Strategies for optimising early detection and obstetric first response management of postpartum haemorrhage at caesarean birth: a modified Delphi-based international expert consensus.

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.

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.

What do healthcare providers think of the quality of uterotonics? A mixed-methods systematic review.

OBJECTIVES: To synthesise evidence on the perceptions of healthcare providers (HCPs) about the quality of oxytocin and misoprostol available in their settings, and their actions as a result of these perceptions. DESIGN: Mixed-methods systematic review. ELIGIBILITY CRITERIA: We included quantitative and qualitative studies reporting HCPs' perceptions about oxytocin or misoprostol quality. DATA SOURCES: We searched CINAHL, Cochrane Library, Ebscohost, Embase, PubMed, Global Index Medicus, Portal regional BVS, PsycNET, Scopus and Web of Science from inception to 31 March 2022 and grey literature. RISK OF BIAS: We used the Center for Evidence-Based Management critical appraisal tool for surveys. For qualitative studies, we used the Critical Appraisal Skills Programme tool. DATA EXTRACTION AND SYNTHESIS: Two independent reviewers performed study selection, data extraction and quality assessment. We conducted separate quantitative and qualitative syntheses and integrated the evidence into a narrative synthesis (convergent segregated review design). RESULTS: We included five (three quantitative and two qualitative) studies, of moderate or high quality, conducted in low-income and middle-income countries (LMICs). In the three quantitative studies (N=7065 participants), 8.2-21.3% of HCPs had experienced problems due to known/suspected low-quality oxytocin and 3.3% due to low-quality misoprostol. In the two qualitative studies, perception of oxytocin quality varied. In quantitative studies, when confronted with suspected/known low-quality oxytocin, 29-78% of HCPs would inform a supervisor, 62% would document this in writing, 45-54% would change to another drug and 5-37% would double the dose of oxytocin. Qualitative evidence suggests that many HCPs do not formally report suspected low-quality oxytocin or misoprostol, and use higher doses or additional uterotonics. CONCLUSIONS: A proportion of HCPs from LMICs perceive oxytocin to be of low quality. There is very limited evidence on their perceptions about misoprostol. Many HCPs do not report suspected low-quality uterotonics but change to another medicine or double the dose of oxytocin. PROSPERO REGISTRATION NUMBER: CRD42022323812.

Randomized Trial of Early Detection and Treatment of Postpartum Hemorrhage.

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.).

Treatment selection in multi-arm multi-stage designs: With application to a postpartum haemorrhage trial.

BACKGROUND: Multi-arm multi-stage trials are an efficient, adaptive approach for testing many treatments simultaneously within one protocol. In settings where numbers of patients available to be entered into trials and resources might be limited, such as primary postpartum haemorrhage, it may be necessary to select a pre-specified subset of arms at interim stages even if they are all showing some promise against the control arm. This will put a limit on the maximum number of patients required and reduce the associated costs. Motivated by the World Health Organization Refractory HaEmorrhage Devices trial in postpartum haemorrhage, we explored the properties of such a selection design in a randomised phase III setting and compared it with other alternatives. The objectives are: (1) to investigate how the timing of treatment selection affects the operating characteristics; (2) to explore the use of an information-rich (continuous) intermediate outcome to select the best-performing arm, out of four treatment arms, compared with using the primary (binary) outcome for selection at the interim stage; and (3) to identify factors that can affect the efficiency of the design. METHODS: We conducted simulations based on the refractory haemorrhage devices multi-arm multi-stage selection trial to investigate the impact of the timing of treatment selection and applying an adaptive allocation ratio on the probability of correct selection, overall power and familywise type I error rate. Simulations were also conducted to explore how other design parameters will affect both the maximum sample size and trial timelines. RESULTS: The results indicate that the overall power of the trial is bounded by the probability of 'correct' selection at the selection stage. The results showed that good operating characteristics are achieved if the treatment selection is conducted at around 17% of information time. Our results also showed that although randomising more patients to research arms before selection will increase the probability of selecting correctly, this will not increase the overall efficiency of the (selection) design compared with the fixed allocation ratio of 1:1 to all arms throughout. CONCLUSIONS: Multi-arm multi-stage selection designs are efficient and flexible with desirable operating characteristics. We give guidance on many aspects of these designs including selecting the intermediate outcome measure, the timing of treatment selection, and choosing the operating characteristics.

Tranexamic acid at cesarean delivery: drug-error deaths.

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.

Tranexamic acid at cesarean delivery: Drug-error deaths.

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.

Tranexamic acid at cesarean delivery: drug-error deaths.

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.

Tranexamic acid at cesarean delivery: drug-error deaths.

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.

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.

Route of oxytocin administration for preventing blood loss at caesarean section: a systematic review with meta-analysis.

