CClinicalTrials.gg
Sign In
CompletedNCT03278847Updated Sep 14, 2023Results posted

Optimising Newborn Nutrition During Therapeutic Hypothermia.

An observational study in Infant, Newborn, Asphyxia Neonatorum and Hypothermia, Induced, sponsored by Imperial College London. Completed at 2 sites in United Kingdom. Open to participants aged Up to 4 Days. Per ClinicalTrials.gov, last updated 2023-09-14.

Sponsored by Imperial College London · Observational

Study type
Observational
Model
Cohort
Time perspective
Retrospective
Enrollment
6,030
Ages
Up to 4 Days
Sex
All
01

Study summary

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.

Read the 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.

02

Conditions studied

  • Infant, Newborn
  • Asphyxia Neonatorum
  • Hypothermia, Induced
  • Parenteral Nutrition
  • Infant Nutrition
  • Necrotizing Enterocolitis
  • Neonatal Sepsis

Keywords

  • NNRD
  • matching
  • propensity score
03

Who can participate

Ages eligible
Up to 4 Days
Sexes eligible
All
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.

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

Exclusion Criteria:

  1. Infants with missing data for principal background and outcome variables.
04

Study design

Observational model
Cohort
Time perspective
Retrospective
Enrollment
6,030 participants (actual)
Patient registry
No

Groups and cohorts

  • Enteral nutrition comparison

    This comparison refers to differences in enteral nutrition during therapeutic hypothermia

    Dietary Supplement: Received enteral (milk) feeds during therapeutic hypothermia · Dietary Supplement: Enteral (milk) feeds withheld during therapeutic hypothermia

  • Parenteral nutrition comparison

    This comparison refers to differences in parenteral nutrition during therapeutic hypothermia

    Dietary Supplement: Received parenteral nutrition during therapeutic hypothermia · Dietary Supplement: Did not receive parenteral nutrition during therapeutic hypothermia

Interventions

  • Dietary supplementReceived 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 supplementEnteral (milk) feeds withheld during therapeutic hypothermia

    Withholding enteral feeds (keeping a baby nil per os) for the duration of hypothermia.

  • Dietary supplementReceived 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 supplementDid not receive parenteral nutrition during therapeutic hypothermia

    Received standard intravenous fluids (10% dextrose with additional electrolytes added where required) for the duration of hypothermia.

05

What researchers measure

Primary outcomes

  1. Necrotising Enterocolitis - for the Enteral Nutrition Comparison

    Defined according to the case definition of Battersby et al., 2017, JAMA Pediatrics

    Time frame: From date of birth until date of final neonatal unit discharge, assessed up to 1 year

  2. 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

    Time frame: From date of birth until date of final neonatal unit discharge, assessed up to 1 year

Secondary outcomes

  1. Survival

    Survival at neonatal unit discharge

    Time frame: From date of birth until date of final neonatal unit discharge, assessed up to 1 year

  2. Length of Stay

    Number of days between first neonatal unit admission and final neonatal unit discharge for surviving infants

    Time frame: From date of birth until date of final neonatal unit discharge, assessed up to 1 year

  3. Breastfeeding

    Any breastfeeding (suckling at the breast) at discharge

    Time frame: At the point of final discharge from neonatal care, assessed up to 1 year

  4. Hypoglycaemia

    Any diagnosis of hypoglycaemia recorded after therapeutic hypothermia is commenced and before the final neonatal unit discharge

    Time frame: From date of birth until date of final neonatal unit discharge, assessed up to 1 year

  5. Duration of Central Venous Line

    The number of days until an infant is recorded as not having a central venous line

    Time frame: From date of birth until date of final neonatal unit discharge, assessed up to 1 year

  6. 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)

    Time frame: From date of birth until date of final neonatal unit discharge, assessed up to 1 year

06

Results

Posted Sep 14, 2023

Participant flow

Participant flow — Overall Study
MilestoneReceived Enteral (Milk) Feeds During Therapeutic HypothermiaEnteral (Milk) Feeds Withheld During Therapeutic HypothermiaReceived Parenteral Nutrition During Therapeutic Hypothermia:Did Not Receive Parenteral Nutrition During Therapeutic Hypothermia
Started1618161812401240
Completed1618161812401240
Not completed0000

