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Despite the 2017 WHO recommendations on tranexamic acid (TXA) for the treatment of postpartum hemorrhage (PPH), the 2018 uterotonic recommendations (which included heat-stable carbetocin (HSC) for the prevention of PPH) and their inclusion in the WHO Essential Medicines List (EML), both drugs are still underused or not used at all to manage PPH in many countries with a high burden. HSC is currently being registered in low- and middle-income countries and its policy inclusion is limited and slow. TXA (also heat stable) is available in many countries but is not registered for PPH treatment, which may have contributed to the delay in its inclusion in national guidelines and EMLs. For both drugs, national guidelines will need to be revised and updated for their optimal uptake. We implemented an advocacy initiative to accelerate the necessary normative policy change to ensure access to quality-assured and heat-stable medicines for the prevention and treatment of PPH in Sub-Saharan African countries. Our initiative aimed to raise awareness of the importance of recently recommended medicines for the prevention and treatment of PPH and support the process to update PPH guidelines and EMLs to include these drugs. We highlight the lessons learned during the initiative, including the challenges and opportunities identified in updating PPH policies at the national level., (© 2022 Concept Foundation. International Journal of Gynecology & Obstetrics published by John Wiley & Sons Ltd on behalf of International Federation of Gynecology and Obstetrics.)

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: A significant barrier to improving prevention and treatment of postpartum hemorrhage (PPH) is a lack of innovative medicines that meet the needs of women and providers, particularly those in low-and middle-income countries (LMICs). The Accelerating Innovation for Mothers (AIM) project established a new database of candidate medicines under development for five pregnancy-related conditions between 2000 and 2021., Objective: To systematically identify and rank candidates for prevention and treatment of PPH., Search Strategy: Adis Insight, Pharmaprojects, WHO ICTRP, PubMed, and grant databases were searched to develop the AIM database., Selection Criteria: AIM database was searched for candidates being evaluated for PPH prevention and treatment, regardless of phase., Data Collection and Analysis: Candidates were ranked as high, medium, or low potential based on prespecified criteria. Analysis was primarily descriptive, describing candidates and development potential., Main Results: Of the 444 unique candidates, only 39 pertained to PPH. One was high potential (heat-stable/inhaled oxytocin) and three were medium potential (melatonin, vasopressin and dofetilide via nanoparticle delivery)., Conclusion: The pipeline for new PPH medicines is concerningly limited, lacking diversity, and showing little evidence of novel technologies. Without significant investment in early-phase research, it is unlikely that new products will emerge., (© 2022 The Authors. International Journal of Gynecology & Obstetrics published by John Wiley & Sons Ltd on behalf of International Federation of Gynecology and Obstetrics.)

Objective: Access to quality, effective lifesaving uterotonics in low and middle-income countries (LMICs) remains a major barrier to reducing maternal deaths from postpartum haemorrhage (PPH). Our objective was to assess the costs of care for women who receive different preventative uterotonics, and with PPH and no-PPH so that the differences, if significant, can inform better resource allocation for maternal health care., Methods: The costs of direct hospital care of women who received oxytocin or heat-stable carbetocin for prevention of PPH in selected tertiary care facilities in India, Kenya, Nigeria, and Uganda were assessed. We collected data from all women who had PPH, as well as a random sample of women without PPH. Cost data was collected for the cost of stay, PPH interventions, transfusions and medications for 2966 women. We analyzed the difference in cost of care at a facility level between women who experienced a PPH event and those who did not. Key findings The mean cost of care of a woman experiencing PPH in the study sites in India, Kenya, Nigeria, and Uganda exceeded the cost of care of a woman who did not experience PPH by between 21% and 309%. There was a large variation in cost across hospitals within a country and across countries., Conclusion: Our results quantify the increased cost of PPH of up to 4.1 times that for a birth without PPH. PPH cost information can help countries to evaluate options across different conditions and in the formulation of appropriate guidelines for intrapartum care, including rational selection of quality-assured, effective medicines. This information can be applied to national assessment and adaptation of international recommendations such as the World Health Organization's recommendations on uterotonics for the prevention of PPH or other interventions used to treat PPH. Trial registration HRP Trial A65870; UTN U1111-1162-8519; ACTRN12614000870651; CTRI/2016/05/006969, EUDRACT 2014-004445-26. Date of registration 14 August 2014 Access to quality, effective lifesaving medicines in low and middle-income countries remains a major barrier to reducing maternal deaths from bleeding after childbirth. Information on to what extent treatments for bleeding increases the cost of care of women after childbirth is important for informed resource allocation. We collected data from all women who had bleeding after childbirth, as well as a random sample of women without bleeding in selected hospitals in India, Kenya, Nigeria, and Uganda. Cost data was collected for the cost of stay and interventions to manage bleeding for 2966 women. We compared the difference in cost of care between women who experienced a bleeding event and those who did not. The mean cost of care of a woman with bleeding in the study sites exceeded the cost of care of a woman who did not experience PPH by between 21% and 309%. There was a large variation in cost across hospitals within a country and across countries. Our results indicate an increased cost of bleeding of up to 4.1 times that for birth without bleeding. Effective prevention reduces the cost of care. Cost information can help countries to evaluate options across different conditions and in the formulation of appropriate guidelines for intrapartum care, including rational selection of quality-assured, effective medicines. This information can be applied to national assessment and adaptation of international recommendations such as the World Health Organization's recommendations on medications for the prevention of bleeding after childbirth or other interventions used to treat bleeding.

