Neonatal Death, Prematurity
Conditions
Keywords
Preterm neonate, Parenteral nutrition
Brief summary
BACKGROUND An essential part of neonatal care is providing nutrition to ensure that babies grow and develop. Providing this can be difficult in premature babies because their intestines are underdeveloped. They often have difficulty digesting milk so feeds are introduced gradually. To help babies grow and develop during this period, additional nutrition may be provided as a fluid into a vein; this is called parenteral nutrition (PN). Unfortunately, PN increases the risk of serious complications like bloodstream infection (also known as sepsis). For babies who are moderately premature there is little evidence to guide decision making about which babies will benefit from PN. This group of babies have more reserves of fat and are less dependent on PN, but are still at risk of sepsis. As a consequence, some doctors use PN and others do not. AIMS Firstly, to describe which babies are given PN during the first postnatal week in neonatal units in England, Scotland and Wales. Secondly, to determine whether in babies born 7-10 weeks preterm (moderately premature), providing PN in the first week after birth, compared to not to providing PN, improves survival to discharge from the neonatal unit. Finally, to evaluate if the early use of PN in moderately preterm babies affects other important outcomes in the neonatal core outcomes set. IMPORTANCE This work will describe the extent of PN use in England, Scotland and Wales. This is currently unknown. This project will improve understanding of the balance of benefits and harms of PN use in premature babies and will help doctors and parents make informed treatment choices. METHODS The investigators will use the National Neonatal Research Database (NNRD) to study all babies born in England, Scotland and Wales; they will identify which babies were given PN during the first week, and which were not. The investigators will use the NNRD to identify babies born 7-10 weeks prematurely and compare outcomes in babies that were given and not given PN in the first week after birth. The investigators will use statistical techniques to identify two sets of babies in the NNRD who are very similar (in terms of how prematurely they were born, their birth weight, and so on), the only difference being whether they were given PN or not. As the two groups will be similar any difference in their outcomes (such as survival) is likely to be due to whether or not they received PN.
Detailed description
Premature birth abruptly ends the transplacental transmission of nutrients that allows normal foetal growth and development. Providing adequate nutrition is essential to allow premature babies to continue to grow and mature. Very preterm infants often have difficulty tolerating adequate volumes of milk feeds shortly after birth and so are given supplemental parenteral nutrition (PN). Preterm babies are among the highest PN users of all NHS patients. It has been estimated that PN is received by around 70% of neonatal unit admissions but it is not known exactly which babies receive PN. In addition, how PN affects outcomes has never been tested in a large scale, randomized, placebo controlled neonatal trial. It is known that PN carries well established risks, of which the most serious and the most common is sepsis with estimates of risk ratios varying from 2.2 to 14.6. In addition there is a growing body of evidence that use of PN within the first seven days of admission to an intensive care unit is associated with worse outcomes in critically unwell adults and children. A subgroup analysis of the paediatric intensive care unit population focusing on neonates showed an increase in infections with early PN use. This suggests that uncertainty exists over the benefit of giving neonates PN in the early postnatal period. It is generally accepted that PN is beneficial to extremely preterm neonates, but in moderately preterm neonates the effect that PN use has on neonatal survival has never been conclusively demonstrated. The uncertainty over how PN use affects neonatal outcomes is reflected by the wide variety in how PN is used in different units with large variation in use, timing and composition of PN. This is, in part, due to the lack of clear evidence of how PN affects neonatal outcomes like growth and survival. Neonates are also vulnerable to unanticipated treatment effects which can occur in different organ systems and so it is important to show that PN is not detrimental to important neonatal outcomes. The postmenstrual age at which the nutritional benefits of PN outweigh the risks in moderately preterm babies (30-33 weeks postmenstrual age) is unknown. It is therefore unsurprising that their nutritional management is very variable. In moderately preterm neonates in 2012 and 2013 across England, Scotland and Wales PN was given to 45% of neonates, suggesting clinician equipoise around the balance of benefit to risk. Identifying whether moderately preterm neonates benefit from PN would have important implications for practice in the UK. This work will provide information to guide practice and inform future research. In summary, PN is widely used in neonates but it is not known exactly how it is used in the UK. It is known to have risks and benefits but there is insufficient evidence to guide practice in moderately preterm neonates. Study objectives: * To describe the use of PN in neonatal units across England, Scotland and Wales. * To identify if use of PN in the first seven postnatal days affects survival in neonates born between 30 and 33 weeks postmenstrual age. * To explore how PN use in the first seven postnatal days affects other important neonatal outcomes in neonates born between 30 and 33 weeks postmenstrual age. Study design: Project A: an epidemiological survey of practice using the National Neonatal Research Database (NNRD). Project B: a retrospective cohort study of matched groups of babies using data held in the NNRD.