OBJECTIVES: Assess the effects of different routes of prophylactic oxytocin administration for preventing blood loss at caesarean section (CS). DESIGN: Systematic review and meta-analysis. METHODS: Medline, EMBASE, CINAHL, Cochrane Library, BVS, SciELO and Global Index Medicus were searched through 24 May 2020 for randomised controlled trials (RCTs) comparing different routes of prophylactic oxytocin administration during CS. Study selection, data extraction and quality assessment were conducted by two investigators independently. We pooled results in fixed effects meta-analyses and calculated average risk ratio (RR), mean difference (MD) and 95% CI. We used GRADE to assess the overall quality of evidence for each outcome. RESULTS: Three trials (180 women) were included in the review. All studies compared intramyometrial (IMY) versus intravenous oxytocin in women having prelabour CS. IMY compared with intravenous oxytocin administration may result in little or no difference in the incidence of postpartum haemorrhage (RR 0.14, 95% CI 0.01 to 2.70; N=100 participants; 1 RCT), hypotension (RR 1.00, 95% CI 0.29 to 3.45; N=40; 1 RCT), headache (RR 3.00, 95% CI 0.13 to 69.52; N=40; 1 RCT) or facial flushing (RR 0.50, 95% CI 0.05 to 5.08; N=40; 1 RCT); IMY oxytocin may reduce nausea/vomiting (RR 0.13, 95% CI 0.02 to 0.69; N=140; 2 RCTs). We are very uncertain about the effect IMY versus intravenous oxytocin on the need for additional uterotonics (RR 0.82; 95% CI 0.25 to 2.69; N=140; 2 RCTs). IMY oxytocin may reduce blood loss slightly (MD -57.40 mL, 95% CI -101.71 to -13.09; N=40; 1 RCT). CONCLUSIONS: There is limited, low to very low certainty evidence on the effects of IMY versus intravenous oxytocin at CS for preventing blood loss. The evidence is insufficient to support choosing one route over another. More trials, including studies that assess intramuscular oxytocin administration, are needed on this relevant question. PROSPERO REGISTRATION NUMBER: CRD42020186797.

Timing of oxytocin administration to prevent post-partum hemorrhage in women delivered by cesarean section: A systematic review and metanalysis.

BACKGROUND: There is no consensus on the best timing for prophylactic oxytocin administration during cesarean section (CS) to prevent post-partum hemorrhage (PPH). OBJECTIVES: Assess the effects of administrating prophylactic oxytocin at different times during CS. METHODS: We searched nine databases to identify relevant randomized controlled trials (RCT). We pooled results and calculated average risk ratios (RR), mean differences (MD), and 95% confidence intervals (CI). We used GRADE to assess the overall evidence certainty. RESULTS: We screened 13,389 references and included four trials. We found no statistically significant differences between oxytocin given before versus after fetal delivery on PPH (RR 0.60, 95%CI 0.15-2.47; 1 RCT, N = 300) or nausea/vomiting (RR 1.21, 95%CI 0.69-2.13; 1 RCT, N = 300). There was a significant reduction in the need for additional uterotonics when oxytocin was given immediately before uterine incision versus after fetal delivery (RR 0.37, 95%CI 0.18-0.73; I2 = 0%; 2 RCTs; N = 301). Oxytocin given before fetal delivery significantly reduced intra-operative blood loss (MD -146.77mL, 95%CI -168.10 to -125.43; I2 = 0%; 3 RCTs, N = 601) but did not change the incidence of blood transfusion (RR 0.50, 95%CI 0.13-1.95; I2 = 0%; 2 RCTs, N = 301) or hysterectomy (RR 3.00; 95%CI 0.12-72.77; I2 = 0%; 2 RCTs, N = 301). One trial (N = 100) compared prophylactic oxytocin before versus after placental separation and found no significant differences on PPH, additional uterotonics, or nausea/vomiting. CONCLUSIONS: In women having pre-labor CS, there is limited evidence indicating no significant differences between prophylactic oxytocin given before versus after fetal delivery on PPH, nausea/vomiting, blood transfusion, or hysterectomy. Earlier oxytocin administration may reduce the volume of blood loss and need for additional uterotonics. There is very limited evidence suggesting no significant differences between prophylactic oxytocin given before versus after placental separation on PPH, need for additional uterotonic, or nausea/vomiting. The overall certainty of the evidence was mostly low or very low due to imprecision. Protocol: CRD42020186797.

Healthcare providers experiences of using uterine balloon tamponade (UBT) devices for the treatment of post-partum haemorrhage: A meta-synthesis of qualitative studies.

