Showing papers by "Peter Brocklehurst published in 2019"

Stunted microbiota and opportunistic pathogen colonization in caesarean-section birth

Abstract: Immediately after birth, newborn babies experience rapid colonization by microorganisms from their mothers and the surrounding environment1. Diseases in childhood and later in life are potentially mediated by the perturbation of the colonization of the infant gut microbiota2. However, the effects of delivery via caesarean section on the earliest stages of the acquisition and development of the gut microbiota, during the neonatal period (≤1 month), remain controversial3,4. Here we report the disrupted transmission of maternal Bacteroides strains, and high-level colonization by opportunistic pathogens associated with the hospital environment (including Enterococcus, Enterobacter and Klebsiella species), in babies delivered by caesarean section. These effects were also seen, to a lesser extent, in vaginally delivered babies whose mothers underwent antibiotic prophylaxis and in babies who were not breastfed during the neonatal period. We applied longitudinal sampling and whole-genome shotgun metagenomic analysis to 1,679 gut microbiota samples (taken at several time points during the neonatal period, and in infancy) from 596 full-term babies born in UK hospitals; for a subset of these babies, we collected additional matched samples from mothers (175 mothers paired with 178 babies). This analysis demonstrates that the mode of delivery is a significant factor that affects the composition of the gut microbiota throughout the neonatal period, and into infancy. Matched large-scale culturing and whole-genome sequencing of over 800 bacterial strains from these babies identified virulence factors and clinically relevant antimicrobial resistance in opportunistic pathogens that may predispose individuals to opportunistic infections. Our findings highlight the critical role of the local environment in establishing the gut microbiota in very early life, and identify colonization with antimicrobial-resistance-containing opportunistic pathogens as a previously underappreciated risk factor in hospital births.

Effects of repeat prenatal corticosteroids given to women at risk of preterm birth: An individual participant data meta-analysis.

Abstract: Background Infants born preterm compared with infants born at term are at an increased risk of dying and of serious morbidities in early life, and those who survive have higher rates of neurological impairments. It remains unclear whether exposure to repeat courses of prenatal corticosteroids can reduce these risks. This individual participant data (IPD) meta-analysis (MA) assessed whether repeat prenatal corticosteroid treatment given to women at ongoing risk of preterm birth in order to benefit their infants is modified by participant or treatment factors. Methods and findings Trials were eligible for inclusion if they randomised women considered at risk of preterm birth who had already received an initial, single course of prenatal corticosteroid seven or more days previously and in which corticosteroids were compared with either placebo or no placebo. The primary outcomes for the infants were serious outcome, use of respiratory support, and birth weight z-scores; for the children, they were death or any neurosensory disability; and for the women, maternal sepsis. Studies were identified using the Cochrane Pregnancy and Childbirth search strategy. Date of last search was 20 January 2015. IPD were sought from investigators with eligible trials. Risk of bias was assessed using criteria from the Cochrane Collaboration. IPD were analysed using a one-stage approach. Eleven trials, conducted between 2002 and 2010, were identified as eligible, with five trials being from the United States, two from Canada, and one each from Australia and New Zealand, Finland, India, and the United Kingdom. All 11 trials were included, with 4,857 women and 5,915 infants contributing data. The mean gestational age at trial entry for the trials was between 27.4 weeks and 30.2 weeks. There was no significant difference in the proportion of infants with a serious outcome (relative risk [RR] 0.92, 95% confidence interval [CI] 0.82 to 1.04, 5,893 infants, 11 trials, p = 0.33 for heterogeneity). There was a reduction in the use of respiratory support in infants exposed to repeat prenatal corticosteroids compared with infants not exposed (RR 0.91, 95% CI 0.85 to 0.97, 5,791 infants, 10 trials, p = 0.64 for heterogeneity). The number needed to treat (NNT) to benefit was 21 (95% CI 14 to 41) women/fetus to prevent one infant from needing respiratory support. Birth weight z-scores were lower in the repeat corticosteroid group (mean difference −0.12, 95%CI −0.18 to −0.06, 5,902 infants, 11 trials, p = 0.80 for heterogeneity). No statistically significant differences were seen for any of the primary outcomes for the child (death or any neurosensory disability) or for the woman (maternal sepsis). The treatment effect varied little by reason the woman was considered to be at risk of preterm birth, the number of fetuses in utero, the gestational age when first trial treatment course was given, or the time prior to birth that the last dose was given. Infants exposed to between 2–5 courses of repeat corticosteroids showed a reduction in both serious outcome and the use of respiratory support compared with infants exposed to only a single repeat course. However, increasing numbers of repeat courses of corticosteroids were associated with larger reductions in birth z-scores for weight, length, and head circumference. Not all trials could provide data for all of the prespecified subgroups, so this limited the power to detect differences because event rates are low for some important maternal, infant, and childhood outcomes. Conclusions In this study, we found that repeat prenatal corticosteroids given to women at ongoing risk of preterm birth after an initial course reduced the likelihood of their infant needing respiratory support after birth and led to neonatal benefits. Body size measures at birth were lower in infants exposed to repeat prenatal corticosteroids. Our findings suggest that to provide clinical benefit with the least effect on growth, the number of repeat treatment courses should be limited to a maximum of three and the total dose to between 24 mg and 48 mg.

