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In order to address this crucial question, central to preterm newborn care, a multicentre United Kingdom (UK) -wide study randomising 4000 preterm babies would be necessary to achieve sufficient power to evaluate the impact on the short-term outcomes necrotising enterocolitis and bloodstream infection, and establish cohorts large enough to address long-term metabolic (such as obesity, type 2 diabetes), cardiovascular (such as blood pressure) and developmental outcomes. This pilot trial will evaluate the practicability and feasibility of such a large multicentre UK randomised controlled trial. In addition to evaluating feasibility and to ensure maximal use of resources allocated, this study will also assess outcomes that are indicative of long term metabolic health.
Mother's Own Milk (MOM) is recommended for preterm babies. However, on average, mothers giving birth preterm are able to provide less than half their baby's milk requirements. Standard clinical practice is to make up any shortfall in MOM with either pasteurised Human Donor Milk (HDM) or Preterm Formula (PTF). Which option is more beneficial to clinical outcomes is unknown.
Pasteurisation reduces or destroys many biologically active components and HDM, unlike PTF, is very variable in composition. Clinicians who use HDM do so primarily in the hope that despite pasteurisation it will reduce bloodstream infection and necrotising enterocolitis, a serious, devastating inflammatory disease characterised by bowel death and multisystem failure. These are two of the most feared conditions in newborn medicine as described above. Landmark nutritional trials in the early 1980's suggest positive effects of human milk on insulin sensitivity, and other metabolic outcomes. Clinicians who prefer PTF believe it benefits growth, including brain growth, and improves neurodevelopmental outcome.
Neonates born below 32 weeks gestational age will be randomised to receive fortified HDM, unfortified HDM, or PTF to make up any shortfall in MOM until 35 weeks postmenstrual age with a sample size of 22 in each group. The trial is designed to reflect current preterm feeding practice. The trial will take place in neonatal units in London and parent consent obtained within 48hr of birth. Permission will be sought for long term follow up, initially from parents (later from children themselves). Outcomes will be body composition using magnetic resonance imaging and other imaging techniques. This pilot study will specifically assess feasibility by testing 1) provision of HDM by Human Milk Banks in London 2) acceptability to parents and clinicians using feedback on trial design 3) recruitment to target and 4) retrieval of clinical data for all recruited babies form the National Neonatal Database.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Unfortified Human Donor Milk | Active Comparator | Used to make up any shortfall in mother's own milk |
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| Fortified Human Donor Milk | Active Comparator | Used to make up any shortfall in mother's own milk |
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| Preterm Formula | Active Comparator | Used to make up any shortfall in mother's own milk |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Unfortified Human donor Milk used to make up any shortfall in mother's own milk | Other |
| ||
| Fortified Human donor Milk used to make up any shortfall in mother's own milk |
| Measure | Description | Time Frame |
|---|---|---|
| Total Body Adiposity | As measured by whole body Magnetic Resonance Imaging (MRI). MR images were acquired using a rapid T1-weighted spin-echo sequence allowing whole body imaging. Images obtained give good contrast between adipose tissue and other tissues, and allows direct measurement of adipose compartment volumes, whole body adipose volume being the sum of these compartments. The time taken to reach term age equivalent will vary depending on the birth gestational age of the infant. The range will be 8-15 weeks (representing gestational birth age from 25-32 weeks). | Measured as close as possible to the baby's due date, at an average age of 10 weeks (range 8 to 15 weeks) |
| Measure | Description | Time Frame |
|---|---|---|
| Consent Rate for Feeding Intervention (Opt Out Approach) | Consent rate for feeding intervention of number of parents of eligible infants approached and study discussed with (opt out approach) | Up to the first 48hrs of life |
| Parental Withdrawal From Feed Intervention |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Neena Modi, MBChB | Imperial College London | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Chelsea and Westminster Hospital Neonatal Unit | London | SW10 9NH | United Kingdom |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 39239939 | Derived | Quigley M, Embleton ND, Meader N, McGuire W. Donor human milk for preventing necrotising enterocolitis in very preterm or very low-birthweight infants. Cochrane Database Syst Rev. 2024 Sep 6;9(9):CD002971. doi: 10.1002/14651858.CD002971.pub6. |
