Review question

What is the effectiveness of uterotonics for the prevention of postpartum haemorrhage?

Summary of the protocol

See Table 1 for a summary of the Population, Intervention, Comparison and Outcome (PICO) characteristics of this review.

Table 1

Summary of the protocol (PICO table).

For further details see the review protocol in appendix A.

Clinical evidence profile for outcomes included in the network meta-analysis

NMA was used to synthesise evidence for the following outcomes (both for the whole population of women and for the subgroups of either vaginal or caesarean birth):

• PPH ≥ 1000 mL
• Additional uterotonics
• Blood transfusion
• ICU admission (severe maternal morbidity)
• Mean blood loss (mL).

Where possible, placebo was used as the reference treatment in the NMAs. In two of the outcomes for the caesarean birth subgroup, placebo was not included in the evidence network and therefore another treatment (carbetocin) was used as the reference for those two analyses.

PPH ≥ 1000ml

98 studies, comparing 13 interventions in 113,135 women were included in this analysis. Of these studies, 1 included women who had either vaginal or caesarean births, 71 were conducted in women who had vaginal births only, and 26 in women who had caesarean births only.

Of the 122 studies that reported this outcome, 24 studies were excluded as they reported no events in any arm for this outcome.

The network plot for this outcome is shown below at Figure 1, the odds ratios and log odds ratios compared to placebo in Table 2, the Forest plot at Figure 2 and the median treatment ranks in Table 3.

Figure 1

Network of evidence for PPH ≥ 1000 mL, full dataset. Abbreviations: Plac, placebo; Mis_b600, misoprostol ≤600mcg; Carb, carbetocin; CarbProst, carboprost; Erg, ergometrine; Erg_Oxy, ergometrine plus oxytocin; Mis_a600b800, misoprostol (more...)

Table 2

Odds ratio, log odds ratio and 95% CrIs for PPH ≥ 1000 mL for all interventions compared with placebo.

In this analysis only one study included the high-dose misoprostol arm and reported no PPH ≥ 1000 mL events in that arm which led to high uncertainty in the comparison with this treatment. Therefore high-dose misoprostol has been excluded from the ranking in Table 3 as the probability of being best can be biased for highly uncertain estimates.

Figure 2

Forest plot, PPH ≥ 1000 mL full population (OR<1 favours the intervention).

Table 3

Median treatment ranks and probability of being the best treatment for all interventions for PPH ≥ 1000 mL.

Vaginal birth subgroup analysis

71 studies comparing 13 treatments in 107,322 women were included in this subgroup analysis.

Of the 91 studies that reported this outcome, 20 studies were excluded as they reported no events in any arm for this outcome.

The network plot for this outcome is shown below at Figure 3, the odds ratios compared to placebo in Table 4, the Forest plot at Figure 4 and the median treatment ranks in Table 5.

Figure 3

Network of evidence for PPH ≥ 1000 mL, vaginal birth subgroup. Abbreviations: Plac, placebo; Mis_b600, misoprostol ≤600mcg; Carb, carbetocin; CarbProst, carboprost; Erg, ergometrine; Erg_Oxy, ergometrine plus oxytocin; Mis_a600b800, misoprostol (more...)

Table 4

Odds ratio, log odds ratio and 95% CrIs for PPH ≥ 1000mL for all interventions compared with placebo, vaginal birth subgroup.

In this analysis only one study included the high-dose misoprostol arm, and reported no PPH ≥ 1000 mL events in that arm which led to high uncertainty in the comparison with this treatment. Therefore high-dose misoprostol has been excluded from the ranking in Table 5 as the probability of being best can be biased for highly uncertain estimates.

Figure 4

Forest plot, PPH ≥ 1000mL vaginal birth (OR< 1 favours intervention).

Table 5

Median treatment ranks and probability of being the best treatment for all interventions for PPH ≥ 1000mL, vaginal birth subgroup.

Caesarean birth subgroup analysis

26 studies comparing 8 treatments in 5,284 women were included in this subgroup analysis.

Of the 30 studies that reported this outcome, 4 studies were excluded as they reported no events in any arm for this outcome.

The network plot for this outcome is shown below at Figure 5, the odds ratios compared to carbetocin in Table 6, the Forest plot at Figure 6 and the median treatment ranks in Table 7.