When to keep it simple – adaptive designs are not always useful

Abstract: Adaptive designs are a wide class of methods focused on improving the power, efficiency and participant benefit of clinical trials. They do this through allowing information gathered during the trial to be used to make changes in a statistically robust manner – the changes could include which treatment arms patients are enrolled to (e.g. dropping non-promising treatment arms), the allocation ratios, the target sample size or the enrolment criteria of the trial. Generally, we are enthusiastic about adaptive designs and advocate their use in many clinical situations. However, they are not always advantageous. In some situations, they provide little efficiency advantage or are even detrimental to the quality of information provided by the trial. In our experience, factors that reduce the efficiency of adaptive designs are routinely downplayed or ignored in methodological papers, which may lead researchers into believing they are more beneficial than they actually are. In this paper, we discuss situations where adaptive designs may not be as useful, including situations when the outcomes take a long time to observe, when dropping arms early may cause issues and when increased practical complexity eliminates theoretical efficiency gains. Adaptive designs often provide notable efficiency benefits. However, it is important for investigators to be aware that they do not always provide an advantage. There should always be careful consideration of the potential benefits and disadvantages of an adaptive design.

What are the most important unanswered research questions in trial retention? A James Lind Alliance Priority Setting Partnership: the PRioRiTy II (Prioritising Retention in Randomised Trials) study

Abstract: One of the top three research priorities for the UK clinical trial community is to address the gap in evidence-based approaches to improving participant retention in randomised trials. Despite this, there is little evidence supporting methods to improve retention. This paper reports the PRioRiTy II project, a Priority Setting Partnership (PSP) that identified and prioritised unanswered questions and uncertainties around trial retention in collaboration with key stakeholders. This PSP was conducted in collaboration with the James Lind Alliance, a non-profit making initiative, to support key stakeholders (researchers, patients, and the public) in jointly identifying and agreeing on priority research questions. There were three stages. (1) First an initial online survey was conducted consisting of six open-ended questions about retention in randomised trials. Responses were coded into thematic groups to create a longlist of questions. The longlist of questions was checked against existing evidence to ensure that they had not been answered by existing research. (2) An interim stage involved a further online survey where stakeholders were asked to select questions of key importance from the longlist. (3) A face-to-face consensus meeting was held, where key stakeholder representatives agreed on an ordered list of 21 unanswered research questions for methods of improving retention in randomised trials. A total of 456 respondents yielded 2431 answers to six open-ended questions, from which 372 questions specifically about retention were identified. Further analysis included thematically grouping all data items within answers and merging questions in consultation with the Steering Group. This produced 27 questions for further rating during the interim survey. The top 21 questions from the interim online survey were brought to a face-to-face consensus meeting in which key stakeholder representatives prioritised the order. The ‘Top 10’ of these are reported in this paper. The number one ranked question was ’What motivates a participant’s decision to complete a clinical trial?’ The entire list will be available at www.priorityresearch.ie . The Top 10 list can inform the direction of future research on trial methods and be used by funders to guide projects aiming to address and improve retention in randomised trials.

Prioritizing research for patients requiring surgery in low- and middle-income countries

Abstract: The National Institute for Health Research Global Health Research Unit on Global Surgery is establishing research Hubs in low‐ and middle‐income countries (LMICs). The aim of this study was for the Hubs to prioritize future research into areas of unmet clinical need for patients in LMICs requiring surgery.

