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Effects of iron supplementation on iron status, health and neurological development in marginally low birth weight infants.
Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
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.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1481
Keyword [en]
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
Pediatrics
Identifiers
URN: urn:nbn:se:umu:diva-52079ISBN: 978-91-7459-371-6 (print)OAI: oai:DiVA.org:umu-52079DiVA: diva2:495843
Public defence
NUS 6A–L - Biomedicinhuset, Sal E04 (byggnad R1), Umeå Universitetssjukhus, Umeå (English)
Opponent
Supervisors
Available from: 2012-02-10 Created: 2012-02-09 Last updated: 2012-02-09Bibliographically approved
List of papers
1. Iron supplements reduce the risk of iron deficiency anemia in marginally low birth weight infants
Open this publication in new window or tab >>Iron supplements reduce the risk of iron deficiency anemia in marginally low birth weight infants
2010 (English)In: Pediatrics, ISSN 0031-4005, E-ISSN 1098-4275, Vol. 126, no 4, e874-e883 p.Article in journal (Refereed) Published
Abstract [en]

OBJECTIVE: Low birth weight infants are at risk for iron deficiency (ID). Most LBW infants have marginally low birth weight (MLBW, 2000–2500 g) and it is not known whether they benefit from iron supplements. The objective of this trial was to study the effects of iron supplementation in MLBW infants.

METHOD: In a randomized controlled trial, we assigned 285 healthy, MLBW infants to receive iron supplements at a dose of 0 (placebo), 1, or 2 mg/kg per day between 6 weeks and 6 months of age. Hemoglobin levels, ferritin levels, transferrin saturation, mean cell volume, and transferrin receptor levels were analyzed at 6 months. Growth and morbidity were monitored.

RESULTS: Iron supplementation resulted in significant dose-dependent effects on hemoglobin and all iron status indicators at 6 months. The prevalence of ID at 6 months was 36% in the placebo group, 8.2% in the 1 mg/kg per day group, and 3.8% in the 2 mg/kg per day group (P < .001). The prevalence rates of ID anemia (IDA) were 9.9%, 2.7%, and 0%, respectively (P = .004). Among infants who were exclusively breastfed at 6 weeks, the prevalence of IDA was 18% in the placebo group. There were no significant differences between groups in growth or morbidity.

CONCLUSIONS: MLBW infants have relatively high risks of ID and IDA, especially if they are breastfed. Iron supplementation at 2 mg/kg per day from 6 weeks to 6 months reduces this risk effectively, with no short-term adverse effects on morbidity or growth.

Place, publisher, year, edition, pages
American Academy of Pediatrics, 2010
Keyword
low birth weight, iron deficiency, iron deficiency anemia, preterm, small for gestational age, randomized controlled trial, morbidity, growth, adverse effect
National Category
Pediatrics
Identifiers
urn:nbn:se:umu:diva-38499 (URN)10.1542/peds.2009-3624 (DOI)000282526100015 ()20819898 (PubMedID)
Available from: 2010-12-15 Created: 2010-12-15 Last updated: 2017-12-11Bibliographically approved
2. Effects of iron supplementation on auditory brainstem response in marginally LBW infants
Open this publication in new window or tab >>Effects of iron supplementation on auditory brainstem response in marginally LBW infants
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2011 (English)In: Pediatric Research, ISSN 0031-3998, E-ISSN 1530-0447, Vol. 70, no 6, 601-606 p.Article in journal (Refereed) Published
Abstract [en]

LBW infants are at risk of iron deficiency (ID), which is associated with impaired nervous system development and may lead to prolonged auditory brainstem response (ABR) latencies. We hypothesized that iron supplementation shortens ABR latencies in marginally LBW (MLBW, 2000-2500 g) infants. In a randomized, controlled trial, 285 healthy MLBW infants received 0, 1, or 2 mg iron/kg/d of iron supplements from 6 wk to 6 mo of age. ABR absolute wave V latencies and central conduction time (CCT) were measured at the endpoint. There were no significant differences between groups in ABR wave V latencies (n = 218). Furthermore, there were no significantly prolonged ABR latencies in infants with ID (n = 32). CCT was significantly higher in the 2 mg group than in the placebo group (n = 126). However, there were no significant correlations between CCT and iron intake or any iron status variable, suggesting that differences in CCT were not caused by iron. We conclude that iron supplements did not improve ABR latencies, and iron-deficient MLBW infants did not have impaired ABR latencies at 6 mo, suggesting that ABR is not a sensitive measure of impaired neurological development or that mild/moderate ID causes no such impairment in MLBW infants.

