Effect of Infant Formula With Bovine Lactoferrin and Low Iron Concentration on Infant Health and Immune Function (LIME)

Breast milk is the gold standard of early infant nutrition and breastfed infants have advantages in several short and long term outcomes compared to those formula-fed.

The first aim of this study is to evaluate the effect of adding bovine lactoferrin to infant formula. The general hypothesis is that bovine lactoferrin reduces some of the previously observed differences between formula-fed and breast-fed infants with regard to health and development. The main outcome studied is the effect on immune function. The second aim is to study the effects of lower iron concentration in infant formula and to test the hypothesis that iron can be lowered without negative effects on health and development. The main outcome studied here is iron status. Other outcomes in this trial are microbiota composition, metabolomics, growth, body composition and cognitive development.

To test the lactoferrin hypothesis, formula-fed infants will be recruited and fed a low iron (2 mg/L) control formula, or the same formula supplemented with bovine lactoferrin. To test the iron hypothesis, a third group will be fed the same formula (no lactoferrin) with higher iron concentration (8 mg/L). Group allocation for all formula-fed infants will be double-blind randomized. Additionally, breast-fed infants will be recruited and used as a reference group (gold standard).

Study Overview

• Status: Active, not recruiting
• Conditions: Health of Formula-fed Children; Infant Infections in Formula-fed Children; Iron Status of Formula-fed Children
• Intervention / Treatment: Dietary supplement: Formula with low iron concentration (2 mg/L) supplemented with bovine lactoferrin; Dietary supplement: Formula with low iron concentration (2mg/L) without lactoferrin; Dietary supplement: Formula with normal iron concentration (8 mg/L) without lactoferrin

• Study Type: Interventional
• Enrollment (Actual): 252
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Sweden
  • Umeå, Sweden, SE-901 87
    • Umeå University, Department of Clinical Sciences

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 4 weeks to 1 month (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

Formula-fed healthy infants at 6 +/- 2 weeks of age with:

• birth weight 2500-4500 g
• gestational age at birth ≥ 37 completed weeks
• no chronic disease or neonatal diagnoses believed to affect any outcome
• no given blood transfusions or iron supplements

Exclusion Criteria:

-

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Low iron, with lactoferrin	Dietary supplement: Formula with low iron concentration (2 mg/L) supplemented with bovine lactoferrin
Active Comparator: Low iron, no lactoferrin	Dietary supplement: Formula with low iron concentration (2mg/L) without lactoferrin
Placebo Comparator: Normal iron, no lactoferrin	Dietary supplement: Formula with normal iron concentration (8 mg/L) without lactoferrin

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of infections	Morbidity journal, Health questionnaire	Up to 12 months of age
Cytokine levels	IL-2, TNF-alpha	At 6 months of age
Iron status	s-ferritin, s-transferrin, s-iron, s-transferrin receptor concentration, reticulocyte Hb	At 6 months of age

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Dietary intake	Dietary journal	At baseline, 3, 4, 5, 6 and 12 months of age
Growth	Anthropometric data, Body Composition (PeaPod)	At baseline, 4, 6, 12 months of age and 6 years of age
Bloodpressure		At baseline, 4, 6, 12 months of age and 6 years of age
Antibody response to vaccines	s-levels of specific antibodies to vaccines (DTP, Hib, PC)	At baseline, 4, 6 and 12 months of age
Gut microbiota	Stool samples	At baseline, 4, 6, 12 months of age and 6 years of age
Saliva proteins	Saliva total protein content, lactoferrin, saliva-peroxidase, IgA and amylase	At 4 months of age
Inflammatory markers	s-hsCRP, s-calprotectin	At baseline, 4, 6 and 12 months of age and 6 years age
Cognitive development and behavior	Bayley III, Wechsler Intelligence Scale for Children (WISC), Behavioral questionnaire	At 1 and 6 years of age
s-hepcidin		At baseline, 4, 6, 12 months of age and 6 years of age
Metabolomics	Analyzed in urine and serum samples	At baseline, 4, 6, 12 months of age and 6 years of age
Amino acids	p-amino acids	At 4 and 6 months of age
Blood urea nitrogen	p-urea nitrogen	At 4 and 6 months of age
Cytokine levels	IL-2 and TNF alpha at baseline, 4 and 12 months of age and 6 years of age. Six additional cytokines at baseline, 4, 6 and 12 months of age and 6 years of age.	At baseline, 4, 6, 12 months of age and 6 years of age
Iron status	s-ferritin, s-transferrin, s-iron, s-transferrin saturation, s-transferrin receptor concentration, retuiculocyte Hb	At baseline, 4 and 12 months of age and 6 years of age

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Lactoferrin in breastmilk	Analyzed from mothers to the control group of breast fed infants.	At baseline, 4 and 6 months of age

Collaborators and Investigators

• Sponsor: Umeå University
• Collaborators: University of California; Mead Johnson Nutrition
• Investigators: Principal Investigator: Staffan K Berglund, MD, PhD, Umea University; Principal Investigator: Olle Hernell, Professor, Umea University; Principal Investigator: Bo Lönnerdal, Professor, University of California; Principal Investigator: Carolyn Slupsky, PhD, University of California

Publications and helpful links

General Publications

• Björmsjö M, Hernell O, Lönnerdal B, Berglund SK. Immunological Effects of Adding Bovine Lactoferrin and Reducing Iron in Infant Formula: A Randomized Controlled Trial. J Pediatr Gastroenterol Nutr. 2022 Mar 1;74(3):e65-e72. doi: 10.1097/MPG.0000000000003367.

Study record dates

Study Major Dates

• Study Start: June 1, 2014
• Primary Completion (Actual): May 1, 2019
• Study Completion (Anticipated): May 1, 2024

Study Registration Dates

• First Submitted: March 31, 2014
• First Submitted That Met QC Criteria: March 31, 2014
• First Posted (Estimate): April 3, 2014

Study Record Updates

• Last Update Posted (Actual): May 24, 2022
• Last Update Submitted That Met QC Criteria: May 23, 2022
• Last Verified: May 1, 2022

More Information

Terms related to this study

• Keywords: Infant formula; Iron; Lactoferrin
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Anti-Infective Agents; Trace Elements; Micronutrients; Iron; Lactoferrin
• Other Study ID Numbers: LIME2014