Outcome measures

PrimaryNecrotising Enterocolitis - for the Enteral Nutrition Comparison

Defined according to the case definition of Battersby et al., 2017, JAMA Pediatrics

Time frame:
From date of birth until date of final neonatal unit discharge, assessed up to 1 year
Reported as:
Count of participants · Participants
Necrotising Enterocolitis - for the Enteral Nutrition Comparison
ParticipantsReceived Enteral (Milk) Feeds During Therapeutic HypothermiaEnteral (Milk) Feeds Withheld During Therapeutic HypothermiaReceived Parenteral Nutrition During Therapeutic Hypothermia:Did Not Receive Parenteral Nutrition During Therapeutic Hypothermia
Necrotising Enterocolitis - for the Enteral Nutrition ComparisonNANANA7
PrimaryBlood 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

Time frame:
From date of birth until date of final neonatal unit discharge, assessed up to 1 year
Reported as:
Count of participants · Participants
Blood Stream Infection - for the Parenteral Nutrition Comparison
ParticipantsReceived Enteral (Milk) Feeds During Therapeutic HypothermiaEnteral (Milk) Feeds Withheld During Therapeutic HypothermiaReceived Parenteral Nutrition During Therapeutic Hypothermia:Did Not Receive Parenteral Nutrition During Therapeutic Hypothermia
Blood Stream Infection - for the Parenteral Nutrition ComparisonNA811NA
SecondarySurvival

Survival at neonatal unit discharge

Time frame:
From date of birth until date of final neonatal unit discharge, assessed up to 1 year
Reported as:
Count of participants · Participants
Survival
ParticipantsReceived Enteral (Milk) Feeds During Therapeutic HypothermiaEnteral (Milk) Feeds Withheld During Therapeutic HypothermiaReceived Parenteral Nutrition During Therapeutic Hypothermia:Did Not Receive Parenteral Nutrition During Therapeutic Hypothermia
Survival1552146511541116
SecondaryLength of Stay

Number of days between first neonatal unit admission and final neonatal unit discharge for surviving infants

Time frame:
From date of birth until date of final neonatal unit discharge, assessed up to 1 year
Reported as:
Mean · Days
Length of Stay
DaysReceived Enteral (Milk) Feeds During Therapeutic HypothermiaEnteral (Milk) Feeds Withheld During Therapeutic HypothermiaReceived Parenteral Nutrition During Therapeutic Hypothermia:Did Not Receive Parenteral Nutrition During Therapeutic Hypothermia
Length of Stay12.7 (12.0 to 13.3)14.8 (14.2 to 15.5)15.0 (14.1 to 15.8)14.1 (13.6 to 14.7)
SecondaryBreastfeeding

Any breastfeeding (suckling at the breast) at discharge

Time frame:
At the point of final discharge from neonatal care, assessed up to 1 year
Reported as:
Count of participants · Participants
Breastfeeding
ParticipantsReceived Enteral (Milk) Feeds During Therapeutic HypothermiaEnteral (Milk) Feeds Withheld During Therapeutic HypothermiaReceived Parenteral Nutrition During Therapeutic Hypothermia:Did Not Receive Parenteral Nutrition During Therapeutic Hypothermia
Breastfeeding883752575582
SecondaryHypoglycaemia

Any diagnosis of hypoglycaemia recorded after therapeutic hypothermia is commenced and before the final neonatal unit discharge

Time frame:
From date of birth until date of final neonatal unit discharge, assessed up to 1 year
Reported as:
Count of participants · Participants
Hypoglycaemia
ParticipantsReceived Enteral (Milk) Feeds During Therapeutic HypothermiaEnteral (Milk) Feeds Withheld During Therapeutic HypothermiaReceived Parenteral Nutrition During Therapeutic Hypothermia:Did Not Receive Parenteral Nutrition During Therapeutic Hypothermia
Hypoglycaemia293269212235
SecondaryDuration of Central Venous Line

