Efficacy of Pharmacologic Hemorrhage Prophylactics in Second Trimester Abortions: A Systematic Review.

OBJECTIVE: To evaluate prophylactic uterotonics, antifibrinolytic medications, and vasoconstrictive agents in prevention of hemorrhage during second trimester abortions. DATA SOURCES: PubMed, EMBASE (Elsevier platform), EBM reviews (Ovid platform), and Web of Science were searched from database creation to October 30th, 2023. STUDY ELIGIBILITY CRITERIA: Randomized control trials, cohort studies, case-control studies, and case series evaluating pregnant individuals (between 13 weeks gestation and 27 weeks, 6 days gestation) undergoing dilation and evacuation who received prophylactic uterotonics (methylergonovine, carboprost, oxytocin, misoprostol), antifibrinolytic medications (tranexamic acid), or vasoconstrictive agents (vasopressin, lidocaine with epinephrine). Outcomes of interest included post-procedural bleeding, rate of medications to treat bleeding, blood transfusion, re-operation, or transfer to a higher level of care for hemorrhage. STUDY APPRAISAL AND SYNTHESIS METHODS: Two authors independently screened abstracts using the Systematic Review Data Repository. A third reviewer resolved discrepancies. Full text of accepted abstracts were retrieved and assessed for eligibility by two independent authors. Eligible studies were independently assessed for quality and bias by three authors. Consensus review resolved discrepancies. RESULTS: Among 5,834 abstracts screened, 11 studies met inclusion criteria: five randomized control trials, three retrospective cohort studies, and three case series, totaling 3,857 individuals. The paucity of studies combined with the heterogeneity of included trials precluded performance of a metanalysis. Four studies evaluating misoprostol were of overall low-quality evidence and primarily assessed misoprostol's use for cervical dilation, thus its efficacy for bleeding prophylaxis remains unclear. Two high quality trials evaluating oxytocin concluded that oxytocin use resulted in decreased blood loss, without difference in interventions to control bleeding. Two studies provided moderate quality evidence that paracervical vasopressin use decreased blood loss, particularly at advanced gestational ages, but subsequent intervention outcomes were not assessed. The high quality evidence evaluating methylergonovine found this medication increased blood loss at time of procedure. CONCLUSIONS: Current evidence for hemorrhage prophylaxis at time of dilation and evacuation supports use of intravenous oxytocin or paracervical vasopressin to decrease procedural blood loss, without an associated decrease in transfusion rate or use of other interventions. Future research into outcomes by gestational age can identify subgroups with potential to derive the most benefit.

Understanding maternal Ethnomedical Folklore in Central Uganda: a cross-sectional study of herbal remedies for managing Postpartum hemorrhage, inducing uterine contractions and abortion in Najjembe sub-county, Buikwe district.

Pregnant women in rural Uganda largely rely on medicinal plants for inducing labor, treating postpartum hemorrhage (PPH), and inducing abortion. 90% of the women in both rural and urban Uganda use plants to manage pregnancy symptoms like constipation, heartburn, morning sickness, body aches, nausea, and vomiting. After delivery women continue using plants to manage postpartum complications and for infant care especially herbal baths. This study documented how ethnomedical folklore has been used to aid childbirth, manage postpartum hemorrhage, and induce abortion. METHODS: A cross-sectional ethnobotanical survey was conducted from May - December 2023 in Najjemebe sub-county, Buikwe district. 206 respondents from 12 villages were selected using snowball sampling. Key informants included Traditional Birth Attendants (TBAs) and herbalists. Data was collected using semi-structured questionnaires and focus group discussions. Voucher specimens of the plants were identified and authenticated at Makerere University Herbarium. Data were analyzed using descriptive statistics, Informant Consensus factor (ICF), Use Reports (URs), paired comparisons, and GraphPad Prism® version 9.0.0 software. RESULTS: All respondents (N = 206, 100%), used plants to induce labour, treat PPH, and induce abortion. One hundred four plant species were documented: most cited or preferred were: Hoslundia opposita (N = 109, 53%), Phytolacca dodecandra (N = 72, 35%), and Commelina erecta (N = 47, 23%). The plants belonged to 49 families, Lamiaceae (16.3%) and Fabaceae (14.3%) having the majority of the species. Herbs were 42 (40%) and trees 23 (22%). Oral administration 95(72%) was the commonest, then topical 19 (14.4%) and vaginal 14(10.6%). CONCLUSION: Health surveys revealed that about 27% of deliveries in Uganda take place outside a health facility. Due to the oxytocic effects of plant species reported in this study, they play a triple role of being uterotonics, abortifacients, and treating postpartum haemmorhage. The dilemma lies in the unknown dosages and toxicity levels that could endanger both the mother's and the unborn child's lives. Due to Uganda's high rates of population growth, overall fertility, maternal mortality, and morbidity, policies, and programmes on gendered health provision need to be reevaluated. Integrating herbal medicine into health care systems appears to be a feasible solution.

