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Background Vasa praevia is an obstetric condition in which the fetal vessels run through the membrane over the internal cervical os, unprotected by the placenta or umbilical cord. It is associated with perinatal mortality if not diagnosed antenatally. We estimated the incidence and investigated outcomes of vasa praevia in the UK. Methods We conducted a population-based descriptive study using the UK Obstetric Surveillance System (UKOSS). Cases were identified prospectively through monthly UKOSS submissions from all UK hospitals with obstetrician-led maternity units. All women diagnosed with vasa praevia who gave birth between 1st December 2014 and 30th November 2015 were included. The main outcome was estimated incidence of vasa praevia with 95% confidence intervals, using 2015 maternities as the denominator. Results Fifty-one women met the case definition. The estimated incidence of diagnosed vasa praevia was 6.64 per 100,000 maternities (95% CI 5.05-8.73). Of 198 units, 10 (5%) had a vasa praevia screening programme; one of these 10 units identified 25% of the antenatally diagnosed cases. Among women who had vasa praevia diagnosed or suspected antenatally (n=28, 55%), there were no perinatal deaths or hypoxic ischaemic encephalopathy (HIE). Twenty-four women with antenatal diagnosis were hospitalised at a median 32 weeks’ gestation and caesarean section was scheduled at a median 36 weeks’ gestation. When vasa praevia was diagnosed peripartum (n=23, 45%), the perinatal mortality rate was 37.5% and 47% of survivors developed HIE. Conclusions The incidence of diagnosed vasa praevia was lower than anticipated. There was high perinatal mortality and morbidity for cases not diagnosed antenatally. The incidence of antenatally identified cases was much higher in the few centres that actively screened for this condition, and the perinatal outcomes were better. However, this group were all delivered by caesarean section and may include women who would not have experienced any adverse perinatal outcome.

Abstract There are few population-based studies of sufficient size and follow-up duration to have reliably assessed perinatal outcomes for pregnant women hospitalised with SARS-CoV-2 infection. The United Kingdom Obstetric Surveillance System (UKOSS) covers all 194 consultant-led UK maternity units and included all pregnant women admitted to hospital with an ongoing SARS-CoV-2 infection. Here we show that in this large national cohort comprising two years’ active surveillance over four SARS-CoV-2 variant periods and with near complete follow-up of pregnancy outcomes for 16,627 included women, severe perinatal outcomes were more common in women with moderate to severe COVID-19, during the delta dominant period and among unvaccinated women. We provide strong evidence to recommend continuous surveillance of pregnancy outcomes in future pandemics and to continue to recommend SARS-CoV-2 vaccination in pregnancy to protect both mothers and babies.

Background Vasa praevia is an obstetric condition in which the fetal vessels run through the membrane over the internal cervical os, unprotected by the placenta or umbilical cord. It is associated with perinatal mortality if not diagnosed antenatally. We investigated the incidence and outcomes of vasa praevia in the UK. Methods We conducted a population-based descriptive study using the UK Obstetric Surveillance System (UKOSS). Cases were identified prospectively through monthly UKOSS submissions form all UK hospitals with obstetrician-led maternity units. All women diagnosed with vasa praevia who gave birth between 1st December 2014 and 30th November 2015 were included. The main outcome was incidence of vasa praevia with 95% confidence intervals, using 2015 maternities as the denominator. Results Fifty-one women met the case definition. The incidence of diagnosed vasa praevia was 6.64 per 100,000 maternities (95% CI 5.05-8.73). Of 198 units, 10 (5%) had a vasa praevia screening programme; one of these 10 units identified 25% of the antenatally diagnosed cases. Among women who had vasa praevia diagnosed or suspected antenatally (n=28, 55%), there were no perinatal deaths or hypoxic ischaemic encephalopathy (HIE). Twenty-four women with antenatal diagnosis were hospitalised at a median gestation of 32 weeks and caesarean section was scheduled at a median gestation of 36 weeks. When vasa praevia was diagnosed peripartum (n=23, 45%), the perinatal mortality rate was 37.5% and 47% of survivors developed HIE. Conclusions The incidence of diagnosed vasa praevia was lower than anticipated. There was high perinatal mortality and morbidity for cases not diagnosed antenatally. The incidence of antenatally identified cases was much higher in the few centres that actively screened for this condition, and the perinatal outcomes were better. However, this group were all delivered by caesarean section and may include women who would not have experienced any adverse perinatal outcome.

Introduction Physical frailty is associated with increased mortality and poor quality of life (QoL) before and after liver transplantation (LT). Evidence is lacking on how to tailor exercise and behavioural techniques in this patient population.Methods and analysis Home-based EXercise and motivAtional programme before and after Liver Transplantation (EXALT) is a phase 2b, open-label, two-centre randomised controlled clinical trial designed to investigate whether a remotely monitored ‘home-based exercise and theory-based motivation support programme (HBEP)’ before and after LT improves QoL in LT recipients. Adult patients awaiting a primary LT will be assessed for eligibility at two LT centres (Birmingham, Royal Free London). Participants will be randomly assigned (1:1) to receive either an HBEP while on the LT waiting list through to 24 weeks after LT (Intervention) or a patient exercise advice leaflet (Control). Using a standard method of difference in means (two-sided significance level 0.05; power 0.90) and accounting for a 35% attrition/withdrawal rate, a minimum of 133 patients will be randomised to each treatment group. The primary outcome measure will be assessed using intention-to-treat analysis of the difference in the Physical Component Score of Short form-36 version 2.0 health-related QoL questionnaire between the groups at 24 weeks post-LT.Ethics and dissemination The protocol was approved by the South Central-Hampshire A National Research Ethics Committee. Recruitment into the EXALT trial started in May 2022 and is due to end in June 2024, with 217/266 patients randomised to date. The intervention follow-up is due to finish in May 2026. The findings of this trial will be disseminated through peer-reviewed publications, conferences and social media.Trial registration number ISRCTN13476586.