Developing routinely recorded clinical data from electronic patient records as a national resource to improve neonatal health care: the Medicines for Neonates research programme

Abstract: Background Clinical data offer the potential to advance patient care. Neonatal specialised care is a high-cost NHS service received by approximately 80,000 newborn infants each year. Objectives (1) To develop the use of routinely recorded operational clinical data from electronic patient records (EPRs), secure national coverage, evaluate and improve the quality of clinical data, and develop their use as a national resource to improve neonatal health care and outcomes. To test the hypotheses that (2) clinical and research data are of comparable quality, (3) routine NHS clinical assessment at the age of 2 years reliably identifies children with neurodevelopmental impairment and (4) trial-based economic evaluations of neonatal interventions can be reliably conducted using clinical data. (5) To test methods to link NHS data sets and (6) to evaluate parent views of personal data in research. Design Six inter-related workstreams; quarterly extractions of predefined data from neonatal EPRs; and approvals from the National Research Ethics Service, Health Research Authority Confidentiality Advisory Group, Caldicott Guardians and lead neonatal clinicians of participating NHS trusts. Setting NHS neonatal units. Participants Neonatal clinical teams; parents of babies admitted to NHS neonatal units. Interventions In workstream 3, we employed the Bayley-III scales to evaluate neurodevelopmental status and the Quantitative Checklist of Autism in Toddlers (Q-CHAT) to evaluate social communication skills. In workstream 6, we recruited parents with previous experience of a child in neonatal care to assist in the design of a questionnaire directed at the parents of infants admitted to neonatal units. Data sources Data were extracted from the EPR of admissions to NHS neonatal units. Main outcome measures We created a National Neonatal Research Database (NNRD) containing a defined extract from real-time, point-of-care, clinician-entered EPRs from all NHS neonatal units in England, Wales and Scotland (n = 200), established a UK Neonatal Collaborative of all NHS trusts providing neonatal specialised care, and created a new NHS information standard: the Neonatal Data Set (ISB 1595) (see http://webarchive.nationalarchives.gov.uk/±/http://www.isb.nhs.uk/documents/isb-1595/amd-32–2012/index_html; accessed 25 June 2018). Results We found low discordance between clinical (NNRD) and research data for most important infant and maternal characteristics, and higher prevalence of clinical outcomes. Compared with research assessments, NHS clinical assessment at the age of 2 years has lower sensitivity but higher specificity for identifying children with neurodevelopmental impairment. Completeness and quality are higher for clinical than for administrative NHS data; linkage is feasible and substantially enhances data quality and scope. The majority of hospital resource inputs for economic evaluations of neonatal interventions can be extracted reliably from the NNRD. In general, there is strong parent support for sharing routine clinical data for research purposes. Limitations We were only able to include data from all English neonatal units from 2012 onwards and conduct only limited cross validation of NNRD data directly against data in paper case notes. We were unable to conduct qualitative analyses of parent perspectives. We were also only able to assess the utility of trial-based economic evaluations of neonatal interventions using a single trial. We suggest that results should be validated against other trials. Conclusions We show that it is possible to obtain research-standard data from neonatal EPRs, and achieve complete population coverage, but we highlight the importance of implementing systematic examination of NHS data quality and completeness and testing methods to improve these measures. Currently available EPR data do not enable ascertainment of neurodevelopmental outcomes reliably in very preterm infants. Measures to maintain high quality and completeness of clinical and administrative data are important health service goals. As parent support for sharing clinical data for research is underpinned by strong altruistic motivation, improving wider public understanding of benefits may enhance informed decision-making. Future work We aim to implement a new paradigm for newborn health care in which continuous incremental improvement is achieved efficiently and cost-effectively by close integration of evidence generation with clinical care through the use of high-quality EPR data. In future work, we aim to automate completeness and quality checks and make recording processes more ‘user friendly’ and constructed in ways that minimise the likelihood of missing or erroneous entries. The development of criteria that provide assurance that data conform to prespecified completeness and quality criteria would be an important development. The benefits of EPR data might be extended by testing their use in large pragmatic clinical trials. It would also be of value to develop methods to quality assure EPR data including involving parents, and link the NNRD to other health, social care and educational data sets to facilitate the acquisition of lifelong outcomes across multiple domains. Study registration This study is registered as PROSPERO CRD42015017439 (workstream 1) and PROSPERO CRD42012002168 (workstream 3). Funding The National Institute for Health Research Programme Grants for Applied Research programme (£1,641,471). Unrestricted donations were supplied by Abbott Laboratories (Maidenhead, UK: £35,000), Nutricia Research Foundation (Schiphol, the Netherlands: £15,000), GE Healthcare (Amersham, UK: £1000). A grant to support the use of routinely collected, standardised, electronic clinical data for audit, management and multidisciplinary feedback in neonatal medicine was received from the Department of Health and Social Care (£135,494).

