<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT03254329</url>
  </required_header>
  <id_info>
    <org_study_id>MILQ</org_study_id>
    <nct_id>NCT03254329</nct_id>
  </id_info>
  <brief_title>Establishing Global Reference Values for Human Milk</brief_title>
  <acronym>MILQ</acronym>
  <official_title>Establishing Global Reference Values for Human Milk Composition in a Multi-Center Collaborative Study</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>USDA, Western Human Nutrition Research Center</agency>
      <agency_class>U.S. Fed</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>University of Copenhagen</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Medical Research Council Unit, The Gambia</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>International Centre for Diarrhoeal Disease Research, Bangladesh</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Universidade Federal do Rio de Janeiro</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Bill and Melinda Gates Foundation</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>USDA, Western Human Nutrition Research Center</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      The primary purpose of the proposed research is to establish Reference Values (RVs) for&#xD;
      micronutrients (MN) and macronutrients in human milk. The investigators' research to date has&#xD;
      revealed highly variable milk MN concentrations among populations, and very low values in&#xD;
      some low income countries (LICs) likely caused by poor maternal status and/or diet but RVs&#xD;
      are needed to interpret these values. During the past year the investigators conducted a&#xD;
      review of human milk nutrient composition, and formed a Technical Advisory Group (TAG) which&#xD;
      developed the current proposal. Here, the investigators are conducting a longitudinal project&#xD;
      on well-nourished women and infants. The Mothers, Infants and Lactation Quality (MILQ) study&#xD;
      is a multi-center cohort project, investigating breast milk nutrient composition in&#xD;
      well-nourished women across the first 8.5 months of lactation in four different populations.&#xD;
      The countries involved are Denmark, Brazil, Bangladesh and The Gambia. Exclusive&#xD;
      breastfeeding is an eligibility criterion up until the second post-partum study visit&#xD;
      (between 1 - 3.4 months postpartum), with the exception of the first week after delivery.&#xD;
      Other data collected on mothers and infants, including maternal and infant nutrient intake&#xD;
      and status, morbidity, milk volume, and infant development, will inform interpretation and&#xD;
      support application of the results. While the priority is to develop RVs for MN, other&#xD;
      analyses will include human milk oligosaccharides (HMOs) and proteins, and free amino acids&#xD;
      (FAA) in infant plasma. Thus, with the samples obtained the investigators will perform (a)&#xD;
      laboratory analyses of milk, plasma and urine nutrients to construct RVs for global&#xD;
      application, (b) analyses of HMOs and proteins in milk, and (c) metabolomic analysis of FAA&#xD;
      and other metabolites in infant plasma. By request of the Bill and Melinda Gates Foundation&#xD;
      (BMGF), colostrum and fecal microbiota samples will also be collected and stored for later&#xD;
      analyses.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      The investigators will collect breast milk samples at four visits, at 2-3 days after birth&#xD;
      (colostrum) and at 1-3.4, 3.5-5.9, and 6-8.5 months of lactation from well-nourished mothers&#xD;
      age ≥18 to ≤40 years, in a systematic, identical way in four countries. The four sites are:&#xD;
      Copenhagen, Denmark; Banjul, The Gambia; Rio de Janeiro, Brazil; and Mirpur, Dhaka,&#xD;
      Bangladesh. The most important site selection criteria were that multiple micronutrient&#xD;
      supplements are not consumed after week 28 of pregnancy; maternal diet is adequate but&#xD;
      consumption of highly fortified foods is limited; and exclusive breastfeeding is 60% at 4&#xD;
      months.&#xD;
&#xD;
      In order to have 250 women and infants per site complete the study at 8.5 months,&#xD;
      approximately 500 women will be recruited during the third trimester of pregnancy. This&#xD;
      should allow for mothers and infants not meeting study eligibility criteria in pregnancy or&#xD;
      early lactation, and drop-outs from the study. Recruitment during pregnancy will increase the&#xD;
      opportunity to locate and recruit women since recruitment in the immediate post-delivery&#xD;
      period will be difficult. It will also enable the women to be counselled on the importance of&#xD;
