Carbetocin 100micrograms/1ml solution for injection ampoules

BackgroundPostpartum haemorrhage is a leading cause of maternal mortality, particularly in low-income and middle-income countries. Several pharmacological agents, such as oxytocin, ergot alkaloids, prostaglandins, and tranexamic acid, have been used prophylactically to prevent postpartum haemorrhage. However, the optimal prophylactic regimen and the comparative efficacy of these agents and their combinations have not been fully elucidated for individuals undergoing caesarean delivery. We aimed to conduct a network meta-analysis to assess different agents for postpartum haemorrhage prophylaxis in caesarean deliveries.MethodsIn this systematic review and meta-analysis, we conducted a Bayesian network meta-analysis of randomised controlled trials (RCTs) evaluating the relative effectiveness of different prophylactic agents and their combinations for postpartum haemorrhage in caesarean deliveries. We searched MEDLINE, the Cochrane Central Register of Controlled Trials, Embase, and Web of Science from database inception to Nov 7, 2023, for RCTs that enrolled adult pregnant women (ie, older than 18 years) undergoing a caesarean delivery; compared prophylactic strategies (monotherapy or combination drug therapy) with placebo or another active prophylactic regimen; administered prophylactic strategies of any parenteral dosage or regimen systemically before surgical incision or immediately after birth for preventing postpartum haemorrhage; and reported our prespecified endpoints of interest. Quasi-randomised trials, trials evaluating prophylactic strategies exclusively comparing different dosages, routes, or regimens of the same prophylactic agent, trials that included vaginal delivery, single-arm studies, conference abstracts, studies not published in English, and studies with overlapping populations were excluded. Ten authors reviewed study reports and supplementary materials and extracted the data. Two authors performed these tasks independently for each study. For data reported in graphical format, extraction was performed with graph digitising web software. The primary outcome was postpartum haemorrhage (ie, blood loss of ≥1000 mL following caesarean delivery). We fitted a Bayesian random-effects network meta-analysis model to compare multiple regimens simultaneously, with results presented as risk ratios (RRs) and their respective 95% credible intervals (CrIs). Only strategies reported by two or more studies were included in the network. If a prophylactic strategy was reported by only one study, it was included if at least 1000 patients were allocated in each study group. We also synthesised head-to-head RCTs separately to assess differences between regimens with league tables. To assess the hierarchy of treatments based on efficacy, we estimated surface under the cumulative ranking curve (SUCRA) probabilities. This review is registered at PROSPERO, CRD42023488236.FindingsThe search strategy yielded 3339 studies. After removing duplicates, 2241 studies remained, of which a total of 2022 were excluded on the basis of title or abstract screening. After full-text review, 167 RCTs (with 44 817 patients) evaluating monotherapy with or various combinations of oxytocin, carbetocin, carboprost, ergot alkaloids, misoprostol, and tranexamic acid were included in the final analysis. Across all 167 studies, 12 868 patients received oxytocin monotherapy, 5849 patients received tranexamic acid monotherapy, 2964 patients received carbetocin monotherapy, 1773 patients received misoprostol monotherapy, and 100 patients received carboprost monotherapy. The most common combination therapy was tranexamic acid plus oxytocin (n=5331) followed by misoprostol plus oxytocin (n=2983). Oxytocin plus tranexamic acid (RR 0·44 [95% CrI 0·33-0·58]) and carbetocin (0·54 [0·37-0·74]) were the only interventions that were more effective than oxytocin alone in reducing postpartum haemorrhage. Oxytocin plus tranexamic acid ranked as the most effective intervention for postpartum haemorrhage prophylaxis with a SUCRA probability value of 0·85. Most prophylactic combinations reduced intraoperative blood transfusions and the need for additional uterotonics. Two maternal deaths were reported among 29 412 patients. No significant heterogeneity was detected for postpartum haemorrhage (I2=6%), blood transfusion (I2=0%), and additional uterotonics (I2=7%).InterpretationCarbetocin alone and oxytocin plus tranexamic acid were superior to oxytocin monotherapy for preventing postpartum haemorrhage in caesarean deliveries. Oxytocin plus tranexamic acid ranked as the most effective intervention for postpartum haemorrhage prevention. These results are crucial in highlighting the comparative efficacy and hierarchy of prophylactic agents for postpartum haemorrhage prevention, especially given the widespread availability and low cost associated with oxytocin and tranexamic acid.FundingNone.

