Heat stable carbetocin or oxytocin for prevention of postpartum hemorrhage among women at risk: A secondary analysis of the CHAMPION trial.

OBJECTIVE: To examine whether the observed non-inferiority of heat-stable carbetocin (HSC), compared with oxytocin, was influenced by biologic (macrosomia, parity 3 or more, or history of postpartum hemorrhage [PPH]) and/or pharmacologic (induction or augmentation) risk factors for PPH. METHODS: The present study is a secondary analysis of the CHAMPION non-inferiority randomized trial-a two-arm, double-blind, active-controlled study conducted at 23 hospitals in 10 countries, between July 2015 and January 2018. Women with singleton pregnancies, expected to deliver vaginally with cervical dilatation up to 6 cm were eligible. Randomization was stratified by country, with 1:1 assignment. Women in the intervention and control groups received a single intramuscular injection of 100 µg of HSC or 10 IU of oxytocin, respectively. The drugs were administered immediately after birth, and the third stage of labor was managed according to the WHO guidelines. Blood was collected using a plastic drape. For this analysis, we defined a woman as being at risk if she had any one or more of the biologic or pharmacologic risk factor(s). RESULTS: The HSC and oxytocin arms contained 14 770 and 14 768 women, respectively. The risk ratios (RR) for PPH were 1.29 (95% confidence interval [CI] 1.08-1.53) or 1.73 (95% CI 1.51-1.98) for those with only biologic (macrosomia, parity 3 or more, and PPH in the previous pregnancy) or only pharmacologic (induced or augmented) risk factors, respectively, compared with those with neither risk factors. CONCLUSIONS: Findings reinforce previous evidence that macrosomia, high parity, history of PPH, and induction/augmentation are risk factors for PPH. We did not find a difference in effects between HSC and oxytocin for PPH among women who were neither induced nor augmented or among those who were induced or augmented.

Challenges in updating national guidelines and essential medicines lists in Sub-Saharan African countries to include WHO-recommended postpartum hemorrhage medicines.

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.

Implementing Heat-Stable Carbetocin for Postpartum Haemorrhage Prevention in Low-Resource Settings: A Rapid Scoping Review.

Heat-stable carbetocin (HSC), a long-acting oxytocin analogue that does not require cold-chain transportation and storage, is effective in preventing postpartum haemorrhage (PPH) in vaginal and caesarean deliveries in tertiary-care settings. We aimed to identify literature documenting how it is implemented in resource-limited and lower-level maternity care settings to inform policies and practices that enable its introduction in these contexts. A rapid scoping review was conducted with an 8-week timeframe by two reviewers. MEDLINE, EMBASE, Emcare, the Joanna Briggs Institute Evidence-Based Practice Database, the Maternity and Infant Care Database, and the Cochrane Library were searched for publications in English, French, and Spanish from January 2011 to September 2021. Randomized and non-randomized studies examining the feasibility, acceptability, and health system considerations in low-income and lower-middle-income countries were included. Relevant data were extracted using pretested forms, and results were synthesized descriptively. The search identified 62 citations, of which 12 met the eligibility criteria. The review did not retrieve studies focusing on acceptability and health system considerations to inform HSC implementation in low-resource settings. There were no studies located in rural or lower-level maternity settings. Two economic evaluations concluded that HSC is not feasible in terms of cost-effectiveness in lower-middle-income economies with private sector pricing, and a third one found superior care costs in births with PPH than without. The other nine studies focused on demonstrating HSC effectiveness for PPH prevention in tertiary hospital settings. There is a lack of evidence on the feasibility (beyond cost-effectiveness), acceptability, and health system considerations related to implementing HSC in resource-constrained and lower-level maternity facilities. Further implementation research is needed to help decision-makers and practitioners offer an HSC-inclusive intervention package to prevent excessive bleeding among pregnant women living in settings where oxytocin is not available or of dubious quality.

Effect of heat stable carbetocin vs oxytocin for preventing postpartum haemorrhage on post delivery hemoglobin-a randomized controlled trial.

OBJECTIVE: To compare the effect of heat-stable carbetocin 100 µg IM versus oxytocin 10 IU IM on post-delivery hemoglobin level. SETTING: Hospital based study in Southern India. POPULATION: Women delivering vaginally who were enrolled in the WHO CHAMPION trial in a single facility in India. WHO CHAMPION Trial was a randomized, double-blind, noninferiority trial comparing intramuscular injections of heat-stable carbetocin with oxytocin administered immediately after vaginal birth in women across 23 sites in 10 countries. METHODS: This was a nested randomized controlled trial designed to compare the effect of heat-stable carbetocin 100 µg IM versus oxytocin 10 IU IM, administered within one minute of vaginal delivery of the baby for prevention of postpartum hemorrhage, on post-delivery 48-72 h hemoglobin level, adjusted for pre-delivery hemoglobin level. 1,799 women from one hospital in India participated in this study. RESULTS: Pre-delivery hemoglobin and postpartum blood loss were not significantly different between carbetocin and oxytocin. Post-delivery hemoglobin, unadjusted or adjusted for pre-delivery hemoglobin, was slightly lower for carbetocin (10.09 g/dL) compared to oxytocin (10.21) (p value of 0.0432). The drop in hemoglobin was slightly higher for carbetocin, although the difference was very small (1.2 g/dL for carbetocin, 1.1 g/dL for oxytocin) (p value of .0786). The proportion of participants with a drop in hemoglobin of 2 g/dL or more, adjusted for pre-delivery hemoglobin, was higher for carbetocin (RR = 1.29, 95% CI 1.02-1.63). From the regression coefficients it can be derived that post-delivery hemoglobin, adjusted for pre-delivery hemoglobin, decreases on average 0.12 g/dL for each dL of blood lost, for the two treatments combined. CONCLUSION: The present ancillary study showed that intramuscular administration of 100 µg of heat stable carbetocin can result in a slightly lower post-delivery hemoglobin, slightly higher drop and higher percentage of women having a drop of 2 g/dL or larger, compared to 10 IU of oxytocin.

Duration of third stage labour and postpartum blood loss: a secondary analysis of the WHO CHAMPION trial data.

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.

The duration of the third stage of labour (TSL) seems to be an important risk factor for greater postpartum blood loss, as literature shows that a longer TSL can be associated with more blood loss. Active management of third stage of labour (AMTSL), included in the WHO guidelines for prevention of postpartum haemorrhage (PPH), is effective in reducing both the amount of postpartum blood loss and the duration of the third stage. To better describe the association between duration of TSL and postpartum blood loss in women receiving AMTSL, we conducted this secondary analysis of WHO CHAMPION trial data.To assess the association between the duration of third stage of labour and postpartum blood loss, a subcohort of the CHAMPION modified ITT population was selected by excluding women with missing blood loss or missing TSL duration or TSL duration more than 60 min and women with interventions. Thus, the subcohort consisted of 10,040 women.In women with vaginal birth and not receiving interventions for treating atonic PPH or other sources of bleeding, and with TSL duration up to 60 min, there was a positive association between duration of the TSL and postpartum blood loss. The blood loss rose steeply with duration in women with TSL of 10 min or less, while in women with longer TSL duration the slope was less steep.There was no evidence of a difference between oxytocin and HS carbetocin in the pattern of association of duration of the TSL and blood loss.

Cost of hospital care of women with postpartum haemorrhage in India, Kenya, Nigeria and Uganda: a financial case for improved prevention.

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.