Iron Supplementation and Intestinal Health

Enteral Iron Supplementation and Intestinal Health in Preterm Infants

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.

Study Overview

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

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 Type: Interventional
• Enrollment (Estimated): 183
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Marcia Kneusel; Phone Number: 813-844-3395; Email: mkneusel@usf.edu

Study Locations

• United States
  • Florida
    • Tampa, Florida, United States, 33606
      • Recruiting
      • Tampa General Hospital
      • Contact: Marcia Kneusel; Phone Number: 813-844-3395

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 day to 6 months (Child)
• Accepts Healthy Volunteers: Yes

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Low Iron Sulfate Supplementation; 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; Iron Sulfate will be given in liquid form via nasal or oral gastric tube with feeds.; Other Names: Low dose iron supplementation
Active Comparator: High Iron Sulfate Supplementation; 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; Iron Sulfate will be given in liquid form via nasal or oral gastric tube with feeds.; Other Names: High dose iron supplementation

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: University of South Florida
• Collaborators: National Heart, Lung, and Blood Institute (NHLBI)

Publications and helpful links

General Publications

• Zimmermann MB, Chassard C, Rohner F, N'goran EK, Nindjin C, Dostal A, Utzinger J, Ghattas H, Lacroix C, Hurrell RF. The effects of iron fortification on the gut microbiota in African children: a randomized controlled trial in Cote d'Ivoire. Am J Clin Nutr. 2010 Dec;92(6):1406-15. doi: 10.3945/ajcn.110.004564. Epub 2010 Oct 20.
• Krebs NF, Sherlock LG, Westcott J, Culbertson D, Hambidge KM, Feazel LM, Robertson CE, Frank DN. Effects of different complementary feeding regimens on iron status and enteric microbiota in breastfed infants. J Pediatr. 2013 Aug;163(2):416-23. doi: 10.1016/j.jpeds.2013.01.024. Epub 2013 Feb 26.
• Jaeggi T, Kortman GA, Moretti D, Chassard C, Holding P, Dostal A, Boekhorst J, Timmerman HM, Swinkels DW, Tjalsma H, Njenga J, Mwangi A, Kvalsvig J, Lacroix C, Zimmermann MB. Iron fortification adversely affects the gut microbiome, increases pathogen abundance and induces intestinal inflammation in Kenyan infants. Gut. 2015 May;64(5):731-42. doi: 10.1136/gutjnl-2014-307720. Epub 2014 Aug 20.
• Strauss RG. Anaemia of prematurity: pathophysiology and treatment. Blood Rev. 2010 Nov;24(6):221-5. doi: 10.1016/j.blre.2010.08.001.
• Mills RJ, Davies MW. Enteral iron supplementation in preterm and low birth weight infants. Cochrane Database Syst Rev. 2012 Mar 14;2012(3):CD005095. doi: 10.1002/14651858.CD005095.pub2.
• Tang M, Frank DN, Hendricks AE, Ir D, Esamai F, Liechty E, Hambidge KM, Krebs NF. Iron in Micronutrient Powder Promotes an Unfavorable Gut Microbiota in Kenyan Infants. Nutrients. 2017 Jul 19;9(7):776. doi: 10.3390/nu9070776.

Study record dates

Study Major Dates

• Study Start (Actual): November 17, 2020
• Primary Completion (Estimated): March 30, 2025
• Study Completion (Estimated): July 31, 2025

Study Registration Dates

• First Submitted: July 20, 2020
• First Submitted That Met QC Criteria: July 31, 2020
• First Posted (Actual): August 4, 2020

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: January 17, 2025
• Last Verified: January 1, 2024

More Information

Terms related to this study

• Keywords: intestinal dysbiosis
• Additional Relevant MeSH Terms: Body Weight; Birth Weight; Physiological Effects of Drugs; Trace Elements; Micronutrients; Iron
• Other Study ID Numbers: Pro00041470

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes