The compatibility of oxytocin and tranexamic acid injection products when mixed for co-administration by infusion for the treatment of postpartum haemorrhage: An in vitro investigation.

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

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.

Methods for managing miscarriage: a network meta-analysis.

BACKGROUND: Miscarriage, defined as the spontaneous loss of a pregnancy before 24 weeks' gestation, is common with approximately 25% of women experiencing a miscarriage in their lifetime. An estimated 15% of pregnancies end in miscarriage. Miscarriage can lead to serious morbidity, including haemorrhage, infection, and even death, particularly in settings without adequate healthcare provision. Early miscarriages occur during the first 14 weeks of pregnancy, and can be managed expectantly, medically or surgically. However, there is uncertainty about the relative effectiveness and risks of each option. OBJECTIVES: To estimate the relative effectiveness and safety profiles for the different management methods for early miscarriage, and to provide rankings of the available methods according to their effectiveness, safety, and side-effect profile using a network meta-analysis. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth's Trials Register (9 February 2021), ClinicalTrials.gov and the WHO International Clinical Trials Registry Platform (ICTRP) (12 February 2021), and reference lists of retrieved studies. SELECTION CRITERIA: We included all randomised controlled trials assessing the effectiveness or safety of methods for miscarriage management. Early miscarriage was defined as less than or equal to 14 weeks of gestation, and included missed and incomplete miscarriage. Management of late miscarriages after 14 weeks of gestation (often referred to as intrauterine fetal deaths) was not eligible for inclusion in the review. Cluster- and quasi-randomised trials were eligible for inclusion. Randomised trials published only as abstracts were eligible if sufficient information could be retrieved. We excluded non-randomised trials. DATA COLLECTION AND ANALYSIS: At least three review authors independently assessed the trials for inclusion and risk of bias, extracted data and checked them for accuracy. We estimated the relative effects and rankings for the primary outcomes of complete miscarriage and composite outcome of death or serious complications. The certainty of evidence was assessed using GRADE. Relative effects for the primary outcomes are reported subgrouped by the type of miscarriage (incomplete and missed miscarriage). We also performed pairwise meta-analyses and network meta-analysis to determine the relative effects and rankings of all available methods. MAIN RESULTS: Our network meta-analysis included 78 randomised trials involving 17,795 women from 37 countries. Most trials (71/78) were conducted in hospital settings and included women with missed or incomplete miscarriage. Across 158 trial arms, the following methods were used: 51 trial arms (33%) used misoprostol; 50 (32%) used suction aspiration; 26 (16%) used expectant management or placebo; 17 (11%) used dilatation and curettage; 11 (6%) used mifepristone plus misoprostol; and three (2%) used suction aspiration plus cervical preparation. Of these 78 studies, 71 (90%) contributed data in a usable form for meta-analysis. Complete miscarriage Based on the relative effects from the network meta-analysis of 59 trials (12,591 women), we found that five methods may be more effective than expectant management or placebo for achieving a complete miscarriage: · suction aspiration after cervical preparation (risk ratio (RR) 2.12, 95% confidence interval (CI) 1.41 to 3.20, low-certainty evidence), · dilatation and curettage (RR 1.49, 95% CI 1.26 to 1.75, low-certainty evidence), · suction aspiration (RR 1.44, 95% CI 1.29 to 1.62, low-certainty evidence), · mifepristone plus misoprostol (RR 1.42, 95% CI 1.22 to 1.66, moderate-certainty evidence), · misoprostol (RR 1.30, 95% CI 1.16 to 1.46, low-certainty evidence). The highest ranked surgical method was suction aspiration after cervical preparation. The highest ranked non-surgical treatment was mifepristone plus misoprostol. All surgical methods were ranked higher than medical methods, which in turn ranked above expectant management or placebo. Composite outcome of death and serious complications Based on the relative effects from the network meta-analysis of 35 trials (8161 women), we found that four methods with available data were compatible with a wide range of treatment effects compared with expectant management or placebo: · dilatation and curettage (RR 0.43, 95% CI 0.17 to 1.06, low-certainty evidence), · suction aspiration (RR 0.55, 95% CI 0.23 to 1.32, low-certainty evidence), · misoprostol (RR 0.50, 95% CI 0.22 to 1.15, low-certainty evidence), · mifepristone plus misoprostol (RR 0.76, 95% CI 0.31 to 1.84, low-certainty evidence). Importantly, no deaths were reported in these studies, thus this composite outcome was entirely composed of serious complications, including blood transfusions, uterine perforations, hysterectomies, and intensive care unit admissions. Expectant management and placebo ranked the lowest when compared with alternative treatment interventions. Subgroup analyses by type of miscarriage (missed or incomplete) agreed with the overall analysis in that surgical methods were the most effective treatment, followed by medical methods and then expectant management or placebo, but there are possible subgroup differences in the effectiveness of the available methods.  AUTHORS' CONCLUSIONS: Based on relative effects from the network meta-analysis, all surgical and medical methods for managing a miscarriage may be more effective than expectant management or placebo. Surgical methods were ranked highest for managing a miscarriage, followed by medical methods, which in turn ranked above expectant management or placebo. Expectant management or placebo had the highest chance of serious complications, including the need for unplanned or emergency surgery. A subgroup analysis showed that surgical and medical methods may be more beneficial in women with missed miscarriage compared to women with incomplete miscarriage. Since type of miscarriage (missed and incomplete) appears to be a source of inconsistency and heterogeneity within these data, we acknowledge that the main network meta-analysis may be unreliable. However, we plan to explore this further in future updates and consider the primary analysis as separate networks for missed and incomplete miscarriage.