Interventions
OTHERParenteral nutrition
Parenteral nutrition is the administration of an intravenous solution containing amino acids (with or without lipids) to provide nutritional support.
Sponsors
Imperial College London
Study design
Observational model
COHORT
Time perspective
RETROSPECTIVE
Eligibility
Sex/Gender
ALL
Age
No minimum to 2 Years
Healthy volunteers
Yes
Inclusion criteria
Project A: * Must be born between 1st January 2012 and 31st December 2017 * Must be admitted to a National Health Service (NHS) neonatal unit in England, Scotland or Wales Project B: * Must be born between 30 and 33 weeks postmenstrual age * Must be born between 1st January 2012 and 31st December 2017 * Must be admitted to an NHS neonatal unit in England, Scotland or Wales
Exclusion criteria
Project A: No
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Use of Parenteral Nutrition (Project A) | From birth until discharge home, assessed up to 1 year | Any use of parenteral nutrition in the first seven days of postnatal life (assessed using daily data extracted from the National Neonatal Research Database as described in the project protocol) This outcome formed part of Project A ONLY, and in keeping with the research protocol is only analysed and reported for the babies in this research arm. |
| Survival to Discharge Home (Project B) | From birth until discharge home, assessed up to 1 year | Defined as recorded alive at final neonatal unit discharge This outcome formed part of Project B ONLY, and in keeping with the research protocol is only analysed and reported for the babies in this research arm. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Brain Injury on Imaging (Project B) | From birth until discharge home, assessed up to 1 year | Number of participants with diagnosed brain injury on imaging: defined as documented diagnosis of intraventricular haemorrhage (grade 3-4) or cystic periventricular leucomalacia |
| Retinopathy of Prematurity (Project B) | From birth until discharge home, assessed up to 1 year | Number of participants with diagnosed retinopathy of prematurity: defined as a record of any retinopathy of prematurity on routine screening in the National Neonatal Dataset retinopathy of prematurity ad-hoc form |
| Bronchopulmonary Dysplasia (Project B) | From birth until discharge home, assessed up to 1 year | Number of participants with diagnosed bronchopulmonary dysplasia: defined using the NNAP definition of significant bronchopulmonary dysplasia: Receiving respiratory support at 36 weeks corrected gestational age. |
| Need for Surgical Procedures (Project B) | From birth until discharge home, assessed up to 1 year | Defined as any record of surgical procedure during the neonatal admission |
| Seizures (Project B) | From birth until discharge home, assessed up to 1 year | Number of participants diagnosed as having a seizure: defined as any recorded diagnosis of seizures or seizure disorder |
| Late Onset Sepsis (Project B) | 72 hours of postnatal life to discharge home, assessed up to 1 year | Number of participants with diagnosed Later Onset Sepsis: defined in line with the Royal College of Paediatrics and Child Health National Neonatal Audit Programme (NNAP) definition pure growth of a pathogen from blood or pure growth of a skin commensal or a mixed growth after the first 72 hours of life |
| Head Circumference (Project B) | From birth until discharge home, assessed up to 1 year | Head circumference in centimetres at discharge; head circumference velocity (measured as increase in head circumference in centimetres/day) from birth until discharge |
| Blindness (Project B) | From birth until two years of age | Defined as an answer of Yes to the question Does this child have a visual impairment? on the NNAP follow up form |
