An observational study in Human Milk Nutrient Reference Values, sponsored by USDA, Western Human Nutrition Research Center. Status unknown at 4 sites in 4 countries. Open to female participants aged 18 Years to 40 Years, including healthy volunteers. Per ClinicalTrials.gov, last updated 2021-07-07.
Sponsored by USDA, Western Human Nutrition Research Center · Observational
The primary purpose of the proposed research is to establish Reference Values (RVs) for micronutrients (MN) and macronutrients in human milk. The investigators' research to date has revealed highly variable milk MN concentrations among populations, and very low values in some low income countries (LICs) likely caused by poor maternal status and/or diet but RVs are needed to interpret these values. During the past year the investigators conducted a review of human milk nutrient composition, and formed a Technical Advisory Group (TAG) which developed the current proposal. Here, the investigators are conducting a longitudinal project on well-nourished women and infants. The Mothers, Infants and Lactation Quality (MILQ) study is a multi-center cohort project, investigating breast milk nutrient composition in well-nourished women across the first 8.5 months of lactation in four different populations. The countries involved are Denmark, Brazil, Bangladesh and The Gambia. Exclusive breastfeeding is an eligibility criterion up until the second post-partum study visit (between 1 - 3.4 months postpartum), with the exception of the first week after delivery. Other data collected on mothers and infants, including maternal and infant nutrient intake and status, morbidity, milk volume, and infant development, will inform interpretation and support application of the results. While the priority is to develop RVs for MN, other analyses will include human milk oligosaccharides (HMOs) and proteins, and free amino acids (FAA) in infant plasma. Thus, with the samples obtained the investigators will perform (a) laboratory analyses of milk, plasma and urine nutrients to construct RVs for global application, (b) analyses of HMOs and proteins in milk, and (c) metabolomic analysis of FAA and other metabolites in infant plasma. By request of the Bill and Melinda Gates Foundation (BMGF), colostrum and fecal microbiota samples will also be collected and stored for later analyses.
The investigators will collect breast milk samples at four visits, at 2-3 days after birth (colostrum) and at 1-3.4, 3.5-5.9, and 6-8.5 months of lactation from well-nourished mothers age ≥18 to ≤40 years, in a systematic, identical way in four countries. The four sites are: Copenhagen, Denmark; Banjul, The Gambia; Rio de Janeiro, Brazil; and Mirpur, Dhaka, Bangladesh. The most important site selection criteria were that multiple micronutrient supplements are not consumed after week 28 of pregnancy; maternal diet is adequate but consumption of highly fortified foods is limited; and exclusive breastfeeding is 60% at 4 months.
In order to have 250 women and infants per site complete the study at 8.5 months, approximately 500 women will be recruited during the third trimester of pregnancy. This should allow for mothers and infants not meeting study eligibility criteria in pregnancy or early lactation, and drop-outs from the study. Recruitment during pregnancy will increase the opportunity to locate and recruit women since recruitment in the immediate post-delivery period will be difficult. It will also enable the women to be counselled on the importance of exclusive breastfeeding (EBF). Colostrum will be collected at 2-3 days postpartum for future analysis. The first collection of mature milk will occur between 1 and 3.4 months postpartum, when maternal and infant blood samples will also be collected on all participants. At the final two visits, in addition to milk collection, blood will be taken from all mothers but only half of the infants each time, primarily for the assessment of micronutrient status.
A requirement is that infants must be EBF in the 1-3.4 month period, and breastfed (BF) in the second and third period. Longitudinal measurements on the same mother after the BF period are not necessary for statistical reasons, as the investigators are not creating RVs for change in milk composition. The investigators expect that due to attrition and cessation of BF, the sample size will need to be augmented in later months; the alternative would have been to recruit and measure many more women in earlier stages in order to have an adequate sample size in the 7-8.5 month interval, which would be a much less efficient approach. Therefore after 6 months, if women are not breastfeeding, additional lactating women will be recruited from the group that was not EBF in the 3.4 month period, or from the local health center or community.
