A mixed-methods study to investigate feasibility and acceptability of an early warning score for preterm infants in neonatal units in Kenya: results of the NEWS-K study : Neonatal early warning scores in Kenya.

Preterm birth (< 37 weeks gestation) complications are the leading cause of neonatal mortality. Early-warning scores (EWS) are charts where vital signs (e.g., temperature, heart rate, respiratory rate) are recorded, triggering action. To evaluate whether a neonatal EWS improves clinical outcomes in low-middle income countries, a randomised trial is needed. Determining whether the use of a neonatal EWS is feasible and acceptable in newborn units, is a prerequisite to conducting a trial. We implemented a neonatal EWS in three newborn units in Kenya. Staff were asked to record infants' vital signs on the EWS during the study, triggering additional interventions as per existing local guidelines. No other aspects of care were altered. Feasibility criteria were pre-specified. We also interviewed health professionals (n = 28) and parents/family members (n = 42) to hear their opinions of the EWS. Data were collected on 465 preterm and/or low birthweight (< 2.5 kg) infants. In addition to qualitative study participants, 45 health professionals in participating hospitals also completed an online survey to share their views on the EWS. 94% of infants had the EWS completed at least once during their newborn unit admission. EWS completion was highest on the day of admission (93%). Completion rates were similar across shifts. 15% of vital signs triggered escalation to a more senior member of staff. Health professionals reported liking the EWS, though recognised the biggest barrier to implementation was poor staffing. Newborn unit infant to staff ratios varied between 10 and 53 staff per 1 infant, depending upon time of shift and staff type. A randomised trial of neonatal EWS in Kenya is possible and acceptable, though adaptations are required to the form before implementation.

Impact of NICE clinical guidelines for prevention and treatment of neonatal infections on antibiotic use in very preterm infants in England and Wales: an interrupted time series analysis.

OBJECTIVE: To assess the impact of publication of UK National Institute for Health and Care Excellence (NICE) guidelines on the prevention and treatment of early-onset infections (EOIs) in neonates (clinical guideline 149 (CG149), published in 2012, and its 2021 update (NG195) on antibiotic use in very preterm infants. DESIGN: Interrupted time series analysis using data from the National Neonatal Research Database. SETTING: Neonatal units in England and Wales. PARTICIPANTS: Infants born at 22-31 weeks' gestation from 1 January 2010 to 31 December 2022 and survived to discharge. INTERVENTIONS: Publication of CG149 (August 2012) and NG195 (April 2021). MAIN OUTCOME MEASURES: Measures of antibiotic use, aggregated by month of birth: antibiotic use rate (AUR), the proportion of care days in receipt of at least one antibiotic; percentage of infants who received ≥1 day of antibiotics on days 1-3 for EOI and after day 3 for late-onset infection (LOI); percentage who received ≥1 prolonged antibiotic course ≥5 days for EOI and LOI. RESULTS: 96% of infants received an antibiotic during inpatient stay. AUR declined at publication of CG149, without further impact at NG195 publication. There was no impact of CG149 on the underlying trend in infants receiving ≥1 day antibiotics for EOI or LOI, but post-NG195 the monthly trend began to decline for EOI (-0.20%, -0.26 to -0.14) and LOI (-0.23%, -0.33 to -0.12). Use of prolonged antibiotic courses for EOI and LOI declined at publication of CG149 and for LOI this trend accelerated post-NG195. CONCLUSIONS: Publications of NICE guidance were associated with reductions in antibiotic use; however neonatal antibiotic exposure remains extremely high.

Association between opioid use during mechanical ventilation in preterm infants and evidence of brain injury: a propensity score-matched cohort study.

