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Objective: There are no globally agreed on strategies on early detection and first response management of postpartum haemorrhage (PPH) during and after caesarean birth. Our study aimed to develop an international expert's consensus on evidence-based approaches for early detection and obstetric first response management of PPH intraoperatively and postoperatively in caesarean birth., Design: Systematic review and three-stage modified Delphi expert consensus., Setting: International., Population: Panel of 22 global experts in PPH with diverse backgrounds, and gender, professional and geographic balance., Outcome Measures: Agreement or disagreement on strategies for early detection and first response management of PPH at caesarean birth., Results: Experts agreed that the same PPH definition should apply to both vaginal and caesarean birth. For the intraoperative phase, the experts agreed that early detection should be accomplished via quantitative blood loss measurement, complemented by monitoring the woman's haemodynamic status; and that first response should be triggered once the woman loses at least 500 mL of blood with continued bleeding or when she exhibits clinical signs of haemodynamic instability, whichever occurs first. For the first response, experts agreed on immediate administration of uterotonics and tranexamic acid, examination to determine aetiology and rapid initiation of cause-specific responses. In the postoperative phase, the experts agreed that caesarean birth-related PPH should be detected primarily via frequently monitoring the woman's haemodynamic status and clinical signs and symptoms of internal bleeding, supplemented by cumulative blood loss assessment performed quantitatively or by visual estimation. Postoperative first response was determined to require an individualised approach., Conclusion: These agreed on proposed approaches could help improve the detection of PPH in the intraoperative and postoperative phases of caesarean birth and the first response management of intraoperative PPH. Determining how best to implement these strategies is a critical next step., Competing Interests: Competing interests: Disclosure forms provided by the authors are available with the full text of this article., (© World Health Organization 2024. Licensee BMJ.)

The third stage of labor is defined as the time period between delivery of the fetus through delivery of the placenta. During a normal third stage, uterine contractions lead to separation and expulsion of the placenta from the uterus. Postpartum hemorrhage is a relatively common complication of the third stage of labor. Strategies have been studied to mitigate the risk of postpartum hemorrhage, leading to the widespread implementation of active management of the third stage of labor. Initially, active management of the third stage of labor consisted of a bundle of interventions including administration of a uterotonic agent, early cord clamping, controlled cord traction, and external uterine massage. However, the effectiveness of these interventions as a bundle has been questioned, leading to abandonment of some components in recent years. Despite this, upon review of selected international guidelines, we found that the term "active management of the third stage of labor" was still used, but recommendations for and against individual interventions were variable and not necessarily supported by current evidence. In this review, we: (1) examine the physiology of the third stage of labor, (2) present evidence related to interventions that prevent postpartum hemorrhage and promote maternal and neonatal health, (3) review current global guidelines and recommendations for practice, and (4) propose future areas of investigation. The interventions in this review include pharmacologic agents to prevent postpartum hemorrhage, cord clamping, cord milking, cord traction, cord drainage, early skin-to-skin contact, and nipple stimulation. Treatment of complications of the third stage of labor is outside of the scope of this review. We conclude that current evidence supports the use of effective pharmacologic postpartum hemorrhage prophylaxis, delayed cord clamping, early skin-to-skin contact, and controlled cord traction at delivery when feasible. The most effective uterotonic regimens for preventing postpartum hemorrhage after vaginal delivery include oxytocin plus ergometrine; oxytocin plus misoprostol; or carbetocin. After cesarean delivery, carbetocin or oxytocin as a bolus are the most effective regimens. There is inconsistent evidence regarding the use of tranexamic acid in addition to a uterotonic compared with a uterotonic alone for postpartum hemorrhage prevention after all deliveries. Because of differences in patient comorbidities, costs, and availability of resources and staff, decisions to use specific prevention strategies are dependent on patient- and system-level factors. We recommend that the term "active management of the third stage of labor" as a combined intervention no longer be used. Instead, we recommend that "third stage care" be adopted, which promotes the implementation of evidence-based interventions that incorporate practices that are safe and beneficial for both the woman and neonate., (Copyright © 2022 Elsevier Inc. All rights reserved.)

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.)., (Copyright © 2023 Massachusetts Medical Society.)

Background: Postpartum haemorrhage (PPH) is the leading cause of global maternal deaths, accounting for 30-50% of maternal deaths in sub-Saharan Africa. Most PPH-related deaths are preventable with timely detection and initiation of care, which may be facilitated by using a clinical care bundle. We explore influences on current PPH detection and management and on the future implementation of a new PPH bundle (E-MOTIVE) in low-resource, high-burden settings., Methods: Semi-structured qualitative interviews based on the Theoretical Domains Framework were conducted with 45 healthcare providers across nine hospitals in Nigeria, Kenya and South Africa, to identify barriers and enablers to current PPH detection and management and future implementation of a new PPH care bundle. Data were analysed using thematic and framework analysis. The Behaviour Change Wheel was used to identify potential interventions to address identified barriers and enablers., Results: Influences on current PPH detection and management fell under 12 domains: Environmental Context and Resources (drug and staff shortages), Skills (limited in-service training), Knowledge (variable understanding of the recommended practice), Behaviour Regulation (limited quality improvement culture), Beliefs about Consequences (drawbacks from inaccurate detection), Emotion (stress from the unpredictability of PPH), Social Influence (teamwork), Memory, Attention and Decision-making (limited guideline use), Social/Professional Role and Identity (role clarity), Beliefs about Capabilities (confidence in managing PPH), Reinforcement (disciplinary procedures) and Goals (PPH as a priority). Influences on bundle uptake included: Beliefs about Consequences (perceived benefits of new blood loss measurement tool), Environmental Context and Resources (high cost of drugs and new tools), Memory, Attention and Decision-making (concerns about whether bundle fits current practice), Knowledge (not understanding 'bundled' approach), Social Influence (acceptance by women and staff) and Intention (limited acceptance of 'bundled' approach over existing practice). These influences were consistent across countries. Proposed interventions included: Education, Training, Modelling (core and new skills), Enablement (monitoring uptake), Persuasion (leadership role) and Environmental Restructuring (PPH emergency trolley/kit)., Conclusions: A wide range of individual, socio-cultural and environmental barriers and enablers to improving PPH detection and management exist in these settings. We identified a range of interventions that could improve PPH care and the implementation of new care bundles in this context., Trial Registration: ClinicalTrials.gov : NCT04341662., (© 2023. The Author(s).)

The use of tranexamic acid for postpartum hemorrhage has entered obstetrical practice globally with the evidence-based expectation of saving lives. This improvement in the care of women with postpartum hemorrhage has come at a price. For the anesthetist, having tranexamic acid ampoules close at hand would seem an obvious strategy to facilitate its use during cesarean delivery, an important setting for severe hemorrhage. Tragically, we have identified a number of recent instances of inadvertent intrathecal administration of tranexamic acid instead of local anesthetic for spinal anesthesia. Reported cases of this catastrophic error seem to be increasing. The profound neurotoxicity of tranexamic acid causes rapid-onset convulsions, with mortality of 50%. How can these tragic errors be averted? Drug safety alerts have been issued by the US Food and Drug Administration and the World Health Organization, but that is not enough. We recommend extensive dissemination of information to raise awareness of this potential hazard, and local hospital protocols to ensure that tranexamic acid is stored separately from anesthetic drugs, preferably outside the operating room and with an auxiliary warning label. Implementation of safety strategies on a very large scale will be needed to ensure that the life-saving potential of tranexamic acid is not eclipsed by drug-error mortality., (© 2022 The Authors. Published by Elsevier Inc /Elsevier B.V./ Wiley on behalf of The International Federation of Gynecology and Obstetrics (FIGO) / John Wiley & Son Ltd.)