Association Between Oxygen Saturation Targeting and Death or Disability in Extremely Preterm Infants in the Neonatal Oxygenation Prospective Meta-Analysis Collaboration

Abstract: later. No neonatal complications were reported. Of the 6 women who had a first trimester termination, none had a relapse. There were no significant cardiac events or maternal deaths in the cohort. Four women (6.6%) had a sterilization procedure. None of the women were treated with bromocriptine to prevent relapse. More than half (62%) of the 13 women who had subsequent pregnancies were advised against doing so because of risks of recurrent PPCM. This study was the first nationwide study of subsequent reproductive outcomes in a cohort of women with PPCM. They found 1 in 7 women relapsed in a subsequent pregnancy, which is consistent with previous studies on PPCM relapse. These results support the finding that few subsequent pregnancies after PPCM result in a liveborn child. Further research involving multicenter studies should be performed to identify predictors of relapse.

Uncertainties in Screening and Prevention of Group B Streptococcus Disease.

Abstract: In autumn 2016, the UK Department of Health (now Department of Health and Social Care) convened 2 meetings to discuss how to address research evidence gaps in order to minimize the impact of infant group B streptococcus (GBS) disease in the United Kingdom. At that meeting, a number of research priorities were highlighted, including improving the screening for GBS colonization in pregnant women, offering intrapartum antibiotic prophylaxis and point-of-care testing, and understanding the effect of widespread intrapartum antibiotic use on long-term infant health. Further discussions involved investigating the feasibility of a large prospective study of pregnant women and their infants in order to understand the role of antibodies in the protection against GBS disease in infancy following maternal exposure to GBS colonization. Here, we summarize the research uncertainties identified at that meeting.

Planned delivery or expectant management for late preterm pre-eclampsia: study protocol for a randomised controlled trial (PHOENIX trial).

Abstract: Pre-eclampsia is a pregnancy disorder, characterised by hypertension and multisystem complications in the mother. The adverse outcomes of pre-eclampsia include severe hypertension, stroke, renal and hepatic injury, haemorrhage, fetal growth restriction and even death. The optimal time to instigate delivery to prevent morbidity when pre-eclampsia occurs between 34 and 37 weeks’ gestation, without increasing problems related to infant immaturity or complications, remains unclear. The PHOENIX trial is a non-masked, randomised controlled trial, comparing planned early delivery (with initiation of delivery within 48 h of randomisation) with usual care (expectant management) in women with pre-eclampsia between 34+ 0 and 36+ 6 weeks’ gestation. The primary objectives of the trial are to determine if planned delivery reduces adverse maternal outcomes, without increasing the short-term harm to infants (composite of perinatal deaths or neonatal unit admissions up to infant hospital discharge) or impacting long-term infant neurodevelopmental status at 2 years corrected age (Parent Report of Cognitive Abilities-Revised). Current practice in the UK at the time of trial commencement for management of pre-eclampsia varies by gestation. Previous trials have shown that in women with pre-eclampsia after 37 weeks of gestion, delivery is initiated, as maternal complications are reduced without increasing fetal risks. Prior to 34 weeks of gestation, usual management aims to prolong pregnancy for fetal benefit, unless severe complications occur, necessitating preterm delivery. This trial aims to address the uncertainty for women where the balance of benefits and risks of delivery compared to expectant management are uncertain. Previous trials in this area have been undertaken, but have not provided a definitive answer, and the research question remains active. The results of this trial are expected to influence clinical practice internationally, through direct adoption and by incorporation into guidelines in countries with similar settings. ISRCTN01879376 . Registered on 25 November 2013.

Study protocol for a randomised controlled trial of carvedilol versus variceal band ligation in primary prevention of variceal bleeding in liver cirrhosis (CALIBRE trial)