Abstract licence: CC BY

RationalePostpartum haemorrhage (PPH) is the leading cause of maternal mortality worldwide. Prophylactic uterotonic agents can prevent PPH. The current World Health Organization (WHO) recommendation for preventing PPH is 10 IU (international units) of intramuscular or intravenous oxytocin. Several uterotonics prevent PPH, but there remains uncertainty about the most effective agent with the fewest side effects. This is an update of a review first published in April 2018, and incorporates trustworthiness screening of eligible trials.ObjectivesTo identify the most effective uterotonic agent(s) to prevent PPH with the fewest side effects, and generate a ranking according to their effectiveness and side effect profile.Search methodsOn 5 February 2024, we searched CENTRAL, MEDLINE, Embase and CINAHL in collaboration with the Cochrane Information Specialist.Eligibility criteriaAll randomised controlled trials (RCTs) or cluster-RCTs that compared the effectiveness and side effects of uterotonic agents with other uterotonic agents, placebo or no treatment for preventing PPH were eligible for inclusion. We screened eligible trials for trustworthiness. We included randomised trials published only as abstracts if we could retrieve sufficient information; we excluded quasi-randomised trials.OutcomesPrimary outcomes were PPH ≥ 500 mL and PPH ≥ 1000 mL. Secondary outcomes included use of additional uterotonics, blood transfusion, vomiting, hypertension, and fever.Risk of biasWe used RoB 1 to assess risk of bias.Synthesis methodsAt least three review authors independently assessed trials for inclusion, trustworthiness, risk of bias, and certainty of evidence using GRADE. We estimated the relative effects and rankings for the primary and secondary outcomes. We reported primary outcomes for prespecified subgroups, stratified by mode of birth (caesarean versus vaginal), setting (hospital versus community), prior risk of PPH (high versus low), dose of misoprostol (≥ 600 μg versus Included studiesThe network meta-analysis included 122 trials (121,931 women), involving seven uterotonic agents and placebo or no treatment, conducted across 48 high-, middle- and low-income countries. Most were in a hospital setting (115/122, 94%), with women having a vaginal birth (87/122, 71%).Synthesis of resultsRelative effects from the network meta-analysis suggested that all agents, except injectable prostaglandins, for which data were limited, were effective for preventing PPH ≥ 500 mL compared with placebo or no treatment. The two highest-ranked agents were ergometrine plus oxytocin and misoprostol plus oxytocin. Compared with oxytocin, ergometrine plus oxytocin reduces PPH ≥ 500 mL (risk ratio (RR) 0.76, 95% confidence interval (CI) 0.64 to 0.90, high-certainty evidence), and misoprostol plus oxytocin probably reduces PPH ≥ 500 mL (RR 0.70, 95% CI 0.57 to 0.87; moderate-certainty evidence). Carbetocin (high-), injectable prostaglandins (moderate-) and ergometrine (low-certainty evidence) have similar effects compared with oxytocin. The evidence for misoprostol is very low certainty. All agents, except ergometrine and injectable prostaglandins, for which data were limited, were effective for preventing PPH ≥ 1000 mL compared with placebo or no treatment. Ergometrine plus oxytocin, and misoprostol plus oxytocin were the highest-ranked agents. Compared with oxytocin, carbetocin and injectable prostaglandins (both moderate-certainty evidence), and misoprostol plus oxytocin (low-certainty evidence) make little or no difference to PPH ≥ 1000 mL. Misoprostol may be less effective in preventing PPH ≥ 1000 mL compared with oxytocin (RR 1.24, 95% CI 1.06 to 1.46; low-certainty evidence). The certainty of evidence for ergometrine and ergometrine plus oxytocin was very low. Compared with oxytocin, misoprostol plus oxytocin probably reduces the use of additional uterotonics (RR 0.55, 95% CI 0.42 to 0.72, moderate-certainty evidence), and carbetocin (RR 0.74, 95% CI 0.59 to 0.94; low-certainty evidence), and ergometrine plus oxytocin may reduce the use of additional uterotonics (RR 0.68, 95% CI 0.56 to 0.83; low-certainty evidence). Misoprostol (low-certainty evidence) makes little or no difference to this outcome. Misoprostol plus oxytocin probably reduces the risk of needing a blood transfusion (RR 0.40, 95% CI 0.28 to 0.58; moderate-certainty-evidence), and ergometrine plus oxytocin may reduce the risk of blood transfusion compared with oxytocin (RR 0.73, 95% CI 0.56 to 0.96, low-certainty evidence). Carbetocin (moderate-certainty evidence) and misoprostol (low-certainty evidence) probably make little or no difference to this outcome compared with oxytocin. All uterotonic agents, except for carbetocin, were associated with increased risks of side effects compared with oxytocin. Misoprostol may increase the likelihood of nausea, vomiting and fever, and probably increases the risk of diarrhoea. Injectable prostaglandins may increase the likelihood of diarrhoea. Ergometrine probably increases the likelihood of nausea and vomiting, and may increase the likelihood of hypertension, headache, and diarrhoea. Ergometrine plus oxytocin may increase the likelihood of nausea, vomiting, and diarrhoea. Misoprostol plus oxytocin probably increases the likelihood of nausea, vomiting and diarrhoea, and may increase the likelihood of fever. Analyses of the prespecified subgroups did not reveal important subgroup differences. Evidence for outcomes not presented above but reported in the summary of findings tables was very low certainty.Authors' conclusionsMost agents are effective for preventing PPH when compared with placebo or no treatment. Ergometrine plus oxytocin, and misoprostol plus oxytocin may be more effective than the current standard oxytocin. All agents, except for carbetocin, are associated with an increased risk of some side effects compared with oxytocin.FundingSupported by UNDP/UNFPA/UNICEF/WHO/World Bank Special Programme of Research, Development and Research Training in Human Reproduction (HRP), a cosponsored programme executed by the WHO (Award No. HQHRP2220228-22.1-74309).RegistrationCochrane Library; Registration number: CD011689 and protocol [and previous versions] available via DOI: 10.1002/14651858.CD011689 [DOI: 10.1002/14651858.CD011689.pub3 and DOI: 10.1002/14651858.CD011689.pub2].