| Deafness (Project B) | From birth until two years of age | Defined as an answer of Yes to the question Does this child have a hearing impairment? on the NNAP follow up form |
| Ability to Walk (Project B) | From birth until two years of age | Defined as an answer of Yes to the question Is this child unable to walk without assistance? on the NNAP follow up form |
| Weight (Project B) | From birth until discharge home, assessed up to 1 year | Weight z-score at discharge home. Weights at discharge home were converted to a z-score: a z-score of 0 represents the population mean, while score higher scores indicate a greater weight. |
| Necrotising Enterocolitis (Project B) | From birth until discharge home, assessed up to 1 year | Number of participants with diagnosed necrotising enterocolitis: defined using the NNAP definition: NEC may be diagnosed at surgery, post-mortem or on the basis of the following clinical and radiographic signs: At least one clinical feature from: (i) Bilious gastric aspirate or emesis (ii) Abdominal distension (iii) Occult or gross blood in stool (no fissure) And at least one radiographic feature from: (i) Pneumatosis (ii) Hepato-biliary gas (iii) Pneumoperitoneum |
Countries
United Kingdom
Participant flow
Pre-assignment details
Project A: 4,196,314 neonates were born in England and Wales. 347,959 neonates were admitted to NHS neonatal units . 62,147 neonates received PN during the first postnatal week. Project B: 37,302 neonates were born over the study period. 36,644 were admitted to an NHS neonatal unit. Prior to the propensity score analysis 843 neonates were excluded due to congenital conditions and 439 were excluded due to missing key data. This left 35,362 included in the propensity score analysis
Participants by arm
| Arm | Count |
|---|---|
| Neonatal Population (Project A) Neonates born between 1st January 2012 and 31st December 2017 and admitted to a neonatal unit in England and Wales). | 62,145 |
| No PN Use (Project B) All neonates born between 30 and 33 weeks postmenstrual age in England and Wales and admitted to a NHS neonatal unit between 1st January 2012 and 31st December 2017 who did not receive any parenteral nutrition (for any duration, by any intravenous route) in the first seven postnatal days. | 8,146 |
| PN Use (Project B) All neonates born between 30 and 33 weeks postmenstrual age in England and Wales and admitted to a NHS neonatal unit between 1st January 2012 and 31st December 2017 who received any parenteral nutrition (for any duration, by any intravenous route) in the first seven postnatal days.
Parenteral nutrition: Parenteral nutrition is the administration of an intravenous solution containing amino acids (with or without lipids) to provide nutritional support. | 8,146 |
| Total | 78,437 |
Baseline characteristics
| Characteristic | Neonatal Population (Project A) | No PN Use (Project B) | PN Use (Project B) | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 62145 Participants | 8146 Participants | 8146 Participants | 78437 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race and Ethnicity Not Collected | — | — | — | 0 Participants |
| Sex: Female, Male Female | 27965 Participants | 3664 Participants | 3733 Participants | 35362 Participants |
| Sex: Female, Male Male | 34180 Participants | 4482 Participants | 4413 Participants | 43075 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 5,725 / 62,145 | 163 / 8,146 | 90 / 8,146 |
| other Total, other adverse events | 0 / 62,145 | 0 / 8,146 | 0 / 8,146 |
| serious Total, serious adverse events | 0 / 62,145 | 0 / 8,146 | 0 / 8,146 |
Outcome results
Primary
Survival to Discharge Home (Project B)
Defined as recorded alive at final neonatal unit discharge This outcome formed part of Project B ONLY, and in keeping with the research protocol is only analysed and reported for the babies in this research arm.