Efficacy of early intrauterine balloon tamponade for immediate postpartum hemorrhage after vaginal delivery: a randomized clinical trial.

BACKGROUND: Many questions remain about the appropriate use of intrauterine balloon devices in postpartum hemorrhage after vaginal delivery refractory to first-line uterotonics. Available data suggest that early use of intrauterine balloon tamponade might be beneficial. OBJECTIVE: This study aimed to compare the effect of intrauterine balloon tamponade used in combination with second-line uterotonics vs intrauterine balloon tamponade used after the failure of second-line uterotonic treatment on the rate of severe postpartum hemorrhage in women with postpartum hemorrhage after vaginal delivery refractory to first-line uterotonics. STUDY DESIGN: This multicenter, randomized, controlled, parallel-group, nonblinded trial was conducted at 18 hospitals and enrolled 403 women who had just given birth vaginally at 35 to 42 weeks of gestation. The inclusion criteria were a postpartum hemorrhage refractory to first-line uterotonics (oxytocin) and requiring a second-line uterotonic treatment with sulprostone (E1 prostaglandin). In the study group, the sulprostone infusion was combined with intrauterine tamponade by an ebb balloon performed within 15 minutes of randomization. In the control group, the sulprostone infusion was started alone within 15 minutes of randomization, and if bleeding persisted 30 minutes after the start of sulprostone infusion, intrauterine tamponade using the ebb balloon was performed. In both groups, if the bleeding persisted 30 minutes after the insertion of the balloon, an emergency radiological or surgical invasive procedure was performed. The primary outcome was the proportion of women who either received ≥3 units of packed red blood cells or had a calculated peripartum blood loss of >1000 mL. The prespecified secondary outcomes were the proportions of women who had a calculated blood loss of ≥1500 mL, any transfusion, an invasive procedure and women who were transferred to the intensive care unit. The analysis of the primary outcome with the triangular test was performed sequentially throughout the trial period. RESULTS: At the eighth interim analysis, the independent data monitoring committee concluded that the incidence of the primary outcome did not differ between the 2 groups and stopped inclusions. After 11 women were excluded because they met an exclusion criterion or withdrew their consent, 199 and 193 women remained in the study and control groups, respectively, for the intention-to-treat analysis. The women's baseline characteristics were similar in both groups. Peripartum hematocrit level change, which was needed for the calculation of the primary outcome, was missing for 4 women in the study group and 2 women in the control group. The primary outcome occurred in 131 of 195 women (67.2%) in the study group and 142 of 191 women (74.3%) in the control group (risk ratio, 0.90; 95% confidence interval, 0.79-1.03). The groups did not differ substantially for rates of calculated peripartum blood loss pf ≥1500 mL, any transfusion, invasive procedure, and admission to an intensive care unit. Endometritis occurred in 5 women (2.7%) in the study group and none in the control group (P=.06). CONCLUSION: The early use of intrauterine balloon tamponade did not reduce the incidence of severe postpartum hemorrhage compared with its use after the failure of second-line uterotonic treatment and before recourse to invasive procedures.

Tranexamic acid, as an adjunct to oxytocin prophylaxis, in the prevention of postpartum haemorrhage in women undergoing elective caesarean section: A single-centre double-blind randomised controlled trial.

OBJECTIVE: To evaluate the effectiveness of tranexamic acid (TXA) in reducing blood loss during elective caesarean sections in women with and without risk factors for postpartum haemorrhage (PPH). DESIGN: A double-blind, randomised placebo-controlled trial. SETTING: An academic tertiary referral centre in Singapore. POPULATION: Multiethnic women aged 21 years or older undergoing elective caesarean section. METHODS: Randomisation to intravenous TXA or normal saline (placebo) 10 minutes before skin incision. MAIN OUTCOME MEASURES: Calculated estimated blood loss (cEBL), derived from blood volume and haematocrit levels. RESULTS: Between June 2020 and October 2021, 200 women were randomised to the placebo or TXA groups. Women who received prophylactic TXA had a significantly lower mean cEBL compared with those receiving placebo (adjusted mean difference -126.4 mL, 95% CI -243.7 to -9.1, p = 0.035). The effect was greatest in those at high risk for PPH, with a reduction in cEBL (mean difference -279.6 mL, 95% CI -454.8 to -104.3, p = 0.002) and a lower risk of cEBL ≥500 mL (risk ratio [RR] 0.54, 95% CI 0.36-0.83, p = 0.007) and cEBL ≥1000 mL (RR 0.44, 95% CI 0.20-0.98, p = 0.016). Subgroup analysis showed benefit for women with preoperative haemoglobin <10.5 g/dL (mean difference -281.9 mL, 95% CI -515.0 to -48.8, p = 0.019). There was no significant difference in need for additional medical or surgical interventions. There were no maternal or neonatal adverse outcomes. CONCLUSION: Prophylactic TXA should be considered in women with risk factors for PPH, and those most likely to benefit are those with preoperative haemoglobin <10.5 g/dL.