Figure 5

Network of evidence for PPH ≥ 1000mL, caesarean birth subgroup. Abbreviations: Plac, placebo; Mis_b600, misoprostol ≤600mcg; Carb, carbetocin; Erg_Oxy, ergometrine plus oxytocin; Mis_a600b800, misoprostol >600mcg and ≤800mcg; (more...)

Table 6

Odds ratio, log odds ratio and 95% CrIs for PPH ≥ 1000mL for all interventions compared with carbetocin, caesarean birth subgroup.

Figure 6

Forest plot, PPH ≥ 1000mL caesarean birth (OR< 1 favours intervention, compared to carbetocin).

Table 7

Median treatment ranks and probability of being the best treatment for all interventions for PPH ≥ 1000mL, caesarean birth subgroup.

Additional uterotonics

161 studies, comparing 14 interventions in 123,183 women were included in this analysis. Of these studies, 1 included women who had either vaginal or caesarean births, 109 were conducted in women who had vaginal births only, and 51 in women who had caesarean births only.

Of the 163 studies that reported this outcome, 2 studies were excluded as they reported no events in any arm for this outcome.

The network plot for this outcome is shown below at Figure 7, the odds ratios compared to placebo in Table 8, the Forest plot at Figure 8 and the median treatment ranks in Table 9.

Figure 7

Network of evidence for additional uterotonics, full dataset. Abbreviations: Plac, placebo; Mis_b600, misoprostol ≤600mcg; Carb, carbetocin; CarbProst, carboprost; Erg, ergometrine; Erg_Oxy, ergometrine plus oxytocin; Mis_a600b800, misoprostol (more...)

Table 8

Odds ratio, log odds ratio and 95% CrIs for additional uterotonics for all interventions compared with placebo.

Figure 8

Forest plot, Additional uterotonics full population (OR < 1 favours intervention).

Table 9

Median treatment ranks and probability of being the best treatment for all interventions for additional uterotonics.

Vaginal birth subgroup analysis

109 studies comparing 12 treatments in 112,805 women were included in this subgroup analysis.

Of the 109 studies that reported this outcome, 0 studies were excluded as they reported no events in any arm for this outcome.

The network plot for this outcome is shown below at Figure 9, the odds ratios compared to placebo in Table 10, the Forest plot at Figure 10 and the median treatment ranks in Table 11.

Figure 9

Network of evidence for additional uterotonics, vaginal birth subgroup. Abbreviations: Plac, placebo; Mis_b600, misoprostol ≤600mcg; Carb, carbetocin; CarbProst, carboprost; Erg, ergometrine; Erg_Oxy, ergometrine plus oxytocin; Mis_a600b800, misoprostol (more...)

Table 10

Odds ratio, log odds ratio and 95% CrIs for additional uterotonics for all interventions compared with placebo, vaginal birth subgroup.

Figure 10

Forest plot, Additional uterotonics vaginal birth (OR <1 favours intervention).

Table 11

Median treatment ranks and probability of being the best treatment for all interventions for additional uterotonics, vaginal birth subgroup.

Caesarean birth subgroup analysis

51 studies comparing 12 treatments in 10,323 women were included in this subgroup analysis.

Of the 53 studies that reported this outcome, 2 studies were excluded as they reported no events in any arm for this outcome.

The network plot for this outcome is shown below at Figure 11, the odds ratios compared to placebo in Table 12, the Forest plot at Figure 12 and the median treatment ranks in Table 13.

Figure 11

Network of evidence for additional uterotonics, caesarean birth subgroup.

Table 12

Odds ratio, log odds ratio and 95% CrIs for additional uterotonics for all interventions compared with placebo, caesarean birth subgroup.

In this analysis only one study included the ergometrine arm, and reported no additional uterotonic events in that arm which led to high uncertainty in the comparison with this treatment. Therefore, ergometrine has been excluded from the ranking in Table 13 as the probability of being best can be biased for highly uncertain estimates.

Figure 12

Forest plot, Additional uterotonics caesarean birth (OR <1 favours intervention).

Table 13

Median treatment ranks and probability of being the best treatment for all interventions for additional uterotonics, caesarean birth subgroup.

Blood transfusion

113 studies, comparing 13 interventions in 115,872 women were included in this analysis. Of these studies, 1 included women who had either vaginal or caesarean births, 80 were conducted in women who had vaginal births only, and 32 in women who had caesarean births only.

