Outcomes following the adoption of standard parenteral nutrition in preterm infants: a whole-population non-concurrent control study.

OBJECTIVE: To evaluate the impact of a quality improvement project of the adoption of standard parenteral nutrition (SPN) in preterm infants. DESIGN: Retrospective, multicentre, whole-population, non-concurrent control study using data from the UK National Neonatal Research Database between 1 January 2014 and 31 December 2020. SETTING: Neonatal units in London UK organised by geographical network. PATIENTS: Preterm infants <31 weeks' gestation. INTERVENTIONS: Introduction of two SPN formulations previously tested in randomised controlled trials (NEON and SCAMP). SCAMP delivers a higher target macronutrient intake. MAIN OUTCOME MEASURES: The primary outcome was survival to discharge from neonatal care without major morbidities. Secondary outcomes included the individual components of the primary outcome and a comparison of outcomes between the NEON and the SCAMP formulations. RESULTS: Of 6538 eligible infants, 4693 were admitted to neonatal care before and 1845 after the adoption of SPN. Morbidity-free survival decreased by an average of 8.6% (95% CI 5.8% to 11.4%, p<0.0001) following adoption. The effect varied by type of formulation; the cohort that adopted NEON showed no difference in morbidity-free survival, whereas the cohort that adopted SCAMP showed a statistically significant decrease in morbidity-free survival. Overall survival decreased by an average of 2.0% (95% CI 0.01% to 4.0%, p=0.048). CONCLUSIONS: Research is urgently needed to identify the optimal composition of parenteral nutrition for preterm babies. This study also adds to the growing body of evidence that suggests that early and high intakes of macronutrients in preterm babies may be harmful.

Two-year neurodevelopmental data for preterm infants born over an 11-year period in England and Wales, 2008-2018: a retrospective study using the National Neonatal Research Database.

OBJECTIVE: United Kingdom guidelines recommend all infants born <30 weeks' gestation receive neurodevelopmental follow-up at 2 years corrected age. In this study, we describe completeness and results of 2-year neurodevelopmental records in the National Neonatal Research Database (NNRD). DESIGN: This retrospective cohort study uses data from the NNRD, which holds data on all neonatal admissions in England and Wales, including 2year follow-up status. PATIENTS: We included all preterm infants born <30 weeks' gestation between 1 January 2008 and 31 December 2018 in England and Wales, who survived to discharge from neonatal care. MAIN OUTCOME MEASURES: Presence of a 2-year neurodevelopmental assessment record in the NNRD, use of standardised assessment tools, results of functional 2-year neurodevelopmental assessments (visual, auditory, neuromotor, communication, overall development). RESULTS: Of the 41 505 infants included, 24 125 (58%) had a 2-year neurodevelopmental assessment recorded. This improved over time, from 32% to 71% for births in 2008 and 2018, respectively.Of those with available data: 0.4% were blind; 1% had a hearing impairment not correctable with aids; 13% had <5 meaningful words, vocalisations or signs; 8% could not walk without assistance and 9% had severe (≥12 months) developmental delay. CONCLUSIONS: The proportion of infants admitted to neonatal units in England and Wales with a 2-year neurodevelopmental record has improved over time. Rates of follow-up data from recent years are comparable to those of bespoke observational studies. With continual improvement in data completeness, the potential for use of NNRD as a source of longer-term outcome data can be realised.

Preterm Formula, Fortified or Unfortified Human Milk for Very Preterm Infants, the PREMFOOD Study: A Parallel Randomised Feasibility Trial.

OBJECTIVE: Uncertainty exists regarding optimal supplemental diet for very preterm infants if the mother's own milk (MM) is insufficient. We evaluated feasibility for a randomised controlled trial (RCT) powered to detect important differences in health outcomes. METHODS: In this open, parallel, feasibility trial, we randomised infants 25+0-31+6 weeks of gestation by opt-out consent to one of three diets: unfortified human milk (UHM) (unfortified MM and/or unfortified pasteurised human donor milk (DM) supplement), fortified human milk (FHM) (fortified MM and/or fortified DM supplement), and unfortified MM and/or preterm formula (PTF) supplement from birth to 35+0 weeks post menstrual age. Feasibility outcomes included opt-outs, adherence rates, and slow growth safety criteria. We also obtained anthropometry, and magnetic resonance imaging body composition data at term and term plus 6 weeks (opt-in consent). RESULTS: Of 35 infants randomised to UHM, 34 to FHM, and 34 to PTF groups, 21, 19, and 24 infants completed imaging at term, respectively. Study entry opt-out rate was 38%; 6% of parents subsequently withdrew from feeding intervention. Two infants met predefined slow weight gain thresholds. There were no significant between-group differences in term total adipose tissue volume (mean [SD]: UHM: 0.870 L [0.35 L]; FHM: 0.889 L [0.31 L]; PTF: 0.809 L [0.25 L], p = 0.66), nor in any other body composition measure or anthropometry at either timepoint. CONCLUSIONS: Randomisation to UHM, FHM, and PTF diets by opt-out consent was acceptable to parents and clinical teams, associated with safe growth profiles and no significant differences in body composition. Our data provide justification to proceed to a larger RCT.

