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Background Heterogeneity in the outcomes collected and reported in trials of interventions to prevent obesity in the first five years of life highlights the need for a core outcome set to streamline intervention evaluation and synthesis of effects. This study aimed to develop a core outcome set for use in early childhood obesity prevention intervention studies in children from birth to five years of age (COS-EPOCH). Methods The development of the core outcome set followed published guidelines and consisted of three stages: (1) systematic scoping review of outcomes collected and reported in early childhood obesity prevention trials; (2) e-Delphi study with stakeholders to prioritise outcomes; (3) meeting with stakeholders to reach consensus on outcomes. Stakeholders included parents/caregivers of children aged ≤ five years, policy-makers/funders, researchers, health professionals, and community and organisational stakeholders interested in obesity prevention interventions. Results Twenty-two outcomes from nine outcome domains (anthropometry, dietary intake, sedentary behaviour, physical activity, sleep, outcomes in parents/caregivers, environmental, emotional/cognitive functioning, economics) were included in the core outcome set: infant tummy time; child diet quality, dietary intake, fruit and vegetable intake, non-core food intake, non-core beverage intake, meal patterns, weight-based anthropometry, screentime, time spent sedentary, physical activity, sleep duration, wellbeing; parent/caregiver physical activity, sleep and nutrition parenting practices; food environment, sedentary behaviour or physical activity home environment, family meal environment, early childhood education and care environment, household food security; economic evaluation. Conclusions The systematic stakeholder-informed study identified the minimum outcomes recommended for collection and reporting in early childhood obesity prevention trials. Future work will investigate the recommended instruments to measure each of these outcomes. The core outcome set will standardise guidance on the measurement and reporting of outcomes from early childhood obesity prevention interventions, to better facilitate evidence comparison and synthesis, and maximise the value of data collected across studies.

Background: Internationally recognized guidelines recommend the judicious use of low oxygen (21–30%), titrated to peripheral oxygen saturation targets, for the initiation of resuscitation of very and extremely preterm infants (Aims: This study aims to assess the effect of various initial oxygen concentrations on (1) all-cause mortality, chronic lung disease, intraventricular hemorrhage, and retinopathy of prematurity; and (2) reaching the prescribed oxygen saturation targets by 5 min after birth, in preterm infants requiring resuscitation. Methods: We will conduct a systematic review and network meta-analysis using individual participant data. Studies of preterm infants Discussion: This is the first individual participant data network meta-analysis of initial oxygen concentrations for the resuscitation of preterm infants. This novel approach may address long-standing uncertainty regarding optimal oxygen supplementation practice for the resuscitation of preterm infants

The cornerstone of obesity treatment is behavioural weight management, resulting in significant improvements in cardio-metabolic and psychosocial health. However, there is ongoing concern that dietary interventions used for weight management may precipitate the development of eating disorders. Systematic reviews demonstrate that, while for most participants medically supervised obesity treatment improves risk scores related to eating disorders, a subset of people who undergo obesity treatment may have poor outcomes for eating disorders. This review summarises the background and rationale for the formation of the Eating Disorders In weight-related Therapy (EDIT) Collaboration. The EDIT Collaboration will explore the complex risk factor interactions that precede changes to eating disorder risk following weight management. In this review, we also outline the programme of work and design of studies for the EDIT Collaboration, including expected knowledge gains. The EDIT studies explore risk factors and the interactions between them using individual-level data from international weight management trials. Combining all available data on eating disorder risk from weight management trials will allow sufficient sample size to interrogate our hypothesis: that individuals undertaking weight management interventions will vary in their eating disorder risk profile, on the basis of personal characteristics and intervention strategies available to them. The collaboration includes the integration of health consumers in project development and translation. An important knowledge gain from this project is a comprehensive understanding of the impact of weight management interventions on eating disorder risk.

The Eating Disorders In weight-related Therapy (EDIT) Collaboration brings together data from randomised controlled trials of behavioural weight management interventions to identify individual participant risk factors and intervention strategies that contribute to eating disorder risk. We present a protocol for a systematic review and individual participant data (IPD) meta-analysis which aims to identify participants at risk of developing eating disorders, or related symptoms, during or after weight management interventions conducted in adolescents or adults with overweight or obesity. We systematically searched four databases up to March 2022 and clinical trials registries to May 2022 to identify randomised controlled trials of weight management interventions conducted in adolescents or adults with overweight or obesity that measured eating disorder risk at pre- and post-intervention or follow-up. Authors from eligible trials have been invited to share their deidentified IPD. Two IPD meta-analyses will be conducted. The first IPD meta-analysis aims to examine participant level factors associated with a change in eating disorder scores during and following a weight management intervention. To do this we will examine baseline variables that predict change in eating disorder risk within intervention arms. The second IPD meta-analysis aims to assess whether there are participant level factors that predict whether participation in an intervention is more or less likely than no intervention to lead to a change in eating disorder risk. To do this, we will examine if there are differences in predictors of eating disorder risk between intervention and no-treatment control arms. The primary outcome will be a standardised mean difference in global eating disorder score from baseline to immediately post-intervention and at 6- and 12-months follow-up. Identifying participant level risk factors predicting eating disorder risk will inform screening and monitoring protocols to allow early identification and intervention for those at risk.

Clinicians favour low oxygen concentrations when resuscitating preterm infants immediately after birth despite inconclusive evidence to support this practice. Prospective meta-analysis (PMA) is a novel approach where studies are identified as eligible for inclusion in the meta-analysis before their results are known.To explore whether high (60%) or low (30%) oxygen is associated with greater efficacy and safety for the initial resuscitation (immediately after birth) of preterm infants born at29 weeks' gestation.We will conduct a prospective meta-analysis (PMA) with individual participant data (IPD). We will perform a systematic search to identify ongoing RCTs including infants29 weeks' gestation randomised to high (60%) or low (30%) oxygen for initial resuscitation after birth. IPD will be sought for all infants randomised for the purpose of meta-analysis. We will employ a one-stage random-effects approach to IPD meta-analysis. Potential heterogeneity and the differential effect of high or low oxygen will be explored through subgroup and interaction analyses. The primary outcome of this study is all-cause mortality prior to hospital discharge. There will be a follow-up analysis of neurodevelopmental outcomes once available.The results of neonatal outcomes at hospital discharge are expected by 2025, and neurodevelopmental outcomes by 2027.

Although early childhood obesity prevention has become an important issue internationally, little evidence exists regarding longer term effects (i.e., sustainability) of early interventions.To determine whether intervention benefits at 2 years of age were sustained at 3.5 and 5 years.Follow-up of the Early Prevention of Obesity in Children (EPOCH) individual participant data prospective meta-analysis of four randomized controlled trials including 2196 mother-child dyads at baseline. Interventions were home- or community-based, commenced within 6 months of birth, ended by 2 years of age, and comprised multiple sessions. Controls received standard care. BMI z-score (primary outcome), other anthropometric measures and weight-related behaviours were initially measured at 1.5-2 years and followed up at 3.5 and 5 years.Positive intervention effects on BMI z-scores at 1.5-2 years of age were not apparent by 3.5 years (-0.04 adjusted mean difference; 95% CI:-0.14, 0.06; p = 0.424), and 5 years (0.03; 95% CI: -0.08, 0.14; p = 0.60). While prolonged intervention benefits were detected for a few, but not the majority of, weight-related behaviours at 3.5 years, these effects diminished over time.This meta-analysis found that initial positive effects of childhood obesity interventions faded out after interventions ended, pointing toward the importance of a suite of interventions implemented at multiple stages across childhood.

