm Hg between delivery of the baby and discharge from the labour ward2660Risk Ratio (M-H, Random, 95% CI)0.53 [0.19, 1.52]
11 Vomiting between delivery of the baby and discharge from the labour ward31091Risk Ratio (M-H, Random, 95% CI)0.07 [0.02, 0.25]
12 Nausea between delivery of the baby and discharge from the labour ward31091Risk Ratio (M-H, Random, 95% CI)0.18 [0.06, 0.53]
13 Headaches between delivery of the baby and discharge from the labour ward2943Risk Ratio (M-H, Random, 95% CI)0.08 [0.00, 9.46]
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).

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 discharge from the labour ward.

Analysis 3.12.

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

Analysis 3.13.

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

Comparison 4. Oxytocin versus ergot alkaloids--subgroup analyses
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 PPH (clinically estimated blood loss > or = 500 mL); randomised v. quasi-randomised trials52226Risk Ratio (M-H, Random, 95% CI)0.76 [0.61, 0.94]
1.1 Randomised trials (low risk of bias)2824Risk Ratio (M-H, Random, 95% CI)0.82 [0.58, 1.15]
1.2 Quasi-randomised trials (high risk of bias)31402Risk Ratio (M-H, Random, 95% CI)0.71 [0.53, 0.96]
2 PPH (clinically estimated blood loss > or = 500 mL); active v. expectant management42216Risk Ratio (M-H, Random, 95% CI)0.76 [0.61, 0.95]
2.1 Active management2943Risk Ratio (M-H, Random, 95% CI)0.58 [0.38, 0.89]
2.2 Expectant management21273Risk Ratio (M-H, Random, 95% CI)0.84 [0.65, 1.09]
3 PPH (clinically estimated blood loss > or = 500 mL); IM v. IV oxytocin52226Risk Ratio (M-H, Random, 95% CI)0.76 [0.61, 0.94]
3.1 IM oxytocin2567Risk Ratio (M-H, Random, 95% CI)0.71 [0.44, 1.13]
3.2 IV oxytocin31659Risk Ratio (M-H, Random, 95% CI)0.78 [0.57, 1.07]
4 PPH (clinically estimated blood loss > 500 mL); oxytocin dose < 10 IU v. 10 IU42216Risk Ratio (M-H, Random, 95% CI)0.76 [0.61, 0.95]
4.1 Oxytocin dose < 10 IU2567Risk Ratio (M-H, Random, 95% CI)0.71 [0.44, 1.13]
4.2 Oxytocin dose 10 IU21649Risk Ratio (M-H, Random, 95% CI)0.79 [0.57, 1.08]
5 Therapeutic uterotonics; randomised v. quasi-randomised trials31167Risk Ratio (M-H, Random, 95% CI)0.70 [0.38, 1.29]
5.1 Randomised trials (low risk of bias)2824Risk Ratio (M-H, Random, 95% CI)0.86 [0.43, 1.74]
5.2 Quasi-randomised trials (high risk of bias)1343Risk Ratio (M-H, Random, 95% CI)0.42 [0.19, 0.91]
6 Therapeutic uterotonics; active v. expectant management31167Risk Ratio (M-H, Random, 95% CI)0.70 [0.38, 1.29]
6.1 Active management2943Risk Ratio (M-H, Random, 95% CI)0.54 [0.34, 0.85]
6.2 Expectant management1224Risk Ratio (M-H, Random, 95% CI)1.25 [0.67, 2.31]
7 Therapeutic uterotonics; IM v. IV oxytocin31167Risk Ratio (M-H, Random, 95% CI)0.70 [0.38, 1.29]
7.1 IM oxytocin2567Risk Ratio (M-H, Random, 95% CI)0.74 [0.25, 2.19]
7.2 IV oxytocin1600Risk Ratio (M-H, Random, 95% CI)0.61 [0.35, 1.07]
8 Therapeutic uterotonics; oxytocin dose < 10 IU v. 10 IU31167Risk Ratio (M-H, Random, 95% CI)0.70 [0.38, 1.29]
8.1 Oxytocin dose < 10 IU2567Risk Ratio (M-H, Random, 95% CI)0.74 [0.25, 2.19]
8.2 Oxytocin dose 10 IU1600Risk Ratio (M-H, Random, 95% CI)0.61 [0.35, 1.07]
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.

