1.
Randomized Trial of Early Detection and Treatment of Postpartum Hemorrhage
Gallos I, Devall A, Martin J, Middleton L, Beeson L, Galadanci H, Alwy Al-Beity F, Qureshi Z, Hofmeyr GJ, Moran N, et al
The New England journal of medicine. 2023
-
-
-
-
Editor's Choice
Abstract
BACKGROUND Delays in the detection or treatment of postpartum hemorrhage can result in complications or death. A blood-collection drape can help provide objective, accurate, and early diagnosis of postpartum hemorrhage, and delayed or inconsistent use of effective interventions may be able to be addressed by a treatment bundle. METHODS We conducted an international, cluster-randomized trial to assess a multicomponent clinical intervention for postpartum hemorrhage in patients having vaginal delivery. The intervention included a calibrated blood-collection drape for early detection of postpartum hemorrhage and a bundle of first-response treatments (uterine massage, oxytocic drugs, tranexamic acid, intravenous fluids, examination, and escalation), supported by an implementation strategy (intervention group). Hospitals in the control group provided usual care. The primary outcome was a composite of severe postpartum hemorrhage (blood loss, ≥1000 ml), laparotomy for bleeding, or maternal death from bleeding. Key secondary implementation outcomes were the detection of postpartum hemorrhage and adherence to the treatment bundle. RESULTS A total of 80 secondary-level hospitals across Kenya, Nigeria, South Africa, and Tanzania, in which 210,132 patients underwent vaginal delivery, were randomly assigned to the intervention group or the usual-care group. Among hospitals and patients with data, a primary-outcome event occurred in 1.6% of the patients in the intervention group, as compared with 4.3% of those in the usual-care group (risk ratio, 0.40; 95% confidence interval [CI], 0.32 to 0.50; P<0.001). Postpartum hemorrhage was detected in 93.1% of the patients in the intervention group and in 51.1% of those in the usual-care group (rate ratio, 1.58; 95% CI, 1.41 to 1.76), and the treatment bundle was used in 91.2% and 19.4%, respectively (rate ratio, 4.94; 95% CI, 3.88 to 6.28). CONCLUSIONS Early detection of postpartum hemorrhage and use of bundled treatment led to a lower risk of the primary outcome, a composite of severe postpartum hemorrhage, laparotomy for bleeding, or death from bleeding, than usual care among patients having vaginal delivery. (Funded by the Bill and Melinda Gates Foundation; E-MOTIVE ClinicalTrials.gov number, NCT04341662.).
PICO Summary
Population
Patients undergoing vaginal delivery enrolled in the E-MOTIVE cluster-randomised trial in 80 hospitals across Kenya, Nigeria, South Africa and Tanzania (n= 210,132).
Intervention
Multicomponent clinical intervention, including a calibrated blood-collection drape for early detection of postpartum haemorrhage and a bundle of first-response treatments (uterine massage, oxytocic drugs, tranexamic acid, intravenous fluids, examination, and escalation), supported by an implementation strategy, (intervention group, 40 hospitals).
Comparison
Usual care, estimating blood loss visually and using various interventions for postpartum haemorrhage in accordance with local or national guidelines, (usual-care group, 40 hospitals).
Outcome
The primary outcome was a composite of severe postpartum haemorrhage (blood loss, ≥1000 ml), laparotomy for bleeding, or maternal death from bleeding. Among hospitals and patients with data, a primary-outcome event occurred in 1.6% of the patients in the intervention group, as compared with 4.3% of those in the usual-care group (risk ratio, 0.40; 95% confidence interval (CI), [0.32, 0.50]). Postpartum haemorrhage was detected in 93.1% of the patients in the intervention group and in 51.1% of those in the usual-care group (rate ratio, 1.58; 95% CI [1.41, 1.76]), and the treatment bundle was used in 91.2% and 19.4%, respectively (rate ratio, 4.94; 95% CI [3.88, 6.28]).
2.