Internationally recognized guidelines recommend the judicious use of low oxygen (21-30%), titrated to peripheral oxygen saturation targets, for the initiation of resuscitation of very and extremely preterm infants (32 weeks' gestation). However, despite more than 10 randomized controlled trials on this question, the ideal initial oxygen concentration for this group of vulnerable infants remains uncertain.This study aims to assess the effect of various initial oxygen concentrations on (1) all-cause mortality, chronic lung disease, intraventricular hemorrhage, and retinopathy of prematurity; and (2) reaching the prescribed oxygen saturation targets by 5 min after birth, in preterm infants requiring resuscitation.We will conduct a systematic review and network meta-analysis using individual participant data. Studies of preterm infants32 weeks' gestation, randomized to initial oxygen concentration, will be included. We will systematically search medical databases and trial registries for eligible studies (published or unpublished). Records will be screened by two independent reviewers, with conflicts resolved by the inclusion of a third reviewer. Identified initial oxygen concentrations will be grouped into the following nodes: low (≤30%), intermediate (60%), and high (≥90%) oxygen. A two-step random-effects contrast-based network meta-regression will be calculated to compare and rank different oxygen concentrations. Analyses will be intention-to-treat, with the primary outcome of all-cause mortality.This is the first individual participant data network meta-analysis of initial oxygen concentrations for the resuscitation of preterm infants. This novel approach may address long-standing uncertainty regarding optimal oxygen supplementation practice for the resuscitation of preterm infants32 weeks' gestation.

Childhood obesity remains a major public health issue and priority area for action. Promisingly, obesity prevention interventions in the first 2000 days of life have shown modest effectiveness in improving health behaviours and healthy weight status in children. Yet, researchers in this field face several challenges. This can lead to research waste and impede progress towards delivering effective, scalable solutions. In this perspective article, we describe some of the key challenges in early childhood obesity prevention and outline innovative and collaborative solutions to overcome these. Combining these solutions will accelerate the generation of high-quality evidence that can be implemented into policy and practice.

This scoping review was undertaken as the first stage of development of the Core Outcome Sets for Early Prevention of Obesity in CHildhood (COS-EPOCH). The aim of this review is to identify the outcomes collected and reported in randomized controlled trials of early childhood obesity prevention interventions. A systematic scoping review was undertaken following published guidelines. Trial registries and Medline were searched, and records retrieved were screened by two reviewers. Included trials aimed to prevent childhood obesity in the first 5 years of life and were randomized. Data were extracted using a standardized form. Outcomes were assigned to outcome domains, and similar definitions within each domain were merged, based on key literature and expert consensus. Outcome and domain frequencies were estimated and presented in outcome matrices. Eighteen outcome domains were identified from 161 included studies: "anthropometry," "dietary intake," "physical activity," "sedentary behaviour," "emotional functioning/wellbeing," "feeding," "cognitive/executive functioning," "sleep," "other," "study-related," "parenting practices," "motor skill development," "environmental," "blood and lymphatic system," "perceptions and preferences," "quality of life," and "economic," "oral health." The most frequently reported outcome domain was anthropometry (92% of studies), followed by dietary intake (77%) and physical activity (60%). 221 unique outcomes were identified, indicating a high degree of heterogeneity. Body mass index was the only outcome reported in >50% of studies. The considerable heterogeneity in outcomes supports the need for the development of COS-EPOCH.

Behaviour change technique (BCT) taxonomies provide one approach to unpack the complexity of childhood obesity prevention interventions. This scoping review sought to examine how BCT taxonomies have been applied to understand childhood obesity prevention interventions targeting children aged 12 years or under and/or their caregivers. A systematic search was conducted in Medline, Embase, PsycINFO, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, CINAHL and PROSPERO, to capture all eligible research up to February 2021. No limits were placed on country, language, publication dates, or full text availability. Eligible studies included any study design that applied a BCT taxonomy and evaluated behavioural childhood obesity prevention interventions targeting children aged 12 years or under and/or their parents or caregivers. Sixty-three records, describing 54 discrete studies were included; 32 applied a BCT taxonomy prospectively (i.e., to design interventions) and 23 retrospectively (i.e., to assess interventions), 1 study did both. There was substantial variation in the methods used to apply BCT taxonomies and to report BCT-related methods and results. There was a paucity of detail reported in how BCTs were selected in studies applying BCT taxonomies prospectively. Our review provides important insight into the application of BCT taxonomies in childhood obesity prevention and several ongoing challenges, pointing to the need for best practice reporting guidance.

Background There are major health disparities between Indigenous and non-Indigenous Australians. To address this, it is vital to understand the landscape of Indigenous trial activity. Methods We extracted data from all Australian trials registered between 2008-2018 on the Australian New Zealand Clinical Trials Registry or ClinicalTrials.gov. Indigenous-focused trials were identified by searching for relevant terms such as ‘Indigenous’ and ‘Aboriginal’. Indigenous versus non-Indigenous trials and Australian trials overall were compared by conditions studied, intervention type, study design and funding. Results Of the 9206 included trials, 139 (1.5%) focused on Indigenous health, and these were mostly in ‘Public Health’ (n = 69, 50%), ‘Mental Health’ (n = 35, 25%) and ‘Cardiovascular’ (n = 25, 18%) (Figure). Compared to other Australian trials, Indigenous trials more frequently studied ear conditions (OR 16.47, 95%CI=8.43-29.99) and public health (OR 4.87, 95%CI=3.65-6.41), and were more likely to focus on screening (OR 3.57, 95%CI=2.10-5.70) and prevention (OR 2.24, 95%CI=1.61-3.08) rather than treatment (OR 0.40, 95%CI =0.30-0.52). They were less likely to be blinded (OR 1.72, 95%CI=1.20-2.49), or have any industry involvement (OR 2.52, 95%CI=1.54-4.43). Conclusions Indigenous trials differed from other Australian trials in health conditions studied, intervention focus, blinding and industry involvement. Relative to population size and burden of disease, the number of trials focusing on Indigenous health is low. Key messages Trial registries can be used to explore whether research appropriately addresses diverse populations such as Indigenous Australians. This can inform future research prioritisation.

Background Row-by-row individual participant data (IPD) from a set of similar studies allows meta-analyses with exposure, confounder and outcome standardisation, and additional analyses at little extra cost. The ICMJE recently declared data sharing an ethical obligation. Consequently, registries have introduced mandatory data sharing statements. Our aims were to analyse data sharing willingness, and identify barriers and facilitators to data sharing. Methods We included all trials registered on the Australian New Zealand Clinical Trials Registry (ANZCTR) in 2019. We analysed data sharing statements from registry records, and conducted an in-depth survey. Associations between willingness to share data and trial characteristics (e.g. trial purpose, funding) were analysed. Results Of the 1,517 included trials, 23% planned to share IPD upon completion. Investigators were less willing to share IPD for industry-funded trials (OR = 0.50,95%CI=0.34-0.70), but there was no difference by sample size or health condition. The main reasons for not sharing IPD were concerns about participant privacy (22%), ethics approval limitations (19%) and lack of understanding for the need of IPD (17%). Among the 281 survey respondents, 78% supported data sharing, but only 40% intended to share their data. Major barriers included concerns about time/resources (96%) and insufficient academic recognition (91%). Conclusions There is insufficient willingness to share data, particularly among industry funders. Addressing the identified barriers can improve this. Key messages Data sharing enables the use of new methodologies, such as improved meta-analysis. Low willingness to share data jeopardises the use of these new methodologies and needs to be addressed.