Analysis 4.2.

Comparison 4 Oxytocin versus ergot alkaloids--subgroup analyses, Outcome 2 PPH (clinically estimated blood loss > or = 500 mL); active v. expectant management.

Analysis 4.3.

Comparison 4 Oxytocin versus ergot alkaloids--subgroup analyses, Outcome 3 PPH (clinically estimated blood loss > or = 500 mL); IM v. IV oxytocin.

Analysis 4.4.

Comparison 4 Oxytocin versus ergot alkaloids--subgroup analyses, Outcome 4 PPH (clinically estimated blood loss > 500 mL); oxytocin dose < 10 IU v. 10 IU.

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.

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.

Comparison 5. Oxytocin + ergometrine versus ergot alkaloids
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 PPH (clinically estimated blood loss > or = 500 mL)52891Risk Ratio (M-H, Random, 95% CI)0.90 [0.34, 2.41]
2 Therapeutic uterotonics00Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
3 Severe PPH (clinically estimated blood loss > or = 1000 mL)11120Risk Ratio (M-H, Fixed, 95% CI)1.67 [0.40, 6.94]
4 Mean blood loss (mL)134Mean Difference (IV, Fixed, 95% CI)61.0 [6.00, 116.00]
5 Maternal haemoglobin concentration (Hb) < 9 g/dL 24 to 48 hours postpartum00Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
6 Blood transfusion11120Risk Ratio (M-H, Fixed, 95% CI)0.71 [0.23, 2.24]
7 Third stage > 30 minutes00Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
8 Mean length of the third stage (minutes)1372Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
9 Manual removal of the placenta21927Risk Ratio (M-H, Random, 95% CI)1.02 [0.48, 2.20]
10 Diastolic blood pressure >100 mm Hg between delivery of the baby and discharge from the labour ward00Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
11 Vomiting between delivery of the baby and discharge from the labour ward00Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
12 Nausea between delivery of the baby and discharge from the labour ward00Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
13 Headaches between delivery of the baby and discharge from the labour ward00Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
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.

Comparison 6. Oxytocin + ergometrine versus ergot alkaloids--subgroup analyses
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 PPH (clinically estimated blood loss > or = 500 mL); randomised v. quasi-randomised trials52891Risk Ratio (M-H, Random, 95% CI)0.90 [0.34, 2.41]
1.1 Randomised trials (low risk of bias)00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]
1.2 Quasi-randomised trials (high risk of bias)52891Risk Ratio (M-H, Random, 95% CI)0.90 [0.34, 2.41]
2 PPH (clinically estimated blood loss > or = 500 mL); active v. expectant management21474Risk Ratio (M-H, Random, 95% CI)0.80 [0.45, 1.43]
2.1 Active management1354Risk Ratio (M-H, Random, 95% CI)0.48 [0.15, 1.52]
2.2 Expectant management11120Risk Ratio (M-H, Random, 95% CI)0.95 [0.50, 1.79]
3 PPH (clinically estimated blood loss > or = 500 mL); IM v. IV oxytocin52891Risk Ratio (M-H, Random, 95% CI)0.90 [0.34, 2.41]
3.1 IM oxytocin42881Risk Ratio (M-H, Random, 95% CI)0.98 [0.34, 2.78]
3.2 IV oxytocin110Risk Ratio (M-H, Random, 95% CI)0.33 [0.02, 6.65]
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.

Analysis 6.2.

Comparison 6 Oxytocin + ergometrine versus ergot alkaloids--subgroup analyses, Outcome 2 PPH (clinically estimated blood loss > or = 500 mL); active v. expectant management.

Analysis 6.3.

Comparison 6 Oxytocin + ergometrine versus ergot alkaloids--subgroup analyses, Outcome 3 PPH (clinically estimated blood loss > or = 500 mL); IM v. IV oxytocin.

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.

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 I² 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.