      exclusive breastfeeding (EBF). Colostrum will be collected at 2-3 days postpartum for future&#xD;
      analysis. The first collection of mature milk will occur between 1 and 3.4 months postpartum,&#xD;
      when maternal and infant blood samples will also be collected on all participants. At the&#xD;
      final two visits, in addition to milk collection, blood will be taken from all mothers but&#xD;
      only half of the infants each time, primarily for the assessment of micronutrient status.&#xD;
&#xD;
      A requirement is that infants must be EBF in the 1-3.4 month period, and breastfed (BF) in&#xD;
      the second and third period. Longitudinal measurements on the same mother after the BF period&#xD;
      are not necessary for statistical reasons, as the investigators are not creating RVs for&#xD;
      change in milk composition. The investigators expect that due to attrition and cessation of&#xD;
      BF, the sample size will need to be augmented in later months; the alternative would have&#xD;
      been to recruit and measure many more women in earlier stages in order to have an adequate&#xD;
      sample size in the 7-8.5 month interval, which would be a much less efficient approach.&#xD;
      Therefore after 6 months, if women are not breastfeeding, additional lactating women will be&#xD;
      recruited from the group that was not EBF in the 3.4 month period, or from the local health&#xD;
      center or community.&#xD;
&#xD;
      At all three points of mature milk collection the investigators will measure breast milk&#xD;
      volume; diet, anthropometry and morbidity of the mother and infant; and infant development at&#xD;
      3.5-5.9 and 6 to 8.5 months; and will collect infant fecal samples for future analyses of the&#xD;
      microbiome. Milk volume will be measured at three sites using the International Atomic Energy&#xD;
      Agency's protocol that requires dosing the mother with deuterated water and collecting&#xD;
      maternal and infant saliva urine samples at 0, 1, 2, 3, 4, 13 and 14 days after the dose. In&#xD;
      Denmark breast milk volume will be measured by 24 hour infant weighing.&#xD;
&#xD;
      Most of the laboratory analyses will be conducted at the United States Department of&#xD;
      Agriculture, Agricultural Research Service, Western Human Nutrition Research Center (WHNRC)&#xD;
      in Davis, California. Other analyses will be performed in the Department of Chemistry at&#xD;
      University of California, Davis (HMOs and other bioactive compounds in milk), and the Swiss&#xD;
      Federal Institute of Technology in Zurich (iodine status). RVs will be constructed following&#xD;
      the methods and principles developed for the World Health Organization (WHO) Child Growth&#xD;
      Standards and the Intergrowth-21st Project.&#xD;
&#xD;
      An add-on study &quot;Evaluation of maternal insulin resistance, metabolic and inflammatory&#xD;
      biomarkers for prediction of successful initiation and duration of breastfeeding&quot; is being&#xD;
      conducted at the Danish site and was approved by The Regional Committee on Health Research&#xD;
      Ethics with (H-17015174).&#xD;
&#xD;
      The aims of the add-on study are to evaluate if maternal metabolic and inflammatory&#xD;
      biomarkers can predict successful initiation and duration of breastfeeding in a population of&#xD;
      healthy non-obese Danish women, to evaluate the impact of maternal inflammatory biomarkers&#xD;
      during pregnancy on the offspring's growth and risk factors for later disease, and to relate&#xD;
      the impact of maternal metabolic and inflammatory biomarkers during pregnancy on&#xD;
      breastfeeding behavior and on the offspring's growth and risk factors for later disease in&#xD;
      this population to corresponding outcomes in an established cohort of infants born of obese&#xD;
      mothers.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Recruiting</last_known_status>
  <start_date type="Actual">September 1, 2017</start_date>
  <completion_date type="Anticipated">November 30, 2021</completion_date>
  <primary_completion_date type="Anticipated">November 30, 2021</primary_completion_date>
  <study_type>Observational</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <observational_model>Family-Based</observational_model>
    <time_perspective>Prospective</time_perspective>
  </study_design_info>
  <primary_outcome>
    <measure>Change in vitamin and mineral concentrations in human breast milk</measure>
    <time_frame>Breast milk samples collected 1-3.4, 3.5-5.9, and 6-8.5 months postpartum</time_frame>
    <description>To establish reference values, the vitamin and mineral concentrations will be measured in milk of well-nourished women</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Variation in other constituents of human breast milk</measure>
