FERN: is it possible to conduct a randomised controlled trial of intervention or expectant management for early-onset selective fetal growth restriction in monochorionic twin pregnancy - protocol for a prospective multicentre mixed-methods feasibility study.

INTRODUCTION: Selective fetal growth restriction (sFGR) in monochorionic twin pregnancy, defined as an estimated fetal weight (EFW) of one twin <10th centile and EFW discordance ≥25%, is associated with stillbirth and neurodisability for both twins. The condition poses unique management difficulties: on the one hand, continuation of the pregnancy carries a risk of death of the smaller twin, with a high risk of co-twin demise (40%) or co-twin neurological sequelae (30%). On the other, early delivery to prevent the death of the smaller twin may expose the larger twin to prematurity, with the associated risks of long-term physical, emotional and financial costs from neurodisability, such as cerebral palsy.When there is severe and early sFGR, before viability, delivery is not an option. In this scenario, there are currently three main management options: (1) expectant management, (2) selective termination of the smaller twin and (3) placental laser photocoagulation of interconnecting vessels. These management options have never been investigated in a randomised controlled trial (RCT). The best management option is unknown, and there are many challenges for a potential RCT. These include the rarity of the condition resulting in a small number of eligible pregnancies, uncertainty about whether pregnant women will agree to participate in such a trial and whether they will agree to be randomised to expectant management or active fetal intervention, and the challenges of robust and long-term outcome measures. Therefore, the main objective of the FERN study is to assess the feasibility of conducting an RCT of active intervention vs expectant management in monochorionic twin pregnancies with early-onset (prior to 24 weeks) sFGR. METHODS AND ANALYSIS: The FERN study is a prospective mixed-methods feasibility study. The primary objective is to recommend whether an RCT of intervention vs expectant management of sFGR in monochorionic twin pregnancy is feasible by exploring women's preference, clinician's preference, current practice and equipoise and numbers of cases. To achieve this, we propose three distinct work packages (WPs). WP1: A Prospective UK Multicentre Study, WP2A: a Qualitative Study Exploring Parents' and Clinicians' Views and WP3: a Consensus Development to Determine Feasibility of a Trial. Eligible pregnancies will be recruited to WP1 and WP2, which will run concurrently. The results of these two WPs will be used in WP3 to develop consensus on a future definitive study. The duration of the study will be 53 months, composed of 10 months of setup, 39 months of recruitment, 42 months of data collection, and 5 months of data analysis, report writing and recommendations. The pragmatic sample size for WP1 is 100 monochorionic twin pregnancies with sFGR. For WP2, interviews will be conducted until data saturation and sample variance are achieved, that is, when no new major themes are being discovered. Based on previous similar pilot studies, this is anticipated to be approximately 15-25 interviews in both the parent and clinician groups. Engagement of at least 50 UK clinicians is planned for WP3. ETHICS AND DISSEMINATION: This study has received ethical approval from the Health Research Authority (HRA) South West-Cornwall and Plymouth Ethics Committee (REC reference 20/SW/0156, IRAS ID 286337). All participating sites will undergo site-specific approvals for assessment of capacity and capability by the HRA. The results of this study will be published in peer-reviewed journals and presented at national and international conferences. The results from the FERN project will be used to inform future studies. TRIAL REGISTRATION NUMBER: This study is included in the ISRCTN Registry (ISRCTN16879394) and the NIHR Central Portfolio Management System (CPMS), CRN: Reproductive Health and Childbirth Specialty (UKCRN reference 47201).

Balancing key stakeholder priorities and ethical principles to design a trial comparing intervention or expectant management for early-onset selective fetal growth restriction in monochorionic twin pregnancy: FERN qualitative study.

