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Human-derived Human Milk Fortifiers (H2MF), Gut Microbiota and Oxidative Stress in Premature Infants

Primary Purpose

Very Low Birth Weight Baby, Premature Birth, Microbial Colonization

Status
Completed
Phase
Not Applicable
Locations
Canada
Study Type
Interventional
Intervention
H2MF
Sponsored by
University of Manitoba
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional basic science trial for Very Low Birth Weight Baby focused on measuring Microbiome

Eligibility Criteria

undefined - 7 Days (Child)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Male or female infant with birth weight <1250 grams
  • Gestational age between 26+0 to 30+0 weeks at birth
  • Able to adhere to feeding protocol
  • Parenteral nutrition must be started by day of life 2
  • Enteral feeding >80 ml/kg/d should be reached by day of life 14
  • Subject's parent(s)/legal guardian(s) has provided signed and dated informed consent and authorization to use protected health information, as required by national and local regulations.
  • In the investigator's opinion, the subject's parent(s)/legal guardian(s) understands and is able to comply with protocol requirements, instructions, and protocol-stated restrictions, and is likely to complete the study as planned.

Exclusion Criteria:

  • Gestational age > 30+0 weeks at birth (to guarantee a minimum of 3 weeks H2MF treatment, since fortification ends at 33+0 AGA)
  • Gestational age < 26+0 weeks at birth (to minimize baseline heterogeneity, since gestational age influences gut microbiota)
  • Received antibiotics on the first day of specimen collection (to minimize baseline heterogeneity, since antibiotics influence gut microbiota) Note: all infants are expected to receive up to 48 hr antibiotic prophylaxis at birth according to standard NICU protocol; this criterion will exclude infants receiving extended courses of antibiotics.
  • Received probiotics at any time (to minimize baseline heterogeneity, since probiotics influence gut microbiota)
  • Unlikely to survive the study period
  • Presence of clinically significant congenital heart disease or other major congenital malformation
  • Presence prior to enrollment of intestinal perforation or stage 2 necrotizing enterocolitis (NEC) prior to tolerating fortified feeds

Sites / Locations

  • Health Sciences Centre

Arms of the Study

Arm 1

Arm 2

Arm Type

No Intervention

Experimental

Arm Label

HMF (standard of care)

H2MF

Arm Description

The HMF "Control Group" will receive the current standard feeding protocol of human milk fortified with bovine (cow) human milk fortifier (HMF)

The H2MF "Intervention Group" will receive identical treatment with human-derived human milk fortifier (H2MF) replacing standard bovine HMF until the baby reaches an adjusted gestation age of 33 weeks; followed by a 5 day ween to standard HMF according to the manufacturer's recommendation.

Outcomes

Primary Outcome Measures

Fecal microbiome composition at end of intervention
Relative abundance of operational taxonomic units (OTUs) determined by 16S rRNA Illumina sequencing
Fecal microbiome diversity at end of intervention
Shannon diversity index of microbiota, determined by 16S rRNA Illumina sequencing
Fecal microbiome community structure at end of intervention
Principal coordinate analysis using UniFrac distance matrices based on 16S rRNA Illumina sequencing

Secondary Outcome Measures

Fecal microbiome at 1 week after intervention begins
Fecal microbiome composition, diversity and community structure from 16S rRNA Illumina Sequencing.
Fecal microbiome at 2 weeks after intervention ends
Fecal microbiome composition, diversity and community structure from 16S rRNA Illumina Sequencing.
Oxidative stress (urinary biomarkers) at end of intervention
F2-isoprostanes, 8-hydroxy deoxyguanine, and visfatin measured in urine.
Oxidative stress (fecal calprotectin) at end of intervention
Calprotectin measured in feces
Oxidative stress at 1 week after intervention begins
Fecal and urinary biomarkers of oxidative stress (fecal calprotectin, urinary F2-isoprostanes, urinary 8-hydroxy deoxyguanine, urinary visfatin).
Oxidative stress at 2 weeks after intervention ends
Fecal and urinary biomarkers of oxidative stress (fecal calprotectin, urinary F2-isoprostanes, urinary 8-hydroxy deoxyguanine, urinary visfatin).

