Data-driven approach to understanding neonatal palliative care needs in England and Wales: a population-based study 2015-2020.

OBJECTIVE: To quantify admissions to neonatal units in England and Wales with potential need for palliative care. DESIGN, SETTING AND PATIENTS: Diagnoses and clinical attributes indicating a high likelihood of requiring palliative care were mapped to categories within the British Association of Perinatal Medicine's (BAPM) framework on palliative care. We extracted data from the National Neonatal Research Database on all babies born and admitted to neonatal units in England and Wales 2015-2020. OUTCOMES: The number and proportion of babies meeting BAPM categories, their discharge outcomes and the characteristics of babies who died during neonatal care but did not fulfil any BAPM category. RESULTS: 12 123/574 954 (2.1%) babies met one or more BAPM category: 6239/12 123 (51%) conformed to BAPM category 4 (postnatal conditions with high risk of severe impairment), 3796 (31%) to category 2 (antenatal/postnatal diagnosis with high risk of significant morbidity or death), 1399 (12%) to category 3 (born at margin of viability) and 288 (2%) to category 1 (antenatal/postnatal diagnosis not compatible with long-term survival); 401 babies (3%) met criteria for multiple categories. 6814/12 123 (56%) were discharged home, 2385 (20%) were discharged to other settings and 2914 (24%) died before neonatal discharge. 3000/5914 (51%) babies who died during neonatal care did not conform to any BAPM category. Of these, 2630/3000 (88%) were born preterm. CONCLUSIONS: At least 2% of babies admitted to neonatal units had palliative care needs according to existing BAPM categories; most survived to discharge. Of deaths, 51% were not captured by the BAPM categories; most were extremely preterm.

Postnatal corticosteroid use for prevention or treatment of bronchopulmonary dysplasia in England and Wales 2012-2019: a retrospective population cohort study.

OBJECTIVE: Describe the population of babies who do and do not receive postnatal corticosteroids for prevention or treatment of bronchopulmonary dysplasia (BPD). DESIGN: Retrospective cohort study using data held in the National Neonatal Research Database. SETTING: National Health Service neonatal units in England and Wales. PATIENTS: Babies born less than 32 weeks gestation and admitted to neonatal units from 1 January 2012 to 31 December 2019. MAIN OUTCOMES: Proportion of babies given postnatal corticosteroid; type of corticosteroid; age at initiation and duration, trends over time. SECONDARY OUTCOMES: Survival to discharge, treatment for retinopathy of prematurity, BPD, brain injury, severe necrotising enterocolitis, gastrointestinal perforation. RESULTS: 8% (4713/62019) of babies born <32 weeks and 26% (3525/13527) born <27 weeks received postnatal corticosteroids for BPD. Dexamethasone was predominantly used 5.3% (3309/62019), followed by late hydrocortisone 1.5%, inhaled budesonide 1.5%. prednisolone 0.8%, early hydrocortisone 0.3% and methylprednisolone 0.05%. Dexamethasone use increased over time (2012: 4.5 vs 2019: 5.8%, p=0.04). Median postnatal age of initiation of corticosteroid course was around 3 weeks for late hydrocortisone, 4 weeks for dexamethasone, 6 weeks for inhaled budesonide, 12 weeks for prednisolone and 16 weeks for methylprednisolone. Babies who received postnatal corticosteroids were born more prematurely, had a higher incidence of comorbidities and a longer length of stay. CONCLUSIONS: In England and Wales, around 1 in 12 babies born less than 32 weeks and 1 in 4 born less than 27 weeks receive postnatal corticosteroids to prevent or treat BPD. Given the lack of convincing evidence of efficacy, challenges of recruiting to and length of time taken to conduct randomised controlled trial, our data highlight the need to monitor long-term outcomes in children who received neonatal postnatal corticosteroids.

Early antibiotic use and incidence of necrotising enterocolitis in very preterm infants: a protocol for a UK based observational study using routinely recorded data.

INTRODUCTION: Necrotising enterocolitis (NEC) remains a major contributor to preterm mortality and morbidity. Prolonged duration of antibiotic therapy after delivery is associated with later NEC development but recent evidence suggests that absence of antibiotic treatment after delivery may also increase NEC risk. We will explore this controversy using a large pre-existing dataset of preterm infants in the UK. METHODS AND ANALYSIS: This is a retrospective cohort study using data from UK National Neonatal Research Database (NNRD) for infants born 1 January 2012 to 31 December 2020. Eligible infants will be <32 weeks gestation, alive on day 3. Primary outcome is development of severe NEC, compared in infants receiving early antibiotics (days 1-2 after birth) and those not. Subgroup analysis on duration of early antibiotic exposure will also occur. Secondary outcomes are: late onset sepsis, total antibiotic use, predischarge mortality, retinopathy of prematurity, intraventricular haemorrhage, bronchopulmonary dysplasia, focal intestinal perforation and any abdominal surgery. To address competing risks, incidence of death before day 7, 14 and 28 will be analysed. We will perform logistic regression and propensity score matched analyses. Statistical analyses will be guided by NEC risk factors, exposures and outcome presented in a causal diagram. These covariates include but are not limited to gestational age, birth weight, small for gestational age, sex, ethnicity, delivery mode, delivery without labour, Apgar score, early feeding and probiotic use. Sensitivity analyses of alternate NEC definitions, specific antibiotics and time of initiation will occur. ETHICS AND DISSEMINATION: We will use deidentified data from NNRD, which holds permissions for the original data, from which parents can opt out and seek study-specific research ethics approval. The results will help to determine optimal use of early antibiotics for very preterm infants. IMPLICATIONS: This data will help optimise early antibiotic use in preterm infants. TRIAL REGISTRATION NUMBER: ISRCTN55101779.

Randomised controlled trial of human derived breast milk fortifier versus bovine milk fortifier on body composition in very preterm babies.

BACKGROUND: Preterm infants receiving a diet of exclusive human milk compared to predominantly preterm formula have lower weight and non-adipose tissue mass by term. Human milk fortification is recommended. However, it is not known if the protein source affects body composition. AIMS: To compare the effect of an exclusive human milk based diet (intervention) with a diet containing cow milk products (control) on body composition. PARTICIPANTS: Infants born below 30 weeks gestation. STUDY DESIGN: Randomised multicentre, open label, controlled trial. Infants preferentially received their own mother's milk. Infants were randomised to either an exclusive human milk diet (human milk formula to make up a shortfall in own mother's milk and human milk derived fortifier) or cow milk-based supplementation (preterm formula to make up a shortfall in own mother's milk and cow milk-based fortifier). Fortification began at an enteral intake of 150 ml/kg/day. Infants underwent whole-body magnetic resonance imaging at term. PRIMARY OUTCOME: Body composition (adipose tissue (ATM) and non-adipose tissue mass (N-ATM)) at term. RESULTS: We randomly assigned 38 infants to intervention (n = 19) and control arms (n = 19). Primary outcomes were analysed in 15 infants in the intervention arm and 12 in the control arm. The estimates of the effect of the intervention following adjustment for length and sex, were non-significant (ATM (kg): 0.137, 95 % confidence interval (CI) -0.01, 0.29; N-ATM: -0.137; -0.01, 0.29). CONCLUSIONS: We identified no clinically relevant differences in body composition in preterm babies <30 weeks gestation receiving a macronutrient-equivalent exclusive human milk diet compared with a diet containing cow milk products.

Outcomes in relation to early parenteral nutrition use in preterm neonates born between 30 and 33 weeks' gestation: a propensity score matched observational study.

OBJECTIVE: To evaluate whether in preterm neonates parenteral nutrition use in the first 7 postnatal days, compared with no parenteral nutrition use, is associated with differences in survival and other important morbidities. Randomised trials in critically ill older children show that harms, such as nosocomial infection, outweigh benefits of early parenteral nutrition administration; there is a paucity of similar data in neonates. DESIGN: Retrospective cohort study using propensity matching including 35 maternal, infant and organisational factors to minimise bias and confounding. SETTING: National, population-level clinical data obtained for all National Health Service neonatal units in England and Wales. PATIENTS: Preterm neonates born between 30+0 and 32+6 weeks+days. INTERVENTIONS: The exposure was parenteral nutrition administered in the first 7 days of postnatal life; the comparator was no parenteral nutrition. MAIN OUTCOME MEASURES: The primary outcome was survival to discharge from neonatal care. Secondary outcomes comprised the neonatal core outcome set. RESULTS: 16 292 neonates were compared in propensity score matched analyses. Compared with matched neonates not given parenteral nutrition in the first postnatal week, neonates who received parenteral nutrition had higher survival at discharge (absolute rate increase 0.91%; 95% CI 0.53% to 1.30%), but higher rates of necrotising enterocolitis (absolute rate increase 4.6%), bronchopulmonary dysplasia (absolute rate increase 3.9%), late-onset sepsis (absolute rate increase 1.5%) and need for surgical procedures (absolute rate increase 0.92%). CONCLUSIONS: In neonates born between 30+0 and 32+6 weeks' gestation, those given parenteral nutrition in the first postnatal week had a higher rate of survival but higher rates of important neonatal morbidities. Clinician equipoise in this area should be resolved by prospective randomised trials. TRIAL REGISTRATION NUMBER: NCT03767634.