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.

Effect of an Exclusive Human Milk Diet on the Gut Microbiome in Preterm Infants: A Randomized Clinical Trial.

Importance: The effect of using an exclusive human milk diet compared with one that uses bovine products in preterm infants is uncertain, but some studies demonstrate lower rates of key neonatal morbidities. A potential mediating pathway is the gut microbiome. Objective: To determine the effect of an exclusive human milk diet on gut bacterial richness, diversity, and proportions of specific taxa in preterm infants from enrollment to 34 weeks' postmenstrual age. Design, Setting, and Participants: In this randomized clinical trial conducted at 4 neonatal intensive care units in the United Kingdom from 2017 to 2020, microbiome analyses were blind to group. Infants less than 30 weeks' gestation who had only received own mother's milk were recruited before 72 hours of age. Statistical analysis was performed from July 2019 to September 2021. Interventions: Exclusive human milk diet using pasteurized human milk for any shortfall in mother's own milk supply and human milk-derived fortifiers (intervention) compared with bovine formula and bovine-derived fortifier (control) until 34 weeks' postmenstrual age. Fortifier commenced less than 48 hours of tolerating 150 mL/kg per day. Main Outcomes and Measures: Gut microbiome profile including alpha and beta diversity, and presence of specific bacterial taxa. Results: Of 126 preterm infants enrolled in the study, 63 were randomized to control (median [IQR] gestation: 27.0 weeks [26.0-28.1 weeks]; median [IQR] birthweight: 910 g [704-1054 g]; 32 [51%] male) and 63 were randomized to intervention (median [IQR] gestation: 27.1 weeks [25.7-28.1 weeks]; median [IQR] birthweight: 930 g [733-1095 g]; 38 [60%] male); 472 stool samples from 116 infants were analyzed. There were no differences in bacterial richness or Shannon diversity over time, or at 34 weeks between trial groups. The exclusive human milk diet group had reduced relative abundance of Lactobacillus after adjustment for confounders (coefficient estimate, 0.056; P = .03), but not after false discovery rate adjustment. There were no differences in time to full feeds, necrotizing enterocolitis, or other key neonatal morbidities. Conclusions and Relevance: In this randomized clinical trial in preterm infants using human milk-derived formula and/or fortifier to enable an exclusive human milk diet, there were no effects on overall measures of gut bacterial diversity but there were effects on specific bacterial taxa previously associated with human milk receipt. These findings suggest that the clinical impact of human milk-derived products is not modulated via microbiomic mechanisms. Trial Registration: ISRCTN trial registry identifier: ISRCTN16799022.

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.

Use of parenteral nutrition in the first postnatal week in England and Wales: an observational study using real-world data.

BACKGROUND: Parenteral nutrition (PN) is used to provide supplemental support to neonates while enteral feeding is being established. PN is a high-cost intervention with beneficial and harmful effects. Internationally, there is substantial variation in how PN is used, and there are limited contemporary data describing use across Great Britain. OBJECTIVE: To describe PN use in the first postnatal week in infants born and admitted to neonatal care in England, Scotland and Wales. METHOD: Data describing neonates admitted to National Health Service neonatal units between 1 January 2012 and 31 December 2017, extracted from routinely recorded data held the National Neonatal Research Database (NNRD); the denominator was live births, from Office for National Statistics. RESULTS: Over the study period 62 145 neonates were given PN in the first postnatal week (1.4% of all live births); use was higher in more preterm neonates (76% of livebirths at <28 weeks, 0.2% of term livebirths) and in neonates with lower birth weight. 15% (9181/62145) of neonates given PN in the first postnatal week were born at term. There was geographic variation in PN administration: the proportion of live births given PN within neonatal regional networks ranged from 1.0% (95% CIs 1.0 to 1.0) to 2.8% (95% CI 2.7 to 2.9). CONCLUSIONS AND RELEVANCE: Significant variation exists in neonatal PN use; it is unlikely this reflects optimal use of an expensive intervention. Research is needed to identify which babies will benefit most and which are at risk of harm from early PN. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov: NCT03767634; registration date: 6 December 2018.