OBJECTIVES: As part of the FERN feasibility study, this qualitative research aimed to explore parents' and clinicians' views on the acceptability, feasibility and design of a randomised controlled trial (RCT) of active intervention versus expectant management in monochorionic (MC) diamniotic twin pregnancies with early-onset (prior to 24 weeks) selective fetal growth restriction (sFGR). Interventions could include laser treatment or selective termination which could lead to the death or serious disability of one or both twins. DESIGN: Qualitative semi-structured interviews with parents and clinicians. Data were analysed using reflexive thematic analysis and considered against the Principles of Biomedical Ethics. PARTICIPANTS AND SETTING: We interviewed 19 UK parents experiencing (six mothers, two partners) or had recently experienced (eight mothers, three partners) early-onset sFGR in MC twin pregnancy and 14 specialist clinicians from the UK and Europe. RESULTS: Participants viewed the proposed RCT as 'ethically murky' because they believed that the management of sFGR in MC twin pregnancy should be individualised according to the type and severity of sFGR. Clinicians prioritised the gestational age, size, decrease in growth velocity, access to the placental vessels and acceptability of intervention for parents. Discussions and decision-making about selective termination appeared to cause long-term harm (maleficence). The most important outcome for parents and clinicians was 'live birth'. For clinicians, this was the live birth of at least one twin. For parents, this meant the live birth of both twins, even if this meant that their babies had neurodevelopmental impairment or disabilities. CONCLUSIONS: All three pregnancy management approaches for sFGR in MC twin pregnancy carry risks and benefits, and the ultimate goal for parents is to receive individualised care to achieve the best possible outcome for both twins. An RCT was not acceptable to parents or clinicians or seen as ethically appropriate. Alternative study designs should be considered to answer this important research question.

Whole-body hypothermia in mild neonatal encephalopathy: protocol for a multicentre phase III randomised controlled trial.

BACKGROUND: Mild hypoxic ischemic encephalopathy is associated with sub optimal cognition and learning difficulties at school age. Although whole-body hypothermia reduces death and disability after moderate or severe encephalopathy in high-income countries, the safety and efficacy of hypothermia in mild encephalopathy is not known. The cooling in mild encephalopathy (COMET) trial will examine if whole-body hypothermia improves cognitive development of neonates with mild encephalopathy. METHODS: The COMET trial is a phase III multicentre open label two-arm randomised controlled trial with masked outcome assessments. A total of 426 neonates with mild encephalopathy will be recruited from 50 to 60 NHS hospitals over 2 ½ years following parental consent. The neonates will be randomised to 72 h of whole-body hypothermia (33.5 ± 0.5 C) or normothermia (37.0 ± 0.5 C) within six hours or age. Prior to the recruitment front line clinical staff will be trained and certified on expanded modified Sarnat staging for encephalopathy. The neurological assessment of all screened and recruited cases will be video recorded and centrally assessed for quality assurance. If recruitment occurs at a non-cooling centre, neonates in both arms will be transferred to a cooling centre for continued care, after randomisation. All neonates will have continuous amplitude integrated electroencephalography (aEEG) at least for the first 48 h to monitor for seizures. Predefined safety outcomes will be documented, and data collected to assess resource utilization of health care. A central team masked to trial group allocation will assess neurodevelopmental outcomes at 2 years of age. The primary outcome is mean difference in composite cognitive scores on Bayley scales of Infant and Toddler development 4th Edition. DISCUSSION: The COMET trial will establish the safety and efficacy of whole-body hypothermia for mild hypoxic ischaemic encephalopathy and inform national and international guidelines in high income countries. It will also provide an economic assessment of whole-body hypothermia therapy for mild encephalopathy in the NHS on cost-effectiveness grounds. TRIAL REGISTRATION NUMBER: NCT05889507 June 5, 2023.

Diagnosis and management of selective fetal growth restriction in monochorionic twin pregnancies: A cross-sectional international survey.