Cost-effectiveness and budget impact of heat-stable carbetocin compared to oxytocin and misoprostol for the prevention of postpartum hemorrhage (PPH) in women giving birth in India.

INTRODUCTION: Low- and middle-income countries (LMICs) are committed to achieving the Sustainable Development Goal 3.1 to reduce maternal mortality. The Ministry of Health and Family Welfare of India recommends prophylactic uterotonic administration to every woman following delivery to reduce the risk of postpartum hemorrhage (PPH), as PPH is the leading cause of maternal mortality in LMICs, including India. In 2018, the World Health Organization first recognized heat-stable carbetocin for PPH prevention. Governments are now considering its introduction into their public health systems. METHODS: A decision-tree model was developed from the public healthcare system perspective to compare the value of heat-stable carbetocin versus oxytocin and misoprostol among women giving birth in public sector healthcare facilities in India. The model accounted for differences in PPH risk and costs based on mode of delivery and healthcare setting, as well as provider behavior to mitigate quality concerns of oxytocin. Model outcomes for each prophylactic uterotonic included the number of PPH events, DALYs due to PPH, deaths due to PPH, and direct medical care costs. The budget impact was estimated based on projected uterotonic uptake between 2022-2026. RESULTS: Compared to oxytocin, heat-stable carbetocin avoided 5,468 additional PPH events, 5 deaths, and 244 DALYs per 100,000 births. Projected direct medical costs to the public healthcare system were lowered by US $171,700 (₹12.8 million; exchange rate of ₹74.65 = US$1 from 2 Feb 2022) per 100,000 births. Benefits were even greater when compared to misoprostol (7,032 fewer PPH events, 10 fewer deaths, 470 fewer DALYs, and $230,248 saved per 100,000 births). In the budget impact analysis, India's public health system is projected to save US$11.4 million (₹849 million) over the next five years if the market share for heat-stable carbetocin grows to 19% of prophylactic uterotonics administered. CONCLUSIONS: Heat-stable carbetocin is expected to reduce the number of PPH events and deaths, avoid more DALYs, and reduce costs to the public healthcare system of India. Greater adoption of heat-stable carbetocin for the prevention of PPH could advance India's efforts to achieve its maternal health goals and increase efficiency of its public health spending.

Peripartum Haemorrhage: Haemostatic Aspects of the Updated Peripartum Haemorrhage Guideline of the German-Speaking Countries.

Background: Peripartum haemorrhage (PPH) is a potentially life-threatening complication. Although still rare, the incidence of peripartal haemorrhage is rising in industrialised countries and refractory bleeding remains among the leading causes of death in the peripartal period. Summary: The interdisciplinary German, Austrian, and Swiss guideline on "Peripartum Haemorrhage: Diagnostics and Therapies" has reviewed the evidence for the diagnostics and medical, angiographic, haemostatic, and surgical treatment and published an update in September 2022 . This article reviews the updated recommendations regarding the early diagnosis and haemostatic treatment of PPH. Keystones of the guideline recommendations are the early diagnosis of the bleeding by measuring blood loss using calibrated collector bags, the development of a multidisciplinary treatment algorithm adapted to the severity of bleeding, and the given infrastructural conditions of each obstetric unit, the early and escalating use of uterotonics, the therapeutic, instead of preventative, use of tranexamic acid, the early diagnostics of progressive deficiencies of coagulation factors or platelets to facilitate a tailored and guided haemostatic treatment with coagulation factors, platelets as well as packed red blood cells and fresh frozen plasma when a massive transfusion is required. Key Messages: Essential for the effective and safe treatment of PPH is the timely diagnosis. The diagnosis of PPH requires the measurement rather than estimation of blood loss. Successful treatment of PPH consists of a multidisciplinary approach involving surgical and haemostatic treatments to stop the bleeding. Haemostatic treatment of PPH starts early after diagnosis and combines tranexamic acid, an initially ratio-driven transfusion with RBC:plasma:PC = 4:4:1 (when using pooled or apheresis PC) and finally a goal-directed substitution with coagulation factor concentrates for proven deficiencies. Early monitoring of coagulation either by standard parameters or viscoelastic methods facilitates goal-directed haemostatic treatment.