At all three points of mature milk collection the investigators will measure breast milk volume; diet, anthropometry and morbidity of the mother and infant; and infant development at 3.5-5.9 and 6 to 8.5 months; and will collect infant fecal samples for future analyses of the microbiome. Milk volume will be measured at three sites using the International Atomic Energy Agency's protocol that requires dosing the mother with deuterated water and collecting maternal and infant saliva urine samples at 0, 1, 2, 3, 4, 13 and 14 days after the dose. In Denmark breast milk volume will be measured by 24 hour infant weighing.
Most of the laboratory analyses will be conducted at the United States Department of Agriculture, Agricultural Research Service, Western Human Nutrition Research Center (WHNRC) in Davis, California. Other analyses will be performed in the Department of Chemistry at University of California, Davis (HMOs and other bioactive compounds in milk), and the Swiss Federal Institute of Technology in Zurich (iodine status). RVs will be constructed following the methods and principles developed for the World Health Organization (WHO) Child Growth Standards and the Intergrowth-21st Project.
An add-on study "Evaluation of maternal insulin resistance, metabolic and inflammatory biomarkers for prediction of successful initiation and duration of breastfeeding" is being conducted at the Danish site and was approved by The Regional Committee on Health Research Ethics with (H-17015174).
The aims of the add-on study are to evaluate if maternal metabolic and inflammatory biomarkers can predict successful initiation and duration of breastfeeding in a population of healthy non-obese Danish women, to evaluate the impact of maternal inflammatory biomarkers during pregnancy on the offspring's growth and risk factors for later disease, and to relate the impact of maternal metabolic and inflammatory biomarkers during pregnancy on breastfeeding behavior and on the offspring's growth and risk factors for later disease in this population to corresponding outcomes in an established cohort of infants born of obese mothers.
Well-nourished pregnant women in the third trimester of pregnancy at recruitment, then lactating with their infant from 1-8.5 months postpartum.
Inclusion Criteria for Mother
Inclusion Criteria for Infant
Exclusion Criteria at 1 to 3.4 Months Postpartum
Exclusion criteria 3.5 to 8.5 months postpartum
Assessment of human milk nutrient composition. Approximately 500 women and their infants recruited, 250 dyads completing study
Other: Assessment of human milk nutrient composition
Assessment of human milk nutrient composition. Approximately 500 women and their infants recruited, 250 dyads completing study
Other: Assessment of human milk nutrient composition
Assessment of human milk nutrient composition. Approximately 500 women and their infants recruited, 250 dyads completing study
Other: Assessment of human milk nutrient composition
Assessment of human milk nutrient composition. Approximately 500 women and their infants recruited, 250 dyads completing study
Other: Assessment of human milk nutrient composition
Observational study to measure nutrients in human milk during lactation and their relationship to maternal and infant nutritional status.
Change in vitamin and mineral concentrations in human breast milk
To establish reference values, the vitamin and mineral concentrations will be measured in milk of well-nourished women
Time frame: Breast milk samples collected 1-3.4, 3.5-5.9, and 6-8.5 months postpartum
Variation in other constituents of human breast milk
Macronutrients, and human milk oligosaccharides and proteins will be analyzed
Time frame: Breast milk samples collected at 1-3.4, 3.5-5.9, and 6-8.5 months postpartum
Micronutrient status of mothers and infants
Vitamin and mineral status of mothers and infants will be assessed in blood and urine
Time frame: Blood and urine samples surveyed at 1-3.4, 3.5-5.9, and 6-8.5 months postpartum
Milk volume
