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Background Tubal ectopic pregnancies can cause significant morbidity or even death. Current treatment is with methotrexate or surgery. However, methotrexate treatment can fail in approximately 30% of women. Gefitinib, an epidermal growth factor receptor inhibitor, may improve the effects of methotrexate. We assessed the efficacy of administering oral gefitinib with methotrexate, versus methotrexate alone, to treat a tubal ectopic pregnancy. Objectives To test the hypothesis a combination of gefitinib with methotrexate can increase resolution of stable tubal ectopic pregnancy without the need for surgery, compared with methotrexate alone. Design A randomised, double-blind, placebo-controlled, multicentre, superiority trial. Setting Fifty UK hospitals. Participants A target of 328 women with a stable, tubal ectopic pregnancy. Intervention Women were randomised to combination of methotrexate and gefitinib or methotrexate and placebo. All participants received a single intramuscular dose of methotrexate 50 mg/m2 and were randomised in a 1:1 ratio of oral gefitinib (250 mg daily for 7 days) or placebo. Main outcome measures The primary outcome was surgical intervention for resolution of ectopic pregnancy. Secondary outcomes were the need for an additional dose of methotrexate, time to resolution of the ectopic pregnancy, number of treatment-associated hospital visits, safety and tolerability, acceptability of treatment and return to menses. Results Between 2 November 2016 and 6 October 2021, 328 women were randomly allocated to methotrexate and gefitinib (n = 165) or methotrexate and placebo (n = 163). Three women in the placebo group withdrew. Surgical intervention occurred in 30% (50/165) of the gefitinib group and in 29% (47/160) of the placebo group (adjusted risk ratio 1.15, 95% confidence interval 0.85 to 1.58; adjusted risk difference −0.01, 95% confidence interval −0.10 to 0.09; p = 0.37). Without surgical intervention, median time to resolution was 28.0 days in the gefitinib group and 28.0 days in the placebo group (subdistribution hazard ratio 1.03, 95% confidence interval 0.75 to 1.40). The need for additional methotrexate doses, number of additional hospital visits, participant acceptability, time to return of menses and serious adverse events were similar in both groups. Diarrhoea and rash were more common in the gefitinib group. Conclusions The addition of gefitinib to standard medical management with methotrexate to treat tubal ectopic pregnancy is not clinically effective as it does not reduce subsequent surgical intervention and is associated with higher rates of reported symptoms than placebo. Limitations We were unable to investigate how different gefitinib doses or modes of delivery would impact on the results. Future work Questions that remain unaddressed relate to the use of methotrexate and gefitinib combination treatment for other extrauterine and uterine ectopic pregnancy, such as caesarean scar pregnancies, or in the management of choriocarcinoma. Trial registration This trial is registered as ISRCTN 67795930 and EudraCT 2015-005013-76. Funding This project was funded by the National Institute for Health and Care Research (NIHR) Efficacy and Mechanism Evaluation (EME) programme and will be published in full in Efficacy and Mechanistic Evaluation; Vol. 10, No. 1. The gefitinib and placebo were supplied by Astra Zeneca. See the NIHR Journals Library website for further project information. Plain language summary What was the question? A tubal ectopic pregnancy is where a fertilised egg is not growing in the womb. The pregnancy cannot be saved and the woman is at risk of losing her fallopian tube and if this pregnancy is left to grow can even die. Current treatment is with methotrexate or surgery. An operation can happen because either the ectopic pregnancy has ruptured and caused internal bleeding, the medical treatment has not worked and the ectopic pregnancy needs to be removed or the patient can chose to have an operation. However, methotrexate treatment can fail in approximately 30% of women. We carried out research to see if the addition of a new drug (gefitinib, a drug used for lung cancer) to methotrexate could lower the number of women needing an operation to remove their ectopic pregnancy. What did we do? We involved 328 women with a stable tubal ectopic pregnancy, who were being treated medically with methotrexate, and randomly assigned them to have methotrexate alone or a combination of methotrexate and gefitinib. The gefitinib was taken in tablet form for 7 days, and the methotrexate was given as an injection. We followed the women up in line with their clinical care until their ectopic pregnancy resolved or they had surgery to remove the ectopic pregnancy. What did we find? The addition of gefitinib to methotrexate did not reduce the number of women who required surgery to remove their ectopic pregnancy. More women taking gefitinib experienced side effects, such as a facial rash or diarrhoea. What does this mean? Treatment with methotrexate remains the only drug treatment option for ectopic pregnancy. More research is needed. Scientific summary Background Tubal ectopic pregnancy (EP) can cause significant morbidity or even death. Current treatment is with methotrexate (MTX) or surgery. However, MTX treatment can fail in approximately 30% of women. Preclinical studies have shown that tubal implantation sites express high levels of epidermal growth factor receptor (EGFR) and that gefitinib (an EGFR antagonist) augments MTX-induced regression of pregnancy-like tissue. Clinical evidence from uncontrolled phase I and II trials has raised the possibility that a combination of MTX and gefitinib could be a more effective medical treatment than MTX alone to treat stable tubal EP. Objectives To test the hypothesis, a combination of gefitinib with MTX can increase resolution of stable tubal EP without the need for surgery, compared with MTX alone. Design A randomised, double-blind, placebo-controlled, multicentre, superiority trial. Setting This trial took place in 50 hospitals in the UK. Participants A target of 328 women with a stable, tubal EP. Intervention Participants were randomly assigned in a 1:1 ratio to receive either gefitinib and MTX or matched placebo and MTX with the use of minimisation to balance trial-group assignments according to baseline human chorionic gonadotropin levels (