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| ID | Title | Description |
|---|---|---|
| FG000 | Unfortified Human Donor Milk | Used to make up any shortfall in mother's own milk Unfortified Human donor Milk used to make up any shortfall in unfortified mother's own milk |
| FG001 | Fortified Human Donor Milk |
| Title | Milestones | Reasons Not Completed | |||||
|---|---|---|---|---|---|---|---|
| Feeding Intervention |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Mar 4, 2014 |
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| Other |
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| Preterm Formula used when there is a shortfall in mother's own milk | Other |
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Parental withdrawal rate from feed intervention |
| From birth to 35 weeks post menstrual age |
| Parental Withdrawal Rate From Feed Intervention by Arm | Parental withdrawal rate from feed intervention by feed intervention arm | From birth to 35 weeks post menstrual age |
| Clinician Refusal to Randomise | Attending clinician refusal to randomise eligible infant into feeding intervention | Up to the first 48hrs of life. |
| Safety Criteria Threshold | Number of infants who met the weight gain safety criteria. Safety criteria defined by slow growth were based on the UK Neonatal and Infant Close Monitoring growth chart 2009: if after two weeks of reaching a milk volume of 120ml/kg/d, the infant showed a 3 marked centile downward crossing (equating to approximately a 1.4-2.0 z-score change from birthweight) fortification or formula was commenced | Birth to 35 weeks post menstrual age |
| Weight at Term | Weight at term by feed intervention arm | Measured as close as possible to the baby's due date, at an average age of 10 weeks (range 8 to 15 weeks) |
| Length at Term | Length at term by feed intervention arm | Term corrected age (as close as possible to due date) |
| Head Circumference at Term | Head circumference at term by feed intervention arm | Term corrected age (as close as possible to due date) |
| Regional Adiposity, as Measured by Whole Body MRI, at Term. | Internal Abdominal Adipose Tissue at Term reported here. As measured by whole body Magnetic Resonance Imaging (MRI). MR images were acquired using a rapid T1-weighted spin-echo sequence allowing whole body imaging. Images obtained give good contrast between adipose tissue and other tissues, and allows direct measurement of adipose compartment volumes. These adipose compartments are defined as superficial subcutaneous, deep subcutaneous, and internal. Each of these three compartments are further subdivided into abdominal and non-abdominal. | Measured as close as possible to the baby's due date, at an average age of 10 weeks (range 8 to 15 weeks) |
| Non Adipose Tissue, as Measured by Whole Body MRI, at Term | Non adipose tissue, as measured by whole body Magnetic Resonance Imaging (MRI) at term. MR images were acquired using a rapid T1-weighted spin-echo sequence allowing whole body imaging. Images obtained give good contrast between adipose tissue and other tissues, and allows direct measurement of adipose compartment volumes, whole body adipose tissue volume being the sum of these adipose compartment volumes. This volume may be converted to adipose tissue mass on the assumption that the density of adipose tissue is 0.9 g/cm³. Non adipose tissue mass reported here is weight (g) minus whole body adipose mass (g) | Measured as close as possible to the baby's due date, at an average age of 10 weeks (range 8 to 15 weeks) |
| Weight at Term Plus 6 Weeks | Weight at Term plus 6 weeks by feed intervention arm | Term plus 6 weeks corrected age |
| Length at Term Plus 6 Weeks | Length at Term plus 6 weeks by feed intervention group | Term plus 6 weeks |
| Head Circumference at Term Plus 6 Weeks | Head circumference at Term plus 6 weeks by feed intervention arm | Term plus 6 weeks |
| Total Body Adiposity at Term Plus 6 Weeks | As measured by whole body Magnetic Resonance Imaging (MRI). MR images were acquired using a rapid T1-weighted spin-echo sequence allowing whole body imaging. Images obtained give good contrast between adipose tissue and other tissues, and allows direct measurement of adipose compartment volumes, total body adipose tissue volume being the sum of all these compartment volumes. | Term plus 6 weeks |
| Regional Adiposity, as Measured by Whole Body MRI at Term Plus 6 Weeks | Regional adiposity, as measured by whole body MRI at Term plus 6 weeks, Internal Abdominal Adipose Tissue reported here. As measured by whole body Magnetic Resonance Imaging (MRI). MR images were acquired using a rapid T1-weighted spin-echo sequence allowing whole body imaging. Images obtained give good contrast between adipose tissue and other tissues, and allows direct measurement of adipose compartment volumes. These adipose compartments are defined as superficial subcutaneous, deep subcutaneous, and internal. Each of these three compartments are further subdivided into abdominal and non-abdominal. | Term plus 6 weeks corrected age |