The use of tranexamic acid for postpartum hemorrhage has entered obstetrical practice globally with the evidence-based expectation of saving lives. This improvement in the care of women with postpartum hemorrhage has come at a price. For the anesthetist, having tranexamic acid ampoules close at hand would seem an obvious strategy to facilitate its use during cesarean delivery, an important setting for severe hemorrhage. Tragically, we have identified a number of recent instances of inadvertent intrathecal administration of tranexamic acid instead of local anesthetic for spinal anesthesia. Reported cases of this catastrophic error seem to be increasing. The profound neurotoxicity of tranexamic acid causes rapid-onset convulsions, with mortality of 50%. How can these tragic errors be averted? Drug safety alerts have been issued by the US Food and Drug Administration and the World Health Organization, but that is not enough. We recommend extensive dissemination of information to raise awareness of this potential hazard, and local hospital protocols to ensure that tranexamic acid is stored separately from anesthetic drugs, preferably outside the operating room and with an auxiliary warning label. Implementation of safety strategies on a very large scale will be needed to ensure that the life-saving potential of tranexamic acid is not eclipsed by drug-error mortality., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Fetal malposition (occipito-posterior and persistent occipito-transverse) in labour is associated with adverse maternal and infant outcomes. Whether use of maternal postures can improve these outcomes is unclear. This Cochrane Review of maternal posture in labour is one of two new reviews replacing a 2007 review of maternal postures in pregnancy and labour., Objectives: To assess the effect of specified maternal postures for women with fetal malposition in labour on maternal and infant morbidity compared to other postures.  SEARCH METHODS: We searched Cochrane Pregnancy and Childbirth's Trials Register, ClinicalTrials.gov, the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) (13 July 2021), and reference lists of retrieved studies., Selection Criteria: We included randomised controlled trials (RCTs) or cluster-RCTs conducted among labouring women with a fetal malposition confirmed by ultrasound or clinical examination, comparing a specified maternal posture with another posture. Quasi-RCTs and cross-over trials were not eligible for inclusion., Data Collection and Analysis: Two review authors independently assessed trials for inclusion, risk of bias, and performed data extraction. We used mean difference (MD) for continuous variables, and risk ratios (RRs) for dichotomous variables, with 95% confidence intervals (CIs). We assessed the certainty of the evidence using the GRADE approach., Main Results: We included eight eligible studies with 1766 women.  All studies reported some form of random sequence generation but were at high risk of performance bias due to lack of blinding. There was a high risk of selection bias in one study, detection bias in two studies, attrition bias in two studies, and reporting bias in two studies. Hands and knees The use of hands and knees posture may have little to no effect on operative birth (average RR 1.14, 95% CI 0.87 to 1.50; 3 trials, 721 women; low-certainty evidence) and caesarean section (RR 1.34, 95% CI 0.96 to 1.87; 3 trials, 721 women; low-certainty evidence) but the evidence is uncertain; and very uncertain for epidural use (average RR 0.74, 95% CI 0.41 to 1.31; 2 trials, 282 women; very low-certainty evidence), instrumental vaginal birth (average RR 1.04, 95% CI 0.57 to 1.90; 3 trials, 721 women; very low-certainty evidence), severe perineal tears (average RR 0.88, 95% CI 0.03 to 22.30; 2 trials, 586 women; very low-certainty evidence), maternal satisfaction (average RR 1.02, 95% CI 0.68 to 1.54; 3 trials, 350 women; very low-certainty evidence), and Apgar scores less than seven at five minutes (RR 0.71, 95% CI 0.21 to 2.34; 2 trials, 586 babies; very low-certainty evidence).  No data were reported for the hands and knees comparisons for postpartum haemorrhage, serious neonatal morbidity, death (stillbirth or death of liveborn infant), admission to neonatal intensive care, neonatal encephalopathy, need for respiratory support, and neonatal jaundice requiring phototherapy.  Lateral postures The use of lateral postures may have little to no effect on reducing operative birth (average RR 0.72, 95% CI 0.43 to 1.19; 4 trials, 871 women; low-certainty evidence), caesarean section (average RR 0.78, 95% CI 0.44 to 1.39; 4 trials, 871 women; low-certainty evidence), instrumental vaginal birth (average RR 0.73, 95% CI 0.39 to 1.36; 4 trials, 871 women; low-certainty evidence), and maternal satisfaction (RR 0.96, 95% CI 0.84 to 1.09; 2 trials, 451 women; low-certainty evidence), but the evidence is uncertain. The evidence is very uncertain about the effect of lateral postures on severe perineal tears (RR 0.66, 95% CI 0.17 to 2.48; 3 trials, 609 women; very low-certainty evidence), postpartum haemorrhage (RR 0.90, 95% CI 0.48 to 1.70; 1 trial, 322 women; very low-certainty evidence), serious neonatal morbidity (RR 1.41, 95% CI 0.64 to 3.12; 3 trials, 752 babies; very low-certainty evidence), Apgar scores less than seven at five minutes (RR 0.25, 95% CI 0.03 to 2.24; 1 trial, 322 babies; very low-certainty evidence), admissions to neonatal intensive care (RR 1.41, 95% CI 0.64 to 3.12; 2 trials, 542 babies; very low-certainty evidence) and neonatal death (stillbirth or death of liveborn) (1 trial, 210 women and their babies; no events).  For the lateral posture comparisons, no data were reported for epidural use, neonatal encephalopathy, need for respiratory support, and neonatal jaundice requiring phototherapy. We were not able to estimate the outcome death (stillbirth or death of liveborn infant) due to no events (1 trial, 210 participants).  AUTHORS' CONCLUSIONS: We found low- and very low-certainty evidence which indicated that the use of hands and knees posture or lateral postures in women in labour with a fetal malposition may have little or no effect on health outcomes of the mother or her infant. If a woman finds the use of hands and knees or lateral postures in labour comfortable there is no reason why they should not choose to use them. Further research is needed on the use of hands and knees and lateral postures for women with a malposition in labour. Trials should include further assessment of semi-prone postures, same-side-as-fetus lateral postures with or without hip hyperflexion, or both, and consider interventions of longer duration or that involve the early second stage of labour., (Copyright © 2022 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.)

Objective: To check the quality of oxytocin and tranexamic acid-two recommended products for prevention and treatment of postpartum hemorrhage (PPH)-used in facilities taking part in an implementation research project to improve PPH diagnosis and management., Methods: Between September 2020 and August 2021, oxytocin and tranexamic acid products used in the study facilities in Kenya, Nigeria, South Africa, and Tanzania were collected and transported in cold storage for analysis. Samples were analyzed according to the International (oxytocin) and British Pharmacopeia (tranexamic acid) standards., Results: Of the 17 unique oxytocin products, 33 individual measurements were made. Only six unique products had adequate content and no related substances exceeding the recommended limits. Of 14 tranexamic acid samples, 10 showed adequate content. One product in Kenya and two products in Nigeria from different manufacturers had a high content of related substances, which classified them as substandard., Conclusion: While we were unable to investigate the origin regarding poor manufacturing or poor storage or both, the high number of substandard oxytocin samples is of great concern. Most of the tranexamic acid samples had adequate content but the presence of impurities in multiple products is worrying and requires further study., (© 2022 The Authors. International Journal of Gynecology & Obstetrics published by John Wiley & Sons Ltd on behalf of International Federation of Gynecology and Obstetrics.)

