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Effects of iron supplementation on serum hepcidin and serum erythropoietin in low-birth-weight infants
Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
The Department of Nutrition, University of California, Davis, CA, USA.
The Department of Women and Child Health, Division of Neonatology, Karolinska Institute, Stockholm, Sweden.
Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
2011 (English)In: American Journal of Clinical Nutrition, ISSN 0002-9165, E-ISSN 1938-3207, Vol. 94, no 6, 1553-1561 p.Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: The iron-regulatory hormone hepcidin has not been studied in infants, who experience large physiologic changes in iron status. OBJECTIVE: The objective was to study hepcidin and erythropoietin and their correlation with iron status in iron-replete and iron-deficient low-birth-weight (LBW) infants-a group at particular risk of iron deficiency (ID). DESIGN: We randomly assigned 285 otherwise healthy LBW infants to receive, from 6 wk to 6 mo of age, 3 doses of iron supplements: 0 (placebo), 1, or 2 mg/kg daily. Hepcidin, erythropoietin, hemoglobin, and variables of iron status were analyzed. RESULTS: Serum hepcidin did not change over time in the placebo group, despite a rapid decrease in serum ferritin. In iron-supplemented infants, hepcidin increased significantly, reaching a mean (±SD) concentration of 19.2 ± 2.5 ng/mL in the 2-mg/kg group compared with 13.0 ± 2.6 ng/mL in the placebo group at age 6 mo (P < 0.001). The difference was even larger between iron-deficient and iron-replete infants. Hepcidin was independently positively correlated with ferritin at all ages and was negatively correlated with the transferrin receptor concentration at age 6 wk and with transferrin at age 6 mo. Erythropoietin was initially similar between groups but decreased significantly in iron-supplemented infants. In addition to being negatively correlated with hemoglobin, it was also independently negatively correlated with indicators of iron status. CONCLUSIONS: Hepcidin is closely associated with iron status and may be a useful indicator of iron stores and ID in infants. Erythropoietin is negatively correlated with iron status, which suggests a feedback mechanism that needs further study. This trial is registered at as NCT00558454.

Place, publisher, year, edition, pages
American Society for Nutrition , 2011. Vol. 94, no 6, 1553-1561 p.
National Category
URN: urn:nbn:se:umu:diva-49774DOI: 10.3945/ajcn.111.013938PubMedID: 22071701OAI: diva2:457474
Available from: 2011-11-17 Created: 2011-11-17 Last updated: 2012-02-09Bibliographically approved
In thesis
1. Effects of iron supplementation on iron status, health and neurological development in marginally low birth weight infants.
Open this publication in new window or tab >>Effects of iron supplementation on iron status, health and neurological development in marginally low birth weight infants.
2012 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Background Due to small iron stores and rapid growth during the first months of life, infants with low birth weight (LBW) are at risk of iron deficiency (ID). ID in infancy is associated with irreversible impaired neurodevelopment. Preventive iron supplementation may reduce the risk of ID and benefit neurodevelopment, but there is also a possible risk of adverse effects. More than 50% of all LBW infants are born with marginally LBW (MLBW, 2000-2500g), and it is not known if they benefit from iron supplementation.

Methods We randomized 285 healthy, Swedish, MLBW infants to receive 3 different doses of oral iron supplements; 0 (Placebo), 1, and 2 mg/kg/day from six weeks to six months of age. Iron status, during and after the intervention was assessed and so was the prevalence of ID and ID anemia (IDA), growth, morbidity and the interplay with iron and the erythropoetic hormones hepcidin and erythropoietin (EPO). As a proxy for conduction speed in the developing brain, auditory brainstem response (ABR) was analyzed at six months. In a follow up at 3.5 years of age, the children were assessed with a cognitive test (WPPSI-III) and a validated parental checklist of behavioral problems (CBCL), and compared to a matched reference group of 95 children born with normal birth weight.

Results At six months of age, the prevalence of ID and IDA was significantly higher in the placebo group compared to the iron supplemented infants. 36% had ID in the placebo group, compared to 8% and 4 % in the 1 and 2mg/kg/day-groups, respectively. The prevalence of IDA was 10%, 3% and 0%, respectively. ABR-latencies did not correlate with the iron intake and was not increased in infants with ID or IDA. ABR wave V latencies were similar in all three groups. Hepcidin correlated to ferritin and increased in supplemented infants while EPO, which was negatively correlated to iron status indicators, decreased. At follow up there were no differences in cognitive scores between the groups but the prevalence of behavioral problems was significantly higher in the placebo group compared to those supplemented and to controls. The relative risk increase of CBCL-scores above a validated cutoff was 4.5 (1.4 – 14.2) in the placebo-group compared to supplemented children. There was no detected difference in growth or morbidity at any age.

Conclusion MLBW infants are at risk of ID in infancy and behavioral problems at 3 years of age. Iron supplementation at a dose of 1-2 mg/kg/day from six weeks to six months of age reduces the risks with no adverse effects, suggesting both short and long term benefit. MLBW infants should be included in general iron supplementation programs during their first six months of life.

Place, publisher, year, edition, pages
Umeå: Umeå Universitet, 2012. 75 p.
Umeå University medical dissertations, ISSN 0346-6612 ; 1481
Auditory brainstem response, behavior, breast feeding, cognition, erythropoietin, ferritin, growth, hemoglobin, hepcidin, human infant, iron, iron deficiency, iron deficiency anemia, iron status, iron supplementation, low birth weight, morbidity, neurodevelopment, nutritional requirements, randomized controlled trial
National Category
Clinical Medicine Pediatrics
Research subject
urn:nbn:se:umu:diva-52079 (URN)978-91-7459-371-6 (ISBN)
Public defence
NUS 6A–L - Biomedicinhuset, Sal E04 (byggnad R1), Umeå Universitetssjukhus, Umeå (English)
Available from: 2012-02-10 Created: 2012-02-09 Last updated: 2012-02-09Bibliographically approved

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