Time frame: From birth until discharge home, assessed up to 1 year
Population: Analysis of propensity score matched cohorts as per the pre-specified analysis plan This outcome formed part of Project B ONLY, and in keeping with the research protocol is only analysed and reported for the babies in this research arm.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Neonatal Population (Project A) | Survival to Discharge Home (Project B) | 7987 Participants |
| PN Use (Project B) | Survival to Discharge Home (Project B) | 8057 Participants |
Primary
Use of Parenteral Nutrition (Project A)
Any use of parenteral nutrition in the first seven days of postnatal life (assessed using daily data extracted from the National Neonatal Research Database as described in the project protocol) This outcome formed part of Project A ONLY, and in keeping with the research protocol is only analysed and reported for the babies in this research arm.
Time frame: From birth until discharge home, assessed up to 1 year
Population: This outcome formed part of Project A ONLY, and in keeping with the research protocol has only been collected, analysed and reported for the neonates in this research arm. In Project B 'use of parenteral nutrition' formed a key background characteristic, and so this outcome is not reported for the two arms of Project B.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Neonatal Population (Project A) | Use of Parenteral Nutrition (Project A) | 62145 Participants |
Secondary
Ability to Walk (Project B)
Defined as an answer of Yes to the question Is this child unable to walk without assistance? on the NNAP follow up form
Time frame: From birth until two years of age
Population: Initial analyses revealed considerable amounts of missing data (\>90% missing): as the data represented under 10% of the true population it would not be possible to meaningfully summarise this data and it was highly unreliable (due to the high risk of systematic bias in this unrepresentative sample). For this reason full data relating to this outcome was not extracted from the National Neonatal Research Database as it was not in any way informative, and any further analysis was unjustified.
Secondary
Blindness (Project B)
Defined as an answer of Yes to the question Does this child have a visual impairment? on the NNAP follow up form
Time frame: From birth until two years of age
Population: Initial analyses revealed considerable amounts of missing data (\>90% missing): as the data represented under 10% of the true population it would not be possible to meaningfully summarise this data and it was highly unreliable (due to the high risk of systematic bias in this unrepresentative sample). For this reason full data relating to this outcome was not extracted from the National Neonatal Research Database as it was not in any way informative, and any further analysis was unjustified.
Secondary
Brain Injury on Imaging (Project B)
Number of participants with diagnosed brain injury on imaging: defined as documented diagnosis of intraventricular haemorrhage (grade 3-4) or cystic periventricular leucomalacia
Time frame: From birth until discharge home, assessed up to 1 year
Population: Analysis of propensity score matched cohorts as per the pre-specified analysis plan
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Neonatal Population (Project A) | Brain Injury on Imaging (Project B) | 48 Participants |
| PN Use (Project B) | Brain Injury on Imaging (Project B) | 73 Participants |
Secondary
Bronchopulmonary Dysplasia (Project B)
Number of participants with diagnosed bronchopulmonary dysplasia: defined using the NNAP definition of significant bronchopulmonary dysplasia: Receiving respiratory support at 36 weeks corrected gestational age.
Time frame: From birth until discharge home, assessed up to 1 year
Population: Analysis of propensity score matched cohorts as per the pre-specified analysis plan
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Neonatal Population (Project A) | Bronchopulmonary Dysplasia (Project B) | 302 Participants |
| PN Use (Project B) | Bronchopulmonary Dysplasia (Project B) | 619 Participants |
Secondary
Deafness (Project B)
Defined as an answer of Yes to the question Does this child have a hearing impairment? on the NNAP follow up form
Time frame: From birth until two years of age
Population: Initial analyses revealed considerable amounts of missing data (\>90% missing): as the data represented under 10% of the true population it would not be possible to meaningfully summarise this data and it was highly unreliable (due to the high risk of systematic bias in this unrepresentative sample). For this reason full data relating to this outcome was not extracted from the National Neonatal Research Database as it was not in any way informative, and any further analysis was unjustified.