Background: Preterm infants often require mechanical ventilation (MV), which can be a painful experience. Opioids (such as morphine) are used to provide analgesia, despite conflicting evidence about their impact on the developing brain. We aimed to quantify the use of opioids during MV in infants born at <32 weeks' gestational age and to investigate the association between opioid use and evidence of brain injury. Methods: In this retrospective propensity score-matched cohort study, we used routinely recorded data from the National Neonatal Research Database to study infants born at 22-31 weeks gestational age who were admitted to neonatal units in England and Wales (between Jan 1, 2012, and Dec 31, 2020) and who were mechanically ventilated on one or more days during their hospital stay. We used propensity score matching to identify pairs of infants (one who received opioids during MV and one who did not) with similar demographic and clinical characteristics. The pre-specified primary outcome was preterm brain injury assessed in all infants who received MV for more than two days and had evidence of preterm brain injury at or before discharge from neonatal care. Adjusted analyses accounted for differences in infants' characteristics, including illness severity and painful/surgical conditions. Findings: Of 67,206 infants included, 45,193 (67%) were mechanically ventilated for one or more days and 26,201 (58% of 45,193) received an opioid whilst ventilated. Opioids were given for a median of 67% of ventilated days (IQR 43-92%) and the median exposure was 4 days (2-11). The percentage of mechanically ventilated infants who received opioids while ventilated increased from 52% in 2012 to 60% in 2020 (morphine, 51%-56%; fentanyl, 6%-18%). In the propensity score-matched cohort of 3608 pairs who were ventilated for >2 consecutive days, the odds of any preterm brain injury (adjusted odds ratio 1.22, 95% CI 1.10-1.35) were higher in those who received opioids compared with those who did not (received opioids, 990/3608 (27.4%) vs. did not receive opioids, 855/3608 (23.7%). The adjusted odds of these adverse outcomes increased with increasing number of days of opioid exposure. Interpretation: Use of opioids during mechanical ventilation of preterm infants increased during the study period (2012-2020). Although causation cannot be determined, among those ventilated for >2 consecutive days, these data suggest that opioid use is associated with an increased risk of preterm brain injury and the risk increases with longer durations of exposure. Funding: University of Nottingham Impact Fund.

Breast feeding in infants diagnosed with phenylketonuria (PKU): a scoping review.

BACKGROUND: Phenylketonuria (PKU) is the most common inherited disease of amino acid metabolism, characterised by elevated levels of phenylalanine (Phe). There is a lack of infant feeding guidance for those with PKU. From birth to 6 months of age, breast feeding is the optimal nutrition for an infant and continuing breast feeding for infants with PKU is recommended by European guidelines. However, human breast milk contains Phe in varying quantities, and therefore, the effects breast feeding might have on infants with PKU needs careful consideration. AIM: To assess the effects of breast feeding (exclusive or partial) compared with low-Phe formula feeding in infants diagnosed with PKU, on blood Phe levels, growth and neurodevelopmental scores. METHODS: The Cochrane Inborn Errors of Metabolism Trials Register, MEDLINE and Embase were searched (date of latest search: 9 August 2022). Studies were included if they looked at the effects of breast feeding in infants diagnosed with PKU compared with formula feeding. Predetermined outcomes included blood Phe levels, growth in the first 2 years of life and neurodevelopmental scores. RESULTS: Seven observational studies (282 participants) met the inclusion criteria. All studies compared continuation of breast feeding with low-Phe formula versus formula feeding only. While most studies concluded that there was no difference in mean serum Phe levels in their follow-up period, two reported that breastfed infants were more likely to have a normal mean Phe level. Two studies described no difference in mean weight gain after birth, while one found that breastfed infants were more likely to have higher mean weight gain. Two studies commented that breastfed infants achieved higher developmental scores in childhood as compared with formula fed infants. CONCLUSION: Although there are no randomised trials, observational evidence suggests that continuation of breast feeding and supplementation with low-Phe formula is safe and may be beneficial for infants diagnosed with PKU.

How frequent is routine use of probiotics in UK neonatal units?