| Non Adipose Tissue, as Measured by Whole Body MRI at Term Plus 6 Weeks | Non adipose tissue, as measured by whole body MRI, at Term plus 6 weeks. As measured by whole body Magnetic Resonance Imaging (MRI). MR images were acquired using a rapid T1-weighted spin-echo sequence allowing whole body imaging. Images obtained give good contrast between adipose tissue and other tissues, and allows direct measurement of adipose compartment volumes, whole body adipose tissue volume being the sum of these adipose compartment volumes. This volume may be converted to adipose tissue mass on the assumption that the density of adipose tissue is 0.9 g/cm³. Non adipose tissue mass reported here is weight (g) minus whole body adipose mass (g) | Term plus 6 weeks corrected age |
| Blood Quantitative Insulin Sensitivity Check Index (QUICKI) | The quantitative insulin sensitivity check index (QUICKI) is derived using the inverse of the sum of the logarithms of the fasting insulin and fasting glucose: 1 / (log(fasting insulin μU/mL) + log(fasting glucose mg/dL)). This index correlates well with glucose clamp studies and is useful for measuring insulin sensitivity (IS), which is the inverse of insulin resistance (IR). The higher the value of QUICKI, the higher the measure of insulin sensitivity. Reference ranges for adults, and less so preterm newborns, have not been fully established; values of 0.3 in adults or below are typically associated with insulin resistance or diabetes. In a large cohort of 115 term, normoweight newborns at birth (Gesteiro E. Eur J Pediatr. 2009 Mar;168(3):281-8), mean (95% confidence interval) QUICKI was 0.45 (0.43-0.48) | Measured at 35 weeks Post Menstrual Age |
Used to make up any shortfall in mother's own milk
Fortified Human donor Milk used to make up any shortfall in fortified mother's own milk
| FG002 | Preterm Formula | Used to make up any shortfall in mother's own milk Preterm Formula used when there is a shortfall in mother's own milk |
| COMPLETED |
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| NOT COMPLETED |
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| Primary Outcome Term Scan |
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| Term Plus 6 Week Scan (End of Study) |
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| ID | Title | Description |
|---|---|---|
| BG000 | Unfortified Human Donor Milk | Used to make up any shortfall in mother's own milk Unfortified Human donor Milk used to make up any shortfall in mother's own milk |
| BG001 | Fortified Human Donor Milk | Used to make up any shortfall in mother's own milk Fortified Human donor Milk used to make up any shortfall in mother's own milk |
| BG002 | Preterm Formula | Used to make up any shortfall in mother's own milk Preterm Formula used when there is a shortfall in mother's own milk |
| BG003 | Total | Total of all reporting groups |
| Units | Counts |
|---|---|
| Participants |
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| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Completed gestational weeks (decimal) | Mean | Standard Deviation | Completed gestational weeks |
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| Sex: Female, Male | Count of Participants | Participants |
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| Ethnicity (NIH/OMB) | Count of Participants | Participants |
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| Region of Enrollment | Number | participants |
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| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Total Body Adiposity | As measured by whole body Magnetic Resonance Imaging (MRI). MR images were acquired using a rapid T1-weighted spin-echo sequence allowing whole body imaging. Images obtained give good contrast between adipose tissue and other tissues, and allows direct measurement of adipose compartment volumes, whole body adipose volume being the sum of these compartments. The time taken to reach term age equivalent will vary depending on the birth gestational age of the infant. The range will be 8-15 weeks (representing gestational birth age from 25-32 weeks). | Posted | Mean | Standard Deviation | Litres | Measured as close as possible to the baby's due date, at an average age of 10 weeks (range 8 to 15 weeks) |
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| Secondary | Consent Rate for Feeding Intervention (Opt Out Approach) | Consent rate for feeding intervention of number of parents of eligible infants approached and study discussed with (opt out approach) | Parents of 165 eligible infants for which the study was discussed with and opportunity offered to opt-out from randomisation to feed intervention | Posted | Count of Participants | Participants | Up to the first 48hrs of life |