BACKGROUND: Postpartum haemorrhage (PPH), defined as blood loss of 500 mL or more after childbirth, is the leading cause of maternal mortality worldwide. It is possible to prevent complications of PPH with timely and appropriate detection and management. However, implementing the best methods of PPH prevention, detection and management can be challenging, particularly in low- and middle-income countries. OBJECTIVES: Our overall objective was to explore the perceptions and experiences of women, community members, lay health workers, and skilled healthcare providers who have experience with PPH or with preventing, detecting, and managing PPH, in community or health facility settings. SEARCH METHODS: We searched MEDLINE, CINAHL, Scopus, and grey literature on 13 November 2022 with no language restrictions. We then performed reference checking and forward citation searching of the included studies. SELECTION CRITERIA: We included qualitative studies and mixed-methods studies with an identifiable qualitative component. We included studies that explored perceptions and experiences of PPH prevention, detection, and management among women, community members, traditional birth attendants, healthcare providers, and managers. DATA COLLECTION AND ANALYSIS: We used three-stage maximum variation sampling to ensure diversity in terms of relevance of the study to the review objectives, richness of data, and coverage of critical contextual elements: setting (region, country income level), perspective (type of participant), and topic (prevention, detection, management). We extracted data using a data extraction form designed for this review. We used thematic synthesis to analyse and synthesise the evidence, and we used the GRADE-CERQual (Confidence in the Evidence from Reviews of Qualitative research) approach to assess our confidence in each finding. To identify factors that may influence intervention implementation, we mapped each review finding to the Theoretical Domains Framework (TDF) and the Capability, Motivation, and Opportunity model of Behaviour change (COM-B). We used the Behaviour Change Wheel to explore implications for practice. MAIN RESULTS: We included 67 studies and sampled 43 studies for our analysis. Most were from low- or middle-income countries (33 studies), and most included the perspectives of women and health workers. We downgraded our confidence in several findings from high confidence to moderate, low, or very-low confidence, mainly due to concerns about how the studies were conducted (methodological limitations) or concerns about missing important perspectives from some types of participants or in some settings (relevance). In many communities, bleeding during and after childbirth is considered normal and necessary to expel impurities and restore and cleanse the womans body after pregnancy and birth (moderate confidence). In some communities, people have misconceptions about causes of PPH or believe that PPH is caused by supernatural powers or evil spirits that punish women for ignoring or disobeying social rules or for past mistakes (high confidence). For women who give birth at home or in the community, female family members or traditional birth attendants are the first to recognise excess bleeding after birth (high confidence). Family members typically take the decision of whether and when to seek care if PPH is suspected, and these family members are often influenced by trusted traditional birth attendants or community midwives (high confidence). If PPH is identified for women birthing at home or in the community, decision-making about the subsequent referral and care pathway can be multifaceted and complex (high confidence). First responders to PPH are not always skilled or trained healthcare providers (high confidence). In health facilities, midwives may consider it easy to implement visual estimation of blood loss with a kidney dish or under-pad, but difficult to accurately interpret the amount of blood loss (very low confidence). Quantifying (rather than estimating) blood loss may be a complex and contentious change of practice for health workers (low confidence). Women who gave birth in health facilities and experienced PPH described it as painful, embarrassing, and traumatic. Partners or other family members also found the experience stressful. While some women were dissatisfied with their level of involvement in decision-making for PPH management, others felt health workers were best placed to make decisions (moderate confidence). Inconsistent availability of resources (drugs, medical supplies, blood) causes delays in the timely management of PPH (high confidence). There is limited availability of misoprostol in the community owing to stockouts, poor supply systems, and the difficulty of navigating misoprostol procurement for community health workers (moderate confidence). Health workers described working on the maternity ward as stressful and intense due to short staffing, long shifts, and the unpredictability of emergencies. Exhausted and overwhelmed staff may be unable to appropriately monitor all women, particularly when multiple women are giving birth simultaneously or on the floor of the health facility; this could lead to delays in detecting PPH (moderate confidence). Inadequate staffing, high turnover of skilled health workers, and appointment of lower-level cadres of health workers are key challenges to the provision of quality PPH care (high confidence). Through team-based simulation training, health workers of different cadres (doctors, midwives, lay health workers) can develop a shared mental model to help them work quickly, efficiently, and amicably as a team when managing women with PPH (moderate confidence). AUTHORS CONCLUSIONS: Our findings highlight how improving PPH prevention, detection, and management is underpinned by a complex system of interacting roles and behaviours (community, women, health workers of different types and with different experiences). Multiple individual, sociocultural, and environmental factors influence the decisions and behaviours of women, families, communities, health workers, and managers. It is crucial to consider the broader health and social systems when designing and implementing PPH interventions to change or influence these behaviours. We have developed a set of prompts that may help programme managers, policymakers, researchers, and other key stakeholders to identify and address factors that affect implementation and scale-up of interventions to improve PPH prevention, detection, and management.