OBJECTIVE: There is a lack of UK guidance regarding routine use of probiotics in preterm infants to prevent necrotising enterocolitis, late-onset sepsis and death. As practices can vary, we aimed to determine the current usage of probiotics within neonatal units in the UK. DESIGN AND SETTING: Using NeoTRIPS, a trainee-led neonatal research network, an online survey was disseminated to neonatal units of all service levels within England, Scotland, Northern Ireland and Wales in 2022. Trainees were requested to complete one survey per unit regarding routine probiotic administration. RESULTS: 161 of 188 (86%) neonatal units responded to the survey. 70 of 161 (44%) respondents routinely give probiotics to preterm infants. 45 of 70 (64%) use the probiotic product Lactobacillus acidophilus NCFM/Bifidobacterium bifidum Bb-06/B. infantis Bi-26 (Labinic™). 57 of 70 (81%) start probiotics in infants ≤32 weeks' gestation. 33 of 70 (47%) had microbiology departments that were aware of the use of probiotics and 64 of 70 (91%) had a guideline available. Commencing enteral feeds was a prerequisite to starting probiotics in 62 of 70 (89%) units. The majority would stop probiotics if enteral feeds were withheld (59 of 70; 84%) or if the infant was being treated for necrotising enterocolitis (69 of 70; 99%). 24 of 91 (26%) units that did not use probiotics at the time of the survey were planning to introduce them within the next 12 months. CONCLUSIONS: More than 40% of all UK neonatal units that responded are now routinely administering probiotics, with variability in the product used. With increased probiotic usage in recent years, there is a need to establish whether this translates to improved clinical outcomes.

Parents and healthcare professionals' attitudes to Kangaroo Care for preterm infants in the United Kingdom.

AIM: To explore the attitudes of parents and healthcare professionals (HCPs), and facilitators and barrier to implementation of Kangaroo Care (KC) in the United Kingdom. METHODS: Online cross-sectional survey; distributed via the British Association of Perinatal Medicine, Bliss (UK-based charity), social media. RESULTS: Sixty HCPs responded. 37 (62%) were nurses/nurse practitioners. 57 (95%) regularly implement KC. The most important factor that supported KC implementation was the team's belief in benefits of KC. Increased workload, staff shortage and fear about safely of KC in unwell infants were recognised as the challenges preventing implementation. Five hundred eighteen parents responded. 421 (81%) had a preterm baby within 3 years. 338 (80%) were familiar with KC. The main facilitator was the belief that their baby enjoyed it. Excess noise and crowding on the unit were the most frequently reported barriers. Lack of opportunity and limited staff support were the main reasons why they had been unable to practice KC. CONCLUSION: We found that most HCPs and parents believe that KC is beneficial and would like to practice it. Lack of resources to enable effective implementation is the main barrier. Service development and implementation research is required to ensure that KC is delivered in all UK neonatal units.

Assessing and investigating children with suspected bone and abdominal tumours: an e-Delphi consensus process.

BACKGROUND: The incidence of childhood cancer has risen by 15% since the 1990s. Early diagnosis is key to optimising outcomes, however diagnostic delays are widely reported. Presenting symptoms are often non-specific causing a diagnostic dilemma for clinicians. This Delphi consensus process was conducted to develop a new clinical guideline for children and young people presenting with signs/symptoms suggestive of a bone or abdominal tumour. METHODS: Invitation emails were sent to primary and secondary healthcare professionals to join the Delphi panel. 65 statements were derived from evidence review by a multidisciplinary team. Participants were asked to rank their level of agreement with each statement on a 9-point Likert scale (1=strongly disagree, 9=strongly agree), with responses ≥7 taken to indicate agreement. Statements not reaching consensus were rewritten and reissued in a subsequent round. RESULTS: All statements achieved consensus after two rounds. 96/133 (72%) participants responded to round 1 (R1) and 69/96 (72%) completed round 2 (R2). 62/65 (94%) statements achieved consensus in R1 with 29/65 (47%) gaining more than 90% consensus. Three statements did not reach consensus scoring between 61% and 69%. All reached numerical consensus at the end of R2. Strong consensus was reached on best practice of conducting the consultation, acknowledging parental instinct and obtaining telephone advice from a paediatrician to decide the timing and place of review, rather than adult cancer urgent referral pathways. Dissensus in statements was due to unachievable targets within primary care and valid concerns over a potential overinvestigation of abdominal pain. CONCLUSIONS: This consensus process has consolidated statements that will be included in a new clinical guideline for suspected bone and abdominal tumours for use in both primary and secondary care. This evidence base will be translated into awareness tools for the public as part of the Child Cancer Smart national awareness campaign.