Background: Obstetric haemorrhage continues to be a leading cause of maternal mortality, contributing to more than a quarter of the 2,443,000 maternal deaths reported between 2003 and 2009. During this period, about 70% of the haemorrhagic deaths occurred postpartum. In addition to other identifiable risk factors for greater postpartum blood loss, the duration of the third stage of labour (TSL) seems to be important, as literature shows that a longer TSL can be associated with more blood loss. To better describe the association between the duration of TSL and postpartum blood loss in women receiving active management of third stage of labour (AMTSL), this secondary analysis of the WHO CHAMPION trial data has been conducted., Methods: This was a secondary analysis of the WHO CHAMPION trial conducted in twenty-three sites in ten countries. We studied the association between the TSL duration and blood loss in the sub cohort of women from the CHAMPION trial (all of whom received AMTSL), with TSL upto 60 min and no interventions for postpartum haemorrhage. We used a general linear model to fit blood loss as a function of TSL duration on the log scale, arm and center, using a normal distribution and the log link function. We showed this association separately for oxytocin and for Heat stable (HS) carbetocin., Results: For the 10,040 women analysed, blood loss rose steeply with third stage duration in the first 10 min, but more slowly after 10 min. This trend was observed for both Oxytocin and HS carbetocin and the difference in the trends for both drugs was not statistically significant (p-value = 0.2070)., Conclusions: There was a positive association between postpartum blood loss and TSL duration with either uterotonic. Blood loss rose steeply with TSL duration until 10 min, and more slowly after 10 min. Study registration The main trial was registered with Australian New Zealand Clinical Trials Registry ACTRN12614000870651 and Clinical Trial Registry of India CTRI/2016/05/006969., (© 2021. The Author(s).)

Background: Assisted vaginal births are carried out to expedite birth for the benefit of mothers and babies but are sometimes associated with significant morbidity for both. Various instruments are available, broadly divided into forceps and vacuum cups, and choice may be influenced by clinical circumstances, operator preference, experience and availability.  OBJECTIVES: To evaluate the different instruments in terms of success in achieving a vaginal birth, and the risk of morbidity for mother and baby., Search Methods: We searched Cochrane Pregnancy and Childbirth's Trials Register, ClinicalTrials.gov, the WHO International Clinical Trials Registry Platform (ICTRP) (14 May 2021), and reference lists of retrieved studies., Selection Criteria: We selected randomised controlled trials of assisted vaginal birth using different instruments. The review did not include quasi-randomised trials, cluster-randomised trials or cross-over designs. The review included trials for which abstracts alone were available as long as there was sufficient information to assess eligibility.  DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods. We used the GRADE approach to assess the certainty of evidence.  The main outcomes assessed included failed delivery with allocated instrument, any maternal trauma, third- and fourth-degree tears, postpartum haemorrhage, any neonatal trauma, low Apgar and low umbilical artery pH.  MAIN RESULTS: We included 31 studies involving a total of 5754 women.  Risk of bias criteria were largely assessed as 'unclear', due to a lack of detail in trial reports. Blinding would have been challenging for all trials due to their inability to conceal the type of instrument used from either the woman or the operator, which is reflected in the risk of bias assessment. Any type of forceps versus any type of vacuum cup (12 studies, 3129 women) Forceps may be less likely to fail in achieving vaginal birth: risk ratio (RR) 0.58, 95% confidence interval (CI) 0.39 to 0.88; 11 studies, 3080 women; low certainty. 'Any maternal trauma' may be slightly more likely with forceps: odds ratio (OR) 1.53, 95% CI 0.98 to 2.40; 5 studies, 1356 women; low certainty; and third- or fourth-degree tears may also be more likely with forceps: RR 1.83, 95% CI 1.32 to 2.55; 9 studies, 2493 women; low certainty. There is no evidence of a difference in the incidence of postpartum haemorrhage (PPH) between the two groups: RR 1.71, 95% CI 0.59 to 4.95; 2 studies, 523 women; low certainty, because the evidence is very imprecise due to a very wide CI.  More women in the forceps group reported requiring pain relief. There is probably no evidence of difference in rates of low Apgar: RR 0.83, 95% CI 0.46 to 1.51; 7 studies, 1644 women; moderate certainty; or low umbilical artery pH in the forceps group compared to any vacuum: RR 1.33, 95% CI 0.91 to 1.93; 2 studies, 789 women; low certainty; both of these outcomes are imprecise and have wide CIs that include both benefit and harm. There were also lower rates of fetal trauma with 'any forceps' (cephalhematoma, retinal haemorrhage and jaundice). The composite outcome of 'any neonatal trauma' was not reported. Low-cavity forceps versus any vacuum cup (2 studies, 218 women) We included two small studies with 218 participants in this comparison, but we judged most of the evidence as very low certainty, hence it was not feasible to make judgements on the difference in the rates of failed delivery, any maternal trauma or third- and fourth- degree tears. PPH and low umbilical artery pH were not reported. Soft vacuum cup versus any rigid cup (9 studies, 1148 women) Failed delivery may be more likely in the soft vacuum cup group: RR 1.62, 95% CI 1.21 to 2.17; 9 studies, 1148 women; low certainty. There may be no difference in the rates of 'any maternal trauma': OR 0.63, 95% CI 0.24 to 1.67; 2 studies, 348 women; low certainty, but the confidence interval is wide, indicating possible benefit or harm. There may be no difference in the rates of third- or fourth-degree tears: RR 0.93, 95% CI 0.35 to 2.44; 4 studies, 619 women; low certainty. There is probably no difference in the rates of PPH: RR 0.89, 95% CI 0.49 to 1.61; 5 studies, 737 women; moderate certainty between the soft and rigid cup groups.   There may be little or no difference in the incidence of low Apgar scores: RR 0.82, 95% CI 0.49 to 1.37; 9 studies, 1148; low certainty; or low umbilical artery pH: RR 0.80, 95% CI 0.47 to 1.36; 1 study, 100 women; low certainty. Handheld vacuum versus any vacuum cup (4 studies, 968 women) There may be no difference in the rates of failures with allocated instrument: RR 1.35, 95% CI 0.81 to 2.25; 4 studies, 962 women; low certainty, any maternal trauma: OR 1.16, 95% CI 0.71 to 1.88; 2 studies; 394 women; low certainty, PPH: RR 0.31, 95% CI 0.03 to 2.92; 1 study, 164 women; low certainty, low umbilical artery pH: RR 1.06, 95% CI 0.71 to 1.59; 1 study, 164 women; low certainty, or low Apgar scores: RR 1.25, 95% CI 0.34 to 4.61; 3 studies, 784 women; low certainty) between the two groups. There is probably no difference in the rates of third- or fourth-degree tears between the 'handheld vacuum' and 'any vacuum cup' groups: RR 1.15, 95% CI 0.62 to 2.12; 4 studies, 962 women; moderate certainty., Authors' Conclusions: This review provides low-certainty evidence that forceps may be more likely to achieve vaginal birth and have lower rates of fetal trauma, but at a greater risk of perineal trauma and higher pain relief requirements compared with vacuum cups. There was low-certainty evidence that rigid vacuum cups may be more likely to achieve a vaginal birth than soft cups but with more fetal trauma, whilst handheld vacuum cups had similar success rates compared to other cups. There was no evidence of a difference in the rates of third- or fourth-degree tears or postpartum haemorrhages between types of cups, but wide confidence intervals around the estimates indicate further research is needed in this area., (Copyright © 2021 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.)

