1.
Uterotonic agents for first-line treatment of postpartum haemorrhage: a network meta-analysis
Parry Smith WR, Papadopoulou A, Thomas E, Tobias A, Price MJ, Meher S, Alfirevic Z, Weeks AD, Hofmeyr GJ, Gülmezoglu AM, et al
The Cochrane database of systematic reviews. 2020;11:Cd012754
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Abstract
BACKGROUND Postpartum haemorrhage (PPH), defined as a blood loss of 500 mL or more after birth, is the leading cause of maternal death worldwide. The World Health Organization (WHO) recommends that all women giving birth should receive a prophylactic uterotonic agent. Despite the routine administration of a uterotonic agent for prevention, PPH remains a common complication causing one-quarter of all maternal deaths globally. When prevention fails and PPH occurs, further administration of uterotonic agents as 'first-line' treatment is recommended. However, there is uncertainty about which uterotonic agent is best for the 'first-line' treatment of PPH. OBJECTIVES To identify the most effective uterotonic agent(s) with the least side-effects for PPH treatment, and generate a meaningful ranking among all available agents according to their relative effectiveness and side-effect profile. SEARCH METHODS We searched the Cochrane Pregnancy and Childbirth's Trials Register, ClinicalTrials.gov, the WHO International Clinical Trials Registry Platform (ICTRP) (5 May 2020), and the reference lists of all retrieved studies. SELECTION CRITERIA All randomised controlled trials or cluster-randomised trials comparing the effectiveness and safety of uterotonic agents with other uterotonic agents for the treatment of PPH were eligible for inclusion. DATA COLLECTION AND ANALYSIS Two review authors independently assessed all trials for inclusion, extracted data and assessed each trial for risk of bias. Our primary outcomes were additional blood loss of 500 mL or more after recruitment to the trial until cessation of active bleeding and the composite outcome of maternal death or severe morbidity. Secondary outcomes included blood loss-related outcomes, morbidity outcomes, and patient-reported outcomes. We performed pairwise meta-analyses and indirect comparisons, where possible, but due to the limited number of included studies, we were unable to conduct the planned network meta-analysis. We used the GRADE approach to assess the certainty of evidence. MAIN RESULTS Seven trials, involving 3738 women in 10 countries, were included in this review. All trials were conducted in hospital settings. Randomised women gave birth vaginally, except in one small trial, where women gave birth either vaginally or by caesarean section. Across the seven trials (14 trial arms) the following agents were used: six trial arms used oxytocin alone; four trial arms used misoprostol plus oxytocin; three trial arms used misoprostol; one trial arm used Syntometrine® (oxytocin and ergometrine fixed-dose combination) plus oxytocin infusion. Pairwise meta-analysis of two trials (1787 participants), suggests that misoprostol, as first-line treatment uterotonic agent, probably increases the risk of blood transfusion (risk ratio (RR) 1.47, 95% confidence interval (CI) 1.02 to 2.14, moderate-certainty) compared with oxytocin. Low-certainty evidence suggests that misoprostol administration may increase the incidence of additional blood loss of 1000 mL or more (RR 2.57, 95% CI 1.00 to 6.64). The data comparing misoprostol with oxytocin is imprecise, with a wide range of treatment effects for the additional blood loss of 500 mL or more (RR 1.66, 95% CI 0.69 to 4.02, low-certainty), maternal death or severe morbidity (RR 1.98, 95% CI 0.36 to 10.72, low-certainty, based on one study n = 809 participants, as the second study had zero events), and the use of additional uterotonics (RR 1.30, 95% CI 0.57 to 2.94, low-certainty). The risk of side-effects may be increased with the use of misoprostol compared with oxytocin: vomiting (2 trials, 1787 participants, RR 2.47, 95% CI 1.37 to 4.47, high-certainty) and fever (2 trials, 1787 participants, RR 3.43, 95% CI 0.65 to 18.18, low-certainty). According