Focus of Presentation In a prospective meta-analysis (PMA), studies are included before their results are known. This can reduce risk of publication bias and selective outcome reporting, and enables researchers to harmonise their research efforts. Despite rising numbers, there is little guidance on how to conduct PMA. We, the Cochrane PMA Methods Group, developed step-by-step guidance based on a scoping review, and expert opinions and experiences. Each step is illustrated with a recent case study. Findings We describe seven steps for conducting PMA. After developing a protocol (Steps 1), a systematic search for eligible planned/ongoing studies should be conducted, including a search of registries, medical databases and contacting stakeholders (Step 2-3). These studies are then invited to form a collaboration (Step 4), ideally including a steering and data analysis committee. Next, important study features such as common core outcomes and confounders are agreed upon (Step 5). This reduces heterogeneity and increases the number of available outcomes for meta-analysis. Certainty of evidence is assessed by adapting tools such as GRADE (Step 6). Results should be reported using adapted versions of reporting tools such as PRISMA (Step 7). Conclusions/Implications PMA reduce many problems of traditional retrospective systematic reviews and meta-analysis. Updated guidance and recent technical advances will help increase their numbers further. Key messages PMA are ‘next generation systematic reviews’ that allow for greatly improved use of data, whilst reducing bias and research waste. This step-by-step guidance will enable more researchers to conduct successful PMA.

IntroductionChildhood overweight and obesity is prevalent in the first 5 years of life, and can result in significant health and economic consequences over the lifetime. The outcomes currently measured and reported in randomised controlled trials of early childhood obesity prevention interventions to reduce this burden of obesity are heterogeneous, and measured in a variety of ways. This variability limits the comparability of findings between studies, and contributes to research waste. This protocol presents the methodology for the development of two core outcome sets (COS) for obesity prevention interventions in children aged from 1 to 5 years from a singular development process: (1) a COS for interventions targeting physical activity and sedentary behaviour and (2) a COS for interventions targeting child feeding and dietary intake. Core outcomes related to physical activity and sedentary behaviour in children aged ≤1 year will also be identified to complement an existing COS for early feeding interventions, and provide a broader set of core outcomes in this age range. This will result in a suite of COS useful for measuring and reporting outcomes in early childhood obesity prevention studies, including multicomponent interventions.Methods and analysisDevelopment of the COS will follow international best practice guidelines. A scoping review of trial registries will identify commonly reported outcomes and associated measurement instruments. Key stakeholders involved in obesity prevention, including policy-makers/funders, parents, researchers, health practitioners and community and organisational stakeholders will participate in an e-Delphi study and consensus meeting regarding inclusion of outcomes in the COS. Finally, recommended outcome measure instruments will be identified through literature review and group consensus.Ethics and disseminationDeakin University Human Research Ethics Committee (HEAG-H 231_2020). The COS will be disseminated through peer-reviewed publications and engagement with key stakeholders.

Background Aboriginal and Torres Strait Islander peoples (hereafter respectfully referred to as Indigenous Australians) represent about 3% of the total Australian population. Major health disparities exist between Indigenous and Non-Indigenous Australians. To address this, it is vital to understand key health priorities and knowledge gaps in the current landscape of clinical trial activity focusing on Indigenous health in Australia. Methods Australian-based clinical trials registered on the Australian New Zealand Clinical Trials Registry or ClinicalTrials.gov from 2008 to 2018 were analysed. Australian clinical trials with and without a focus on Indigenous health were compared in terms of total numbers, participant size, conditions studied, design, intervention type and funding source. Results Of the 9206 clinical trials included, 139 (1.5%) focused on Indigenous health, with no proportional increase in Indigenous trials over the decade (p = 0.30). Top conditions studied in Indigenous-focused trials were mental health (n = 35, 28%), cardiovascular disease (n = 20, 20%) and infection (n = 16, 16%). Compared to General Australian trials, Indigenous-focused trials more frequently studied ear conditions (OR 20.26, 95% CI 10.32–37.02, p p p p p = 0.021) and surgery (OR 0.17, 95% CI 0.01–0.73, p = 0.027). For intervention types, Indigenous trials focused more on prevention (n = 48, 36%) and screening (n = 18, 13%). They were far less involved in treatment (n = 72, 52%) as an intervention than General Australian trials (n = 6785, 75%), and were less likely to be blinded (n = 48, 35% vs n = 4273, 47%) or have industry funding (n = 9, 7% vs 1587, 17%). Conclusions Trials with an Indigenous focus differed from General Australian trials in the conditions studied, design and funding source. The presented findings may inform research prioritisation and alleviate the substantial burden of disease for Indigenous population.

BackgroundFor prospective meta-analyses (PMAs), eligible studies are identified, and the PMA hypotheses, selection criteria, and analysis methods are pre-specifiedbeforethe results of any of the studies are known. This reduces publication bias and selective outcome reporting and provides a unique opportunity for outcome standardisation/harmonisation. We conducted a world-first PMA of four trials investigating interventions to prevent early childhood obesity. The aims of this study were to quantitatively analyse the effects of prospective planning on variations across trials, outcome harmonisation, and the power to detect intervention effects, and to derive recommendations for future PMA.MethodsWe examined intervention design, participant characteristics, and outcomes collected across the four trials included in the EPOCH PMA using their registration records, protocol publications, and variable lists. The outcomes that trials planned to collect prior to inclusion in the PMA were compared to the outcomes that trials collected after PMA inclusion. We analysed the proportion of matching outcome definitions across trials, the number of outcomes per trial, and how collaboration increased the statistical power to detect intervention effects.ResultsThe included trials varied in intervention design and participants, this improved external validity and the ability to perform subgroup analyses for the meta-analysis. While individual trials had limited power to detect the main intervention effect (BMIz-score), synthesising data substantially increased statistical power. Prospective planning led to an increase in the number of collected outcome categories (e.g. weight, child’s diet, sleep), and greater outcome harmonisation. Prior to PMA inclusion, only 18% of outcome categories were included in all trials. After PMA inclusion, this increased to 91% of outcome categories. However, while trials mostly collected the same outcome categories after PMA inclusion, some inconsistencies in how the outcomes were measured remained (such as measuring physical activity by hours of outside play versus using an activity monitor).ConclusionProspective planning led to greater outcome harmonisation and greater power to detect intervention effects, while maintaining acceptable variation in trial designs and populations, which improved external validity. Recommendations for future PMA include more detailed harmonisation of outcome measures and careful pre-specification of analyses to avoid research waste by unnecessary over-collection of data.