Women's use of non-conventional herbal uterotonic in pregnancy and labour: evidence from birth attendants.

BACKGROUND: Over the years, governments and stakeholders have implemented various policies/programmes to improve maternal health outcomes in low-middle-income countries. In Ghana, Community Health Officers were trained as midwives to increase access to skilled maternal healthcare. The government subsequently banned traditional birth attendants from providing direct maternal healthcare in 2000. Despite these, there is an unprecedented utilisation of TBAs' services, including herbal uterotonics. This has attempted to defeat stakeholders' campaigns to improve maternal health outcomes. Thus, we explored and highlighted herbal uterotonic consumption in pregnancy and birth and the implications on maternal and newborn health outcomes in North-Western Ghana. METHODS: This was an exploratory qualitative study that investigated traditional birth attendants (n = 17) and healthcare providers' (n = 26) perspectives on the intake of herbal uterotonics in pregnancy and childbirth in rural Ghana, using in-depth interviews. A combination of convenience, purposive and snowball sampling procedures were employed in selecting participants. RESULTS: Findings were captured in two domains: (1) perceived rationale for herbal uterotonic intake, and (2) potential adverse impacts of herbal uterotonic intake in pregnancy and labour, and nine topics: (i) confidence in unskilled attendance at birth, (ii) cost and a shortage of essential medicines, (iii) herbal uterotonics as a remedy for obstetric problems, (iv) herbal uterotonics facilitate birth, (v) attraction of home birth for cultural reasons, (vi) affordability of herbal uterotonics, (vii) unintended consequences and adverse outcomes, (viii) risks using herbal uterotonics to manage fertility and (ix) risks using herbal uterotonics to facilitate home birth. CONCLUSION: The findings have suggested that the intake of non-conventional herbal uterotonic is widespread in the study area, although the constituents of the herb are unknown. However, complex and multiple factors of healthcare cost, desire for homebirth, unawareness of the negative effects of such substances, perceived way of addressing obstetric problems and cultural undertones, among others, accounted for herbal uterotonics consumption. We also encourage research into the constituents of 'mansugo' and the potential benefits and adverse effects. We recommend qualitative studies involving previous users of this herbal uterotonic to inform policy and healthcare provision.

Heat stable carbetocin vs. oxytocin for the prevention of post-partum hemorrhage in emergency caesarean delivery: a randomized controlled trial.

OBJECTIVES: To evaluate the uterotonic effect of carbetocin compared with oxytocin in emergency cesarean delivery in Iraq. METHODS: A double-blinded randomized noninferiority single center trial. Three-hundred patients were systematically randomized to intravenous bolus injection of 10 IU oxytocin or 100 mcg carbetocin after delivery in a ratio of 2:1. The primary outcome was additional uterotonic use when inadequate uterine tone occur in the first 24 h after delivery. Secondary outcomes include the need for blood transfusion, blood pressure and pulse rate changes within an hour of drugs administration. Noninferiority margins for the relative risks outcomes was 4%. RESULTS: Addition uterotonics use was significantly lower in carbetocin group with a risk ratio of 0.36. Carbetocin was superior to oxytocin in reducing the need for additional uterotonic drugs by 12% and non-inferior to oxytocin for blood transfusion 3.5%. Noninferiority was not shown for the outcome of sever blood loss. Miner changes in blood pressure and pulse rate were observed in carbetocin group compared to oxytocin but clinically were not significant. CONCLUSIONS: Heat stable carbetocin is effective in reducing additional uterotonics use compared to oxytocin without clinically significant change in blood pressure or pulse rate, therefore, can be a potential alternative in Iraq.

[Postpartum hemorrhage : Interdisciplinary consideration in the context of patient blood management]. / Postpartale Hämorrhagie : Interdisziplinäre Betrachtung im Kontext des Patient Blood Management.

Postpartum hemorrhage (PPH) nowadays still represents a severe complication of both a vaginal delivery and a cesarean section. In German-speaking areas a new definition of the term has recently become established and the nomenclature with respect to the severe form of PPH was dropped. The handling of misoprostol as a uterotonic during treatment of PPH is also new, which is available in Germany only as a medical direct import. For adequate diagnostics and targeted treatment interdisciplinary and standardized algorithms should be established and the specialist disciplines involved should be sensitized to this problem. In addition to an adequate hemostasis, a developing coagulopathy must be recognized at an early stage and treated with targeted coagulation management. Through implementation concepts, particularly the second pillar (minimization of blood loss) and the third pillar (rational use of blood transfusions) of patient blood management, various aspects for improvement of treatment of a PPH can be identified.

Intravenous oxytocin dosing regimens for postpartum hemorrhage prevention following cesarean delivery: a systematic review and meta-analysis.