Full Information

First Posted
July 5, 2017
Last Updated
September 26, 2019
Sponsor
University of Manitoba
Collaborators
Manitoba Developmental Origins of Chronic Diseases in Children Network (DEVOTION), Prolacta Bioscience, Children's Hospital Foundation
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1. Study Identification

Unique Protocol Identification Number
NCT03214822
Brief Title
Human-derived Human Milk Fortifiers (H2MF), Gut Microbiota and Oxidative Stress in Premature Infants
Official Title
The Impact of Human-derived Human Milk Fortifiers (H2MF) on Gut Microbiota Development and Oxidative Stress in Premature Infants
Study Type
Interventional

2. Study Status

Record Verification Date
September 2019
Overall Recruitment Status
Completed
Study Start Date
August 1, 2017 (Actual)
Primary Completion Date
July 30, 2019 (Actual)
Study Completion Date
July 30, 2019 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
University of Manitoba
Collaborators
Manitoba Developmental Origins of Chronic Diseases in Children Network (DEVOTION), Prolacta Bioscience, Children's Hospital Foundation

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Product Manufactured in and Exported from the U.S.
Yes
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
This is a randomized controlled trial of a human-derived human milk fortifier (H2MF) vs standard bovine-derived human milk fortifier (HMF) evaluating fecal microbiota and fecal and urinary biomarkers of oxidative stress in premature infants.
Detailed Description
While breast milk provides complete nutrition for full term infants, supplementation with human milk fortifiers (HMF) is required to achieve optimal weight gain in very low birthweight (VLBW) preterm neonates. Traditionally, HMF have been derived from bovine milk. Bovine-based infant formula has been shown to cause dysbiosis of the infant gut microbiome (Azad et al 2013) and increased oxidative stress in preterm neonates (Friel et al 2011). Microbiome dysbiosis and oxidative stress have been implicated in numerous inflammatory conditions, including both acute (eg. necrotizing enterocolitis, NEC) and long-term (eg. asthma, metabolic syndrome) sequela of preterm birth (Torrazza et al 2013, Goulet et al 2015, Flora et al 2007, Perrone et al 2014). Recent studies show that new human-derived HMF (H2MF) are superior to standard bovine HMF for nourishing VLBW preterm infants and preventing NEC (Sullivan et al 2010, Cristofalo et al 2013). However, the biological basis for these clinical benefits is unknown, which limits our ability to inform and improve feeding strategies for VLBW preterm infants. This will be the first study to evaluate the impact of H2MF on gut microbiota and oxidative stress in preterm infants. Specific Objectives: To evaluate the effect of H2MF vs. HMF on gut microbiota composition in premature infants born <1250 gr between 26 and 30 weeks of gestational age. To evaluate the effect of H2MF vs. HMF on fecal and urinary biomarkers of oxidative stress in premature infants born <1250 gr between 26 and 30 weeks of gestational age.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Very Low Birth Weight Baby, Premature Birth, Microbial Colonization, Oxidative Stress
Keywords
Microbiome

7. Study Design

Primary Purpose
Basic Science
Study Phase
Not Applicable
Interventional Study Model
Parallel Assignment
Model Description
Using a randomized, controlled, un-blinded parallel design we will enroll 30 VLBW premature neonates (birth weight < 1250 grams, gestational age 26+0 to 30+0 weeks) from the NICU at the Health Sciences Centre Children's Hospital in Winnipeg, MB, Canada. Currently, H2MF is not routinely used in this population at this centre.
Masking
InvestigatorOutcomes Assessor
Masking Description
Masking of care providers is not feasible since the procedures of preparation for HMF and H2MF are different. Outcome assessors (personnel analyzing microbiome profiles and oxidative stress biomarkers) will be masked.
Allocation
Randomized
Enrollment
30 (Actual)

