Prophylactic oxytocin for the third stage of labour to prevent postpartum haemorrhage
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.
PICOs
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).
Authors' conclusions
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:
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oxytocin versus no uterotonics;
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oxytocin versus ergot alkaloids;
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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:
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use of prophylactic oxytocin at any dose for the third stage of labour versus placebo;
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use of prophylactic oxytocin at any dose for the third stage of labour versus ergot alkaloids;
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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
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Postpartum haemorrhage (PPH) (reported estimates of blood loss greater than or equal to 500 mL)
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Use of additional therapeutic uterotonics
Secondary outcomes
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Severe PPH (clinically estimated blood loss greater than or equal to 1000 mL)
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Mean blood loss (mL)
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Maternal haemoglobin concentration (Hb) less than 9 g/dL 24 to 48 hours postpartum
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Blood transfusion
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Third stage greater than 30 minutes
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Mean length of third stage (minutes)
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Manual removal of the placenta
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Diastolic blood pressure greater than 100 mmHg between delivery of baby and discharge from the labour ward
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Vomiting between delivery of baby and discharge from the labour ward
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Nausea between delivery of baby and discharge from the labour ward
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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:
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monthly searches of the Cochrane Central Register of Controlled Trials (CENTRAL);
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weekly searches of MEDLINE;
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weekly searches of Embase;
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handsearches of 30 journals and the proceedings of major conferences;
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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, seeAppendix 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:
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low risk of bias (any truly random process, e.g. random number table; computer random number generator);
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high risk of bias (any non‐random process, e.g. odd or even date of birth; hospital or clinic record number);
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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:
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low risk of bias (e.g. telephone or central randomisation; consecutively numbered sealed opaque envelopes);
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high risk of bias (open random allocation; unsealed or non‐opaque envelopes, alternation; date of birth);
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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:
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low, high or unclear risk of bias for participants;
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low, high or unclear risk of bias for personnel;
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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:
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low risk of bias (e.g. no missing outcome data; missing outcome data balanced across groups;
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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);
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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:
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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);
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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);
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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:
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low risk of other bias;
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high risk of other bias;
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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 ‐ seeSensitivity 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.
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Extent of selection bias: randomised trials with low risk of bias versus quasi‐randomised trials with high risk of bias.
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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.
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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.
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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.
Comparison 1 Oxytocin versus no uterotonics, Outcome 1 PPH (clinically estimated blood loss > or = 500 mL).
Comparison 1 Oxytocin versus no uterotonics, Outcome 2 Therapeutic uterotonics.
Comparison 1 Oxytocin versus no uterotonics, Outcome 3 Severe PPH (clinically estimated blood loss > or = 1000 mL).
Comparison 1 Oxytocin versus no uterotonics, Outcome 4 Mean blood loss (mL).
Comparison 1 Oxytocin versus no uterotonics, Outcome 5 Maternal haemoglobin concentration (Hb) < 9 g/dL 24 to 48 hours postpartum.
Comparison 1 Oxytocin versus no uterotonics, Outcome 6 Blood transfusion.
Comparison 1 Oxytocin versus no uterotonics, Outcome 7 Third stage greater than 30 minutes.
Comparison 1 Oxytocin versus no uterotonics, Outcome 8 Mean length of third stage (minutes).
Comparison 1 Oxytocin versus no uterotonics, Outcome 9 Manual removal of the placenta.
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 1 PPH (clinically estimated blood loss > or = 500 mL); randomised v. quasi‐randomised trials.
Comparison 2 Oxytocin versus no uterotonics‐‐subgroup analyses, Outcome 2 PPH (clinically estimated blood loss > or = 500 mL); active v. expectant management.
Comparison 2 Oxytocin versus no uterotonics‐‐subgroup analyses, Outcome 3 PPH (clinically estimated blood loss > or = 500 mL); IM v. IV oxytocin.
Comparison 2 Oxytocin versus no uterotonics‐‐subgroup analyses, Outcome 4 PPH (clinically estimated blood loss > 500 mL); oxytocin dose < 10 IU v. 10 IU.
