Iron Supplementation and Intestinal Health

Study Overview
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Brief Summary
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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
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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: 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. 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). 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.

Official Title
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Enteral Iron Supplementation and Intestinal Health in Preterm Infants

Conditions
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Anemia of Prematurity, Very Low Birth Weight Infant

Intervention / Treatment
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* Drug: 2mg/kg/day Iron Sulfate
* Drug: 6 mg/kg/day Iron Sulfate


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 1 Day
Maximum Age: 6 Months

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Randomize subjects to low and high dose iron supplementations
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Low Iron Sulfate Supplementation<br>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. | Drug: 2mg/kg/day Iron Sulfate<br>* Iron Sulfate will be given in liquid form via nasal or oral gastric tube with feeds.<br>* Other names: Low dose iron supplementation;|
| Active Comparator: High Iron Sulfate Supplementation<br>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. | Drug: 6 mg/kg/day Iron Sulfate<br>* Iron Sulfate will be given in liquid form via nasal or oral gastric tube with feeds.<br>* Other names: High dose iron supplementation;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in stool bacterial percentages from before to after iron supplementation | 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 | from baseline to 1 week and 2 weeks after iron supplementation started | 
| Change in fecal calprotectin from before to after iron supplementation | 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. | from baseline to 1 week and 2 weeks after iron supplementation started | 
| Change in urine Claudin-3 and I-FABP from before to after iron supplementation | 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 | from baseline to 1 week and 2 weeks after iron supplementation started | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of auditory myelination | Comparing the mean auditory latency levels between the two groups at 36 weeks corrected gestational age or at discharge. | up to 36 weeks corrected gestational age | 
| Level of Iron storage | Comparing the mean Ferritin levels between the two groups at 4 weeks after birth | at 4 weeks after birth | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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intestinal dysbiosis