Contributors

Feedback: Jose Luis Pastrana

Response: Gina Westhoff

What's new

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

DateEventDescription
24 June 2013New 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 2013New search has been performed

Search updated. Six new trials have been included (Abdel-Aleem 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

DateEventDescription
6 July 2011Feedback has been incorporatedThe authors have responded to feedback from Pastrana (March 2007) - see Feedback 1.
1 October 2009AmendedSearch updated. Ten reports added to Studies awaiting classification.
20 September 2008AmendedConverted to new review format.
1 March 2007Feedback has been incorporatedFeedback added from Pastrana, March 2007.
1 December 2004New search has been performedSearch updated. We identified 16 new studies; however, none fulfilled the inclusion criteria.

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 I² greater than 30% to greater than 40%.

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.

ParticipantsPregnant woman who were expected to have a vaginal delivery at Women's 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 mother's 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.

OutcomesBlood 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
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskWomen were randomly allocated to 1 of 3 groups by selecting the next number in a computer-generated random number sequence.
Allocation concealment (selection bias)Low riskThe allocated group was noted inside opaque sealed envelopes.
Blinding (performance bias and detection bias)
All outcomes
Unclear riskNo mention of blinding procedures.
Incomplete outcome data (attrition bias)
All outcomes
Low riskMinimal loss.
Selective reporting (reporting bias)Unclear riskUnclear.
Other biasUnclear riskUnclear.

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.

OutcomesPrimary outcomes included blood loss and the length of the placental delivery period. The duration of the birth and the delivery period were also recorded.
NotesOnly the oxytocin and control group data is used in the analysis.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskMethod of randomisation not described other than "allocation was randomised".
Allocation concealment (selection bias)Unclear riskNot described.
Blinding (performance bias and detection bias)
All outcomes
High riskNot blinded.
Incomplete outcome data (attrition bias)
All outcomes
High riskThere 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.
Selective reporting (reporting bias)Low riskAll outcomes reported.

Barbaro 1961

Methods

Quasi-randomised controlled trial.

No randomisation methodology described.
Timing of randomisation not stated.
Not blinded.

ParticipantsWomen 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.

OutcomesPPH (> 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 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNo randomisation method described.
Allocation concealment (selection bias)Unclear riskNo concealment method described.
Blinding (performance bias and detection bias)
All outcomes
High riskNot blinded.
Incomplete outcome data (attrition bias)
All outcomes
Low riskAdequate.
Selective reporting (reporting bias)Low riskAll outcomes reported.
Other biasUnclear riskUnclear.

Bonham 1963

Methods

Randomised controlled trial.

Selection of drug was made by random numbers. Timing of randomisation not stated.
Not blinded.

ParticipantsAll 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.

OutcomesPrimary 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 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskRandomisation by numbers; procedure not described in detail.
Allocation concealment (selection bias)Unclear riskNot described.
Blinding (performance bias and detection bias)
All outcomes
High riskInadequate.
Incomplete outcome data (attrition bias)
All outcomes
Low riskAttrition described; no loss of data.
Selective reporting (reporting bias)Low riskAll outcomes reported.
Other biasUnclear riskUnclear.

De Groot 1996

Methods

Randomised controlled trial.

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 baby's 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.

Participants2 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 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.

OutcomesMean 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
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskNumbered boxes of tablets and ampoules according to computer-generated randomisation list.
Allocation concealment (selection bias)Low riskNo difference could be detected between boxes.
Blinding (performance bias and detection bias)
All outcomes
High riskNot blinded.
Incomplete outcome data (attrition bias)
All outcomes
Low riskAttrition minimal and described.
Selective reporting (reporting bias)Low riskAll outcomes described.
Other biasUnclear riskUnclear.

Francis 1965

Methods

Quasi-randomised controlled trial.

'Ampoules used in rotation and participants were unselected'.
Blinded.

Participants2 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).
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.

OutcomesBlood 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
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)High riskTreatments were rotated, no random sequence generated.
Allocation concealment (selection bias)Unclear riskNot described.
Blinding (performance bias and detection bias)
All outcomes
Low riskVials were blinded to personnel, participants and outcome assessors.
Incomplete outcome data (attrition bias)
All outcomes
Low riskAll outcomes reported.
Selective reporting (reporting bias)Low riskNo attrition.
Other biasUnclear riskUnclear.

