The Mothers, Infants, and Lactation Quality (MILQ) Study: A Multi-Center Collaboration

Lindsay H Allen, Daniela Hampel, Setareh Shahab-Ferdows, Maria Andersson, Erica Barros, Andrew M Doel, Kamilla Gehrt Eriksen, Sophie Hilario Christensen, Munirul Islam, Gilberto Kac, Farhana Khanam Keya, Kim F Michaelsen, Daniela de Barros Mucci, Fanta Njie, Janet M Peerson, Sophie E Moore, Lindsay H Allen, Daniela Hampel, Setareh Shahab-Ferdows, Maria Andersson, Erica Barros, Andrew M Doel, Kamilla Gehrt Eriksen, Sophie Hilario Christensen, Munirul Islam, Gilberto Kac, Farhana Khanam Keya, Kim F Michaelsen, Daniela de Barros Mucci, Fanta Njie, Janet M Peerson, Sophie E Moore

Abstract

Little valid information is available on human milk nutrient concentrations, especially for micronutrients (MNs), and there are no valid reference values (RVs) across lactation. In this multi-center collaborative study, RVs will be established for human milk nutrients across the first 8.5 mo postpartum. Well-nourished, unsupplemented women in Bangladesh, Brazil, Denmark, and The Gambia (n = 250/site) were recruited during the third trimester of pregnancy. Milk, blood, saliva, urine, and stool samples from mothers and their infants are collected identically at 3 visits (1-3.49, 3.5-5.99, 6.0-8.49 mo postpartum). Milk analyses include macronutrients, selected vitamins, trace elements and minerals, iodine, metabolomics, amino acids, human milk oligosaccharides, and bioactive peptides. We measure milk volume; maternal and infant diets, anthropometry, and morbidity; infant development, maternal genome, and the infant and maternal microbiome. RVs will be constructed based on methods for the WHO Child Growth Standards and the Intergrowth-21st Project. This trial was registered at clinical trials.gov as NCT03254329.

Keywords: composition; human milk; macronutrients; micronutrients; reference values.

© The Author(s) 2021. Published by Oxford University Press on behalf of the American Society for Nutrition.

Figures

FIGURE 1
FIGURE 1
Mothers, Infants, and Lactation Quality Study timeline, questionnaires, and data and sample collection form schedule. 13rd trimester. 2Late 3rd trimester, not done in Bangladesh. 3Maternal stool samples are not collected in Bangladesh. 4Not collected in Denmark. 5Only at visit 4 in The Gambia.
FIGURE 2
FIGURE 2
Mothers, Infants, and Lactation Quality Study participant flow chart, for all 4 study sites. 1Denmark will use 24-h test weighing, instead of the Dose-to Mother deuterium method and saliva collections, for milk volume measurements. C, child; DBS, dried blood spots; M, mother.
FIGURE 3
FIGURE 3
Hypothetical graphical illustration of reference values that may result for a micronutrient.