Observational cohort study of use of caffeine in preterm infants and association between early caffeine use and neonatal outcomes.

OBJECTIVE: To quantify trends in caffeine use in infants born at <32 weeks' gestational age (GA), and to investigate the effects of early vs late caffeine on neonatal outcomes. STUDY DESIGN: Retrospective propensity score matched cohort study using routinely recorded data from the National Neonatal Research Database of infants born at <32 weeks' GA admitted to neonatal units in England and Wales (2012-2020). RESULTS: 89% (58 913/66 081) of infants received caffeine. In 70%, caffeine was started early (on the day of birth or the day after), increasing from 55% in 2012 to 83% in 2020. Caffeine was given for a median (IQR) of 28 (17-43) days starting on day 2 (1-3) and continued up to 34 (33-34) weeks postmenstrual age.In the propensity score matched cohort of 13 045 pairs of infants, the odds of preterm brain injury (early caffeine, 2306/13 045 (17.7%) vs late caffeine, 2528/13 045 (19.4%), OR=0.89 (95% CI 0.84 to 0.95)) and bronchopulmonary dysplasia (BPD) (early caffeine, 4020/13 045 (32.8%) vs late caffeine, 4694/13 045 (37.7%), OR=0.81 (95% CI 0.76 to 0.85)) were lower in the group that received early caffeine compared with those who received it later. CONCLUSIONS: Early use of caffeine has increased in England and Wales. This is associated with reduced risks of BPD and preterm brain injury. Randomised trials are needed to find the optimal timing of caffeine use and the groups of infants who will benefit most from early administration of caffeine.

Implementing two-stage consent pathway in neonatal trials.

Perinatal trials sometimes require rapid recruitment processes to facilitate inclusion of participants when interventions are time-critical. A two-stage consent pathway has been used in some trials and is supported by national guidance. This pathway includes seeking oral assent for participation during the time-critical period followed by informed written consent later. This approach is being used in the fluids exclusively enteral from day one (FEED1) trial where participants need to be randomised within 3 hours of birth. There is some apprehension about approaching parents for participation via the oral assent pathway. The main reasons for this are consistent with previous research: lack of a written record, lack of standardised information and unfamiliarity with the process. Here, we describe how the pathway has been implemented in the FEED1 trial and the steps the trial team have taken to support sites. We provide recommendations for future trials to consider if they are considering implementing a similar pathway. Trial registration number: ISRCTN89654042.

Sedation and analgesia from prolonged pain and stress during mechanical ventilation in preterm infants: is dexmedetomidine an alternative to current practice?

Mechanical ventilation is an uncomfortable and potentially painful intervention. Opioids, such as morphine and fentanyl, are used for analgesia and sedation but there is uncertainty whether they reduce pain in mechanically ventilated infants. Moreover, there may be short-term and long-term adverse consequences such as respiratory depression leading to prolonged mechanical ventilation and detrimental long-term neurodevelopmental effects. Despite this, opioids are widely used, possibly due to a lack of alternatives.Dexmedetomidine, a highly selective alpha-2-adrenergic agonist with analgesic and sedative effects, currently approved for adults, has come into use in newborn infants. It provides analgesia and simulates natural sleep with maintenance of spontaneous breathing and upper airway tone. Although data on pharmacokinetics-pharmacodynamics in preterm infants are scant, observational studies report that using dexmedetomidine in conjunction with opioids/benzodiazepines or on its own can reduce the cumulative exposure to opioids/benzodiazepines. As it does not cause respiratory depression, dexmedetomidine could enable quicker weaning and extubation. Dexmedetomidine has also been suggested as an adjunct to therapeutic hypothermia in hypoxic ischaemic encephalopathy and others have used it during painful procedures and surgery. Dexmedetomidine infusion can cause bradycardia and hypotension although most report clinically insignificant effects.The increasing number of publications of observational studies and clinical use demonstrates that dexmedetomidine is being used in newborn infants but data on safety and efficacy are scant and not of high quality. Importantly, there are no data on long-term neurodevelopmental impact on preterm or term-born infants. The acceptance of dexmedetomidine in routine clinical practice must be preceded by clinical evidence. We need adequately powered and well-designed randomised controlled trials investigating whether dexmedetomidine alone or with opioids/benzodiazepines in infants on mechanical ventilation reduces the need for opioids/benzodiazepine and improves neurodevelopment at 24 months and later as compared with the use of opioids/benzodiazepines alone.