Introduction: Breast cancer (BC) screening using digital breast tomosynthesis (DBT) has been shown to increase cancer detection compared with mammography; however, it is unknown whether DBT impacts interval cancer rate (ICR). Methods: We systematically identified prospective DBT studies reporting data on screen detected and interval BCs to perform a study-level meta-analysis of the comparative effect of DBT on ICR in population screening. Meta-analysis of cancer detection rate (CDR), ICR, and the differences between DBT and mammography in CDR and ICR pooled estimates, included random-effects. Sensitivity analysis examined whether study methods (imaging used, comparison group design, interval BC ascertainment) affected pooled estimates. Results: Five eligible prospective (non-randomised) studies of DBT population screening reported on 129,969 DBT-screened participants and 227,882 mammography-only screens, including follow-up publications reporting interval BC data. Pooled CDR was 9.03/1000 (95% confidence interval [CI] 8.53-9.56) for DBT, and 5.95/1000 (95% CI 5.65-6.28) for mammography: the pooled difference in CDR was 3.15/1000 (95% CI 2.53-3.77), and was evident for the detection of invasive and in-situ malignancy. Pooled ICR was 1.56/1000 DBT screens (95% CI 1.22-2.00), and 1.75/1000 mammography screens (95% CI 1.46 -2.11): the estimated pooled difference in ICR was-0.15/1000 (95% CI-0.59 to 0.29) and was not substantially altered in several sensitivity analyses. Conclusions: Meta-analysis shows consistent evidence that DBT significantly increased CDR compared with mammography screening; however, there was little difference between DBT and mammography in pooled ICR. This could suggest, but does not demonstrate, some over-detection. Meta-analysis using individual participant data, randomised trials and comparative studies quantifying cumulative detection and ICR over repeat DBT screen rounds would provide valuable evidence to inform screening programs. (c) 2021 Elsevier Ltd. All rights reserved

This perspective explores the landscape of COVID-19 trials recruiting in Australia using trial registry data. We identified 56 trials addressing treatment and prevention of COVID-19, and 12 trials addressing indirect effects of the pandemic. Whilst there was substantial innovation in drug development and digital health, the potential of innovation in methodology, such as adaptive trials, remains largely untapped. Data sharing intentions were low, sample sizes were too small to detect differences in clinical outcomes, such as mortality, and lack of core outcome collection precludes evidence synthesis. Infrastructure for innovation would support coordination of research efforts, and reduce research waste.

Cochrane systematic reviews and meta-analyses are regarded as the ‘gold standard’ for high-quality information and are widely used to inform healthcare policy and practice. The nature of how conventional systematic reviews are conceived and conducted after at least some of the included studies are completed means that reviewers can inadvertently introduce bias when faced with heterogeneous studies that cannot be easily synthesized. Prospective meta-analysis (PMA) is now gaining traction as a means of reducing research waste and producing meaningful and less biased evidence syntheses. PMA has been lauded as a ‘next- generation’ method, and Ioannidis has argued that “all primary original research may be designed, executed, and interpreted as prospective meta-analysis”.

BACKGROUND : Childhood obesity is a global problem. Early obesity prevention interventions are complex and differ in effectiveness. Novel frameworks, taxonomies and experience from the Early Prevention of Obesity in CHildren (EPOCH) trials were applied to unpack interventions. OBJECTIVES : Deconstruct interventions into their components (target behaviours, delivery features and behaviour change techniques [BCTs]). Identify lessons learned and future recommendations for intervention planning, delivery, evaluation and implementation. METHODS : This multi-methods study deconstructed the four EPOCH interventions into target behaviours, delivery features and BCTs from unpublished and published materials using systematic frameworks. Additionally, semi-structured interviews were conducted with intervention facilitators and principal investigators. RESULTS : Each trial targeted between 10 and 14 obesity-related behaviours. Key variations in delivery features related to intensity, delivery mode and tailoring. BCTs consistently used across trials included goal-setting, social support, shaping knowledge, role-modelling and credible source. Recommendations from interview analyses include the importance of stakeholder collaboration and consideration of implementation throughout the study process. CONCLUSIONS : The combination of frameworks, methodologies and interviews used in this study is a major step towards understanding complex early obesity prevention interventions. Future work will link systematic intervention deconstruction with quantitative models to identify which intervention components are most effective and for whom.

Background Childhood obesity is a significant global problem. Childhood obesity prevention interventions may be more effective when started very early in life before metabolic and behavioural patterns are established. Methods and findings A prospectively planned, individual participant data meta-analysis of four randomized controlled trials. Participants were first-time mothers of term infants. Trial interventions commenced during pregnancy or early infancy and comprised education and support delivered via group sessions and/or home visits. Control group families accessed existing local well-child health care. The primary outcome was body mass index (BMI) z score at 18 to 24 months; 2196 mother-child dyads were available for analysis. Intervention children had lower BMI z scores at 18 to 24 months than control children (-0.12 adjusted mean; 95% confidence interval, -0.22 to -0.02, P = .017). There was some evidence that the BMI z score reduction was greater in settings with limited well-child health care programmes (interaction P value = .03). Improvements were also detected in television viewing time, feeding practices, and breastfeeding duration. Conclusions Parent-focused intervention programmes that commence by early infancy and which aim to establish a trajectory of healthy lifestyle behaviours produced a modest but statistically significant reduction in BMI z score, which if replicated on a wider scale may have important public health implications.

In a prospective meta-analysis (PMA), study selection criteria, hypotheses, and analyses are specified before the results of the studies related to the PMA research question are known, reducing many of the problems associated with a traditional (retrospective) meta-analysis. PMAs have many advantages: they can help reduce research waste and bias, and they are adaptive, efficient, and collaborative. Despite an increase in the number of health research articles labelled as PMAs, the methodology remains rare, novel, and often misunderstood. This paper provides detailed guidance on how to address the key elements for conducting a high quality PMA with a case study to illustrate each step.

IntroductionRates of medical interventions in normal labour and birth are increasing. This prospective meta-analysis (PMA) proposes to assess whether the addition of a comprehensive multicomponent birth preparation programme reduces caesarean section (CS) in nulliparous women compared with standard hospital care. Additionally, do participant characteristics, intervention components or hospital characteristics modify the effectiveness of the programme?Methods and analysisPopulation: women with singleton vertex pregnancies, no planned caesarean section (CS) or epidural.Intervention: in addition to hospital-based standard care, a comprehensive antenatal education programme that includes multiple components for birth preparation, addressing the three objectives: preparing women and their birth partner/support person for childbirth through education on physiological/hormonal birth (knowledge and understanding); building women’s confidence through psychological preparation (positive mindset) and support their ability to birth without pain relief using evidence-based tools (tools and techniques). The intervention could occur in a hospital-based or community setting.Comparator: standard care alone in hospital-based maternity units.OutcomesPrimary: CS.Secondary: epidural analgesia, mode of birth, perineal trauma, postpartum haemorrhage, newborn resuscitation, psychosocial well-being.Subgroup analysis: parity, model of care, maternal risk status, maternal education, maternal socio-economic status, intervention components.Study designAn individual participant data (IPD) prospective meta-analysis (PMA) of randomised controlled trials, including cluster design. Each trial is conducted independently but share core protocol elements to contribute data to the PMA. Participating trials are deemed eligible for the PMA if their results are not yet known outside their Data Monitoring Committees.Ethics and disseminationParticipants in the individual trials will consent to participation, with respective trials receiving ethical approval by their local Human Research Ethics Committees. Individual datasets remain the property of trialists, and can be published prior to the publication of final PMA results. The overall data for meta-analysis will be held, analysed and published by the collaborative group, led by the Cochrane PMA group.Trial registration numberCRD42020103857.