References

    1. World Health Organization. Guidelines on HIV and Infant Feeding 2010: Principles and Recommendations for Infant Feeding in the Context of HIV and a Summary of Evidence. Geneva (Switzerland): WHO, 2010.
    1. World Health Organization [Internet]. Geneva (Switzerland): Breastfeeding c2021 [cited 7 Aug, 2021]. Available from: .
    1. Hampel D, Dror DK, Allen LH. Micronutrients in human milk: analytical methods. Adv Nutr. 2018;9(suppl_1):313S–31S.
    1. Allen LH, Dror DK. Introduction to current knowledge on micronutrients in human milk: adequacy, analysis, and need for research. Adv Nutr. 2018;9(suppl_1):275S–7S.
    1. Allen LH. Maternal micronutrient malnutrition: effects on breast milk and infant nutrition, and priorities for intervention. SCN News. 1994;11:21–4.
    1. Allen LH. B vitamins in breast milk: relative importance of maternal status and intake, and effects on infant status and function. Adv Nutr. 2012;3(3):362–9.
    1. Dror DK, Allen LH. Retinol-to-fat ratio and retinol concentration in human milk show similar time trends and associations with maternal factors at the population level: a systematic review and meta-analysis. Adv Nutr. 2018;9(suppl_1):332S–46S.
    1. Dror DK, Allen LH. Vitamin B-12 in human milk: a systematic review. Adv Nutr. 2018;9(suppl_1):358S–66S.
    1. Dror DK, Allen LH. Iodine in human milk: a systematic review. Adv Nutr. 2018;9(suppl_1):347S–57S.
    1. Allen LH, Graham JM. Assuring micronutrient adequacy in the diets of young infants. In: Delange FM, West KP, editors. Micronutrient Deficiencies in the First Months of Life. Basel (Switzerland): Nestec Ltd./S. Karger AG, 2003. p. 55–88.
    1. Dror DK, Allen LH. Effect of vitamin B12 deficiency on neurodevelopment in infants: current knowledge and possible mechanisms. Nutr Rev. 2008;66(5):250–5.
    1. Victora CG, de Onis M, Hallal PC, Blössner M, Shrimpton R. Worldwide timing of growth faltering: revisiting implications for interventions. Pediatrics. 2010;125(3):e473–e80.
    1. Gallant J, Chan K, Green TJ, Wieringa FT, Leemaqz S, Ngik R, Measelle JR, Baldwin DA, Borath M, Sophonneary Pet al. . Low-dose thiamine supplementation of lactating Cambodian mothers improves human milk thiamine concentrations: a randomized controlled trial. Am J Clin Nutr. 2021;114(1):90–100.
    1. Eneroth H, El Arifeen S, Persson LÅ, Lönnerdal B, Hossain MB, Stephensen CB, Ekström EC. Maternal multiple micronutrient supplementation has limited impact on micronutrient status of Bangladeshi infants compared with standard iron and folic acid supplementation. J Nutr. 2010;140(3):618–24.
    1. World Health Organization. The quality and quantity of breast milk: report on the WHO collaborative study on breast-feeding. Geneva (Switzerland)1985.
    1. Dror DK, Allen LH. Overview of nutrients in human milk. Adv Nutr. 2018;9(suppl_1):278S–94S.
    1. Allen LH, Donohue JA, Dror DK. Limitations of the evidence base used to set recommended nutrient intakes for infants and lactating women. Adv Nutr. 2018;9(suppl_1):295S–312S.
    1. Hampel D, Allen LH. Analyzing B-vitamins in human milk: methodological approaches. Crit Rev Food Sci Nutr. 2016;56(3):494–511.
    1. Squires J, Bricker D. Ages and stages questionnaire [Internet]. Third edition. 2009. Brookes Publishing. Available from: .
    1. Walker E, Nowacki AS. Understanding equivalence and noninferiority testing. J Gen Intern Med. 2011;26(2):192–6.
    1. Altman D, Ohuma E, Fetal I, Century NGCfts . Statistical considerations for the development of prescriptive fetal and newborn growth standards in the INTERGROWTH-21st project. BJOG: An International Journal of Obstetrics & Gynaecology. 2013;120:71–76.