Introduction Postpartum haemorrhage (PPH) remains the leading cause of maternal death. Yet there is a lack of clarity around what research is needed to determine what works and how best to deliver proven PPH interventions. This article describes a WHO-led effort to develop a global PPH research agenda for 2023–2030, to reinvigorate research and innovation while avoiding duplication and waste.Methods Potential questions were culled from evidence gaps in a forthcoming Lancet PPH series, a pipeline analysis on PPH medicines and devices, international PPH guidelines, previous research prioritisation efforts and submissions from a reference group of PPH experts and stakeholders. Questions were deduplicated and consolidated, categorised into three tracks (innovation, implementation and cross-cutting) and subjected to an online prioritisation survey. Survey participants (n=120) assessed these questions using five criteria (answerability, effectiveness, deliverability, maximum potential for disease burden reduction and equity) following the Child Health and Nutrition Research Initiative methodology. The outcome of this exercise was complemented by an in-person consensus meeting (Global PPH Summit from 7 March 2023 to 10 March 2023 in Dubai, United Arab Emirates) to finalise the research agenda.Results Fifteen research questions (five per track) were identified as top priority. The top question per track called for research on the comparative effectiveness and safety of alternative routes of administration (other than the intravenous route) of tranexamic acid in the treatment of PPH (innovation); identifying barriers and facilitators affecting the adoption and use of evidence-based recommendations for PPH management (implementation) and the effectiveness of a strategy of early detection and first response treatment using a bundle of recommended interventions for improving PPH-related outcomes (cross-cutting).Conclusion This shared research agenda should guide future investments into PPH studies with high potential to transform policy and clinical practice in the near term to medium term. Funding for the new research priorities is urgently needed.

BackgroundPostpartum haemorrhage (PPH) is the leading cause of global maternal deaths, accounting for 30-50% of maternal deaths in sub-Saharan Africa. Most PPH-related deaths are preventable with timely detection and initiation of care, which may be facilitated by using a clinical care bundle. We explore influences on current PPH detection and management and on the future implementation of a new PPH bundle (E-MOTIVE) in low-resource, high-burden settings.MethodsSemi-structured qualitative interviews based on the Theoretical Domains Framework were conducted with 45 healthcare providers across nine hospitals in Nigeria, Kenya and South Africa, to identify barriers and enablers to current PPH detection and management and future implementation of a new PPH care bundle. Data were analysed using thematic and framework analysis. The Behaviour Change Wheel was used to identify potential interventions to address identified barriers and enablers.ResultsInfluences on current PPH detection and management fell under 12 domains: Environmental Context and Resources (drug and staff shortages), Skills (limited in-service training), Knowledge (variable understanding of the recommended practice), Behaviour Regulation (limited quality improvement culture), Beliefs about Consequences (drawbacks from inaccurate detection), Emotion (stress from the unpredictability of PPH), Social Influence (teamwork), Memory, Attention and Decision-making (limited guideline use), Social/Professional Role and Identity (role clarity), Beliefs about Capabilities (confidence in managing PPH), Reinforcement (disciplinary procedures) and Goals (PPH as a priority). Influences on bundle uptake included: Beliefs about Consequences (perceived benefits of new blood loss measurement tool), Environmental Context and Resources (high cost of drugs and new tools), Memory, Attention and Decision-making (concerns about whether bundle fits current practice), Knowledge (not understanding 'bundled' approach), Social Influence (acceptance by women and staff) and Intention (limited acceptance of 'bundled' approach over existing practice). These influences were consistent across countries. Proposed interventions included: Education, Training, Modelling (core and new skills), Enablement (monitoring uptake), Persuasion (leadership role) and Environmental Restructuring (PPH emergency trolley/kit).ConclusionsA wide range of individual, socio-cultural and environmental barriers and enablers to improving PPH detection and management exist in these settings. We identified a range of interventions that could improve PPH care and the implementation of new care bundles in this context.Trial registrationClinicalTrials.gov : NCT04341662.

Background Fetal growth restriction is associated with perinatal morbidity and mortality. Early identification of women having at-risk fetuses can reduce perinatal adverse outcomes. Objectives To assess the predictive performance of existing models predicting fetal growth restriction and birthweight, and if needed, to develop and validate new multivariable models using individual participant data. Design Individual participant data meta-analyses of cohorts in International Prediction of Pregnancy Complications network, decision curve analysis and health economics analysis. Participants Pregnant women at booking. External validation of existing models (9 cohorts, 441,415 pregnancies); International Prediction of Pregnancy Complications model development and validation (4 cohorts, 237,228 pregnancies). Predictors Maternal clinical characteristics, biochemical and ultrasound markers. Primary outcomes fetal growth restriction defined as birthweight 32 weeks). To assess if the performance of the prediction models is generalisable for various definitions of FGR, and assess the association between various birthweight centiles calculated using customised and population-based standards and perinatal morbidity and mortality. To estimate the net benefit (clinical utility) of the developed prediction models using decision curve analysis (DCA). To assess the costs and outcomes and the potential impact of resource use of the prediction models. Methods We followed existing recommendations for prediction model development and validation and reported in line with guidelines for prognostic research and IPD meta-analysis. Our meta-analysis utilised IPD within the IPPIC Network database. IPPIC is a living data repository of cleaned and harmonised data of pregnant women from large birth or population-based cohorts, study cohort data, registries or unpublished data from hospital records. The primary outcomes were (1) FGR defined as birthweight