Comparison 2 Oxytocin versus no uterotonics‐‐subgroup analyses, Outcome 5 Therapeutic uterotonics; randomised v. quasi‐randomised trials.
Comparison 2 Oxytocin versus no uterotonics‐‐subgroup analyses, Outcome 6 Therapeutic uterotonics; active v. expectant management.
Comparison 2 Oxytocin versus no uterotonics‐‐subgroup analyses, Outcome 7 Therapeutic uterotonics; IM v. IV oxytocin.
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 1 PPH (clinically estimated blood loss > or = 500 mL).
Comparison 3 Oxytocin versus ergot alkaloids, Outcome 2 Therapeutic uterotonics.
Comparison 3 Oxytocin versus ergot alkaloids, Outcome 3 Severe PPH (clinically estimated blood loss > or = 1000 mL).
Comparison 3 Oxytocin versus ergot alkaloids, Outcome 4 Mean blood loss (mL).
Comparison 3 Oxytocin versus ergot alkaloids, Outcome 6 Blood transfusion.
Comparison 3 Oxytocin versus ergot alkaloids, Outcome 8 Mean length of third stage (minutes).
Comparison 3 Oxytocin versus ergot alkaloids, Outcome 9 Manual removal of the placenta.
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.
Comparison 3 Oxytocin versus ergot alkaloids, Outcome 11 Vomiting between delivery of the baby and discharge from the labour ward.
Comparison 3 Oxytocin versus ergot alkaloids, Outcome 12 Nausea between delivery of the baby and discharge from the labour ward.
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 1 PPH (clinically estimated blood loss > or = 500 mL); randomised v. quasi‐randomised trials.
Comparison 4 Oxytocin versus ergot alkaloids‐‐subgroup analyses, Outcome 2 PPH (clinically estimated blood loss > or = 500 mL); active v. expectant management.
Comparison 4 Oxytocin versus ergot alkaloids‐‐subgroup analyses, Outcome 3 PPH (clinically estimated blood loss > or = 500 mL); IM v. IV oxytocin.
Comparison 4 Oxytocin versus ergot alkaloids‐‐subgroup analyses, Outcome 4 PPH (clinically estimated blood loss > 500 mL); oxytocin dose < 10 IU v. 10 IU.
Comparison 4 Oxytocin versus ergot alkaloids‐‐subgroup analyses, Outcome 5 Therapeutic uterotonics; randomised v. quasi‐randomised trials.
Comparison 4 Oxytocin versus ergot alkaloids‐‐subgroup analyses, Outcome 6 Therapeutic uterotonics; active v. expectant management.
Comparison 4 Oxytocin versus ergot alkaloids‐‐subgroup analyses, Outcome 7 Therapeutic uterotonics; IM v. IV oxytocin.
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 1 PPH (clinically estimated blood loss > or = 500 mL).
Comparison 5 Oxytocin + ergometrine versus ergot alkaloids, Outcome 3 Severe PPH (clinically estimated blood loss > or = 1000 mL).
Comparison 5 Oxytocin + ergometrine versus ergot alkaloids, Outcome 4 Mean blood loss (mL).
Comparison 5 Oxytocin + ergometrine versus ergot alkaloids, Outcome 6 Blood transfusion.
Comparison 5 Oxytocin + ergometrine versus ergot alkaloids, Outcome 8 Mean length of the third stage (minutes).
Comparison 5 Oxytocin + ergometrine versus ergot alkaloids, Outcome 9 Manual removal of the placenta.
Comparison 6 Oxytocin + ergometrine versus ergot alkaloids‐‐subgroup analyses, Outcome 1 PPH (clinically estimated blood loss > or = 500 mL); randomised v. quasi‐randomised trials.
Comparison 6 Oxytocin + ergometrine versus ergot alkaloids‐‐subgroup analyses, Outcome 2 PPH (clinically estimated blood loss > or = 500 mL); active v. expectant management.
Comparison 6 Oxytocin + ergometrine versus ergot alkaloids‐‐subgroup analyses, Outcome 3 PPH (clinically estimated blood loss > or = 500 mL); IM v. IV oxytocin.