Understanding abortion-related complications in health facilities: results from WHO multicountry survey on abortion (MCS-A) across 11 sub-Saharan African countries.

INTRODUCTION: Complications due to unsafe abortions are an important cause of morbidity and mortality in many sub-Saharan African countries. We aimed to characterise abortion-related complication severity, describe their management, and to report women's experience of abortion care in Africa. METHODS: A cross-sectional study was implemented in 210 health facilities across 11 sub-Saharan African countries. Data were collected on women's characteristics, clinical information and women's experience of abortion care (using the audio computer-assisted self-interviewing (ACASI) system). Severity of abortion complications were organised in five hierarchical mutually exclusive categories based on indicators present at assessment. Descriptive bivariate analysis was performed for women's characteristics, management of complications and reported experiences of abortion care by severity. Generalised linear estimation models were used to assess the association between women's characteristics and severity of complications. RESULTS: There were 13 657 women who had an abortion-related complication: 323 (2.4%) women were classified with severe maternal outcomes, 957 (7.0%) had potentially life-threatening complications, 7953 (58.2%) had moderate complications and 4424 (32.4%) women had mild complications. Women who were single, multiparous, presenting ≥13 weeks of gestational age and where expulsion of products of conception occurred prior to arrival to facility were more likely to experience severe complications. For management, the commonly used mechanical methods of uterine evacuation were manual vacuum aspiration (76.9%), followed by dilation and curettage (D&C) (20.1%). Most frequently used uterotonics were oxytocin (50∙9%) and misoprostol (22.7%). Via ACASI, 602 (19.5%) women reported having an induced abortion. Of those, misoprostol was the most commonly reported method (54.3%). CONCLUSION: There is a critical need to increase access to and quality of evidence-based safe abortion, postabortion care and to improve understanding around women's experiences of abortion care.

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®.

Developing and applying a 'living guidelines' approach to WHO recommendations on maternal and perinatal health.

How should the WHO most efficiently keep its global recommendations up to date? In this article we describe how WHO developed and applied a 'living guidelines' approach to its maternal and perinatal health (MPH) recommendations, based on a systematic and continuous process of prioritisation and updating. Using this approach, 25 new or updated WHO MPH recommendations have been published in 2017-2018. The new approach helps WHO ensure its guidance is responsive to emerging evidence and remains up to date for end users.

Provision and uptake of routine antenatal services: a qualitative evidence synthesis.