OBJECTIVE: To compare the available evidence on intravenous oxytocin dosing regimens for the prevention of postpartum hemorrhage following cesarean delivery. DATA SOURCES: We searched Ovid MEDLINE, Embase, Global Index Medicus, Cumulative Index of Nursing and Allied Health Literature, Cochrane Controlled Register of Trials, ClinicalTrials.gov, and the International Clinical Trials Registry Platform for eligible studies published until February 2020. STUDY ELIGIBILITY CRITERIA: We included any randomized or nonrandomized study published in peer-reviewed journals that compared at least 2 different dosing regimens of intravenous oxytocin for postpartum hemorrhage prevention in women undergoing cesarean delivery. METHODS: Two authors independently assessed the eligibility of studies, extracted the data, and assessed the risk of bias. The primary outcome was incidence of postpartum hemorrhage ≥1000 mL. Other review outcomes included use of additional uterotonics, blood loss, and adverse maternal events. Data were analyzed according to the type of intravenous administration (bolus only, infusion only, or bolus plus infusion) and total oxytocin dose. A meta-analysis was performed on randomized trials and the results were reported as risk ratios or mean differences with 95% confidence intervals. The Grading of Recommendations, Assessment, Development, and Evaluations scale was used to rate the certainty of evidence. Findings from dose-finding trials and nonrandomized studies were reported narratively. RESULTS: A total of 35 studies (7333 women) met our inclusion criteria and included 30 randomized trials and 5 nonrandomized studies. There were limited data available from the trials for most outcomes, and the results were not conclusive. Compared with bolus plus infusion regimens, bolus only regimens probably result in slightly higher mean blood loss (mean difference, 52 mL; 95% confidence interval, 0.4-104 mL; moderate certainty). Among the bolus plus infusion regimens, initial bolus doses <5 IU may reduce nausea (risk ratio, 0.26; 95% confidence interval, 0.11-0.63; low certainty) when compared with doses of 5-9 IU. Total oxytocin doses of 5-9 IU vs total doses of 10-19 IU may increase the use of additional uterotonics (risk ratio, 13.00; 95% confidence interval, 1.75-96.37; low certainty). Effects on other outcomes were generally inconclusive. CONCLUSION: There are limited data available for comparisons of IV oxytocin regimens for postpartum hemorrhage prevention following cesarean delivery. Bolus plus infusion regimens may lead to minor reductions in mean blood loss and initial bolus doses of <5 IU may minimize nausea. Bolus only regimens of 10 IU vs bolus only regimens of 5 IU may decrease the need for additional uterotonics, however, further comparative trials are required to understand the effects on other key outcomes, particularly hypotension.

Uterotonics for prevention of postpartum haemorrhage: EN-BIRTH multi-country validation study.

BACKGROUND: Postpartum haemorrhage (PPH) is a leading cause of preventable maternal mortality worldwide. The World Health Organization (WHO) recommends uterotonic administration for every woman after birth to prevent PPH. There are no standardised data collected in large-scale measurement platforms. The Every Newborn Birth Indicators Research Tracking in Hospitals (EN-BIRTH) is an observational study to assess the validity of measurement of maternal and newborn indicators, and this paper reports findings regarding measurement of coverage and quality for uterotonics. METHODS: The EN-BIRTH study took place in five hospitals in Bangladesh, Nepal and Tanzania, from July 2017 to July 2018. Clinical observers collected tablet-based, time-stamped data. We compared observation data for uterotonics to routine hospital register-records and women's report at exit-interview survey. We analysed the coverage and quality gap for timing and dose of administration. The register design was evaluated against gap analyses and qualitative interview data assessing the barriers and enablers to data recording and use. RESULTS: Observed uterotonic coverage was high in all five hospitals (> 99%, 95% CI 98.7-99.8%). Survey-report underestimated coverage (79.5 to 91.7%). "Don't know" replies varied (2.1 to 14.4%) and were higher after caesarean (3.7 to 59.3%). Overall, there was low accuracy in survey data for details of uterotonic administration (type and timing). Register-recorded coverage varied in four hospitals capturing uterotonics in a specific column (21.6, 64.5, 97.6, 99.4%). The average coverage measurement gap was 18.1% for register-recorded and 6.0% for survey-reported coverage. Uterotonics were given to 15.9% of women within the "right time" (1 min) and 69.8% within 3 min. Women's report of knowing the purpose of uterotonics after birth ranged from 0.4 to 64.9% between hospitals. Enabling register design and adequate staffing were reported to improve routine recording. CONCLUSIONS: Routine registers have potential to track uterotonic coverage - register data were highly accurate in two EN-BIRTH hospitals, compared to consistently underestimated coverage by survey-report. Although uterotonic coverage was high, there were gaps in observed quality for timing and dose. Standardisation of register design and implementation could improve data quality and data flow from registers into health management information reporting systems, and requires further assessment.