Objective To predict birth weight at various potential gestational ages of delivery based on data routinely available at the first antenatal visit.Design Individual participant data meta-analysis.Data sources Individual participant data of four cohorts (237 228 pregnancies) from the International Prediction of Pregnancy Complications (IPPIC) network dataset.Eligibility criteria for selecting studies Studies in the IPPIC network were identified by searching major databases for studies reporting risk factors for adverse pregnancy outcomes, such as pre-eclampsia, fetal growth restriction, and stillbirth, from database inception to August 2019. Data of four IPPIC cohorts (237 228 pregnancies) from the US (National Institute of Child Health and Human Development, 2018; 233 483 pregnancies), UK (Allen et al, 2017; 1045 pregnancies), Norway (STORK Groruddalen research programme, 2010; 823 pregnancies), and Australia (Rumbold et al, 2006; 1877 pregnancies) were included in the development of the model.Results The IPPIC birth weight model was developed with random intercept regression models with backward elimination for variable selection. Internal-external cross validation was performed to assess the study specific and pooled performance of the model, reported as calibration slope, calibration-in-the-large, and observed versus expected average birth weight ratio. Meta-analysis showed that the apparent performance of the model had good calibration (calibration slope 0.99, 95% confidence interval (CI) 0.88 to 1.10; calibration-in-the-large 44.5 g, −18.4 to 107.3) with an observed versus expected average birth weight ratio of 1.02 (95% CI 0.97 to 1.07). The proportion of variation in birth weight explained by the model (R2) was 46.9% (range 32.7-56.1% in each cohort). On internal-external cross validation, the model showed good calibration and predictive performance when validated in three cohorts with a calibration slope of 0.90 (Allen cohort), 1.04 (STORK Groruddalen cohort), and 1.07 (Rumbold cohort), calibration-in-the-large of −22.3 g (Allen cohort), −33.42 (Rumbold cohort), and 86.4 g (STORK Groruddalen cohort), and observed versus expected ratio of 0.99 (Rumbold cohort), 1.00 (Allen cohort), and 1.03 (STORK Groruddalen cohort); respective pooled estimates were 1.00 (95% CI 0.78 to 1.23; calibration slope), 9.7 g (−154.3 to 173.8; calibration-in-the-large), and 1.00 (0.94 to 1.07; observed v expected ratio). The model predictions were more accurate (smaller mean square error) in the lower end of predicted birth weight, which is important in informing clinical decision making.Conclusions The IPPIC birth weight model allowed birth weight predictions for a range of possible gestational ages. The model explained about 50% of individual variation in birth weights, was well calibrated (especially in babies at high risk of fetal growth restriction and its complications), and showed promising performance in four different populations included in the individual participant data meta-analysis. Further research to examine the generalisability of performance in other countries, settings, and subgroups is required.Trial registration PROSPERO CRD42019135045

Objective There are no globally agreed on strategies on early detection and first response management of postpartum haemorrhage (PPH) during and after caesarean birth. Our study aimed to develop an international expert’s consensus on evidence-based approaches for early detection and obstetric first response management of PPH intraoperatively and postoperatively in caesarean birth.Design Systematic review and three-stage modified Delphi expert consensus.Setting International.Population Panel of 22 global experts in PPH with diverse backgrounds, and gender, professional and geographic balance.Outcome measures Agreement or disagreement on strategies for early detection and first response management of PPH at caesarean birth.Results Experts agreed that the same PPH definition should apply to both vaginal and caesarean birth. For the intraoperative phase, the experts agreed that early detection should be accomplished via quantitative blood loss measurement, complemented by monitoring the woman’s haemodynamic status; and that first response should be triggered once the woman loses at least 500 mL of blood with continued bleeding or when she exhibits clinical signs of haemodynamic instability, whichever occurs first. For the first response, experts agreed on immediate administration of uterotonics and tranexamic acid, examination to determine aetiology and rapid initiation of cause-specific responses. In the postoperative phase, the experts agreed that caesarean birth-related PPH should be detected primarily via frequently monitoring the woman’s haemodynamic status and clinical signs and symptoms of internal bleeding, supplemented by cumulative blood loss assessment performed quantitatively or by visual estimation. Postoperative first response was determined to require an individualised approach.Conclusion These agreed on proposed approaches could help improve the detection of PPH in the intraoperative and postoperative phases of caesarean birth and the first response management of intraoperative PPH. Determining how best to implement these strategies is a critical next step.

