Iron Supplementation and Intestinal Health

Phase 4

Recruiting

• Conditions: Anemia of Prematurity; Very Low Birth Weight Infant
• Interventions: Drug: 2mg/kg/day Iron Sulfate; Drug: 6 mg/kg/day Iron Sulfate

• Registration Number: NCT04497012
• Lead Sponsor: University of South Florida

Brief Summary

This is a randomized double-blinded study of enteral iron supplementation in Very Low Birth Weight infants. The subjects will be randomized into low dose (2 mg/kg/day) and high dose (6 mg/kg/day) of daily iron supplementation. The primary outcomes are intestinal health including microbiome, inflammation, and barrier function.

Detailed Description

Infants and mothers will be recruited at a single academic level III NICU at Tampa General Hospital, Tampa, FL. Inclusion criteria infants: \<1500 g at birth, expected to live beyond 2 weeks, not yet started on oral iron supplementation (OIS), and parental consent. Exclusion criteria infants: congenital intestinal defects, history of intestinal infection or perforation before OIS. Infants who require epogen for religious reason to prevent them from getting blood transfusions will be excluded from the study.

Intervention: Participants will be randomized to either 6 mg/kg/day or 2 mg/kg/day total of elemental iron once a day when they are consuming 150-160 ml/kg/day of enteral feeds and are at least 14 days old. The total iron doses will be provided by fortification of feeds and liquid iron sulfate and will be weight adjusted once a week. The participants will receive the study OIS doses until 36 week corrected gestational age or discharge, whichever comes first.

Sample collection and testing:

1. Stool and urine collection: We will collect weekly stool and urine samples non-invasively starting at enrollment until study completion. Samples will be collected from soiled diapers.

2. Blood tests: We will collect C-reactive protein (CRP) and ferritin level at 4 weeks after birth at the same time as other routine labs (complete blood count, reticulocyte count, and liver function test).

3. Monaural auditory brainstem response (ABR): for each ear will be performed at 36 weeks corrected gestational age or at discharge under the supervision of an audiologist who is blinded to the infants assigned iron doses and test results (stool microbiome, blood and urine tests).

Monitoring: iron supplementation dose will be increased by 2 mg/kg/day if ferritin level \<100 mg/dL and the dose will be held if ferritin level \>400 mg/dL. Ferritin level will be rechecked every 2 weeks until normalized. Hematocrit and reticulocyte count will be monitored by the medical team.

Study Timeline

• Study First Submitted: 2020-07-20
• Study First Submitted QC: 2020-07-31
• Study First Posted: 2020-08-04
• Study Start: 2020-11-17
• Status Verified: 2024-01
• Last Update Submitted: 2025-01-17
• Last Update Posted: 2025-01-22
• Primary Completion: 2025-03-30
• Study Completion: 2025-07-31

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 183

Inclusion Criteria

• <1500 g at birth, expected to live beyond 2 weeks, not yet started on oral iron supplementation (OIS), with mother at least 18 years of age, and parental consent.

Exclusion Criteria

• congenital intestinal defects, history of intestinal infection or perforation before OIS. Infants who require epogen for religious reason to prevent them from getting blood transfusions will be excluded from the study.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Low Iron Sulfate Supplementation	2mg/kg/day Iron Sulfate	Participants will be given 2 mg/kg/day total of elemental iron once a day when they are consuming 150-160 ml/kg/day of enteral feeds and are at least 14 days old. The total iron doses will be provided by fortification of feeds and liquid iron sulfate and will be weight adjusted once a week. The participants will receive the study iron dose until 36 week corrected gestational age or discharge, whichever comes first.
High Iron Sulfate Supplementation	6 mg/kg/day Iron Sulfate	Participants will be given 6 mg/kg/day total of elemental iron once a day when they are consuming 150-160 ml/kg/day of enteral feeds and are at least 14 days old. The total iron doses will be provided by fortification of feeds and liquid iron sulfate and will be weight adjusted once a week. The participants will receive the study iron dose until 36 week corrected gestational age or discharge, whichever comes first.

Primary Outcome Measures

Name	Time	Method
Change in stool bacterial percentages from before to after iron supplementation	from baseline to 1 week and 2 weeks after iron supplementation started	Comparing the changes in the median percentages of stool bacteria between the two groups. Change = post-iron (1 week, 2 weeks after iron and at discharge) - pre-iron
Change in fecal calprotectin from before to after iron supplementation	from baseline to 1 week and 2 weeks after iron supplementation started	Comparing the mean fecal calprotectin levels, an inflammatory stool biomarker, between the two groups. Change = post-iron (1 week, 2 weeks after iron and at discharge) - pre-iron.
Change in urine Claudin-3 and I-FABP from before to after iron supplementation	from baseline to 1 week and 2 weeks after iron supplementation started	Comparing the mean urine claudin-3 and I-FABP levels, biomarkers for intestinal barrier function, between the two groups. Change = post-iron (1 week, 2 weeks after iron and at discharge) - pre-iron

Secondary Outcome Measures

Name	Time	Method
Level of Iron storage	at 4 weeks after birth	Comparing the mean Ferritin levels between the two groups at 4 weeks after birth
Rate of auditory myelination	up to 36 weeks corrected gestational age	Comparing the mean auditory latency levels between the two groups at 36 weeks corrected gestational age or at discharge.

Trial Locations

Locations (1)

Tampa General Hospital; 🇺🇸 Tampa, Florida, United States