Of the 140 studies that reported this outcome, 27 studies were excluded as they reported no events in any arm for this outcome.

The network plot for this outcome is shown below at Figure 13, the odds ratios compared to placebo in Table 14, the Forest plot at Figure 14 and the median treatment ranks in Table 15.

Figure 13

Network of evidence for blood transfusion, full dataset. Abbreviations: Plac, placebo; Mis_b600, misoprostol ≤600mcg; Carb, carbetocin; CarbProst, carboprost; Erg, ergometrine; Erg_Oxy, ergometrine plus oxytocin; Mis_a600b800, misoprostol >600mcg (more...)

Table 14

Odds ratio, log odds ratio and 95% CrIs for blood transfusion for all interventions compared with placebo.

In this analysis only one study included the high-dose misoprostol arm, and reported no transfusion events in that arm which led to high uncertainty in the comparison with this treatment. Therefore, high-dose misoprostol has been excluded from the ranking in Table 15 as the probability of being best can be biased for highly uncertain estimates.

Figure 14

Forest plot, blood transfusion full population (OR< 1 favours intervention).

Table 15

Median treatment ranks and probability of being the best treatment for all interventions for blood transfusion.

Vaginal birth subgroup analysis

80 studies comparing 12 treatments in 107,850 women were included in this subgroup analysis.

Of the 99 studies that reported this outcome, 19 studies were excluded as they reported no events in any arm for this outcome.

The network plot for this outcome is shown below at Figure 15, the odds ratios compared to placebo in Table 16, the Forest plot at Figure 16 and the median treatment ranks in Table 17.

Figure 15

Network of evidence for blood transfusion, vaginal birth subgroup. Abbreviations: Plac, placebo; Mis_b600, misoprostol ≤600mcg; Carb, carbetocin; CarbProst, carboprost; Erg, ergometrine; Erg_Oxy, ergometrine plus oxytocin; Mis_a600b800, misoprostol (more...)

Table 16

Odds ratio, log odds ratio and 95% CrIs for blood transfusion for all interventions compared with placebo, vaginal birth subgroup.

In this analysis only one study included the high-dose misoprostol arm, and reported no transfusion events in that arm which led to high uncertainty in the comparison with this treatment. Therefore, high-dose misoprostol has been excluded from the ranking in Table 17 as the probability of being best can be biased for highly uncertain estimates.

Figure 16

Forest plot, blood transfusion vaginal birth (OR <1 favours intervention).

Table 17

Median treatment ranks and probability of being the best treatment for all interventions for blood transfusion, vaginal birth subgroup.

Caesarean birth subgroup analysis

32 studies comparing 9 treatments in 8,114 women were included in this subgroup analysis.

Of the 40 studies that reported this outcome, 8 studies were excluded as they reported no events in any arm for this outcome.

The network plot for this outcome is shown below at Figure 17, the odds ratios compared to carbetocin in Table 18, the Forest plot at Figure 18 and the median treatment ranks in Table 19.

Figure 17

Network of evidence for blood transfusion, caesarean birth subgroup. Abbreviations: Mis_b600, misoprostol ≤600mcg; Carb, carbetocin; Erg_Oxy, ergometrine plus oxytocin; Mis_a600b800, misoprostol >600mcg and ≤800mcg; Mis_Oxy, misoprostol (more...)

Table 18

Odds ratio, log odds ratio and 95% CrIs for blood transfusion for all interventions compared with carbetocin, caesarean birth subgroup.

In this analysis only one study included the misoprostol >600 mcg and ≤ 800 mcg arm, and reported no transfusion events in that arm which led to high uncertainty in the comparison with this treatment. Therefore, misoprostol >600 mcg and ≤ 800 mcg has been excluded from the ranking in Table 19 as the probability of being best can be biased for highly uncertain estimates.

Figure 18

Forest plot, blood transfusion caesarean birth (OR <1 favours intervention compared to carbetocin).

Table 19

Median treatment ranks and probability of being the best treatment for all interventions for blood transfusion, caesarean birth subgroup.

ICU admission (morbidity)

9 studies, comparing 8 interventions in 54,377 women were included in this analysis. Of these studies, 8 were conducted in women who had vaginal births only, and 1 in women who had caesarean births only.

Of the 22 studies that reported this outcome, 13 studies were excluded as they reported no events in any arm for this outcome.

