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

Not Applicable

Completed

• Conditions: Premature Birth; Oxidative Stress; Very Low Birth Weight Baby; Microbial Colonization
• Interventions: Dietary Supplement: H2MF

• Registration Number: NCT03214822
• Lead Sponsor: University of Manitoba

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:

1. 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.

2. 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.

Basic Information
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Recruitment & Eligibility
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Study & Design
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Trial Locations

Study Timeline

• Study First Submitted: 2017-07-05
• Study First Submitted QC: 2017-07-07
• Study First Posted: 2017-07-12
• Study Start: 2017-08-01
• Primary Completion: 2019-07-30
• Study Completion: 2019-07-30
• Status Verified: 2019-09
• Last Update Submitted: 2019-09-26
• Last Update Posted: 2019-09-30

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 30

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.

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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

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
H2MF	H2MF	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.

Primary Outcome Measures

Name	Time	Method
Fecal microbiome composition at end of intervention	33+0 weeks adjusted gestational age (end of intervention)	Relative abundance of operational taxonomic units (OTUs) determined by 16S rRNA Illumina sequencing
Fecal microbiome diversity at end of intervention	33+0 weeks adjusted gestational age (end of intervention)	Shannon diversity index of microbiota, determined by 16S rRNA Illumina sequencing
Fecal microbiome community structure at end of intervention	33+0 weeks adjusted gestational age (end of intervention)	Principal coordinate analysis using UniFrac distance matrices based on 16S rRNA Illumina sequencing

Secondary Outcome Measures

Name	Time	Method
Fecal microbiome at 1 week after intervention begins	Study day 7 (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	35+0 weeks adjusted gestational age (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	33+0 weeks adjusted gestational age (end of intervention)	F2-isoprostanes, 8-hydroxy deoxyguanine, and visfatin measured in urine.
Oxidative stress (fecal calprotectin) at end of intervention	33+0 weeks adjusted gestational age (end of intervention)	Calprotectin measured in feces
Oxidative stress at 1 week after intervention begins	Study day 7 (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	35+0 weeks adjusted gestational age (2 weeks after intervention ends)	Fecal and urinary biomarkers of oxidative stress (fecal calprotectin, urinary F2-isoprostanes, urinary 8-hydroxy deoxyguanine, urinary visfatin).

Trial Locations

Locations (1)

Health Sciences Centre; 🇨🇦 Winnipeg, Manitoba, Canada