BACKGROUND: Antenatal care (ANC) is a core component of maternity care. However, both quality of care provision and rates of attendance vary widely between and within countries. Qualitative research can assess factors underlying variation, including acceptability, feasibility, and the values and beliefs that frame provision and uptake of ANC programmes.This synthesis links to the Cochrane Reviews of the effectiveness of different antenatal models of care. It was designed to inform the World Health Organization guidelines for a positive pregnancy experience and to provide insights for the design and implementation of improved antenatal care in the future. OBJECTIVES: To identify, appraise, and synthesise qualitative studies exploring:· Women's views and experiences of attending ANC; and factors influencing the uptake of ANC arising from women's accounts;· Healthcare providers' views and experiences of providing ANC; and factors influencing the provision of ANC arising from the accounts of healthcare providers. SEARCH METHODS: To find primary studies we searched MEDLINE, Ovid; Embase, Ovid; CINAHL, EbscoHost; PsycINFO, EbscoHost; AMED, EbscoHost; LILACS, VHL; and African Journals Online (AJOL) from January 2000 to February 2019. We handsearched reference lists of included papers and checked the contents pages of 50 relevant journals through Zetoc alerts received during the searching phase. SELECTION CRITERIA: We included studies that used qualitative methodology and that met our quality threshold; that explored the views and experiences of routine ANC among healthy, pregnant and postnatal women or among healthcare providers offering this care, including doctors, midwives, nurses, lay health workers and traditional birth attendants; and that took place in any setting where ANC was provided.We excluded studies of ANC programmes designed for women with specific complications. We also excluded studies of programmes that focused solely on antenatal education. DATA COLLECTION AND ANALYSIS: Two authors undertook data extraction, logged study characteristics, and assessed study quality. We used meta-ethnographic and Framework techniques to code and categorise study data. We developed findings from the data and presented these in a 'Summary of Qualitative Findings' (SoQF) table. We assessed confidence in each finding using GRADE-CERQual. We used these findings to generate higher-level explanatory thematic domains. We then developed two lines of argument syntheses, one from service user data, and one from healthcare provider data. In addition, we mapped the findings to relevant Cochrane effectiveness reviews to assess how far review authors had taken account of behavioural and organisational factors in the design and implementation of the interventions they tested. We also translated the findings into logic models to explain full, partial and no uptake of ANC, using the theory of planned behaviour. MAIN RESULTS: We include 85 studies in our synthesis. Forty-six studies explored the views and experiences of healthy pregnant or postnatal women, 17 studies explored the views and experiences of healthcare providers and 22 studies incorporated the views of both women and healthcare providers. The studies took place in 41 countries, including eight high-income countries, 18 middle-income countries and 15 low-income countries, in rural, urban and semi-urban locations. We developed 52 findings in total and organised these into three thematic domains: socio-cultural context (11 findings, five moderate- or high-confidence); service design and provision (24 findings, 15 moderate- or high-confidence); and what matters to women and staff (17 findings, 11 moderate- or high-confidence) The third domain was sub-divided into two conceptual areas; personalised supportive care, and information and safety. We also developed two lines of argument, using high- or moderate-confidence findings:For women, initial or continued use of ANC depends on a perception that doing so will be a positive experience. This is a result of the provision of good-quality local services that are not dependent on the payment of informal fees and that include continuity of care that is authentically personalised, kind, caring, supportive, culturally sensitive, flexible, and respectful of women's need for privacy, and that allow staff to take the time needed to provide relevant support, information and clinical safety for the woman and the baby, as and when they need it. Women's perceptions of the value of ANC depend on their general beliefs about pregnancy as a healthy or a risky state, and on their reaction to being pregnant, as well as on local socio-cultural norms relating to the advantages or otherwise of antenatal care for healthy pregnancies, and for those with complications. Whether they continue to use ANC or not depends on their experience of ANC design and provision when they access it for the first time.The capacity of healthcare providers to deliver the kind of high-quality, relationship-based, locally accessible ANC that is likely to facilitate access by women depends on the provision of sufficient resources and staffing as well as the time to provide flexible personalised, private appointments that are not overloaded with organisational tasks. Such provision also depends on organisational norms and values that overtly value kind, caring staff who make effective, culturally-appropriate links with local communities, who respect women's belief that pregnancy is usually a normal life event, but who can recognise and respond to complications when they arise. Healthcare providers also require sufficient training and education to do their job well, as well as an adequate salary, so that they do not need to demand extra informal funds from women and families, to supplement their income, or to fund essential supplies. AUTHORS' CONCLUSIONS: This review has identified key barriers and facilitators to the uptake (or not) of ANC services by pregnant women, and in the provision (or not) of good-quality ANC by healthcare providers. It complements existing effectiveness reviews of models of ANC provision and adds essential insights into why a particular type of ANC provided in specific local contexts may or may not be acceptable, accessible, or valued by some pregnant women and their families/communities. Those providing and funding services should consider the three thematic domains identified by the review as a basis for service development and improvement. Such developments should include pregnant and postnatal women, community members and other relevant stakeholders.