OBJECTIVE: To identify current practices in the management of selective fetal growth restriction (sFGR) in monochorionic diamniotic (MCDA) twin pregnancies. DESIGN: Cross-sectional survey. SETTING: International. POPULATION: Clinicians involved in the management of MCDA twin pregnancies with sFGR. METHODS: A structured, self-administered survey. MAIN OUTCOME MEASURES: Clinical practices and attitudes to diagnostic criteria and management strategies. RESULTS: Overall, 62.8% (113/180) of clinicians completed the survey; of which, 66.4% (75/113) of the respondents reported that they would use an estimated fetal weight (EFW) of <10th centile for the smaller twin and an inter-twin EFW discordance of >25% for the diagnosis of sFGR. For early-onset type I sFGR, 79.8% (75/94) of respondents expressed that expectant management would be their routine practice. On the other hand, for early-onset type II and type III sFGR, 19.3% (17/88) and 35.7% (30/84) of respondents would manage these pregnancies expectantly, whereas 71.6% (63/88) and 57.1% (48/84) would refer these pregnancies to a fetal intervention centre or would offer fetal intervention for type II and type III cases, respectively. Moreover, 39.0% (16/41) of the respondents would consider fetoscopic laser surgery (FLS) for early-onset type I sFGR, whereas 41.5% (17/41) would offer either FLS or selective feticide, and 12.2% (5/41) would exclusively offer selective feticide. For early-onset type II and type III sFGR cases, 25.9% (21/81) and 31.4% (22/70) would exclusively offer FLS, respectively, whereas 33.3% (27/81) and 32.9% (23/70) would exclusively offer selective feticide. CONCLUSIONS: There is significant variation in clinician practices and attitudes towards the management of early-onset sFGR in MCDA twin pregnancies, especially for type II and type III cases, highlighting the need for high-level evidence to guide management.

Exploring communication preferences and risk thresholds of clinicians and parents of febrile infants under 90 days presenting to the emergency department: a qualitative study.

BACKGROUND: Febrile infants under 3 months of age are at higher risk of invasive bacterial illness (IBI) when compared with older children. Increasingly sequential assessment based on age, clinical appearance and biomarkers is used to determine the risk of IBI, and appropriateness of invasive procedures such as lumbar puncture. The purpose of this qualitative study is to report parents and clinicians' opinions on communication of risks and benefits of sequential assessment and tailored treatment. METHODS: 18 parents enrolled in the Febrile Infant Diagnostic Assessment and Outcomes study and seven clinicians from England, Wales and Northern Ireland were purposively selected to participate in virtual qualitative interviews. Data were analysed thematically. RESULTS: Tailored treatment plans were widely supported. Confidence in the clinician was central to parents' attitude towards management recommendations. Parents' decision-making preferences change throughout their child's clinical journey, with an initial preference for clinician-led decisions evolving towards collaborative decision-making as their stress and anxiety reduce. There were widespread differences in preferences for how risk was discussed. Parents self-reported poor retention of information and felt communication adjuncts helped their understanding. Clinicians were generally positive about the use of clinical decision aids as a communication tool, rather than relying on them for decision-making. DISCUSSION: Parents want to feel informed, but their desire to be involved in shared decision-making evolves over time.Clinicians appear to use their clinical judgement to provide individualised information, evolving their communication in response to perceived parental needs.Poor information retention highlights the need for repetition of information and use of communication adjuncts. TRIAL REGISTRATION NUMBER: NCT05259683.

Developments in the Design, Conduct, and Reporting of Child Health Trials.

To identify priority areas to improve the design, conduct, and reporting of pediatric clinical trials, the international expert network, Standards for Research (StaR) in Child Health, was assembled and published the first 6 Standards in Pediatrics in 2012. After a recent review summarizing the 247 publications by StaR Child Health authors that highlight research practices that add value and reduce research "waste," the current review assesses the progress in key child health trial methods areas: consent and recruitment, containing risk of bias, roles of data monitoring committees, appropriate sample size calculations, outcome selection and measurement, and age groups for pediatric trials. Although meaningful change has occurred within the child health research ecosystem, measurable progress is still disappointingly slow. In this context, we identify and review emerging trends that will advance the agenda of increased clinical usefulness of pediatric trials, including patient and public engagement, Bayesian statistical approaches, adaptive designs, and platform trials. We explore how implementation science approaches could be applied to effect measurable improvements in the design, conducted, and reporting of child health research.

Use of selective gut decontamination in critically ill children: PICnIC a pilot RCT and mixed-methods study.

