Iron Supplementation for Anemia of Prematurity

Overseen By Marcia Kneusel

Age: < 18

Sex: Any

Trial Phase: Phase 4

Sponsor: University of South Florida

Must not be taking: Epogen

Disqualifiers: Congenital intestinal defects, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 3

Duration: Up to 22 weeks

183 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests iron sulfate supplements to assess their effects on the gut health of very low birth weight infants. Researchers compare two doses of iron—low and high—to evaluate their impact on intestinal health, including the gut's natural bacteria, inflammation, and overall function. Infants who weighed less than 1500 grams at birth and have not yet started oral iron supplements may be suitable candidates. As a Phase 4 trial, this research aims to understand how the already FDA-approved treatment benefits a broader range of patients.

Will I have to stop taking my current medications?

The trial does not specify whether participants must stop taking their current medications. However, infants who require epogen (a medication to prevent blood transfusions) for religious reasons are excluded from the study.

What is the safety track record for this treatment?

Research shows that iron supplements are usually safe for preterm and low birth weight babies. Studies have found that long-term iron intake improves iron levels and reduces the risk of iron deficiency and anemia (a condition where there aren't enough healthy red blood cells) in these babies.

Iron deficiency is common in preterm babies, with research suggesting that 25% to 85% may develop it during infancy. Providing iron, such as in iron sulfate supplements, helps reduce this risk.

While this study examines different amounts of iron sulfate, other research has used even higher amounts in stable premature babies, indicating these amounts are safe.

Overall, iron supplements like iron sulfate are considered safe for these babies, especially when their use is carefully managed and monitored. ^{1 2 3 4 5}

Why are researchers enthusiastic about this study treatment?

Unlike traditional treatments for anemia of prematurity, which often involve varying doses of iron supplements, this trial explores the specific impact of high versus low doses of iron sulfate. Researchers are particularly interested in how these precise dosages, adjusted weekly based on the infant's weight and development, might more effectively support early growth and health while minimizing potential side effects. This approach could lead to a more tailored and potentially more effective treatment protocol, offering exciting new insights into optimal iron supplementation for premature infants.

What evidence suggests that iron sulfate supplementation could be effective for anemia of prematurity?

Research has shown that iron supplements can improve iron levels and reduce anemia in babies born early or with low birth weight. Studies have found that iron sulfate lowers the risk of iron deficiency in these infants. In this trial, participants will receive either a high dose of iron sulfate (6 mg/kg/day) or a low dose (2 mg/kg/day) to assess the effectiveness of different supplementation levels. Both smaller and larger doses of iron have proven helpful for very low birth weight babies. Overall, starting iron supplements early may also lead to better long-term health, such as improved brain development. ^{1 4 5 6 7}

Are You a Good Fit for This Trial?

This trial is for very low birth weight infants under 1500g who haven't started oral iron supplements, are expected to live beyond two weeks, and have parental consent. Infants with congenital intestinal defects or a history of intestinal issues before starting supplements can't join.

Inclusion Criteria

parental consent

I weighed less than 1500 grams at birth.

I have not started taking oral iron supplements.

Exclusion Criteria

My infant does not need epogen for religious reasons to avoid blood transfusions.

I have had an intestinal infection or perforation before.

You were born with a defect in your intestines.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Treatment

Participants receive either 6 mg/kg/day or 2 mg/kg/day of elemental iron until 36 weeks corrected gestational age or discharge

Up to 22 weeks

Weekly monitoring and dose adjustment

Sample Collection and Testing

Weekly stool and urine samples collected; blood tests at 4 weeks after birth; auditory brainstem response at 36 weeks corrected gestational age or discharge

Throughout treatment phase

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

2 visits (in-person)

What Are the Treatments Tested in This Trial?

Interventions

• Iron Sulfate

Trial Overview The study tests the effects of two different doses of iron sulfate (2 mg/kg/day vs. 6 mg/kg/day) on the intestinal health of very low birth weight infants, focusing on their microbiome, inflammation levels, and barrier function.

How Is the Trial Designed?

Group I: High Iron Sulfate Supplementation Active Control 1 Intervention

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.