Abstract licence: CC BY-NC

Postpartum haemorrhage (PPH) is a leading cause of maternal death. Preventing PPH can spare women from experiencing the trauma and risks of PPH, reduce the strain on overstretched health systems, and probably produce better outcomes than a strategy solely focused on PPH treatment. Prevention of PPH is often interpreted as provision of uterotonic drugs to contract the uterus at the time of childbirth. Although uterotonics are a central strategy for PPH prevention, several other approaches can prevent PPH or ameliorate its severity. These approaches include addressing the unmet need for contraception, remedying anaemia and other modifiable risk factors for PPH, optimising medical conditions that predispose to PPH, and tackling the rise in caesarean births in many countries. Effective delivery of preventive care requires early and regular antenatal care and planned birth at appropriately resourced health facilities. Social and behavioural change interventions for improving contraceptive provision and uptake, targeting adolescents, postpartum women, geographically remote communities, and families on low income, are a priority. Effective interventions to tackle anaemia include the management of heavy menstrual bleeding, pre-pregnancy or antenatal haemoglobin testing and oral or intravenous iron treatment, dietary improvements, and-on rare occasions-blood transfusion. Risk factors for PPH that need attention include high BMI, multiple pregnancy, gestational diabetes, pre-eclampsia, macrosomia, and several medical conditions. Caesarean births are associated with a substantial increase in PPH risk and should therefore only be done when medically indicated. A Cochrane network meta-analysis of 122 trials, with 121 931 women, found that the combinations of oxytocin plus misoprostol, or oxytocin plus ergometrine, were the most effective prophylaxis for PPH when given at the time of childbirth; however, these combinations had a higher risk of side-effects compared with single-drug prophylaxis. Oxytocin and carbetocin were the most effective single drugs for PPH prophylaxis, with minimal side-effects. Single uterotonic prophylaxis with either oxytocin or carbetocin is, therefore, recommended for routine prophylaxis. However, if oxytocin or carbetocin is not accessible, misoprostol is an alternative. Combination prophylaxis with oxytocin plus misoprostol can be considered for women at high risk of PPH. Ergometrine alone and oxytocin plus ergometrine combination are no longer recommended due to hypertension-related safety concerns. A robust implementation approach that engages various stakeholders to promote change, ensures the supply of quality-assured medicines and devices, provides training and support, and secures ongoing political and financial commitment is necessary to translate evidence into global impact.

Abstract licence: CC BY-NC-ND