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 PPH (clinically estimated blood loss > or = 500 mL) Show forest plot | 6 | 4203 | Risk Ratio (M‐H, Random, 95% CI) | 0.53 [0.38, 0.74] |
| 2 Therapeutic uterotonics Show forest plot | 4 | 3174 | Risk Ratio (M‐H, Random, 95% CI) | 0.56 [0.36, 0.87] |
| 3 Severe PPH (clinically estimated blood loss > or = 1000 mL) Show forest plot | 5 | 4162 | Risk Ratio (M‐H, Random, 95% CI) | 0.62 [0.44, 0.87] |
| 4 Mean blood loss (mL) Show forest plot | 5 | 1402 | Mean Difference (IV, Random, 95% CI) | ‐99.46 [‐181.97, ‐16.95] |
| 5 Maternal haemoglobin concentration (Hb) < 9 g/dL 24 to 48 hours postpartum Show forest plot | 3 | 1645 | Risk Ratio (M‐H, Random, 95% CI) | 0.78 [0.60, 1.00] |
| 6 Blood transfusion Show forest plot | 3 | 3120 | Risk Ratio (M‐H, Random, 95% CI) | 0.89 [0.44, 1.78] |
| 7 Third stage greater than 30 minutes Show forest plot | 1 | 1947 | Risk Ratio (M‐H, Fixed, 95% CI) | 2.55 [0.88, 7.44] |
| 8 Mean length of third stage (minutes) Show forest plot | 3 | 294 | Mean Difference (IV, Random, 95% CI) | ‐3.61 [‐9.06, 1.83] |
| 9 Manual removal of the placenta Show forest plot | 6 | 4320 | Risk 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 ward | 0 | 0 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] |
| 11 Vomiting between delivery of the baby and discharge from the labour ward | 0 | 0 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] |
| 12 Nausea between delivery of the baby and discharge from the labour ward Show forest plot | 1 | 52 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.29 [0.01, 6.74] |
| 13 Headace between delivery of the baby and discharge from the labour ward | 0 | 0 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 PPH (clinically estimated blood loss > or = 500 mL); randomised v. quasi‐randomised trials Show forest plot | 6 | 4203 | Risk Ratio (M‐H, Random, 95% CI) | 0.53 [0.38, 0.74] |
| 1.1 Randomised trials only (low risk of bias) | 3 | 3171 | Risk Ratio (M‐H, Random, 95% CI) | 0.61 [0.48, 0.77] |
| 1.2 Quasi‐randomised trials (high risk of bias) | 3 | 1032 | Risk Ratio (M‐H, Random, 95% CI) | 0.38 [0.19, 0.76] |
| 2 PPH (clinically estimated blood loss > or = 500 mL); active v. expectant management Show forest plot | 5 | 4193 | Risk Ratio (M‐H, Random, 95% CI) | 0.53 [0.38, 0.74] |
| 2.1 Active management | 2 | 2920 | Risk Ratio (M‐H, Random, 95% CI) | 0.39 [0.22, 0.72] |
| 2.2 Expectant management | 3 | 1273 | Risk Ratio (M‐H, Random, 95% CI) | 0.64 [0.49, 0.84] |
| 3 PPH (clinically estimated blood loss > or = 500 mL); IM v. IV oxytocin Show forest plot | 6 | 4203 | Risk Ratio (M‐H, Random, 95% CI) | 0.53 [0.38, 0.74] |
| 3.1 IV oxytocin | 3 | 1980 | Risk Ratio (M‐H, Random, 95% CI) | 0.41 [0.21, 0.79] |
| 3.2 IM oxytocin | 3 | 2223 | Risk Ratio (M‐H, Random, 95% CI) | 0.65 [0.47, 0.89] |
| 4 PPH (clinically estimated blood loss > 500 mL); oxytocin dose < 10 IU v. 10 IU Show forest plot | 5 | 4193 | Odds Ratio (M‐H, Random, 95% CI) | 0.44 [0.30, 0.64] |