8. Arms, Groups, and Interventions

Arm Title
HMF (standard of care)
Arm Type
No Intervention
Arm Description
The HMF "Control Group" will receive the current standard feeding protocol of human milk fortified with bovine (cow) human milk fortifier (HMF)
Arm Title
H2MF
Arm Type
Experimental
Arm Description
The H2MF "Intervention Group" will receive identical treatment with human-derived human milk fortifier (H2MF) replacing standard bovine HMF until the baby reaches an adjusted gestation age of 33 weeks; followed by a 5 day ween to standard HMF according to the manufacturer's recommendation.
Intervention Type
Dietary Supplement
Intervention Name(s)
H2MF
Intervention Description
As described in the Experimental Arm description.
Primary Outcome Measure Information:
Title
Fecal microbiome composition at end of intervention
Description
Relative abundance of operational taxonomic units (OTUs) determined by 16S rRNA Illumina sequencing
Time Frame
33+0 weeks adjusted gestational age (end of intervention)
Title
Fecal microbiome diversity at end of intervention
Description
Shannon diversity index of microbiota, determined by 16S rRNA Illumina sequencing
Time Frame
33+0 weeks adjusted gestational age (end of intervention)
Title
Fecal microbiome community structure at end of intervention
Description
Principal coordinate analysis using UniFrac distance matrices based on 16S rRNA Illumina sequencing
Time Frame
33+0 weeks adjusted gestational age (end of intervention)
Secondary Outcome Measure Information:
Title
Fecal microbiome at 1 week after intervention begins
Description
Fecal microbiome composition, diversity and community structure from 16S rRNA Illumina Sequencing.
Time Frame
Study day 7 (1 week after intervention begins)
Title
Fecal microbiome at 2 weeks after intervention ends
Description
Fecal microbiome composition, diversity and community structure from 16S rRNA Illumina Sequencing.
Time Frame
35+0 weeks adjusted gestational age (2 weeks after intervention ends)
Title
Oxidative stress (urinary biomarkers) at end of intervention
Description
F2-isoprostanes, 8-hydroxy deoxyguanine, and visfatin measured in urine.
Time Frame
33+0 weeks adjusted gestational age (end of intervention)
Title
Oxidative stress (fecal calprotectin) at end of intervention
Description
Calprotectin measured in feces
Time Frame
33+0 weeks adjusted gestational age (end of intervention)
Title
Oxidative stress at 1 week after intervention begins
Description
Fecal and urinary biomarkers of oxidative stress (fecal calprotectin, urinary F2-isoprostanes, urinary 8-hydroxy deoxyguanine, urinary visfatin).
Time Frame
Study day 7 (1 week after intervention begins)
Title
Oxidative stress at 2 weeks after intervention ends
Description
Fecal and urinary biomarkers of oxidative stress (fecal calprotectin, urinary F2-isoprostanes, urinary 8-hydroxy deoxyguanine, urinary visfatin).
Time Frame
35+0 weeks adjusted gestational age (2 weeks after intervention ends)

10. Eligibility

Sex
All
Maximum Age & Unit of Time
7 Days
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Male or female infant with birth weight <1250 grams Gestational age between 26+0 to 30+0 weeks at birth Able to adhere to feeding protocol Parenteral nutrition must be started by day of life 2 Enteral feeding >80 ml/kg/d should be reached by day of life 14 Subject's parent(s)/legal guardian(s) has provided signed and dated informed consent and authorization to use protected health information, as required by national and local regulations. In the investigator's opinion, the subject's parent(s)/legal guardian(s) understands and is able to comply with protocol requirements, instructions, and protocol-stated restrictions, and is likely to complete the study as planned. Exclusion Criteria: Gestational age > 30+0 weeks at birth (to guarantee a minimum of 3 weeks H2MF treatment, since fortification ends at 33+0 AGA) Gestational age < 26+0 weeks at birth (to minimize baseline heterogeneity, since gestational age influences gut microbiota) Received antibiotics on the first day of specimen collection (to minimize baseline heterogeneity, since antibiotics influence gut microbiota) Note: all infants are expected to receive up to 48 hr antibiotic prophylaxis at birth according to standard NICU protocol; this criterion will exclude infants receiving extended courses of antibiotics. Received probiotics at any time (to minimize baseline heterogeneity, since probiotics influence gut microbiota) Unlikely to survive the study period Presence of clinically significant congenital heart disease or other major congenital malformation Presence prior to enrollment of intestinal perforation or stage 2 necrotizing enterocolitis (NEC) prior to tolerating fortified feeds
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Meghan Azad, PhD
Organizational Affiliation
University of Manitoba
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Geert T'Jong
Organizational Affiliation
University of Manitoba
Official's Role
Study Director
Facility Information:
Facility Name
Health Sciences Centre
City
Winnipeg
State/Province
Manitoba
Country
Canada