Abstract: Introduction Liver cirrhosis is the fifth largest cause of adult deaths, and a major complication, variceal bleeding is associated with a 1-year mortality of 40%. There is uncertainty on the first-line therapy for prevention of variceal bleeding owing to a lack of adequately powered trials comparing non-selective beta blockers, in particular carvedilol, with variceal band ligation. Methods and analysis CALIBRE is a multicentre, pragmatic, randomised controlled, open-label trial with an internal pilot. The two interventions are carvedilol 12.5 mg od or variceal band ligation (VBL). Patients with liver cirrhosis and medium to large oesophageal varices that have never bled are eligible for inclusion. The primary outcome is any variceal bleeding within 1 year of randomisation. Secondary endpoints include time to variceal bleed, mortality, transplant-free survival, adverse events, complications of cirrhosis, health-related quality of life, use of healthcare resources, patient preference and use of alternative or crossover therapies. The sample size is 2630 patients over a 4-year recruitment period, across 66 hospitals in the UK. Ethics and dissemination The study has been approved by a National Health Service (NHS) Research Ethics Committee (REC) (reference number 18/NE/0296). The results of this trial will be submitted for publication in a peer reviewed journal. Participants will be informed via a link to a preview of the publication. A lay summary will also be provided via email or posted to participants prior to publication (ISRCTN reference number: 73887615).

Long-term impact of giving antibiotics before skin incision versus after cord clamping on children born by caesarean section: protocol for a longitudinal study based on UK electronic health records

Abstract: Introduction In the UK, about a quarter of women give birth by caesarean section (CS) and are offered prophylactic broad-spectrum antibiotics to reduce the risk of maternal postpartum infection. In 2011, national guidance was changed from recommending antibiotics after the umbilical cord was cut to giving antibiotics prior to skin incision based on evidence that earlier administration reduces maternal infectious morbidity. Although antibiotics cross the placenta, there are no known short-term harms to the baby. This study aims to address the research gap on longer term impact of these antibiotics on child health. Methods and analysis A controlled interrupted time series study will use anonymised mother-baby linked routine electronic health records for children born during 2006–2018 recorded in UK primary care (The Health Improvement Network, THIN and Clinical Practice Research Datalink, CPRD) and secondary care (Hospital Episode Statistics, HES) databases. The primary outcomes of interest are asthma and eczema, two common allergy-related diseases in childhood. In-utero exposure to antibiotics immediately prior to CS will be compared with no exposure when given after cord clamping. The risk of outcomes in children delivered by CS will also be compared with a control cohort delivered vaginally to account for time effects. We will use all available data from THIN, CPRD and HES with estimated power of 80% and 90% to detect relative increase in risk of asthma of 16% and 18%, respectively at the 5% significance level. Ethics and dissemination Ethical approval has been obtained from the University of Birmingham Ethical Review Committee with scientific approvals obtained from the independent scientific advisory committees from the Medicines and Healthcare products Regulatory Agency for CPRD and the data provider, IQVIA for THIN. The results will be published in peer-reviewed journals, presented at national and international conferences and disseminated to stakeholders.

The Incidence, Characteristics, Management, and Outcomes of Anaphylaxis in Pregnancy: A Population-based Descriptive Study

Abstract: Objective The aim of this study was to estimate the incidence of anaphylaxis in pregnancy and describe the management and outcomes in the UK. Design A population-based descriptive study using the UK Obstetric Surveillance System (UKOSS). Setting All consultant-led maternity units in the UK. Population All pregnant women who had anaphylaxis between 1 October 2012 and 30 September 2015. Anaphylaxis was defined as a severe, life-threatening generalised or systemic hypersensitivity reaction. Methods Prospective case notification using UKOSS. Main outcome measures Maternal mortality, severe maternal morbidity, neonatal mortality and severe neonatal morbidity. Results There were 37 confirmed cases of anaphylaxis in pregnancy, giving an estimated incidence of 1.6 (95% CI: 1.1–2.2) per 100 000 maternities. Four cases of anaphylaxis were in women with known penicillin allergies: two received co-amoxiclav and two cephalosporins. Twelve women had anaphylaxis following prophylactic use of antibiotics at the time of a caesarean delivery. Prophylactic use of antibiotics for Group B streptococcal infection accounted for anaphylaxis in one woman. Two women died (5%), 14 (38%) women were admitted to intensive care and seven women (19%) had one or more additional severe maternal morbidities, which included three haemorrhagic events, two cardiac arrests, one thrombotic event and one pneumonia. No infants died; however, in those infants whose mother had anaphylaxis before delivery (n = 18) there were seven (41%) neonatal intensive care unit admissions, three preterm births and one baby was cooled for neonatal encephalopathy. Conclusions Anaphylaxis is a rare severe complication of pregnancy and frequently the result of a reaction to antibiotic administration. This study highlights the seriousness of the outcomes of this condition for the mother. The low incidence is reassuring given the large proportion of the pregnant population that receive prophylactic antibiotics during delivery. Tweetable abstract Anaphylaxis is a rare severe complication of pregnancy and frequently the result of a reaction to antibiotic administration.