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

NCT03214822 | Completed DMC

• 1 other identifier: H2MF Study
• Study Type: interventional
• Target: 30
• Locations: 1 country
• Sites: 1

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.

Conditions

Very Low Birth Weight Baby; Premature Birth; Microbial Colonization; Oxidative Stress

Keywords

Microbiome

Outcome Measures

Primary Outcomes (3)

• Fecal microbiome composition at end of intervention

  Relative abundance of operational taxonomic units (OTUs) determined by 16S rRNA Illumina sequencing

  33+0 weeks adjusted gestational age (end of intervention)

• Fecal microbiome diversity at end of intervention

  Shannon diversity index of microbiota, determined by 16S rRNA Illumina sequencing

  33+0 weeks adjusted gestational age (end of intervention)

• Fecal microbiome community structure at end of intervention

  Principal coordinate analysis using UniFrac distance matrices based on 16S rRNA Illumina sequencing

  33+0 weeks adjusted gestational age (end of intervention)

Secondary Outcomes (6)

• Fecal microbiome at 1 week after intervention begins

  Study day 7 (1 week after intervention begins)

• Fecal microbiome at 2 weeks after intervention ends

  35+0 weeks adjusted gestational age (2 weeks after intervention ends)

• Oxidative stress (urinary biomarkers) at end of intervention

  33+0 weeks adjusted gestational age (end of intervention)

• Oxidative stress (fecal calprotectin) at end of intervention

  33+0 weeks adjusted gestational age (end of intervention)

• Oxidative stress at 1 week after intervention begins

  Study day 7 (1 week after intervention begins)

Study Arms (2)

HMF (standard of care)

NO INTERVENTION

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

H2MF

EXPERIMENTAL

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.

Dietary Supplement: H2MF

Interventions

H2MF DIETARY_SUPPLEMENT

As described in the Experimental Arm description.

H2MF

Eligibility Criteria

• Age: Up to 7 Days
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• 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.

You may not qualify if:

• 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

Sponsors & Collaborators

• University of Manitoba: lead
• Manitoba Developmental Origins of Chronic Diseases in Children Network (DEVOTION): collaborator
• Prolacta Bioscience: collaborator
• Children's Hospital Foundation: collaborator

Study Sites (1)

Health Sciences Centre

Winnipeg, Manitoba, Canada

Location

Related Publications (9)

• 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.

  PMID: 23401405 BACKGROUND

• 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.

  PMID: 21045751 BACKGROUND

• 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.

  PMID: 24386174 BACKGROUND

• 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.

  PMID: 26175488 BACKGROUND

• 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.

  PMID: 17535753 BACKGROUND

• 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.

  PMID: 25088341 BACKGROUND

• 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.

  PMID: 20036378 BACKGROUND

• 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.

  PMID: 23968744 BACKGROUND

• 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.

  PMID: 36029771 DERIVED

MeSH Terms

Conditions

Premature Birth; Communicable Diseases

Condition Hierarchy (Ancestors)

Obstetric Labor, Premature; Obstetric Labor Complications; Pregnancy Complications; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Infections; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Study Officials

• Meghan Azad, PhD

  University of Manitoba

  PRINCIPAL INVESTIGATOR

• Geert T'Jong

  University of Manitoba

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: 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.
• Purpose: BASIC SCIENCE
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Prinicpal Investigator

Model Details: 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.

Study Record Dates

• First Submitted: July 5, 2017
• First Posted: July 12, 2017
• Study Start: August 1, 2017
• Primary Completion: July 30, 2019
• Study Completion: July 30, 2019
• Last Updated: September 30, 2019

Record last verified: 2019-09

Locations

CA (1)