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Establishing Global Reference Values for Human Milk (MILQ)

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ClinicalTrials.gov Identifier: NCT03254329
Recruitment Status : Recruiting
First Posted : August 18, 2017
Last Update Posted : March 26, 2019
Sponsor:
Collaborators:
University of Copenhagen
Medical Research Council Unit, The Gambia
International Centre for Diarrhoeal Disease Research, Bangladesh
Universidade Federal do Rio de Janeiro
Bill and Melinda Gates Foundation
Information provided by (Responsible Party):
USDA, Western Human Nutrition Research Center

Tracking Information
First Submitted Date August 3, 2017
First Posted Date August 18, 2017
Last Update Posted Date March 26, 2019
Actual Study Start Date September 1, 2017
Estimated Primary Completion Date January 1, 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures
 (submitted: March 22, 2018)
Change in vitamin and mineral concentrations in human breast milk [ Time Frame: Breast milk samples collected 1-3.4, 3.5-5.9, and 6-8.5 months postpartum ]
To establish reference values, the vitamin and mineral concentrations will be measured in milk of well-nourished women
Original Primary Outcome Measures
 (submitted: August 15, 2017)
  • Variation in vitamin concentration of breast milk [ Time Frame: Breast milk samples surveyed at 1-3.4, 3.5-5.9, and 7-8.5 months postpartum ]
    Vitamin concentration measured in breast milk
  • Variation in mineral concentration of breast milk [ Time Frame: Breast milk samples surveyed at 1-3.4, 3.5-5.9, and 7-8.5 months postpartum ]
    Mineral concentration measured, such as zinc, copper, iron and iodine
  • Variation in carbohydrate concentration in breast milk [ Time Frame: Breast milk samples surveyed at 1-3.4, 3.5-5.9, and 7-8.5 months postpartum ]
    Carbohydrates such as milk oligosaccharides will be measured
  • Variation in protein concentration in breast milk [ Time Frame: Breast milk samples surveyed at 1-3.4, 3.5-5.9, and 7-8.5 months postpartum ]
    Proteins, glycosylated proteins, and amino acids will be measured
  • Variation in fat concentration in breast milk [ Time Frame: Breast milk samples surveyed at 1-3.4, 3.5-5.9, and 7-8.5 months postpartum ]
    Lipids in breast milk will be measured
Change History Complete list of historical versions of study NCT03254329 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures
 (submitted: March 22, 2018)
  • Variation in other constituents of human breast milk [ Time Frame: Breast milk samples collected at 1-3.4, 3.5-5.9, and 6-8.5 months postpartum ]
    Macronutrients, and human milk oligosaccharides and proteins will be analyzed
  • Micronutrient status of mothers and infants [ Time Frame: Blood and urine samples surveyed at 1-3.4, 3.5-5.9, and 6-8.5 months postpartum ]
    Vitamin and mineral status of mothers and infants will be assessed in blood and urine
  • Milk volume [ Time Frame: 1-3.4, 3.5-5.9, and 6-8.5 months postpartum ]
    Measurements of usual daily milk volume using deuterated water or, in Denmark, 24 hour infant weighing
  • Maternal and infant iodine status [ Time Frame: 1-3.4, 3.5-5.9, and 6-8.5 months postpartum ]
    Urinary iodine; thyroid stimulating hormone, thyroglobulin and thyroxine in dried blood spots
  • Milk iodine [ Time Frame: 1-3.4, 3.5-5.9, and 6-8.5 months postpartum ]
    Milk iodine
  • Maternal nutrient intake during pregnancy [ Time Frame: Measured during gestational week 35-37 ]
    Assessment of dietary intake by two days 24-hour recall in Denmark and Brazil
  • Maternal nutrient intake [ Time Frame: 1-3.4, 3.5-5.9, and 6-8.5 months postpartum ]
    Assessment of dietary intake by two days 24-hour recall
  • Infant nutrient intake [ Time Frame: 1-3.4, 3.5-5.9, and 6-8.5 months ]
    Assessment of dietary intake by two days 24-hour recall of the infant's diet
  • Infant dietary habits [ Time Frame: 1-3.4, 3.5-5.9, and 6-8.5 months ]
    Assessment of dietary intake by diet habits questionnaire
  • Maternal weight [ Time Frame: 1-3.4, 3.5-5.9, and 6-8.5 months postpartum ]
    Measure of weight in kilograms (kg)
  • Infant weight [ Time Frame: 1-3.4, 3.5-5.9, and 6-8.5 months ]
    Measure of weight in grams (g) or kilograms (kg)
  • Maternal height [ Time Frame: 1-3.4, 3.5-5.9, and 6-8.5 months postpartum ]
    measured in centimeters (cm)
  • Infant length [ Time Frame: 1-3.4, 3.5-5.9, and 6-8.5 months ]
    measured in cm
  • Maternal body mass index [ Time Frame: 1-3.4, 3.5-5.9, and 6-8.5 months postpartum ]
    Maternal weight and height will be combined to determine body mass index (kg/m2)
  • Infant growth [ Time Frame: 1-3.4, 3.5-5.9, and 6-8.5 months postpartum ]
    Infant weight and length will be aggregated to determine infant growth status
  • Maternal body composition [ Time Frame: 1-3.4, 3.5-5.9, and 6-8.5 months postpartum ]