12. IPD Sharing Statement

Plan to Share IPD
Undecided
IPD Sharing Plan Description
At this time we plan to share IPD within our research team only. We will consider sharing with other researchers in the future.
Citations:
PubMed Identifier
23401405
Citation
Azad MB, Konya T, Maughan H, Guttman DS, Field CJ, Chari RS, Sears MR, Becker AB, Scott JA, Kozyrskyj AL; CHILD Study Investigators. Gut microbiota of healthy Canadian infants: profiles by mode of delivery and infant diet at 4 months. CMAJ. 2013 Mar 19;185(5):385-94. doi: 10.1503/cmaj.121189. Epub 2013 Feb 11.
Results Reference
background
PubMed Identifier
21045751
Citation
Friel JK, Diehl-Jones B, Cockell KA, Chiu A, Rabanni R, Davies SS, Roberts LJ 2nd. Evidence of oxidative stress in relation to feeding type during early life in premature infants. Pediatr Res. 2011 Feb;69(2):160-4. doi: 10.1203/PDR.0b013e3182042a07.
Results Reference
background
PubMed Identifier
24386174
Citation
Torrazza RM, Ukhanova M, Wang X, Sharma R, Hudak ML, Neu J, Mai V. Intestinal microbial ecology and environmental factors affecting necrotizing enterocolitis. PLoS One. 2013 Dec 30;8(12):e83304. doi: 10.1371/journal.pone.0083304. eCollection 2013.
Results Reference
background
PubMed Identifier
26175488
Citation
Goulet O. Potential role of the intestinal microbiota in programming health and disease. Nutr Rev. 2015 Aug;73 Suppl 1:32-40. doi: 10.1093/nutrit/nuv039.
Results Reference
background
PubMed Identifier
17535753
Citation
Flora SJ. Role of free radicals and antioxidants in health and disease. Cell Mol Biol (Noisy-le-grand). 2007 Apr 15;53(1):1-2. No abstract available.
Results Reference
background
PubMed Identifier
25088341
Citation
Perrone S, Tataranno ML, Santacroce A, Negro S, Buonocore G. The role of oxidative stress on necrotizing enterocolitis in very low birth weight infants. Curr Pediatr Rev. 2014;10(3):202-7.
Results Reference
background
PubMed Identifier
20036378
Citation
Sullivan S, Schanler RJ, Kim JH, Patel AL, Trawoger R, Kiechl-Kohlendorfer U, Chan GM, Blanco CL, Abrams S, Cotten CM, Laroia N, Ehrenkranz RA, Dudell G, Cristofalo EA, Meier P, Lee ML, Rechtman DJ, Lucas A. An exclusively human milk-based diet is associated with a lower rate of necrotizing enterocolitis than a diet of human milk and bovine milk-based products. J Pediatr. 2010 Apr;156(4):562-7.e1. doi: 10.1016/j.jpeds.2009.10.040. Epub 2009 Dec 29.
Results Reference
background
PubMed Identifier
23968744
Citation
Cristofalo EA, Schanler RJ, Blanco CL, Sullivan S, Trawoeger R, Kiechl-Kohlendorfer U, Dudell G, Rechtman DJ, Lee ML, Lucas A, Abrams S. Randomized trial of exclusive human milk versus preterm formula diets in extremely premature infants. J Pediatr. 2013 Dec;163(6):1592-1595.e1. doi: 10.1016/j.jpeds.2013.07.011. Epub 2013 Aug 20.
Results Reference
background
PubMed Identifier
36029771
Citation
Kumbhare SV, Jones WD, Fast S, Bonner C, Jong G', Van Domselaar G, Graham M, Narvey M, Azad MB. Source of human milk (mother or donor) is more important than fortifier type (human or bovine) in shaping the preterm infant microbiome. Cell Rep Med. 2022 Sep 20;3(9):100712. doi: 10.1016/j.xcrm.2022.100712. Epub 2022 Aug 26.
Results Reference
derived

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Human-derived Human Milk Fortifiers (H2MF), Gut Microbiota and Oxidative Stress in Premature Infants

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