Background: Postpartum hemorrhage (PPH) is the leading cause of maternal death worldwide. When PPH occurs, early identification of bleeding and prompt management using evidence-based guidelines, can avert most PPH-related severe morbidities and deaths. However, adherence to the World Health Organization recommended practices remains a critical challenge. A potential solution to inefficient and inconsistent implementation of evidence-based practices is the application of a 'clinical care bundle' for PPH management. A clinical care bundle is a set of discrete, evidence-based interventions, administered concurrently, or in rapid succession, to every eligible person, along with teamwork, communication, and cooperation. Once triggered, all bundle components must be delivered. The E-MOTIVE project aims to improve the detection and first response management of PPH through the implementation of the "E-MOTIVE" bundle, which consists of (1) Early PPH detection using a calibrated drape, (2) uterine Massage, (3) Oxytocic drugs, (4) Tranexamic acid, (5) Intra Venous fluids, and (6) genital tract Examination and escalation when necessary. The objective of this paper is to describe the protocol for the formative phase of the E-MOTIVE project, which aims to design an implementation strategy to support the uptake of this bundle into practice., Methods: We will use behavior change and implementation science frameworks [e.g. capability, opportunity, motivation and behavior (COM-B) and theoretical domains framework (TDF)] to guide data collection and analysis, in Kenya, Nigeria, South Africa, Sri Lanka, and Tanzania. There are four methodological components: qualitative interviews; surveys; systematic reviews; and design workshops. We will triangulate findings across data sources, participant groups, and countries to explore factors influencing current PPH detection and management, and potentially influencing E-MOTIVE bundle implementation. We will use these findings to develop potential strategies to improve implementation, which will be discussed and agreed with key stakeholders from each country in intervention design workshops., Discussion: This formative protocol outlines our strategy for the systematic development of the E-MOTIVE implementation strategy. This focus on implementation considers what it would take to support roll-out and implementation of the E-MOTIVE bundle. Our approach therefore aims to maximize internal validity in the trial alongside future scalability, and implementation of the E-MOTIVE bundle in routine practice, if proven to be effective., Trial Registration: ClinicalTrials.gov: NCT04341662., (© 2021. The Author(s).)

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®., (Copyright © 2020 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.)

Objective: To identify an inexpensive catheter suitable for uterine suction tamponade (UST) for postpartum hemorrhage and assess its functionality., Methods: Randomized, single-center, double-blind feasibility study in East London, South Africa, among 45 women undergoing cesarean delivery between October and November 2018. A search of medical supply websites for catheters with predefined characteristics (inexpensive, flexible, wide-bore, circumferentially-arranged side apertures, rounded tip) identified the FG36 Levin stomach tube. During cesarean, the tube was placed in the uterus and connected transvaginally to a suction unit. Participants were randomized via a computer-generated random sequence to early (after uterine closure; n=24) or delayed (after skin closure; n=21) UST., Results: The tube functioned well with respect to stability in the uterus and aspirating blood from the uterine cavity without blockage. Blood loss was similar between the groups (mean difference, 7.3 mL; 95% confidence interval, -61 to 75; P=0.433), as were secondary outcomes. There were no complications. Absolute effectiveness was not tested because there was no non-suction group., Conclusion: The FG36 Levin tube was found to be a suitable device for "suction-tube uterine tamponade". There was no difference in functionality between early and late UST. Future trials should assess the effectiveness of this approach for postpartum hemorrhage., Clinical Trial Registration: Registered in the Pan African Clinical Trial Registry as PACTR201809584199573., (© 2019 International Federation of Gynecology and Obstetrics.)

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.

Background: Postpartum hemorrhage is the most common cause of maternal death. Oxytocin is the standard therapy for the prevention of postpartum hemorrhage, but it requires cold storage, which is not available in many countries. In a large trial, we compared a novel formulation of heat-stable carbetocin with oxytocin., Methods: We enrolled women across 23 sites in 10 countries in a randomized, double-blind, noninferiority trial comparing intramuscular injections of heat-stable carbetocin (at a dose of 100 μg) with oxytocin (at a dose of 10 IU) administered immediately after vaginal birth. Both drugs were kept in cold storage (2 to 8°C) to maintain double-blinding. There were two primary outcomes: the proportion of women with blood loss of at least 500 ml or the use of additional uterotonic agents, and the proportion of women with blood loss of at least 1000 ml. The noninferiority margins for the relative risks of these outcomes were 1.16 and 1.23, respectively., Results: A total of 29,645 women underwent randomization. The frequency of blood loss of at least 500 ml or the use of additional uterotonic agents was 14.5% in the carbetocin group and 14.4% in the oxytocin group (relative risk, 1.01; 95% confidence interval [CI], 0.95 to 1.06), a finding that was consistent with noninferiority. The frequency of blood loss of at least 1000 ml was 1.51% in the carbetocin group and 1.45% in the oxytocin group (relative risk, 1.04; 95% CI, 0.87 to 1.25), with the confidence interval crossing the margin of noninferiority. The use of additional uterotonic agents, interventions to stop bleeding, and adverse effects did not differ significantly between the two groups., Conclusions: Heat-stable carbetocin was noninferior to oxytocin for the prevention of blood loss of at least 500 ml or the use of additional uterotonic agents. Noninferiority was not shown for the outcome of blood loss of at least 1000 ml; low event rates for this outcome reduced the power of the trial. (Funded by Merck Sharpe & Dohme; CHAMPION Australian New Zealand Clinical Trials Registry number, ACTRN12614000870651 ; EudraCT number, 2014-004445-26 ; and Clinical Trials Registry-India number, CTRI/2016/05/006969 .).

Prevention of deaths from obstetric haemorrhage requires effective health systems including family planning, commodities, personnel, infrastructure and ultimately universal access to comprehensive obstetric care for women giving birth. The main causes of death associated with antepartum haemorrhage are placental abruption, placenta praevia and uterine rupture. Preventive measures include preconceptual folate supplementation, management of hypertensive disorders, early diagnosis of placenta praevia and use of uterine stimulants cautiously, particularly misoprostol. Preventive measures for post-partum haemorrhage include routine active management of the third stage of labour. Treatment involves a cascade of increasingly invasive interventions in rapid sequence until the bleeding is stopped. These interventions include fluid resuscitation, removal of the placenta, bimanual uterine compression, uterotonics, tranexamic acid, suturing of lower genital tract injury, blood product replacement, balloon tamponade, laparotomy, stepwise uterine devascularization, uterine compression sutures and hysterectomy. Emergency temporizing measures include application of the non-pneumatic anti-shock garment, and at laparotomy, aortic compression and uterine tourniquet application. The effectiveness of treatment methods and the optimal dosage of misoprostol are research priorities. Interesting new approaches include transvaginal uterine artery clamping and suction uterine tamponade., (Copyright © 2016. Published by Elsevier Ltd.)