    Assessment of body composition by bioimpedance in Denmark, The Gambia, and Brazil only.
  • Infant body composition [ Time Frame: 1-3.4, 3.5-5.9, and 6-8.5 months ]
    Assessment of body composition by Air Displacement Plethysmography, in The Gambia, and by bioimpedance in Denmark and Brazil.
  • Infant morbidity [ Time Frame: 1-3.4, 3.5-5.9, and 6-8.5 months ]
    Data collected from mothers on infant health
  • Infant development [ Time Frame: 6-8.5 months ]
    Ages and Stages questionnaire
  • Infant motor development [ Time Frame: 3.5-5.9 and 6-8.5 months ]
    Infant motor development measured using a World Health Organization (WHO) assessment of motor milestones
  • Change in infant microbiome [ Time Frame: 1-3.4, 3.5-5.9, and 6-8.5 months ]
    DNA analyses of infant gut bacteria derived from fecal samples
  • Change in maternal microbiome [ Time Frame: Collected at gestational week 28-40, and 1-3.4, 3.5-5.9, and 6-8.5 months postpartum ]
    DNA analyses of maternal gut bacteria derived from fecal samples in The Gambia and Brazil only
  • Maternal Glucose Tolerance [ Time Frame: Measured once at gestational week 28-30 ]
    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.
  • Maternal Hemoglobin A1c (HbA1c) [ Time Frame: Measured once at gestational week 28-30 ]
    In Denmark only, maternal Hemoglobin A1c will be measured in whole blood
  • Maternal markers of insulin sensitivity [ Time Frame: Measured once at gestational week 28-30 ]
    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)
  • Maternal lipid panel [ Time Frame: Measured once at gestational week 28-30 ]
    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).
  • Maternal inflammatory markers [ Time Frame: Measured once at gestational week 28-30 ]
    In Denmark only, a serum sample will be collected and stored for measurement of high sensitivity C-reactive protein (mg/l).
Original Secondary Outcome Measures
 (submitted: August 15, 2017)
  • Change in maternal fat soluble vitamin status [ Time Frame: 1-3.4, 3.5-5.9, and 7-8.5 months postpartum ]
    Vitamins A and D measured in blood
  • Change in maternal Vitamin B status [ Time Frame: 1-3.4, 3.5-5.9, and 7-8.5 months postpartum ]
    Vitamin B measured in blood
  • Change in maternal micronutrient status [ Time Frame: 1-3.4, 3.5-5.9, and 7-8.5 months postpartum ]
    Minerals measured in blood such as zinc, copper, iron
  • Change in maternal iodine status [ Time Frame: 1-3.4, 3.5-5.9, and 7-8.5 months postpartum ]
    Iodine measured in urine
  • Change in maternal Body Mass Index (BMI) [ Time Frame: 1-3.4, 3.5-5.9, and 7-8.5 months postpartum ]
    BMI measured as kg/meter squared
  • Maternal diet [ Time Frame: 1-3.4, 3.5-5.9, and 7-8.5 months postpartum ]
    Assessment of 24 hr dietary intake, nutrient data
  • Change in infant fat soluble vitamin status [ Time Frame: 1-3.4, 3.5-5.9, and 7-8.5 months postpartum ]
    Fat soluble vitamins A and D measured in blood
  • Change in infant vitamin B status [ Time Frame: 1-3.4, 3.5-5.9, and 7-8.5 months postpartum ]
    Vitamin B measured in blood
  • Change in infant micronutrient status [ Time Frame: 1-3.4, 3.5-5.9, and 7-8.5 months postpartum ]
    Minerals measured in blood such as zinc, copper and iron
  • Change in infant iodine status [ Time Frame: 1-3.4, 3.5-5.9, and 7-8.9 months postpartum ]
    Iodine measured in urine
  • Change in infant weight [ Time Frame: 1-3.4, 3.5-5.9, and 7-8.5 months postpartum ]
    infant weight and calculated z scores
  • Change in infant length [ Time Frame: 1-3.4, 3.5-5.5, and 7-8.5 months postpartum ]
    infant length and calculated z scores
  • Change in infant blood amino acids [ Time Frame: 1-3.4, 3.5-5.9, and 7-8.5 months postpartum ]
    single amino acids
  • Infant morbidity [ Time Frame: 1-3.4, 3.5-5.9, and 7-8.5 months postpartum ]
    Data collected from mothers on infant health
  • Infant diet [ Time Frame: 7-8.5 months postpartum ]
    Nutrient data from infant food intake
  • Infant development [ Time Frame: 3.5-5.9, and 7-8.5 months postpartum ]
    Ages and stages data
  • Infant microbiome [ Time Frame: 3.5-5.9, and 7-8.9 months postpartum ]
    DNA analyses of infant gut bacteria derived from fecal samples
  • Infant body composition in Denmark [ Time Frame: 3.5-5.9, and 7-8.9 months postpartum ]
    Measuring body composition
  • Maternal body composition in Denmark [ Time Frame: 3.5-5.9, and 7-8.9 months postpartum ]
    Measuring body composition
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title Establishing Global Reference Values for Human Milk
Official Title Establishing Global Reference Values for Human Milk Composition in a Multi-Center Collaborative Study
Brief Summary 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.
Detailed Description

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.