More than words: Parent, Patient and Public Involvement perspectives on language used by clinical researchers in neonatal care.

In this qualitative study exploring parent views of information about research studies, we found they accepted uncertainty as justification, and that three key aspects of language - words, tone, and pace - influence parents' decision about their baby's inclusion. We recommend parents are routinely involved in developing information materials.

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.

Nutrition for the micro preemie: Beyond milk.

Nutritional support is a fundamental component of the care of the extremely preterm infant, including the "micro preemie" (here defined as a baby born weighing less than 500 g), but goes beyond considerations of milk as a food. This is because milk from an infant's own mother, unlike currently available substitutes, additionally provides invaluable non-nutritive benefits. Nutritional support requires suitable devices or techniques to administer nutrients enterally or intravenously, products shown to be safe in preterm populations, and efficacy demonstrated in respect of important functional outcomes. Sadly, preterm feeding remains characterised by a deficit of evidence. In this chapter, we will briefly describe the history of preterm nutrition, discuss current enteral and parenteral practice, important evidence gaps, a summary of approaches for evaluating nutritional practice, and key considerations for future endeavour. Our discussion refers to all extremely preterm infants and it not confined to the micro preemie.

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.

Changes in neonatal admissions, care processes and outcomes in England and Wales during the COVID-19 pandemic: a whole population cohort study.

OBJECTIVES: The COVID-19 pandemic instigated multiple societal and healthcare interventions with potential to affect perinatal practice. We evaluated population-level changes in preterm and full-term admissions to neonatal units, care processes and outcomes. DESIGN: Observational cohort study using the UK National Neonatal Research Database. SETTING: England and Wales. PARTICIPANTS: Admissions to National Health Service neonatal units from 2012 to 2020. MAIN OUTCOME MEASURES: Admissions by gestational age, ethnicity and Index of Multiple Deprivation, and key care processes and outcomes. METHODS: We calculated differences in numbers and rates between April and June 2020 (spring), the first 3 months of national lockdown (COVID-19 period), and December 2019-February 2020 (winter), prior to introduction of mitigation measures, and compared them with the corresponding differences in the previous 7 years. We considered the COVID-19 period highly unusual if the spring-winter difference was smaller or larger than all previous corresponding differences, and calculated the level of confidence in this conclusion. RESULTS: Marked fluctuations occurred in all measures over the 8 years with several highly unusual changes during the COVID-19 period. Total admissions fell, having risen over all previous years (COVID-19 difference: -1492; previous 7-year difference range: +100, +1617; p<0.001); full-term black admissions rose (+66; -64, +35; p<0.001) whereas Asian (-137; -14, +101; p<0.001) and white (-319; -235, +643: p<0.001) admissions fell. Transfers to higher and lower designation neonatal units increased (+129; -4, +88; p<0.001) and decreased (-47; -25, +12; p<0.001), respectively. Total preterm admissions decreased (-350; -26, +479; p<0.001). The fall in extremely preterm admissions was most marked in the two lowest socioeconomic quintiles. CONCLUSIONS: Our findings indicate substantial changes occurred in care pathways and clinical thresholds, with disproportionate effects on black ethnic groups, during the immediate COVID-19 period, and raise the intriguing possibility that non-healthcare interventions may reduce extremely preterm births.

Better preterm parenteral nutrition practice.

At birth preterm babies are unable to tolerate sufficient enteral nutrition to support growth and development. Parenteral nutrition provides a means to bridge the transition from placental transfer of nutrients to the establishment of enteral feeds. Despite preterm babies being one of the highest users of parenteral nutrition amongst all patient groups and that it has been in use in preterm infants for several decades, the evidence base for its use remains weak. There are several areas of uncertainty in practice, including the optimal and relative intakes of macronutrients and the optimal timing of initiation of parenteral nutrition after birth. High quality randomised controlled trials powered to detect differences in long term functional outcomes are needed to determine best practice in preterm parenteral nutrition practice.