    1. Borghi E, de Onis M, Garza C, Van den Broeck J, Frongillo EA, Grummer-Strawn L, Van Buuren S, Pan H, Molinari L, Martorell R. Construction of the World Health Organization child growth standards: selection of methods for attained growth curves. Stat Med. 2006;25(2):247–65.
    1. Institute of Medicine. Dietary Reference Intakes for Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline. Washington (DC): National Academies Press, 1998.
    1. Hampel D, Shahab-Ferdows S, Gertz E, Flax VL, Adair LS, Bentley ME, Jamieson DJ, Tegha G, Chasela CS, Kamwendo Det al. . The effects of a lipid-based nutrient supplement and antiretroviral therapy in a randomized controlled trial on iron, copper, and zinc in milk from HIV-infected Malawian mothers and associations with maternal and infant biomarkers. Maternal & Child Nutrition. 2018;14(2):e12503.
    1. Whitfield KC, Shahab-Ferdows S, Kroeun H, Sophonneary P, Green TJ, Allen LH, Hampel D. Macro- and micronutrients in milk from healthy Cambodian mothers: status and interrelations. J Nutr. 2020;150(6):1461–9.
    1. Oshin O, Hampel D, Idachaba F, Atayero A. The first 1,000 days: trends towards biosensing in assessing micronutrient deficiencies. J Phys Conf Ser. 2019;1299:012136.
    1. Hampel D, York ER, Allen LH. Ultra-performance liquid chromatography tandem mass-spectrometry (UPLC-MS/MS) for the rapid, simultaneous analysis of thiamin, riboflavin, flavin adenine dinucleotide, nicotinamide and pyridoxal in human milk. J Chromatogr B. 2012;903:7–13.
    1. Hampel D, Shahab-Ferdows S, Domek JM, Siddiqua T, Raqib R, Allen LH. Competitive chemiluminescent enzyme immunoassay for vitamin B12 analysis in human milk. Food Chem. 2014;153:60–65.
    1. Hampel D, Shahab-Ferdows S, Islam MM, Peerson JM, Allen LH. Vitamin concentrations in human milk vary with time within feed, circadian rhythm, and single-dose supplementation. J Nutr. 2017;147(4):603–11.
    1. Hampel D, Shahab-Ferdows S, Hossain M, Islam MM, Ahmed T, Allen LH. Validation and application of Biocrates AbsoluteIDQ® p180 targeted metabolomics kit using human milk. Nutrients. 2019;11(8):1733.
    1. Turner T, Burri BJ. Rapid isocratic HPLC method and sample extraction procedures for measuring carotenoid, retinoid, and tocopherol concentrations in human blood and breast milk for intervention studies. Chromatographia. 2012;75(5–6):241–52.
    1. Roche Diagnostics. Vitamin D total II for cobase 411 analyzer. Mannheim (Germany): Roche Diagnostics GmbH, 2017.
    1. Hampel D, Shahab-Ferdows S, Adair LS, Bentley ME, Flax VL, Jamieson DJ, Ellington SR, Tegha G, Chasela CS, Kamwendo Det al. . Thiamin and riboflavin in human milk: effects of lipid-based nutrient supplementation and stage of lactation on vitamer secretion and contributions to total vitamin content. PLoS One. 2016;11(2):e0149479.
    1. Roche Diagnostics. Elecsys folate III. Mannheim (Germany): Roche Diagnostics GmbH, 2018.
    1. Roche Diagnostics. Vitamin B12 II. Mannheim (Germany): Roche Diagnostics GmbH, 2017.
    1. Hampel D, Shahab-Ferdows S, Nguyen N, Kac G, Allen LH. High-throughput analysis of water-soluble forms of choline and related metabolites in human milk by UPLC-MS/MS and its application. Frontiers in Nutrition. 2021;7:604570.
    1. Pedersen TL, Keyes WR, Shahab-Ferdows S, Allen LH, Newman JW. Methylmalonic acid quantification in low serum volumes by UPLC-MS/MS. J Chromatogr B. 2011;879(19):1502–6.
    1. Gilfix BM, Blank DW, Rosenblatt DS. Novel reductant for determination of total plasma homocysteine. Clin Chem. 1997;43(4):687–8.