An outcome-based definition of low birthweight for births in low- and middle-income countries: a secondary analysis of the WHO global survey on maternal and perinatal health.

BACKGROUND: 2500 g has been used worldwide as the definition of low birthweight (LBW) for almost a century. While previous studies have used statistical approaches to define LBW cutoffs, a LBW definition using an outcome-based approach has not been evaluated. We aimed to identify an outcome-based definition of LBW for live births in low- and middle-income countries (LMICs), using data from a WHO cross-sectional survey on maternal and perinatal health outcomes in 23 countries. METHODS: We performed a secondary analysis of all singleton live births in the WHO Global Survey (WHOGS) on Maternal and Perinatal Health, conducted in African and Latin American countries (2004-2005) and Asian countries (2007-2008). We used a two-level logistic regression model to assess the risk of early neonatal mortality (ENM) associated with subgroups of birthweight (< 1500 g, 1500-2499 g with 100 g intervals; 2500-3499 g as the reference group). The model adjusted for potential confounders, including maternal complications, gestational age at birth, mode of birth, fetal presentation and facility capacity index (FCI) score. We presented adjusted odds ratios (aORs) with 95% confidence intervals (CIs). A lower CI limit of at least two was used to define a clinically important definition of LBW. RESULTS: We included 205,648 singleton live births at 344 facilities in 23 LMICs. An aOR of at least 2.0 for the ENM outcome was observed at birthweights below 2200 g (aOR 3.8 (95% CI; 2.7, 5.5) of 2100-2199 g) for the total population. For Africa, Asia and Latin America, the 95% CI lower limit aORs of at least 2.0 were observed when birthweight was lower than 2200 g (aOR 3.6 (95% CI; 2.0, 6.5) of 2100-2199 g), 2100 g (aOR 7.4 (95% CI; 5.1, 10.7) of 2000-2099 g) and 2200 g (aOR 6.1 (95% CI; 3.4, 10.9) of 2100-2199 g) respectively. CONCLUSION: A birthweight of less than 2200 g may be an outcome-based threshold for LBW in LMICs. Regional-specific thresholds of low birthweight (< 2200 g in Africa, < 2100 g in Asia and < 2200 g in Latin America) may also be warranted.

Developing measures for WHO recommendations on antenatal care for a positive pregnancy experience: a conceptual framework and scoping review.

OBJECTIVES: In response to the newest WHO recommendations on routine antenatal care (ANC) for pregnant women and adolescent girls, this paper identifies the literature on existing ANC measures, presents a conceptual framework for quality ANC, maps existing measures to specific WHO recommendations, identifies gaps where new measures are needed to monitor the implementation and impact of routine ANC and prioritises measures for capture. METHODS: We conducted searches in four databases and five websites. Searches and application of inclusion/exclusion criteria followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses flow approach for scoping reviews. Data were extracted on measure information, methodology, methodological work and implementation. We adapted and refined a conceptual framework for routine ANC based on these measures. RESULTS: This scoping review uncovered 58 resources describing 46 existing measures that align with WHO recommendations and good clinical practices for ANC. Of the 42 WHO-recommended ANC interventions and four good clinical practices included in this scoping review, only 14 WHO-recommended interventions and three established good clinical practices could potentially be measured immediately using existing measures. Recommendations addressing the integration of ANC with allied fields are likelier to have existing measures than recommendations that focus on maternal health. When mapped to our conceptual framework, existing measures prioritise content of care and health systems; measures for girls' and women's experiences of care are notably lacking. Available data sources for non-existent measures are currently limited. CONCLUSION: Our research updates prior efforts to develop comprehensive measures of quality ANC and raises awareness of the need to better assess experiences of ANC. Given the inadequate number and distribution of existing ANC measures across the quality of care conceptual framework domains, new standardised measures are required to assess quality of routine ANC. Girls' and women's voices deserve greater acknowledgement when measuring the quality and delivery of ANC.

Uterotonic agents for preventing postpartum haemorrhage: a network meta-analysis.

BACKGROUND: Postpartum haemorrhage (PPH) is the leading cause of maternal mortality worldwide. Prophylactic uterotonic agents can prevent PPH, and are routinely recommended. The current World Health Organization (WHO) recommendation for preventing PPH is 10 IU (international units) of intramuscular or intravenous oxytocin. There are several uterotonic agents for preventing PPH but there is still uncertainty about which agent is most effective with the least side effects. This is an update of a Cochrane Review which was first published in April 2018 and was updated to incorporate results from a recent large WHO trial. OBJECTIVES: To identify the most effective uterotonic agent(s) to prevent PPH with the least side effects, and generate a ranking according to their effectiveness and side-effect profile. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth's Trials Register, ClinicalTrials.gov, the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) (24 May 2018), and reference lists of retrieved studies. SELECTION CRITERIA: All randomised controlled trials or cluster-randomised trials comparing the effectiveness and side effects of uterotonic agents with other uterotonic agents, placebo or no treatment for preventing PPH were eligible for inclusion. Quasi-randomised trials were excluded. Randomised trials published only as abstracts were eligible if sufficient information could be retrieved. DATA COLLECTION AND ANALYSIS: At least three review authors independently assessed trials for inclusion and risk of bias, extracted data and checked them for accuracy. We estimated the relative effects and rankings for preventing PPH ≥ 500 mL and PPH ≥ 1000 mL as primary outcomes. Secondary outcomes included blood loss and related outcomes, morbidity outcomes, maternal well-being and satisfaction and side effects. Primary outcomes were also reported for pre-specified subgroups, stratifying by mode of birth, prior risk of PPH, healthcare setting, dosage, regimen and route of administration. We performed pairwise meta-analyses and network meta-analysis to determine the relative effects and rankings of all available agents. MAIN RESULTS: The network meta-analysis included 196 trials (135,559 women) involving seven uterotonic agents and placebo or no treatment, conducted across 53 countries (including high-, middle- and low-income countries). Most trials were performed in a hospital setting (187/196, 95.4%) with women undergoing a vaginal birth (71.5%, 140/196).Relative effects from the network meta-analysis suggested that all agents were effective for preventing PPH ≥ 500 mL when compared with placebo or no treatment. The three highest ranked uterotonic agents for prevention of PPH ≥ 500 mL were ergometrine plus oxytocin combination, misoprostol plus oxytocin combination and carbetocin. There is evidence that ergometrine plus oxytocin (RR 0.70, 95% CI 0.59 to 0.84, moderate certainty), carbetocin (RR 0.72, 95% CI 0.56 to 0.93, moderate certainty) and misoprostol plus oxytocin (RR 0.70, 95% CI 0.58 to 0.86, low certainty) may reduce PPH ≥ 500 mL compared with oxytocin. Low-certainty evidence suggests that misoprostol, injectable prostaglandins, and ergometrine may make little or no difference to this outcome compared with oxytocin.All agents except ergometrine and injectable prostaglandins were effective for preventing PPH ≥ 1000 mL when compared with placebo or no treatment. High-certainty evidence suggests that ergometrine plus oxytocin (RR 0.83, 95% CI 0.66 to 1.03) and misoprostol plus oxytocin (RR 0.88, 95% CI 0.70 to 1.11) make little or no difference in the outcome of PPH ≥ 1000 mL compared with oxytocin. Low-certainty evidence suggests that ergometrine may make little or no difference to this outcome compared with oxytocin meanwhile the evidence on carbetocin was of very low certainty. High-certainty evidence suggests that misoprostol is less effective in preventing PPH ≥ 1000 mL when compared with oxytocin (RR 1.19, 95% CI 1.01 to 1.42). Despite the comparable relative treatment effects between all uterotonics (except misoprostol) and oxytocin, ergometrine plus oxytocin, misoprostol plus oxytocin combinations and carbetocin were the highest ranked agents for PPH ≥ 1000 mL.Misoprostol plus oxytocin reduces the use of additional uterotonics (RR 0.56, 95% CI 0.42 to 0.73, high certainty) and probably also reduces the risk of blood transfusion (RR 0.51, 95% CI 0.37 to 0.70, moderate certainty) when compared with oxytocin. Carbetocin, injectable prostaglandins and ergometrine plus oxytocin may also reduce the use of additional uterotonics but the certainty of the evidence is low. No meaningful differences could be detected between all agents for maternal deaths or severe morbidity as these outcomes were rare in the included randomised trials where they were reported.The two combination regimens were associated with important side effects. When compared with oxytocin, misoprostol plus oxytocin combination increases the likelihood of vomiting (RR 2.11, 95% CI 1.39 to 3.18, high certainty) and fever (RR 3.14, 95% CI 2.20 to 4.49, moderate certainty). Ergometrine plus oxytocin increases the likelihood of vomiting (RR 2.93, 95% CI 2.08 to 4.13, moderate certainty) and may make little or no difference to the risk of hypertension, however absolute effects varied considerably and the certainty of the evidence was low for this outcome.Subgroup analyses did not reveal important subgroup differences by mode of birth (caesarean versus vaginal birth), setting (hospital versus community), risk of PPH (high versus low risk for PPH), dose of misoprostol (≥ 600 mcg versus < 600 mcg) and regimen of oxytocin (bolus versus bolus plus infusion versus infusion only). AUTHORS' CONCLUSIONS: All agents were generally effective for preventing PPH when compared with placebo or no treatment. Ergometrine plus oxytocin combination, carbetocin, and misoprostol plus oxytocin combination may have some additional desirable effects compared with the current standard oxytocin. The two combination regimens, however, are associated with significant side effects. Carbetocin may be more effective than oxytocin for some outcomes without an increase in side effects.

Interventions to reduce unnecessary caesarean sections in healthy women and babies.

Optimising the use of caesarean section (CS) is of global concern. Underuse leads to maternal and perinatal mortality and morbidity. Conversely, overuse of CS has not shown benefits and can create harm. Worldwide, the frequency of CS continues to increase, and interventions to reduce unnecessary CSs have shown little success. Identifying the underlying factors for the continuing increase in CS use could improve the efficacy of interventions. In this Series paper, we describe the factors for CS use that are associated with women, families, health professionals, and health-care organisations and systems, and we examine behavioural, psychosocial, health system, and financial factors. We also outline the type and effects of interventions to reduce CS use that have been investigated. Clinical interventions, such as external cephalic version for breech delivery at term, vaginal breech delivery in appropriately selected women, and vaginal birth after CS, could reduce the frequency of CS use. Approaches such as labour companionship and midwife-led care have been associated with higher proportions of physiological births, safer outcomes, and lower health-care costs relative to control groups without these interventions, and with positive maternal experiences, in high-income countries. Such approaches need to be assessed in middle-income and low-income countries. Educational interventions for women should be complemented with meaningful dialogue with health professionals and effective emotional support for women and families. Investing in the training of health professionals, eliminating financial incentives for CS use, and reducing fear of litigation is fundamental. Safe, private, welcoming, and adequately resourced facilities are needed. At the country level, effective medical leadership is essential to ensure CS is used only when indicated. We conclude that interventions to reduce overuse must be multicomponent and locally tailored, addressing women's and health professionals' concerns, as well as health system and financial factors.

Uterotonic agents for preventing postpartum haemorrhage: a network meta-analysis.