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-effectiveness of inhaled oxytocin for prevention of postpartum haemorrhage: a modelling study applied to two high burden settings.

BACKGROUND: Access to oxytocin for prevention of postpartum haemorrhage (PPH) in resource-poor settings is limited by the requirement for a consistent cold chain and for a skilled attendant to administer the injection. To overcome these barriers, heat-stable, non-injectable formulations of oxytocin are under development, including oxytocin for inhalation. This study modelled the cost-effectiveness of an inhaled oxytocin product (IHO) in Bangladesh and Ethiopia. METHODS: A decision analytic model was developed to assess the cost-effectiveness of IHO for the prevention of PPH compared to the standard of care in Bangladesh and Ethiopia. In Bangladesh, introduction of IHO was modelled in all public facilities and home deliveries with or without a skilled attendant. In Ethiopia, IHO was modelled in all public facilities and home deliveries with health extension workers. Costs (costs of introduction, PPH prevention and PPH treatment) and effects (PPH cases averted, deaths averted) were modelled over a 12-month program. Life years gained were modelled over a lifetime horizon (discounted at 3%). Cost of maintaining the cold chain or effects of compromised oxytocin quality (in the absence of a cold chain) were not modelled. RESULTS: In Bangladesh, IHO was estimated to avert 18,644 cases of PPH, 76 maternal deaths and 1954 maternal life years lost. This also yielded a cost-saving, with the majority of gains occurring among home deliveries where IHO would replace misoprostol. In Ethiopia, IHO averted 3111 PPH cases, 30 maternal deaths and 767 maternal life years lost. The full IHO introduction program bears an incremental cost-effectiveness ratio (ICER) of between 2 and 3 times the per-capita Gross Domestic Product (GDP) ($1880 USD per maternal life year lost) and thus is unlikely to be considered cost-effective in Ethiopia. However, the ICER of routine IHO administration considering recurring cost alone falls under 25% of per-capita GDP ($175 USD per maternal life-year saved). CONCLUSIONS: IHO has the potential to expand access to uterotonics and reduce PPH-associated morbidity and mortality in high burden settings. This can facilitate reduced spending on PPH management, making the product highly cost-effective in settings where coverage of institutional delivery is lagging.

Uterine balloon tamponade for the treatment of postpartum hemorrhage: a systematic review and meta-analysis.

OBJECTIVE: To assess the efficacy, effectiveness, and safety of uterine balloon tamponade for treating postpartum hemorrhage. STUDY DESIGN: We searched electronic databases (from their inception to August 2019) and bibliographies. We included randomized controlled trials, nonrandomized studies, and case series that reported on the efficacy, effectiveness, and/or safety of uterine balloon tamponade in women with postpartum hemorrhage. The primary outcome was the success rate of uterine balloon tamponade for treating postpartum hemorrhage (number of uterine balloon tamponade success cases/total number of women treated with uterine balloon tamponade). For meta-analyses, we calculated pooled success rate for all studies, and relative risk with 95% confidence intervals for studies that included a comparative arm. RESULTS: Ninety-one studies, including 4729 women, met inclusion criteria (6 randomized trials, 1 cluster randomized trial, 15 nonrandomized studies, and 69 case series). The overall pooled uterine balloon tamponade success rate was 85.9% (95% confidence interval, 83.9-87.9%). The highest success rates corresponded to uterine atony (87.1%) and placenta previa (86.8%), and the lowest to placenta accreta spectrum (66.7%) and retained products of conception (76.8%). The uterine balloon tamponade success rate was lower in cesarean deliveries (81.7%) than in vaginal deliveries (87.0%). A meta-analysis of 2 randomized trials that compared uterine balloon tamponade vs no uterine balloon tamponade in postpartum hemorrhage due to uterine atony after vaginal delivery showed no significant differences between the study groups in the risk of surgical interventions or maternal death (relative risk, 0.59; 95% confidence interval, 0.02-16.69). A meta-analysis of 2 nonrandomized before-and-after studies showed that introduction of uterine balloon tamponade in protocols for managing severe postpartum hemorrhage significantly decreased the use of arterial embolization (relative risk, 0.29; 95% confidence interval, 0.14-0.63). A nonrandomized cluster study reported that use of invasive procedures was significantly lower in the perinatal network that routinely used uterine balloon tamponade than that which did not use uterine balloon tamponade (3.0/1000 vs 5.1/1000; P < .01). A cluster randomized trial reported that the frequency of postpartum hemorrhage-related invasive procedures and/or maternal death was significantly higher after uterine balloon tamponade introduction than before uterine balloon tamponade introduction (11.6/10,000 vs 6.7/10,000; P = .04). Overall, the frequency of complications attributed to uterine balloon tamponade use was low (≤6.5%). CONCLUSION: Uterine balloon tamponade has a high success rate for treating severe postpartum hemorrhage and appears to be safe. The evidence on uterine balloon tamponade efficacy and effectiveness from randomized and nonrandomized studies is conflicting, with experimental studies suggesting no beneficial effect, in contrast with observational studies. Further research is needed to determine the most effective programmatic and healthcare delivery strategies on uterine balloon tamponade introduction and use.

