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

Oxidative Stress Clinical Trial

Official title:

The Impact of Human-derived Human Milk Fortifiers (H2MF) on Gut Microbiota Development and Oxidative Stress in Premature Infants

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03214822
• Other study ID #: H2MF Study
• Status: Completed
• Phase: N/A
• Start date: August 1, 2017
• Est. completion date: July 30, 2019

Study information

• Verified date: September 2019
• Source: University of Manitoba
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 30
• Est. completion date: July 30, 2019
• Est. primary completion date: July 30, 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: N/A to 7 Days

Eligibility

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

Related Conditions & MeSH terms

• Birth Weight
• Communicable Diseases
• Infection
• Microbial Colonization
• Oxidative Stress
• Premature Birth
• Very Low Birth Weight Baby

Intervention

Dietary Supplement:
• H2MF
As described in the Experimental Arm description.

Locations

Country	Name	City	State
Canada	Health Sciences Centre	Winnipeg	Manitoba

Sponsors (4)

Lead Sponsor	Collaborator
University of Manitoba	Children's Hospital Foundation, Manitoba Developmental Origins of Chronic Diseases in Children Network (DEVOTION), Prolacta Bioscience

Country where clinical trial is conducted

Canada, 

References & Publications (8)

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. — View 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. — View 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. — View 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. — View 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. Review. — View 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. Review. — View Citation

Sullivan S, Schanler RJ, Kim JH, Patel AL, Trawöger 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. — View 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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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)
Primary	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)
Primary	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	Fecal microbiome at 1 week after intervention begins	Fecal microbiome composition, diversity and community structure from 16S rRNA Illumina Sequencing.	Study day 7 (1 week after intervention begins)
Secondary	Fecal microbiome at 2 weeks after intervention ends	Fecal microbiome composition, diversity and community structure from 16S rRNA Illumina Sequencing.	35+0 weeks adjusted gestational age (2 weeks after intervention ends)
Secondary	Oxidative stress (urinary biomarkers) at end of intervention	F2-isoprostanes, 8-hydroxy deoxyguanine, and visfatin measured in urine.	33+0 weeks adjusted gestational age (end of intervention)
Secondary	Oxidative stress (fecal calprotectin) at end of intervention	Calprotectin measured in feces	33+0 weeks adjusted gestational age (end of intervention)
Secondary	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).	Study day 7 (1 week after intervention begins)
Secondary	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).	35+0 weeks adjusted gestational age (2 weeks after intervention ends)