Place, publisher, year, edition, pages
Baltimore: International Pediatrics Research Foundation, Inc, 2011
National Category
Pediatrics
Identifiers
urn:nbn:se:umu:diva-50927 (URN)10.1203/PDR.0b013e3182320cd0 (DOI)000297433900010 ()
Funder
Formas, 222-2005-1894
Note
Supported by grants from the Swedish Research Council Formas 222-2005-1894, Västerbotten County Council (ALF), the Jerring foundation, the Oskar foundation, and the Medical Faculty, Umeå University. The iron drops were provided from Astra Zeneca, Sweden.Available from: 2012-01-18 Created: 2012-01-02 Last updated: 2017-12-08Bibliographically approved
3. Effects of iron supplementation on serum hepcidin and serum erythropoietin in low-birth-weight infants
Open this publication in new window or tab >>Effects of iron supplementation on serum hepcidin and serum erythropoietin in low-birth-weight infants
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 clinicaltrials.gov as NCT00558454.

Place, publisher, year, edition, pages
American Society for Nutrition, 2011
National Category
Pediatrics
Identifiers
urn:nbn:se:umu:diva-49774 (URN)10.3945/ajcn.111.013938 (DOI)22071701 (PubMedID)
Available from: 2011-11-17 Created: 2011-11-17 Last updated: 2017-12-08Bibliographically approved
4. Effects of iron supplementation of LBW infants on cognition and behavior at 3 years
Open this publication in new window or tab >>Effects of iron supplementation of LBW infants on cognition and behavior at 3 years
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2013 (English)In: Pediatrics, ISSN 0031-4005, E-ISSN 1098-4275, Vol. 131, 47-55 p.Article in journal (Refereed) Published
Abstract [en]

OBJECTIVE: Low birth weight (LBW) infants are at increased risk of cognitive and behavioral problems and at risk for iron deficiency, which is associated with impaired neurodevelopment. We hypothesized that iron supplementation of LBW infants would improve cognitive scores and reduce behavioral problems. METHODS: In a randomized controlled trial, 285 marginally LBW (2000-2500 g) infants received 0, 1, or 2 mg/kg/day of iron supplements from 6 weeks to 6 months of age. At 3.5 years of age, these infants and 95 normal birth weight controls were assessed with a psychometric test (Wechsler Preschool and Primary Scale of Intelligence) and a questionnaire of behavioral problems (Child Behavior Checklist; CBCL). RESULTS: There were no significant differences in IQ between the LBW groups or LBW infants versus controls. Mean (SD) full-scale IQ was 105.2 (14.5), 104.2 (14.7), and 104.5 (12.7) in the placebo, 1 mg, and 2 mg groups, respectively (P = .924). However, for behavioral problems, there was a significant effect of intervention. The prevalence of children with CBCL scores above the US subclinical cutoff was 12.7%, 2.9%, and 2.7% in the placebo, 1-mg, and 2-mg groups, respectively (P = .027), compared with 3.2% in controls. Relative risk (95% confidence interval) for CBCL score above cutoff in placebo-treated children versus supplemented was 4.5 (1.4-14.2). CONCLUSIONS: Early iron supplementation of marginally LBW infants does not affect cognitive functions at 3.5 years of age but significantly reduces the prevalence of behavioral problems. The study suggests a causal relation between infant iron deficiency and later behavioral problems.

Keyword
behavioral problems, children, cognitive score, iron, infant, iron deficiency, iron deficiency anemia, low birth weight, neurodevelopment, preterm, randomized controlled trial, small for gestational age
National Category
Pediatrics
Identifiers
urn:nbn:se:umu:diva-51400 (URN)10.1542/peds.2012-0989 (DOI)000313012400051 ()
Available from: 2012-01-19 Created: 2012-01-19 Last updated: 2017-12-08Bibliographically approved

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