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

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