    <time_frame>Breast milk samples collected at 1-3.4, 3.5-5.9, and 6-8.5 months postpartum</time_frame>
    <description>Macronutrients, and human milk oligosaccharides and proteins will be analyzed</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Micronutrient status of mothers and infants</measure>
    <time_frame>Blood and urine samples surveyed at 1-3.4, 3.5-5.9, and 6-8.5 months postpartum</time_frame>
    <description>Vitamin and mineral status of mothers and infants will be assessed in blood and urine</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Milk volume</measure>
    <time_frame>1-3.4, 3.5-5.9, and 6-8.5 months postpartum</time_frame>
    <description>Measurements of usual daily milk volume using deuterated water or, in Denmark, 24 hour infant weighing</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Maternal and infant iodine status</measure>
    <time_frame>1-3.4, 3.5-5.9, and 6-8.5 months postpartum</time_frame>
    <description>Urinary iodine; thyroid stimulating hormone, thyroglobulin and thyroxine in dried blood spots</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Milk iodine</measure>
    <time_frame>1-3.4, 3.5-5.9, and 6-8.5 months postpartum</time_frame>
    <description>Milk iodine</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Maternal nutrient intake during pregnancy</measure>
    <time_frame>Measured during gestational week 35-37</time_frame>
    <description>Assessment of dietary intake by two days 24-hour recall in Denmark and Brazil</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Maternal nutrient intake</measure>
    <time_frame>1-3.4, 3.5-5.9, and 6-8.5 months postpartum</time_frame>
    <description>Assessment of dietary intake by two days 24-hour recall</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Infant nutrient intake</measure>
    <time_frame>1-3.4, 3.5-5.9, and 6-8.5 months</time_frame>
    <description>Assessment of dietary intake by two days 24-hour recall of the infant's diet</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Infant dietary habits</measure>
    <time_frame>1-3.4, 3.5-5.9, and 6-8.5 months</time_frame>
    <description>Assessment of dietary intake by diet habits questionnaire</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Maternal weight</measure>
    <time_frame>1-3.4, 3.5-5.9, and 6-8.5 months postpartum</time_frame>
    <description>Measure of weight in kilograms (kg)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Infant weight</measure>
    <time_frame>1-3.4, 3.5-5.9, and 6-8.5 months</time_frame>
    <description>Measure of weight in grams (g) or kilograms (kg)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Maternal height</measure>
    <time_frame>1-3.4, 3.5-5.9, and 6-8.5 months postpartum</time_frame>
    <description>measured in centimeters (cm)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Infant length</measure>
    <time_frame>1-3.4, 3.5-5.9, and 6-8.5 months</time_frame>
    <description>measured in cm</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Maternal body mass index</measure>
    <time_frame>1-3.4, 3.5-5.9, and 6-8.5 months postpartum</time_frame>
    <description>Maternal weight and height will be combined to determine body mass index (kg/m2)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Infant growth</measure>
    <time_frame>1-3.4, 3.5-5.9, and 6-8.5 months postpartum</time_frame>
    <description>Infant weight and length will be aggregated to determine infant growth status</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Maternal body composition</measure>
    <time_frame>1-3.4, 3.5-5.9, and 6-8.5 months postpartum</time_frame>
    <description>Assessment of body composition by bioimpedance in Denmark, The Gambia, and Brazil only.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Infant body composition</measure>
    <time_frame>1-3.4, 3.5-5.9, and 6-8.5 months</time_frame>
    <description>Assessment of body composition by Air Displacement Plethysmography, in The Gambia, and by bioimpedance in Denmark and Brazil.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Infant morbidity</measure>
    <time_frame>1-3.4, 3.5-5.9, and 6-8.5 months</time_frame>
    <description>Data collected from mothers on infant health</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Infant development</measure>
    <time_frame>6-8.5 months</time_frame>
    <description>Ages and Stages questionnaire</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Infant motor development</measure>
    <time_frame>3.5-5.9 and 6-8.5 months</time_frame>
    <description>Infant motor development measured using a World Health Organization (WHO) assessment of motor milestones</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in infant microbiome</measure>
    <time_frame>1-3.4, 3.5-5.9, and 6-8.5 months</time_frame>
