Optimising Newborn Nutrition During Therapeutic Hypothermia.

Optimising Newborn Nutrition During Therapeutic Hypothermia: an Observational Study Using Routinely Collected Data

The overarching aim of this project is to determine the optimum enteral and parenteral nutrition strategy for newborns with Hypoxic Ischaemic Encephalopathy (HIE) during and after therapeutic hypothermia. To do this the investigators will perform two primary comparisons:

1. ENTERAL: to determine whether any enteral (milk) feeding, when compared to withholding enteral feeding (no milk), during therapeutic hypothermia, is associated with a difference in the incidence of necrotising enterocolitis.
2. PARENTERAL: to determine whether provision of intravenous dextrose, when compared to provision of parenteral nutrition, during therapeutic hypothermia, is associated with a difference in the incidence of blood stream infection.

The investigators will use de-identified data held in an established research database called the National Neonatal Research Database (NNRD) and we will use the potential outcomes framework with application of propensity scoring to define matched subgroups for comparison.

Study Overview

• Status: Completed
• Conditions: Necrotizing Enterocolitis; Asphyxia Neonatorum; Parenteral Nutrition; Neonatal Sepsis; Infant Nutrition; Infant, Newborn; Hypothermia, Induced
• Intervention / Treatment: Dietary supplement: Received enteral (milk) feeds during therapeutic hypothermia; Dietary supplement: Enteral (milk) feeds withheld during therapeutic hypothermia; Dietary supplement: Received parenteral nutrition during therapeutic hypothermia; Dietary supplement: Did not receive parenteral nutrition during therapeutic hypothermia

Detailed Description

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). Doctors 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.

The investigators have worked closely with parents and charities in developing the NNRD. The investigators will use the NNRD to study all term babies who received cooling in England, Scotland and Wales since 2008. The investigators will compare the milk feeding and intravenous nutrition they receive.

• MILK FEEDING: The investigators will compare babies who are fed milk while cooled with those that are not fed any milk. The investigator's main goal is to establish whether there is any difference in rates of necrotising enterocolitis.
• INTRAVENOUS NUTRITION: The investigators 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. The investigators 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.

The investigators 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.

• Study Type: Observational
• Enrollment (Actual): 6030

Contacts and Locations

• Study Contact: Name: Richard Colquhoun; Phone Number: 44(0)20 3315 5841; Email: ndau@imperial.ac.uk

Study Locations

• United Kingdom
  • London, United Kingdom, SW10 9NH
    • Chelsea and Westminster Hospital and NHS Foundation Trust
  • London, United Kingdom, SW10 9NH
    • Imperial College London, Chelsea and Westminster Hospital campus

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 1 year (Child)
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

Infants born at 36 gestational weeks or later who received therapeutic hypothermia for Hypoxic Ischaemic Encephalopathy (HIE) for least 72 hours, or who died during therapeutic hypothermia.

Description

Inclusion Criteria:

1. Received neonatal care at a unit that is part of the UK Neonatal Collaborative; this includes all NHS neonatal units in England, Scotland and Wales
2. Recorded gestational age at birth ≥36 weeks
3. Recorded as receiving therapeutic hypothermia for 72 hours or died during therapeutic hypothermia

Exclusion Criteria:

1. Infants with missing data for principal background and outcome variables.

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Retrospective

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Enteral nutrition comparison; This comparison refers to differences in enteral nutrition during therapeutic hypothermia	Dietary supplement: Received enteral (milk) feeds during therapeutic hypothermia; In the enteral component of nutrition, the health technology to be assessed is the gradual introduction of enteral (milk) feeds during therapeutic hypothermia: Included in this is any type of milk (e.g. expressed maternal breast milk, expressed donor breast milk and artificial formula); This health technology includes different routes of administering enteral feeds such as nasogastric tube (gavage feeding) and bottle; This health technology also includes different rates of increasing enteral feeds (for example by 15ml/kg/day, by 30ml/kg/day or faster); Dietary supplement: Enteral (milk) feeds withheld during therapeutic hypothermia; Withholding enteral feeds (keeping a baby nil per os) for the duration of hypothermia.
Parenteral nutrition comparison; This comparison refers to differences in parenteral nutrition during therapeutic hypothermia	Dietary supplement: Received parenteral nutrition during therapeutic hypothermia; In the parenteral component, the health technology being assessed is administration of parenteral nutrition during therapeutic hypothermia: Included in this are different compositions of parenteral nutrition (for example standard, pre-prepared bags of nutrition and individually tailored parenteral nutrition); This health technology includes different routes of administration of parenteral nutrition such as via a peripheral intravenous cannula, percutaneous central venous catheter ('long line') or umbilical venous catheter.; This health technology also includes different volumes of parenteral nutrition (e.g. 40ml/kg/day, 60ml/kg/day or greater).; Dietary supplement: Did not receive parenteral nutrition during therapeutic hypothermia; Received standard intravenous fluids (10% dextrose with additional electrolytes added where required) for the duration of hypothermia.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Necrotising Enterocolitis - for the Enteral Nutrition Comparison	Defined according to the case definition of Battersby et al., 2017, JAMA Pediatrics	From date of birth until date of final neonatal unit discharge, assessed up to 1 year
Blood Stream Infection - for the Parenteral Nutrition Comparison	defined according to the Healthcare Quality Improvement Partnership (HQIP) National Neonatal Audit Programme (NNAP) case definition: pure growth of a recognised pathogen from a normally sterile site	From date of birth until date of final neonatal unit discharge, assessed up to 1 year