Background Tomosynthesis approximates a 3D mammogram of the breast, reducing parenchymal overlap that masks cancers or creates false "lesions" on 2D mammography, and potentially enabling more accurate detection of breast cancer. We compared breast cancer screening detection and recall in asymptomatic women for tomosynthesis vs 2D mammography. Methods A systematic review and random effects meta-analysis were undertaken. Electronic databases (2009-July 2017) were searched for studies comparing tomosynthesis and 2D mammography in asymptomatic women who attended population breast cancer screening and reporting cancer detection rate (CDR) and recall rate. All statistical tests were two-sided. Results Seventeen studies (1 009 790 participants) were included from 413 citations. The pooled incremental CDR for tomosynthesis was 1.6 cancers per 1000 screens (95% confidence interval [CI] = 1.1 to 2.0, P

IntroductionIn 2015, the Australian Army commissioned a systematic review to assess the evidence on effectiveness and safety of pharmacological and biotechnological products for cognitive enhancement specifically in Army personnel.MethodsSearches for studies examining biotechnological and pharmacological products in Army populations were conducted in December 2015. Cochrane CENTRAL, MEDLINE, EMBASE, CINAHL and PsycINFO were searched without date or language restrictions. WHO’s International Clinical Trials Registry Platform and ClinicalTrials.gov were searched to identify ongoing trials. Studies meeting inclusion criteria were evaluated for risk of bias using Cochrane’s Risk of Bias tool. Due to heterogeneity of findings, meta-analysis could not be conducted. Findings were synthesised narratively and by vote-counting method.ResultsSixteen pharmacological enhancement products were evaluated in 22 randomised controlled trials (RCTs), involving 1284 personnel. Only three of the studies were published since 2010. The interventions evaluated were varied, including supplements (eg, carbohydrate), stimulants (eg, caffeine) and hormones (eg, melatonin). Generally, caffeine provided an improvement in performance compared with placebo on 5/7 reported cognitive outcomes, followed by levothyroxine (four cognitive outcomes) and prazosin (three cognitive outcomes). Performance results were mixed (finding an improvement and no effect in comparison to placebo) for caffeine and melatonin on two outcomes. No evidence was found pertaining to biotechnological products. Studies rarely reported safety outcomes (eg, adverse events and addiction).ConclusionFindings from this review need to be interpreted with considerable caution. Future studies should include outcomes such as acute and long-term adverse events, and should evaluate cognitive performance using cognitive tests that are specific to the Army population.

Background: There is accumulating evidence that digital breast tomosynthesis, referred to as 3D-mammography in this protocol, improves screen-detection measures compared to standard 2D-mammography in the context of population screening for breast cancer. However, the effect of 3D-mammography at follow-up of screened women is not yet known: it is unknown whether additional cancer detection from 3D-mammography leads to incremental screening benefit through a reduction of interval cancers, or whether it is mostly over-detecting indolent cancers. Methods: The aim of this study is to examine whether 3D-mammography population screening improves breast cancer screening effectiveness by reducing interval cancer rates compared to standard digital (2D) mammography screening, using individual participant data (IPD) meta-analysis. In this protocol, we outline the research plan which includes systematic identification of studies eligible to contribute data into the IPD meta-analysis, and sourcing and assembling IPD for participants screened with 3D-mammography (3D alone or integrated 2D/3D or integrated 2Dsynthetic/3D) and comparison participants screened with 2D-mammography (standard of care in breast screening). The primary end-point of this work is the interval breast cancer rate per 10,000 screens for 3D-mammography versus 2D-mammography screening. The IPD meta-analysis will also assess secondary outcomes including: screening sensitivity, cancer detection rates, cancer (prognostic) characteristics, and recall rates, for 3D-mammography versus 2D-mammography screening. The use of IPD meta-analysis will allow stratification of results by age and breast density, and will also facilitate analysis of cancer histological (prognostic) characteristics. Discussion: Finalization of data collection procedures and analysis plans will be complete by the end of 2017. Data collection will occur from late 2017 to late 2018 (screen-detection measures: cancer detection and recall data) and from mid-2018 to mid-2019 (interval cancer data). Results of detection measures should be available by 2019, and interval cancer results in 2020. By addressing the critical evidence gap on whether 3D-mammography screening reduces interval cancer rates (compared to 2D-mammography), we expect that our findings will inform timely translation of 3D-mammography technology into breast screening practice in population-based health programs.

An interval breast cancer is a cancer that emerges following a negative mammographic screen. This overview describes the epidemiology, and the radiological and biological characteristics of interval breast cancers in population mammography screening. Notwithstanding possible differences in ascertainment of interval breast cancers, there was broad variability in reported interval breast cancer rates (range 7.0 to 49.3 per 10,000 screens) reflecting heterogeneity in underlying breast cancer rates, screening rounds (initial or repeat screens), and the length and phase of the inter-screening interval. The majority of studies (based on biennial screening) reported interval breast cancer rates in the range of 8.4 to 21.1 per 10,000 screens spanning the two-year interval with the larger proportion occurring in the second year. Despite methodological limitations inherent in radiological surveillance (retrospective mammographic review) of interval breast cancers, this form of surveillance consistently reveals that the majority of interval cancers represent either true interval or occult cancers that were not visible on the index mammographic screen; approximately 20–25% of interval breast cancers are classified as having been missed (false-negatives). The biological characteristics of interval breast cancers show that they have relatively worse tumour prognostic characteristics and biomarker profile, and also survival outcomes, than screen-detected breast cancers; however, they have similar characteristics and prognosis as breast cancers occurring in non-screened women. There was limited evidence on the effect on interval breast cancer frequency and outcomes following transition from film to digital mammography screening.

Although the introduction of prospective trial registration policies has been successful in reducing waste in research, diagnostic accuracy studies are rarely registered. We describe why diagnostic accuracy studies should be registered, and where and how this can be done. Advantages of registration include the identification of unpublished studies, prevention of selective outcome reporting, prevention of unnecessary duplication of research, collaboration between researchers, and linkage of study materials. In a survey among representatives of 16 major trial registries, such as ClinicalTrials. gov, ANZCTR (Australian New Zealand Clinical Trials Registry), and the UK-based ISRCTN registry (International Standard Randomised Controlled Trial Number), 13 responded, of which 8 (62%) indicated they always accept registration of diagnostic accuracy studies and 5 (38%) do so in some cases. However, all but one of them (92%) indicated that their registry currently does not provide specific guidance for registering diagnostic accuracy studies. A second survey among the 85 members of the STARD Group (Standards for Reporting Diagnostic Accuracy) resulted in the identification of 14 essential protocol items and was used for developing a guide on how these items can be registered in existing major trial registries. We propose that investigators responsible for diagnostic accuracy studies should register their study, before recruiting patients, in 1 of the existing major trial registries that are willing to host such studies. We also propose that governmental, research, and academic institutions that provide funding for and journals that publish diagnostic accuracy studies require such registration. (C) 2017 American Association for Clinical Chemistry

Background Commercial or industry funding is associated with outcomes that favour the study funder in published studies, across various areas of research. However, it is currently unclear whether there are differences between trials with and without industry involvement at the stage of trial registration. Objective To determine whether industry involvement (industry sponsorship, funding, or collaboration) is associated with trial characteristics at the time of trial registration. Methods We conducted a cross-sectional analysis of all interventional studies registered on the Australian New Zealand Clinical Trials Registry in 2017 and classified them by industry involvement. We analysed whether there were differences in study characteristics (including type of control, sample size, study phase, randomisation, registration timing, and purpose of study) by industry involvement. Results Industry involvement was reported by 21% of the 1,433 included trials. Only 40% of trials with industry involvement used an active control compared to 58% of non-industry trials (OR = 0.49, 95%CI = 0.38 to 0.63, p < .001), and industry trials reported smaller sample sizes (Median(IQR)industry = 45(24–100), Median(IQR)non-industry = 70(35–160), Mean Difference = -153, 95% CI = -233 to -75, p < .001). Industry trials were more likely to be earlier phase trials (Χ2(df) = 71.46(4), p < .001). There was no difference in use of randomisation between industry (70%) and non-industry trials (73%) (OR = 0.88, 95%CI = 0.67–1.20, p = .38). Eighty-three percent of industry trials compared to 70% of non-industry trials were prospectively registered (OR = 2.02, 95%CI = 1.47–2.82, p < .001). Industry trials were more likely to assess treatment (85%), rather than prevention, education or diagnosis compared to non-industry trials (64%) (OR = 3.02, 95%CI = 2.17–4.32, p < .001). Conclusion The current study gives insight into differences in trial characteristics by industry involvement at registration stage. There was a reduced use of active controls in trials with industry involvement which has previously been proposed as a mechanism behind more favourable results. Non-industry funders and sponsors are crucial to ensure research addresses not only treatments, but also prevention, diagnosis and education questions.