The number of days until an infant is recorded as not having a central venous line

Time frame:
From date of birth until date of final neonatal unit discharge, assessed up to 1 year
Reported as:
Mean · Days
Duration of Central Venous Line
DaysReceived Enteral (Milk) Feeds During Therapeutic HypothermiaEnteral (Milk) Feeds Withheld During Therapeutic HypothermiaReceived Parenteral Nutrition During Therapeutic Hypothermia:Did Not Receive Parenteral Nutrition During Therapeutic Hypothermia
Duration of Central Venous Line4.3 (4.1 to 4.5)5.5 (5.3 to 5.7)6 (5.7 to 6.3)5.1 (5 to 5.3)
SecondaryGrowth

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)

Time frame:
From date of birth until date of final neonatal unit discharge, assessed up to 1 year
Reported as:
Mean · Standard deviation score
Growth
Standard deviation scoreReceived Enteral (Milk) Feeds During Therapeutic HypothermiaEnteral (Milk) Feeds Withheld During Therapeutic HypothermiaReceived Parenteral Nutrition During Therapeutic Hypothermia:Did Not Receive Parenteral Nutrition During Therapeutic Hypothermia
Growth-0.54 (-0.59 to -0.48)-0.6 (-0.65 to -0.55)-0.65 (-0.71 to -0.58)-0.66 (-0.71 to -0.61)

Adverse events

Collected over Until end of neonatal unit stay. Non-serious events are listed at a 0% frequency threshold.

Adverse event summary by group
GroupDeathsSeriousOther
Received Enteral (Milk) Feeds During Therapeutic Hypothermia66/1,618 (4.1%)0/1,618 (0%)0/1,618 (0%)
Enteral (Milk) Feeds Withheld During Therapeutic Hypothermia153/1,618 (9.5%)0/1,618 (0%)0/1,618 (0%)
Received Parenteral Nutrition During Therapeutic Hypothermia:86/1,240 (6.9%)0/1,240 (0%)0/1,240 (0%)
Did Not Receive Parenteral Nutrition During Therapeutic Hypothermia124/1,240 (10%)0/1,240 (0%)0/1,240 (0%)