The network plot for this outcome is shown below at Figure 19, the odds ratios compared to placebo in Table 20 and the Forest plot at Figure 20.

Figure 19

Network of evidence for ICU admission, full dataset. Abbreviations: Plac, placebo; Mis_b600, misoprostol ≤600mcg; Carb, carbetocin; Erg, ergometrine; Erg_Oxy, ergometrine plus oxytocin; Mis_Oxy, misoprostol plus oxytocin; Oxy_a1b5, oxytocin >1IU (more...)

Table 20

Odds ratio, log odds ratio and 95% CrIs for ICU admission for all interventions compared with placebo.

In this analysis all of the estimates are highly uncertain given the sparse evidence network, and the treatment ranking has not been presented as the probability of being best is likely to be biased.

Figure 20

Forest plot, ICU admission full population (OR <1 favours intervention).

The forest plot in Figure 20 does not show the point estimate or upper error bar for ergometrine plus oxytocin. This is because these values are very large, so are much further to the right on the graph than all other strategies.

Vaginal birth subgroup analysis

8 studies comparing 7 treatments in 54,000 women were included in this subgroup analysis.

Of the 18 studies that reported this outcome, 10 studies were excluded as they reported no events in any arm for this outcome.

The network plot for this outcome is shown below at Figure 21, the odds ratios compared to placebo in Table 21 and the Forest plot at Figure 22.

Figure 21

Network of evidence for ICU admission, vaginal birth subgroup.

Table 21

Odds ratio, log odds ratio and 95% CrIs for ICU admission for all interventions compared with placebo, vaginal birth subgroup.

In this analysis all of the estimates are highly uncertain given the sparse evidence network, and the treatment ranking has not been presented as the probability of being best is likely to be biased.

Figure 22

Forest plot, ICU admission vaginal birth (OR <1 favours intervention).

The forest plot in Figure 22 does not show the point estimate or upper error bar for ergometrine plus oxytocin. This is because these values are very large, so are much further to the right on the graph than all other strategies.

Caesarean birth subgroup analysis

Only 1 study comparing 2 treatments was identified for this outcome in the caesarean birth subgroup, therefore an NMA could not be conducted. These results were analysed using pairwise analysis, which can be found in supplement 5.

Mean blood loss (ml)

156 studies, comparing 14 interventions in 85,514 women were included in this analysis. Of these studies, 1 included women who had either vaginal or caesarean births, 109 were conducted in women who had vaginal births only, and 46 in women who had caesarean births only.

The network plot for this outcome is shown below at Figure 23, the odds ratios compared to placebo in Table 22, the Forest plot at Figure 24 and the median treatment ranks in Table 23.

Figure 23

Network of evidence for mean blood loss, full dataset. Abbreviations: Plac, placebo; Mis_b600, misoprostol ≤600mcg; Carb, carbetocin; CarbProst, carboprost; Erg, ergometrine; Erg_Oxy, ergometrine plus oxytocin; Mis_a600b800, misoprostol >600mcg (more...)

Table 22

blood loss ratio and 95% CrI for mean blood loss for all interventions compared with placebo.

Figure 24

Forest plot, mean blood loss full population (OR< 1 favours intervention).

Table 23

Median treatment ranks and probability of being the best treatment for all interventions for mean blood loss.

Vaginal birth subgroup analysis

109 studies comparing 13 treatments in 76,400 women were included in this subgroup analysis.

The network plot for this outcome is shown below at Figure 25, the odds ratios compared to placebo in Table 24, the Forest plot at Figure 26 and the median treatment ranks in Table 25.

Figure 25

Network of evidence for mean blood loss, vaginal birth subgroup. Abbreviations: Plac, placebo; Mis_b600, misoprostol ≤600mcg; Carb, carbetocin; CarbProst, carboprost; Erg, ergometrine; Erg_Oxy, ergometrine plus oxytocin; Mis_a600b800, misoprostol (more...)

Table 24

blood loss ratio and 95% CrI for mean blood loss for all interventions compared with placebo, vaginal birth subgroup.

Figure 26

Forest plot, mean blood loss vaginal birth (OR < 1 favours intervention).

Table 25

Median treatment ranks and probability of being the best treatment for all interventions for mean blood loss, vaginal birth subgroup.

Caesarean birth subgroup analysis

46 studies comparing 12 treatments in 8,585 women were included in this subgroup analysis.