Group II: Low Iron Sulfate Supplementation Active Control 1 Intervention

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.

Who Is Running the Clinical Trial?

University of South Florida

Lead Sponsor

Trials

433

Recruited

198,000+

National Heart, Lung, and Blood Institute (NHLBI)

Collaborator

Trials

3,987

Recruited

47,860,000+

Published Research Related to This Trial

Human milk (HM)-fed preterm infants showed a higher prevalence of low ferritin levels (<12 μg/l) compared to iron-fortified formula (IFF)-fed infants at both 3 and 6 months post-term, indicating a potential need for iron supplementation in HM-fed infants.

In contrast, IFF-fed infants achieved adequate iron levels without additional supplementation, suggesting that the iron content in IFF (0.8-1.0 mg iron/100 ml) is sufficient to meet their needs until 6 months post-term.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Iron deficiency and anemia in iron-fortified formula and human milk-fed preterm infants until 6 months post-term. van de Lagemaat, M., Amesz, EM., Schaafsma, A., et al.[2021]

Early iron supplementation during pregnancy can reduce the risk of low birth weight but does not significantly lower the risk of preterm delivery, based on randomized clinical trials in the U.S. and Nepal.

While iron is essential for preventing maternal anemia, excessive iron supplementation in non-deficient women may lead to complications such as gestational diabetes and increased oxidative stress, indicating that supplementation should be carefully considered based on individual iron status.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Iron status during pregnancy: setting the stage for mother and infant. Scholl, TO.[2023]

A randomized clinical trial involving 297 infants aged 6 to 12 months found that daily supplementation with iron sulfate significantly increased serum hemoglobin levels and reduced the prevalence of anemia compared to a weekly regimen.

The study concluded that daily iron supplementation is more effective than weekly dosing in preventing anemia in infants, highlighting the importance of adherence to the daily regimen for optimal outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effectiveness of daily and weekly iron supplementation in the prevention of anemia in infants. Engstrom, EM., Castro, IR., Portela, M., et al.[2019]

In a study of 402 very low birth weight preterm infants, those receiving restrictive red blood cell transfusions showed significantly improved iron status, including higher hemoglobin and ferritin levels, after iron supplementation compared to non-transfused infants.

Iron supplementation (5 mg/kg/day) was deemed safe, as it did not increase the incidence of morbidities associated with prematurity, indicating that this practice can effectively support the iron needs of VLBW preterm infants.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Iron supplementation for preterm infants receiving restrictive red blood cell transfusions: reassessment of practice safety. Arnon, S., Dolfin, T., Bauer, S., et al.[2013]

Early screening for iron deficiency before anemia develops can improve treatment outcomes for pregnant women, as it allows for timely intervention.

Intravenous iron treatment is highlighted as a beneficial alternative to oral supplementation, which often causes gastrointestinal side effects that can hinder adherence to treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Screening, Treatment, and Monitoring of Iron Deficiency Anemia in Pregnancy and Postpartum. Elmore, C., Ellis, J.[2022]

A study comparing two forms of iron supplementation in preterm infants found that both the divalent form (Fe2+) and the nonionic trivalent form (FeIII) were equally effective over a 14-week period, with no significant differences in health outcomes.

While both forms were well tolerated, the Fe2+ group experienced slightly more gastrointestinal side effects like vomiting and diarrhea, suggesting that nonionic trivalent iron could be a safer alternative for iron supplementation in preterm infants.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Iron supplementation in preterm infants: a study comparing the effect and tolerance of a Fe2+ and a nonionic FeIII compound. Naude, S., Clijsen, S., Naulaers, G., et al.[2006]

This study established gestational age-specific reference ranges for hepcidin concentrations in cord blood of preterm and term infants, revealing that hepcidin levels increase with gestational age, with term infants showing the highest levels (103.9 ng/ml).

Infants with iron deficiency had significantly lower hepcidin levels (36.9 ng/ml) compared to iron-replete infants (86.6 ng/ml), indicating that hepcidin can be a useful marker for assessing iron status in newborns.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Gestational age-specific reference ranges of hepcidin in cord blood. Lorenz, L., Herbst, J., Engel, C., et al.[2015]

Early supplementation of 5 mg/kg/d enteral iron polymaltose complex (IPC) starting at 2 weeks of age in preterm infants significantly improved iron status compared to starting at 4 weeks, as shown by better hemoglobin levels at 4 and 8 weeks of age.