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| Secondary | Parental Withdrawal From Feed Intervention | Parental withdrawal rate from feed intervention | All participants | Posted | Count of Participants | Participants | From birth to 35 weeks post menstrual age |
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| Secondary | Parental Withdrawal Rate From Feed Intervention by Arm | Parental withdrawal rate from feed intervention by feed intervention arm | Parental withdrawal rate from feed intervention by arm | Posted | Count of Participants | Participants | From birth to 35 weeks post menstrual age |
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| Secondary | Clinician Refusal to Randomise | Attending clinician refusal to randomise eligible infant into feeding intervention | All eligible participants who consented for feed intervention who were then not randomised due to clinician refusal | Posted | Count of Participants | Participants | Up to the first 48hrs of life. |
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| |||||||||||||||||||||||||||||||||
| Secondary | Safety Criteria Threshold | Number of infants who met the weight gain safety criteria. Safety criteria defined by slow growth were based on the UK Neonatal and Infant Close Monitoring growth chart 2009: if after two weeks of reaching a milk volume of 120ml/kg/d, the infant showed a 3 marked centile downward crossing (equating to approximately a 1.4-2.0 z-score change from birthweight) fortification or formula was commenced | All participants who consented for feed intervention | Posted | Count of Participants | Participants | Birth to 35 weeks post menstrual age |
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| Secondary | Weight at Term | Weight at term by feed intervention arm | Posted | Mean | Standard Deviation | Grams | Measured as close as possible to the baby's due date, at an average age of 10 weeks (range 8 to 15 weeks) |
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| Secondary | Length at Term | Length at term by feed intervention arm | Feed intervention arm | Posted | Mean | Standard Deviation | Cm | Term corrected age (as close as possible to due date) |
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| Secondary | Head Circumference at Term | Head circumference at term by feed intervention arm | Feed intervention arm | Posted | Mean | Standard Deviation | Cm | Term corrected age (as close as possible to due date) |
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| Secondary | Regional Adiposity, as Measured by Whole Body MRI, at Term. | Internal Abdominal Adipose Tissue at Term reported here. As measured by whole body Magnetic Resonance Imaging (MRI). MR images were acquired using a rapid T1-weighted spin-echo sequence allowing whole body imaging. Images obtained give good contrast between adipose tissue and other tissues, and allows direct measurement of adipose compartment volumes. These adipose compartments are defined as superficial subcutaneous, deep subcutaneous, and internal. Each of these three compartments are further subdivided into abdominal and non-abdominal. | Feed intervention arm | Posted | Mean | Standard Deviation | Litres | Measured as close as possible to the baby's due date, at an average age of 10 weeks (range 8 to 15 weeks) |
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| Secondary | Non Adipose Tissue, as Measured by Whole Body MRI, at Term | Non adipose tissue, as measured by whole body Magnetic Resonance Imaging (MRI) at term. MR images were acquired using a rapid T1-weighted spin-echo sequence allowing whole body imaging. Images obtained give good contrast between adipose tissue and other tissues, and allows direct measurement of adipose compartment volumes, whole body adipose tissue volume being the sum of these adipose compartment volumes. This volume may be converted to adipose tissue mass on the assumption that the density of adipose tissue is 0.9 g/cm³. Non adipose tissue mass reported here is weight (g) minus whole body adipose mass (g) | Feed intervention arm | Posted | Mean | Standard Deviation | Grams | Measured as close as possible to the baby's due date, at an average age of 10 weeks (range 8 to 15 weeks) |
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| Secondary | Weight at Term Plus 6 Weeks | Weight at Term plus 6 weeks by feed intervention arm | Feed intervention arm | Posted | Mean | Standard Deviation | Grams | Term plus 6 weeks corrected age |
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| Secondary | Length at Term Plus 6 Weeks | Length at Term plus 6 weeks by feed intervention group | Feed intervention arm | Posted | Mean | Standard Deviation | Cm | Term plus 6 weeks |
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| Secondary | Head Circumference at Term Plus 6 Weeks | Head circumference at Term plus 6 weeks by feed intervention arm | Feed intervention arm | Posted | Mean | Standard Deviation | Cm | Term plus 6 weeks |