Early versus later initiation of parenteral nutrition for very preterm infants: a propensity score-matched observational study.

OBJECTIVE: To evaluate the impact of timing of initiation of parenteral nutrition (PN) after birth in very preterm infants. DESIGN: Propensity-matched analysis of data from the UK National Neonatal Research Database. PATIENTS: 65 033 babies <31 weeks gestation admitted to neonatal units in England and Wales between 2008 and 2019. INTERVENTIONS: PN initiated in the first 2 days (early) versus after the second postnatal day (late). Babies who died in the first 2 days without receiving PN were analysed as 'late'. MAIN OUTCOME MEASURES: The main outcome measure was morbidity-free survival to discharge. The secondary outcomes were survival to discharge, growth and other core neonatal outcomes. FINDINGS: No difference was found in the primary outcome (absolute rate difference (ARD) between early and late 0.50%, 95% CI -0.45 to 1.45, p=0.29). The early group had higher rates of survival to discharge (ARD 3.3%, 95% CI 2.7 to 3.8, p<0.001), late-onset sepsis (ARD 0.84%, 95% CI 0.48 to 1.2, p<0.001), bronchopulmonary dysplasia (ARD 1.24%, 95% CI 0.30 to 2.17, p=0.01), treated retinopathy of prematurity (ARD 0.50%, 95% CI 0.17 to 0.84, p<0.001), surgical procedures (ARD 0.80%, 95% CI 0.20 to 1.40, p=0.01) and greater drop in weight z-score between birth and discharge (absolute difference 0.019, 95% CI 0.003 to 0.035, p=0.02). Of 4.9% of babies who died in the first 2 days, 3.4% were in the late group and not exposed to PN. CONCLUSIONS: Residual confounding and survival bias cannot be excluded and justify the need for a randomised controlled trial powered to detect differences in important functional outcomes.

Outcomes following early parenteral nutrition use in preterm neonates: protocol for an observational study.

INTRODUCTION: Preterm babies are among the highest users of parenteral nutrition (PN) of any patient group, but there is wide variation in commencement, duration, and composition of PN and uncertainty around which groups will benefit from early introduction. Recent studies in critically unwell adults and children suggest that harms, specifically increased rates of nosocomial infection, outweigh the benefits of early administration of PN. In this study, we will describe early PN use in neonatal units in England, Wales and Scotland. We will also evaluate if this is associated with differences in important neonatal outcomes in neonates born between 30+0 and 32+6 weeks+days gestation. METHODS AND ANALYSIS: We will use routinely collected data from all neonatal units in England, Wales and Scotland, available in the National Neonatal Research Database (NNRD). We will describe clinical practice in relation to any use of PN during the first 7 postnatal days among neonates admitted to neonatal care between 1 January 2012 and 31 December 2017. We will compare outcomes in neonates born between 30+0 and 32+6 weeks+days gestation who did or did not receive PN in the first week after birth using a propensity score-matched approach. The primary outcome will be survival to discharge home. Secondary outcomes will include components of the neonatal core outcome set: outcomes identified as important by former patients, parents, clinicians and researchers. ETHICS AND DISSEMINATION: We have obtained UK National Research Ethics Committee approval for this study (Ref: 18/NI/0214). The results of this study will be presented at academic conferences; the UK charity Bliss will aid dissemination to former patients and parents. TRIAL REGISTRATION NUMBER: NCT03767634.

Body Composition following Necrotising Enterocolitis in Preterm Infants.