Background Second trimester miscarriage and preterm birth is a significant global problem. Surgical cervical cerclage is performed to prevent pregnancy loss and preterm birth. It utilises either a monofilament or braided suture. It is hypothesised that a braided material becomes colonised with pathogenic bacteria that causes vaginal dysbiosis, infection and cerclage failure. Objectives The primary objective of the study was to examine the effectiveness of using a monofilament suture material as opposed to a braided suture material on pregnancy loss in women requiring a vaginal cervical cerclage. Design Superiority open randomised controlled trial. Setting Seventy-five maternity sites across the UK. Participants Women experiencing a singleton pregnancy requiring a cervical cerclage. Interventions Monofilament suture or braided suture. Main outcome measures The primary outcome was pregnancy loss (miscarriage and perinatal mortality, including any stillbirth or neonatal death in the first week of life). Secondary outcomes included the core outcome set for preterm birth. Methods Women were randomised on a 1 : 1 basis to monofilament or braided cerclage utilising a bespoke randomisation service with minimisation dependent on the site, indication for cerclage, intention to use progesterone and planned surgical technique. The inclusion criteria were three or more previous mid-trimester losses or preterm births, insertion of a cerclage in a previous pregnancy, a history of a mid-trimester loss or preterm birth with a shortened cervical length in the current pregnancy or in women who clinicians deemed at risk of preterm birth. The exclusion criteria were an emergency or rescue cerclage, age of < 18 years, being unable to give informed consent or the cerclage having to be placed abdominally. The original sample size was calculated based on a relative risk reduction of 41% from a pregnancy loss rate of 19% in the braided group to 11% in the monofilament group with 90% power and alpha at p = 0.05. The independent data monitoring committee noted a lower-than-anticipated pooled event rate within the trial and recommended an increase in sample size to 2050. The outcome data were collected using clinical record forms from the maternal and neonatal medical records and reported to Birmingham Clinical Trials Unit. Results A total of 2049 women were randomised, after withdrawals and loss to follow-up, data on 1005 women in the monofilament group and 993 women in the braided group were included. The baseline demographics between the groups were similar. There was no evidence of a difference in pregnancy loss rates between the monofilament and braided groups (80/1003 vs. 75/993; adjusted risk ratio: 1.05, 95% confidence interval: 0.79 to 1.40; adjusted risk difference: 0.002, 95% confidence interval: −0.02 to 0.03). Limitations The trial did not collect long-term paediatric outcomes. There were no safety concerns. Conclusions There was no evidence of a difference in pregnancy loss between a monofilament suture and a braided suture. Future work Long-term follow-up of neonates born within the C-STICH (cerclage suture type for an insufficient cervix and its effects on health outcomes) trial. Trial registration This trial is registered as ISRCTN15373349. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 13/04/107) and is published in full in Health Technology Assessment; Vol. 28, No. 40. See the NIHR Funding and Awards website for further award information. Plain language summary Cervical cerclage is an operation performed in pregnancy to prevent miscarriage and preterm birth. A cervical cerclage is sometimes recommended in women who have had babies born prematurely before or who have had previous cervical surgery. A cerclage operation involves a stitch being inserted around the neck of the womb (cervix) to keep it closed during pregnancy and to prevent it opening prematurely. When performing the operation, the doctor can use different types of threads made of different materials. The threads used to perform the operation are called sutures. One suture type is a single strand or monofilament thread, and the other is a multifilament braided thread with lots of thin strands woven together. Some evidence has suggested that using a monofilament suture thread prevented pregnancy loss by preventing infection. Therefore, we performed a randomised controlled trial of the use of monofilament suture thread versus braided suture thread, aiming to reduce pregnancy loss in women who were having a cerclage as part of their routine care. The women consented to take part in the study and were randomly allocated to their cerclage performed with either a monofilament or braided suture thread; there was no other change to their planned pregnancy care. What happened in their pregnancy was recorded from their medical records and analysed. A total of 2049 women agreed to take part in the study and consented to the analysis of their pregnancy and neonatal outcomes. Cerclage suture type for an insufficient cervix and its effects on health outcomes showed that there was no difference in pregnancy loss between the two suture threads. There was decreased maternal sepsis and decreased chorioamnionitis (which is an infection inside the womb during labour) in the women who received a monofilament suture, which needs further investigation. Although more women who had a cerclage using the monofilament thread needed a small operation and an anaesthetic, often between 36 and 37 weeks, to remove the monofilament suture prior to a vaginal birth, there were no differences in the outcomes for their babies. Scientific summary Background Preterm birth and second trimester miscarriage is a significant cause of worldwide neonatal morbidity and mortality. The aetiology is complex and multifactorial with a number of causes, including cervical insufficiency. One treatment to prevent preterm birth and second trimester miscarriage caused by cervical insufficiency is the placement of a vaginal cervical cerclage (CC). A CC is the placement of a purse string suture thread around the cervix aiming to prevent pregnancy loss and preterm birth. A CC can be performed with either a monofilament suture thread or a braided suture thread. The choice of thread used during surgical operations is dependent on the properties of the thread, with braided threads being multifilament in nature with lots of single strands woven together, which predisposes it to potentially becoming colonised with pathogenic bacteria. A prior feasibility study suggested a difference in pregnancy loss outcomes between monofilament and braided suture threads and the acceptability of either thread for clinicians and women. Therefore, a randomised controlled trial was designed to explore this discrepancy, aiming to reduce pregnancy loss for women at high risk of preterm birth. Objectives The primary objective of the study was to examine the effectiveness of using a monofilament suture material compared to a braided suture material on minimising the risk of pregnancy loss in women requiring a vaginal CC. The secondary objectives of the study included exploring the impact of suture material on maternal and neonatal outcomes. Design A pragmatic open, parallel, multicentre, randomised superiority trial of monofilament versus braided suture type during CC to prevent pregnancy loss. Setting The study was conducted in hospital settings across the UK (75 sites) between 2015 and 2022. Participants Women were eligible for the trial if they required a vaginal CC as part of their routine care within their current pregnancy and they fulfilled the following eligibility criteria: Inclusion Singleton pregnancy. Indication for CC for either: a history of three or more previous mid-term losses or premature births (≤ 28 weeks), OR insertion of cervical sutures in previous pregnancies, OR a history of mid-trimester loss or premature birth with a shortened (≤ 25 mm) cervix, OR women whom clinicians deemed to be at risk of preterm birth either because of their history or because of the results of an ultrasound scan. Exclusion Had taken part in C-STICH previously. Aged < 18 years old at the time of presentation. Requiring a rescue cerclage. Unwilling or unable to give informed consent. Those in whom a cerclage was to be placed by any route other than vaginally (e.g. via an abdominal route). Immediate need for insertion of a suture. Membranes that had ruptured or were surfacing. Interventions Women were randomised at a 1 : 1 ratio via a secure internet facility to have their CC performed using either a monofilament or braided suture thread. Minimisation was employed to balance for the following: indication for cerclage, planned bladder dissection, intention to commence patient on progesterone and recruiting site. Outcome measures The primary outcome measure was pregnancy loss (miscarriage and perinatal mortality). Key secondary outcome: Time from conception to pregnancy end (any reason). Maternal outcomes: Miscarriage and previable neonatal death (defined as delivery < 24 weeks). Stillbirth (defined as intrauterine death ≥ 24 weeks). Gestation at delivery (in live births ≥ 24 weeks). Gestational age of < 28/< 32/< 37 weeks at delivery (in live births ≥ 24 weeks). Time from conception to onset of spontaneous vaginal delivery (in live births ≥ 24 weeks). Sepsis (at any time in pregnancy and until 7 days postnatal). Preterm prelabour rupture of membranes (PPROM). Mode of initiation of labour (spontaneous or induced). Mode of delivery (vaginal, operative vaginal or caesarean). Cerclage placement complications (cervical laceration/bleeding from cervix/ruptured membranes/bladder injury). Cerclage removal complications (cervical tears/need for anaesthetic/difficult to remove). Other maternal complications: vaginal bleeding/steroid use/chorioamnionitis/maternal pyrexia of 38°C (intrapartum/postnatal)/admission to high dependency unit (HDU) or intensive therapy unit (ITU) (pre/post delivery). Neonatal outcomes: Early neonatal death (defined as a death within 7 days after delivery) (in live births ≥ 24 weeks). Late neonatal death (defined as a death beyond 7 days and before 28 days after delivery) (in live births ≥ 24 weeks). Birth-weight centile adjusted for gestational age and sex (in live births ≥ 24 weeks). Small for gestational age and sex (< 10th centile, in live births ≥ 24 weeks). Resuscitation at birth (in live births ≥ 24 weeks). Additional care required [special care baby unit (SCBU)/neonatal intensive care unit (NICU)/HDU/transitional care] and length of stay in additional care (in live births ≥ 24 weeks). Antibiotics within 72 hours (in live births ≥ 24 weeks). Sepsis (clinically diagnosed/proven) (in live births ≥ 24 weeks). Early neurodevelopmental morbidity (severe abnormality on cranial ultrasound scan) (in live births ≥ 24 weeks). Respiratory support and days on respiratory support (in live births ≥ 24 weeks). Supplementary oxygen requirements at 36 weeks post menstrual age (in live births ≥ 24 weeks). Necrotising enterocolitis (Bell’s stage 2 or 3) (in live births ≥ 24 weeks). Retinopathy of prematurity requiring laser treatment (in live births ≥ 24 weeks). Disabilities (live births ≥ 24 weeks). Congenital anomalies (in live births ≥ 24 weeks). The core outcome set for preterm birth was fully collected within the trial. Sample size The original sample size was based on a meta-analysis of non-randomised studies, where the pooled pregnancy loss rate in the monofilament group was 7% compared to 19% in the braided group. To allow for the observational nature of these data, we powered the study to detect a more plausible relative reduction of 41% (19% with braided sutures to 11.2% with monofilament sutures) with 90% power (alpha = 0.05). We planned to recruit 900 women. As a result of some uncertainty around the sample size parameters, the data monitoring committee reviewed the pooled event rate throughout the study. The sample size was subsequently increased to 2050 women to allow for a lower-than-anticipated event rate in order to maintain sufficient power to detect the same relative risk reduction. The primary analysis was by intention to treat. Results The trial opened for recruitment in August 2015 and completed recruitment in January 2021. A total of 2049 women were randomised into the trial and data for analysis was available for 1003 women in the monofilament group and 993 women in the braided group. The baseline demographic characteristics of women in the monofilament and braided group were similar. There was no evidence of a difference in pregnancy loss rates between the monofilament and braided groups [80/1003 vs. 75/993; adjusted risk ratio (RR) 1.05, 95% confidence interval (CI) 0.79 to 1.40; adjusted risk difference 0.002, 95% CI −0.02 to 0.03]. There was no difference in conception to pregnancy end (median time to pregnancy end: 37.9 weeks vs. 38.0 weeks; adjusted hazard ratio 1.04, 95% CI 0.95 to 1.14). Regarding maternal outcomes there was a decrease in maternal sepsis in the monofilament group (4%) compared to the braided group (7%) (RR 0.58, 95% CI 0.40 to 0.82) and a decreased risk of chorioamnionitis in the monofilament group (3%) compared to the braided group (6%) (RR 0.45, 95% CI 0.29 to 0.71). There was no difference in any neonatal outcomes. CC removal complications showed an increase in the monofilament group (56% vs. 42%, RR 1.25, 95% CI 1.15 to 1.36), with increased difficulty of removal and an increased need for anaesthetic for removal being the most common complications. Conclusions There was no evidence of a difference between a monofilament suture thread and a braided suture for pregnancy outcomes. We can be relatively confident that using a monofilament suture is unlikely to have a substantial impact on pregnancy loss compared to a braided suture. The uncertainty around our comparative estimate for this outcome is at most 2% in favour of the monofilament in absolute terms. While this margin may not completely rule out missing a clinically important difference, we consider this scenario to be unlikely. Therefore, clinicians should consider the relative merits and disadvantages of the physical suture properties when selecting the material to perform a vaginal CC. The trial was robustly conducted with minimal limitations. An important strength of the study is the recognition early in the trial that the event rate was lower than anticipated and, therefore, the sample size was increased allowing the effectiveness of a monofilament versus braided suture thread to be fully evaluated. Trial registration This trial is registered as ISRCTN15373349. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 13/04/107) and is published in full in Health Technology Assessment; Vol. 28, No. 40. See the NIHR Funding and Awards website for further award project information.

Abstract Background Heterogeneity in reported outcomes can limit the synthesis of research evidence. A core outcome set informs what outcomes are important and should be measured as a minimum in all future studies. We report the development of a core outcome set applicable to observational and interventional studies of pregnant women with multimorbidity. Methods We developed the core outcome set in four stages: (i) a systematic literature search, (ii) three focus groups with UK stakeholders, (iii) two rounds of Delphi surveys with international stakeholders and (iv) two international virtual consensus meetings. Stakeholders included women with multimorbidity and experience of pregnancy in the last 5 years, or are planning a pregnancy, their partners, health or social care professionals and researchers. Study adverts were shared through stakeholder charities and organisations. Results Twenty-six studies were included in the systematic literature search (2017 to 2021) reporting 185 outcomes. Thematic analysis of the focus groups added a further 28 outcomes. Two hundred and nine stakeholders completed the first Delphi survey. One hundred and sixteen stakeholders completed the second Delphi survey where 45 outcomes reached Consensus In (≥70% of all participants rating an outcome as Critically Important). Thirteen stakeholders reviewed 15 Borderline outcomes in the first consensus meeting and included seven additional outcomes. Seventeen stakeholders reviewed these 52 outcomes in a second consensus meeting, the threshold was ≥80% of all participants voting for inclusion. The final core outcome set included 11 outcomes. The five maternal outcomes were as follows: maternal death, severe maternal morbidity, change in existing long-term conditions (physical and mental), quality and experience of care and development of new mental health conditions. The six child outcomes were as follows: survival of baby, gestational age at birth, neurodevelopmental conditions/impairment, quality of life, birth weight and separation of baby from mother for health care needs. Conclusions Multimorbidity in pregnancy is a new and complex clinical research area. Following a rigorous process, this complexity was meaningfully reduced to a core outcome set that balances the views of a diverse stakeholder group.

Introduction Considering the high prevalence of polypharmacy in pregnant women and the knowledge gap in the risk–benefit safety profile of their often-complex treatment plan, more research is needed to optimise prescribing. In this study, we aim to detect adverse and protective effect signals of exposure to individual and pairwise combinations of medications during pregnancy.Methods and analysis Using a range of real-world data sources from the UK, we aim to conduct a pharmacovigilance study to assess the safety of medications prescribed during the preconception period (3 months prior to conception) and first trimester of pregnancy. Women aged between 15 and 49 years with a record of pregnancy within the Clinical Practice Research Datalink (CPRD) Pregnancy Register, the Welsh Secure Anonymised Information Linkage (SAIL), the Scottish Morbidity Record (SMR) data sets and the Northern Ireland Maternity System (NIMATS) will be included. A series of case control studies will be conducted to estimate measures of disproportionality, detecting signals of association between a range of pregnancy outcomes and exposure to individual and combinations of medications. A multidisciplinary expert team will be invited to a signal detection workshop. By employing a structured framework, signals will be transparently assessed by each member of the team using a questionnaire appraising the signals on aspects of temporality, selection, time and measurement-related biases and confounding by underlying disease or comedications. Through group discussion, the expert team will reach consensus on each of the medication exposure–outcome signal, thereby excluding spurious signals, leaving signals suggestive of causal associations for further evaluation.Ethics and dissemination Ethical approval has been obtained from the Independent Scientific Advisory Committee, SAIL Information Governance Review Panel, University of St. Andrews Teaching and Research Ethics Committee and Office for Research Ethics Committees Northern Ireland (ORECNI) for access and use of CPRD, SAIL, SMR and NIMATS data, respectively.

Abstract Background The number of medications prescribed during pregnancy has increased over the past few decades. Few studies have described the prevalence of multiple medication use among pregnant women. This study aims to describe the overall prevalence over the last two decades among all pregnant women and those with multimorbidity and to identify risk factors for polypharmacy in pregnancy. Methods A retrospective cohort study was conducted between 2000 and 2019 using the Clinical Practice Research Datalink (CPRD) pregnancy register. Prescription records for 577 medication categories were obtained. Prevalence estimates for polypharmacy (ranging from 2+ to 11+ medications) were presented along with the medications commonly prescribed individually and in pairs during the first trimester and the entire pregnancy period. Logistic regression models were performed to identify risk factors for polypharmacy. Results During the first trimester (812,354 pregnancies), the prevalence of polypharmacy ranged from 24.6% (2+ medications) to 0.1% (11+ medications). During the entire pregnancy period (774,247 pregnancies), the prevalence ranged from 58.7 to 1.4%. Broad-spectrum penicillin (6.6%), compound analgesics (4.5%) and treatment of candidiasis (4.3%) were commonly prescribed. Pairs of medication prescribed to manage different long-term conditions commonly included selective beta 2 agonists or selective serotonin re-uptake inhibitors (SSRIs). Risk factors for being prescribed 2+ medications during the first trimester of pregnancy include being overweight or obese [aOR: 1.16 (1.14–1.18) and 1.55 (1.53–1.57)], belonging to an ethnic minority group [aOR: 2.40 (2.33–2.47), 1.71 (1.65–1.76), 1.41 (1.35–1.47) and 1.39 (1.30–1.49) among women from South Asian, Black, other and mixed ethnicities compared to white women] and smoking or previously smoking [aOR: 1.19 (1.18–1.20) and 1.05 (1.03–1.06)]. Higher and lower age, higher gravidity, increasing number of comorbidities and increasing level of deprivation were also associated with increased odds of polypharmacy. Conclusions The prevalence of polypharmacy during pregnancy has increased over the past two decades and is particularly high in younger and older women; women with high BMI, smokers and ex-smokers; and women with multimorbidity, higher gravidity and higher levels of deprivation. Well-conducted pharmaco-epidemiological research is needed to understand the effects of multiple medication use on the developing foetus.