Objectives The objective of this study was to determine the prevalence of trial registration in health research, whether trial registration status and timing vary depending on trial characteristics, and the relationship between trial registration status and risk of bias. Study Design and Setting We systematically reviewed all clinical trials published from January to June 2017 in 28 high- and low-impact factor general and specialty medicine journals. Results We identified 370 trials and assessed risk of bias in 183 trials. Trial registration rates were high; 95% of trials were registered prospectively or retrospectively before enrollment completion. Larger sample size, multiple recruitment countries, and primary industry funding were all predictors of earlier trial registration. Prospectively registered trials had a significantly lower risk of bias compared to unregistered trials across all domains. Prospectively registered trials had a similar risk of bias compared to retrospectively registered trials across four out of six domains, and a lower risk of bias across the remaining two domains. Conclusion Trial registration is an imperfect proxy for risk of bias. Systematic reviewers should assess risk of bias on a case-by-case basis and conduct sensitivity analyses excluding high risk of bias studies. In the longer term, mechanisms should be implemented to facilitate prospective registration of all trials.

Background: Digital breast tomosynthesis (DBT) improves breast cancer (BC) detection compared to mammography, however, it is unknown whether this reduces interval cancer rate (ICR) at follow-up. Methods: Using individual participant data (IPD) from DBT screening studies (identified via periodic literature searches July 2016 to November 2019) we performed an IPD meta-analysis. We estimated ICR for DBT-screened participants and the difference in pooled ICR for DBT and mammography-only screening, and compared interval BC characteristics. Two-stage meta-analysis (study-specific estimation, pooled synthesis) of ICR included random-effects, adjusting for study and age, and was estimated in age and density subgroups. Comparative screening sensitivity was calculated using screen-detected and interval BC data. Findings: Four prospective DBT studies, from European population-based programs, contributed IPD for 66,451 DBT-screened participants: age-adjusted pooled ICR was 13.17/10,000 (95%CI: 8.25-21.02). Pooled ICR was higher in the high-density (21.08/10,000; 95%CI: 6.71-66.27) than the low-density (8.63/10,000; 95%CI: 5.25-14.192) groups (P = 0.03) however estimates did not differ across age-groups (P = 0.32). Based on two studies that also provided data for 153,800 mammography screens (age-adjusted ICR 17.69/10,000; 95%CI: 13.22-23.66), DBT's pooled ICR was 16.83/10,000 (95%CI: 11.89-23.82). Comparative meta-analysis showed a non-significant difference in ICR (-0.44/10,000; 95%CI: -11.00-10.11) and non-significant difference in screening sensitivity (6.79%; 95%CI: -0.73-14.87%) between DBT and DM but a significant pooled difference in cancer detection rate of 33.49/10,000 (95%CI: 23.88-43.10). Distribution of interval BC prognostic characteristics did not differ between screening modalities except that those occurring in DBT-screened participants were significantly more likely to be negative for axillary-node metastases (P = 0.005). Interpretation: Although heterogeneity in ICR estimates and few datasets limit recommendations, there was no difference between DBT and mammography in pooled ICR despite DBT increasing cancer detection. (C) 2021 The Author(s). Published by Elsevier Ltd.

Childhood overweight and obesity is a worldwide public health issue. Our objective was to describe planned, ongoing and completed randomized controlled trials (RCTs) designed for the prevention of obesity in early childhood. Two databases (World Health Organization International Clinical Trials Registry Platform, ClinicalTrials.gov) were searched to identify RCTs with the primary aim of preventing childhood obesity and at least one outcome related to child weight. Interventions needed to start in the first two years of childhood or earlier, continue for at least 6 months postnatally, include a component related to lifestyle or behaviours, and have a follow up time of at least 2 years. We identified 29 unique RCTs, implemented since 2008, with most being undertaken in high income countries. Interventions ranged from advice on diet, activity, sleep, emotion regulation, and parenting education through to individual home visits, clinic-based consultations, or group education sessions. Eleven trials published data on child weight-related outcomes to date, though most were not sufficiently powered to detect significant effects. Many trials detected improvements in practices such as breastfeeding, screen time, and physical activity in the intervention groups compared to the control groups. Further follow-up of ongoing trials is needed to assess longer-term effects.

The Verona population-based breast cancer (BC) screening program provides biennial mammography to women aged 50–69 years. Based on emerging evidence of enhanced detection, the program transitioned to digital breast tomosynthesis (DBT) screening. This is a prospective pilot evaluation of DBT with synthesised 2D mammography screening implemented during April 2015–March 2017; the rate and characteristics of cancers detected at DBT screening were compared with those detected at the preceding digital mammography (DM) screening round (April 2013–March 2015) in the same screening program. Distribution of imaging and tumour characteristics were compared. Amongst 34,071 women screened in the Verona DBT pilot, 315 BCs were detected; 153 BCs were detected amongst 29,360 women in the DM screening round. Estimated CDRs were 9.2/1000 (95% CI 8.3–10.3) DBT screens versus 5.2/1000 (95% CI 4.4–6.1) DM screens, P

Background Metabolic and behavioural patterns are established in early life. Childhood obesity prevention interventions may be more effective when begun before 6 months of age. The aim of this prospectively planned meta-analysis (PMA) was to synthesise evidence from trials that commenced during pregnancy or early infancy and targeted lifestyle behaviours to prevent childhood obesity at age 18-24 months. Methods Four randomised controlled trials (RCTs) were identified for inclusion in the PMA before individual trial outcomes were known. Participants were first-time mothers and individual participant data (IPD) were supplied by trial investigators. The interventions comprised education and support delivered via group sessions and/or home visits. Control groups accessed existing local well-child health care. The primary outcome was body mass index (BMI) z-score at 18-24 months. A one-step fixed-effect linear modelling approach was used for the meta-analysis. Registration number: ACTRN12610000789066. Findings 2,196 mother-child dyads were available for analysis. Intervention children had lower BMI z-scores at 18-24 months than control children (-0·12 adjusted mean, 95% Confidence Interval: -0·22 to -0·02, p=0·017). There was some evidence that the effect on BMI z-scores was greater in settings with limited well-child health care programs (interaction p-value = 0·03). Improvements were also detected in television viewing time, feeding practices, and breastfeeding duration. Heterogeneity and risk of bias were low. Interpretation Parent-focused intervention programs that commence by early infancy and aim to establish a trajectory of healthy lifestyle behaviours produced a modest but clinically significant reduction in childhood obesity indicators that have major public health implications. Trial Registration Number: ACTRN12610000789066 Funding: National Health and Medical Research Council of Australia (Grant ID: 1028555 and 1101675), Meat and Livestock Australia (Grant ID: QUT2010001469) Declaration of Interest: The authors have no conflicts of interest relevant to this article to disclose. Ethical Approval: The EPOCH project was approved by the University of Sydney Human Research Ethics Committee (2016/822).