Management of patent ductus arteriosus in very preterm infants in England and Wales: a retrospective cohort study.

OBJECTIVE: To describe the diagnosis and treatment of patent ductus arteriosus (PDA) in infants born at <32 weeks' gestational age (GA) in England and Wales between 2010 and 2017. STUDY DESIGN: Retrospective cohort study using routinely recorded data from the National Neonatal Research Database of infants born at <32 weeks admitted to neonatal units in England and Wales from 2010 to 2017. RESULTS: Among 58 108 infants born at <32 weeks' GA, 28.3% (n=16 440) had a PDA diagnosed clinically or with echocardiographic confirmation. Of these, 34.8% (n=5721; 9.8% of total <32 weeks' infants included) had PDA treatment including 7.6% (n=1255) with indomethacin, 23.5% (n=3857) with ibuprofen and 5.6% (n=916) with surgical closure. The highest incidence of PDA was among infants born at 24 and 25 weeks' GA (70.2% and 70.8%, respectively), decreasing to 6.1% among infants born at 31 weeks' GA. The percentage of infants with a PDA increased over the study period (25.5% in 2010 to 28.5% in 2017). The percentage of infants who received ibuprofen or indomethacin or had PDA surgery decreased from 41.3% in 2010 to 33.7% in 2017, with an increase in use of ibuprofen from 20.2% to 27.3% while use of indomethacin decreased from 20.0% to 8.8%. Surgical closure of PDA decreased from 9.1% to 3.0%. Indomethacin was used for median (IQR) 3 (2-5) days while ibuprofen was given for 3 (2-4) days, at a median of 8 and 10 days after birth, respectively; surgical treatment was used later at 33 (24-45) days after birth. CONCLUSIONS: Ibuprofen is the preferred drug and surgical interventions are becoming less frequent for PDA closure among very preterm infants in England and Wales. TRIAL REGISTRATION NUMBER: NCT03773289.

Impact of the coronavirus disease 2019 pandemic on breastfeeding during and at discharge from neonatal care: An observational cohort study.

Importance: During the coronavirus disease 2019 (COVID-19) lockdown, changes in the visiting rules in neonatal units might have affected the initiation and continuation of breastfeeding. Objective: To investigate the effects of the implementation of the COVID-19 lockdown in the UK on mother's own milk (MOM) feeding in hospital and at the time of discharge in two UK neonatal units. Methods: Retrospective cohort study using routinely recorded data from electronic patient records. Data were retrieved from two neonatal services in the UK East Midlands region. Adjusted logistic regression was used to compare the odds of MOM feeding before, and after the implementation of the UK lockdown. Results: Among 2073 infants, after adjusting for maternal and infant characteristics and underlying trends over time, there were no differences in the odds of infants receiving any MOM during admission; any MOM at discharge or exclusive MOM at discharge before and after the imposition of the lockdown. Infants with birthweight <1000 g were three times less likely to receive any MOM at discharge compared to those with birthweight >2500 g (adjusted odds ratio [OR] 0.33, 95% confidence interval [CI]: 0.22-0.50). Younger mothers were less likely, and Black British mothers more likely, to be feeding MOM to their infants at discharge, while women in the least deprived Index of Multiple Deprivation (IMD) quintiles were 2-4 times more likely to do so, compared to those in the most deprived IMD quintile (adjusted OR 2.78, 95% CI: 1.97-3.90). Interpretation: Despite the difficulties faced during COVID-19 pandemic-induced restrictions, infants in the participating neonatal units continued to receive MOM in similar proportions as before the pandemic.