    <description>DNA analyses of infant gut bacteria derived from fecal samples</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in maternal microbiome</measure>
    <time_frame>Collected at gestational week 28-40, and 1-3.4, 3.5-5.9, and 6-8.5 months postpartum</time_frame>
    <description>DNA analyses of maternal gut bacteria derived from fecal samples in The Gambia and Brazil only</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Maternal Glucose Tolerance</measure>
    <time_frame>Measured once at gestational week 28-30</time_frame>
    <description>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.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Maternal Hemoglobin A1c (HbA1c)</measure>
    <time_frame>Measured once at gestational week 28-30</time_frame>
    <description>In Denmark only, maternal Hemoglobin A1c will be measured in whole blood</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Maternal markers of insulin sensitivity</measure>
    <time_frame>Measured once at gestational week 28-30</time_frame>
    <description>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)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Maternal lipid panel</measure>
    <time_frame>Measured once at gestational week 28-30</time_frame>
    <description>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).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Maternal inflammatory markers</measure>
    <time_frame>Measured once at gestational week 28-30</time_frame>
    <description>In Denmark only, a serum sample will be collected and stored for measurement of high sensitivity C-reactive protein (mg/l).</description>
  </secondary_outcome>
  <number_of_groups>4</number_of_groups>
  <enrollment type="Anticipated">2000</enrollment>
  <condition>Human Milk Nutrient Reference Values</condition>
  <arm_group>
    <arm_group_label>Bangladesh</arm_group_label>
    <description>Assessment of human milk nutrient composition. Approximately 500 women and their infants recruited, 250 dyads completing study</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Brazil</arm_group_label>
    <description>Assessment of human milk nutrient composition. Approximately 500 women and their infants recruited, 250 dyads completing study</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Denmark</arm_group_label>
    <description>Assessment of human milk nutrient composition. Approximately 500 women and their infants recruited, 250 dyads completing study</description>
  </arm_group>
  <arm_group>
    <arm_group_label>The Gambia</arm_group_label>
    <description>Assessment of human milk nutrient composition. Approximately 500 women and their infants recruited, 250 dyads completing study</description>
  </arm_group>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Assessment of human milk nutrient composition</intervention_name>
    <description>Observational study to measure nutrients in human milk during lactation and their relationship to maternal and infant nutritional status.</description>
    <arm_group_label>Bangladesh</arm_group_label>
    <arm_group_label>Brazil</arm_group_label>
    <arm_group_label>Denmark</arm_group_label>
    <arm_group_label>The Gambia</arm_group_label>
  </intervention>
  <biospec_retention>Samples With DNA</biospec_retention>
  <biospec_descr>
    <textblock>
      Breast milk, blood, saliva, urine and feces&#xD;
    </textblock>
  </biospec_descr>
  <eligibility>
    <study_pop>
      <textblock>
        Well-nourished pregnant women in the third trimester of pregnancy at recruitment, then&#xD;
        lactating with their infant from 1-8.5 months postpartum.&#xD;
      </textblock>
    </study_pop>
    <sampling_method>Non-Probability Sample</sampling_method>
    <criteria>
      <textblock>
        Inclusion Criteria for Mother&#xD;
&#xD;
          -  No vitamin-mineral supplements during third trimester of pregnancy or during lactation&#xD;
             except for iron + folic acid, also vitamin D and Ca in Denmark.&#xD;
&#xD;
          -  Low habitual intake of highly-fortified foods (iodized salt excepted).&#xD;
&#xD;
          -  No relevant past or current medical problems including gestational diabetes or&#xD;
             pre-eclampsia.&#xD;
&#xD;
          -  Singleton delivery, not preterm.&#xD;
&#xD;
          -  BMI ≥18.5 to &lt;30.0 kg/m2, height ≥150 cm.&#xD;
&#xD;
          -  Mid-upper arm circumference (MUAC) ≥23 and ≤33 cm in pregnancy&#xD;
&#xD;
          -  Consuming a nutritionally adequate diet i.e. not vegan or macrobiotic, ≥5 food&#xD;
             groups/d each ≥15g. At screening this information will be collected with a&#xD;
             locally-appropriate and validated food frequency questionnaire.&#xD;
&#xD;
          -  Non-anemic in pregnancy (Hb &gt;100 g/L)&#xD;
&#xD;