Study Type Observational
Study Design Observational Model: Family-Based
Time Perspective: Prospective
Target Follow-Up Duration Not Provided
Biospecimen Retention:   Samples With DNA
Description:
Breast milk, blood, saliva, urine and feces
Sampling Method Non-Probability Sample
Study Population Well-nourished pregnant women in the third trimester of pregnancy at recruitment, then lactating with their infant from 1-8.5 months postpartum.
Condition Human Milk Nutrient Reference Values
Intervention 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.
Study Groups/Cohorts
  • Bangladesh
    Assessment of human milk nutrient composition. Approximately 500 women and their infants recruited, 250 dyads completing study
    Intervention: Other: Assessment of human milk nutrient composition
  • Brazil
    Assessment of human milk nutrient composition. Approximately 500 women and their infants recruited, 250 dyads completing study
    Intervention: Other: Assessment of human milk nutrient composition
  • Denmark
    Assessment of human milk nutrient composition. Approximately 500 women and their infants recruited, 250 dyads completing study
    Intervention: Other: Assessment of human milk nutrient composition
  • The Gambia
    Assessment of human milk nutrient composition. Approximately 500 women and their infants recruited, 250 dyads completing study
    Intervention: Other: Assessment of human milk nutrient composition
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status Recruiting
Estimated Enrollment
 (submitted: March 22, 2018)
2000
Original Estimated Enrollment
 (submitted: August 15, 2017)
1000
Estimated Study Completion Date May 1, 2020
Estimated Primary Completion Date January 1, 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria

Inclusion Criteria for Mother

  • No vitamin-mineral supplements during third trimester of pregnancy or during lactation except for iron + folic acid, also vitamin D and Ca in Denmark.
  • Low habitual intake of highly-fortified foods (iodized salt excepted).
  • No relevant past or current medical problems including gestational diabetes or pre-eclampsia.
  • Singleton delivery, not preterm.
  • BMI ≥18.5 to <30.0 kg/m2, height ≥150 cm.
  • Mid-upper arm circumference (MUAC) ≥23 and ≤33 cm in pregnancy
  • Consuming a nutritionally adequate diet i.e. not vegan or macrobiotic, ≥5 food groups/d each ≥15g. At screening this information will be collected with a locally-appropriate and validated food frequency questionnaire.
  • Non-anemic in pregnancy (Hb >100 g/L)
  • Alcohol intake ≤5 units (50 mL pure alcohol)/week.
  • Non-smoker.

Inclusion Criteria for Infant

  • Birth weight 2500-4200 g, 37-42 weeks of gestation.
  • No congenital malformations that interfere with feeding or growth and development.

Exclusion Criteria at 1 to 3.4 Months Postpartum

  • Cessation of or non-exclusive breastfeeding.
  • Serious maternal illness.
  • Infant length-for-age, weight-for-age or weight-for-length < -2 Z.

Exclusion criteria 3.5 to 8.5 months postpartum

  • Cessation of breastfeeding.
  • Serious maternal illness.
  • Infant length-for-age, weight-for-age or weight-for-length < -2 Z.
Sex/Gender
Sexes Eligible for Study: Female
Gender Based Eligibility: Yes
Gender Eligibility Description: Pregnant and lactating women
Ages 18 Years to 40 Years   (Adult)
Accepts Healthy Volunteers Yes
Contacts
Contact: Lindsay H Allen, PhD 530 752 5268 lindsay.allen@ars.usda.gov
Contact: Setareh Shahab-Ferdows, PhD 530 752 9540 setti.shahab-ferdows@ARS.USDA.GOV
Listed Location Countries Bangladesh,   Brazil,   Denmark,   Gambia
Removed Location Countries  
 
Administrative Information
NCT Number NCT03254329
Other Study ID Numbers MILQ
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement
Plan to Share IPD: No
Plan Description: Individual participants data will only be available as de-identified data.
Responsible Party USDA, Western Human Nutrition Research Center
Study Sponsor USDA, Western Human Nutrition Research Center
Collaborators
  • University of Copenhagen
  • Medical Research Council Unit, The Gambia
  • International Centre for Diarrhoeal Disease Research, Bangladesh
  • Universidade Federal do Rio de Janeiro
  • Bill and Melinda Gates Foundation
Investigators
Principal Investigator: Lindsay H Allen, PhD USDA/WHNRC
PRS Account USDA, Western Human Nutrition Research Center
Verification Date March 2019