to pairwise meta-analysis of four trials (1881 participants) generating high-certainty evidence, misoprostol plus oxytocin makes little or no difference to the use of additional uterotonics (RR 0.99, 95% CI 0.94 to 1.05) and to blood transfusion (RR 0.95, 95% CI 0.77 to 1.17) compared with oxytocin. We cannot rule out an important benefit of using the misoprostol plus oxytocin combination over oxytocin alone, for additional blood loss of 500 mL or more (RR 0.84, 95% CI 0.66 to 1.06, moderate-certainty). We also cannot rule out important benefits or harms for additional blood loss of 1000 mL or more (RR 0.76, 95% CI 0.43 to 1.34, moderate-certainty, 3 trials, 1814 participants, one study reported zero events), and maternal mortality or severe morbidity (RR 1.09, 95% CI 0.35 to 3.39, moderate-certainty). Misoprostol plus oxytocin increases the incidence of fever (4 trials, 1866 participants, RR 3.07, 95% CI 2.62 to 3.61, high-certainty), and vomiting (2 trials, 1482 participants, RR 1.85, 95% CI 1.16 to 2.95, high-certainty) compared with oxytocin alone. For all outcomes of interest, the available evidence on the misoprostol versus Syntometrine® plus oxytocin combination was of very low-certainty and these effects remain unclear. Although network meta-analysis was not performed, we were able to compare the misoprostol plus oxytocin combination with misoprostol alone through the common comparator of oxytocin. This indirect comparison suggests that the misoprostol plus oxytocin combination probably reduces the risk of blood transfusion (RR 0.65, 95% CI 0.42 to 0.99, moderate-certainty) and may reduce the risk of additional blood loss of 1000 mL or more (RR 0.30, 95% CI 0.10 to 0.89, low-certainty) compared with misoprostol alone. The combination makes little or no difference to vomiting (RR 0.75, 95% CI 0.35 to 1.59, high-certainty) compared with misoprostol alone. Misoprostol plus oxytocin compared to misoprostol alone are compatible with a wide range of treatment effects for additional blood loss of 500 mL or more (RR 0.51, 95% CI 0.20 to 1.26, low-certainty), maternal mortality or severe morbidity (RR 0.55, 95% CI 0.07 to 4.24, low-certainty), use of additional uterotonics (RR 0.76, 95% CI 0.33 to 1.73, low-certainty), and fever (RR 0.90, 95% CI 0.17 to 4.77, low-certainty). AUTHORS' CONCLUSIONS The available evidence suggests that oxytocin used as first-line treatment of PPH probably is more effective than misoprostol with less side-effects. Adding misoprostol to the conventional treatment of oxytocin probably makes little or no difference to effectiveness outcomes, and is also associated with more side-effects. The evidence for most uterotonic agents used as first-line treatment of PPH is limited, with no evidence found for commonly used agents, such as injectable prostaglandins, ergometrine, and Syntometrine®.
PICO Summary
Population
Women with postpartum haemorrhage (PPH), (7 studies, n= 3,738).
Intervention
Systematic review and network meta-analysis identifying the most effective uterotonic agent(s) for first-line PPH treatment with the least side-effects.
Comparison
Oxytocin alone; misoprostol plus oxytocin; misoprostol alone; and Syntometrine® (oxytocin and ergometrine fixed-dose combination) plus oxytocin infusion.
Outcome
Pairwise meta-analysis of two trials (n= 1,787), suggested that misoprostol, as first-line treatment uterotonic agent, probably increases the risk of blood transfusion compared with oxytocin. Low-certainty evidence suggested that misoprostol administration may increase the incidence of additional blood loss of 1,000 mL or more. The data comparing misoprostol with oxytocin was imprecise, with a wide range of treatment effects for the additional blood loss of 500 mL or more, maternal death or severe morbidity. The risk of side-effects may be increased with the use of misoprostol compared with oxytocin. According to pairwise meta-analysis of four trials (n= 1,881 participants) generating high-certainty evidence, misoprostol plus oxytocin made little or no difference to the use of additional uterotonics and to blood transfusion compared with oxytocin.
2.