Introduction There is uncertainty about the advantages and disadvantages of laparoscopic hysterectomy compared with abdominal hysterectomy, particularly the relative rate of complications of the two procedures. While uptake of laparoscopic hysterectomy has been slow, the situation is changing with greater familiarity, better training, better equipment and increased proficiency in the technique. Thus, a large, robust, multicentre randomised controlled trial (RCT) is needed to compare contemporary laparoscopic hysterectomy with abdominal hysterectomy to determine the safest and most cost-effective technique.Methods and analysis A parallel, open, non-inferiority, multicentre, randomised controlled, expertise-based surgery trial with integrated health economic evaluation and an internal pilot with an embedded qualitative process evaluation. A within trial-based economic evaluation will explore the cost-effectiveness of laparoscopic hysterectomy compared with open abdominal hysterectomy. We will aim to recruit 3250 women requiring a hysterectomy for a benign gynaecological condition and who were suitable for either laparoscopic or open techniques. The primary outcome is major complications up to six completed weeks postsurgery and the key secondary outcome is time from surgery to resumption of usual activities using the personalised Patient-Reported Outcomes Measurement Information System Physical Function questionnaire. The principal outcome for the economic evaluation is to be cost per QALY at 12 months’ postsurgery. A secondary analysis is to be undertaken to generate costs per major surgical complication avoided and costs per return to normal activities.Ethics and dissemination The study was approved by the West Midlands-Edgbaston Research Ethics Committee, 18 February 2021 (Ethics ref: 21/WM/0019). REC approval for the protocol version 2.0 dated 2 February 2021 was issued on 18 February 2021.We will present the findings in national and international conferences. We will also aim to publish the findings in high impact peer-reviewed journals. We will disseminate the completed paper to the Department of Health, the Scientific Advisory Committees of the RCOG, the Royal College of Nurses (RCN) and the BSGE.Trial registration number ISRCTN14566195.

Resumo Fundamento A associação entre o status de saúde cardiovascular ideal ( ideal cardiovascular health ( ICVH) e diagnóstico de fibrilação ou flutter atrial (FFA) foi menos estudado em comparação a outras doenças cardiovasculares. Objetivos Analisar a associação entre o diagnóstico de FFA e métricas e escores de ICVH no Estudo Longitudinal de Saúde do Adulto (ELSA-Brasil). Métodos Este estudo analisou dados de 13141 participantes com dados completos. Os traçados eletrocardiográficos foram codificados de acordo com o Sistema de Minnesota, em um centro de leitura centralizado. As métricas do ICVH (dieta, atividade física, índice de massa corporal, tabagismo, glicemia de jeju, e colesterol total) e escores do ICVH foram calculados conforme proposto pela American Heart Association . Modelos de regressão logística bruta e ajustada foram construídos para analisar associações de métricas e escores do ICVH com diagnóstico de FFA. O nível de significância foi estabelecido em 0,05. Resultados A idade mediana da amostra foi de 55 anos, e 54,4% eram mulheres. Nos modelos ajustados, os escores de ICVH não apresentaram associação significativa com diagnóstico de FFA prevalente [odds ratio (OR):0,96; intervalo de confiança de 95% (IC95%):0,80-1,16; p=0,70). Perfis de pressão arterial ideal (OR:0,33; IC95%:0,1-0,74; p=0,007) e colesterol total ideal (OR:1,88; IC95%:1,19-2,98; p=0,007) foram significativamente associados com o diagnóstico de FFA. Conclusões Não foram identificadas associações significativas entre escores de ICVH global e diagnóstico de FFA após ajuste multivariado em nossas análises, devido, ao menos em parte, às associações antagônicas da FFA com métricas de pressão arterial e de colesterol total do ICVH. Nossos resultados sugerem que estimar a prevenção da FFA por meio de escore de ICVH global pode não ser adequado, e as métricas do ICVH devem ser consideradas separadamente.

Abstract Malnutrition is an independent predictor for postoperative complications in low- and middle-income countries (LMICs). We systematically reviewed evidence on the impact of preoperative oral nutrition supplementation (ONS) on patients undergoing gastrointestinal cancer surgery in LMICs. We searched EMBASE, Cochrane Library, Web of Science, Scopus, WHO Global Index Medicus, SciELO, Latin American and Caribbean Health Sciences Literature (LILACS) databases from inception to March 21, 2022 for randomised controlled trials evaluating preoperative ONS in gastrointestinal cancer within LMICs. We evaluated the impact of ONS on all postoperative outcomes using random-effects meta-analysis. Seven studies reported on 891 patients (446 ONS group, 445 control group) undergoing surgery for gastrointestinal cancer. Preoperative ONS reduced all cause postoperative surgical complications (risk ratio (RR) 0.53, 95% CI 0.46–0.60, P

Abstract Background Although maternal death is rare in the United Kingdom, 90% of these women had multiple health/social problems. This study aims to estimate the prevalence of pre-existing multimorbidity (two or more long-term physical or mental health conditions) in pregnant women in the United Kingdom (England, Northern Ireland, Wales and Scotland). Study design Pregnant women aged 15–49 years with a conception date 1/1/2018 to 31/12/2018 were included in this population-based cross-sectional study, using routine healthcare datasets from primary care: Clinical Practice Research Datalink (CPRD, United Kingdom, n = 37,641) and Secure Anonymized Information Linkage databank (SAIL, Wales, n = 27,782), and secondary care: Scottish Morbidity Records with linked community prescribing data (SMR, Tayside and Fife, n = 6099). Pre-existing multimorbidity preconception was defined from 79 long-term health conditions prioritised through a workshop with patient representatives and clinicians. Results The prevalence of multimorbidity was 44.2% (95% CI 43.7–44.7%), 46.2% (45.6–46.8%) and 19.8% (18.8–20.8%) in CPRD, SAIL and SMR respectively. When limited to health conditions that were active in the year before pregnancy, the prevalence of multimorbidity was still high (24.2% [23.8–24.6%], 23.5% [23.0–24.0%] and 17.0% [16.0 to 17.9%] in the respective datasets). Mental health conditions were highly prevalent and involved 70% of multimorbidity CPRD: multimorbidity with ≥one mental health condition/s 31.3% [30.8–31.8%]). After adjusting for age, ethnicity, gravidity, index of multiple deprivation, body mass index and smoking, logistic regression showed that pregnant women with multimorbidity were more likely to be older (CPRD England, adjusted OR 1.81 [95% CI 1.04–3.17] 45–49 years vs 15–19 years), multigravid (1.68 [1.50–1.89] gravidity ≥ five vs one), have raised body mass index (1.59 [1.44–1.76], body mass index 30+ vs body mass index 18.5–24.9) and smoked preconception (1.61 [1.46–1.77) vs non-smoker). Conclusion Multimorbidity is prevalent in pregnant women in the United Kingdom, they are more likely to be older, multigravid, have raised body mass index and smoked preconception. Secondary care and community prescribing dataset may only capture the severe spectrum of health conditions. Research is needed urgently to quantify the consequences of maternal multimorbidity for both mothers and children.

Objectives The use of medications among pregnant women has been rising over the past few decades but the reporting of polypharmacy has been sporadic. The objective of this review is to identify literature reporting the prevalence of polypharmacy among pregnant women, the prevalence of multimorbidity in women taking multiple medications in pregnancy and associated effects on maternal and offspring outcomes.Design MEDLINE and Embase were searched from their inception to 14 September 2021 for interventional trials, observational studies and systematic reviews reporting on the prevalence of polypharmacy or the use of multiple medications in pregnancy were included.Data on prevalence of polypharmacy, prevalence of multimorbidity, combinations of medications and pregnancy and offspring outcomes were extracted. A descriptive analysis was performed.Results Fourteen studies met the review criteria. The prevalence of women being prescribed two or more medications during pregnancy ranged from 4.9% (4.3%–5.5%) to 62.4% (61.3%–63.5%), with a median of 22.5%. For the first trimester, prevalence ranged from 4.9% (4.7%–5.14%) to 33.7% (32.2%–35.1%). No study reported on the prevalence of multimorbidity, or associated pregnancy outcomes in women exposed to polypharmacy.Conclusion There is a significant burden of polypharmacy among pregnant women. There is a need for evidence on the combinations of medications prescribed in pregnancy, how this specifically affects women with multiple long-term conditions and the associated benefits and harms.Tweetable abstract Our systematic review shows significant burden of polypharmacy in pregnancy but outcomes for women and offspring are unknown.PROSPERO registration number CRD42021223966.

Summary: Background: Malnutrition represents a key priority for global health policy, yet the impact of nutritional state on cancer surgery worldwide remains poorly described. We aimed to analyse the effect of malnutrition on early postoperative outcomes following elective surgery for colorectal or gastric cancer. Methods: We did an international, multicentre, prospective cohort study of patients undergoing elective surgery for colorectal or gastric cancer between April 1, 2018, and Jan 31, 2019. Patients were excluded if the primary pathology was benign, they presented with cancer recurrence, or if they underwent emergency surgery (within 72 h of hospital admission). Malnutrition was defined with the Global Leadership Initiative on Malnutrition criteria. The primary outcome was death or a major complication within 30 days of surgery. Multilevel logistic regression and a three-way mediation analysis were done to establish the relationship between country income group, nutritional status, and 30-day postoperative outcomes. Findings: This study included 5709 patients (4593 with colorectal cancer and 1116 with gastric cancer) from 381 hospitals in 75 countries. The mean age was 64·8 years (SD 13·5) and 2432 (42·6%) patients were female . Severe malnutrition was present in 1899 (33·3%) of 5709 patients, with a disproportionate burden in upper-middle-income countries (504 [44·4%] of 1135) and low-income and lower-middle-income countries (601 [62·5%] of 962). After adjustment for patient and hospital risk factors, severe malnutrition was associated with an increased risk of 30-day mortality across all country income groups (high income: adjusted odds ratio [aOR] 1·96 [95% CI 1·14–3·37], p=0·015; upper-middle income: 3·05 [1·45–6·42], p=0·003; low income and lower-middle income: 11·57 [5·87–22·80], p

Introduction One in five pregnant women has multiple pre-existing long-term conditions in the UK. Studies have shown that maternal multiple long-term conditions are associated with adverse outcomes. This observational study aims to compare maternal and child outcomes for pregnant women with multiple long-term conditions to those without multiple long-term conditions (0 or 1 long-term conditions).Methods and analysis Pregnant women aged 15–49 years old with a conception date between 2000 and 2019 in the UK will be included with follow-up till 2019. The data source will be routine health records from all four UK nations (Clinical Practice Research Datalink (England), Secure Anonymised Information Linkage (Wales), Scotland routine health records and Northern Ireland Maternity System) and the Born in Bradford birth cohort. The exposure of two or more pre-existing, long-term physical or mental health conditions will be defined from a list of health conditions predetermined by women and clinicians. The association of maternal multiple long-term conditions with (a) antenatal, (b) peripartum, (c) postnatal and long-term and (d) mental health outcomes, for both women and their children will be examined. Outcomes of interest will be guided by a core outcome set. Comparisons will be made between pregnant women with and without multiple long-term conditions using modified Poisson and Cox regression. Generalised estimating equation will account for the clustering effect of women who had more than one pregnancy episode. Where appropriate, multiple imputation with chained equation will be used for missing data. Federated analysis will be conducted for each dataset and results will be pooled using random-effects meta-analyses.Ethics and dissemination Approval has been obtained from the respective data sources in each UK nation. Study findings will be submitted for publications in peer-reviewed journals and presented at key conferences.

