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.

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.

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.

The participants, care givers, medical teams, investigator, and outcome assessors are blinded from the iron treatment dose for the duration of the study. Only research pharmacists and members of the Data and Safety Monitor Board are unblinded during the study period.

In an event when the medical team urgently needs to know the iron dose the participant is receiving for proper clinical management of the subject, the principal investigator or a designee will be notified by cell phone. Their contact information are located in the medical workrooms and the unit pharmacy. The principal investigator or the designee will immediately call the research pharmacy phone to request an emergency unblinding of that particular participant. The principal investigator will inform IRB and the sponsor of the unblinding event within 24 hours.