Availability of active therapeutic hypothermia at birth for neonatal hypoxic ischaemic encephalopathy: a UK population study from 2011 to 2018.

OBJECTIVE: Therapeutic hypothermia (TH) commenced soon after birth for neonatal hypoxic ischaemic encephalopathy (HIE) improves survival and reduces neurodisability. Availability of active TH at the place of birth (Immediate-TH) in the UK is unknown. DESIGN: Population-based observational study. SETTING: UK maternity centres. PATIENTS: 5 975 056 births from 2011 to 2018. INTERVENTION METHODS: For each maternity centre, the year active Immediate-TH was available and the annual birth rates were established. Admission temperatures of infants with HIE transferred from non-tertiary centres with and without Immediate-TH were compared. MAIN OUTCOME MEASURES: Quantify the annual number of births with access to Immediate-TH. Secondary outcomes included temporal changes in Immediate-TH and admission temperatures for infants requiring transfer to tertiary centres. RESULTS: In UK maternity centres, 75 of 194 (38.7%) provided Immediate-TH in 2011 rising to 95 of 192 (49.5%, p=0.003) in 2018 with marked regional variations. In 2011, 394 842 (51.2%) of 771 176 births had no access to Immediate-TH compared with 276 258 (39.3%) of 702 794 births in 2018 (p<0.001). More infants with HIE arrived in the therapeutic temperature range (76.5% vs 67.3%; OR 1.58, 95% CI 1.25 to 2.0, p<0.001) with less overcooling (10.6% vs 14.3%; OR 0.71, 95% CI 0.51 to 0.98, p=0.036) from centres with Immediate-TH compared with those without. CONCLUSIONS: Availability of active Immediate-TH has slowly increased although many newborns still have no access and rely on transport team arrival to commence active TH. This is associated with delayed optimal hypothermic management. Provision of Immediate-TH across all units, with appropriate training and support, could improve care of infants with HIE.

The natural history of ataxia-telangiectasia (A-T): A systematic review.

BACKGROUND: Ataxia-telangiectasia is an autosomal recessive, multi-system, and life-shortening disease caused by mutations in the ataxia-telangiectasia mutated gene. Although widely reported, there are no studies that give a comprehensive picture of this intriguing condition. OBJECTIVES: Understand the natural history of ataxia-telangiectasia (A-T), as reported in scientific literature. SEARCH METHODS: 107 search terms were identified and divided into 17 searches. Each search was performed in PubMed, Ovid SP (MEDLINE) 1946-present, OVID EMBASE 1980 -present, Web of Science core collection, Elsevier Scopus, and Cochrane Library. SELECTION CRITERIA: All human studies that report any aspect of A-T. DATA COLLECTION AND ANALYSIS: Search results were de-duplicated, data extracted (including author, publication year, country of origin, study design, population, participant characteristics, and clinical features). Quality of case-control and cohort studies was assessed by the Newcastle-Ottawa tool. Findings are reported descriptively and where possible data collated to report median (interquartile range, range) of outcomes of interest. MAIN RESULTS: 1314 cases reported 2134 presenting symptoms. The most common presenting symptom was abnormal gait (1160 cases; 188 studies) followed by recurrent infections in classical ataxia-telangiectasia and movement disorders in variant ataxia-telangiectasia. 687 cases reported 752 causes of death among which malignancy was the most frequently reported cause. Median (IQR, range) age of death (n = 294) was 14 years 0 months (10 years 0 months to 23 years 3 months, 1 year 3 months to 76 years 0 months). CONCLUSIONS: This review demonstrates the multi-system involvement in A-T, confirms that neurological symptoms are the most frequent presenting features in classical A-T but variants have diverse manifestations. We found that most individuals with A-T have life limited to teenage or early adulthood. Predominance of case reports, and case series demonstrate the lack of robust evidence to determine the natural history of A-T. We recommend population-based studies to fill this evidence gap.