BackgroundPostpartum haemorrhage (PPH) is the leading cause of maternal death globally. Most PPH deaths can be avoided with timely detection and management; however, critical challenges persist. A multi-country cluster-randomised trial (E-MOTIVE) will introduce a clinical care bundle for early detection and first-response PPH management in hospital settings. This formative qualitative study aimed to explore healthcare providers' knowledge and practices of PPH detection and management after vaginal birth, to inform design and implementation of E-MOTIVE.MethodsBetween July 2020-June 2021, semi-structured qualitative interviews were conducted with 45 maternity healthcare providers (midwives, nurses, doctors, managers) of nine hospitals in Kenya, Nigeria, and South Africa. A thematic analysis approach was used.ResultsFour key themes were identified, which varied across contexts: in-service training on emergency obstetric care; limited knowledge about PPH; current approaches to PPH detection; and current PPH management and associated challenges. PPH was recognised as an emergency but understanding of PPH varied. Early PPH detection was limited by the subjective nature of visual estimation of blood loss. Lack of expertise on PPH detection and using visual estimation can result in delays in initiation of PPH management. Shortages of trained staff and essential resources, and late inter-hospital referrals were common barriers to PPH management.ConclusionThere are critical needs to address context-specific barriers to early and timely detection and management of PPH in hospital settings. These findings will be used to develop evidence-informed implementation strategies, such as improved in-service training, and objective measurement of blood loss, which are key components of the E-MOTIVE trial (Trial registration: ClinicalTrials.gov: NCT04341662).

BackgroundPostpartum hemorrhage (PPH) is the leading cause of maternal death worldwide. When PPH occurs, early identification of bleeding and prompt management using evidence-based guidelines, can avert most PPH-related severe morbidities and deaths. However, adherence to the World Health Organization recommended practices remains a critical challenge. A potential solution to inefficient and inconsistent implementation of evidence-based practices is the application of a 'clinical care bundle' for PPH management. A clinical care bundle is a set of discrete, evidence-based interventions, administered concurrently, or in rapid succession, to every eligible person, along with teamwork, communication, and cooperation. Once triggered, all bundle components must be delivered. The E-MOTIVE project aims to improve the detection and first response management of PPH through the implementation of the "E-MOTIVE" bundle, which consists of (1) Early PPH detection using a calibrated drape, (2) uterine Massage, (3) Oxytocic drugs, (4) Tranexamic acid, (5) Intra Venous fluids, and (6) genital tract Examination and escalation when necessary. The objective of this paper is to describe the protocol for the formative phase of the E-MOTIVE project, which aims to design an implementation strategy to support the uptake of this bundle into practice.MethodsWe will use behavior change and implementation science frameworks [e.g. capability, opportunity, motivation and behavior (COM-B) and theoretical domains framework (TDF)] to guide data collection and analysis, in Kenya, Nigeria, South Africa, Sri Lanka, and Tanzania. There are four methodological components: qualitative interviews; surveys; systematic reviews; and design workshops. We will triangulate findings across data sources, participant groups, and countries to explore factors influencing current PPH detection and management, and potentially influencing E-MOTIVE bundle implementation. We will use these findings to develop potential strategies to improve implementation, which will be discussed and agreed with key stakeholders from each country in intervention design workshops.DiscussionThis formative protocol outlines our strategy for the systematic development of the E-MOTIVE implementation strategy. This focus on implementation considers what it would take to support roll-out and implementation of the E-MOTIVE bundle. Our approach therefore aims to maximize internal validity in the trial alongside future scalability, and implementation of the E-MOTIVE bundle in routine practice, if proven to be effective.Trial registrationClinicalTrials.gov: NCT04341662.

The rate of decline in the global burden of avoidable maternal deaths has stagnated and remains an issue of concern in many sub-Saharan Africa countries. As per the most recent evidence, an average maternal mortality ratio (MMR) of 223 deaths per 100,000 live births has been estimated globally, with sub-Saharan Africa's average MMR at 536 per 100,000 live births-more than twice the global average. Despite the high MMR, there is variation in MMR between and within sub-Saharan Africa countries. Differences in the behaviour of those accessing and/or delivering maternal healthcare may explain variations in outcomes and provide a basis for quality improvement in health systems. There is a gap in describing the landscape of interventions aimed at modifying the behaviours of those accessing and delivering maternal healthcare for improving maternal health outcomes in sub-Saharan Africa. Our objective was to extract and synthesise the target behaviours, component behaviour change strategies and outcomes of behaviour change interventions for improving maternal health outcomes in sub-Saharan Africa. We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines. Our protocol was published a priori on PROSPERO (registration number CRD42022315130). We searched ten electronic databases (PsycINFO, Cochrane Database of Systematic Reviews, International Bibliography of Social Sciences, EMBASE, MEDLINE, Scopus, CINAHL PLUS, African Index Medicus, African Journals Online, and Web of Science) and included randomised trials and quasi-experimental studies. We extracted target behaviours and specified the behavioural interventions using the Action, Actor, Context, Time, and Target (AACTT) framework. We categorised the behaviour change strategies using the intervention functions described in the Behaviour Change Wheel (BCW). We reviewed 52 articles (26 randomized trials and 26 quasi-experimental studies). They had a mixed risk of bias. Out of these, 41 studies (78.8%) targeted behaviour change of those accessing maternal healthcare services, while seven studies (13.5%) focused on those delivering maternal healthcare. Four studies (7.7%) targeted mixed stakeholder groups. The studies employed a range of behaviour change strategies, including education 37 (33.3%), persuasion 20 (18%), training 19 (17.1%), enablement 16 (14.4%), environmental restructuring 8 (7.2%), modelling 6 (5.4%) and incentivisation 5 (4.5%). No studies used restriction or coercion strategies. Education was the most common strategy for changing the behaviour of those accessing maternal healthcare, while training was the most common strategy in studies targeting the behaviour of those delivering maternal healthcare. Of the 52 studies, 40 reported effective interventions, 7 were ineffective, and 5 were equivocal. A meta-analysis was not feasible due to methodological and clinical heterogeneity across the studies. In conclusion, there is evidence of effective behaviour change interventions targeted at those accessing and/or delivering maternal healthcare in sub-Saharan Africa. However, more focus should be placed on behaviour change by those delivering maternal healthcare within the health facilities to fast-track the reduction of the huge burden of avoidable maternal deaths in sub-Saharan Africa.