Uterotonic Drugs for the Prevention of Postpartum Haemorrhage: A Cost-Effectiveness Analysis
Pickering K, Gallos ID, Williams H, Price MJ, Merriel A, Lissauer D, Tobias A, Hofmeyr GJ, Coomarasamy A, Roberts TE
PharmacoEconomics - open. 2018
Abstract
OBJECTIVE The objective of this study was to estimate the relative cost effectiveness for the full range of uterotonic drugs available for preventing postpartum haemorrhage (PPH). METHODS A model-based economic evaluation was constructed using effectiveness data from a network meta-analysis, and supplemented by the literature. A UK National Health Service (NHS) perspective was adopted for the analysis, which is based on UK costs from published sources. The primary outcome measure is cost per case of PPH avoided (≥ 500 mL blood loss), with secondary outcome measures of cost per case of severe PPH avoided (≥ 1000 mL) and cost per major outcome (surgery) averted also being analysed. RESULTS Carbetocin is shown to be the most effective strategy. Excluding adverse events, 'ergometrine plus oxytocin' was shown to be the least costly strategy. The incremental cost-effectiveness ratio for prevention of PPH with carbetocin compared with prevention with 'ergometrine plus oxytocin' was pound1889 per case of PPH ≥ 500 mL avoided; pound30,013 per case of PPH ≥ 1000 mL avoided; and pound1,172,378 per major outcome averted. Including adverse events in the analysis showed oxytocin to be the least costly strategy. The incremental cost-effectiveness ratio for prevention of PPH with carbetocin compared with prevention with oxytocin was pound928 per case of PPH ≥ 500 mL avoided; pound22,900 per case of PPH ≥ 1000 mL avoided; and pound894,514 per major outcome averted. CONCLUSION The results suggest carbetocin, oxytocin and 'ergometrine plus oxytocin' could all be favourable options for being the most cost-effective strategy for preventing PPH. Carbetocin could be the preferred choice, especially if the price of carbetocin decreased. Mixed findings mean a clear-cut conclusion cannot be made as to which uterotonic is the most cost effective. Future research should focus on collecting more robust evidence on the probability of having adverse events from the uterotonic drugs, and on adapting the model for low- and middle-income countries.
3.
Uterotonic agents for preventing postpartum haemorrhage: a network meta-analysis
Gallos ID, Papadopoulou A, Man R, Athanasopoulos N, Tobias A, Price MJ, Williams MJ, Diaz V, Pasquale J, Chamillard M, et al
The Cochrane database of systematic reviews. 2018;12:Cd011689
Abstract
BACKGROUND Postpartum haemorrhage (PPH) is the leading cause of maternal mortality worldwide. Prophylactic uterotonic agents can prevent PPH, and are routinely recommended. The current World Health Organization (WHO) recommendation for preventing PPH is 10 IU (international units) of intramuscular or intravenous oxytocin. There are several uterotonic agents for preventing PPH but there is still uncertainty about which agent is most effective with the least side effects. This is an update of a Cochrane Review which was first published in April 2018 and was updated to incorporate results from a recent large WHO trial. OBJECTIVES To identify the most effective uterotonic agent(s) to prevent PPH with the least side effects, and generate a ranking according to their effectiveness and side-effect profile. SEARCH METHODS We searched the Cochrane Pregnancy and Childbirth's Trials Register, ClinicalTrials.gov, the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) (24 May 2018), and reference lists of retrieved studies. SELECTION CRITERIA All randomised controlled trials or cluster-randomised trials comparing the effectiveness and side effects of uterotonic agents with other uterotonic agents, placebo or no treatment for preventing PPH were eligible for inclusion. Quasi-randomised trials were excluded. Randomised trials published only as abstracts were eligible if sufficient information could be retrieved. DATA COLLECTION AND ANALYSIS At least three review authors independently assessed trials for inclusion and risk of bias, extracted data and checked them for accuracy. We estimated the relative effects and rankings for preventing PPH ≥ 500 mL and PPH ≥ 1000 mL as primary outcomes. Secondary outcomes included blood loss and related outcomes, morbidity outcomes, maternal well-being and satisfaction and