Background: Healthcare-associated infections are a major cause of morbidity and mortality in critically ill children. In adults, data suggest the use of selective decontamination of the digestive tract may reduce the incidence of healthcare-associated infections. Selective decontamination of the digestive tract has not been evaluated in the paediatric intensive care unit population. Objectives: To determine the feasibility of conducting a multicentre, cluster-randomised controlled trial in critically ill children comparing selective decontamination of the digestive tract with standard infection control. Design: Parallel-group pilot cluster-randomised controlled trial with an integrated mixed-methods study. Setting: Six paediatric intensive care units in England. Participants: Children (> 37 weeks corrected gestational age, up to 16 years) requiring mechanical ventilation expected to last for at least 48 hours were eligible for the PICnIC pilot cluster-randomised controlled trial. During the ecology periods, all children admitted to the paediatric intensive care units were eligible. Parents/legal guardians of recruited patients and healthcare professionals working in paediatric intensive care units were eligible for inclusion in the mixed-methods study. Interventions: The interventions in the PICnIC pilot cluster-randomised controlled trial included administration of selective decontamination of the digestive tract as oro-pharyngeal paste and as a suspension given by enteric tube during the period of mechanical ventilation. Main outcome measures: The decision as to whether a definitive cluster-randomised controlled trial is feasible is based on multiple outcomes, including (but not limited to): (1) willingness and ability to recruit eligible patients; (2) adherence to the selective decontamination of the digestive tract intervention; (3) acceptability of the definitive cluster-randomised controlled trial; (4) estimation of recruitment rate; and (5) understanding of potential clinical and ecological outcome measures. Results: A total of 368 children (85% of all those who were eligible) were enrolled in the PICnIC pilot cluster-randomised controlled trial across six paediatric intensive care units: 207 in the baseline phase (Period One) and 161 in the intervention period (Period Two). In sites delivering selective decontamination of the digestive tract, the majority (98%) of children received at least one dose of selective decontamination of the digestive tract, and of these, 68% commenced within the first 6 hours. Consent for the collection of additional swabs was low (44%), though data completeness for potential outcomes, including microbiology data from routine clinical swab testing, was excellent. Recruited children were representative of the wider paediatric intensive care unit population. Overall, 3.6 children/site/week were recruited compared with the potential recruitment rate for a definitive cluster-randomised controlled trial of 3 children/site/week, based on data from all UK paediatric intensive care units. The proposed trial, including consent and selective decontamination of the digestive tract, was acceptable to parents and staff with adaptations, including training to improve consent and communication, and adaptations to the administration protocol for the paste and ecology monitoring. Clinical outcomes that were considered important included duration of organ failure and hospital stay, healthcare-acquired infections and survival. Limitations: The delivery of the pilot cluster-randomised controlled trial was disrupted by the COVID-19 pandemic, which led to slow set-up of sites, and a lack of face-to face training. Conclusions: PICnIC's findings indicate that a definitive cluster-randomised controlled trial in selective decontamination of the digestive tract in paediatric intensive care units is feasible with the inclusion modifications, which would need to be included in a definitive cluster-randomised controlled trial to ensure that the efficiency of trial processes is maximised. Future work: A definitive trial that incorporates the protocol adaptations and outcomes arising from this study is feasible and should be conducted. Trial registration: This trial is registered as ISRCTN40310490. Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 16/152/01) and is published in full in Health Technology Assessment; Vol. 28, No. 8. See the NIHR Funding and Awards website for further award information.

Each year, around 20,000 critically ill children are admitted to paediatric intensive care units in the UK. These children are at a higher risk of healthcare-associated infections, one of the main sources of which is the large number of bacteria in the digestive tract. Spread of bacteria from the digestive tract into other organs, such as the lung (causing ventilator-associated pneumonia) or bloodstream (causing sepsis), can be life-threatening. The risk is highest in those children whose illness is so severe that they require prolonged mechanical ventilation. Stopping the growth of bacteria in the digestive tract (called selective decontamination of the digestive tract) has been shown in adults to reduce the number of hospital-acquired infections. However, there have been no trials in children. We wanted to assess how practical and acceptable such a trial would be comparing standard infection control to selective decontamination of the digestive tract-enhanced infection control and monitoring how each intervention affected antimicrobial resistance. We undertook a pilot study to examine whether clinicians could identify eligible children, enrol them in the study and follow study procedures during the course of paediatric intensive care unit admission. Alongside this, we interviewed parents and clinicians to get their views on the proposed trial. Six hospitals recruited 559 patients over a period of roughly 7 months. Hospitals were randomly allocated to continue with the standard infection control procedure or to give selective decontamination of the digestive tract. Overall, recruitment was higher than expected. Alongside this, we examined the views of patients, caregivers and healthcare professionals to assess their views on whether a trial should be carried out to see if selective decontamination of the digestive tract should become part of the infection control regime for children most at risk of hospital-acquired infection in the paediatric intensive care unit. Overall results suggest that a larger PICnIC trial incorporating patient stakeholder and clinical staff feedback on design and outcomes is feasible and that it is appropriate to conduct a trial into the effectiveness of selective decontamination of the digestive tract administration to minimise hospital-acquired infections.