Abstract Background The success rate of IVF treatment is low. A recent systematic review and meta-analysis found that the outcome of IVF treatment could be improved in patients who have experienced recurrent implantation failure if an outpatient hysteroscopy (OH) is performed before starting the new treatment cycle. However, the trials were of variable quality, leading to a call for a large and high-quality randomised trial. This protocol describes a multi-centre randomised controlled trial to test the hypothesis that performing an OH prior to starting an IVF cycle improves the live birth rate of the subsequent IVF cycle in women who have experienced two to four failed IVF cycles. Methods and design Eligible and consenting women will be randomised to either OH or no OH using an internet based trial management programme that ensures allocation concealment and employs minimisation for important stratification variables including age, body mass index, basal follicle stimulating hormone level and number of previous failed IVF cycles. The primary outcome is live birth rate per IVF cycle started. Other outcomes include implantation, clinical pregnancy and miscarriage rates. The sample size for this study has been estimated as 758 participants with 379 participants in each arm. Interim analysis will be conducted by an independent Data Monitoring Committee (DMC), and final analysis will be by intention to treat. A favourable ethical opinion has been obtained (REC reference: 09/H0804/32). Trail Registration The trial has been assigned the following ISRCTN number: ISRCTN35859078

Abstract Background Proteinuria is one of the essential criteria for the clinical diagnosis of pre-eclampsia. Increasing levels of proteinuria is considered to be associated with adverse maternal and fetal outcomes. We aim to determine the accuracy with which the amount of proteinuria predicts maternal and fetal complications in women with pre-eclampsia by systematic quantitative review of test accuracy studies. Methods We conducted electronic searches in MEDLINE (1951 to 2007), EMBASE (1980 to 2007), the Cochrane Library (2007) and the MEDION database to identify relevant articles and hand-search of selected specialist journals and reference lists of articles. There were no language restrictions for any of these searches. Two reviewers independently selected those articles in which the accuracy of proteinuria estimate was evaluated to predict maternal and fetal complications of pre-eclampsia. Data were extracted on study characteristics, quality and accuracy to construct 2 × 2 tables with maternal and fetal complications as reference standards. Results Sixteen primary articles with a total of 6749 women met the selection criteria with levels of proteinuria estimated by urine dipstick, 24-hour urine proteinuria or urine protein:creatinine ratio as a predictor of complications of pre-eclampsia. All 10 studies predicting maternal outcomes showed that proteinuria is a poor predictor of maternal complications in women with pre-eclampsia. Seventeen studies used laboratory analysis and eight studies bedside analysis to assess the accuracy of proteinuria in predicting fetal and neonatal complications. Summary likelihood ratios of positive and negative tests for the threshold level of 5 g/24 h were 2.0 (95% CI 1.5, 2.7) and 0.53 (95% CI 0.27, 1) for stillbirths, 1.5 (95% CI 0.94, 2.4) and 0.73 (95% CI 0.39, 1.4) for neonatal deaths and 1.5 (95% 1, 2) and 0.78 (95% 0.64, 0.95) for Neonatal Intensive Care Unit admission. Conclusion Measure of proteinuria is a poor predictor of either maternal or fetal complications in women with pre-eclampsia.

Abstract Background Pre-eclampsia is associated with several complications. Early prediction of complications and timely management is needed for clinical care of these patients to avert fetal and maternal mortality and morbidity. There is a need to identify best testing strategies in pre eclampsia to identify the women at increased risk of complications. We aim to determine the accuracy of various tests to predict complications of pre-eclampsia by systematic quantitative reviews. Method We performed extensive search in MEDLINE (1951–2004), EMBASE (1974–2004) and also will also include manual searches of bibliographies of primary and review articles. An initial search has revealed 19500 citations. Two reviewers will independently select studies and extract data on study characteristics, quality and accuracy. Accuracy data will be used to construct 2 × 2 tables. Data synthesis will involve assessment for heterogeneity and appropriately pooling of results to produce summary Receiver Operating Characteristics (ROC) curve and summary likelihood ratios. Discussion This review will generate predictive information and integrate that with therapeutic effectiveness to determine the absolute benefit and harm of available therapy in reducing complications in women with pre-eclampsia.

