National priority setting partnership using a Delphi consensus process to develop neonatal research questions suitable for practice-changing randomised trials in the UK

Background The provision of neonatal care is variable and commonly lacks adequate evidence base; strategic development of methodologically robust clinical trials is needed to improve outcomes and maximise research resources. Historically, neonatal research topics have been selected by researchers; prioritisation processes involving wider stakeholder groups have generally identified research themes rather than specific questions amenable to interventional trials. Objective To involve stakeholders including parents, healthcare professionals and researchers to identify and prioritise research questions suitable for answering in neonatal interventional trials in the UK. Design Research questions were submitted by stakeholders in population, intervention, comparison, outcome format through an online platform. Questions were reviewed by a representative steering group; duplicates and previously answered questions were removed. Eligible questions were entered into a three-round online Delphi survey for prioritisation by all stakeholder groups. Participants One hundred and eight respondents submitted research questions for consideration; 144 participants completed round one of the Delphi survey, 106 completed all three rounds. Results Two hundred and sixty-five research questions were submitted and after steering group review, 186 entered into the Delphi survey. The top five ranked research questions related to breast milk fortification, intact cord resuscitation, timing of surgical intervention in necrotising enterocolitis, therapeutic hypothermia for mild hypoxic ischaemic encephalopathy and non-invasive respiratory support. Conclusions We have identified and prioritised research questions suitable for practice-changing interventional trials in neonatal medicine in the UK at the present time. Trials targeting these uncertainties have potential to reduce research waste and improve neonatal care.

In preterm infants with insufficient maternal milk available; does the use of pasturised human milk (donor) as compared with preterm formula reduce necrotising enterocolitis requiring surgery and improve two-year neurodevelopmental outcomes?
6.507 6.917 8.333 6.705In any baby with seizures does levetiracetam improve need for second-line anticonvulsants when compared to phenobarbitone?6.649 6.643 6.333 6.637In term infants with a bilious vomit who are assessed by a senior neonatologist as being well; does transfer to a specialised unit for urgent upper gastrointestinal contrast improve survival; quality of life and adverse events compared to close clinical monitoring by the local neonatal team?6.640 6.688 6.250 6.632In babies above 34 weeks gestation on the postnatal ward; is a blood glucose threshold of 2.0mmol/L non-inferior to a blood glucose threshold of 2.6mmol/L with regards to adverse events?6.667 6.688 4.000 6.585In infants born extremely preterm (< 28 weeks) does 1 to 1 nursing care until 28 weeks corrected gestation improve survival and all core neonatal outcomes compared to standard nursing allocations based on intensive care support required?6.392 6.826 8.000 6.582In babies born preterm does a post-discharge home intervention package of brain stimulation exercises improve neurodevelopment when compared to standard care?6.216 7.500 8.000 6.551 Does therapeutic hypothermia (cooling) improve brain injury and long term neurodevelopmental outcomes in preterm infants (> 30 weeks) who have suffered a hypoxic injury?6.237 7.474 7.600 6.540In infants with a prenatally diagnosed gastrointestinal anomaly does planned delivery in a unit with co-located neonatal surgical unit (no ambulance transfer required) improve survival; parental experience and adverse events?6.347 7.000 7.500 6.505In preterm babies does high dose caffeine (10-20mg/kg/day) improve survival; brain injury and cognition compared to low dose caffeine (5mg/kg/day)?6.316 6.667 7.800

6.455
In preterm infants does enhanced monitoring from birth to 72 hours of life (with near infrared spectroscopy (NIRS); transcutaneous CO2; spO2; heart rate and arterial BP) improve core neonatal outcomes compared to standard monitoring?In babies diagnosed with gastro-oesophageal reflux does the use of anti-reflux medications improve outcomes such as bronchopulmonary dysplasia; sepsis and quality of life when compared with non-pharmacological support?
6.107 6.750 7.200 6.308In preterm babies showing feeding cues whilst on non-invasive respiratory support; does commencing oral feeding (compared to waiting) improve outcomes such as breastfeeding rates; oral aversion and reflux?6.027 7.080 6.500 6.302 Does point of care ultrasound guided umbilical venous catheter (UVC) position adjustments reduce workload; X-ray exposure and adverse events compared to standard X-ray guided UVC position adjustments?In preterm babies receiving donor milk due to insufficient mothers milk; is it superior to switch to preterm formula once on full feeds or wait until term corrected gestational age? 5.885 6.254 6.125 5.996 In preterm babies with chronic lung disease does extending caffeine therapy until term (rather than standard care of discontinuing around 34 weeks corrected gestation) improve survival and cognition?5.783 6.077 7.889 5.992 In preterm babies requiring parenteral nutrition does higher range lipid (fats) intake or lower range lipid (fats) intake improve growth and long term metabolic outcomes?6.097 5.827 5.231 5.987 In preterm infants does high dose vitamin D supplementation (>800 units) improve metabolic bone disease when compared to low dose vitamin D supplementation (< 400 units)?5.981 6.000 5.909

5.982
In preterm babies whose mothers would like to establish exclusive breastfeeding; does exposure to routine bottle feeding reduce breast-feeding success compared to exposure to routine nasogastric feeding?In preterm infants at risk of necrotising enterocolitis does treatment with gutderived IFN-y-releasing CD4+ T cells improve survival; brain injury and quality of life when compared to current practice?5.403 6.875 6.833 5.671 In babies requiring long term parenteral nutrition (PN); does supporting an earlier discharge home (when stable PN established) compared to standard care improve quality of life for families without increased risk?5.333 6.147 7.125 5.667 In term infants with congenital diaphragmatic hernia is extracorporeal membrane oxygenation (ECMO) or high-frequency oscillatory ventilation (HFOV) superior to improve survival; brain injury and quality of life?5.358 6.360 7.125 5.664 In preterm babies requiring parenteral nutrition does high vitamin D intake improve growth and long-term metabolic outcomes compared to standard intake?5.678 5.655 5.375