Maternal characteristics and causes associated with refractory postpartum haemorrhage after vaginal birth: a secondary analysis of the WHO CHAMPION trial data.

OBJECTIVE: To assess the maternal characteristics and causes associated with refractory postpartum haemorrhage (PPH). DESIGN: Secondary analysis of the WHO CHAMPION trial data. SETTING: Twenty-three hospitals in ten countries. POPULATION: Women from the CHAMPION trial who received uterotonics as first-line treatment of PPH. METHODS: We assessed the association between sociodemographic, pregnancy and childbirth factors and refractory PPH, and compared the causes of PPH between women with refractory PPH and women responsive to first-line PPH treatment. MAIN OUTCOME MEASURES: Maternal characteristics; causes of PPH. RESULTS: Women with labour induced or augmented with uterotonics (adjusted odds ratio [aOR] 1.35; 95% CI 1.07-1.72), with episiotomy or tears requiring suturing (aOR 1.82; 95% CI 1.34-2.48) and who had babies with birthweights ≥3500 g (aOR 1.33; 95% CI 1.04-1.69) showed significantly higher odds of refractory PPH compared with the reference categories in the multivariate analysis adjusted by centre and trial arm. While atony was the sole PPH cause in 53.2% (116/218) of the women in the responsive PPH group, it accounted for only 31.5% (45/143) of the causes in the refractory PPH group. Conversely, tears were the sole cause in 12.8% (28/218) and 28% (40/143) of the responsive PPH and refractory PPH groups, respectively. Placental problems were the sole cause in 11 and 5.6% in the responsive and refractory PPH groups, respectively. CONCLUSION: Women with refractory PPH showed a different pattern of maternal characteristics and PPH causes compared with those with first-line treatment responsive PPH. TWEETABLE ABSTRACT: Women with refractory postpartum haemorrhage are different from those with first-line treatment responsive PPH.

Uterotonics in elective caesarean delivery: a randomised non-inferiority study comparing carbetocin 20 µg and 100 µg.

Postpartum haemorrhage is the leading cause of maternal mortality worldwide and prophylactic uterotonic drug administration after the delivery of the infant is advised. Carbetocin is recommended as an uterotonic, but the minimum effective dose has not been verified. We compared the efficacy of two doses of intravenous carbetocin (20 µg and 100 µg) in women undergoing elective caesarean delivery. This was a randomised, double-blind, non-inferiority study in women at low risk of postpartum haemorrhage. Carbetocin was administered on delivery of the anterior shoulder of the neonate. Uterine tone was assessed by the obstetrician 2 min and 5 min after carbetocin administration according to an 11-point numerical rating scale (0 = atonic uterus and 10 = firm uterus). The primary outcome was uterine tone 2 min after carbetocin administration. The pre-specified non-inferiority margin was 1 point on the 11-point scale. Secondary outcomes included: uterine tone at 5 min; use of additional uterotonics within 24 h; blood loss; and adverse effects. Data were available for 53 women in the carbetocin-20 group and for 55 women in the carbetocin-100 group. The mean (SD) uterine tone at 2 min was 7.5 (1.9) in the carbetocin-20 group and 8.0 (1.5) in the carbetocin-100 group. The lower limit of the one-sided 95%CI for the mean difference was outside the non-inferiority margin (at -1.1; p = 0.11) meaning non-inferiority of carbetocin 20 µg compared with carbetocin 100 µg could not be confirmed. However, the secondary outcome measures of uterine tone at 5 min, blood loss and use of additional uterotonics were similar in both groups.

Current research on carbetocin and implications for prevention of postpartum haemorrhage.