| 4.1 Oxytocin dose < 10 IU | 3 | 1243 | Odds Ratio (M‐H, Random, 95% CI) | 0.42 [0.17, 1.01] |
| 4.2 Oxytocin dose 10 IU | 2 | 2950 | Odds Ratio (M‐H, Random, 95% CI) | 0.47 [0.38, 0.59] |
| 5 Therapeutic uterotonics; randomised v. quasi‐randomised trials Show forest plot | 4 | 3174 | Risk Ratio (M‐H, Random, 95% CI) | 0.56 [0.36, 0.87] |
| 5.1 Randomised trials (low risk of bias) | 3 | 3122 | Risk Ratio (M‐H, Random, 95% CI) | 0.58 [0.36, 0.92] |
| 5.2 Quasi‐randomised trials (high‐risk of bias) | 1 | 52 | Risk Ratio (M‐H, Random, 95% CI) | 0.17 [0.01, 3.42] |
| 6 Therapeutic uterotonics; active v. expectant management Show forest plot | 4 | 3174 | Risk Ratio (M‐H, Random, 95% CI) | 0.56 [0.36, 0.87] |
| 6.1 Active management | 1 | 1901 | Risk Ratio (M‐H, Random, 95% CI) | 0.39 [0.26, 0.58] |
| 6.2 Expectant management | 3 | 1273 | Risk Ratio (M‐H, Random, 95% CI) | 0.68 [0.41, 1.12] |
| 7 Therapeutic uterotonics; IM v. IV oxytocin Show forest plot | 4 | 3174 | Risk Ratio (M‐H, Random, 95% CI) | 0.56 [0.36, 0.87] |
| 7.1 IV oxytocin | 1 | 1000 | Risk Ratio (M‐H, Random, 95% CI) | 0.57 [0.39, 0.82] |
| 7.2 IM oxytocin | 3 | 2174 | Risk Ratio (M‐H, Random, 95% CI) | 0.56 [0.24, 1.27] |
| 8 Therapeutic uterotonics; oxytocin dose < 10 IU v. 10 IU Show forest plot | 4 | 3174 | Risk Ratio (M‐H, Random, 95% CI) | 0.56 [0.36, 0.87] |
| 8.1 Oxytocin dose < 10 IU | 2 | 273 | Risk Ratio (M‐H, Random, 95% CI) | 0.77 [0.23, 2.56] |
| 8.2 Oxytocin dose 10 IU | 2 | 2901 | Risk Ratio (M‐H, Random, 95% CI) | 0.48 [0.33, 0.68] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 PPH (clinically estimated blood loss > or = 500 mL) Show forest plot | 5 | 2226 | Risk Ratio (M‐H, Random, 95% CI) | 0.76 [0.61, 0.94] |
| 2 Therapeutic uterotonics Show forest plot | 3 | 1167 | Risk Ratio (M‐H, Random, 95% CI) | 0.70 [0.38, 1.29] |
| 3 Severe PPH (clinically estimated blood loss > or = 1000 mL) Show forest plot | 3 | 1616 | Risk Ratio (M‐H, Random, 95% CI) | 1.07 [0.62, 1.85] |
| 4 Mean blood loss (mL) Show forest plot | 6 | 2748 | Mean Difference (IV, Random, 95% CI) | ‐12.49 [‐37.66, 12.68] |
| 5 Maternal haemoglobin concentration (Hb) < 9 g/dL 24 to 48 hours postpartum | 0 | 0 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] |
| 6 Blood transfusion Show forest plot | 2 | 567 | Risk Ratio (M‐H, Random, 95% CI) | 3.74 [0.34, 40.64] |
| 7 Third stage > 30 minutes | 0 | 0 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] |
| 8 Mean length of third stage (minutes) Show forest plot | 3 | 1992 | Mean Difference (IV, Random, 95% CI) | ‐0.43 [‐0.89, 0.04] |
| 9 Manual removal of the placenta Show forest plot | 4 | 2216 | Risk 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 ward Show forest plot | 2 | 660 | Risk Ratio (M‐H, Random, 95% CI) | 0.53 [0.19, 1.52] |
| 11 Vomiting between delivery of the baby and discharge from the labour ward Show forest plot | 3 | 1091 | Risk Ratio (M‐H, Random, 95% CI) | 0.07 [0.02, 0.25] |