          -  Alcohol intake ≤5 units (50 mL pure alcohol)/week.&#xD;
&#xD;
          -  Non-smoker.&#xD;
&#xD;
        Inclusion Criteria for Infant&#xD;
&#xD;
          -  Birth weight 2500-4200 g, 37-42 weeks of gestation.&#xD;
&#xD;
          -  No congenital malformations that interfere with feeding or growth and development.&#xD;
&#xD;
        Exclusion Criteria at 1 to 3.4 Months Postpartum&#xD;
&#xD;
          -  Cessation of or non-exclusive breastfeeding.&#xD;
&#xD;
          -  Serious maternal illness.&#xD;
&#xD;
          -  Infant length-for-age, weight-for-age or weight-for-length &lt; -2 Z.&#xD;
&#xD;
        Exclusion criteria 3.5 to 8.5 months postpartum&#xD;
&#xD;
          -  Cessation of breastfeeding.&#xD;
&#xD;
          -  Serious maternal illness.&#xD;
&#xD;
          -  Infant length-for-age, weight-for-age or weight-for-length &lt; -2 Z.&#xD;
      </textblock>
    </criteria>
    <gender>Female</gender>
    <gender_based>Yes</gender_based>
    <gender_description>Pregnant and lactating women</gender_description>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>40 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Lindsay H Allen, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>USDA/WHNRC</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Lindsay H Allen, PhD</last_name>
    <phone>530 752 5268</phone>
    <email>lindsay.allen@ars.usda.gov</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Setareh Shahab-Ferdows, PhD</last_name>
    <phone>530 752 9540</phone>
    <email>setti.shahab-ferdows@ARS.USDA.GOV</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>International Centre for Diarrhoeal Disease Research, Bangladesh (icddr,b)</name>
      <address>
        <city>Dhaka</city>
        <zip>1212</zip>
        <country>Bangladesh</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Md. Munirul Islam, MD, PhD</last_name>
      <phone>+880 2 9827001-10</phone>
      <phone_ext>2352</phone_ext>
      <email>mislam@icddrb.org</email>
    </contact>
    <investigator>
      <last_name>Munir Islam, Ph.D.</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Federal University of Rio de Janeiro</name>
      <address>
        <city>Rio de Janeiro</city>
        <zip>RJ21941-590</zip>
        <country>Brazil</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Gilberto Kac, MD, PhD</last_name>
      <email>Gilberto.Kac@gmail.com</email>
    </contact>
    <contact_backup>
      <last_name>Erica Barros</last_name>
      <email>ericabarros86@gmail.com</email>
    </contact_backup>
  </location>
  <location>
    <facility>
      <name>University of Copenhagen</name>
      <address>
        <city>Copenhagen</city>
        <state>Frederiksberg</state>
        <zip>1958</zip>
        <country>Denmark</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Kim F Michaelsen, MD, PhD</last_name>
      <phone>+45 35 33 22 21</phone>
      <email>kfm@nexs.ku.dk</email>
    </contact>
    <contact_backup>
      <last_name>Kamilla G Eriksen, PhD</last_name>
      <phone>+45 35 32 61 76</phone>
      <email>kge@nexs.ku.dk</email>
    </contact_backup>
  </location>
  <location>
    <facility>
      <name>Medical Research Council Gambia</name>
      <address>
        <city>Bakau</city>
        <state>Kombo Saint Mary's</state>
        <country>Gambia</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Sophie Moore, PhD</last_name>
      <email>sophie.moore@kcl.ac.uk</email>
    </contact>
    <contact_backup>
      <last_name>Andrew Doel</last_name>
      <phone>+44 758081041</phone>
      <email>andrew.doel@kcl.ac.uk</email>
    </contact_backup>
  </location>
  <location_countries>
    <country>Bangladesh</country>
    <country>Brazil</country>
    <country>Denmark</country>
    <country>Gambia</country>
  </location_countries>
  <verification_date>July 2021</verification_date>
  <study_first_submitted>August 3, 2017</study_first_submitted>
  <study_first_submitted_qc>August 15, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">August 18, 2017</study_first_posted>
  <last_update_submitted>July 2, 2021</last_update_submitted>
  <last_update_submitted_qc>July 2, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">July 7, 2021</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>human milk</keyword>
  <keyword>micronutrients</keyword>
  <keyword>lactation</keyword>
  <keyword>milk volume</keyword>
  <keyword>milk composition</keyword>
  <keyword>reference values</keyword>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
    <ipd_description>Individual participants data will only be available as de-identified data.</ipd_description>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03254329
org study id: MILQ
nct id: NCT03254329
lead sponsor: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
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.