Abstract Background Poor response to ovarian stimulation with exogenous gonadotrophins occurs in 9–24% of women undergoing in vitro fertilisation (IVF) treatment, which represents an estimated 4000–10,000 women per year in the UK. Poor responders often have their treatment cycle cancelled because of expected poor outcome. One treatment strategy that may influence outcome is the choice of pituitary suppression regimen prior to the initiation of ovarian stimulation. The three commonly used pituitary suppression regimens in IVF treatment are: (1) the GnRH agonist long regimen, (2) the GnRH agonist short regimen and (3) the GnRH antagonist regimen. A systematic review of randomised controlled trials of these pituitary suppression regimens has shown the evidence to be either inconclusive or inconsistent. We therefore designed a three arm randomised trial to evaluate the effectiveness of these regimens in women who had poor ovarian response in a previous IVF treatment cycle. Methods/design Consenting, eligible women will be randomised to one of the three regimens using an internet-based trial management programme that ensures allocation concealment and employs block randomisation and minimisation for prognostic variables. The primary outcome is the number of oocytes retrieved. Other outcomes include total dose of follicle stimulating hormone (FSH) used for ovarian stimulation, mature oocytes retrieved, embryos available for transfer, implantation rate and clinical pregnancy rate. The sample size for this trial has been estimated as 102 participants with 34 participants in each of the three arms. Appropriate interim analysis will be conducted by a Data Monitoring and Ethics Committee (DMEC), and the final analysis will be by intention to treat. Trial registration ISRCTN27044628

Abstract Background At postgraduate level evidence based medicine (EBM) is currently taught through tutor based lectures. Computer based sessions fit around doctors' workloads, and standardise the quality of educational provision. There have been no randomized controlled trials comparing computer based sessions with traditional lectures at postgraduate level within medicine. Methods This was a randomised controlled trial involving six postgraduate education centres in the West Midlands, U.K. Fifty five newly qualified foundation year one doctors (U.S internship equivalent) were randomised to either computer based sessions or an equivalent lecture in EBM and systematic reviews. The change from pre to post-intervention score was measured using a validated questionnaire assessing knowledge (primary outcome) and attitudes (secondary outcome). Results Both groups were similar at baseline. Participants' improvement in knowledge in the computer based group was equivalent to the lecture based group (gain in score: 2.1 [S.D = 2.0] versus 1.9 [S.D = 2.4]; ANCOVA p = 0.078). Attitudinal gains were similar in both groups. Conclusion On the basis of our findings we feel computer based teaching and learning is as effective as typical lecture based teaching sessions for educating postgraduates in EBM and systematic reviews.

Abstract Background Restriction of fetal growth and compromise of fetal wellbeing remain significant causes of perinatal death and childhood disability. At present, there is a lack of scientific consensus about the best strategies for predicting these conditions before birth. Therefore, there is uncertainty about the best management of pregnant women who might have a growth restricted baby. This is likely to be due to a dearth of clear collated information from individual research studies drawn from different sources on this subject. Methods/Design A series of systematic reviews and meta-analyses will be undertaken to determine, among pregnant women, the accuracy of various tests to predict and/or diagnose fetal growth restriction and compromise of fetal wellbeing. We will search Medline, Embase, Cochrane Library, MEDION, citation lists of review articles and eligible primary articles and will contact experts in the field. Independent reviewers will select studies, extract data and assess study quality according to established criteria. Language restrictions will not be applied. Data synthesis will involve meta-analysis (where appropriate), exploration of heterogeneity and publication bias. Discussion The project will collate and synthesise the available evidence regarding the value of the tests for predicting restriction of fetal growth and compromise of fetal wellbeing. The systematic overviews will assess the quality of the available evidence, estimate the magnitude of potential benefits, identify those tests with good predictive value and help formulate practice recommendations.

Abstract Background A variety of methods exists for teaching and learning evidence-based medicine (EBM). However, there is much debate about the effectiveness of various EBM teaching and learning activities, resulting in a lack of consensus as to what methods constitute the best educational practice. There is a need for a clear hierarchy of educational activities to effectively impart and acquire competence in EBM skills. This paper develops such a hierarchy based on current empirical and theoretical evidence. Discussion EBM requires that health care decisions be based on the best available valid and relevant evidence. To achieve this, teachers delivering EBM curricula need to inculcate amongst learners the skills to gain, assess, apply, integrate and communicate new knowledge in clinical decision-making. Empirical and theoretical evidence suggests that there is a hierarchy of teaching and learning activities in terms of their educational effectiveness: Level 1, interactive and clinically integrated activities; Level 2(a), interactive but classroom based activities; Level 2(b), didactic but clinically integrated activities; and Level 3, didactic, classroom or standalone teaching. Summary All health care professionals need to understand and implement the principles of EBM to improve care of their patients. Interactive and clinically integrated teaching and learning activities provide the basis for the best educational practice in this field.