The Childhood Cancer Diagnosis (CCD) Study: a UK observational study to describe referral pathways and quantify diagnostic intervals in children and young people with cancer.

INTRODUCTION: Childhood cancer is diagnosed in 400 000 children and young people (CYP) aged 0-19 years worldwide annually. In the UK, a child's cumulative cancer risk increases from 1 in 4690 from birth to aged 1, to 1 in 470 by age 15. Once diagnosed, access to treatments offers survival to adulthood for over 80%. Tumour diagnoses are at a later stage and mortality is higher when compared with those in other parts of Europe. This means higher risk, more intensive therapies for a cure. Some CYPs are known to experience delays to diagnosis which may further contribute to poor outcomes. This study aims to understand the current pathway of childhood cancer referrals and diagnosis and quantify diagnostic intervals in the UK. METHODS AND ANALYSIS: This is a prospective multicentre observational study including all tertiary childhood cancer treatment centres in the UK. CYP (0-18 years) with a new diagnosis of cancer over the study period will be invited to participate. Data will be collected at initial diagnosis and 5 years after diagnosis. Data will include demographic details, clinical symptoms, tumour location, stage and clinical risk group. In addition, key diagnostic dates and referral routes will be collected to calculate the diagnostic intervals. At 5 years' follow-up, data will be collected on refractory disease, relapse and 1-year and 5-year survival. Population characteristics will be presented with descriptive analyses with further analyses stratified by age, geographical region and cancer type. Associations between diagnostic intervals/delay and risk factors will be explored using multiple regression and logistic regression. ETHICS: The study has favourable opinion from the York and Humber, Leeds West REC (19/YH/0416). DISSEMINATION: Results will be presented at academic conferences, published in peer-reviewed journals and disseminated through public messaging in collaboration with our charity partners through a national awareness campaign (ChildCancerSmart). STUDY REGISTRATION: researchregistry.com (researchregistry5313).

The FEED1 trial: protocol for a randomised controlled trial of full milk feeds versus intravenous fluids with gradual feeding for preterm infants (30-33 weeks gestational age).

BACKGROUND: In the UK, approximately 8% of live births are preterm (before 37 weeks gestation), more than 90% of whom are born between 30 and 36 weeks, forming the largest proportion of a neonatal units' workload. Neonatologists are cautious in initiating full milk feeds for preterm infants due to fears of necrotising enterocolitis (NEC). There is now evidence to dispute this fear. Small studies have shown that feeding preterm infants full milk feeds enterally from birth could result in a shorter length of hospital stay, which is important to parents, clinicians and NHS services without increasing the risk of NEC. This trial aims to investigate whether full milk feeds initiated in the first 24 h after birth reduces the length of hospital stay in comparison to introduction of gradual milk feeding with IV fluids or parenteral nutrition. METHODS: FEED1 is a multi-centre, open, parallel group, randomised, controlled superiority trial of full milk feeds initiated on the day of birth versus gradual milk feeds for infants born at 30+0 to 32+6 (inclusive) weeks gestation. Recruitment will take place in around 40 UK neonatal units. Mothers will be randomised 1:1 to full milk feeds, starting at 60 ml/kg day, or gradual feeds, as per usual local practice. Mother's expressed breast milk will always be the first choice of milk, though will likely be supplemented with formula or donor breast milk in the first few days. Feeding data will be collected until full milk feeds are achieved (≥ 140 ml/kg/day for 3 consecutive days). The primary outcome is length of infant hospital stay. Additional data will be collected 6 weeks post-discharge. Follow-up at 2 years (corrected gestational age) is planned. The sample size is 2088 infants to detect a between group difference in length of stay of 2 days. Accounting for multiple births, this requires 1700 women to be recruited. Primary analysis will compare the length of hospital stay between groups, adjusting for minimisation variables and accounting for multiple births. DISCUSSION: This trial will provide high-quality evidence on feeding practices for preterm infants. Full milk feeds from day of birth could result in infants being discharged sooner. TRIAL REGISTRATION: ISRCTN ISRCTN89654042 . Prospectively registered on 23 September 2019: ISRCTN is a primary registry of the WHO ICTRP network, and all items from the WHO Trial Registration dataset are included.