Objective To compare the severity of maternal infection and perinatal outcomes during periods in which wildtype, alpha variant, and delta variant of SARS-CoV-2 were dominant in the UK.Design Prospective cohort study.Setting 194 obstetric units across the UK, during the following periods: between 1 March and 30 November 2020 (wildtype dominance), between 1 December 2020 and 15 May 2021 (alpha variant dominance), and between 16 May and 31 October 2021 (delta variant dominance).Participants 4436 pregnant women admitted to hospital with covid-19 related symptoms.Main outcome measures Moderate to severe maternal SARS-CoV-2 infection (indicated by any of the following: oxygen saturation

Objectives To describe the severity of maternal infection when the omicron SARS-CoV-2 variant (B.1.1.529) was dominant (15 December 2021 to 14 March 2022) and describe outcomes by symptoms and vaccination status.Design Prospective, national cohort study using the UK Obstetric Surveillance System.Setting 94 hospitals in the UK with a consultant led maternity unit.Participants Pregnant women admitted to hospital for any cause with a positive SARS-CoV-2 test.Main outcome measures Symptomatic or asymptomatic infection, vaccination status by doses before admission, and severity of maternal infection (moderate or severe infection according to modified World Health Organization's criteria).Results Of 3699 women who were admitted to hospital, 986 (26.7%, 95% confidence interval 25.3% to 28.1%) had symptoms; of these, 144 (14.6%, 12.5% to 17.0%) had a moderate to severe infection, 99 (10.4%, 8.6% to 12.5%) of 953 received respiratory support, and 30 (3.0%, 2.1% to 4.3%) were admitted to an intensive care unit. Covid-19 specific drug treatment was given to 13 (43.3%) of the 30 women in intensive care. Four women with symptoms died (0.4%, 0.1% to 1.1%). Vaccination status was known for 845 (85.6%) women with symptoms; 489 (58.9%) were unvaccinated and only 55 (6.5%) had three doses. Moderate to severe infection was reported for 93 (19.0%) of 489 unvaccinated women with symptoms, decreasing to three (5.5%) of 55 after three doses. Among the 30 women with symptoms who were admitted to intensive care, 23 (76.7%) were unvaccinated and none had received three doses.Conclusion Most women with severe covid-19 disease were unvaccinated and vaccine coverage among pregnant women admitted to hospital with SARS-CoV-2 was low. Ongoing action to prioritise and advocate for vaccine uptake in pregnancy is essential. A better understanding of the persistent low use of drug treatments is an urgent priority.Trial registration ISRCTN 40092247.

Background: In women with late preterm pre-eclampsia (i.e. at 34+0 to 36+6 weeks’ gestation), the optimal delivery time is unclear because limitation of maternal–fetal disease progression needs to be balanced against infant complications. The aim of this trial was to determine whether or not planned earlier initiation of delivery reduces maternal adverse outcomes without substantial worsening of perinatal or infant outcomes, compared with expectant management, in women with late preterm pre-eclampsia. Methods: We undertook an individually randomised, triple non-masked controlled trial in 46 maternity units across England and Wales, with an embedded health economic evaluation, comparing planned delivery and expectant management (usual care) in women with late preterm pre-eclampsia. The co-primary maternal outcome was a maternal morbidity composite or recorded systolic blood pressure of ≥ 160 mmHg (superiority hypothesis). The co-primary short-term perinatal outcome was a composite of perinatal deaths or neonatal unit admission (non-inferiority hypothesis). Analyses were by intention to treat, with an additional per-protocol analysis for the perinatal outcome. The primary 2-year infant neurodevelopmental outcome was measured using the PARCA-R (Parent Report of Children’s Abilities-Revised) composite score. The planned sample size of the trial was 900 women; the trial is now completed. We undertook two linked substudies. Results: Between 29 September 2014 and 10 December 2018, 901 women were recruited; 450 women [448 women (two withdrew consent) and 471 infants] were allocated to planned delivery and 451 women (451 women and 475 infants) were allocated to expectant management. The incidence of the co-primary maternal outcome was significantly lower in the planned delivery group [289 (65%) women] than in the expectant management group [338 (75%) women] (adjusted relative risk 0.86, 95% confidence interval 0.79 to 0.94; p = 0.0005). The incidence of the co-primary perinatal outcome was significantly higher in the planned delivery group [196 (42%) infants] than in the expectant management group [159 (34%) infants] (adjusted relative risk 1.26, 95% confidence interval 1.08 to 1.47; p = 0.0034), but indicators of neonatal morbidity were similar in both groups. At 2-year follow-up, the mean PARCA-R scores were 89.5 points (standard deviation 18.2 points) for the planned delivery group (290 infants) and 91.9 points (standard deviation 18.4 points) for the expectant management group (256 infants), both within the normal developmental range (adjusted mean difference –2.4 points, 95% confidence interval –5.4 to 0.5 points; non-inferiority p = 0.147). Planned delivery was significantly cost-saving (–£2711, 95% confidence interval –£4840 to –£637) compared with expectant management. There were nine serious adverse events in the planned delivery group and 12 in the expectant management group. Conclusion: In women with late preterm pre-eclampsia, planned delivery reduces short-term maternal morbidity compared with expectant management, with more neonatal unit admissions related to prematurity but no indicators of greater short-term neonatal morbidity (such as need for respiratory support). At 2-year follow-up, around 60% of parents reported follow-up scores. Average infant development was within the normal range for both groups; the small between-group mean difference in PARCA-R scores is unlikely to be clinically important. Planned delivery was significantly cost-saving to the health service. These findings should be discussed with women with late preterm pre-eclampsia to allow shared decision-making on timing of delivery. Limitations: Limitations of the trial include the challenges of finding a perinatal outcome that adequately represented the potential risks of both groups and a maternal outcome that reflects the multiorgan manifestations of pre-eclampsia. The incidences of maternal and perinatal primary outcomes were higher than anticipated on the basis of previous studies, but this did not limit interpretation of the analysis. The trial was limited by a higher loss to follow-up rate than expected, meaning that the extent and direction of bias in outcomes (between responders and non-responders) is uncertain. A longer follow-up period (e.g. up to 5 years) would have enabled us to provide further evidence on long-term infant outcomes, but this runs the risk of greater attrition and increased expense. Future work: We identified a number of further questions that could be prioritised through a formal scoping process, including uncertainties around disease-modifying interventions, prognostic factors, longer-term follow-up, the perspectives of women and their families, meta-analysis with other studies, effect of a similar intervention in other health-care settings, and clinical effectiveness and cost-effectiveness of other related policies around neonatal unit admission in late preterm birth. Trial registration: The trial was prospectively registered as ISRCTN01879376. Funding: This project was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme and will be published in Health Technology Assessment. See the NIHR Journals Library website for further project information.

Introduction Atrial fibrillation (AF) is the most common arrhythmia globally. It is associated with a fivefold risk in stroke, but early diagnosis and effective treatment can reduce this risk. AF is often underdiagnosed, particularly in low-income and middle-income countries (LMICs) where screening for AF is not always feasible or considered common practice in primary care settings. Epidemiological data on AF in LMICs is often incomplete particularly in vulnerable populations. This LMIC research collaborative aims to identify the prevalence of AF in the Northern Sri Lankan community.Methods and analysis A cross-sectional household survey piloted and codesigned through a series of community engagement events will be administered in all five districts in Northern Province, Sri Lanka. A multistage cluster sampling approach will be used starting at district level, then the Divisional Secretariats followed by Grama Niladhari divisions. Twenty households will be selected from each cluster. The study aims to recruit 10 000 participants aged 50 years or older, 1 participant per household. Demographic and socioeconomic characteristics, well-being and lifestyle and anthropometric measurements will be collected using a digital data platform (REDCap, Research Electronic Data Capture) by trained data collectors. Participants will be screened for AF using a fingertip single-lead ECG via a smartphone application (AliveCor) with rhythm strips reviewed by a consultant cardiologist. Prevalence of AF and risk factors will be established at province and district-levels. Adjusted ORs and population attributable fractions for AF risk factors will be determined.Ethics and dissemination This study was approved by the Ethics Review Committee of Faculty of Medicine at University of Jaffna. Written informed consent will be obtained from all participants. Findings will be disseminated through publication in a peer-reviewed journal and presentations at conferences. The findings will enable early treatment for new AF diagnoses and inform interventions to improve community-based management of AF in LMICs.

Abstract Background Preterm birth is associated with significant mortality and morbidity for mothers and babies. Women are identified as high risk for preterm birth based on either previous medical/pregnancy history or on ultrasound assessment of the cervix. Women identified as high risk can be offered a cervical cerclage (a purse string stitch) around the cervix (neck of the womb) to reduce the risk of preterm birth. In women who have a cervical cerclage, the procedure can be performed using either a monofilament (single-stranded) or braided (woven) suture material. Both suture materials are routinely used for cervical cerclage and there is uncertainty as to which is superior. Methods A multicentre, open, randomised controlled superiority trial of 2050 women presenting at obstetric units, deemed to be at risk of preterm birth and already scheduled to have a cervical cerclage as part of their standard care. Inclusion criteria include singleton pregnancies and an indication for cervical cerclage for either a history of three or more previous mid-trimester losses or premature births (≤ 28 weeks), insertion of cervical sutures in previous pregnancies, a history of mid trimester loss or premature birth with a (current) shortened (≤ 25 mm) cervix, or women whom clinicians deem to be at risk of preterm birth either by history or the results of an ultrasound scan. Exclusion criteria include women who have taken part in C-STICH previously, are aged less than 18 years old at the time of presentation, require a rescue cerclage, and are unwilling or unable to give informed consent and in whom a cerclage will be placed by any route other than vaginally (e.g. via an abdominal route). Following informed consent, women are randomised on a 1:1 basis to either monofilament or braided suture, by minimisation. The primary outcome is pregnancy loss (miscarriage and perinatal mortality, including any stillbirth or neonatal death in the first week of life), and secondary outcomes include the core outcome set for preterm birth trials. Discussion Optimising established interventions to prevent preterm birth is important in reducing perinatal mortality rates. Trial registration ISRCTN 15373349 . Registered before recruitment on 03 December 2014 prior to first recruit.

