Title: Optimising newborn nutrition during therapeutic hypothermia: an observational study using routinely collected data
Funder: Department of Health and Social Care

Abstract: Purpose: To determine the optimal enteral and parenteral nutrition practices for babies who are undergoing therapeutic hypothermia. Background: Therapeutic hypothermia is the standard of care for babies with moderate to severe Hypoxic Ischaemic Encephalopathy (HIE) in the UK (approximately 1200 annually). The optimal nutrition for babies receiving therapeutic hypothermia in not known; because of this uncertainty there is wide variation in how both enteral and parenteral nutrition are provided to these babies. Research questions: This study will examine research questions about enteral and parenteral nutrition: ENTERAL: In babies treated for HIE (Patient), is withholding enteral feeding (i.e. no milk) during therapeutic hypothermia (Intervention) compared to enteral feeding (i.e. maternal or donor breast milk or formula) during therapeutic hypothermia (Comparator or Control) associated with lower rates of necrotising enterocolitis (Outcome). PARENTERAL: In babies treated for HIE (Patient), is provision of intravenous dextrose during therapeutic hypothermia (Intervention) compared to parenteral nutrition during therapeutic hypothermia (Comparator) associated with lower rates of blood stream infection (Outcome). Study design: Retrospective cohort study Patient group: Infants born at 36 gestational weeks or later who received therapeutic hypothermia for HIE for least 72 hours, or who died during therapeutic hypothermia. Primary outcomes: ENTERAL: Necrotising enterocolitis - United Kingdom Neonatal Collaborative (UKNC) case definition (Battersby et al., JAMA Pediatrics, 2017) PARENTERAL: Blood stream infection - isolation of a recognised pathogen from blood, National Neonatal Audit Programme (NNAP) definition Secondary outcomes: For both enteral and parenteral analyses: death, length of stay, onset of breastfeeding, breastfeeding at discharge, growth at discharge (weight for age standard deviation score) Geographic coverage: NHS neonatal units in England, Scotland and Wales (200 neonatal units) Time period: January 1st 2008-December 31st 2016 (9 years) Data source: The National Neonatal Research Database (NNRD) Data items: The Neonatal Data Set (NHS Data Standard) Statistical analysis: Potential outcomes framework with application of propensity scoring to define matched subgroups for comparison. Research team: The project will be jointly led by a senior statistician with over 25 years’ experience of using health data for causal analysis and with expertise in missing data, and a neonatal academic clinician with expertise in using routinely collected neonatal data. The wider co-applicant team includes neonatal clinicians and parents with lived experience of having a baby that required therapeutic hypothermia. Dissemination: Scientific publications in peer-reviewed journals and presentations, plain English summary prepared by parents for distribution through social media and in UK neonatal units.

Lay abstract: Every year about 1200 babies in England, Wales and Scotland suffer from a lack of oxygen around birth which can lead to long-term brain injury or death. This is called Hypoxic Ischaemic Encephalopathy (HIE). Research has shown that cooling babies with HIE by a few degrees for the first 3 days protects the brain; all babies with moderate or severe HIE in the UK are treated with therapeutic hypothermia (cooling). Doctors do not know how best to care for babies while they are cooled. A key question is “how to provide nutrition to babies during cooling”. There are two main parts to this question, milk feeds (“enteral” nutrition) and intravenous nutrition (“parenteral” nutrition). We don’t know how best to provide either milk or intravenous nutrition to cooled babies. - MILK FEEDS: Some neonatal units in the UK carefully feed babies (usually with maternal breast milk) while they are cooled. This avoids intravenous lines and is believed to help them feed and go home earlier. Other neonatal units do not feed cooled babies because they worry about a condition called necrotising enterocolitis (a devastating and often fatal disease) which might be more common with feeding. - INTRAVENOUS NUTRITION: All cooled babies need intravenous fluid (even when milk feeds are given it takes several days before enough fluid can be given this way). Some neonatal units give babies intravenous nutrition (which contains fat, protein, carbohydrate, vitamins and minerals) as this may improve growth and recovery. Other neonatal units only give intravenous dextrose with simple salts because of concerns that intravenous nutrition leads to more infections. This study will compare these different ways of providing nutrition. It will use a research database called the National Neonatal Research Database (NNRD). In England, Scotland and Wales doctors and nurses looking after babies in neonatal care (including all cooled babies) use an Electronic Health Record system. Data from this system are anonymised (no baby can be identified) and form the NNRD, so the NNRD holds data from all babies who have been looked after on NHS neonatal units. We have worked closely with parents and charities in developing the NNRD. We will use the NNRD to study all term babies who received cooling in England, Scotland and Wales since 2008. We will compare the milk feeding and intravenous nutrition they receive. - MILK FEEDING: We will compare babies who are fed milk while cooled with those that are not fed any milk. Our main goal is to establish whether there is any difference in rates of necrotising enterocolitis. - INTRAVENOUS NUTRITION: We will compare babies who get intravenous nutrition with those that only get intravenous dextrose. The main difference we are looking for is in the rate of infection. We will also study how many babies die, how long they stay in neonatal care, how soon breastfeeding starts and many are breastfed when they go home. We will apply a statistical approach called “potential outcomes framework” in which babies are matched in each group (e.g. babies who are fed and those who are not fed) as closely as possible. This will ensure that any difference in outcomes is due to the different nutritional treatments and not due to background differences or other confounders (like how sick a baby is). The results from this study will help to ensure that babies who need to be cooled for HIE receive the best and safest nutrition in the future.

Research activity codes: 2.4 SURVEILLANCE AND DISTRIBUTION;7.3 MANAGEMENT AND DECISION MAKING
Health categories: REPRODUCTIVE HEALTH AND CHILDBIRTH