Baseline characteristics

Age, Customized
Age, Customized(Weeks)Received Enteral (Milk) Feeds During Therapeutic HypothermiaEnteral (Milk) Feeds Withheld During Therapeutic HypothermiaReceived Parenteral Nutrition During Therapeutic Hypothermia:Did Not Receive Parenteral Nutrition During Therapeutic HypothermiaTotal
Enteral feeding39.5 ± 1.539.5 ± 1.5——39.5 ± 1.5
Parenteral feeding——39.4 ± 1.639.4 ± 1.639.4 ± 1.6
Sex: Female, Male
Sex: Female, Male(Participants)Received Enteral (Milk) Feeds During Therapeutic HypothermiaEnteral (Milk) Feeds Withheld During Therapeutic HypothermiaReceived Parenteral Nutrition During Therapeutic Hypothermia:Did Not Receive Parenteral Nutrition During Therapeutic HypothermiaTotal
Enteral feeding — Female715715001430
Enteral feeding — Male903903001806
Parenteral nutrition — Female005765881164
Parenteral nutrition — Male006646521316
Race/Ethnicity, Customized
Race/Ethnicity, Customized(Participants)Received Enteral (Milk) Feeds During Therapeutic HypothermiaEnteral (Milk) Feeds Withheld During Therapeutic HypothermiaReceived Parenteral Nutrition During Therapeutic Hypothermia:Did Not Receive Parenteral Nutrition During Therapeutic HypothermiaTotal
Enteral feeding - White10401041——2081
Enteral feeding - Asian or mixed Asian169174——343
Enteral feeding - Black or mixed black African10399——202
Enteral feeding - Other and missing306304——610
Parenteral nutrition - White——99110021993
Parenteral nutrition - Asian or Mixed Asian——9398191
Parenteral nutrition - Black or mixed black African——6253115
Parenteral nutrition - Other and missing——9486180
Region of Enrollment
Region of Enrollment(participants)Received Enteral (Milk) Feeds During Therapeutic HypothermiaEnteral (Milk) Feeds Withheld During Therapeutic HypothermiaReceived Parenteral Nutrition During Therapeutic Hypothermia:Did Not Receive Parenteral Nutrition During Therapeutic HypothermiaTotal
United Kingdom16181618——3236
Region of Enrollment
Region of Enrollment(participants)Received Enteral (Milk) Feeds During Therapeutic HypothermiaEnteral (Milk) Feeds Withheld During Therapeutic HypothermiaReceived Parenteral Nutrition During Therapeutic Hypothermia:Did Not Receive Parenteral Nutrition During Therapeutic HypothermiaTotal
United Kingdom00124012402480
Cord pH <6.9
Cord pH <6.9(Participants)Received Enteral (Milk) Feeds During Therapeutic HypothermiaEnteral (Milk) Feeds Withheld During Therapeutic HypothermiaReceived Parenteral Nutrition During Therapeutic Hypothermia:Did Not Receive Parenteral Nutrition During Therapeutic HypothermiaTotal
Enteral feeding368368——736
Parenteral nutrition——280280560
Apgar score 0 or 1 at 5 minutes
Apgar score 0 or 1 at 5 minutes(Participants)Received Enteral (Milk) Feeds During Therapeutic HypothermiaEnteral (Milk) Feeds Withheld During Therapeutic HypothermiaReceived Parenteral Nutrition During Therapeutic Hypothermia:Did Not Receive Parenteral Nutrition During Therapeutic HypothermiaTotal
Enteral feeding678720——1398
Parenteral nutrition——5625531115
Treatment with inotropes on day of admission
Treatment with inotropes on day of admission(Participants)Received Enteral (Milk) Feeds During Therapeutic HypothermiaEnteral (Milk) Feeds Withheld During Therapeutic HypothermiaReceived Parenteral Nutrition During Therapeutic Hypothermia:Did Not Receive Parenteral Nutrition During Therapeutic HypothermiaTotal
Enteral feeding288295——583
Parenteral nutrition——287295582
07

Study locations

2 sites
  • Chelsea and Westminster Hospital and NHS Foundation Trust
    London, SW10 9NH, United Kingdom
  • Imperial College London, Chelsea and Westminster Hospital campus
    London, SW10 9NH, United Kingdom
08

References and documents

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. PubMed 30355795 ↗
  • 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. PubMed 33952628 ↗
  • 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. PubMed 33891879 ↗
  • 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. PubMed 34096500 ↗

Study documents

  • Protocol and statistical analysis plan · Dec 15, 2017

Documents are hosted by the registry — open the source record to download them.

Individual participant data

Plan to share: Yes — 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.

Supporting information: Study protocol, Csr

09

Registry details

Key details

Study ID
NCT03278847
Lead sponsor
Imperial College London
Collaborators
University of Nottingham, Bliss Charity
Responsible party
Sponsor
First posted
Sep 12, 2017
Start date
Jan 1, 2010
Primary completion
Dec 31, 2017
Completion
Jan 1, 2021
Results posted
Sep 14, 2023
Last update
Sep 14, 2023

Study contacts

Chris Gale, MBBS, PhD
principal investigator · Imperial College London

Oversight

Data monitoring committee
No
FDA-regulated drug
No
FDA-regulated device
No
View the source record on ClinicalTrials.gov ↗

Not currently enrolling

This study is completed, as verified in Nov 2022. You cannot join it, but the record below documents what was studied.

Follow this study

Get an email when the registry record changes — status, dates, results — or when someone posts here.

Sign in to follow

Discussion

Questions and observations about this study, from anyone following it. Not medical advice, and not a channel to the study team — their contact details are on the registry record.

Sign in to join the discussion. Reading takes no account; posting does. You choose a display name, and a pseudonym is the default.

Nothing here yet. If you are running this trial, taking part in it, or weighing whether to, this is the place to say so.

Other studies in this condition

Neonatal Sepsis→

Other studies from this sponsor

Imperial College London

Start the discussion