Abstract Background Cervical cerclage is a recognised treatment to prevent late miscarriage and pre-term birth (PTB). Emergency cervical cerclage (ECC) for cervical dilatation with exposed unruptured membranes is less common and the potential benefits of cerclage are less certain. A randomised control trial is needed to accurately assess the effectiveness of ECC in preventing pregnancy loss compared to an expectant approach. Methods C-STICH2 is a multicentre randomised controlled trial in which women presenting with cervical dilatation and unruptured exposed membranes at 16 + 0 to 27 + 6 weeks gestation are randomised to ECC or expectant management. Trial design includes 18 month internal pilot with embedded qualitative process evaluation, minimal data set and a within-trial health economic analysis. Inclusion criteria are ≥16 years, singleton pregnancy, exposed membranes at the external os, gestation 16 + 0–27 + 6 weeks, and informed consent. Exclusion criteria are contraindication to cerclage, cerclage in situ or previous cerclage in this pregnancy. Randomisation occurs via an online service in a 1:1 ratio, using a minimisation algorithm to reduce chance imbalances in key prognostic variables (site, gestation and dilatation). Primary outcome is pregnancy loss; a composite including miscarriage, termination of pregnancy and perinatal mortality defined as stillbirth and neonatal death in the first week of life. Secondary outcomes include all core outcomes for PTB. Two-year development outcomes will be assessed using general health and Parent Report of Children’s Abilities-Revised (PARCA-R) questionnaires. Intended sample size is 260 participants (130 each arm) based on 60% rate of pregnancy loss in the expectant management arm and 40% in the ECC arm, with 90% power and alpha 0.05. Analysis will be by intention-to-treat. Discussion To date there has been one small trial of ECC in 23 participants which included twin and singleton pregnancies. This small trial along with the largest observational study (n = 161) found ECC to prolong pregnancy duration and reduce deliveries before 34 weeks gestation. It is important to generate high quality evidence on the effectiveness of ECC in preventing pregnancy loss, and improve understanding of the prevalence of the condition and frequency of complications associated with ECC. An adequately powered RCT will provide the highest quality evidence regarding optimum care for these women and their babies. Trial registration ISRCTN Registry ISRCTN12981869 . Registered on 13th June 2018.

Summary: Background: Early death after cancer surgery is higher in low-income and middle-income countries (LMICs) compared with in high-income countries, yet the impact of facility characteristics on early postoperative outcomes is unknown. The aim of this study was to examine the association between hospital infrastructure, resource availability, and processes on early outcomes after cancer surgery worldwide. Methods: A multimethods analysis was performed as part of the GlobalSurg 3 study—a multicentre, international, prospective cohort study of patients who had surgery for breast, colorectal, or gastric cancer. The primary outcomes were 30-day mortality and 30-day major complication rates. Potentially beneficial hospital facilities were identified by variable selection to select those associated with 30-day mortality. Adjusted outcomes were determined using generalised estimating equations to account for patient characteristics and country-income group, with population stratification by hospital. Findings: Between April 1, 2018, and April 23, 2019, facility-level data were collected for 9685 patients across 238 hospitals in 66 countries (91 hospitals in 20 high-income countries; 57 hospitals in 19 upper-middle-income countries; and 90 hospitals in 27 low-income to lower-middle-income countries). The availability of five hospital facilities was inversely associated with mortality: ultrasound, CT scanner, critical care unit, opioid analgesia, and oncologist. After adjustment for case-mix and country income group, hospitals with three or fewer of these facilities (62 hospitals, 1294 patients) had higher mortality compared with those with four or five (adjusted odds ratio [OR] 3·85 [95% CI 2·58–5·75]; p

Background: Since changes in the national guidance in 2011, prophylactic antibiotics for women undergoing caesarean section are recommended prior to skin incision, rather than after the baby’s umbilical cord has been clamped. Evidence from randomised controlled trials conducted outside the UK has shown that this reduces maternal infectious morbidity; however, the prophylactic antibiotics also cross the placenta, meaning that babies are exposed to them around the time of birth. Antibiotics are known to affect the gut microbiota of the babies, but the long-term effects of exposure to high-dose broad-spectrum antibiotics around the time of birth on allergy and immune-related diseases are unknown. Objectives: We aimed to examine whether or not in-utero exposure to antibiotics immediately prior to birth compared with no pre-incisional antibiotic exposure increases the risk of (1) asthma and (2) eczema in children born by caesarean section. Design: This was a controlled interrupted time series study. Setting: The study took place in primary and secondary care. Participants: Children born in the UK during 2006–18 delivered by caesarean section were compared with a control cohort delivered vaginally. Interventions: In-utero exposure to antibiotics immediately prior to birth. Main outcome measures: Asthma and eczema in children in the first 5 years of life. Additional secondary outcomes, including other allergy-related conditions, autoimmune diseases, infections, other immune system-related diseases and neurodevelopmental conditions, were also assessed. Data sources: The Health Improvement Network (THIN) and the Clinical Practice Research Datalink (CPRD) primary care databases and the Hospital Episode Statistics (HES) database. Previously published linkage strategies were adapted to link anonymised data on mothers and babies in these databases. Duplicate practices contributing to both THIN and the CPRD databases were removed to create a THIN–CPRD data set. Results: In the THIN–CPRD and HES data sets, records of 515,945 and 3,945,351 mother–baby pairs were analysed, respectively. The risk of asthma was not significantly higher in children born by caesarean section exposed to pre-incision antibiotics than in children whose mothers received post-cord clamping antibiotics, with an incidence rate ratio of 0.91 (95% confidence interval 0.78 to 1.05) for diagnosis of asthma in primary care and an incidence rate ratio of 1.05 (95% confidence interval 0.99 to 1.11) for asthma resulting in a hospital admission. We also did not find an increased risk of eczema, with an incidence rate ratio of 0.98 (95% confidence interval 0.94 to1.03) and an incidence rate ratio of 0.96 (95% confidence interval 0.71 to 1.29) for diagnosis in primary care and hospital admissions, respectively. Limitations: It was not possible to ascertain the exposure to pre-incision antibiotics at an individual level. The maximum follow-up of children was 5 years. Conclusions: There was no evidence that the policy change from post-cord clamping to pre-incision prophylactic antibiotics for caesarean sections during 2006–18 had an impact on the incidence of asthma and eczema in early childhood in the UK. Future work: There is a need for further research to investigate if pre-incision antibiotics have any impact on developing asthma and other allergy and immune-related conditions in older children. Study registration: This study is registered as researchregistry3736. Funding: This project was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 26, No. 30. See the NIHR Journals Library website for further project information.

Introduction The burden of atrial fibrillation (AF) in Thailand is high and associated with increased morbidity, mortality and healthcare costs. Vitamin K antagonists (eg, warfarin), commonly used for stroke prevention in patients with AF in Thailand, are effective but are often suboptimally controlled. We aim to evaluate the impact of an SAMe-TT2R2 score-guided strategy and educational intervention compared to usual care on anticoagulation control expressed by the time in therapeutic range (TTR) at 12 months, in anticoagulant-naïve Thai patients with AF.Methods and analysis Multicentre, open-label, parallel-group, randomised controlled trial conducted in Thailand among adult patients (age: 18 years) with AF who are anticoagulant naïve. Patients will be randomised to one of two groups; an SAMe-TT2R2 score-guided strategy with educational intervention and usual care versus usual care alone. The planned follow-up period is 12 months. The primary outcome is TTR at 12 months. Secondary outcomes include: (1) TTR at 6 months; (2) thromboembolic and bleeding events at 12 months; (3) composite major adverse cardiovascular events at 12 months; (4) change in patients’ knowledge of AF between baseline and 6 months and 12 months; (5) cost effectiveness; (6) quality of life at baseline, 6 months and 12 months using EQ-5D-5L (Thai version) and (7) patient satisfaction/perceptions of the TREAT intervention. An embedded qualitative study will assess patient perceptions of the TREAT intervention.Ethics and dissemination The study has been approved by the Ethical Review Committee, Ministry of Public Health of Thailand, and registered in the Thai Clinical Trials Registry. 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 to all participants prior to publication.Trial registration number TCTR20180711003.

Background: The use of placebo comparisons for randomised trials assessing the efficacy of surgical interventions is increasingly being considered. However, a placebo control is a complex type of comparison group in the surgical setting and, although powerful, presents many challenges. Objectives: To provide a summary of knowledge on placebo controls in surgical trials and to summarise any recommendations for designers, evaluators and funders of placebo-controlled surgical trials. Design: To carry out a state-of-the-art workshop and produce a corresponding report involving key stakeholders throughout. Setting: A workshop to discuss and summarise the existing knowledge and to develop the new guidelines. Results: To assess what a placebo control entails and to assess the understanding of this tool in the context of surgery is considered, along with when placebo controls in surgery are acceptable (and when they are desirable). We have considered ethics arguments and regulatory requirements, how a placebo control should be designed, how to identify and mitigate risk for participants in these trials, and how such trials should be carried out and interpreted. The use of placebo controls is justified in randomised controlled trials of surgical interventions provided that there is a strong scientific and ethics rationale. Surgical placebos might be most appropriate when there is poor evidence for the efficacy of the procedure and a justified concern that results of a trial would be associated with a high risk of bias, particularly because of the placebo effect. Conclusions: The use of placebo controls is justified in randomised controlled trials of surgical interventions provided that there is a strong scientific and ethics rationale. Feasibility work is recommended to optimise the design and implementation of randomised controlled trials. An outline for best practice was produced in the form of the Applying Surgical Placebo in Randomised Evaluations (ASPIRE) guidelines for those considering the use of a placebo control in a surgical randomised controlled trial. Limitations: Although the workshop participants involved international members, the majority of participants were from the UK. Therefore, although every attempt was made to make the recommendations applicable to all health systems, the guidelines may, unconsciously, be particularly applicable to clinical practice in the UK NHS. Future work: Future work should evaluate the use of the ASPIRE guidelines in making decisions about the use of a placebo-controlled surgical trial. In addition, further work is required on the appropriate nomenclature to adopt in this space. Funding: Funded by the Medical Research Council UK and the National Institute for Health Research as part of the Medical Research Council–National Institute for Health Research Methodology Research programme.

Background: The relationship between adherence to traditional Chinese postpartum practices (known as “doing-the-month”) and postpartum depression (PPD) remains unknown. Practices including restrictions on diet, housework and social activity, personal hygiene, and cold contact, could introduce biological, psychological, and socio-environmental changes during postpartum.Methods: The cross-sectional study included 955 postpartum women in obstetric clinics in Hunan Province of China between September 2018 to June 2019. Thirty postpartum practices were collected by a self-report online structured questionnaire. Postpartum depression symptoms were assessed by the Chinese version of the Edinburgh Postnatal Depression Scale (EPDS). Multivariable linear regression was used to estimate the differences in EPDS scores according to adherence to postpartum practices. Firth's bias-reduced logistic regression was employed to analyze the binary classification of having PPD symptoms (EPDS ≥ 10).Results: Overall, both moderate and low adherence to postpartum practices appeared to be associated with higher EPDS scores (adjusted difference 1.07, 95% CI 0.20, 1.94 for overall moderate adherence; and adjusted difference 1.72, 95% CI 0.84, 2.60 for overall low adherence). In analyses by practice domain, low adherence to housework-related and social activity restrictions was associated with having PPD symptoms compared with high adherence (OR 1.61, 95% CI 1.07, 2.43).Conclusions: Low adherence to traditional Chinese postpartum practices was associated with higher EPDS scores indicating PPD symptoms, especially in the domain of housework-related and social activity restrictions. Psychosocial stress and unsatisfactory practical support related to low adherence to postpartum practices might contribute to PPD. Longitudinal study and clinical assessment would be needed to confirm these findings.

