Asphyxia Neonatorum, Hypothermia, Induced, Infant, Newborn, Infant Nutrition, Necrotizing Enterocolitis, Neonatal Sepsis, Parenteral Nutrition
Conditions
Keywords
NNRD, matching, propensity score
Brief 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.
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.
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.
Sponsors
University of Nottingham
Bliss Charity
Imperial College London
Study design
Observational model
COHORT
Time perspective
RETROSPECTIVE
Eligibility
Sex/Gender
ALL
Age
No minimum to 4 Days
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Necrotising Enterocolitis - for the Enteral Nutrition Comparison | From date of birth until date of final neonatal unit discharge, assessed up to 1 year | Defined according to the case definition of Battersby et al., 2017, JAMA Pediatrics |
| Blood Stream Infection - for the Parenteral Nutrition Comparison | From date of birth until date of final neonatal unit discharge, assessed up to 1 year | 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 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Breastfeeding | At the point of final discharge from neonatal care, assessed up to 1 year | Any breastfeeding (suckling at the breast) at discharge |
| Hypoglycaemia | From date of birth until date of final neonatal unit discharge, assessed up to 1 year | Any diagnosis of hypoglycaemia recorded after therapeutic hypothermia is commenced and before the final neonatal unit discharge |
| Survival | From date of birth until date of final neonatal unit discharge, assessed up to 1 year | Survival at neonatal unit discharge |
| Growth | From date of birth until date of final neonatal unit discharge, assessed up to 1 year | 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) |
| Duration of Central Venous Line | From date of birth until date of final neonatal unit discharge, assessed up to 1 year | The number of days until an infant is recorded as not having a central venous line |
| Length of Stay | From date of birth until date of final neonatal unit discharge, assessed up to 1 year | Number of days between first neonatal unit admission and final neonatal unit discharge for surviving infants |
Countries
United Kingdom
Participant flow
Pre-assignment details
This was an observational study. 6030 babies were included in the overall study cohort and from this two pairs of matched groups were formed to examine the impact of enteral feeding during therapeutic hypothermia (two matched groups of 1618) and of parenteral nutrition during therapeutic hypothermia (two matched groups of 1240).
Participants by arm
| Arm | Count |
|---|---|
| Received Enteral (Milk) Feeds During Therapeutic Hypothermia 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) | 1,618 |
| Enteral (Milk) Feeds Withheld During Therapeutic Hypothermia Withholding enteral feeds (keeping a baby nil per os) for the duration of hypothermia. | 1,618 |
| Received Parenteral Nutrition During Therapeutic Hypothermia: 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). | 1,240 |
| 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. | 1,240 |
| Total | 5,716 |
Baseline characteristics
| Characteristic | Received Enteral (Milk) Feeds During Therapeutic Hypothermia | Enteral (Milk) Feeds Withheld During Therapeutic Hypothermia | Total | Received Parenteral Nutrition During Therapeutic Hypothermia: | Did Not Receive Parenteral Nutrition During Therapeutic Hypothermia |
|---|---|---|---|---|---|
| Age, Customized Enteral feeding | 39.5 Weeks STANDARD_DEVIATION 1.5 | 39.5 Weeks STANDARD_DEVIATION 1.5 | 39.5 Weeks STANDARD_DEVIATION 1.5 | — | — |
| Age, Customized Parenteral feeding | — | — | 39.4 Weeks STANDARD_DEVIATION 1.6 | 39.4 Weeks STANDARD_DEVIATION 1.6 | 39.4 Weeks STANDARD_DEVIATION 1.6 |
| Apgar score 0 or 1 at 5 minutes Enteral feeding | 678 Participants | 720 Participants | 1398 Participants | — | — |
| Apgar score 0 or 1 at 5 minutes Parenteral nutrition | — | — | 1115 Participants | 562 Participants | 553 Participants |
| Cord pH <6.9 Enteral feeding | 368 Participants | 368 Participants | 736 Participants | — | — |
| Cord pH <6.9 Parenteral nutrition | — | — | 560 Participants | 280 Participants | 280 Participants |
| Race/Ethnicity, Customized Enteral feeding - Asian or mixed Asian | 169 Participants | 174 Participants | 343 Participants | — | — |
| Race/Ethnicity, Customized Enteral feeding - Black or mixed black African | 103 Participants | 99 Participants | 202 Participants | — | — |
| Race/Ethnicity, Customized Enteral feeding - Other and missing | 306 Participants | 304 Participants | 610 Participants | — | — |
| Race/Ethnicity, Customized Enteral feeding - White | 1040 Participants | 1041 Participants | 2081 Participants | — | — |
| Race/Ethnicity, Customized Parenteral nutrition - Asian or Mixed Asian | — | — | 191 Participants | 93 Participants | 98 Participants |
| Race/Ethnicity, Customized Parenteral nutrition - Black or mixed black African | — | — | 115 Participants | 62 Participants | 53 Participants |
| Race/Ethnicity, Customized Parenteral nutrition - Other and missing | — | — | 180 Participants | 94 Participants | 86 Participants |
| Race/Ethnicity, Customized Parenteral nutrition - White | — | — | 1993 Participants | 991 Participants | 1002 Participants |
| Region of Enrollment United Kingdom | 0 participants | 0 participants | 3236 participants | 1240 participants | 1240 participants |
| Sex: Female, Male Enteral feeding Female | 715 Participants | 715 Participants | 1430 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Enteral feeding Male | 903 Participants | 903 Participants | 1806 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Parenteral nutrition Female | 0 Participants | 0 Participants | 1164 Participants | 576 Participants | 588 Participants |