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| Secondary | Total Body Adiposity at Term Plus 6 Weeks | As measured by whole body Magnetic Resonance Imaging (MRI). MR images were acquired using a rapid T1-weighted spin-echo sequence allowing whole body imaging. Images obtained give good contrast between adipose tissue and other tissues, and allows direct measurement of adipose compartment volumes, total body adipose tissue volume being the sum of all these compartment volumes. | Feed Intervention Arm | Posted | Mean | Standard Deviation | Litres | Term plus 6 weeks |
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| Secondary | Regional Adiposity, as Measured by Whole Body MRI at Term Plus 6 Weeks | Regional adiposity, as measured by whole body MRI at Term plus 6 weeks, Internal Abdominal Adipose Tissue reported here. As measured by whole body Magnetic Resonance Imaging (MRI). MR images were acquired using a rapid T1-weighted spin-echo sequence allowing whole body imaging. Images obtained give good contrast between adipose tissue and other tissues, and allows direct measurement of adipose compartment volumes. These adipose compartments are defined as superficial subcutaneous, deep subcutaneous, and internal. Each of these three compartments are further subdivided into abdominal and non-abdominal. | Feed intervention arm | Posted | Mean | Standard Deviation | Litres | Term plus 6 weeks corrected age |
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| Secondary | Non Adipose Tissue, as Measured by Whole Body MRI at Term Plus 6 Weeks | Non adipose tissue, as measured by whole body MRI, at Term plus 6 weeks. As measured by whole body Magnetic Resonance Imaging (MRI). MR images were acquired using a rapid T1-weighted spin-echo sequence allowing whole body imaging. Images obtained give good contrast between adipose tissue and other tissues, and allows direct measurement of adipose compartment volumes, whole body adipose tissue volume being the sum of these adipose compartment volumes. This volume may be converted to adipose tissue mass on the assumption that the density of adipose tissue is 0.9 g/cm³. Non adipose tissue mass reported here is weight (g) minus whole body adipose mass (g) | Feed intervention arm | Posted | Mean | Standard Deviation | Grams | Term plus 6 weeks corrected age |
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| Secondary | Blood Quantitative Insulin Sensitivity Check Index (QUICKI) | The quantitative insulin sensitivity check index (QUICKI) is derived using the inverse of the sum of the logarithms of the fasting insulin and fasting glucose: 1 / (log(fasting insulin μU/mL) + log(fasting glucose mg/dL)). This index correlates well with glucose clamp studies and is useful for measuring insulin sensitivity (IS), which is the inverse of insulin resistance (IR). The higher the value of QUICKI, the higher the measure of insulin sensitivity. Reference ranges for adults, and less so preterm newborns, have not been fully established; values of 0.3 in adults or below are typically associated with insulin resistance or diabetes. In a large cohort of 115 term, normoweight newborns at birth (Gesteiro E. Eur J Pediatr. 2009 Mar;168(3):281-8), mean (95% confidence interval) QUICKI was 0.45 (0.43-0.48) | Feed intervention arm | Posted | Mean | Standard Deviation | units on a scale | Measured at 35 weeks Post Menstrual Age |
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From period of feed intervention, this is from birth to 35 weeks post menstrual age.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Unfortified Human Donor Milk | Used to make up any shortfall in mother's own milk Unfortified Human donor Milk used to make up any shortfall in unfortified mother's own milk | 1 | 35 | 0 | 35 | 0 | 35 |
| EG001 | Fortified Human Donor Milk | Used to make up any shortfall in mother's own milk Fortified Human donor Milk used to make up any shortfall in fortified mother's own milk | 0 | 34 | 0 | 34 | 0 | 34 |
| EG002 | Preterm Formula | Used to make up any shortfall in mother's own milk Preterm Formula used when there is a shortfall in mother's own milk | 1 | 34 | 0 | 34 | 0 | 34 |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Luke Mills | ImperialC | +447989748017 | l.mills@imperial.ac.uk |
| Oct 28, 2023 |
| Prot_SAP_000.pdf |
| ID | Term |
|---|---|
| D009765 | Obesity |
| D007333 | Insulin Resistance |
| ID | Term |
|---|---|
| D050177 | Overweight |
| D044343 | Overnutrition |
| D009748 | Nutrition Disorders |
| D009750 | Nutritional and Metabolic Diseases |
| D001835 | Body Weight |
| D012816 | Signs and Symptoms |
| D013568 | Pathological Conditions, Signs and Symptoms |
| D006946 | Hyperinsulinism |
| D044882 | Glucose Metabolism Disorders |
| D008659 | Metabolic Diseases |
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| Scanner unavailable to measure primary outcome |
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| Male |
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| Not Hispanic or Latino |
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| Unknown or Not Reported |
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