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Immunological Effects of Adding Bovine Lactoferrin and Reducing Iron in Infant Formula: A Randomized Controlled Trial
Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.ORCID iD: 0009-0007-9083-8630
Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
Department of Nutrition, University of California, Davis, CA.
Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM). Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.ORCID iD: 0000-0002-9263-9578
2022 (English)In: Journal of Pediatric Gastroenterology and Nutrition - JPGN, ISSN 0277-2116, E-ISSN 1536-4801, Vol. 74, no 3, p. e65-e72Article in journal (Refereed) Published
Abstract [en]

OBJECTIVES: Compared to formula-fed infants, breastfed infants have a lower risk of infections. Two possible reasons for this are the presence of the anti-infective and anti-inflammatory protein lactoferrin and the lower level of iron in breast milk. We explored how adding bovine lactoferrin and reducing the iron concentration in infant formula affect immunology and risk of infections in healthy infants.

METHODS: In a double-blind controlled trial, term formula-fed (FF) Swedish infants (n = 180) were randomized to receive, from 6 weeks to 6 months of age, a low-iron formula (2 mg/L) with added bovine lactoferrin (1.0 g/L) (Lf+; n = 72); low-iron formula with no added lactoferrin (Lf-; n = 72); and standard formula at 8 mg/L iron and no added lactoferrin (control formula [CF]; n = 36). Cytokines, infections, and infection related treatments were assessed until 12 months of age.

RESULTS: No adverse effects were observed. There were no apparent effects on transforming growth factor beta (TGF-β)1, TGF-β2, tumor necrosis factor alfa (TNF-α) or interleukin2 (IL-2) at 4, 6, or 12 months, except of higher TGF-β2 at 6 months in the CF group in comparison to the low iron groups combined (P = 0.033). No significant differences in otitis, respiratory infections, gastroenteritis, or other monitored infections and treatments were detected for any of the study feeding groups during the first 6 months and only a few and diverging effects were observed between 6 and 12 months.

CONCLUSIONS: Adding bovine lactoferrin and reducing iron from 8 to 2 mg/L in infant formula was safe. No clinically relevant effects on cytokines or infection related morbidity were observed in this well-nourished and healthy population.

Place, publisher, year, edition, pages
Wolters Kluwer, 2022. Vol. 74, no 3, p. e65-e72
National Category
Pediatrics Gastroenterology and Hepatology
Identifiers
URN: urn:nbn:se:umu:diva-193008DOI: 10.1097/MPG.0000000000003367ISI: 000761954400006PubMedID: 34908015Scopus ID: 2-s2.0-85125554033OAI: oai:DiVA.org:umu-193008DiVA, id: diva2:1643735
Funder
Knut and Alice Wallenberg FoundationThe Kempe FoundationsAvailable from: 2022-03-10 Created: 2022-03-10 Last updated: 2024-07-11Bibliographically approved
In thesis
1. Clinical effects of reduced iron content and fortification with bovine lactoferrin in infant formula
Open this publication in new window or tab >>Clinical effects of reduced iron content and fortification with bovine lactoferrin in infant formula
2023 (English)Doctoral thesis, comprehensive summary (Other academic)
Alternative title[sv]
Kliniska effekter vid minskat järninnehåll och tillägg av bovint laktoferrin i modersmjölksersättning
Abstract [en]

Background: Breast milk, with its complex, individual and over time adapting composition, is considered the optimal source of nutrition for infants during the first months of life. Two possible contributing factors to the benefits of breastfeeding compared to infant formula-feeding are the differences in iron and lactoferrin (Lf) concentrations between breast milk and infant formula. The overall purpose of the LIME (a Swedish acronym) study was to add knowledge on how to reduce the gap in health and development between breastfed and formula-fed infants. The aim of this double-blinded controlled trial, and doctoral thesis, was to investigate how added bovine lactoferrin and reduced iron concentration in infant formula affect health and development.

Methods: Recruitment took place from June 2014 to June 2018. With equal gender distribution, healthy term Swedish formula-fed infants (n=180) were randomly assigned, from 6 weeks to 6 months of age, to receive a low iron formula (2 mg/L) with bovine Lf (1.0 g/L) (Lf+, n=72), a low iron formula without Lf (Lf-, n=72) or a control standard formula with 8 mg/L iron and no Lf (CF, n=36). Additionally, 72 breastfed infants were recruited as a reference (BF) group. Blood samples were drawn at 4, 6, and 12 months. Primary outcomes were cytokine levels and iron status. Secondary outcomes were growth, gastrointestinal symptoms, infection-related morbidity and treatments, antibody response to vaccines and cognitive development.

Findings: All explored outcomes were unaffected by Lf fortification and the two low iron groups (Lf+ and Lf-) were combined and compared to the CF group. At 6 months of age the TGF-β2 levels were lower among the low iron groups and more similar to the BF infants. No other significant differences in cytokine levels were observed. There was a trend of lower geometric mean of ferritin at 4, 6, and 12 months for the combined low iron groups compared to the CF group (67.7 vs 88.7, 39.5 vs 50.9, and 20.5 vs 25.1 μg/L, respectively, p=0.054, p=0.056, and p=0.082). No similar trends or significant differences were found for any of the other iron status indicators, except for hepcidin at 12 months with lower levels in the low iron group compared to CF (37.8 vs 49.4 ng/mL, p=0.027). Overall, infants fed low iron formula had iron status indicators closer to the breastfed reference group and the prevalence of iron deficiency (ID) and iron deficiency anemia (IDA) was generally low with no significant differences among the intervention groups.

There were no clinically relevant effects of the interventions on growth, gastrointestinal symptoms, infection-related morbidity, vaccine antibody response or neurocognitive development.

In secondary analyses, the present study confirmed previous results of higher cognitive scores among breastfed infants compared to formula-fed and observed an unexpected lower IgG response to vaccines against Hib and Diphtheria.

Conclusion: Adding bovine lactoferrin did not affect any of the clinical outcomes explored. Lowering infant formula iron concentration from 8 to 2 mg/L minimally reduced iron stores to levels closer to breastfed infants but did not increase the risk of ID/IDA during the first year of life. Consequently, 2 mg/L is a sufficient level of iron fortification during the first six months of life in a population with low risk of ID. Both adjustments are considered safe with no observed adverse effects.

Place, publisher, year, edition, pages
Umeå: Umeå universitet, 2023. p. 88
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 2230
Keywords
infant formula, lactoferrin, bovine lactoferrin, iron, iron supplementation, iron fortification, iron status, infant nutrition, cytokines, neurodevelopment, vaccine response, infection-related morbidity
National Category
Pediatrics
Research subject
Pediatrics
Identifiers
urn:nbn:se:umu:diva-204950 (URN)978-91-8070-001-6 (ISBN)978-91-8070-002-3 (ISBN)
Public defence
2023-03-17, Hörsal D, by 1D, målpunkt T, 9 tr, Norrlands universitetssjukhus, Umeå, 09:00 (English)
Opponent
Supervisors
Available from: 2023-02-24 Created: 2023-02-17 Last updated: 2024-07-11Bibliographically approved

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Björmsjö, MariaHernell, OlleBerglund, Staffan

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