The network plot for this outcome is shown below at Figure 27, the odds ratios compared to placebo in Table 26, the Forest plot at Figure 28 and the median treatment ranks in Table 27.

Figure 27

Network of evidence for mean blood loss, caesarean birth subgroup. Abbreviations: Plac, placebo; Mis_b600, misoprostol ≤600mcg; Carb, carbetocin; Erg, ergometrine; Erg_Oxy, ergometrine plus oxytocin; Mis_a600b800, misoprostol >600mcg and (more...)

Table 26

blood loss ratio and 95% CrI for mean blood loss for all interventions compared with placebo, caesarean birth subgroup.

Figure 28

Forest plot, mean blood loss caesarean birth (OR < 1 favours intervention).

Table 27

Median treatment ranks and probability of being the best treatment for all interventions for mean blood loss, caesarean birth subgroup.

Summary of included economic evidence

See Table 28 for the economic evidence profile of the included studies.

Table 28

Economic evidence profile of a systematic review of economic evaluations of uterotonics for the prevention of postpartum haemorrhage.

Economic model

A de-novo economic model was developed to answer this question, based on the outputs from the updated NMAs on PPH ≥1000 mL, additional uterotonics, ICU admission, and blood transfusions. The model utilised the decision tree structure as shown in Figure 29, with the time horizon only considering the immediate costs and outcomes in the third stage of labour. The model compares all uterotonics included in the NMAs (where data allows), and due to a lack of utility data in this area, costs are presented alongside outcomes such as number of PPH≥1000 mL events avoided rather than as cost per QALY gained.

Figure 29

Model schematic.

Costs included in the model were; prophylactic drug costs, drug administration costs, treatment-related adverse event costs, cost of additional uterotonics, cost of blood transfusion, and cost of ICU admission (as a scenario analysis). In the base-case, ICU admission and the costs associated with this were excluded due to missing data in the NMA.

Results were generated separately for the full population and the subgroups of vaginal birth and caesarean birth, as agreed by the committee. Efficacy results for each population group were informed by the corresponding NMA.

Deterministic results were presented alongside a probabilistic sensitivity analysis (PSA) which involved repeated Monte Carlo simulation of model inputs from their corresponding probability distributions. This was done in order to capture the inherent uncertainty in the model inputs. In each simulation the total cost, and total number of outcomes was calculated for each uterotonic. These individual simulation values were then aggregated to determine the average total cost and total number of outcomes, to evaluate the cost per event avoided. The probabilistic results were broadly similar to the deterministic results, suggesting that the cost-effectiveness results are fairly stable to the parameter uncertainty.

Scenario analyses were conducted on inclusion of ICU admissions in the model, exclusion of adverse events, and route of administration for carbetocin, to determine the impact of these events in the economic results. These scenarios were selected as there were data gaps and therefore uncertainty in the data informing these aspects of the economic analysis.

For full details of the economic model and results are available in appendix I.

References

Effectiveness

Main references are in bold, followed by additional references to the trial

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Appendix A. Review protocols

Review protocol for review question: What is the effectiveness of uterotonics for the prevention of postpartum haemorrhage? (PDF, 260K)

Appendix B. Literature search strategies

Literature search strategies for review question: What is the effectiveness of uterotonics for the prevention of postpartum haemorrhage? (PDF, 232K)

Appendix C. Effectiveness evidence study selection

Study selection for: What is the effectiveness of uterotonics for the prevention of postpartum haemorrhage? (PDF, 186K)

Appendix D. Evidence tables

Appendix E. Forest plots

Forest plots for review question: What is the effectiveness of uterotonics for the prevention of postpartum haemorrhage? (PDF, 313K)

Appendix F. GRADE tables

Appendix G. Economic evidence study selection

Study selection for: What is the effectiveness of uterotonics for the prevention of postpartum haemorrhage? (PDF, 160K)

Appendix H. Economic evidence tables

Economic evidence tables for review question: What is the effectiveness of uterotonics for the prevention of postpartum haemorrhage? (PDF, 242K)

Appendix I. Economic model

Economic model for review question: What is the effectiveness of uterotonics for the prevention of postpartum haemorrhage? (PDF, 618K)

Appendix J. Excluded studies

Appendix K. Research recommendations – full details

Appendix L. Network meta-analysis methods

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Appendix M. Model fit results

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Appendix N. Inconsistency checks

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