The early iron supplementation also led to a reduced need for red blood cell transfusions (RBCTs), with only 1 infant in the 2-week group requiring a transfusion compared to 10 in the 4-week group, indicating a beneficial effect without increasing morbidity associated with prematurity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The efficacy and safety of early supplementation of iron polymaltose complex in preterm infants. Arnon, S., Shiff, Y., Litmanovitz, I., et al.[2019]

In a study of 60 premature infants, the iron protein succinylate (IPS) oral solution was found to be more effective than polysaccharide iron complex (PIC) in increasing hemoglobin, red blood cell count, and hematocrit levels by day 60 of treatment.

IPS was well-tolerated with no significant adverse events reported, indicating it is a safe option for preventing and treating anemia of prematurity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Clinical study of iron protein succinylate oral solution for preventing and treating anemia of prematurity]. Xing, Y., Tong, XM.[2017]

A study involving 78 low birthweight preterm infants showed that iron intake from formulas significantly differed, with those on the iron-fortified preterm formula receiving the highest amount of iron (1.17 mg/kg/day).

Both iron-fortified formulas (0.5 mg/dl and 0.9 mg/dl) effectively maintained hemoglobin levels and prevented iron deficiency in preterm infants up to 6 months corrected age, indicating that either formula can meet their nutritional needs.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Iron nutritional status in preterm infants fed formulas fortified with iron. Griffin, IJ., Cooke, RJ., Reid, MM., et al.[2019]

A meta-analysis of 15 studies involving 1938 pregnant women with iron deficiency anemia found that intravenous iron therapy may reduce the need for blood transfusions at delivery compared to oral iron, but the evidence quality was low.

While intravenous iron showed some benefits in improving maternal blood parameters and slightly increasing neonatal birth weight, the overall differences in outcomes between intravenous and oral iron were small and not strongly supported by high-quality evidence.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Intravenous or oral iron for treating iron deficiency anaemia during pregnancy: systematic review and meta-analysis. Qassim, A., Grivell, RM., Henry, A., et al.[2020]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC6888764/

Iron supplementation in preterm and low-birth-weight infants Long-term iron supplementation appears to result in improved iron status and a reduction in iron deficiency and anemia in preterm and LBW infants.

2. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/29366419/

Efficacy of Supplementation with Iron Sulfate Compared to ... Results: Supplementation with iron bisglycinate chelate at a dose of 0.75 mg/kg/day demonstrated an efficacy comparable to iron sulfate at a dose of 3 mg/kg/day ...

3. bmcpediatr.biomedcentral.com bmcpediatr.biomedcentral.com/articles/10.1186/s12887-024-04996-5

The effect of iron supplementation in preterm infants at ... Postnatal iron supplementation at 2–4 mg/kg/d in preterm infants significantly decreases the incidence of ID.

4. sciencedirect.com sciencedirect.com/science/article/pii/S0271531700002542

Prematurity anemia: effect of iron supplementation The study was designed to assess the effect of prophylactic iron administration on the occurrence of early and late prematurity anemia and on iron deposits ...

5. jpeds.com jpeds.com/article/S0022-3476(07)00266-1/fulltext

Iron Supplementation in Prematurity: How Much is Too ... Compared with outcomes after the diagnosis of iron deficiency anemia, early iron supplementation of at-risk term infants may improve long-term neurologic ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC2657918/

Iron Therapy for Preterm Infants - PMC RISK OF IRON DEFICIENCY IN PRETERM INFANTS. Between 25% and 85% of preterm infants develop evidence of iron deficiency during infancy [3–8].

7. publications.aap.org publications.aap.org/pediatrics/article/126/5/1040/65343/Diagnosis-and-Prevention-of-Iron-Deficiency-and

Diagnosis and Prevention of Iron Deficiency ... This clinical report covers diagnosis and prevention of iron deficiency and iron-deficiency anemia in infants (both breastfed and formula fed) and toddlers ...