Fugo 1958

Methods

Randomised controlled trial.

Numbered identical drug packages administered in rotation. Number meaningless to obstetrician.
Blinded.

ParticipantsWomen 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.
Interventions

All administered intravenously in 2 mL with anterior shoulder.
(1) 2 IU oxytocin (natural oxytocin) n = 168.
(2) 2 IU syntocinon (synthetic oxytocin) n = 156.
(3) 4 mg ergonovine 149.
(4) 80 mg U3772 (alpha, alpha diphenyl gamma dimethylamino N-methyl valeramide-HCl) n = 151.
Blood lost when the placenta separated was collected in a basin containing 200 mL 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.

OutcomesMethod 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).
NotesGiven 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
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskRandomisation method not described.
Allocation concealment (selection bias)Low riskIdentical packages were used.
Blinding (performance bias and detection bias)
All outcomes
Low riskBlinded.
Incomplete outcome data (attrition bias)
All outcomes
Low riskAll outcomes reported.
Selective reporting (reporting bias)Low riskNo significant attrition.
Other biasUnclear riskUnclear.

Ilancheran 1990

Methods

Quasi-randomised controlled trial.

'Consecutive participants divided equally into 4 subgroups, distribution being done on a random basis'.

ParticipantsWomen 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.

OutcomesProstaglandin 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
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)High riskWomen randomly assigned into groups; no computer sequence.
Allocation concealment (selection bias)Unclear riskUnclear.
Blinding (performance bias and detection bias)
All outcomes
Unclear riskNot described.
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskNot described.
Selective reporting (reporting bias)Unclear riskNot described.

Jago 2007

Methods

Randomised controlled trial.

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

Participants

510 consenting normotensive women with singleton pregnancies and no proteinuria at a Hospital in Nigeria.

Excluded those with history of hypertensive disorders of pregnancy, hypertension, 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
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskComputer-generated table of random numbers.
Allocation concealment (selection bias)Low riskLabelled envelopes containing the drug.
Blinding (performance bias and detection bias)
All outcomes
High riskNot blinded.
Incomplete outcome data (attrition bias)
All outcomes
Low riskNo loss to follow-up reported for the outcome included in the review.
Selective reporting (reporting bias)Unclear riskNo data.
Other biasUnclear riskNo 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).

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
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNot stated.
Allocation concealment (selection bias)Unclear riskNot stated. Authors only say: "...women were randomly allocated to...".
Blinding (performance bias and detection bias)
All outcomes
High riskNot blinded.
Incomplete outcome data (attrition bias)
All outcomes
Low riskNo loss to follow-up reported for the outcomes included in the review.
Selective reporting (reporting bias)Unclear riskNo data.
Other biasUnclear riskNo data.

McGinty 1956

Methods

Quasi-randomised trial.

'Cases picked at random'.
Unblinded.

ParticipantsAll 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.

OutcomesDiastolic 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
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear risk"cases picked at random". Randomisation technique not described.
Allocation concealment (selection bias)Unclear riskAllocation concealment not described.
Blinding (performance bias and detection bias)
All outcomes
High riskUnblinded.
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskUnclear.
Selective reporting (reporting bias)Unclear riskUnclear.

Moodie 1976

Methods

Quasi-randomised trial.

Not stated, authors say "...the allocation being at random..."..

Participants

148 women with instrumental deliveries (143 forceps, 5 vacuum) under epidural anaesthesia in a Hospital in New Zeland.

Excluded multiple births and breech presentation.

Interventions

At delivery of the anterior shoulder:

A. oxytocin 5 IU IV (n = 70);

B. ergometrine 0.5 mg IV (n = 78).

No mention of other aspects of the management of the third stage of labour.

Outcomes

Blood loss (mL).

Emetic sequelae (retching or vomiting and nausea).