side effects. Primary outcomes were also reported for pre-specified subgroups, stratifying by mode of birth, prior risk of PPH, healthcare setting, dosage, regimen and route of administration. We performed pairwise meta-analyses and network meta-analysis to determine the relative effects and rankings of all available agents. MAIN RESULTS The network meta-analysis included 196 trials (135,559 women) involving seven uterotonic agents and placebo or no treatment, conducted across 53 countries (including high-, middle- and low-income countries). Most trials were performed in a hospital setting (187/196, 95.4%) with women undergoing a vaginal birth (71.5%, 140/196).Relative effects from the network meta-analysis suggested that all agents were effective for preventing PPH ≥ 500 mL when compared with placebo or no treatment. The three highest ranked uterotonic agents for prevention of PPH ≥ 500 mL were ergometrine plus oxytocin combination, misoprostol plus oxytocin combination and carbetocin. There is evidence that ergometrine plus oxytocin (RR 0.70, 95% CI 0.59 to 0.84, moderate certainty), carbetocin (RR 0.72, 95% CI 0.56 to 0.93, moderate certainty) and misoprostol plus oxytocin (RR 0.70, 95% CI 0.58 to 0.86, low certainty) may reduce PPH ≥ 500 mL compared with oxytocin. Low-certainty evidence suggests that misoprostol, injectable prostaglandins, and ergometrine may make little or no difference to this outcome compared with oxytocin.All agents except ergometrine and injectable prostaglandins were effective for preventing PPH ≥ 1000 mL when compared with placebo or no treatment. High-certainty evidence suggests that ergometrine plus oxytocin (RR 0.83, 95% CI 0.66 to 1.03) and misoprostol plus oxytocin (RR 0.88, 95% CI 0.70 to 1.11) make little or no difference in the outcome of PPH ≥ 1000 mL compared with oxytocin. Low-certainty evidence suggests that ergometrine may make little or no difference to this outcome compared with oxytocin meanwhile the evidence on carbetocin was of very low certainty. High-certainty evidence suggests that misoprostol is less effective in preventing PPH ≥ 1000 mL when compared with oxytocin (RR 1.19, 95% CI 1.01 to 1.42). Despite the comparable relative treatment effects between all uterotonics (except misoprostol) and oxytocin, ergometrine plus oxytocin, misoprostol plus oxytocin combinations and carbetocin were the highest ranked agents for PPH ≥ 1000 mL.Misoprostol plus oxytocin reduces the use of additional uterotonics (RR 0.56, 95% CI 0.42 to 0.73, high certainty) and probably also reduces the risk of blood transfusion (RR 0.51, 95% CI 0.37 to 0.70, moderate certainty) when compared with oxytocin. Carbetocin, injectable prostaglandins and ergometrine plus oxytocin may also reduce the use of additional uterotonics but the certainty of the evidence is low. No meaningful differences could be detected between all agents for maternal deaths or severe morbidity as these outcomes were rare in the included randomised trials where they were reported.The two combination regimens were associated with important side effects. When compared with oxytocin, misoprostol plus oxytocin combination increases the likelihood of vomiting (RR 2.11, 95% CI 1.39 to 3.18, high certainty) and fever (RR 3.14, 95% CI 2.20 to 4.49, moderate certainty). Ergometrine plus oxytocin increases the likelihood of vomiting (RR 2.93, 95% CI 2.08 to 4.13, moderate certainty) and may make little or no difference to the risk of hypertension, however absolute effects varied considerably and the certainty of the evidence was low for this outcome.Subgroup analyses did not reveal important subgroup differences by mode of birth (caesarean versus vaginal birth), setting (hospital versus community), risk of PPH (high versus low risk for PPH), dose of misoprostol (≥ 600 mcg versus < 600 mcg) and regimen of oxytocin (bolus versus bolus plus infusion versus infusion only). AUTHORS' CONCLUSIONS All agents were generally effective for preventing PPH when compared with placebo or no treatment. Ergometrine plus oxytocin combination, carbetocin, and misoprostol plus oxytocin combination may have some additional desirable effects compared with the current standard oxytocin. The two combination regimens, however, are associated with significant side effects. Carbetocin may be more effective than oxytocin for some outcomes without an increase in side effects.