Abstract Background Systematic reviews and meta-analyses of test accuracy studies are increasingly being recognised as central in guiding clinical practice. However, there is currently no dedicated and comprehensive software for meta-analysis of diagnostic data. In this article, we present Meta-DiSc, a Windows-based, user-friendly, freely available (for academic use) software that we have developed, piloted, and validated to perform diagnostic meta-analysis. Results Meta-DiSc a) allows exploration of heterogeneity, with a variety of statistics including chi-square, I-squared and Spearman correlation tests, b) implements meta-regression techniques to explore the relationships between study characteristics and accuracy estimates, c) performs statistical pooling of sensitivities, specificities, likelihood ratios and diagnostic odds ratios using fixed and random effects models, both overall and in subgroups and d) produces high quality figures, including forest plots and summary receiver operating characteristic curves that can be exported for use in manuscripts for publication. All computational algorithms have been validated through comparison with different statistical tools and published meta-analyses. Meta-DiSc has a Graphical User Interface with roll-down menus, dialog boxes, and online help facilities. Conclusion Meta-DiSc is a comprehensive and dedicated test accuracy meta-analysis software. It has already been used and cited in several meta-analyses published in high-ranking journals. The software is publicly available at http://www.hrc.es/investigacion/metadisc_en.htm.

Abstract Background To empirically evaluate bias in estimation of accuracy associated with delay in verification of diagnosis among studies evaluating tests for predicting endometrial hyperplasia. Methods Systematic reviews of all published research on accuracy of miniature endometrial biopsy and endometr ial ultrasonography for diagnosing endometrial hyperplasia identified 27 test accuracy studies (2,982 subjects). Of these, 16 had immediate histological verification of diagnosis while 11 had verification delayed > 24 hrs after testing. The effect of delay in verification of diagnosis on estimates of accuracy was evaluated using meta-regression with diagnostic odds ratio (dOR) as the accuracy measure. This analysis was adjusted for study quality and type of test (miniature endometrial biopsy or endometrial ultrasound). Results Compared to studies with immediate verification of diagnosis (dOR 67.2, 95% CI 21.7–208.8), those with delayed verification (dOR 16.2, 95% CI 8.6–30.5) underestimated the diagnostic accuracy by 74% (95% CI 7%–99%; P value = 0.048). Conclusion Among studies of miniature endometrial biopsy and endometrial ultrasound, diagnostic accuracy is considerably underestimated if there is a delay in histological verification of diagnosis.

Abstract Background Case reports are frequently published in the health care literature, however advice on preparing such reports using the "instructions to authors" pages of journals is alleged to be limited. However, to our knowledge, this has not been formally evaluated. As roles of case reports may vary according to the case and the clinical specialities, one might expect the advice to authors to vary according to journal clinical grouping. Methods We surveyed the current advice available to authors of case reports from 'instructions to authors' pages of a core collection of 249 journals ('Hague' list). These were examined and compared for advice or recommendation on writing case reports. Of these, 163 (65%) published case reports and provided instructions on this publication type. Data were extracted on items of style and content of case reports, using a piloted data extraction form. Results Journals that published case reports were grouped into medical (n = 81, 50%), surgical (n = 38, 23%) and generic or multidisciplinary (n = 44, 27%) categories. There was a difference among the medical, surgical and generic or multidisciplinary journals in the maximum number of words and pages allowed but no difference in the number of figures, tables, references, authors, abstract or synopsis, indexing or key words and consent. Additionally, there was no statistically significant difference among the three different categories of journals regarding the content of the case reports. Conclusions Of the journals reviewed, we found that 'instructions to authors' pages provided limited and varied information for preparing a case report. There is a need for consensus, and more consistent guidance for authors of case report.

Women and couples who have had the misfortune of losing pregnancies, particularly multiple pregnancies, would often wish to know why the miscarriages happened. This information is important for them to make sense of the loss, help with closure, and seek treatments to avoid future miscarriages. Healthcare practitioners would want to know the reason for the miscarriages so that they can provide accurate prognostic information and offer targeted treatments to improve future pregnancy outcomes. The deeply felt need for finding reasons for miscarriages has led to the proliferation of multiple tests. But which one are useful? And which ones are fake? Which test results show an association with miscarriage, have prognostic value, and guide treatment? Which ones don’t? This lecture takes an evidence-based lens to these questions to tease apart the real news from fake news.

Many miscarriages occur due to chromosomal problems, and may not be preventable. But there are many miscarriages that result from the loss of euploid embryos. Why are these pregnancies lost? Where is the problem, and what can be done? There is a pervasive and harmful idea that miscarriages are nature’s way of dealing with an abnormal pregnancy, and therefore they cannot really be prevented, and we do not need to try to prevent them. This idea ignores the fact that there are several steps that can be taken to reduce the risk of miscarriage. This lecture asks the questions: what can a woman or couple do to reduce their risk of miscarriage? What can a healthcare provider do to reduce the risk of miscarriage? What is evidence? What are the limitations in the evidence? The recently updated evidence-based NICE, RCOG and ESHRE guidelines form the foundation of this lecture.

Background: Postpartum haemorrhage (PPH) is the leading cause of maternal morbidity and mortality worldwide. The reported incidence of PPH varies globally, which is often due to the use of subjective visual estimation of blood loss. The aim of this study was to measure the rate of PPH and severe PPH at a UK hospital using objective measurement of blood loss. Methods: Blood loss after vaginal birth was objectively measured in 2009 women at Birmingham Women’s Hospital, UK using a blood collection drape. Results: The postpartum haemorrhage rate, defined as blood loss of 500 mL or more, was 22.2%. The severe PPH rate, defined as blood loss of 1000 mL or more, was 5.3%. Conclusions: The objective measurement of blood loss following vaginal birth is necessary for the accurate calculation of PPH rates.