Questioning approaches to consent in time critical obstetric trials: findings from a mixed-methods study.

OBJECTIVE: Trial legislation enables research to be conducted without prior consent (RWPC) in emergency situations, yet this approach has rarely been used in time-critical obstetric trials. This study explored views and experiences of antenatal recruitment and consent and RWPC in an emergency intrapartum randomised clinical trial. DESIGN: Embedded, mixed-methods study within a trial, involving questionnaires, recorded recruitment discussions, interviews and focus groups in the first 13 months of trial recruitment (December 2020-January 2022). SETTING: COPE is a double-blind randomised controlled trial, comparing the effectiveness of carboprost or oxytocin as first-line treatment of postpartum haemorrhage. PARTICIPANTS: Two hundred and eighty-six people (190 women/96 birth partners), linked to 198/380 (52%) COPE recruits participated in the embedded study. Of these, 272 completed a questionnaire (178 women/94 birth partners), 22 were interviewed (19 women/3 birth partners) and 16 consent discussions with 12 women were recorded. Twenty-seven staff took part in three focus groups and nine staff were interviewed. RESULTS: Participants recommended that information about the study should be more accessible antenatally for those who wish to be informed. Most women and staff did not think it would be appropriate to seek consent during pregnancy or early labour as it may cause 'unnecessary panic' and lead to research waste, as most women would not become eligible. There was support for the use of RWPC as COPE interventions are used in standard clinical practice and viewed as low risk. Women who were approached about the trial while having a postpartum haemorrhage also supported RWPC as they could not recall research discussions. CONCLUSIONS: Findings support the use of RWPC for time-critical interventions, and raise questions about the appropriateness of other commonly used consent pathways, including antenatal consent and verbal assent.

Stakeholders' perspectives on clinical trial acceptability and approach to consent within a limited timeframe: a mixed methods study.

OBJECTIVES: The Bronchiolitis Endotracheal Surfactant Study (BESS) is a randomised controlled trial to determine the efficacy of endo-tracheal surfactant therapy for critically ill infants with bronchiolitis. To explore acceptability of BESS, including approach to consent within a limited time frame, we explored parent and staff experiences of trial involvement in the first two bronchiolitis seasons to inform subsequent trial conduct. DESIGN: A mixed-method embedded study involving a site staff survey, questionnaires and interviews with parents approached about BESS. SETTING: Fourteen UK paediatric intensive care units. PARTICIPANTS: Of the 179 parents of children approached to take part in BESS, 75 parents (of 69 children) took part in the embedded study. Of these, 55/69 (78%) completed a questionnaire, and 15/69 (21%) were interviewed. Thirty-eight staff completed a questionnaire. RESULTS: Parents and staff found the trial acceptable. All constructs of the Adapted Theoretical Framework of Acceptability were met. Parents viewed surfactant as being low risk and hoped their child's participation would help others in the future. Although parents supported research without prior consent in studies of time critical interventions, they believed there was sufficient time to consider this trial. Parents recommended that prospective informed consent should continue to be sought for BESS. Many felt that the time between the consent process and intervention being administered took too long and should be 'streamlined' to avoid delays in administration of trial interventions. Staff described how the training and trial processes worked well, yet patients were missed due to lack of staff to deliver the intervention, particularly at weekends. CONCLUSION: Parents and staff supported BESS trial and highlighted aspects of the protocol, which should be refined, including a streamlined informed consent process. Findings will be useful to inform proportionate approaches to consent in future paediatric trials where there is a short timeframe for consent discussions. TRIAL REGISTRATION NUMBER: ISRCTN11746266.