Background: Postpartum haemorrhage (PPH) is the leading cause of maternal mortality in low-income countries and contributes to nearly a quarter of maternal deaths globally. The current available interventions for prevention of postpartum haemorrhage, oxytocin and carbetocin, are limited by their need for refrigeration to maintain potency, as the ability to maintain a cold chain across the drug distribution and storage network is inconsistent, thus restricting their use in countries with the highest burden of maternal mortality. We describe a randomized, double-blind non-inferiority trial comparing a newly developed room temperature stable formulation of carbetocin to the standard intervention (oxytocin) for the prevention of PPH after vaginal birth., Methods/design: Approximately 30,000 women delivering vaginally will be recruited across 22 centres in 10 countries. The primary objectives are to evaluate the non-inferiority of room temperature stable carbetocin (100 μg intramuscular) versus oxytocin (10 IU intramuscular) in the prevention of PPH and severe PPH after vaginal birth. The primary endpoints are blood loss ≥500 mL or the use of additional uterotonics (composite endpoint required by drug regulatory authorities) and blood loss ≥1,000 mL (WHO requirement). Non-inferiority will be assessed using a two-sided 95 % confidence interval for the relative risk of the above endpoints for room temperature stable carbetocin versus oxytocin. The upper limit of the two-sided 95 % confidence interval for the relative risk for the composite endpoint of blood loss ≥500 mL or the use of additional uterotonics, and for the endpoint of blood loss ≥1,000 mL, will be compared to a non-inferiority margin of 1.16 and 1.23, respectively. If the upper limit is below the corresponding margin, non-inferiority will have been demonstrated. The safety analysis will include all women receiving treatment. Safety and tolerability will be assessed by a review of adverse events, by conducting inferential testing with significance levels for between-group comparisons., Discussion: If the results of the study show that room temperature stable carbetocin is a safe and effective alternative to oxytocin, this could have a substantial impact on the prevention of postpartum haemorrhage and maternal survival worldwide., Trial Registration: ACTRN12614000870651 (14 August 2014).

Background: Postpartum haemorrhage (PPH) is a common and potentially life-threatening complication of labour. Several options for preventing PPH are available, but further advances in this field are important, especially the identification of safe, easy to use and cost-effective regimens. Tranexamic acid (TA), which is an antifibrinolytic agent that is used widely to prevent and treat haemorrhage, merits evaluation to assess whether it meets these criteria., Objectives: To determine, from the best available evidence, whether TA is effective and safe for preventing PPH in comparison to placebo or no treatment (with or without uterotonic co-treatment), or to uterotonic agents., Search Methods: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (28 January 2015) and reference lists of retrieved studies., Selection Criteria: All published, unpublished and ongoing randomised controlled trials (RCTs) evaluating the use of TA alone or in addition to uterotonics in the third stage of labour or during caesarean section (CS) to prevent PPH., Data Collection and Analysis: Two review authors independently assessed for inclusion all the potential studies identified as a result of the search strategy. We entered the data into Review Manager software and checked for accuracy., Main Results: Twelve trials involving 3285 healthy women at low risk of excessive bleeding undergoing elective CS (nine trials, 2453 participants) or spontaneous birth (three trials, 832 participants) satisfied inclusion criteria and contributed data to the analysis. All participants received routine prophylactic uterotonics in accordance with the local guideline in addition to TA or placebo or no intervention. Overall, included studies had moderate risk of bias for random sequence generation, allocation concealment, blinding, selective reporting and low risk of bias for incomplete data. The quality of evidence was also as assessed using GRADE.Blood loss greater than 400 mL or 500 mL, and more than 1000 mL was less common in women who received TA versus placebo or no intervention (risk ratio (RR) 0.52, 95% confidence interval (CI) 0.42 to 0.63, six trials, 1398 women; moderate quality evidence) and (RR 0.40, 95% CI 0.23 to 0.71, six trials, 2093 women; moderate quality evidence), respectively. TA was effective in decreasing the incidence of blood loss greater than 1000 mL in women who had undergone CS (RR 0.43, 95% CI 0.23, 0.78, four trials, 1534 women), but not vaginal birth (RR 0.28, 95% CI 0.06, 1.36, two trials 559 women). The effect of TA on blood loss greater than 500 mL or 400 mL was more pronounced in the group of women having vaginal birth than in women who had CS. Mean blood loss (from delivery until two hours postpartum) was lower in women who received TA versus placebo or no intervention (mean difference MD - 77.79 mL, 95% CI -97.95, -57.64, five trials, 1186 women) and this effect was similar following vaginal birth and CS.Additional medical interventions (moderate quality evidence) and blood transfusions were less frequent in women receiving TA versus placebo or no interventions. Mild side effects such as nausea, vomiting, dizziness were more common with the use of TA (moderate quality evidence). The effect of TA on maternal mortality, severe morbidity and thromboembolic events is uncertain (low quality evidence)., Authors' Conclusions: TA (in addition to uterotonic medications) decreases postpartum blood loss and prevents PPH and blood transfusions following vaginal birth and CS in women at low risk of PPH based on studies of mixed quality. There is insufficient evidence to draw conclusions about serious side effects, but there is an increase in the incidence of minor side effects with the use of TA. Effects of TA on thromboembolic events and mortality as well as its use in high-risk women should be investigated further.

Background: The primary objective of postpartum haemorrhage (PPH) prevention and treatment is to reduce maternal deaths. Misoprostol has the major public health advantage over injectable medication that it can more easily be distributed at community level. Because misoprostol might have adverse effects unrelated to blood loss which might impact on mortality or severe morbidity, it is important to continue surveillance of all relevant evidence from randomised trials. This is particularly important as misoprostol is being introduced on a large scale for PPH prevention in low-income countries, and is commonly used for PPH treatment in well-resourced settings as well., Objectives: To review maternal deaths and severe morbidity in all randomised trials of misoprostol for prevention or treatment of PPH., Search Methods: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (11 January 2013)., Selection Criteria: We included randomised trials including pregnant women who received misoprostol in the postpartum period, versus placebo/no treatment or other uterotonics for prevention or treatment of PPH, and reporting on maternal death, severe morbidity or pyrexia.We planned to include cluster- and quasi-randomised trials in the analysis, as a very large number of women will be needed to obtain robust estimates of maternal mortality but we did not identify any for this version of the review. In future updates of this review we will include trials reported only as abstracts if sufficient information is available from the abstract or from the authors., Data Collection and Analysis: Two review authors independently assessed trials for inclusion and extracted data., Main Results: We included 78 studies (59,216 women) and excluded 34 studies.There was no statistically significant difference in maternal mortality for misoprostol compared with control groups overall (31 studies; 11/19,715 versus 4/20,076 deaths; risk ratio (RR) 2.08, 95% confidence interval (CI) 0.82 to 5.28); or for the trials of misoprostol versus placebo: 10 studies, 6/4626 versus 1/4707 ; RR 2.70; 95% CI 0.72 to 10.11; or for misoprostol versus other uterotonics: 21 studies, 5/15,089 versus 3/15,369 (19/100,000); RR 1.54; 95% CI 0.40 to 5.92. All 11 deaths in the misoprostol arms occurred in studies of misoprostol ≥ 600 µg.There was a statistically significant difference in the composite outcome 'maternal death or severe morbidity' for the comparison of misoprostol versus placebo (12 studies; average RR 1.70, 95% CI 1.02 to 2.81; Tau² = 0.00, I² = 0%) but not for the comparison of misoprostol versus other uterotonics (17 studies; average RR 1.50, 95% CI 0.50 to 4.52; Tau² = 1.81, I² = 69%). When we excluded hyperpyrexia from the composite outcome in exploratory analyses, there was no significant difference in either of these comparisons.Pyrexia > 38°C was increased with misoprostol compared with controls (56 studies, 2776/25,647 (10.8%) versus 614/26,800 (2.3%); average RR 3.97, 95% CI 3.13 to 5.04; Tau² = 0.47, I² = 80%). The effect was greater for trials using misoprostol 600 µg or more (27 studies; 2197/17,864 (12.3%) versus 422/18,161 (2.3%); average RR 4.64; 95% CI 3.33 to 6.46; Tau² = 0.51, I² = 86%) than for those using misoprostol 400 µg or less (31 studies; 525/6751 (7.8%) versus 185/7668 (2.4%); average RR 3.07; 95% CI 2.25 to 4.18; Tau² = 0.29, I² = 58%)., Authors' Conclusions: Misoprostol does not appear to increase or reduce severe morbidity (excluding hyperpyrexia) when used to prevent or treat PPH. Misoprostol did not increase or decrease maternal mortality. However, misoprostol is associated with an increased risk of pyrexia, particularly in dosages of 600 µg or more. Given that misoprostol is used prophylactically in very large numbers of healthy women, the greatest emphasis should be placed on limiting adverse effects. In this context, the findings of this review support the use of the lowest effective dose. As for any new medication being used on a large scale, continued vigilance for adverse effects is essential and there is a need for large randomised trials to further elucidate both the relative effectiveness and the risks of various dosages of misoprostol.