| 12 Nausea between delivery of the baby and discharge from the labour ward Show forest plot | 3 | 1091 | Risk Ratio (M‐H, Random, 95% CI) | 0.18 [0.06, 0.53] |
| 13 Headaches between delivery of the baby and discharge from the labour ward Show forest plot | 2 | 943 | Risk Ratio (M‐H, Random, 95% CI) | 0.08 [0.00, 9.46] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 PPH (clinically estimated blood loss > or = 500 mL); randomised v. quasi‐randomised trials Show forest plot | 5 | 2226 | Risk Ratio (M‐H, Random, 95% CI) | 0.76 [0.61, 0.94] |
| 1.1 Randomised trials (low risk of bias) | 2 | 824 | Risk Ratio (M‐H, Random, 95% CI) | 0.82 [0.58, 1.15] |
| 1.2 Quasi‐randomised trials (high risk of bias) | 3 | 1402 | Risk Ratio (M‐H, Random, 95% CI) | 0.71 [0.53, 0.96] |
| 2 PPH (clinically estimated blood loss > or = 500 mL); active v. expectant management Show forest plot | 4 | 2216 | Risk Ratio (M‐H, Random, 95% CI) | 0.76 [0.61, 0.95] |
| 2.1 Active management | 2 | 943 | Risk Ratio (M‐H, Random, 95% CI) | 0.58 [0.38, 0.89] |
| 2.2 Expectant management | 2 | 1273 | Risk Ratio (M‐H, Random, 95% CI) | 0.84 [0.65, 1.09] |
| 3 PPH (clinically estimated blood loss > or = 500 mL); IM v. IV oxytocin Show forest plot | 5 | 2226 | Risk Ratio (M‐H, Random, 95% CI) | 0.76 [0.61, 0.94] |
| 3.1 IM oxytocin | 2 | 567 | Risk Ratio (M‐H, Random, 95% CI) | 0.71 [0.44, 1.13] |
| 3.2 IV oxytocin | 3 | 1659 | Risk Ratio (M‐H, Random, 95% CI) | 0.78 [0.57, 1.07] |
| 4 PPH (clinically estimated blood loss > 500 mL); oxytocin dose < 10 IU v. 10 IU Show forest plot | 4 | 2216 | Risk Ratio (M‐H, Random, 95% CI) | 0.76 [0.61, 0.95] |
| 4.1 Oxytocin dose < 10 IU | 2 | 567 | Risk Ratio (M‐H, Random, 95% CI) | 0.71 [0.44, 1.13] |
| 4.2 Oxytocin dose 10 IU | 2 | 1649 | Risk Ratio (M‐H, Random, 95% CI) | 0.79 [0.57, 1.08] |
| 5 Therapeutic uterotonics; randomised v. quasi‐randomised trials Show forest plot | 3 | 1167 | Risk Ratio (M‐H, Random, 95% CI) | 0.70 [0.38, 1.29] |
| 5.1 Randomised trials (low risk of bias) | 2 | 824 | Risk Ratio (M‐H, Random, 95% CI) | 0.86 [0.43, 1.74] |
| 5.2 Quasi‐randomised trials (high risk of bias) | 1 | 343 | Risk Ratio (M‐H, Random, 95% CI) | 0.42 [0.19, 0.91] |
| 6 Therapeutic uterotonics; active v. expectant management Show forest plot | 3 | 1167 | Risk Ratio (M‐H, Random, 95% CI) | 0.70 [0.38, 1.29] |
| 6.1 Active management | 2 | 943 | Risk Ratio (M‐H, Random, 95% CI) | 0.54 [0.34, 0.85] |
| 6.2 Expectant management | 1 | 224 | Risk Ratio (M‐H, Random, 95% CI) | 1.25 [0.67, 2.31] |
| 7 Therapeutic uterotonics; IM v. IV oxytocin Show forest plot | 3 | 1167 | Risk Ratio (M‐H, Random, 95% CI) | 0.70 [0.38, 1.29] |
| 7.1 IM oxytocin | 2 | 567 | Risk Ratio (M‐H, Random, 95% CI) | 0.74 [0.25, 2.19] |
| 7.2 IV oxytocin | 1 | 600 | Risk Ratio (M‐H, Random, 95% CI) | 0.61 [0.35, 1.07] |
| 8 Therapeutic uterotonics; oxytocin dose < 10 IU v. 10 IU Show forest plot | 3 | 1167 | Risk Ratio (M‐H, Random, 95% CI) | 0.70 [0.38, 1.29] |