BACKGROUND: Postpartum haemorrhage (PPH) is a leading cause of maternal mortality and severe morbidity globally. When PPH cannot be controlled using standard medical treatments, uterine balloon tamponade (UBT) may be used to arrest bleeding. While UBT is used by healthcare providers in hospital settings internationally, their views and experiences have not been systematically explored. The aim of this review is to identify, appraise and synthesize available evidence about the views and experiences of healthcare providers using UBT to treat PPH. METHODS: Using a pre-determined search strategy, we searched MEDLINE, CINAHL, PsycINFO, EMBASE, LILACS, AJOL, and reference lists of eligible studies published 1996-2019, reporting qualitative data on the views and experiences of health professionals using UBT to treat PPH. Author findings were extracted and synthesised using techniques derived from thematic synthesis and confidence in the findings was assessed using GRADE-CERQual. RESULTS: Out of 89 studies we identified 5 that met our inclusion criteria. The studies were conducted in five low- and middle-income countries (LMICs) in Africa and reported on the use of simple UBT devices for the treatment of PPH. A variety of cadres (including midwives, medical officers and clinical officers) had experience with using UBTs and found them to be effective, convenient, easy to assemble and relatively inexpensive. Providers also suggested regular, hands-on training was necessary to maintain skills and highlighted the importance of community engagement in successful implementation. CONCLUSIONS: Providers felt that administration of a simple UBT device offered a practical and cost-effective approach to the treatment of uncontrolled PPH, especially in contexts where uterotonics were ineffective or unavailable or where access to surgery was not possible. The findings are limited by the relatively small number of studies contributing to the review and further research in other contexts is required to address wider acceptability and feasibility issues.

Correction: The World Health Organization Fetal Growth Charts: A Multinational Longitudinal Study of Ultrasound Biometric Measurements and Estimated Fetal Weight.

[This corrects the article DOI: 10.1371/journal.pmed.1002220.].

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.

Uterotonic agents for first-line treatment of postpartum haemorrhage: a network meta-analysis.

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®.

Cost-effectiveness of uterine tamponade devices for the treatment of postpartum hemorrhage: A systematic review.

BACKGROUND: Uterine tamponade is widely promoted for treating refractory postpartum hemorrhage (PPH); however, its cost-effectiveness may vary depending on unit costs and setting. OBJECTIVE: To review available data on cost-effectiveness of uterine tamponade devices when used for PPH treatment. SEARCH STRATEGY: PubMed and EMBASE were searched (1980 to January 2020), as well as the National Health Services Economic Evaluation database from inception (1995) to March 2015. SELECTION CRITERIA: Eligible studies were any type of economic evaluation, or effectiveness studies that provided cost or economic data. DATA COLLECTION AND ANALYSIS: Two reviewers independently screened studies, extracted data, and assessed quality. MAIN RESULTS: Eleven studies using a range of devices (condom catheter, uterine suction devices, Bakri, Inpress, Ellavi) were identified. Cost of condom catheter devices or kits ranged from US$0.64 to US$6, whereas purpose-designed device costs were up to US$400. Two studies that took a health system perspective assessed the cost-effectiveness of using uterine balloon tamponade and suggested that it was highly cost-effective because of the low cost per disability-adjusted life-year averted, although both used effect estimates from case series. CONCLUSIONS: Evidence on the cost-effectiveness of uterine tamponade devices was limited and not generalizable. Rigorous economic evaluations based on updated effect estimates are needed.

Quality of medicines for life-threatening pregnancy complications in low- and middle-income countries: A systematic review.

BACKGROUND: There are concerns about the quality of medicines available in low- and middle-income countries (LMIC) to manage hemorrhage, pre-eclampsia/eclampsia and sepsis. We aimed to identify, critically appraise, and synthesize the findings of studies on the quality of these three types of medicines available in LMIC. METHODS: This systematic review searched Medline, EMBASE and LILACS (from inception to 25 May 2020) for studies on the quality of selected medicines available in LMIC that provided at least the amount of active pharmaceutical ingredient. We contacted study authors for additional information. We excluded simulation studies. We used the MEDQUARG tool to assess study quality. The main outcome was the prevalence of failed samples. FINDINGS: We identified 9699 unique citations and included 34 studies (3159 samples from 40 countries) in the review. Most studies (65%) had low quality (scores <6/12). Overall, 48.9% of 1890 uterotonic samples (19 studies) failed quality tests; failures rates were 75% for ergometrine and nearly 40% each for oxytocin and misoprostol. The overall prevalence of failed injectable antibiotics (1090 samples, 18 studies) was 13.4%, ranging from 2.9% for injectable metronidazole (34 samples, 3 studies) to 16.0% for cefazolin (449 samples, 2 studies). The prevalence of low quality magnesium sulphate (179 samples, 2 studies) was 3.4%. We did not find any studies on the quality of carbetocin, tranexamic acid, or clindamycin. CONCLUSIONS: There is a widespread problem with the quality of medicines used to manage life-threatening maternal conditions in LMIC. This can be a contributing factor to high maternal mortality rates in these regions.