Abstract Background 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. Methods 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. Results 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. Conclusion 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.

Abstract Background 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. Main text 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. Conclusion 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.

Abstract Background 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. Methods/design 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). Discussion 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. Trial registration ISRCTN01879376. Registered on 25 November 2013.

Background: Currently, pregnant women are screened using ultrasound to perform gestational aging, typically at around 12 weeks’ gestation, and around the middle of pregnancy. Ultrasound scans thereafter are performed for clinical indications only. Objectives: We sought to assess the case for offering universal late pregnancy ultrasound to all nulliparous women in the UK. The main questions addressed were the diagnostic effectiveness of universal late pregnancy ultrasound to predict adverse outcomes and the cost-effectiveness of either implementing universal ultrasound or conducting further research in this area. Design: We performed diagnostic test accuracy reviews of five ultrasonic measurements in late pregnancy. We conducted cost-effectiveness and value-of-information analyses of screening for fetal presentation, screening for small for gestational age fetuses and screening for large for gestational age fetuses. Finally, we conducted a survey and a focus group to determine the willingness of women to participate in a future randomised controlled trial. Data sources: We searched MEDLINE, EMBASE and the Cochrane Library from inception to June 2019. Review methods: The protocol for the review was designed a priori and registered. Eligible studies were identified using keywords, with no restrictions for language or location. The risk of bias in studies was assessed using the Quality Assessment of Diagnostic Accuracy Studies 2 (QUADAS-2) tool. Health economic modelling employed a decision tree analysed via Monte Carlo simulation. Health outcomes were from the fetal perspective and presented as quality-adjusted life-years. Costs were from the perspective of the public sector, defined as NHS England, and the costs of special educational needs. All costs and quality-adjusted life-years were discounted by 3.5% per annum and the reference case time horizon was 20 years. Results: Umbilical artery Doppler flow velocimetry, cerebroplacental ratio, severe oligohydramnios and borderline oligohydramnios were all either non-predictive or weakly predictive of the risk of neonatal morbidity (summary positive likelihood ratios between 1 and 2) and were all weakly predictive of the risk of delivering a small for gestational age infant (summary positive likelihood ratios between 2 and 4). Suspicion of fetal macrosomia is strongly predictive of the risk of delivering a large infant, but it is only weakly, albeit statistically significantly, predictive of the risk of shoulder dystocia. Very few studies blinded the result of the ultrasound scan and most studies were rated as being at a high risk of bias as a result of treatment paradox, ascertainment bias or iatrogenic harm. Health economic analysis indicated that universal ultrasound for fetal presentation only may be both clinically and economically justified on the basis of existing evidence. Universal ultrasound including fetal biometry was of borderline cost-effectiveness and was sensitive to assumptions. Value-of-information analysis indicated that the parameter that had the largest impact on decision uncertainty was the net difference in cost between an induced delivery and expectant management. Limitations: The primary literature on the diagnostic effectiveness of ultrasound in late pregnancy is weak. Value-of-information analysis may have underestimated the uncertainty in the literature as it was focused on the internal validity of parameters, which is quantified, whereas the greatest uncertainty may be in the external validity to the research question, which is unquantified. Conclusions: Universal screening for presentation at term may be justified on the basis of current knowledge. The current literature does not support universal ultrasonic screening for fetal growth disorders. Future work: We describe proof-of-principle randomised controlled trials that could better inform the case for screening using ultrasound in late pregnancy. Study registration: This study is registered as PROSPERO CRD42017064093. Funding: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 25, No. 15. See the NIHR Journals Library website for further project information.

BackgroundThere is a lack of population level data on risk factors, incidence and impact of SARS-CoV-2 infection in pregnant women and their babies. The primary aim of this study was to describe the incidence, characteristics and outcomes of hospitalized pregnant women with symptomatic and asymptomatic SARS-CoV-2 in the UK compared to pregnant women without SARS-CoV-2.Methods and findingsWe conducted a national, prospective cohort study of all hospitalized pregnant women with confirmed SARS-CoV-2 from 01/03/2020 to 31/08/2020 using the UK Obstetric Surveillance System. Incidence rates were estimated using national maternity data. Overall, 1148 hospitalized women had confirmed SARS-CoV-2 in pregnancy, 63% of which were symptomatic. The estimated incidence of hospitalization with symptomatic SARS-CoV-2 was 2.0 per 1000 maternities (95% CI 1.9-2.2) and for asymptomatic SARS-CoV-2 was 1.2 per 1000 maternities (95% CI 1.1-1.4). Compared to pregnant women without SARS-CoV-2, women hospitalized with symptomatic SARS-CoV-2 were more likely to be overweight or obese (adjusted OR 1.86, (95% CI 1.39-2.48) and aOR 2.07 (1.53-2.29)), to be of Black, Asian or Other minority ethnic group (aOR 6.24, (3.93-9.90), aOR 4.36, (3.19-5.95) and aOR 12.95, (4.93-34.01)), and to have a relevant medical comorbidity (aOR 1.83 (1.32-2.54)). Hospitalized pregnant women with symptomatic SARS-CoV-2 were more likely to be admitted to intensive care (aOR 57.67, (7.80-426.70)) but the absolute risk of poor outcomes was low. Cesarean births and neonatal unit admission were increased regardless of symptom status (symptomatic aOR 2.60, (1.97-3.42) and aOR 3.08, (1.99-4.77); asymptomatic aOR 2.02, (1.52-2.70) and aOR 1.84, (1.12-3.03)). The risks of stillbirth or neonatal death were not significantly increased, regardless of symptom status.ConclusionsWe have identified factors that increase the risk of symptomatic and asymptomatic SARS-CoV-2 in pregnancy. Clinicians can be reassured that the majority of women do not experience severe complications of SARS-CoV-2 in pregnancy.

Introduction Approximately 60 000 (9/100) infants are born into water annually in the UK and this is likely to increase. Case reports identified infants with water inhalation or sepsis following birth in water and there is a concern that women giving birth in water may sustain more complex perineal trauma. There have not been studies large enough to show whether waterbirth increases these poor outcomes. The POOL Study (ISRCTN13315580) plans to answer the question about the safety of waterbirths among women who are classified appropriate for midwifery-led intrapartum care.Methods and analysis A cohort study with a nested qualitative component. Objectives will be answered using retrospective and prospective data captured in electronic National Health Service (NHS) maternity and neonatal systems. The qualitative component aims to explore factors influencing pool use and waterbirth; data will be gathered via discussion groups, interviews and case studies of maternity units.Ethics and dissemination The protocol has been approved by NHS Wales Research Ethics Committee (18/WA/0291) the transfer of identifiable data has been approved by Health Research Authority Confidentiality Advisory Group (18CAG0153).Study findings and innovative methodology will be disseminated through peer-reviewed journals, conferences and events. Results will be of interest to the general public, clinical and policy stakeholders in the UK and will be disseminated accordingly.

ObjectiveTo determine whether the participation of consultant gynaecologists in delivering early pregnancy care results in a lower rate of acute hospital admissions.DesignProspective cohort study and emergency hospital care audit; data were collected as part of the national prospective mixed-methods VESPA study on the "Variations in the organization of EPAUs in the UK and their effects on clinical, Service and PAtient-centred outcomes".Setting44 Early Pregnancy Assessment Units (EPAUs) across the UK randomly selected in balanced numbers from eight pre-defined mutually exclusive strata.Participants6606 pregnant women (≥16 years old) with suspected first trimester pregnancy complications attending the participating EPAUs or Emergency Departments (ED) from December 2016 to July 2017.ExposuresPlanned and actual senior clinician presence, unit size, and weekend opening.Main outcome measuresUnplanned admissions to hospital following any visit for investigations or treatment for first trimester complications as a proportion of women attending EPAUs.Results205/6397 (3.2%; 95% CI 2.8-3.7) women were admitted following their EPAU attendance. The admission rate among 44 units ranged from 0% to 13.7% (median 2.8). Neither planned senior clinician presence (p = 0.874) nor unit volume (p = 0.247) were associated with lower admission rates from EPAU, whilst EPAU opening over the weekend resulted in lower admission rates (p = 0.027). 1445/5464 (26.4%; 95%CI 25.3 to 27.6) women were admitted from ED. There was little evidence of an association with planned senior clinician time (p = 0.280) or unit volume (p = 0.647). Keeping an EPAU open over the weekend for an additional hour was associated with 2.4% (95% CI 0.1% to 4.7%) lower odds of an emergency admission from ED.ConclusionsInvolvement of senior clinicians in delivering early pregnancy care has no significant impact on emergency hospital admissions for early pregnancy complications. Weekend opening, however, may be an effective way of reducing emergency admissions from ED.

Objectives To systematically review (1) The effect of obstetric unit (OU) closures on maternal and neonatal outcomes and (2) The association between travel distance/time to an OU and maternal and neonatal outcomes.Design Systematic review of any quantitative studies with a comparison group.Data sources Embase, MEDLINE, PsycINFO, Applied Social Science Index and Abstracts, Cumulative Index to Nursing and Allied Health and grey literature were searched.Methods Eligible studies explored the impact of closure of an OU or the effect of travel distance/time on prespecified maternal or neonatal outcomes. Only studies of women giving birth in high-income countries with universal health coverage of maternity services comparable to the UK were included. Identification of studies, extraction of data and risk of bias assessment were undertaken by at least two reviewers independently. The risk of bias checklist was based on the Cochrane Effective Practice and Organisation of Care criteria and the Newcastle-Ottawa scale. Heterogeneity across studies precluded meta-analysis and synthesis was narrative, with key findings tabulated.Results 31 studies met the inclusion criteria. There was some evidence to suggest an increase in babies born before arrival following OU closures and/or associated with longer travel distances or time. This may be associated with an increased risk of perinatal or neonatal mortality, but this finding was not consistent across studies. Evidence on other maternal and neonatal outcomes was limited but did not suggest worse outcomes after closures or with longer travel times/distances. Interpretation of findings for some studies was hampered by concerns around how accurately exposures were measured, and/or a lack of adjustment for confounders or temporal changes.Conclusion It is not possible to conclude from this review whether OU closure, increased travel distances or times are associated with worse outcomes for the mother or the baby.PROSPERO registration number CRD42017078503.