| 8.1 Oxytocin dose < 10 IU | 2 | 567 | Risk Ratio (M‐H, Random, 95% CI) | 0.74 [0.25, 2.19] |
| 8.2 Oxytocin dose 10 IU | 1 | 600 | Risk Ratio (M‐H, Random, 95% CI) | 0.61 [0.35, 1.07] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 PPH (clinically estimated blood loss > or = 500 mL) Show forest plot | 5 | 2891 | Risk Ratio (M‐H, Random, 95% CI) | 0.90 [0.34, 2.41] |
| 2 Therapeutic uterotonics | 0 | 0 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] |
| 3 Severe PPH (clinically estimated blood loss > or = 1000 mL) Show forest plot | 1 | 1120 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.67 [0.40, 6.94] |
| 4 Mean blood loss (mL) Show forest plot | 1 | 34 | Mean Difference (IV, Fixed, 95% CI) | 61.0 [6.00, 116.00] |
| 5 Maternal haemoglobin concentration (Hb) < 9 g/dL 24 to 48 hours postpartum | 0 | 0 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] |
| 6 Blood transfusion Show forest plot | 1 | 1120 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.71 [0.23, 2.24] |
| 7 Third stage > 30 minutes | 0 | 0 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] |
| 8 Mean length of the third stage (minutes) Show forest plot | 1 | 372 | Mean Difference (IV, Fixed, 95% CI) | 0.0 [0.0, 0.0] |
| 9 Manual removal of the placenta Show forest plot | 2 | 1927 | Risk 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 ward | 0 | 0 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] |
| 11 Vomiting between delivery of the baby and discharge from the labour ward | 0 | 0 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] |
| 12 Nausea between delivery of the baby and discharge from the labour ward | 0 | 0 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] |
| 13 Headaches between delivery of the baby and discharge from the labour ward | 0 | 0 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 PPH (clinically estimated blood loss > or = 500 mL); randomised v. quasi‐randomised trials Show forest plot | 5 | 2891 | Risk Ratio (M‐H, Random, 95% CI) | 0.90 [0.34, 2.41] |
| 1.1 Randomised trials (low risk of bias) | 0 | 0 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 1.2 Quasi‐randomised trials (high risk of bias) | 5 | 2891 | Risk Ratio (M‐H, Random, 95% CI) | 0.90 [0.34, 2.41] |
| 2 PPH (clinically estimated blood loss > or = 500 mL); active v. expectant management Show forest plot | 2 | 1474 | Risk Ratio (M‐H, Random, 95% CI) | 0.80 [0.45, 1.43] |
| 2.1 Active management | 1 | 354 | Risk Ratio (M‐H, Random, 95% CI) | 0.48 [0.15, 1.52] |
| 2.2 Expectant management | 1 | 1120 | Risk Ratio (M‐H, Random, 95% CI) | 0.95 [0.50, 1.79] |
| 3 PPH (clinically estimated blood loss > or = 500 mL); IM v. IV oxytocin Show forest plot | 5 | 2891 | Risk Ratio (M‐H, Random, 95% CI) | 0.90 [0.34, 2.41] |
| 3.1 IM oxytocin | 4 | 2881 | Risk Ratio (M‐H, Random, 95% CI) | 0.98 [0.34, 2.78] |
| 3.2 IV oxytocin | 1 | 10 | Risk Ratio (M‐H, Random, 95% CI) | 0.33 [0.02, 6.65] |