    1. Astolfi ML, Marconi E, Protano C, Vitali M, Schiavi E, Mastromarino P, Canepari S. Optimization and validation of a fast digestion method for the determination of major and trace elements in breast milk by ICP-MS. Anal Chim Acta. 2018;1040:49–62.
    1. Dold S, Baumgartner J, Zeder C, Krzystek A, Osei J, Haldimann M, Zimmermann M, Andersson M. Optimization of a new mass spectrometry method for measurement of breast milk iodine concentrations (BMIC) and an assessment of the effect of analytic method and timing of within-feed sample collection on BMIC. Thyroid. 2016;26(2):287–95.
    1. Stinca S, Andersson M, Weibel S, Herter-Aeberli I, Fingerhut R, Gowachirapant S, Hess SY, Jaiswal N, Jukić T, Kusic Z. Dried blood spot thyroglobulin as a biomarker of iodine status in pregnant women. The Journal of Clinical Endocrinology & Metabolism. 2017;102(1):23–32.
    1. Unity Scientific. Neonatal Analyzer Package. Milford (MA): Unity Scientific; 2017.
    1. Wu LD, Ruhaak LR, Lebrilla CB. Analysis of milk oligosaccharides by mass spectrometry. In: Lauc G, Wuhrer Meditors. High-Throughput Glycomics and Glycoproteomics. New York: Springer, 2017. p.121–9.
    1. Huang J, Kailemia MJ, Goonatilleke E, Parker EA, Hong Q, Sabia R, Smilowitz JT, German JB, Lebrilla CB. Quantitation of human milk proteins and their glycoforms using multiple reaction monitoring (MRM). Anal Bioanal Chem. 2017;409(2):589–606.
    1. Hampel D, Shahab-Ferdows S, Kac G, Allen LH. Human milk metabolic profiling using biocrates mxp® quant 500 kit. Current Developments in Nutrition. 2021;5(Supplement_2):874.
    1. Roche Diagnostics. AAGP2-Tina-quant alpha-acid glycoprotein Gen.2. Mannheim (Germany): Roche Diagnostics GmbH; 2017.
    1. Roche Diagnostics. CRPHS-Cardiac C-reactive protein (Latex) high sensitivity. Mannheim (Germany): Roche Diagnostics GmbH; 2016.
    1. . [Internet]. Rockville (MD): Meso Scale Diagnostics, LLC; c2021[cited 4 Aug, 2021]. Available from: .
    1. Roche Diagnostics. STFR-Tina-quant Soluble Transferrin Receptor. Mannheim (Germany): Roche Diagnostics GmbH; 2021.
    1. Roche Diagnostics. Elecsys® Ferritin. Rotkreuz (Switzerland): Roche Diagnostics International Ltd; 2014.
    1. Marees AT, de Kluiver H, Stringer S, Vorspan F, Curis E, Marie-Claire C, Derks EM. A tutorial on conducting genome-wide association studies: quality control and statistical analysis. Int J Methods Psychiatr Res. 2018;27(2):e1608.
    1. Kim M, Costello J. DNA methylation: an epigenetic mark of cellular memory. Exp Mol Med. 2017;49(4):e322.
    1. Hald S, Schioldan AG, Moore ME, Dige A, Lærke HN, Agnholt J, Bach Knudsen KE, Hermansen K, Marco ML, Gregersen S. Effects of arabinoxylan and resistant starch on intestinal microbiota and short-chain fatty acids in subjects with metabolic syndrome: a randomised crossover study. PLoS One. 2016;11(7):e0159223.
    1. Treiber ML, Taft DH, Korf I, Mills DA, Lemay DG. Pre- and post-sequencing recommendations for functional annotation of human fecal metagenomes. BMC Bioinformatics. 2020;21(1):1–15.
    1. Lemay DG, Hovey RC, Hartono SR, Hinde K, Smilowitz JT, Ventimiglia F, Schmidt KA, Lee JW, Islas-Trejo A, Silva PI. Sequencing the transcriptome of milk production: milk trumps mammary tissue. BMC Genomics. 2013;14(1):1–17.
    1. Westreich ST, Ardeshir A, Alkan Z, Kable ME, Korf I, Lemay DG. Fecal metatranscriptomics of macaques with idiopathic chronic diarrhea reveals altered mucin degradation and fucose utilization. Microbiome. 2019;7(1):1–17.

Source: PubMed

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