NotesBlood loss was measured only in 54% of women (80/148), so this outcome was not included in this review.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNot stated.
Allocation concealment (selection bias)Unclear riskNot stated. Authors only say: "...the allocation being at random...".
Blinding (performance bias and detection bias)
All outcomes
High riskNot blinded.
Incomplete outcome data (attrition bias)
All outcomes
Low riskNo (for nausea and vomiting). 46% of women excluded from outcome "blood loss", thus this outcome was not included in the review.
Selective reporting (reporting bias)Unclear riskNo data.
Other biasUnclear riskNo data.

Nordstrom 1997

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

OutcomesBlood loss; additional oxytocin (data tables give methylergometrine; clarification about other oxytocics sought from authors), Hb, blood transfusion; manual removal.
NotesAdditional oxytocin (data tables give methylergometrine; clarification about other oxytocics sought from authors).
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk2 sets of ampoules prepared and numbered according to computer-generated schedule.
Allocation concealment (selection bias)Low riskNo difference in appearance of ampoules.
Blinding (performance bias and detection bias)
All outcomes
Low riskContents unknown to women or caregivers.
Incomplete outcome data (attrition bias)
All outcomes
Low riskNo significant attrition.
Selective reporting (reporting bias)Low riskAll outcomes reported.

Orji 2008

Methods

Randomised controlled trial.

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

At delivery of the anterior shoulder:

A. oxytocin 10 IU IV (n = 297);

B. ergometrine 0.25 mg IV (n = 303).

In both groups the third stage of labour was managed 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
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskRandomly assigned to previously determined sequence.
Allocation concealment (selection bias)Low risk"...sealed envelopes arranged serially...".
Blinding (performance bias and detection bias)
All outcomes
High riskNot blinded.
Incomplete outcome data (attrition bias)
All outcomes
Low riskNo (for the outcomes reported).
Selective reporting (reporting bias)Unclear riskNo data.
Other biasUnclear riskNo data.

Pierre 1992

Methods

Quasi-randomised trial.

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'.

ParticipantsWomen 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 patient's bottom from delivery of the infant until delivery of the placenta.

Third stage managed actively.

OutcomesBlood loss; length of third stage, MRP, maternal side effects.
Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)High riskEnvelopes labelled in sequence. selection at entry into the hospital. no random sequence.
Allocation concealment (selection bias)Low riskEnvelopes sealed and randomly labelled.
Blinding (performance bias and detection bias)
All outcomes
High riskNot blinded.
Incomplete outcome data (attrition bias)
All outcomes
Low riskAll outcomes reported.

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.

ParticipantsApril 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.

OutcomesBlood loss; need for additional oxytocics; length of third stage.
Notes77 women were entered into the trial; 3 were excluded because of induction of labour (2) and vacuum extractin (1).
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskA random treatment allocation list was previously prepared.
Allocation concealment (selection bias)Low riskAdequate.
Blinding (performance bias and detection bias)
All outcomes
Low riskNurse not working in labour room prepared the injection. injection type blinded to participant and personnel.
Incomplete outcome data (attrition bias)
All outcomes
Low riskAll outcomes reported.
Other biasHigh riskTrial stopped at 2 years due to organisational issues.

Saito 2007

MethodsQuasi 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.

OutcomesBlood 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
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)High riskQuasi random: "...women were allocated to a group in a temporal manner (...) selected weekly or monthly, as determined by each hospital, in alternate shifts.".
Allocation concealment (selection bias)High riskInadequate. "...women were allocated to a group in a temporal manner (...) selected weekly or monthly, as determined by each hospital, in alternate shifts."
Blinding (performance bias and detection bias)
All outcomes
High riskNot blinded.
Incomplete outcome data (attrition bias)
All outcomes
Low riskNo loss to follow-up reported for the outcomes included in the review.
Selective reporting (reporting bias)Unclear riskNo data.
Other biasUnclear riskNo data.

Soiva 1964

Methods

Quasi-randomised trial.

Every third normal parturient.