Secondary
Head Circumference (Project B)
Head circumference in centimetres at discharge; head circumference velocity (measured as increase in head circumference in centimetres/day) from birth until discharge
Time frame: From birth until discharge home, assessed up to 1 year
Population: Initial analyses revealed considerable amounts of missing data (\>90% missing): as the data represented under 10% of the true population it would not be possible to meaningfully summarise this data and it was highly unreliable (due to the high risk of systematic bias in this unrepresentative sample). For this reason full data relating to this outcome was not extracted from the National Neonatal Research Database as it was not in any way informative, and any further analysis was unjustified.
Secondary
Late Onset Sepsis (Project B)
Number of participants with diagnosed Later Onset Sepsis: defined in line with the Royal College of Paediatrics and Child Health National Neonatal Audit Programme (NNAP) definition pure growth of a pathogen from blood or pure growth of a skin commensal or a mixed growth after the first 72 hours of life
Time frame: 72 hours of postnatal life to discharge home, assessed up to 1 year
Population: Analysis of propensity score matched cohorts as per the pre-specified analysis plan
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Neonatal Population (Project A) | Late Onset Sepsis (Project B) | 59 Participants |
| PN Use (Project B) | Late Onset Sepsis (Project B) | 179 Participants |
Secondary
Necrotising Enterocolitis (Project B)
Number of participants with diagnosed necrotising enterocolitis: defined using the NNAP definition: NEC may be diagnosed at surgery, post-mortem or on the basis of the following clinical and radiographic signs: At least one clinical feature from: (i) Bilious gastric aspirate or emesis (ii) Abdominal distension (iii) Occult or gross blood in stool (no fissure) And at least one radiographic feature from: (i) Pneumatosis (ii) Hepato-biliary gas (iii) Pneumoperitoneum
Time frame: From birth until discharge home, assessed up to 1 year
Population: Analysis of propensity score matched cohorts as per the pre-specified analysis plan
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Neonatal Population (Project A) | Necrotising Enterocolitis (Project B) | 285 Participants |
| PN Use (Project B) | Necrotising Enterocolitis (Project B) | 660 Participants |
Secondary
Need for Surgical Procedures (Project B)
Defined as any record of surgical procedure during the neonatal admission
Time frame: From birth until discharge home, assessed up to 1 year
Population: Analysis of propensity score matched cohorts as per the pre-specified analysis plan
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Neonatal Population (Project A) | Need for Surgical Procedures (Project B) | 69 Participants |
| PN Use (Project B) | Need for Surgical Procedures (Project B) | 147 Participants |
Secondary
Retinopathy of Prematurity (Project B)
Number of participants with diagnosed retinopathy of prematurity: defined as a record of any retinopathy of prematurity on routine screening in the National Neonatal Dataset retinopathy of prematurity ad-hoc form
Time frame: From birth until discharge home, assessed up to 1 year
Population: Analysis of propensity score matched cohorts as per the pre-specified analysis plan
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Neonatal Population (Project A) | Retinopathy of Prematurity (Project B) | 272 Participants |
| PN Use (Project B) | Retinopathy of Prematurity (Project B) | 297 Participants |
Secondary
Seizures (Project B)
Number of participants diagnosed as having a seizure: defined as any recorded diagnosis of seizures or seizure disorder
Time frame: From birth until discharge home, assessed up to 1 year
Population: Analysis of propensity score matched cohorts as per the pre-specified analysis plan
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Neonatal Population (Project A) | Seizures (Project B) | 81 Participants |
| PN Use (Project B) | Seizures (Project B) | 114 Participants |
Secondary
Weight (Project B)
Weight z-score at discharge home. Weights at discharge home were converted to a z-score: a z-score of 0 represents the population mean, while score higher scores indicate a greater weight.
Time frame: From birth until discharge home, assessed up to 1 year
Population: Analysis of propensity score matched cohorts as per the pre-specified analysis plan
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Neonatal Population (Project A) | Weight (Project B) | 0.073 Z-score | Standard Deviation 0.98 |
| PN Use (Project B) | Weight (Project B) | -0.024 Z-score | Standard Deviation 0.96 |