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Breastfeeding	Any breastfeeding (suckling at the breast) at discharge	At the point of final discharge from neonatal care, assessed up to 1 year
Hypoglycaemia	Any diagnosis of hypoglycaemia recorded after therapeutic hypothermia is commenced and before the final neonatal unit discharge	From date of birth until date of final neonatal unit discharge, assessed up to 1 year
Survival	Survival at neonatal unit discharge	From date of birth until date of final neonatal unit discharge, assessed up to 1 year
Length of Stay	Number of days between first neonatal unit admission and final neonatal unit discharge for surviving infants	From date of birth until date of final neonatal unit discharge, assessed up to 1 year
Duration of Central Venous Line	The number of days until an infant is recorded as not having a central venous line	From date of birth until date of final neonatal unit discharge, assessed up to 1 year
Growth	Weight for post-menstrual age standard deviation score at final neonatal unit discharge. Standard deviation score, higher score means higher growth (higher weight for gestational age)	From date of birth until date of final neonatal unit discharge, assessed up to 1 year

Collaborators and Investigators

• Sponsor: Imperial College London
• Collaborators: University of Nottingham; Bliss the charity for babies born premature or sick
• Investigators: Principal Investigator: Chris Gale, MBBS, PhD, Imperial College London

Publications and helpful links

General Publications

• Battersby C, Longford N, Patel M, Selby E, Ojha S, Dorling J, Gale C. Study protocol: optimising newborn nutrition during and after neonatal therapeutic hypothermia in the United Kingdom: observational study of routinely collected data using propensity matching. BMJ Open. 2018 Oct 23;8(10):e026739. doi: 10.1136/bmjopen-2018-026739.
• Gale C, Jeyakumaran D, Longford N, Battersby C, Ojha S, Oughham K, Dorling J. Administration of parenteral nutrition during therapeutic hypothermia: a population level observational study using routinely collected data held in the National Neonatal Research Database. Arch Dis Child Fetal Neonatal Ed. 2021 Nov;106(6):608-613. doi: 10.1136/archdischild-2020-321299. Epub 2021 May 5.
• Gale C, Longford NT, Jeyakumaran D, Ougham K, Battersby C, Ojha S, Dorling J. Feeding during neonatal therapeutic hypothermia, assessed using routinely collected National Neonatal Research Database data: a retrospective, UK population-based cohort study. Lancet Child Adolesc Health. 2021 Jun;5(6):408-416. doi: 10.1016/S2352-4642(21)00026-2. Epub 2021 Apr 21.
• Gale C, Jeyakumaran D, Battersby C, Ougham K, Ojha S, Culshaw L, Selby E, Dorling J, Longford N. Nutritional management in newborn babies receiving therapeutic hypothermia: two retrospective observational studies using propensity score matching. Health Technol Assess. 2021 Jun;25(36):1-106. doi: 10.3310/hta25360.

Study record dates

Study Major Dates

• Study Start (Actual): January 1, 2010
• Primary Completion (Actual): December 31, 2017
• Study Completion (Actual): January 1, 2021

Study Registration Dates

• First Submitted: August 23, 2017
• First Submitted That Met QC Criteria: September 7, 2017
• First Posted (Actual): September 12, 2017

Study Record Updates

• Last Update Posted (Actual): September 14, 2023
• Last Update Submitted That Met QC Criteria: November 7, 2022
• Last Verified: November 1, 2022

More Information

Terms related to this study

• Keywords: NNRD; matching; propensity score
• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Infections; Systemic Inflammatory Response Syndrome; Inflammation; Wounds and Injuries; Gastrointestinal Diseases; Infant, Newborn, Diseases; Gastroenteritis; Intestinal Diseases; Sepsis; Death; Body Temperature Changes; Enterocolitis; Enterocolitis, Necrotizing; Hypothermia; Asphyxia; Asphyxia Neonatorum; Neonatal Sepsis
• Other Study ID Numbers: 17IC4064; 16/79/03 (Other Grant/Funding Number: National Institute for Health Research (NIHR) HTA); 17/EM/0307 (Other Identifier: United Kingdom Health Research Authority)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD Plan Description

All study data will be extracted from the National Neonatal Research Database (NNRD). The NNRD has been created through the collaborative efforts of neonatal services across the country to be a national resource. The NNRD is maintained and managed at the Neonatal Data Analysis Unit (NDAU) at Imperial College London and Chelsea and Westminster NHS Foundation Trust.

Researchers, clinicians, managers, commissioners, and others are welcome and encouraged to utilise the NNRD.

• IPD Sharing Time Frame: The NNRD holds data from 2007 to present.
• IPD Sharing Access Criteria: Access criteria and guidance is found at the URL below
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No