BACKGROUND: Postpartum haemorrhage (PPH) is the leading cause of maternal mortality worldwide. Prophylactic uterotonic drugs can prevent PPH, and are routinely recommended. There are several uterotonic drugs for preventing PPH but it is still debatable which drug is best. OBJECTIVES: To identify the most effective uterotonic drug(s) to prevent PPH, and generate a ranking according to their effectiveness and side-effect profile. SEARCH METHODS: We searched Cochrane Pregnancy and Childbirth's Trials Register (1 June 2015), ClinicalTrials.gov and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) for unpublished trial reports (30 June 2015) and reference lists of retrieved studies. SELECTION CRITERIA: All randomised controlled comparisons or cluster trials of effectiveness or side-effects of uterotonic drugs for preventing PPH.Quasi-randomised trials and cross-over trials are not eligible for inclusion in this review. DATA COLLECTION AND ANALYSIS: At least three review authors independently assessed trials for inclusion and risk of bias, extracted data and checked them for accuracy. We estimated the relative effects and rankings for preventing PPH ≥ 500 mL and PPH ≥ 1000 mL as primary outcomes. We performed pairwise meta-analyses and network meta-analysis to determine the relative effects and rankings of all available drugs. We stratified our primary outcomes according to mode of birth, prior risk of PPH, healthcare setting, dosage, regimen and route of drug administration, to detect subgroup effects.The absolute risks in the oxytocin are based on meta-analyses of proportions from the studies included in this review and the risks in the intervention groups were based on the assumed risk in the oxytocin group and the relative effects of the interventions. MAIN RESULTS: This network meta-analysis included 140 randomised trials with data from 88,947 women. There are two large ongoing studies. The trials were mostly carried out in hospital settings and recruited women who were predominantly more than 37 weeks of gestation having a vaginal birth. The majority of trials were assessed to have uncertain risk of bias due to poor reporting of study design. This primarily impacted on our confidence in comparisons involving carbetocin trials more than other uterotonics.The three most effective drugs for prevention of PPH ≥ 500 mL were ergometrine plus oxytocin combination, carbetocin, and misoprostol plus oxytocin combination. These three options were more effective at preventing PPH ≥ 500 mL compared with oxytocin, the drug currently recommended by the WHO (ergometrine plus oxytocin risk ratio (RR) 0.69 (95% confidence interval (CI) 0.57 to 0.83), moderate-quality evidence; carbetocin RR 0.72 (95% CI 0.52 to 1.00), very low-quality evidence; misoprostol plus oxytocin RR 0.73 (95% CI 0.60 to 0.90), moderate-quality evidence). Based on these results, about 10.5% women given oxytocin would experience a PPH of ≥ 500 mL compared with 7.2% given ergometrine plus oxytocin combination, 7.6% given carbetocin, and 7.7% given misoprostol plus oxytocin. Oxytocin was ranked fourth with close to 0% cumulative probability of being ranked in the top three for PPH ≥ 500 mL.The outcomes and rankings for the outcome of PPH ≥ 1000 mL were similar to those of PPH ≥ 500 mL. with the evidence for ergometrine plus oxytocin combination being more effective than oxytocin (RR 0.77 (95% CI 0.61 to 0.95), high-quality evidence) being more certain than that for carbetocin (RR 0.70 (95% CI 0.38 to 1.28), low-quality evidence), or misoprostol plus oxytocin combination (RR 0.90 (95% CI 0.72 to 1.14), moderate-quality evidence)There were no meaningful differences between all drugs for maternal deaths or severe morbidity as these outcomes were so rare in the included randomised trials.Two combination regimens had the poorest rankings for side-effects. Specifically, the ergometrine plus oxytocin combination had the higher risk for vomiting (RR 3.10 (95% CI 2.11 to 4.56), high-quality evidence; 1.9% versus 0.6%) and hypertension [RR 1.77 (95% CI 0.55 to 5.66), low-quality evidence; 1.2% versus 0.7%), while the misoprostol plus oxytocin combination had the higher risk for fever (RR 3.18 (95% CI 2.22 to 4.55), moderate-quality evidence; 11.4% versus 3.6%) when compared with oxytocin. Carbetocin had similar risk for side-effects compared with oxytocin although the quality evidence was very low for vomiting and for fever, and was low for hypertension. AUTHORS' CONCLUSIONS: Ergometrine plus oxytocin combination, carbetocin, and misoprostol plus oxytocin combination were more effective for preventing PPH ≥ 500 mL than the current standard oxytocin. Ergometrine plus oxytocin combination was more effective for preventing PPH ≥ 1000 mL than oxytocin. Misoprostol plus oxytocin combination evidence is less consistent and may relate to different routes and doses of misoprostol used in the studies. Carbetocin had the most favourable side-effect profile amongst the top three options; however, most carbetocin trials were small and at high risk of bias.Amongst the 11 ongoing studies listed in this review there are two key studies that will inform a future update of this review. The first is a WHO-led multi-centre study comparing the effectiveness of a room temperature stable carbetocin versus oxytocin (administered intramuscularly) for preventing PPH in women having a vaginal birth. The trial includes around 30,000 women from 10 countries. The other is a UK-based trial recruiting more than 6000 women to a three-arm trial comparing carbetocin, oxytocin and ergometrine plus oxytocin combination. Both trials are expected to report in 2018.Consultation with our consumer group demonstrated the need for more research into PPH outcomes identified as priorities for women and their families, such as women's views regarding the drugs used, clinical signs of excessive blood loss, neonatal unit admissions and breastfeeding at discharge. To date, trials have rarely investigated these outcomes. Consumers also considered the side-effects of uterotonic drugs to be important but these were often not reported. A forthcoming set of core outcomes relating to PPH will identify outcomes to prioritise in trial reporting and will inform futures updates of this review. We urge all trialists to consider measuring these outcomes for each drug in all future randomised trials. Lastly, future evidence synthesis research could compare the effects of different dosages and routes of administration for the most effective drugs.