Background: Postpartum haemorrhage (PPH) (bleeding from the genital tract after childbirth) is a major cause of maternal mortality and disability, particularly in under-resourced areas. In these settings, uterotonics are often not accessible. There is a need for simple, inexpensive techniques which can be applied in low-resourced settings to prevent and treat PPH. Uterine massage is recommended as part of the routine active management of the third stage of labour. However, it is not known whether it is effective. If shown to be effective, uterine massage would represent a simple intervention with the potential to have a major effect on PPH and maternal mortality in under-resourced settings., Objectives: To determine the effectiveness of uterine massage after birth and before or after delivery of the placenta, or both, to reduce postpartum blood loss and associated morbidity and mortality., Search Methods: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (30 April 2013)., Selection Criteria: All published, unpublished and ongoing randomised controlled trials comparing uterine massage alone or in addition to uterotonics before or after delivery of the placenta, or both, with non-massage., Data Collection and Analysis: Two researchers independently considered trials for eligibility, assessed risk of bias and extracted the data using the agreed form. Data were checked for accuracy. The effect of uterine massage commenced before or after placental delivery were first assessed separately, and then the combined for an overall result., Main Results: This review included two randomised controlled trials. The first trial included 200 women who were randomised to receive uterine massage or no massage following delivery of the placenta, after active management of the third stage of labour including use of oxytocin. The numbers of women with blood loss more than 500 mL was small, with no statistically significant difference (risk ratio (RR) 0.52, 95% confidence interval (CI) 0.16 to 1.67). There were no cases of retained placenta in either group. The mean blood loss was significantly less in the uterine massage group at 30 minutes (mean difference (MD) -41.60 mL, 95% CI -75.16 to -8.04) and 60 minutes after trial entry (MD -77.40 mL, 95% CI -118.71 to -36.09). The need for additional uterotonics was significantly reduced in the uterine massage group (RR 0.20, 95% CI 0.08 to 0.50).For use of uterine massage before and after delivery of the placenta, one trial recruited 1964 women in Egypt and South Africa. Women were assigned to receive oxytocin, uterine massage or both after delivery of the baby but before delivery of the placenta. There was no added benefit for uterine massage plus oxytocin over oxytocin alone as regards blood loss greater than or equal to 500 mL (average RR 1.56, 95% CI 0.44, 5.49; random-effects) or need for additional use of uterotonics (RR 1.02, 95% CI 0.56 to 1.85).The two trials were combined to examine the effect of uterine massage commenced either before or after delivery of the placenta. There was substantial heterogeneity with respect to the blood loss 500 mL or more after trial entry. The average effect using a random-effects model found no statistically significant differences between groups (average RR 1.14, 95% CI 0.39 to 3.32; random-effects)., Authors' Conclusions: The results of this review are inconclusive, and should not be interpreted as a reason to change current practice. Due to the limitations of the included trials, more trials with sufficient numbers of women are needed in order to estimate the effects of sustained uterine massage. All the women compared in this review received oxytocin as part of the active management of labour. Recent research suggests that once an oxytocic has been given, there is limited scope for further reduction in postpartum blood loss. Trials of uterine massage in settings where uterotonics are not available, and which measure women's experience of the procedure, are needed.

Background: Prostaglandins have mainly been used for postpartum haemorrhage (PPH) when other measures fail. Misoprostol, a new and inexpensive prostaglandin E1 analogue, has been suggested as an alternative for routine management of the third stage of labour., Objectives: To assess the effects of prophylactic prostaglandin use in the third stage of labour., Search Methods: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (7 January 2011). We updated this search on 25 May 2012 and added the results to the awaiting classification section., Selection Criteria: Randomised trials comparing a prostaglandin agent with another uterotonic or no prophylactic uterotonic (nothing or placebo) as part of management of the third stage of labour. The primary outcomes were blood loss 1000 mL or more and the use of additional uterotonics., Data Collection and Analysis: Two review authors independently assessed eligibility and trial quality and extracted data., Main Results: We included 72 trials (52,678 women). Oral or sublingual misoprostol compared with placebo is effective in reducing severe PPH (oral: seven trials, 6225 women, not totalled due to significant heterogeneity; sublingual: risk ratio (RR) 0.66; 95% confidence interval (CI) 0.45 to 0.98; one trial, 661 women) and blood transfusion (oral: RR 0.31; 95% CI 0.10 to 0.94; four trials, 3519 women).Compared with conventional injectable uterotonics, oral misoprostol was associated with higher risk of severe PPH (RR 1.33; 95% CI 1.16 to 1.52; 17 trials, 29,797 women) and use of additional uterotonics, but with a trend to fewer blood transfusions (RR 0.84; 95% CI 0.66 to 1.06; 15 trials; 28,213 women). Additional uterotonic data were not totalled due to heterogeneity. Misoprostol use is associated with significant increases in shivering and a temperature of 38º Celsius compared with both placebo and other uterotonics., Authors' Conclusions: Oral or sublingual misoprostol shows promising results when compared with placebo in reducing blood loss after delivery. The margin of benefit may be affected by whether other components of the management of the third stage of labour are used or not. As side-effects are dose-related, research should be directed towards establishing the lowest effective dose for routine use, and the optimal route of administration.Neither intramuscular prostaglandins nor misoprostol are preferable to conventional injectable uterotonics as part of the management of the third stage of labour especially for low-risk women; however, evidence has been building for the use of oral misoprostol to be effective and safe in areas with low access to facilities and skilled healthcare providers and future research on misoprostol use in the community should focus on implementation issues.

Objective: To assess the effectiveness and safety of the administration of misoprostol, an orally active prostaglandin, in addition to routine uterotonic therapy as part of the active management of the third stage of labor., Methods: The present study was a hospital-based, decentralized, multi-center, randomized, placebo-controlled, double-blind trial. We enrolled 1103 women (out of a target sample size of 1180) at 4 hospitals in South Africa, Uganda, and Nigeria. Participants received a sublingual dose of 400 μg of misoprostol or a placebo, in addition to standard active management of the third stage of labor, after vaginal birth., Results: The baseline characteristics of the participants were comparable. The difference in the primary outcome of blood loss of 500 mL or more within 1 hour of randomization was not significant between the 2 groups (misoprostol 22/546 [4.0%] versus placebo 35/553 [6.3%]; relative risk, 0.64; 95% confidence interval, 0.38-1.07). Shivering and pyrexia occurred more frequently in the misoprostol group. No maternal deaths occurred., Conclusion: The present study did not confirm a beneficial effect of administering 400 μg of misoprostol, in addition to routine uterotonic therapy, during the third stage of labor, but was consistent with other trials showing a cumulative modest benefit. Where routine uterotonics are available for prophylactic use, any potential benefit of misoprostol might not outweigh the likelihood of adverse effects., (Copyright © 2010 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd. All rights reserved.)