Measurements of usual daily milk volume using deuterated water or, in Denmark, 24 hour infant weighing
Time frame: 1-3.4, 3.5-5.9, and 6-8.5 months postpartum
Maternal and infant iodine status
Urinary iodine; thyroid stimulating hormone, thyroglobulin and thyroxine in dried blood spots
Time frame: 1-3.4, 3.5-5.9, and 6-8.5 months postpartum
Milk iodine
Milk iodine
Time frame: 1-3.4, 3.5-5.9, and 6-8.5 months postpartum
Maternal nutrient intake during pregnancy
Assessment of dietary intake by two days 24-hour recall in Denmark and Brazil
Time frame: Measured during gestational week 35-37
Maternal nutrient intake
Assessment of dietary intake by two days 24-hour recall
Time frame: 1-3.4, 3.5-5.9, and 6-8.5 months postpartum
Infant nutrient intake
Assessment of dietary intake by two days 24-hour recall of the infant's diet
Time frame: 1-3.4, 3.5-5.9, and 6-8.5 months
Infant dietary habits
Assessment of dietary intake by diet habits questionnaire
Time frame: 1-3.4, 3.5-5.9, and 6-8.5 months
Maternal weight
Measure of weight in kilograms (kg)
Time frame: 1-3.4, 3.5-5.9, and 6-8.5 months postpartum
Infant weight
Measure of weight in grams (g) or kilograms (kg)
Time frame: 1-3.4, 3.5-5.9, and 6-8.5 months
Maternal height
measured in centimeters (cm)
Time frame: 1-3.4, 3.5-5.9, and 6-8.5 months postpartum
Infant length
measured in cm
Time frame: 1-3.4, 3.5-5.9, and 6-8.5 months
Maternal body mass index
Maternal weight and height will be combined to determine body mass index (kg/m2)
Time frame: 1-3.4, 3.5-5.9, and 6-8.5 months postpartum
Infant growth
Infant weight and length will be aggregated to determine infant growth status
Time frame: 1-3.4, 3.5-5.9, and 6-8.5 months postpartum
Maternal body composition
Assessment of body composition by bioimpedance in Denmark, The Gambia, and Brazil only.
Time frame: 1-3.4, 3.5-5.9, and 6-8.5 months postpartum
Infant body composition
Assessment of body composition by Air Displacement Plethysmography, in The Gambia, and by bioimpedance in Denmark and Brazil.
Time frame: 1-3.4, 3.5-5.9, and 6-8.5 months
Infant morbidity
Data collected from mothers on infant health
Time frame: 1-3.4, 3.5-5.9, and 6-8.5 months
Infant development
Ages and Stages questionnaire
Time frame: 6-8.5 months
Infant motor development
Infant motor development measured using a World Health Organization (WHO) assessment of motor milestones
Time frame: 3.5-5.9 and 6-8.5 months
Change in infant microbiome
DNA analyses of infant gut bacteria derived from fecal samples
Time frame: 1-3.4, 3.5-5.9, and 6-8.5 months
Change in maternal microbiome
DNA analyses of maternal gut bacteria derived from fecal samples in The Gambia and Brazil only
Time frame: Collected at gestational week 28-40, and 1-3.4, 3.5-5.9, and 6-8.5 months postpartum
Maternal Glucose Tolerance
In Denmark only, an Oral Glucose Tolerance Test will be performed. Fasting blood sugar (BS), and BS at 1 and 2 hours after glucose beverage.
Time frame: Measured once at gestational week 28-30
Maternal Hemoglobin A1c (HbA1c)
In Denmark only, maternal Hemoglobin A1c will be measured in whole blood
Time frame: Measured once at gestational week 28-30
Maternal markers of insulin sensitivity
In Denmark only, a serum sample will be collected and stored for measurement of insulin (mU/l), c-peptide (pmol/l), and leptin (ng/l)
Time frame: Measured once at gestational week 28-30
Maternal lipid panel
In Denmark only, a serum sample will be collected and stored for measurement of a lipid profile including Total Cholesterol, High Density Lipoprotein-cholesterol, Low Density Lipoprotein-cholesterol, Very Low Density Lipoprotein-cholesterol, and Triglycerides in mmol/l).
Time frame: Measured once at gestational week 28-30
Maternal inflammatory markers
In Denmark only, a serum sample will be collected and stored for measurement of high sensitivity C-reactive protein (mg/l).
Time frame: Measured once at gestational week 28-30
Plan to share: No — Individual participants data will only be available as de-identified data.
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USDA, Western Human Nutrition Research Center