Uterotonic drugs to prevent postpartum haemorrhage: a network meta-analysis
Gallos I, Williams H, Price M, Pickering K, Merriel A, Tobias A, Lissauer D, Gee H, Tuncalp O, Gyte G, et al
Health technology assessment (Winchester, England). 2019;23(9):1-356
Abstract
BACKGROUND Postpartum haemorrhage (PPH) is the leading cause of maternal mortality worldwide. Prophylactic uterotonic drugs can reduce blood loss and are routinely recommended. There are several uterotonic drugs for preventing PPH, but it is still debatable which drug or combination of drugs is the most effective. OBJECTIVES To identify the most effective and cost-effective uterotonic drug(s) to prevent PPH, and generate a ranking according to their effectiveness and side-effect profile. METHODS The Cochrane Pregnancy and Childbirth's Trials Register (1 June 2015), ClinicalTrials.gov and the World Health Organization (WHO)'s International Clinical Trials Registry Platform (ICTRP) were searched for unpublished trial reports (30 June 2015). In addition, reference lists of retrieved studies (updated October 2017) were searched for randomised trials evaluating uterotonic drugs for preventing PPH. The study estimated relative effects and rankings for preventing PPH, defined as blood loss of ≥ 500 ml and ≥ 1000 ml. Pairwise meta-analyses and network meta-analysis were performed to determine the relative effects and rankings of all available drugs and combinations thereof [ergometrine, misoprostol (Cytotec((R)); Pfizer Inc., New York, NY, USA), misoprostol plus oxytocin (Syntocinon((R)); Novartis International AG, Basel, Switzerland), carbetocin (Pabal((R)); Ferring Pharmaceuticals, Saint-Prex, Switzerland), ergometrine plus oxytocin (Syntometrine((R)); Alliance Pharma plc, Chippenham, UK), oxytocin, and a placebo or no treatment]. Primary outcomes were stratified according to the mode of birth, prior risk of PPH, health-care setting, drug dosage, regimen and route of drug administration. Sensitivity analyses were performed according to study quality and funding source, among others. A model-based economic evaluation compared the relative cost-effectiveness separately for vaginal births and caesareans with or without including side effects. RESULTS From 137 randomised trials and 87,466 women, ergometrine plus oxytocin, carbetocin and misoprostol plus oxytocin were found to reduce the risk of PPH blood loss of ≥ 500 ml compared with the standard drug, oxytocin [ergometrine plus oxytocin: risk ratio (RR) 0.69, 95% confidence interval (CI) 0.57 to 0.83; carbetocin: RR 0.72, 95% CI 0.52 to 1.00; misoprostol plus oxytocin: RR 0.73, 95% CI 0.6 to 0.9]. Each of these three strategies had 100% cumulative probability of being ranked first, second or third most effective. Oxytocin was ranked fourth, with an almost 0% cumulative probability of being ranked in the top three. Similar rankings were noted for the reduction of PPH blood loss of ≥ 1000 ml (ergometrine plus oxytocin: RR 0.77, 95% CI 0.61 to 0.95; carbetocin: RR 0.70, 95% CI 0.38 to 1.28; misoprostol plus oxytocin: RR 0.90, 95% CI 0.72 to 1.14), and most secondary outcomes. Ergometrine plus oxytocin and misoprostol plus oxytocin had the poorest ranking for side effects. Carbetocin had a favourable side-effect profile, which was similar to oxytocin. However, the analysis was restricted to high-quality studies, carbetocin lost its ranking and was comparable to oxytocin. The relative cost-effectiveness of the alternative strategies is inconclusive, and the results are affected by both the uncertainty and inconsistency in the data reported on adverse events. For vaginal delivery, when assuming no adverse events, ergometrine plus oxytocin is less costly and more effective than all strategies except carbetocin. The strategy of carbetocin is both more effective and more costly than all other strategies. When taking adverse events into consideration, all prevention strategies, except oxytocin, are more costly and less effective than carbetocin. For delivery by caesarean section, with and without adverse events, the relative cost-effectiveness is different, again because of the uncertainty in the available data. LIMITATIONS There was considerable uncertainty in findings within the planned subgroup analyses, and subgroup effects cannot be ruled out. CONCLUSIONS Ergometrine plus oxytocin, carbetocin and misoprostol plus oxytocin are more effective uterotonic drug strategies for preventing PPH than the current standard, oxytocin. Ergometrine plus oxytocin and misoprostol plus oxytocin cause significant side effects. Carbetocin has a favourable side-effect profile, which was similar to oxytocin. However, most carbetocin trials are small and of poor quality. There is a need for a large high-quality trial comparing carbetocin with oxytocin; such a trial is currently being conducted by the WHO. The relative cost-effectiveness is inconclusive, and results are affected by uncertainty and inconsistency in adverse events data. STUDY REGISTRATION This study is registered as PROSPERO CRD42015020005; Cochrane Pregnancy and Childbirth Group (substudy) reference number 0871; PROSPERO-Cochrane (substudy) reference number CRD42015026568; and sponsor reference number ERN_13-1414 (University of Birmingham, Birmingham, UK). FUNDING Funding for this study was provided by the National Institute for Health Research Health Technology Assessment programme in a research award to the University of Birmingham and supported by the UK charity Ammalife (UK-registered charity 1120236). The funders of the study had no role in study design, data collection, data synthesis, interpretation or writing of the report. Postpartum haemorrhage (PPH) is the most common reason why mothers die in childbirth worldwide. Although most healthy women can cope well with blood loss after birth, some do not, and this can pose a serious risk to their health and even life. To reduce blood loss after birth, the routine administration of a drug to contract the uterus (uterotonic) has become standard practice across the world. This research seeks to identify which is the most effective and cost-effective drug. Different drugs have been used for reducing the occurrence of PPH. They include oxytocin, misoprostol, ergometrine, carbetocin, and combinations of these drugs, each with different effectiveness and side effects. The study synthesised the available evidence to compare all of these drugs and combinations thereof. After putting the results of all available comparisons together in a network, a ranking among them was calculated, and provided robust effectiveness and side-effect profiles for each drug and their associated costs. The study included 137 randomised trials, involving a total of 87,466 women. The results suggested that ergometrine plus oxytocin, carbetocin and misoprostol plus oxytocin are the most effective strategies for preventing PPH and are more effective than the currently recommended drug, oxytocin. Each of these three strategies had almost 100% probability of being ranked first, second or third most effective. Oxytocin was ranked fourth with an almost 0% probability of being ranked in the top three. Ergometrine plus oxytocin and misoprostol plus oxytocin were the worst drug combinations for side effects, with carbetocin having the most favourable side-effect profile. Carbetocin could prevent approximately one further event of PPH out of three in comparison with oxytocin. However, existing carbetocin studies were small and of poor quality. There is need for a large high-quality study comparing carbetocin with the current standard treatment of oxytocin for the prevention of PPH. The cost analyses of the alternative drug strategies remain inconclusive. eng
3.