Correction to: Towards a consensus definition of maternal sepsis: results of a systematic review and expert consultation.

After publication of the original article [1], it came to the authors' attention that the Acknowledgements section was not completed correctly. The Acknowledgements of the article should have been as follows.

Management of pregnancy at and beyond 41 completed weeks of gestation in low-risk women: a secondary analysis of two WHO multi-country surveys on maternal and newborn health.

BACKGROUND: The World Health Organization (WHO) recommends induction of labour (IOL) for women who have reached 41 completed weeks of pregnancy without spontaneous onset of labour. Many women with prolonged pregnancy and/or their clinicians elect not to induce, and chose either elective caesarean section (ECS) or expectant management (EM). This study intended to assess pregnancy outcomes of IOL, ECS and EM at and beyond 41 completed weeks. METHODS: This study is a secondary analysis of the WHO Global Survey (WHOGS) and the WHO Multi-country Survey (WHOMCS) conducted in Africa, Asia, Latin America and the Middle East. There were 33,003 women with low risk singleton pregnancies at ≥41 completed weeks from 292 facilities in 21 countries. Multilevel logistic regression model was used to assess associations of different management groups with each pregnancy outcome accounted for hierarchical survey design. The results were presented by adjusted odds ratios (aORs) with 95% confidence intervals (CIs) after adjusting for age, education, marital status, parity, previous caesarean section (CS), birth weight, and facility capacity index score. RESULTS: The prevalence of prolonged pregnancy at facility setting in WHOGS, WHOMCS and combined databases were 7.9%, 7.5% and 7.7% respectively. Regarding to maternal adverse outcomes, EM was significantly associated with decreased risk of CS rate consistently in both databases i.e. (aOR0.76; 95% CI: 0.66-0.87) in WHOGS, (aOR0.67; 95% CI: 0.59-0.76) in WHOMCS and (aOR0.70; 95% CI: 0.64-0.77) in combined database, compared to IOL. Regarding the adverse perinatal outcomes, ECS was significantly associated with increased risks of neonatal intensive care unit admission (aOR1.76; 95% CI: 1.28-2.42) in WHOMCS and (aOR1.51; 95% CI: 1.19-1.92) in combined database compared to IOL but not significant in WHOGS database. CONCLUSIONS: Compared to IOL, ECS significantly increased risk of NICU admission while EM was significantly associated with decreased risk of CS. ECS should not be recommended for women at 41 completed weeks of pregnancy. However, the choice between IOL and EM should be cautiously considered since the available evidences are still quite limited.