Objective: To determine the effectiveness of sustained uterine massage started before delivery of the placenta in reducing postpartum hemorrhage., Methods: A randomized controlled trial conducted in Egypt and South Africa between September 2006 and February 2009. A total of 1964 pregnant women were randomly allocated to 1 of 3 treatment groups: intramuscular oxytocin, sustained uterine massage, or both treatments. Blood loss within 30 minutes of delivery was recorded., Results: The incidence of blood loss of 300 mL or more within 30 minutes of delivery was significantly higher in the massage group than in the massage plus oxytocin (RR 1.88; 95% CI, 1.29-2.74 in Assiut, and RR 1.3; 95% CI, 1.00-1.68 in SA) and the oxytocin only group (RR 1.7; 95% CI, 1.11-2.61 in Assiut, and RR 2.24; 95% CI, 1.54-3.27 in SA). In both centers, use of additional uterotonics was significantly higher in the uterine massage group compared with the other 2 groups., Conclusion: Uterine massage was less effective than oxytocin for reducing blood loss after delivery. When oxytocin was used, there was no additional benefit from uterine massage. The effectiveness of uterine massage in the absence of oxytocin was not studied. ACTRN: 12609000372280., (Copyright © 2010 International Federation of Gynecology and Obstetics. Published by Elsevier Ireland Ltd. All rights reserved.)

Background: Postpartum haemorrhage (PPH) is a common and occasionally life-threatening complication of labour. Several options for preventing PPH are available, but further advances in this field are important, especially the identification of safe, easy to use, and cost-effective regimes. Tranexamic acid, which is an antifibrinolytic that is used widely to prevent and treat haemorrhage, merits evaluation to assess whether it meets these criteria., Objectives: To determine, from the best available evidence, whether tranexamic acid is effective for preventing PPH., Search Strategy: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (12 September 2009)., Selection Criteria: All published, unpublished and ongoing randomised controlled trials (RCTs) evaluating the use of tranexamic acid alone or in addition to uterotonics in the third stage of labour or during caesarean section to prevent PPH., Data Collection and Analysis: Two review authors independently assessed for inclusion all the potential studies identified as a result of the search strategy. We entered the data into Review Manager software and checked for accuracy., Main Results: We included two RCTs. One RCT of unclear quality of 273 women compared tranexamic acid in two doses (0.5 g intravenously and 1 g intravenously) with aminomethylbenzoic acid (0.5 g intravenously) and with no treatment in women who had vaginal birth. We excluded the aminomethylbenzoic acid arm of this trial (92 patients).Another RCT of 180 women who underwent caesarean section compared tranexamic acid (1 g intravenously given 10 minutes before incision) with placebo.Blood loss greater than 400 ml was less common in women who received tranexamic acid after vaginal birth or caesarean section in the dosage of 1 g or 0.5 g intravenously (two studies, 453 women, risk ratio (RR) 0.51, 95% confidence interval (CI) 0.36 to 0.72). Mean blood loss was lower in the group of women who received intravenous tranexamic acid postpartum (two studies, 361 women, mean difference (MD) -75.17 ml, 95% CI -108.23 ml to -42.12 ml).No serious side effects were reported in women who received tranexamic acid in these trials., Authors' Conclusions: Tranexamic acid decreases postpartum blood loss after vaginal birth and after caesarean section based on two RCTs of unclear quality which reported on only a few outcomes. Further investigations are needed on efficacy and safety of this regimen for preventing PPH.

Background: Post-partum haemorrhage is a leading cause of global maternal morbidity and mortality. Misoprostol, a prostaglandin analogue with uterotonic activity, is an attractive option for treatment because it is stable, active orally, and inexpensive. We aimed to assess the effectiveness of misoprostol as an adjunct to standard uterotonics compared with standard uterotonics alone for treatment of post-partum haemorrhage., Methods: Women delivering vaginally who had clinically diagnosed post-partum haemorrhage due to uterine atony were enrolled from participating hospitals in Argentina, Egypt, South Africa, Thailand, and Vietnam between July, 2005, and August, 2008. Computer-generated randomisation was used to assign women to receive 600 microg misoprostol or matching placebo sublingually; both groups were also given routine injectable uterotonics. Allocation was concealed by distribution of sealed and sequentially numbered treatment packs in the order that women were enrolled. Providers and women were masked to treatment assignment. The primary outcome was blood loss of 500 mL or more within 60 min after randomisation. Analysis was by intention to treat. This study is registered, number ISRCTN34455240., Findings: 1422 women were assigned to receive misoprostol (n=705) or placebo (n=717). The proportion of women with blood loss of 500 mL or more within 60 min was similar between the misoprostol group (100 [14%]) and the placebo group (100 [14%]; relative risk 1.02, 95% CI 0.79-1.32). In the first 60 min, an increased proportion of women on misoprostol versus placebo, had shivering (455/704 [65%] vs 230/717 [32%]; 2.01, 1.79-2.27) and body temperature of 38 degrees C or higher (303/704 [43%] vs 107/717 [15%]; 2.88, 2.37-2.50)., Interpretation: Findings from this study do not support clinical use of 600 microg sublingual misoprostol in addition to standard injectable uterotonics for treatment of post-partum haemorrhage., Funding: Bill & Melinda Gates Foundation, and UNDP/UNFPA/WHO/World Bank Special Programme of Research, Development and Research Training in Human Reproduction., (Copyright 2010 Elsevier Ltd. All rights reserved.)

Objective: To review maternal deaths and the dose-related effects of misoprostol on blood loss and pyrexia in randomized trials of misoprostol use for the prevention or treatment of postpartum haemorrhage., Methods: We searched the Cochrane Controlled Trials Register and Pubmed, without language restrictions, for '(misoprostol AND postpartum) OR (misoprostol AND haemorrhage) OR (misoprostol AND hemorrhage)', and we evaluated reports identified through the Cochrane Pregnancy and Childbirth Group search strategy. Randomized trials comparing misoprostol with either placebo or another uterotonic to prevent or treat postpartum haemorrhage were checked for eligibility. Data were extracted, tabulated and analysed with Reviewer Manager (RevMan) 4.3 software., Findings: We included 46 trials with more than 40,000 participants in the final analysis. Of 11 deaths reported in 5 trials, 8 occurred in women receiving >or= 600 microg of misoprostol (Peto odds ratio, OR: 2.49; 95% confidence interval, CI: 0.76-8.13). Severe morbidity, defined as the need for major surgery, admission to intensive care, organ failure or body temperature >or= 40 degrees C, was relatively infrequent. In prevention trials, severe morbidity was experienced by 16 of 10,281 women on misoprostol and by 16 of 10,292 women on conventional uterotonics; in treatment trials, it was experienced by 1 of 32 women on misoprostol and by 1 of 32 women on conventional uterotonics. Misoprostol recipients experienced more adverse events than placebo recipients: 8 of 2070 versus 5 of 2032, respectively, in prevention trials, and 5 of 196 versus 2 of 202, respectively, in treatment trials. Meta-analysis of direct and adjusted indirect comparisons of the results of randomized trials showed no evidence that 600 microg are more effective than 400 microg for preventing blood loss > 1000 ml (relative risk, RR: 1.02; 95% CI: 0.71-1.48). Pyrexia was more than twice as common among women who received > 600 microg rather than 400 microg of misoprostol (RR: 2.53; 95% CI: 1.78-3.60)., Conclusion: Further research is needed to more accurately assess the potential beneficial and harmful effects of misoprostol and to determine the smallest dose that is effective and safe. In this review, 400 microg of misoprostol were found to be safer than > 600 microg and just as effective.

