PREterM FOrmula Or Donor Breast Milk for Premature Babies (PREMFOOD)

Preterm Formula or Donor Breast Milk to Make up Any Shortfall in Mother's Own Milk

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.

Study Overview

• Status: Completed
• Conditions: Insulin Resistance; Adiposity; Metabolomic Profile; microRNA Profile
• Intervention / Treatment: Other: 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; Other: Preterm Formula used when there is a shortfall in mother's own milk

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 103
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United Kingdom
  • London, United Kingdom, SW10 9NH
    • Chelsea and Westminster Hospital Neonatal Unit

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 5 months to 7 months (Child)
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

• Preterm infants born between 25+0 to 31+6 weeks gestational age
• Written informed consent from parents

Exclusion Criteria:

• Major congenital or life threatening abnormalities or congenital abnormalities that preclude early milk feeding
• Inability to randomise infant within 48 hours

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Unfortified Human Donor Milk; Used to make up any shortfall in mother's own milk	Other: Unfortified Human donor Milk used to make up any shortfall in mother's own milk
Active Comparator: Fortified 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
Active Comparator: Preterm Formula; Used to make up any shortfall in mother's own milk	Other: Preterm Formula used when there is a shortfall in mother's own milk

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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)

Secondary Outcome Measures

Outcome Measure	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	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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Total Body adiposity		Term (37-42 weeks corrected gestational age) and 6 weeks corrected
Regional adiposity, as measured by whole body MRI		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		Measured as close as possible to the baby's due date, at an average age of 10 weeks (range 8 to 15 weeks)
Anthropometry (weight, length, and head circumference)		Measured as close as possible to the baby's due date, at an average age of 10 weeks (range 8 to 15 weeks)
Intra-hepatocellular Lipid, measured by magnetic resonance spectroscopy		Measured as close as possible to the baby's due date, at an average age of 10 weeks (range 8 to 15 weeks)
Blood pressure		Measured as close as possible to the baby's due date, at an average age of 10 weeks (range 8 to 15 weeks)
Stool and urine metabolomic profile, measured using high throughput nuclear magnetic resonance (NMR) spectroscopy		Measured as close as possible to the baby's due date, at an average age of 10 weeks (range 8 to 15 weeks)
Blood Quantitative Insulin Sensitivity Check Index (QUICKI)	Calculated from fasting pre feed blood glucose and insulin	Measured as close as possible to the baby's due date, at an average age of 10 weeks (range 8 to 15 weeks)
Blood microRNA profile using high throughput sequencing techniques		Measured as close as possible to the baby's due date, at an average age of 10 weeks (range 8 to 15 weeks)
Regional adiposity, as measured by whole body MRI		Term plus 6 weeks corrected age
Non adipose tissue, as measured by whole body MRI		Term plus 6 weeks corrected age
Anthropometry (weight, length, and head circumference)		Term plus 6 weeks corrected age
Intra hepato-cellular Lipid, as measured by magnetic resonance spectroscopy		Term plus 6 weeks corrected age
Blood pressure		Term plus 6 weeks corrected
Stool and urine metabolomic profile, measured using high throughput nuclear magnetic resonance (NMR) spectroscopy		Term plus 6 weeks corrected

Collaborators and Investigators

• Sponsor: Imperial College London
• Investigators: Principal Investigator: Neena Modi, MBChB, Imperial College London

Study record dates

Study Major Dates

• Study Start (Actual): April 2, 2013
• Primary Completion (Actual): October 1, 2020
• Study Completion (Actual): October 1, 2020

Study Registration Dates

• First Submitted: August 7, 2012
• First Submitted That Met QC Criteria: September 12, 2012
• First Posted (Estimated): September 18, 2012

Study Record Updates

• Last Update Posted (Actual): April 26, 2024
• Last Update Submitted That Met QC Criteria: October 31, 2023
• Last Verified: October 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Hyperinsulinism; Insulin Resistance
• Other Study ID Numbers: CRO2006