OBJECTIVE To assess whether Australian clinical trials activity in National Health Priority Areas (NHPAs) reflects the relative disease burden. DESIGN AND SETTING Analysis of trials registered on the Australian New Zealand Clinical Trials Registry (ANZCTR) or ClinicalTrials.gov from January 2008 to December 2012 that planned recruitment in Australia and investigated interventions for NHPA conditions (cancer control, cardiovascular health, mental health, obesity, injury prevention/control, diabetes mellitus, arthritis and musculoskeletal conditions, dementia and asthma). Australian estimates of disability-adjusted life-years (DALYs) were used to quantify the burden of disease for each NHPA. MAIN OUTCOME MEASURES For each NHPA, the total number of registered trials, planned recruitment, and the predicted numbers based on disability-adjusted life-years expressed as a proportion of the total burden of disease in Australia (%DALY). RESULTS 5143 trials with Australian sites were registered in the 5-year study period with total planned recruitment of 2 404 609 participants. Of these, 3032 trials (59%) with planned recruitment of 1 532 064 participants (64%) investigated NHPA conditions. Trial numbers and planned recruitment were highest for cancer, cardiovascular and mental health - reflecting their higher disease burden. In contrast, planned recruitment into obesity and dementia trials was ≤ 50% of that predicted from total trial activity based on their relative disease burden. The number of registered trials for these conditions was also lower than predicted. Overall, of 3032 NHPA trials, 2335 (77%) used randomisation and 1520 (50%) planned to recruit > 100 participants. CONCLUSIONS Australian clinical trial activity for obesity and dementia interventions is lower that would be expected based on their relative disease burden. Trial registries provide a valuable public database to identify and monitor gaps in research activity.

This review of the evidence on digital breast tomosynthesis, a 3D-mammography technology, for breast cancer (BC) screening describes two types of studies. Prospective trials comparing tomosynthesis (combined with 2D mammography) with 2D mammography alone in the same participants were based on double-reading practice in mostly biennial screening. These showed incremental BC detection attributed to use of tomosynthesis ranging from 2.2 to 2.7 per 1000 screens. Retrospective studies reported the difference in BC detection between women screened with tomosynthesis (2D plus 3D mammography) or with 2D mammography alone, using single-reading and mostly annual screening. Differences in cancer detection ranged between 0.2 and 2.1 per 1000 screens favoring tomosynthesis. The impact of using tomosynthesis on recall was heterogeneous; however, significant reduction in recall rates was observed among the retrospective studies.

Background: The effects of delayed cord clamping of the umbilical cord in preterm infants are unclear. Objective: We sought to compare the effects of delayed vs early cord clamping on hospital mortality (primary outcome) and morbidity in preterm infants using Cochrane Collaboration neonatal review group methodology. Study design: We searched MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, and Chinese articles, cross-referencing citations, expert informants, and trial registries to July 31, 2017, for randomized controlled trials of delayed (≥30 seconds) vs early (20% of infants in any arm would be ineligible. Two reviewers independently selected studies, assessed bias, and extracted data. Relative risk (ie, risk ratio), risk difference, and mean difference with 95% confidence intervals were assessed by fixed effects models, heterogeneity by I2 statistics, and the quality of evidence by Grading of Recommendations, Assessment, Development, and Evaluations. Results: Eighteen randomized controlled trials compared delayed vs early clamping in 2834 infants. Most infants allocated to have delayed clamping were assigned a delay of ≥60 seconds. Delayed clamping reduced hospital mortality (risk ratio, 0.68; 95% confidence interval, 0.52-0.90; risk difference, -0.03; 95% confidence interval, -0.05 to -0.01; P = .005; number needed to benefit, 33; 95% confidence interval, 20-100; Grading of Recommendations, Assessment, Development, and Evaluations = high, with I2 = 0 indicating no heterogeneity). In 3 trials in 996 infants ≤28 weeks' gestation, delayed clamping reduced hospital mortality (risk ratio, 0.70; 95% confidence interval, 0.51-0.95; risk difference, -0.05; 95% confidence interval, -0.09 to -0.01; P = .02, number needed to benefit, 20; 95% confidence interval, 11-100; I2 = 0). In subgroup analyses, delayed clamping reduced the incidence of low Apgar score at 1 minute, but not at 5 minutes, and did not reduce the incidence of intubation for resuscitation, admission temperature, mechanical ventilation, intraventricular hemorrhage, brain injury, chronic lung disease, patent ductus arteriosus, necrotizing enterocolitis, late onset sepsis or retinopathy of prematurity. Delayed clamping increased peak hematocrit by 2.73 percentage points (95% confidence interval, 1.94-3.52; P < .00001) and reduced the proportion of infants having blood transfusion by 10% (95% confidence interval, 6-13%; P < .00001). Potential harms of delayed clamping included polycythemia and hyperbilirubinemia. Conclusion: This systematic review provides high-quality evidence that delayed clamping reduced hospital mortality, which supports current guidelines recommending delayed clamping in preterm infants. This review does not evaluate cord milking, which may also be of benefit. Analyses of individual patient data in these and other randomized controlled trials will be critically important in reliably evaluating important secondary outcomes.

BACKGROUND: The optimum time for commencing antiplatelet therapy for the prevention of preeclampsia and its complications is unclear. Aggregate data meta-analyses suggest that aspirin is more effective if given prior to 16 weeks' gestation, but data are limited because of an inability to place women in the correct gestational age subgroup from relevant trials. OBJECTIVE: The objective of the study was to use the large existing individual participant data set from the Perinatal Antiplatelet Review of International Studies Collaboration to assess whether the treatment effects of antiplatelet agents on preeclampsia and its complications vary based on whether treatment is started before or after 16 weeks' gestation. STUDY DESIGN: A meta-analysis of individual participant data including 32,217 women and 32,819 babies recruited to 31 randomized trials comparing low-dose aspirin or other antiplatelet agents with placebo or no treatment for the prevention of preeclampsia has been published previously. Using this existing data set, we performed a prespecified subgroup analysis based on gestation at randomization to antiplatelet agents before 16 weeks, compared with at or after 16 weeks, for 4 of the main outcomes prespecified in the Perinatal Antiplatelet Review of International Studies protocol: preeclampsia, death of baby, preterm birth before 34 weeks, and small-for-gestational-age baby. Individual participant data for the subgroups were combined in a meta-analysis using RevMan software. Heterogeneity was assessed with the I 2 statistic. The chi(2) test for interaction was used to assess statistically significant (P= 16 weeks (interaction test, P=.98); death of baby, relative risk, 0.89 (95% confidence interval, 0.73-1.09; 15 trials, 8626 women) for = 16 weeks (interaction test, P=.80); preterm birth prior to 34 weeks, relative risk, 0.90 (95% confidence interval, 0.77-1.04; 19 trials, 9155 women) for = 16 weeks (interaction test, P=.91); and small-for-gestational-age baby, relative risk, 0.76 (95% confidence interval, 0.61-0.94; 13 trials, 6393 women) for= 16 weeks (interaction test, P=.08). CONCLUSION: The effect of low-dose aspirin and other antiplatelet agents on preeclampsia and its complications is consistent, regardless of whether treatment is started before or after 16 weeks' gestation. Women at an increased risk of preeclampsia should be offered antiplatelet therapy, regardless of whether they are first seen before or after 16 weeks' gestation.

