Enhancing Treatment of Iron Deficiency and Iron Deficiency Anemia With an Antioxidant, Vitamin E
Enhancing Treatment of Iron Deficiency and Iron Deficiency Anemia With an Antioxidant, Vitamin E
The study addresses treatment of iron deficiency, the most common nutritional deficiency that
 infants and young children encounter. With the knowledge that iron deficiency may
 irreversibly affect a baby's long-term neurodevelopment and behavior, the investigators are
 offering free screening blood draws at Children's Hospital Colorado to older babies and
 toddlers (9-24 months old). If their blood results indicate a serum ferritin of ≤ 15
 micrograms/dL without the presence of an elevated C-reactive protein (CRP), they will be
 invited to continue in the intervention portion of the study, where they will receive iron
 supplements as well as vitamin E (or placebo) for an eight week treatment period. The
 rationale for the study is to test whether addition of Vitamin E, an antioxidant and
 anti-inflammatory agent, improves the treatment response to supplemental iron.
Enhancing Treatment of Iron Deficiency and Iron Deficiency Anemia with an Antioxidant,
 Vitamin E

 Synopsis/Abstract Iron Deficiency (ID) and Iron Deficiency Anemia (IDA) are common in older
 breastfed infants and toddlers. Treatment of 3-6 mg iron/kg/day is recommended by the
 American Academy of Pediatrics (AAP), but this regimen often results in only modest changes
 in iron status, despite being a substantially higher dose (relative to body weight) than is
 commonly used for adults. We propose that high therapeutic doses of iron induce an
 inflammatory response, thus increasing hepatic synthesis of a critical regulator of iron
 absorption, hepcidin, which functions to limit iron absorption in the context of
 inflammation. In infants and toddlers found to have ID or IDA, we propose to evaluate the
 efficacy of the addition of Vitamin E to iron therapy compared with the same dose of iron
 alone. Our primary hypothesis is that in infants and toddlers with ID or IDA, 2 months of
 supplemental Vitamin E combined with therapeutic iron supplementation will be more
 efficacious than the same dose of iron alone. The study design is a randomized, double blind
 efficacy trial of 2 months of iron therapy (6 mg/kg/day) with or without Vitamin E (18
 mg/day), in infants and toddlers with ID or IDA from 9 to 24 months of age. Primary outcomes
 include biomarkers of iron status (ferritin, hemoglobin, transferrin saturation, and
 transferrin receptor); secondary outcomes include biomarkers of inflammation and oxidant
 stress. Subjects: We will screen older infants (9-12 months of age) who were predominantly
 breastfed through at least the first 9 months of life, and toddlers (12-24 months of age) who
 were breastfed and/or who have modest dietary iron intakes. Intervention: Sixty-eight
 subjects found to have ID or IDA will be consented and randomized to one of the two treatment
 regimens (34 subjects per group). Liquid supplement preparations of iron (both groups),
 Vitamin E (test) and placebo (control) will be distributed by the research pharmacy at The
 Children's Hospital.Children's Hospital Colorado. Outcomes: Biomarkers of iron status, iron
 homeostasis, oxidant stress, and of systemic and intestinal inflammation will be repeated at
 the end of the intervention. If the hypotheses are supported, the findings would provide a
 simple and effective modification to enhance iron therapy, and to improve the balance between
 adequate iron uptake to meet physiologic needs and excessive iron intake and its potential
 adverse effects.

 I. Goals and objectives:

 The broad goal of this proposal is to improve the health and nutrition of young children by
 improving iron status of infants and toddlers who have developed iron deficiency (ID) or iron
 deficiency anemia (IDA). The specific objective is to test an intervention proposed to
 enhance the efficacy, and minimize potential toxicity, of therapeutic iron for infants and
 young children who have a dietary iron deficiency.

 Iron deficiency is the most common micronutrient deficiency in the world and negatively
 impacts health in several ways 1, 2. ID and IDA contribute to stunting and impaired growth,
 increased behavioral problems, and delayed mental and motor development 3, 4, 5-7. Studies
 have also shown that some of the behavioral and developmental consequences of ID and IDA in
 young children are not reversible with treatment 8. Despite the fortification of infant and
 toddler foods in the United States, a significant number of children still develop ID or IDA
 9. Current treatment recommendations include a wide dosage range (3-6 mg/kg/day), which
 represents amounts that are higher than routine supplementation levels for adults (typically
 equivalent to < 1 mg/kg/day), reflecting the challenge and imprecision of effective treatment
 for ID and IDA in children. Iron excess is not without risk, and studies in adults have shown
 local (intestinal) and systemic inflammatory changes within days of iron therapy initiation
 10, 11. Recent advances in the understanding of the regulation of iron homeostasis and
 metabolism indicate that systemic inflammation induces a protein called hepcidin, which
 blocks the uptake of iron into the body12, 13. Thus, stimulation of inflammation by high dose
 iron supplements may actually counteract the intended beneficial effect of the increase in
 iron intake.

 Vitamin E is an essential nutrient that functions as an antioxidant and anti-inflammatory
 agent, and has been studied for many potentially beneficial facets of human health, including
 potential for protection against heart disease14; accelerated aging mediated through DNA
 damage; and impaired immunity 15. Research in adults giving antioxidants along with iron
 therapy was associated with reduced oxidative potential. In this study, a palm oil extract
 containing approximately 7 mg of Vitamin E was supplemented along with iron therapy and was
 associated with reduced fecal oxidation 16 Alpha-tocopherol is the most studied form of
 Vitamin E, and has been shown to decrease biomarkers of total body oxidative stress and
 inflammation 15, 17. We propose to accomplish our primary specific objective by testing the
 effect on treatment outcomes of administration of Vitamin E along with iron supplements.

 II. Hypotheses:

 Our central hypothesis is that in infants and toddlers with ID or IDA, 2 months of
 supplemental Vitamin E combined with therapeutic iron supplementation at 6 mg/kg/day will be
 more efficacious than the same dose of iron alone. The specific hypotheses to be tested by
 the intervention are:

 Hypothesis 1: Subjects receiving both iron and vitamin E supplements will have significantly
 greater changes in serum ferritin (reflecting greater improvement in their iron status), than
 subjects receiving iron alone after eight weeks of supplementation.

 Hypothesis 2: Significantly more subjects receiving both iron and vitamin E supplements will
 have an improved iron status profile, including ferritin, transferrin saturation, and serum
 transferrin receptor, than subjects receiving iron alone.

 Hypothesis 3 Subjects receiving both iron and vitamin E supplements will have significantly
 lower levels of inflammatory and oxidant stress biomarkers than subjects receiving iron
 alone.

 Hypothesis 4: (exploratory): The exposure to two months of iron therapy will be associated
 with significantly altered intestinal bacterial profiles compared to baseline, and at the end
 of therapy, the placebo group will have a greater predominance of potentially pathogenic
 bacterial phyla.
Inclusion Criteria:

 -  Between 9-24 months of age

 -  Weighed 5.5 lbs or more at birth

 -  Born at 34 week gestation or more

 Exclusion Criteria:

 -  Consumed infant formula within the past 3 months

 -  Inflammatory bowel disease, cystic fibrosis, liver or kidney disease, cancer, HIV,
 primary immune deficiencies, anemia unrelated to iron status, chronic blood loss in
 stool, inherited disorders or iron status, or bleeding or coagulation disorders)

 -  Previous diagnosis of iron deficiency or iron deficiency anemia

 -  Previous treatment of iron deficiency or iron deficiency anemia