Background: The loss of large amounts of blood postpartum can lead to severe maternal morbidity and mortality. Understanding the nature of postpartum blood loss distribution is critical for the development of efficient analysis techniques when comparing treatments to prevent this event. When blood loss is measured, resulting in a continuous volume measure, often this variable is categorized in classes, and reduced to an indicator of volume greater than a cutoff point. This reduction of volume to classes entails a substantial loss of information. As a consequence, very large trials are needed to assess clinically important differences between treatments to prevent postpartum haemorrhage., Methods: The authors explore the nature of postpartum blood loss distribution, assuming that the physical properties of blood loss lead to a lognormal distribution. Data from four clinical trials and one observational study are used to confirm this empirically. Estimates of probabilities of postpartum haemorrhage events 'blood loss greater than a cutoff point' and relative risks are obtained from the fitted lognormal distributions. Confidence intervals for relative risk are obtained by bootstrap techniques., Results: A variant of the lognormal distribution, the three-parameter lognormal distribution, showed an excellent fit to postpartum blood loss data of the four trials and the observational study. A measurement quality assessment showed that problems of digit preference and lower limit of detection were well handled by the lognormal fit. The analysis of postpartum haemorrhage events based on a lognormal distribution improved the efficiency of the estimates. Sample size calculation for a hypothetical future trial showed that the application of this procedure permits a reduction of sample size for treatment comparison., Conclusion: A variant of the lognormal distribution fitted very well postpartum blood loss data from different geographical areas, suggesting that the lognormal distribution might fit postpartum blood loss universally. An approach of analysis of postpartum haemorrhage events based on the lognormal distribution improves efficiency of estimates of probabilities and relative risk, and permits a reduction of sample size for treatment comparison., Trial Registration: This paper reports secondary analyses for trials registered at Australian New Zealand Clinical Trials Registry (ACTRN 12608000434392 and ACTRN12614000870651); and at clinicaltrials.gov (NCT00781066).

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 .).

Background: Although there are a growing number of initiatives aimed at supporting guideline implementation in resource-constrained settings, few studies assess progress on achieving next steps and goals after the initial activities are completed and the initial funding period has ended. The aim of the current study was to conduct a qualitative process evaluation of progress, barriers, facilitators, and proposed solutions to operationalize nine recommendations to prepare Kosovo to implement the 2012 World Health Organization (WHO) prevention and treatment of postpartum haemorrhage guideline., Methods/design: In 2012, we co-created nine recommendations designed to support implementing the WHO's guideline on the prevention and treatment of postpartum haemorrhage in Kosovo. The current study uses a realist evaluation approach to assess activities and progress two years after the recommendations were developed. The study involved conducting qualitative focus groups and one-on-one interviews with participants from the first meeting to evaluate the activities and progress on the nine recommendations., Results: Forty-three participants provided insights into the barriers and opportunities experienced to date and proposed future directions. Although progress has been made towards implementation of a number of the recommendations, scaling up has been limited by barriers, such as lack of awareness, limited resources, and evaluation challenges. Participants proposed addressing these barriers by building within- and between-country partnerships to facilitate guideline implementation. In addition, participants reported less progress on implementing recommendations related to broader cultural changes, which indicates a need for specific and actionable recommendations to operationalize implementation efforts., Conclusions: In the two years since the initial meeting, there has been mixed progress on the recommendations. Based on participant feedback, we refined the recommendations so that they can be operationalized by health care system stakeholders in Kosovo to further support implementation efforts. It is beneficial to share these lessons learned throughout the implementation process to inform next steps in Kosovo and offer ideas for use in other settings.

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).

Recent efforts to prevent post-partum haemorrhage (PPH) in low-income countries have focused on providing women with access to oral misoprostol during home birth. The WHO recommends using lay health workers (LHWs) to administer misoprostol in settings where skilled birth attendants are not available. This review synthesizes current knowledge about the barriers and facilitators affecting implementation of advance community distribution of misoprostol to prevent PPH, where misoprostol may be self-administered or administered by an LHW.We searched for and summarized available empirical evidence, and collected primary data from programme stakeholders about their experiences of programme implementation.We present key outcomes and features of advanced distribution programmes that are in operation or have been piloted globally. We categorized factors influencing implementation into those that operate at the health system level, factors related to the community and policy context and those factors more closely connected to the end user.Debates around advance distribution have centred on the potential risks and benefits of making misoprostol available to pregnant women and community members during pregnancy for administration in the home. However, the risks of advance distribution appear manageable and the benefits of self-administration, especially for women who have little chance of expert care for PPH, are considerable., (© The Author 2015. Published by Oxford University Press in association with The London School of Hygiene and Tropical Medicine.)

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: 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 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.

Objective: To evaluate the side effects of 600 microg misoprostol orally during the first 24 hours after administration in the third stage of labour., Design: Double blind randomised controlled trial., Setting: Tertiary care hospitals in Nigeria and Thailand., Sample: All women participating in the WHO Misoprostol trial in these two hospitals between January 1, 1999 and June 17, 1999., Methods: All women were followed up during the first 24 hours postpartum to evaluate the occurrence of shivering, nausea, vomiting, diarrhoea and other misoprostol-related side effects., Main Outcome Measures: Rates of shivering, nausea, vomiting, diarrhoea and pyrexia within 1 hour and in the intervals 2-6, 7-12, 13-18 and 19-24 hours after delivery., Results: A total of 1686 women were enrolled. Women who received misoprostol had higher incidence than the oxytocin group of 'any' shivering in the first hour (RR 6.4, 95% CI 3.9 to 10.4) and the period covering 2-6 hours following delivery (RR 4.7, 95% CI 1.9 to 11.2). Pyrexia was also more common in the misoprostol group in both the same time intervals (RR 2.8, 95% CI 1.4 to 5.3 and RR 6.3, 95% CI 3.7 to 10.8, respectively). Diarrhoea was not present in the first hour in either group but appeared in the second time period (2-6 hours) and third time period (7-12 hours) more frequently in the misoprostol group than with oxytocin., Conclusion: The increased incidence of shivering and pyrexia that occurs with postpartum use of misoprostol persists up to 6 hours following delivery. Approximately 5% of women experience diarrhoea that starts after 1 hour and subsides within 12 hours.

Objective: To investigate the compatibility of oxytocin and tranexamic acid injection products when mixed for the purpose of co‐administration by intravenous infusion. Design: Compatibility testing. Setting: Hospitals taking part in a multicentre postpartum haemorrhage treatment (E‐MOTIVE) trial in Kenya, Nigeria, Tanzania and South Africa. Sample: Oxytocin and tranexamic acid products. Methods: The compatibility of two sentinel products of oxytocin injection and tranexamic acid injection in 200‐mL infusion bags of both 0.9% w/v saline and Ringer's lactate solution was assessed. We analysed all tranexamic acid–oxytocin combinations, and each evaluation was conducted for up to 3 h. Subsequently, the compatibility of multiple tranexamic acid products with reference oxytocin products when mixed in 0.9% w/v saline over a period of 1 h was investigated. Main outcome measures: Concentration of oxytocin over time after mixing with tranexamic acid products. Results: We found significant interaction between certain oxytocin and tranexamic acid products after mixing them in vitro and observing for 1 h. The interaction substantially impacted oxytocin content leading to reduction in concentration (14.8%–29.0%) immediately on mixing (t = 0 min). In some combinations, the concentration continued to decline throughout the stability assessment period. Oxytocin loss was observed in 7 out of 22 (32%) of combinations tested. Conclusions: In a clinical setting, mixing certain oxytocin and tranexamic acid products before administration may result in an underdosing of oxytocin, compromising care in an emergency life‐threatening situation. The mixing of oxytocin and tranexamic acid injection products for co‐administration with intravenous infusion fluids should be avoided until the exact nature of the observed interaction and its implications are understood. [ABSTRACT FROM AUTHOR]

An amendment to this paper has been published and can be accessed via the original article. [ABSTRACT FROM AUTHOR]