Importance There are potential benefits and harms of hyperoxemia and hypoxemia for extremely preterm infants receiving more vs less supplemental oxygen. Objective To compare the effects of different target ranges for oxygen saturation as measured by pulse oximetry (Spo2) on death or major morbidity. Design, Setting, and Participants Prospectively planned meta-analysis of individual participant data from 5 randomized clinical trials (conducted from 2005-2014) enrolling infants born before 28 weeks’ gestation. Exposures Spo2 target range that was lower (85%-89%) vs higher (91%-95%). Main Outcomes and Measures The primary outcome was a composite of death or major disability (bilateral blindness, deafness, cerebral palsy diagnosed as ≥2 level on the Gross Motor Function Classification System, or Bayley-III cognitive or language score Results A total of 4965 infants were randomized (2480 to the lower Spo2 target range and 2485 to the higher Spo2 range) and had a median gestational age of 26 weeks (interquartile range, 25-27 weeks) and a mean birth weight of 832 g (SD, 190 g). The primary outcome occurred in 1191 of 2228 infants (53.5%) in the lower Spo2 target group and 1150 of 2229 infants (51.6%) in the higher Spo2 target group (risk difference, 1.7% [95% CI, −1.3% to 4.6%]; relative risk [RR], 1.04 [95% CI, 0.98 to 1.09], P = .21). Of the 16 secondary outcomes, 11 were null, 2 significantly favored the lower Spo2 target group, and 3 significantly favored the higher Spo2 target group. Death occurred in 484 of 2433 infants (19.9%) in the lower Spo2 target group and 418 of 2440 infants (17.1%) in the higher Spo2 target group (risk difference, 2.8% [95% CI, 0.6% to 5.0%]; RR, 1.17 [95% CI, 1.04 to 1.31], P = .01). Treatment for retinopathy of prematurity was administered to 220 of 2020 infants (10.9%) in the lower Spo2 target group and 308 of 2065 infants (14.9%) in the higher Spo2 target group (risk difference, −4.0% [95% CI, −6.1% to −2.0%]; RR, 0.74 [95% CI, 0.63 to 0.86], P Conclusions and Relevance In this prospectively planned meta-analysis of individual participant data from extremely preterm infants, there was no significant difference between a lower Spo2 target range compared with a higher Spo2 target range on the primary composite outcome of death or major disability at a corrected age of 18 to 24 months. The lower Spo2 target range was associated with a higher risk of death and necrotizing enterocolitis, but a lower risk of retinopathy of prematurity treatment.

BACKGROUND: Pre‐eclampsia is associated with deficient intravascular production of prostacyclin, a vasodilator, and excessive production of thromboxane, a vasoconstrictor and stimulant of platelet aggregation. These observations led to the hypotheses that antiplatelet agents, low‐dose aspirin in particular, might prevent or delay development of pre‐eclampsia. OBJECTIVES: To assess the effectiveness and safety of antiplatelet agents, such as aspirin and dipyridamole, when given to women at risk of developing pre‐eclampsia. SEARCH METHODS: For this update, we searched Cochrane Pregnancy and Childbirth’s Trials Register, ClinicalTrials.gov, the WHO International Clinical Trials Registry Platform (ICTRP) (30 March 2018), and reference lists of retrieved studies. We updated the search in September 2019 and added the results to the awaiting classification section of the review. SELECTION CRITERIA: All randomised trials comparing antiplatelet agents with either placebo or no antiplatelet agent were included. Studies only published in abstract format were eligible for inclusion if sufficient information was available. We would have included cluster‐randomised trials in the analyses along with individually‐randomised trials, if any had been identified in our search strategy. Quasi‐random studies were excluded. Participants were pregnant women at risk of developing pre‐eclampsia. Interventions were administration of an antiplatelet agent (such as low‐dose aspirin or dipyridamole), comparisons were either placebo or no antiplatelet. DATA COLLECTION AND ANALYSIS: Two review authors assessed trials for inclusion and extracted data independently. For binary outcomes, we calculated risk ratio (RR) and its 95% confidence interval (CI), on an intention‐to‐treat basis. For this update we incorporated individual participant data (IPD) from trials with this available, alongside aggregate data (AD) from trials where it was not, in order to enable reliable subgroup analyses and inclusion of two key new outcomes. We assessed risk of bias for included studies and created a 'Summary of findings' table using GRADE. MAIN RESULTS: Seventy‐seven trials (40,249 women, and their babies) were included, although three trials (relating to 233 women) did not contribute data to the meta‐analysis. Nine of the trials contributing data were large (> 1000 women recruited), accounting for 80% of women recruited. Although the trials took place in a wide range of countries, all of the nine large trials involved only women in high‐income and/or upper middle‐income countries. IPD were available for 36 trials (34,514 women), including all but one of the large trials. Low‐dose aspirin alone was the intervention in all the large trials, and most trials overall. Dose in the large trials was 50 mg (1 trial, 1106 women), 60 mg (5 trials, 22,322 women), 75mg (1 trial, 3697 women) 100 mg (1 trial, 3294 women) and 150 mg (1 trial, 1776 women). Most studies were either low risk of bias or unclear risk of bias; and the large trials were all low risk of bas. Antiplatelet agents versus placebo/no treatment The use of antiplatelet agents reduced the risk of proteinuric pre‐eclampsia by 18% (36,716 women, 60 trials, RR 0.82, 95% CI 0.77 to 0.88; high‐quality evidence), number needed to treat for one women to benefit (NNTB) 61 (95% CI 45 to 92). There was a small (9%) reduction in the RR for preterm birth 500 mL (23,769 women, 19 trials; RR 1.06, 95% CI 1.00 to 1.12; moderate‐quality evidence due to clinical heterogeneity), and they probably marginally increase the risk of placental abruption, although for this outcome the evidence was downgraded due to a wide confidence interval including the possibility of no effect (30,775 women; 29 trials; RR 1.21, 95% CI 0.95 to 1.54; moderate‐quality evidence). Data from two large trials which assessed children at aged 18 months (including results from over 5000 children), did not identify clear differences in development between the two groups. AUTHORS' CONCLUSIONS: Administering low‐dose aspirin to pregnant women led to small‐to‐moderate benefits, including reductions in pre‐eclampsia (16 fewer per 1000 women treated), preterm birth (16 fewer per 1000 treated), the baby being born small‐for‐gestational age (seven fewer per 1000 treated) and fetal or neonatal death (five fewer per 1000 treated). Overall, administering antiplatelet agents to 1000 women led to 20 fewer pregnancies with serious adverse outcomes. The quality of evidence for all these outcomes was high. Aspirin probably slightly increased the risk of postpartum haemorrhage of more than 500 mL, however, the quality of evidence for this outcome was downgraded to moderate, due to concerns of clinical heterogeneity in measurements of blood loss. Antiplatelet agents probably marginally increase placental abruption, but the quality of the evidence was downgraded to moderate due to low event numbers and thus wide 95% CI. Overall, antiplatelet agents improved outcomes, and at these doses appear to be safe. Identifying women who are most likely to respond to low‐dose aspirin would improve targeting of treatment. As almost all the women in this review were recruited to the trials after 12 weeks' gestation, it is unclear whether starting treatment before 12 weeks’ would have additional benefits without any increase in adverse effects. While there was some indication that higher doses of aspirin would be more effective, further studies would be warranted to examine this.