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.
4.
Uterotonic agents for preventing postpartum haemorrhage: a network meta-analysis
Gallos I D, Williams H M, Price M J, Merriel A, Gee H, Lissauer D, Moorthy V, Tobias A, Deeks J J, Widmer M, et al
The Cochrane Database of Systematic Reviews. 2018;4:CD011689.
Abstract
BACKGROUND Postpartum haemorrhage (PPH) is the leading cause of maternal mortality worldwide. Prophylactic uterotonic drugs can prevent PPH, and are routinely recommended. There are several uterotonic drugs for preventing PPH but it is still debatable which drug is best. OBJECTIVES To identify the most effective uterotonic drug(s) to prevent PPH, and generate a ranking according to their effectiveness and side-effect profile. SEARCH METHODS We searched Cochrane Pregnancy and Childbirth's Trials Register (1 June 2015), ClinicalTrials.gov and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) for unpublished trial reports (30 June 2015) and reference lists of retrieved studies. SELECTION CRITERIA All randomised controlled comparisons or cluster trials of effectiveness or side-effects of uterotonic drugs for preventing PPH.Quasi-randomised trials and cross-over trials are not eligible for inclusion in this review. 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. We performed pairwise meta-analyses and network meta-analysis to determine the relative effects and rankings of all available drugs. We stratified our primary outcomes according to mode of birth, prior risk of PPH, healthcare setting, dosage, regimen and route of drug administration, to detect subgroup effects.The absolute risks in the oxytocin are based on meta-analyses of proportions from the studies included in this review and the risks in the intervention groups were based on the assumed risk in the oxytocin group and the relative effects of the interventions. MAIN RESULTS This network meta-analysis included 140 randomised trials with data from 88,947 women. There are two large ongoing studies. The trials were mostly carried out in hospital settings and recruited women who were predominantly more than 37 weeks of gestation having a vaginal birth. The majority of trials were assessed to have uncertain risk of bias due to poor reporting of study design. This primarily impacted on our confidence in comparisons involving carbetocin trials more than other uterotonics.The three most effective drugs for prevention of PPH ≥ 500 mL were ergometrine plus oxytocin combination, carbetocin, and misoprostol plus oxytocin combination. These three options were more effective at preventing PPH ≥ 500 mL compared with oxytocin, the drug currently recommended by the WHO (ergometrine plus oxytocin risk ratio (RR) 0.69 (95% confidence interval (CI) 0.57 to 0.83), moderate-quality evidence; carbetocin RR 0.72 (95% CI 0.52 to 1.00), very low-quality evidence; misoprostol plus oxytocin RR 0.73 (95% CI 0.60 to 0.90), moderate-quality evidence). Based on these results, about 10.5% women given oxytocin would experience a PPH of ≥ 500 mL compared with 7.2% given ergometrine plus oxytocin combination, 7.6% given carbetocin, and 7.7% given misoprostol plus oxytocin. Oxytocin was ranked fourth with close to 0% cumulative probability of being ranked in the top three for PPH ≥ 500 mL.The outcomes and rankings for the outcome of PPH ≥ 1000 mL were similar to those of PPH ≥ 500 mL. with the evidence for ergometrine plus oxytocin combination being more effective than oxytocin (RR 0.77 (95% CI 0.61 to 0.95), high-quality evidence) being more certain than that for carbetocin (RR 0.70 (95% CI 0.38 to 1.28), low-quality evidence), or misoprostol plus oxytocin combination (RR 0.90 (95% CI 0.72 to 1.14), moderate-quality evidence)There were no meaningful differences between all drugs for maternal deaths or severe morbidity as these outcomes were so rare in the included randomised trials.Two combination regimens had the poorest rankings for side-effects. Specifically, the ergometrine plus oxytocin combination had the higher risk for vomiting (RR 3.10 (95% CI 2.11 to 4.56), high-quality evidence; 1.9% ve