ParticipantsHospital, Finland.
Spontaneous, singleton, cephalic.
InterventionsImmediately 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.
OutcomesBlood loss; duration of third stage, retained placenta, complications, MRP.
Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)High risk"every third participant". No random sequence generation used.
Allocation concealment (selection bias)Unclear riskNo allocation concealment described.
Blinding (performance bias and detection bias)
All outcomes
High riskNot blinded.
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskUnclear.
Selective reporting (reporting bias)Unclear riskUnclear.

Sorbe 1978

Methods

Quasi-randomised trial.

Alternate - odd and even numbers of mothers' hospital records.
Not blinded.

ParticipantsHospital 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.

OutcomesBlood loss; MRP, placental separation time.
Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)High riskRandomisation by odd/even hospital record numbers.
Allocation concealment (selection bias)Unclear riskNo allocation concealment described.
Blinding (performance bias and detection bias)
All outcomes
High riskNot blinded.
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskNot described.

Vaughan Williams1974

  1. a

    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

Methods

Quasi-randomised trial.

"Patients were randomly assigned to one of six treatment groups." No information about blinding or allocation concealment described.

Participants51 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.

OutcomesPrimary outcomes were mean CVP and blood loss.
Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskRandomisation not described.
Allocation concealment (selection bias)Unclear riskAllocation concealment not described.
Blinding (performance bias and detection bias)
All outcomes
High riskNo blinding.
Incomplete outcome data (attrition bias)
All outcomes
Low riskAll outcomes reported.
Selective reporting (reporting bias)Unclear riskUnclear.

Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion
  1. a

    IU: international unit
    IV: intravenous
    vs: versus

Boucher 2004Comparison of intramuscular carbetocin to a 2-hour IV oxytocin infusion administered after delivery of the placenta.
Dickinson 2009Comparison of oxytocin, misoprostol and no additional medication for the third-stage management after second trimester medical termination.
Docherty 1982Oxytocin versus ergometrine-oxytocin (subject of separate review).
Dommisse 1980No randomisation of treatment groups.
Dumoulin 1981Oxytocin (different doses) versus ergometrine-oxytocin (subject of separate review).
Friedman 1957Likely 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 2001Comparison of oxytocin with misoprostol (subject of separate review).
Hacker 1979No randomisation of treatment groups.
Hoffman 2006bComparison of oxytocin within the context of active vs expectant management (subject of a separate review).
Howard 1964Oxytocin, methergine or placebo given after delivery of the placenta.
Huh 2000Excluded as only different timing of administration.
Irons 1994Comparison of nipple stimulation to ergometrine-oxytocin which is not a subject of this review.
Jackson 2001Comparison of oxytocin administered before and after placental delivery so the only difference is timing of administration.
Khan 1997Comparison 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 2001Comparison of oxytocin with misoprostol (subject of separate review).
Lokugamage 2001Comparison of oxytocin to misoprostol (subject of separate review) and at caesarean section.
Muller 19965 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 1961Oxytocin or placebo given after delivery of the placenta.
Nieminen 1963No randomisation of treatment groups.
Parsons 2004Comparison of oxytocin with misoprostol (subject of separate review).
Porter 1991Only difference is different route of administration.
Ramirez 2001Inadequate information available about randomisation and available only as abstract.
Rouse 2011Comparison between different doses of oxytocin without placebo or alternate uterotonic.
Sariganont 1999No randomisation of treatment groups.
Schaefer 2004Excluded as only difference is timing of administration.
Schemmer 2001Comparison of oxytocin administered before and after placental delivery so the only difference is timing of administration.
Soriano 1995Compares oxytocin with oxytocin plus ergometrine (subject of separate review).
Stanton 2012Manuscript published is of study protocol only, data planned to be analysed in 2013.
Stearn 1963Allocation 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 1984Compares oxytocin with oxytocin plus ergometrine (subject of separate review).
Tessier 2000Excluded as only different routes of administration.
Thornton 1988Strong 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 2012Comparison between different doses of oxytocin without placebo or alternate uterotonic.
Vasegh 2005Comparison of active vs expectant management of the third stage of labour (subject of a separate review). Study design information not available.
Wetta 2011Comparison between different doses of oxytocin without placebo or alternate uterotonic
Yuen 1995Oxytocin vs ergometrine-oxytocin (subject of separate review).

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