5.653
In formula fed babies born moderately preterm at 34 to 37 weeks gestation does enhanced nutrition support improve growth and long term cognition; when compared to term formula?5.547 5.821 6.000 5.650 Do regular occupational therapy interventions for all babies admitted to NICU improve cognition; adverse events and decrease sensory processing disorders in comparison to minimal (<1 day per week) occupational therapy input?5.218 6.275 6.556 5.646 In all babies does next generation whole genome sequencing improve the diagnostic/prognostic yield compared to current newborn screening practices without adverse ethical issues?5.622 5.333 6.625 5.640 Does an occupational therapist led staff training session about sensitive neonatal handling improve long term outcomes such as sensory processing disorders and improve staff-parent relationships; compared to standard staff training?5.053 6.590 6.200 5.629 Does circadian rhythm entrainment with nocturnal melatonin improve survival and neurodevelopmental impairment in infants at high risk for neurological injury (preterm < 28 weeks with peri-ventricular leukomalacia/ grade 3/4 intra-ventricular haemorrhage or term babies with hypoxic ischaemic encephalopathy) when compared to placebo? 5.506 5.739 6.571

5.624
BMJ Publishing Group Limited (BMJ) disclaims all liability and responsibility arising from any reliance Supplemental material placed on this supplemental material which has been supplied by the author(s) In ex-preterm infants is early or late weaning on solids preferable with regards to growth; feeding behaviours and allergy?5.284 6.079 6.500 5.580 In all babies requiring pre-medications for intubation is propofol or fentanyl / suxamethonium superior in improving survival and bronchopulmonary dysplasia?5.412 5.720 6.900 5.577 In extremely preterm babies in the delivery room; does oxygen targeting based on near infrared spectroscopy (NIRS) (rather than SpO2) lead to improved survival and other core neonatal outcomes?5.265 6.320 7.167 5.558 For parents of preterm infants does detailed information about future health risks (stroke; high blood pressure and heart disease) improve quality of life; parental satisfaction and parental mental health compared to no information?5.193 6.115 7.714 5.552 Does provision of regular neonatal occupational therapy improve parental and staff perceptions of the developmental benefits for high-risk infants; compared to minimal occupational therapy input?5.013 6.325 6.500 5.543 In preterm babies requiring parenteral nutrition do lower energy:protein ratios improve growth and long term metabolic outcomes compared to standard ratios?5.570 5.552 5.143 5.541 In babies born as part of multiple births what is the effect of separation at any part of the neonatal journey on cognition; quality of life and adverse events?4.671 6.718 7.778 5.540 When considering stopping antibiotics on the NNU; does the use of procalcitonin reduce the duration of antibiotics courses without adverse events compared to standard management using C-reactive protein?
In extremely preterm infants who received a dose of surfactant at birth do repeated doses of surfactant at 48 and 72 hours improve survival and bronchopulmonary dysplasia when compared to standard care?For all infants requiring neonatal care does a formal multi-disciplinary discharge pathway with nationally approval parental information and tailored education sessions reduce readmission; A&E attendances and improve parental wellbeing compared to standard local discharge pathways?
BMJ Publishing Group Limited (BMJ) disclaims all liability and responsibility arising from any reliance Supplemental material placed on this supplemental material which has been supplied by the author(s) Arch Dis Child Fetal Neonatal Ed doi: 10.1136/archdischild-2023-325504 -574.:569 108 2023; Arch Dis Child Fetal Neonatal Ed , et al.Evans K Do preterm infants have lower scores on standardised Speech and Language scales at 18 months; 3 years and 5 years compared to term born infants demonstrating the need for fully funded; robust speech and language services at neonatal discharge?
In clinically well babies noted to have a raised cord lactate (but no TOBY criteria met) does observation and detailed clinical assessment lead to reduced length of stay and increased breast-feeding rates when compared to sequential blood gases with possible admission for intravenous fluids?BMJ Publishing Group Limited (BMJ) disclaims all liability and responsibility arising from any reliance Supplemental material placed on this supplemental material which has been supplied by the author(s)In intubated preterm infants does a short course of diuretics prior to extubation improve bronchopulmonary dysplasia and cognition when compared to a placebo?In term babies establishing breast-feeding on the post-natal ward; does the use of cup; syringe or spoon feeding increase the aspiration risk over bottles?In infants born to mothers with a history of maternal thyrotoxicosis; does inpatient observations for 48 hours with follow-up thyroid blood tests on day 5 lead to improved survival; cognition and adverse events when compared to routine postnatal care with detailed safety net advice?In babies receiving end of life care; does specialist neonatal music therapy improve quality of life; parental experience and bereavement support in comparison to standard end of life care?In unwell term infants admitted to the NICU; does the routine addition of anti-viral treatments improve survival and quality of life compared to standard treatment with antibiotics only?In neonates post-surgery does giving prophylactic antibiotics only if there is a left shift on the differential white blood cell count improve survival; sepsis and adverse events compared with no antibiotics?BMJ Publishing Group Limited (BMJ) disclaims all liability and responsibility arising from any reliance Supplemental material placed on this supplemental material which has been supplied by the author(s)In preterm babies does taking a bath on the neonatal unit prior to discharge increase the risk of respiratory infections or other adverse events; when compared with no bath?BMJ Publishing Group Limited (BMJ) disclaims all liability and responsibility arising from any reliance Supplemental material placed on this supplemental material which has been supplied by the author(s)