Background: Early pregnancy complications are common and account for the largest proportion of emergency work in gynaecology. Although early pregnancy assessment units operate in most UK acute hospitals, recent National Institute of Health and Care Excellence guidance emphasised the need for more research to identify configurations that provide the optimal balance between cost-effectiveness, clinical effectiveness and service- and patient-centred outcomes [National Institute for Health and Care Excellence (NICE). Ectopic Pregnancy and Miscarriage: Diagnosis and Initial Management. URL: http://guidance.nice.org.uk/CG154 (accessed 23 March 2016)]. Objectives: The primary aim was to test the hypothesis that the rate of hospital admissions for early pregnancy complications is lower in early pregnancy assessment units with high consultant presence than in units with low consultant presence. The key secondary objectives were to assess the effect of increased consultant presence on other clinical outcomes, to explore patient satisfaction with the quality of care and to make evidence-based recommendations about the future configuration of UK early pregnancy assessment units. Design: The Variations in the organisations of Early Pregnancy Assessment Units in the UK and their effects on clinical, Service and PAtient-centred outcomes (VESPA) study employed a multimethods approach and included a prospective cohort study of women attending early pregnancy assessment units to measure clinical outcomes, an economic evaluation, a patient satisfaction survey, qualitative interviews with service users, an early pregnancy assessment unit staff survey and a hospital emergency care audit. Setting: The study was conducted in 44 early pregnancy assessment units across the UK. Participants: Participants were pregnant women (aged ≥ 16 years) attending the early pregnancy assessment units or other hospital emergency services because of suspected early pregnancy complications. Staff members directly involved in providing early pregnancy care completed the staff survey. Main outcome measure: Emergency hospital admissions as a proportion of women attending the participating early pregnancy assessment units. Methods: Data sources – demographic and routine clinical data were collected from all women attending the early pregnancy assessment units. For women who provided consent to complete the questionnaires, clinical data and questionnaires were linked using the women’s study number. Data analysis and results reporting – the relationships between clinical outcomes and consultant presence, unit volume and weekend opening hours were investigated using appropriate regression models. Qualitative interviews with women, and patient and staff satisfaction, health economic and workforce analyses were also undertaken, accounting for consultant presence, unit volume and weekend opening hours. Results: We collected clinical data from 6606 women. There was no evidence of an association between admission rate and consultant presence (p = 0.497). Health economic evaluation and workforce analysis data strands indicated that lower-volume units with no consultant presence were associated with lower costs than their alternatives. Limitations: The relatively low level of direct consultant involvement could explain the lack of significant impact on quality of care. We were also unable to estimate the potential impact of factors such as scanning practices, level of supervision, quality of ultrasound equipment and clinical care pathway protocols. Conclusions: We have shown that consultant presence in the early pregnancy assessment unit has no significant impact on key outcomes, such as the proportion of women admitted to hospital as an emergency, pregnancy of unknown location rates, ratio of new to follow-up visits, negative laparoscopy rate and patient satisfaction. All data strands indicate that low-volume units run by senior or specialist nurses and supported by sonographers and consultants may represent the optimal early pregnancy assessment unit configuration. Future work: Our results show that further research is needed to assess the potential impact of enhanced clinical and ultrasound training on the performance of all disciplines working in early pregnancy assessment units. Trial registration: Current Controlled Trials ISRCTN10728897. Funding: This project was funded by the National Institute for Health Research (NIHR) Health Services and Delivery Research programme and will be published in full in Health Services and Delivery Research; Vol. 8, No. 46. See the NIHR Journals Library website for further project information.

Background: The traditional method of risk assessment for pre-eclampsia recommended by the National Institute for Health and Care Excellence is based on maternal factors and it recommends that high-risk women should be treated with aspirin. An alternative method of screening is based on the competing risk model, which uses Bayes’ theorem to combine maternal factors with mean arterial pressure, the uterine artery pulsatility index, serum placental growth factor and pregnancy-associated plasma protein-A at 11–13 weeks’ gestation. Objective: The primary aim was to compare the performance of screening by risks obtained using the competing risk model with risk assessment using the National Institute for Health and Care Excellence guidelines. Design: This was a prospective multicentre observational study. Setting: The setting was seven NHS maternity hospitals in England. Participants: Participants were women with singleton pregnancy attending for a routine hospital visit at 11+0–13+6 weeks’ gestation between April and December 2016. Main outcome measures: The performance of screening for pre-eclampsia by the competing risk model was compared with the National Institute for Health and Care Excellence method. Relative reductions in risk with aspirin prophylaxis of 30% and 60% were assumed for all pre-eclampsia and preterm pre-eclampsia, respectively. The primary comparison was the detection rate of the National Institute for Health and Care Excellence method with the detection rate of a mini-combined test (including maternal factors, mean arterial pressure and pregnancy-associated plasma protein-A) in the prediction of all pre-eclampsia for the same screen-positive rate determined by the National Institute for Health and Care Excellence method. Results: In 473 (2.8%) of the 16,747 pregnancies there was development of pre-eclampsia, including 142 (0.8%) women with preterm pre-eclampsia. The screen-positive rate by the National Institute for Health and Care Excellence method was 10.3%. For all pre-eclampsia, the false-positive and detection rates by the National Institute for Health and Care Excellence method were 9.7% and 31.6%, respectively. For preterm pre-eclampsia, the false-positive and detection rates were 10.0% and 42.8%, respectively. Compliance with the National Institute for Health and Care Excellence recommendation that high-risk women should be treated with aspirin from the first trimester was 23%. For the same screen-positive rate, the detection rate of the mini-combined test for all pre-eclampsia was 42.8%, which was superior to that of the National Institute for Health and Care Excellence method by 11.2% (95% confidence interval 6.9% to 15.6%). The increase in detection for the same screen-positive rate was accompanied by a reduction in false-positive rate of 0.3%. For the same screen-positive rate as National Institute for Health and Care Excellence, the detection rate for preterm pre-eclampsia by combining maternal factors, mean arterial pressure and placental growth factor was 67.3% compared with 44.1% with the National Institute for Health and Care Excellence method. With the addition of the uterine artery pulsatility index, the detection rate was 78.6%. This was higher than that of the National Institute for Health and Care Excellence method by 35.5% (95% confidence interval 25.2% to 45.8%). Calibration of risks for pre-eclampsia was generally good, with the calibration slope very close to 1.0. The feasibility of incorporating a new biomarker was demonstrated. However, the addition of inhibin A to the full combined test did not improve the detection rates for all pre-eclampsia and preterm pre-eclampsia (61% and 80%, respectively). The same screening model for preterm pre-eclampsia by a combination of maternal factors, mean arterial pressure, the uterine artery pulsatility index and placental growth factor achieved detection rates of 45.8% and 56.3%, respectively, for preterm small for gestational age and early small for gestational age neonates. Limitation: The study did not include a health economic assessment. Conclusion: The findings suggest that performance of screening for pre-eclampsia provided by a combination of maternal factors and biomarkers is superior to that achieved by current National Institute for Health and Care Excellence guidelines. Future work: Future work is required to identify potential biomarkers for further improvement of the competing risk model and to carry out a health economic assessment. Trial registration: Current Controlled Trials ISRCTN83611527. Funding: This project was funded by the Efficacy and Mechanism Evaluation programme, a Medical Research Council and National Institute for Health Research (NIHR) partnership. This will be published in full in Efficacy and Mechanism Evaluation; Vol. 7, No. 8. See the NIHR Journals Library website for further project information.

BackgroundThe effectiveness of screening for macrosomia is not well established. One of the critical elements of an effective screening program is the diagnostic accuracy of a test at predicting the condition. The objective of this study is to investigate the diagnostic effectiveness of universal ultrasonic fetal biometry in predicting the delivery of a macrosomic infant, shoulder dystocia, and associated neonatal morbidity in low- and mixed-risk populations.Methods and findingsWe conducted a predefined literature search in Medline, Excerpta Medica database (EMBASE), the Cochrane library and ClinicalTrials.gov from inception to May 2020. No language restrictions were applied. We included studies where the ultrasound was performed as part of universal screening and those that included low- and mixed-risk pregnancies and excluded studies confined to high risk pregnancies. We used the estimated fetal weight (EFW) (multiple formulas and thresholds) and the abdominal circumference (AC) to define suspected large for gestational age (LGA). Adverse perinatal outcomes included macrosomia (multiple thresholds), shoulder dystocia, and other markers of neonatal morbidity. The risk of bias was assessed using the Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) tool. Meta-analysis was carried out using the hierarchical summary receiver operating characteristic (ROC) and the bivariate logit-normal (Reitsma) models. We identified 41 studies that met our inclusion criteria involving 112,034 patients in total. These included 11 prospective cohort studies (N = 9986), one randomized controlled trial (RCT) (N = 367), and 29 retrospective cohort studies (N = 101,681). The quality of the studies was variable, and only three studies blinded the ultrasound findings to the clinicians. Both EFW >4,000 g (or 90th centile for the gestational age) and AC >36 cm (or 90th centile) had >50% sensitivity for predicting macrosomia (birthweight above 4,000 g or 90th centile) at birth with positive likelihood ratios (LRs) of 8.74 (95% confidence interval [CI] 6.84-11.17) and 7.56 (95% CI 5.85-9.77), respectively. There was significant heterogeneity at predicting macrosomia, which could reflect the different study designs, the characteristics of the included populations, and differences in the formulas used. An EFW >4,000 g (or 90th centile) had 22% sensitivity at predicting shoulder dystocia with a positive likelihood ratio of 2.12 (95% CI 1.34-3.35). There was insufficient data to analyze other markers of neonatal morbidity.ConclusionsIn this study, we found that suspected LGA is strongly predictive of the risk of delivering a large infant in low- and mixed-risk populations. However, it is only weakly (albeit statistically significantly) predictive of the risk of shoulder dystocia. There was insufficient data to analyze other markers of neonatal morbidity.

BACKGROUND:Surgical site infection (SSI) is a worldwide problem which has morbidity, mortality and financial consequences. The incidence rate of SSI is high in Low- and Middle-Income countries (LMICs) compared to high income countries, and the costly surgical complication can raise the potential risk of financial catastrophe. OBJECTIVE:The aim of the study is to critically appraise studies on the cost of SSI in a range of LMIC studies and compare these estimates with a reference standard of high income European studies who have explored similar SSI costs. METHODS:A systematic review was undertaken using searches of two electronic databases, EMBASE and MEDLINE In-Process & Other Non-Indexed Citations, up to February 2019. Study characteristics, comparator group, methods and results were extracted by using a standard template. RESULTS:Studies from 15 LMIC and 16 European countries were identified and reviewed in full. The additional cost of SSI range (presented in 2017 international dollars) was similar in the LMIC ($174-$29,610) and European countries ($21-$34,000). Huge study design heterogeneity was encountered across the two settings. DISCUSSION:SSIs were revealed to have a significant cost burden in both LMICs and High Income Countries in Europe. The magnitude of the costs depends on the SSI definition used, severity of SSI, patient population, choice of comparator, hospital setting, and cost items included. Differences in study design affected the comparability across studies. There is need for multicentre studies with standardized data collection methods to capture relevant costs and consequences of the infection across income settings.

Abstract Background The classification of phase 3 trials as superiority or non-inferiority has become routine, and it is widely accepted that there are important differences between the two types of trial in their design, analysis and interpretation. Main text There is a clear rationale for the superiority/non-inferiority framework in the context of regulatory trials. The focus of our article is non-regulatory trials with a public health objective. First, using two examples from infectious disease research, we show that the classification of superiority or non-inferiority trials is not always straightforward. Second, we show that several arguments for different approaches to the design, analysis and interpretation of superiority and non-inferiority trials are unconvincing when examined in detail. We consider, in particular, the calculation of sample size (and the choice of delta or the non-inferiority margin), intention-to-treat versus per-protocol analyses, and one-sided versus two-sided confidence intervals. We argue that the superiority/non-inferiority framework is not just unnecessary but can have a detrimental effect, being a barrier to clear scientific thought and communication. In particular, it places undue emphasis on tests for significance or non-inferiority at the expense of estimation. We emphasise that these concerns apply to phase 3 non-regulatory trials in general, not just to those where the classification of the trial as superiority or non-inferiority is ambiguous. Conclusions Guidelines and statistical practice should abandon the sharp division between superiority and non-inferiority phase 3 non-regulatory trials and be more closely aligned to the clinical and public health questions that motivate the trial.