Drug utilisation in neonatal units in England and Wales: a national cohort study.

PURPOSE: To describe drug utilisation patterns in neonatal units. METHODS: Retrospective observational cohort study using data held in the National Neonatal Research Database (NNRD) for neonatal units in England and Wales including infants born at 23 to 44 weeks' gestational age (GA) from 01 January 2010 to 31 December 2017. RESULTS: The cohort included 17,501 (3%) extremely preterm infants; 40,607 (7%) very preterm infants; 193,536 (31%) moderate-to-late preterm infants; and 371,606 (59%) term infants. The number of unique drugs received by an infant (median (IQR)) increased with decreasing GA: 17 (11-24) in extremely preterm, 7 (5-11) in very preterm, 3 (0-4) in moderate-to-late preterm, and 3 (0-3) in term infants. The two most frequently prescribed drugs were benzylpenicillin and gentamicin in all GA groups, and caffeine in extremely preterm. Other frequently used drugs among preterm infants were electrolytes, diuretics and anti-reflux medications. Among infants <32 weeks' GA, the largest increase in use was for surfactant (given on the neonatal unit), caffeine and probiotics, while domperidone and ranitidine had the largest decline. CONCLUSION: Antibiotics, for all GAs and caffeine, among preterm infants, are the most frequently used drugs in neonatal medicine. Preterm infants are exposed to a high burden of drugs, particularly antibiotics. Changing patterns in use reflect the emergence of evidence in some areas but several non-evidence-based drugs continue to be used widely. Improvements are needed to ensure rational drug use on neonatal units. REGISTRATION: ClinicalTrials.gov (NCT03773289). Date of registration 21 Dec 2018.

Anti-reflux medication use in preterm infants.

BACKGROUND: Current recommendations do not support the use of anti-reflux medications to treat gastro-oesophageal reflux disease (GORD) among preterm infants. OBJECTIVE: To describe the prevalence of GORD and the use of anti-reflux medications amongst very preterm infants (<32 weeks' gestational age (GA)) in neonatal units in England and Wales. DESIGN: Retrospective cohort study using the National Neonatal Research Database. RESULTS: Among 58,108 infants [median GA (IQR) 29 (27-30) weeks], 15.8% (n = 9191) had a diagnosis of GORD and 36.9% (n = 12,446) received anti-reflux medications. Those who received anti-reflux medications were more preterm [GA, median (IQR): medications, 28 (26-30) vs. no medications, 30 (28-31); p < 0.001] and had lower birth weight [mean (SD): medications, 1124 g (354) vs. no medications, 1265 g (384); p < 0.001]. Most (57%, n = 12,224) received Gaviscon, or Histamine-2 Receptor Antagonist (H2RA) (56%, n = 11,959). Over time, prokinetic use has declined substantially, the use of H2RAs and Gaviscon has reduced although they continue to be used frequently, whilst the use of PPIs has increased. CONCLUSIONS: Anti-reflux medications are frequently prescribed in very preterm infants, despite evidence to suggest that they are not effective and may be harmful. Clear guidelines for diagnosing GORD and the use of anti-reflux medications are required to rationalise the pharmacological management of GORD in preterm infants. IMPACT: Anti-reflux medications are frequently prescribed, often without a diagnosis of gastro-oesophageal reflux disease, to very preterm infants while in the neonatal unit and at discharge. Half of the infants born at <28 weeks' gestational age receive anti-reflux medications in hospital and a quarter are discharged home on them. Although the use of prokinetics declined following alerts of adverse events, histamine2-receptor antagonists and alginates such as Gaviscon continue to be used and the use of proton-pump inhibitors has increased more than 2-fold.