BACKGROUND: The optimal nutritional regimen for preterm infants, including those that develop necrotising enterocolitis (NEC), is unknown. OBJECTIVE: The objective here was to evaluate body composition at term in infants following NEC, in comparison with healthy infants. The primary outcome measure was non-adipose tissue mass (non-ATM). METHODS: We compared body composition assessed by magnetic resonance imaging at term in infants born <31 weeks of gestational age that participated in NEON, a trial comparing incremental versus immediate delivery of parenteral amino acids on non-ATM, and SMOF versus intralipid on intrahepatocellular lipid content. There were no differences in the primary outcomes. We compared infants that received surgery for NEC (NEC-surgical), infants with medically managed NEC (NEC-medical), and infants without NEC (reference). RESULTS: A total of 133 infants were included (8 NEC-surgical; 15 NEC-medical; 110 reference). In comparison with the reference group, infants in the NEC-surgical and NEC-medical groups were significantly lighter [adjusted mean difference (95% CI) NEC-surgical: -630 g (-1,010, -210), p = 0.003; NEC-medical: -440 g (-760, -110), p = 0.009] and the total adipose tissue volume (ATV) was significantly lower [NEC-surgical: -360 cm3 (-516, -204), p < 0.001; NEC-medical: -127 cm3 (-251, -4); p = 0.043]. There were no significant differences in non-ATM [adjusted mean difference (95% CI) NEC-surgical: -46 g (-281, 189), p = 0.70; NEC-medical: -122 g (-308, 63), p = 0.20]. CONCLUSION: The lower weight at term in preterm infants following surgically and medically managed NEC, in comparison to preterm infants that did not develop the disease, was secondary to a reduction in ATV. This suggests that the nutritional regimen received was adequate to preserve non-ATM but not to support the normal third-trimester deposition of adipose tissue in preterm infants.

Neonatal brain injuries in England: population-based incidence derived from routinely recorded clinical data held in the National Neonatal Research Database.

OBJECTIVE: In 2015, the Department of Health in England announced an ambition to reduce 'brain injuries occurring during or soon after birth'. We describe the development of a pragmatic case definition and present annual incidence rates. DESIGN: Retrospective cohort study using data held in the National Neonatal Research Database (NNRD) extracted from neonatal electronic patient records from all National Health Service (NHS) neonatal units in England, Wales and Scotland. In 2010-2011, population coverage in the NNRD was incomplete, hence rate estimates are presented as a range; from 2012, population coverage is complete, and rates (95% CIs) are presented. Rates are per 1000 live births. SETTING: NHS neonatal units in England. PATIENTS: Infants admitted for neonatal care; denominator: live births in England. MAIN OUTCOME MEASURE: 'Brain injuries occurring at or soon after birth' defined as infants with seizures, hypoxic-ischaemic encephalopathy, stroke, intracranial haemorrhage, central nervous system infection and kernicterus and preterm infants with cystic periventricular leucomalacia. RESULTS: In 2010, the lower estimate of the rate of 'Brain injuries occurring at or soon after birth' in England was 4.53 and the upper estimate was 5.19; in 2015, the rate was 5.14 (4.97, 5.32). For preterm infants, the population incidence in 2015 was 25.88 (24.51, 27.33) and 3.47 (3.33, 3.62) for term infants. Hypoxic-ischaemic encephalopathy was the largest contributor to term brain injury, and intraventricular/periventricular haemorrhage was the largest contributor to preterm brain injury. CONCLUSIONS: Annual incidence rates for brain injuries can be estimated from data held in the NNRD; rates for individual conditions are consistent with published rates. Routinely recorded clinical data can be used for national surveillance, offering efficiencies over traditional approaches.

GATA1-mutant clones are frequent and often unsuspected in babies with Down syndrome: identification of a population at risk of leukemia.

Transient abnormal myelopoiesis (TAM), a preleukemic disorder unique to neonates with Down syndrome (DS), may transform to childhood acute myeloid leukemia (ML-DS). Acquired GATA1 mutations are present in both TAM and ML-DS. Current definitions of TAM specify neither the percentage of blasts nor the role of GATA1 mutation analysis. To define TAM, we prospectively analyzed clinical findings, blood counts and smears, and GATA1 mutation status in 200 DS neonates. All DS neonates had multiple blood count and smear abnormalities. Surprisingly, 195 of 200 (97.5%) had circulating blasts. GATA1 mutations were detected by Sanger sequencing/denaturing high performance liquid chromatography (Ss/DHPLC) in 17 of 200 (8.5%), all with blasts >10%. Furthermore low-abundance GATA1 mutant clones were detected by targeted next-generation resequencing (NGS) in 18 of 88 (20.4%; sensitivity ∼0.3%) DS neonates without Ss/DHPLC-detectable GATA1 mutations. No clinical or hematologic features distinguished these 18 neonates. We suggest the term "silent TAM" for neonates with DS with GATA1 mutations detectable only by NGS. To identify all babies at risk of ML-DS, we suggest GATA1 mutation and blood count and smear analyses should be performed in DS neonates. Ss/DPHLC can be used for initial screening, but where GATA1 mutations are undetectable by Ss/DHPLC, NGS-based methods can identify neonates with small GATA1 mutant clones.