| Sex: Female, Male Parenteral nutrition Male | 0 Participants | 0 Participants | 1316 Participants | 664 Participants | 652 Participants |
| Treatment with inotropes on day of admission Enteral feeding | 288 Participants | 295 Participants | 583 Participants | — | — |
| Treatment with inotropes on day of admission Parenteral nutrition | — | — | 582 Participants | 287 Participants | 295 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 66 / 1,618 | 153 / 1,618 | 86 / 1,240 | 124 / 1,240 |
| other Total, other adverse events | 0 / 1,618 | 0 / 1,618 | 0 / 1,240 | 0 / 1,240 |
| serious Total, serious adverse events | 0 / 1,618 | 0 / 1,618 | 0 / 1,240 | 0 / 1,240 |
Outcome results
Primary
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
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Received Enteral (Milk) Feeds During Therapeutic Hypothermia | Blood Stream Infection - for the Parenteral Nutrition Comparison | NA Participants |
| Enteral (Milk) Feeds Withheld During Therapeutic Hypothermia | Blood Stream Infection - for the Parenteral Nutrition Comparison | 8 Participants |
| Received Parenteral Nutrition During Therapeutic Hypothermia: | Blood Stream Infection - for the Parenteral Nutrition Comparison | 11 Participants |
| Did Not Receive Parenteral Nutrition During Therapeutic Hypothermia | Blood Stream Infection - for the Parenteral Nutrition Comparison | NA Participants |
Primary
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
Population: NA indicates \<5 where the cell value is withheld to avoid identifying participants
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Received Enteral (Milk) Feeds During Therapeutic Hypothermia | Necrotising Enterocolitis - for the Enteral Nutrition Comparison | NA Participants |
| Enteral (Milk) Feeds Withheld During Therapeutic Hypothermia | Necrotising Enterocolitis - for the Enteral Nutrition Comparison | NA Participants |
| Received Parenteral Nutrition During Therapeutic Hypothermia: | Necrotising Enterocolitis - for the Enteral Nutrition Comparison | NA Participants |
| Did Not Receive Parenteral Nutrition During Therapeutic Hypothermia | Necrotising Enterocolitis - for the Enteral Nutrition Comparison | 7 Participants |
Secondary
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
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Received Enteral (Milk) Feeds During Therapeutic Hypothermia | Breastfeeding | 883 Participants |
| Enteral (Milk) Feeds Withheld During Therapeutic Hypothermia | Breastfeeding | 752 Participants |
| Received Parenteral Nutrition During Therapeutic Hypothermia: | Breastfeeding | 575 Participants |
| Did Not Receive Parenteral Nutrition During Therapeutic Hypothermia | Breastfeeding | 582 Participants |
Secondary
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
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Received Enteral (Milk) Feeds During Therapeutic Hypothermia | Duration of Central Venous Line | 4.3 Days |
| Enteral (Milk) Feeds Withheld During Therapeutic Hypothermia | Duration of Central Venous Line | 5.5 Days |
| Received Parenteral Nutrition During Therapeutic Hypothermia: | Duration of Central Venous Line | 6 Days |
| Did Not Receive Parenteral Nutrition During Therapeutic Hypothermia | Duration of Central Venous Line | 5.1 Days |
Secondary
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
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Received Enteral (Milk) Feeds During Therapeutic Hypothermia | Growth | -0.54 Standard deviation score |
| Enteral (Milk) Feeds Withheld During Therapeutic Hypothermia | Growth | -0.6 Standard deviation score |
| Received Parenteral Nutrition During Therapeutic Hypothermia: | Growth | -0.65 Standard deviation score |
| Did Not Receive Parenteral Nutrition During Therapeutic Hypothermia | Growth | -0.66 Standard deviation score |
Secondary
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
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Received Enteral (Milk) Feeds During Therapeutic Hypothermia | Hypoglycaemia | 293 Participants |
| Enteral (Milk) Feeds Withheld During Therapeutic Hypothermia | Hypoglycaemia | 269 Participants |
| Received Parenteral Nutrition During Therapeutic Hypothermia: | Hypoglycaemia | 212 Participants |
| Did Not Receive Parenteral Nutrition During Therapeutic Hypothermia | Hypoglycaemia | 235 Participants |
Secondary
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
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Received Enteral (Milk) Feeds During Therapeutic Hypothermia | Length of Stay | 12.7 Days |
| Enteral (Milk) Feeds Withheld During Therapeutic Hypothermia | Length of Stay | 14.8 Days |
| Received Parenteral Nutrition During Therapeutic Hypothermia: | Length of Stay | 15.0 Days |
| Did Not Receive Parenteral Nutrition During Therapeutic Hypothermia | Length of Stay | 14.1 Days |
Secondary
Survival
Survival at neonatal unit discharge
Time frame: From date of birth until date of final neonatal unit discharge, assessed up to 1 year
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Received Enteral (Milk) Feeds During Therapeutic Hypothermia | Survival | 1552 Participants |
| Enteral (Milk) Feeds Withheld During Therapeutic Hypothermia | Survival | 1465 Participants |
| Received Parenteral Nutrition During Therapeutic Hypothermia: | Survival | 1154 Participants |
| Did Not Receive Parenteral Nutrition During Therapeutic Hypothermia | Survival | 1116 Participants |