Postpartum haemorrhage (PPH) causes preventable maternal deaths, mainly in low-income countries. Misoprostol has powerful uterotonic effects and, because it is well absorbed orally and sublingually, has the potential to be used more widely than would be possible with injectable uterotonics alone. Misoprostol is clearly less effective than oxytocin. Placebo-controlled studies have had variable results, although two recent trials in low-income communities have shown promising results. The main recognized side effects have been dose-related pyrexia and shivering, including occasional hyperpyrexia. In the randomized trials reported to date, there has been a trend to more deaths with misoprostol than with the control groups. The dose that has been most commonly used in clinical trials for preventing PPH is 600 microg orally. Meta-analysis of direct and adjusted indirect comparisons between 600 and 400 microg showed very similar effectiveness. To date, there is very limited evidence for the effectiveness of misoprostol, the lowest effective dose and the magnitude of adverse effects, both direct and indirect. The need for further research is a matter of great urgency.

Background: Postpartum haemorrhage (PPH) (bleeding from the genital tract after childbirth) is a major cause of maternal mortality and disability, particularly in under-resourced areas. In these settings, poor nutrition, malaria and anaemia may aggravate the effects of PPH. In addition to the standard known strategies to prevent and treat PPH, there is a need for simple, non-expensive techniques which can be applied in low-resourced settings to prevent or treat PPH., Objectives: To determine the effectiveness of uterine massage after birth and before or after delivery of the placenta, or both, to reduce postpartum blood loss and associated morbidity and mortality., Search Strategy: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (March 2008), the Cochrane Central Register of Controlled Trials (The Cochrane Library 2007, Issue 2) and PubMed (1966 to June 2007)., Selection Criteria: All published, unpublished and ongoing randomised controlled trials comparing uterine massage alone or in addition to uterotonics before or after delivery of the placenta, or both, to non-massage., Data Collection and Analysis: Both authors extracted the data independently using the agreed form., Main Results: One randomised controlled trial in which 200 women were randomised to receive uterine massage or no massage after active management of the third stage of labour. The numbers of women with blood loss more than 500 ml was small, with wide confidence intervals and no statistically significant difference (risk ratio (RR) 0.52, 95% confidence interval (CI) 0.16 to 1.67). There were no cases of retained placenta in either group. The mean blood loss was less in the uterine massage group at 30 minutes (mean difference (MD) -41.60, 95% CI -75.16 to -8.04) and 60 minutes after enrolment (MD -77.40, 95% CI -118.71 to -36.09 ml) . The need for additional uterotonics was reduced in the uterine massage group (RR 0.20, 95% CI 0.08 to 0.50). Two blood transfusions were administered in the control group., Authors' Conclusions: The present review adds support to the 2004 joint statement of the International Confederation of Midwives and the International Federation of Gynaecologists and Obstetricians on the management of the third stage of labour, that uterine massage after delivery of the placenta is advised to prevent PPH. However, due to the limitations of the one trial reviewed, trials with sufficient numbers to estimate the effects of sustained uterine massage with great precision, both with and in the absence of uterotonics, are needed.

Objective: To assess the effects of prophylactic misoprostol use in the third stage of labor compared with injectable uterotonics or placebo or no treatment., Data Sources: The Cochrane Pregnancy and Childbirth Group trials register; the Cochrane Library, including databases such as the database of systematic reviews and the Cochrane Controlled Trials Register; and MEDLINE were searched. Researchers in the field were also contacted. The date of the latest search was March 1, 2002., Methods of Study Selection: Randomized trials comparing misoprostol with injectable oxytocin or oxytocin-ergot preparations to prevent postpartum hemorrhage or placebo/no treatment as active management of the third stage of labor were eligible for inclusion. Eligibility and trial quality were assessed following selected criteria. Data were extracted and analyzed using RevMan software., Tabulation, Integration, and Results: Sixteen randomized trials with a total of 28,138 women were considered. Data were available for 27,498 women. Oral misoprostol (600 microg) is less effective than injectable uterotonics in reducing blood loss at least 1000 mL (relative risk [RR] 1.36, 95% confidence interval [CI] 1.17, 1.58) and increases the use of additional uterotonics. Shivering and pyrexia (temperature greater than 38C) are the main side effects of misoprostol and are dose related. Compared with injectable uterotonics, the RR of "any shivering" with misoprostol (600 microg) is 3.27 (95% CI 3.01, 3.56) and pyrexia is 6.96 (95% CI 5.65, 8.57). The RR of blood loss of 500 mL or more is 1.11 (95% CI 0.87, 1.43) and the RR of use of additional uterotonics is 1.80 (1.13, 2.85) in the three trials (1441 women) comparing rectal misoprostol (400 microg) with injectable uterotonics., Conclusion: Injectable oxytocin or oxytocin-ergot preparations are more effective than misoprostol as part of the active management of the third stage of labor.

The use of tranexamic acid for postpartum hemorrhage has entered obstetric practice globally with the evidence-based expectation of saving lives. This improvement in the care of women with postpartum hemorrhage has come at a price. For the anesthetist, having tranexamic acid ampoules close at hand would seem an obvious strategy to facilitate its use during caesarean delivery, an important setting for severe hemorrhage. Tragically, we have identified a number of recent instances of inadvertent intrathecal administration of tranexamic acid instead of local anesthetic for spinal anesthesia. Reported cases of this catastrophic error appear to be increasing. The profound neurotoxicity of tranexamic acid causes rapid-onset convulsions, with mortality of 50%. How can these tragic errors be averted? Drug safety alerts have been issued by the US Food and Drug Administration and the World Health Organization, but that is not enough. We recommend extensive dissemination of information to raise awareness of this potential hazard; and local hospital protocols to ensure that tranexamic acid is stored separately from anesthetic drugs, preferably outside the operating room and with an auxiliary warning label. Implementation of safety strategies on a very large scale will be needed to ensure that the life-saving potential of tranexamic acid is not eclipsed by drug error mortality. [ABSTRACT FROM AUTHOR]

Abstract: Objective: To assess the effectiveness and safety of the administration of misoprostol, an orally active prostaglandin, in addition to routine uterotonic therapy as part of the active management of the third stage of labor. Methods: The present study was a hospital-based, decentralized, multi-center, randomized, placebo-controlled, double-blind trial. We enrolled 1103 women (out of a target sample size of 1180) at 4 hospitals in South Africa, Uganda, and Nigeria. Participants received a sublingual dose of 400μg of misoprostol or a placebo, in addition to standard active management of the third stage of labor, after vaginal birth. Results: The baseline characteristics of the participants were comparable. The difference in the primary outcome of blood loss of 500mL or more within 1 hour of randomization was not significant between the 2 groups (misoprostol 22/546 [4.0%] versus placebo 35/553 [6.3%]; relative risk, 0.64; 95% confidence interval, 0.38–1.07). Shivering and pyrexia occurred more frequently in the misoprostol group. No maternal deaths occurred. Conclusion: The present study did not confirm a beneficial effect of administering 400μg of misoprostol, in addition to routine uterotonic therapy, during the third stage of labor, but was consistent with other trials showing a cumulative modest benefit. Where routine uterotonics are available for prophylactic use, any potential benefit of misoprostol might not outweigh the likelihood of adverse effects. Trial registered on clinical trials.gov: NCT 00124540. [Copyright &y& Elsevier]