Abstract Background Despite the problem of inadequate recruitment to randomised trials, there is little evidence to guide researchers on decisions about how people are effectively recruited to take part in trials. The PRioRiTy study aimed to identify and prioritise important unanswered trial recruitment questions for research. The PRioRiTy study - Priority Setting Partnership (PSP) included members of the public approached to take part in a randomised trial or who have represented participants on randomised trial steering committees, health professionals and research staff with experience of recruiting to randomised trials, people who have designed, conducted, analysed or reported on randomised trials and people with experience of randomised trials methodology. Methods This partnership was aided by the James Lind Alliance and involved eight stages: (i) identifying a unique, relevant prioritisation area within trial methodology; (ii) establishing a steering group (iii) identifying and engaging with partners and stakeholders; (iv) formulating an initial list of uncertainties; (v) collating the uncertainties into research questions; (vi) confirming that the questions for research are a current recruitment challenge; (vii) shortlisting questions and (viii) final prioritisation through a face-to-face workshop. Results A total of 790 survey respondents yielded 1693 open-text answers to 6 questions, from which 1880 potential questions for research were identified. After merging duplicates, the number of questions was reduced to 496. Questions were combined further, and those that were submitted by fewer than 15 people and/or fewer than 6 of the 7 stakeholder groups were excluded from the next round of prioritisation resulting in 31 unique questions for research. All 31 questions were confirmed as being unanswered after checking relevant, up-to-date research evidence. The 10 highest priority questions were ranked at a face-to-face workshop. The number 1 ranked question was “How can randomised trials become part of routine care and best utilise current clinical care pathways?” The top 10 research questions can be viewed at www.priorityresearch.ie. Conclusion The prioritised questions call for a collective focus on normalising trials as part of clinical care, enhancing communication, addressing barriers, enablers and motivators around participation and exploring greater public involvement in the research process.

Introduction Observational studies have demonstrated an association between vitamin D deficiency and increased risk of morbidity and mortality in critically ill patients. Cohort studies and pilot trials have suggested promising beneficial effects of vitamin D replacement in the critical ill, at least in patients with severe vitamin D deficiency. As vitamin D is a simple, low-cost and safe intervention, it has potential to improve survival in critically ill patients.Methods and analysis In this randomised, placebo-controlled, double-blind, multicentre, international trial, 2400 adult patients with severe vitamin D deficiency (25-hydroxyvitamin D≤12 ng/mL) will be randomised in a 1:1 ratio by www.randomizer.at to receive a loading dose of 540 000 IU cholecalciferol within 72 hours after intensive care unit (ICU) admission, followed by 4000 IU daily for 90 days or placebo. Hypercalcaemia may occur as a side effect, but is monitored by regular checks of the calcium level. The primary outcome is all-cause mortality at 28 days after randomisation. Secondary outcomes are: ICU, hospital, 90-day and 1-year mortality; hospital and ICU length of stay, change in organ dysfunction on day 5 as measured by Sequential Organ Function Assessment (SOFA) score, number of organ failures; hospital and ICU readmission until day 90; discharge destination, self-reported infections requiring antibiotics until day 90 and health-related quality of life. Recruitment status is ongoing.Ethics and dissemination National ethical approval was obtained by the Ethics Committee of the University of Graz for Austria, Erasme University Brussels (Belgium) and University Hospital Frankfurt (Germany), and will further be gained according to individual national processes. On completion, results will be published in a peer-reviewed scientific journal. The study findings will be presented at national and international meetings with abstracts online.Trial registration NCT03188796, EudraCT-No: 2016-002460-13.

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.

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).

IntroductionLiver 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 analysisCALIBRE 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 disseminationThe 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).

BackgroundInfants 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 findingsTrials 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.ConclusionsIn 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.

Abstract Background A systematic review on the use of incentives to promote questionnaire return in clinical trials suggest they are effective, but not all studies have sufficient funds to use them. Promising an incentive once data are returned can reduce the cost-burden of this approach, with possible further cost-savings if the offer were restricted to reminder letters only. This study aimed to evaluate the effect of promising a monetary incentive at first mailout versus a promise on reminder letters only. Methods This was a randomised Study Within A Trial (SWAT) nested within BUMPES, a multicentre randomised controlled trial of maternal position in the late stage of labour in women with an epidural. The follow-up questionnaire asked for information on the women’s health, wellbeing and health service use one year following the birth of their baby. Women who consented to be contacted were randomised to a promise of a monetary incentive at first mailout or a promise on reminder letters only. Women were given an option of completing the questionnaire on paper or on online. The incentive was posted out on receipt of a completed questionnaire. The primary outcome was the overall return rate, and secondary outcomes were the return rate without any chasing from the study office, and the total cost of the vouchers. Results A total of 1,029 women were randomised, 508 to the first mailout group and 518 to the reminder group. There was no evidence to suggest a difference between groups in the overall return rate (adjusted RR 1.03 (95 % CI 0.96 to 1.11), however the proportion returned without chasing was higher in the first mailout group (adjusted RR 1.22, 95 % CI 1.07 to 1.39). The total cost of the vouchers per participant was higher in the first mailout group (mean difference £4.56, 95 % CI £4.02 to £5.11). Conclusions Offering a monetary incentive when a reminder is required could be cost-effective depending on the sample size of the study and the resources available to administer the reminder letters. Trial registration The BUMPES Trial is registered with Current Controlled Trials: ISRCTN35706297 , 26th August 2009.

Background: Continuous electronic fetal monitoring (EFM) in labour is widely used and computerised interpretation has the potential to increase its utility. Objectives: This trial aimed to find out whether or not the addition of decision support software to assist in the interpretation of the cardiotocograph (CTG) reduced the number of poor neonatal outcomes, and whether or not it was cost-effective. Design: Two-arm individually randomised controlled trial. The allocations were computer generated using stratified block randomisation employing variable block sizes. The trial was not masked. Setting: Labour wards in England, Scotland and the Republic of Ireland. Participants: Women in labour having EFM, with a singleton or twin pregnancy, at ≥ 35 weeks’ gestation. Interventions: Decision support or no decision support. Main outcome measures: The primary outcomes were (1) a composite of poor neonatal outcome {intrapartum stillbirth or early neonatal death (excluding lethal congenital anomalies), or neonatal morbidity [defined as neonatal encephalopathy (NNE)], or admission to a neonatal unit within 48 hours for ≥ 48 hours (with evidence of feeding difficulties, respiratory illness or NNE when there was evidence of compromise at birth)}; and (2) developmental assessment at the age of 2 years in a subset of surviving children. Results: Between 6 January 2010 and 31 August 2013, 47,062 women were randomised and 46,042 were included in the primary analysis (22,987 in the decision support group and 23,055 in the no decision support group). The short-term primary outcome event rate was higher than anticipated. There was no evidence of a difference in the incidence of poor neonatal outcome between the groups: 0.7% (n = 172) of babies in the decision support group compared with 0.7% (n = 171) of babies in the no decision support group [adjusted risk ratio 1.01, 95% confidence interval (CI) 0.82 to 1.25]. There was no evidence of a difference in the long-term primary outcome of the Parent Report of Children’s Abilities-Revised with a mean score of 98.0 points [standard deviation (SD) 33.8 points] in the decision support group and 97.2 points (SD 33.4 points) in the no decision support group (mean difference 0.63 points, 95% CI –0.98 to 2.25 points). No evidence of a difference was found for health resource use and total costs. There was evidence that decision support did change practice (with increased fetal blood sampling and a lower rate of repeated alerts). Limitations: Staff in the control group may learn from exposure to the decision support arm of the trial, resulting in improved outcomes in the control arm. This was identified in the planning stage and felt to be unlikely to have a significant effect on the results. As this was a pragmatic trial, the response to CTG alerts was left to the attending clinicians. Conclusions: This trial does not support the hypothesis that the use of computerised interpretation of the CTG in women who have EFM in labour improves the clinical outcomes for mothers or babies. Future work: There continues to be an urgent need to improve knowledge and training about the appropriate response to CTG abnormalities, including timely intervention. Trial registration: Current Controlled Trials ISRCTN98680152. Funding: This project was funded by the National Institute for Health Research (NIHR) HTA programme and will be published in full in Health Technology Assessment; Vol. 22, No. 9. See the NIHR Journals Library website for further project information. Sara Kenyon was part funded by the NIHR Collaboration for Leadership in Applied Health Research and Care West Midlands.

BackgroundData Monitoring Committees (DMCs) are essential to the good conduct of many trials. Typically they comprise a small expert group which monitors safety, efficacy, progress and early outcome data as trials recruit. DMCs can recommend protocol revisions and early stopping of a trial. As DMC meetings usually consider unblinded interim data confidentially, their deliberations are seldom exposed to research scrutiny. Although there have been some case studies from trials from mixed specialties which offer insights into some of the common issues faced by DMCs, we have, however, little empirical information about the challenges faced within specific clinical settings.MethodsIn-depth interviews with participants in the BRACELET Study on death and bereavement in neonatal intensive care trials produced qualitative accounts of experiences and views of a subgroup of 18 DMC members. These interviews explored views of DMC members in relation to the clinical context of neonatal intensive care and the conduct of neonatal intensive care trials.ResultsInterviewees felt that an understanding of both the neonatal intensive care setting and population was crucial in a DMC. They considered the neonatal intensive care research population especially vulnerable, and that outcomes that included both death and severe disability raised particular challenges rarely faced in other settings. In exploring these key outcomes they were mindful of the need to meet high scientific standards and the needs of babies in the trials and their families. DMC members discussed particular difficulties around the composite outcome of death and severe disability, especially when mortality data were available long before data on longer term disability. While statistical stopping guidance is helpful, DMC members described decisions about stopping, revising or continuing a trial being informed by a wider set of considerations and discussions than a pre-set p value. These included potentially competing needs of current trial participants and future patients, and reflections on the nature of benefit and harm. Given their cognisance of the potential impact and consequences of the decisions made by DMCs in this setting of life, death, and disability, interviewees commonly used the imagery of bravery, and described DMCs either holding or losing their nerve.ConclusionsDMCs for trials in other fields may also face difficult ethical trade-offs in monitoring composite outcomes. The experience from this sample of DMC members suggest that for neonatal intensive care trials there are some very specific challenges seldom faced elsewhere. The vulnerability of the population, and the different timescales for essential data becoming available to inform decisions, presented particular challenges. We suggest that it is important to consider the challenges raised in other settings to better understand the complex work of these committees and to prepare future generations of DMC members.

Background: Epidural analgesia leads to increased risk of instrumental vaginal delivery (IVD). There is debate about whether or not posture in second-stage labour influences the incidence of spontaneous vaginal birth (SVB). Objectives: In nulliparous women with epidural analgesia, does a policy of adopting an ‘upright position’ throughout second-stage labour increase the incidence of SVB compared with a policy of adopting a ‘lying-down’ position? Design: Two-arm randomised controlled trial. Setting: Maternity units in England and Wales. Participants: Nulliparous women aged ≥ 16 years, at ≥ 37 weeks’ gestation with singleton cephalic presentation and intended SVB, in second-stage labour with an epidural providing effective pain relief. Interventions: (1) Upright position to maintain the pelvis in as vertical a plane as possible; and (2) lying-down position to maintain the pelvis in as horizontal a plane as possible. Main outcome measures: The primary outcome measure was incidence of SVB. Secondary outcomes included augmentation, interventions to maintain blood pressure, duration of labour, episiotomy, genital tract trauma, post-partum haemorrhage, maternal satisfaction, neonatal metabolic acidosis, 5-minute Apgar score of