BACKGROUND: Postpartum haemorrhage (PPH) is the leading cause of maternal mortality in low-income countries and is a significant contributor to severe maternal morbidity and long-term disability. Carbetocin may be an underused uterotonic for prevention of PPH. A number of studies are being conducted that may challenge the place of oxytocin as the first choice of uterotonics for prevention of PPH. This paper describes the current research into carbetocin and ranking of effectiveness of uterotonics that may provide important new information to assist healthcare decision makers to ensure that women receive an effective uterotonic for prevention of PPH. METHODS: We searched the WHO International Clinical Trials Registry Platform for current studies on effectiveness of carbetocin for prevention of PPH following vaginal delivery with sample sizes large enough to provide quality evidence to support potential changes to international guidelines. We also searched the Cochrane Library for current systematic reviews including carbetocin used in prevention of PPH. RESULTS: Susceptibility to degradation from exposure to heat is one of the key causes of reduced effectiveness of oxytocin in preventing PPH from uterine atony. Although heat stable and effective in preventing PPH, misoprostol is also subject to degradation due to exposure to moisture and produces some side-effects. Other uterotonics (including ergometrine and combinations of oxytocin, ergometrine and misoprostol) are also available and used with varying safety and effectiveness profiles and quality issues. Efforts to reduce maternal mortality from PPH include research studies seeking to identify safe, stable, effective uterotonics. Heat stable carbetocin is the subject of two major clinical studies into its effectiveness in preventing PPH following vaginal deliveries, information that could expand its application for prevention of PPH. CONCLUSION: Heat stable carbetocin is being investigated as a potential alternative to oxytocin. This paper describes two current clinical trials on carbetocin and a network meta-analysis ranking of all uterotonic agents, including carbetocin, which combined may provide evidence supporting expansion of the use of the heat stable formulation of carbetocin in PPH prevention.

Peripartum Haemorrhage: Haemostatic Aspects of the New German PPH Guideline.

Summary Peripartum haemorrhage remains one of the main causes of maternal mortality world-wide. The German, Austrian and Swiss Societies of Gynaecology and Obstetrics have updated the current guidelines for the treatment of peripartum haemorrhage together with the German Society of Anaesthesiology and Intensive Care Medicine and the Society of Thrombosis and Haemostasis Research. The recommendations have been the result of a thorough review of the available scientific literature and a consensus process involving all members of the guideline group. A key element of the anaesthesiological and haemostatic management is the development of a multidisciplinary standard operating procedure combining surgical as well as medical and haemostatic treatments depending on the severity of bleeding. The guideline underscores the value of clinical and laboratory diagnostics of peripartum haemorrhage as early as possible, even pre-emptively. This allows for an early identification of causes of bleeding and a specific treatment. The guideline comprises evidence-based recommendations for the use of uterotonics, tranexamic acid and blood products such as factor concentrates, fresh frozen plasma, platelet concentrates, packed red blood cells, recombinant activated factor VII and desmopressin. In addition, recommendations for blood conservation strategies involving the use of cell salvage, permissive hypotension and transfusion triggers are given.

Lack of controlled studies investigating the risk of postpartum haemorrhage in cesarean delivery after prior use of oxytocin: a scoping review.

BACKGROUND: Postpartum haemorrhage (PPH) is a major cause of maternal mortality and morbidity worldwide. Experimental and clinical studies indicate that prolonged oxytocin exposure in the first or second stage of labour may be associated with impaired uterine contractility and an increased risk of atonic PPH. Therefore, particularly labouring women requiring cesarean delivery constitute a subset of patients that may exhibit an unpredictable response to oxytocin. We mapped the evidence for comparative studies investigating the hypothesis whether the risk for PPH is increased in women requiring cesarean section after induction or augmentation of labour. METHODS: We performed a systematic literature search for clinical trials in Medline, Embase, Web of Science, and the Cochrane Library (May 2016). Additionally we searched for ongoing or unpublished trials in clinicaltrials.gov and the WHO registry platform. We identified a total of 36 controlled trials investigating the exogenous use of oxytocin in cesarean section. Data were extracted for study key characteristics and the current literature literature was described narratively. RESULTS: Our evidence map shows that the majority of studies investigating the outcome PPH focused on prophylactic oxytocin use compared to other uterotonic agents in the third stage of labour. Only 2 dose-response studies investigated the required oxytocin dose to prevent uterine atony after cesarean delivery for labour arrest. These studies support the hypotheses that labouring women exposed to exogenous oxytocin require a higher oxytocin dose after delivery than non-labouring women to prevent uterine atony after cesarean section. However, the study findings are flawed by limitations of the study design as well as the outcome selection. No clinical trial was identified that directly compared exogenous oxytocin versus no oxytocin application before intrapartum cesarean delivery. CONCLUSION: Despite some evidence from dose-response studies that the use of oxytocin may increase the risk for PPH in intrapartum cesarean delivery, current research has not investigated the prepartal application of oxytocin in well controlled clinical trials. It was striking that most studies on exogenous oxytocin are focused on PPH prophylaxis in the third stage of labour without differing between the indications of cesarean section and hence the prepartal oxytocin status.