observational model: Family-Based
time perspective: Prospective
measure: 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
description: To establish reference values, the vitamin and mineral concentrations will be measured in milk of well-nourished women
measure: 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
description: Macronutrients, and human milk oligosaccharides and proteins will be analyzed
measure: 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
description: Vitamin and mineral status of mothers and infants will be assessed in blood and urine
measure: Milk volume
time frame: 1-3.4, 3.5-5.9, and 6-8.5 months postpartum
description: Measurements of usual daily milk volume using deuterated water or, in Denmark, 24 hour infant weighing
measure: Maternal and infant iodine status
time frame: 1-3.4, 3.5-5.9, and 6-8.5 months postpartum
description: Urinary iodine; thyroid stimulating hormone, thyroglobulin and thyroxine in dried blood spots
measure: Milk iodine
time frame: 1-3.4, 3.5-5.9, and 6-8.5 months postpartum
description: Milk iodine
measure: Maternal nutrient intake during pregnancy
time frame: Measured during gestational week 35-37
description: Assessment of dietary intake by two days 24-hour recall in Denmark and Brazil
measure: Maternal nutrient intake
time frame: 1-3.4, 3.5-5.9, and 6-8.5 months postpartum
description: Assessment of dietary intake by two days 24-hour recall
measure: Infant nutrient intake
time frame: 1-3.4, 3.5-5.9, and 6-8.5 months
description: Assessment of dietary intake by two days 24-hour recall of the infant's diet
measure: Infant dietary habits
time frame: 1-3.4, 3.5-5.9, and 6-8.5 months
description: Assessment of dietary intake by diet habits questionnaire
measure: Maternal weight
time frame: 1-3.4, 3.5-5.9, and 6-8.5 months postpartum
description: Measure of weight in kilograms (kg)
measure: Infant weight
time frame: 1-3.4, 3.5-5.9, and 6-8.5 months
description: Measure of weight in grams (g) or kilograms (kg)
measure: Maternal height
time frame: 1-3.4, 3.5-5.9, and 6-8.5 months postpartum
description: measured in centimeters (cm)
measure: Infant length
time frame: 1-3.4, 3.5-5.9, and 6-8.5 months
description: measured in cm
measure: Maternal body mass index
time frame: 1-3.4, 3.5-5.9, and 6-8.5 months postpartum
description: Maternal weight and height will be combined to determine body mass index (kg/m2)
measure: Infant growth
time frame: 1-3.4, 3.5-5.9, and 6-8.5 months postpartum
description: Infant weight and length will be aggregated to determine infant growth status
measure: Maternal body composition
time frame: 1-3.4, 3.5-5.9, and 6-8.5 months postpartum
description: Assessment of body composition by bioimpedance in Denmark, The Gambia, and Brazil only.
measure: Infant body composition
time frame: 1-3.4, 3.5-5.9, and 6-8.5 months
description: Assessment of body composition by Air Displacement Plethysmography, in The Gambia, and by bioimpedance in Denmark and Brazil.
measure: Infant morbidity
time frame: 1-3.4, 3.5-5.9, and 6-8.5 months
description: Data collected from mothers on infant health
measure: Infant development
time frame: 6-8.5 months
description: Ages and Stages questionnaire
measure: Infant motor development
time frame: 3.5-5.9 and 6-8.5 months
description: Infant motor development measured using a World Health Organization (WHO) assessment of motor milestones
measure: Change in infant microbiome
time frame: 1-3.4, 3.5-5.9, and 6-8.5 months
description: DNA analyses of infant gut bacteria derived from fecal samples
measure: 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
description: DNA analyses of maternal gut bacteria derived from fecal samples in The Gambia and Brazil only
measure: Maternal Glucose Tolerance
time frame: Measured once at gestational week 28-30
description: 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.
measure: Maternal Hemoglobin A1c (HbA1c)
time frame: Measured once at gestational week 28-30
description: In Denmark only, maternal Hemoglobin A1c will be measured in whole blood
measure: Maternal markers of insulin sensitivity
time frame: Measured once at gestational week 28-30
description: 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)
measure: Maternal lipid panel
time frame: Measured once at gestational week 28-30
description: 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).
measure: Maternal inflammatory markers
time frame: Measured once at gestational week 28-30
description: In Denmark only, a serum sample will be collected and stored for measurement of high sensitivity C-reactive protein (mg/l).
arm group label: Bangladesh
description: Assessment of human milk nutrient composition. Approximately 500 women and their infants recruited, 250 dyads completing study
arm group label: Brazil
description: Assessment of human milk nutrient composition. Approximately 500 women and their infants recruited, 250 dyads completing study
arm group label: Denmark
description: Assessment of human milk nutrient composition. Approximately 500 women and their infants recruited, 250 dyads completing study
arm group label: The Gambia
description: Assessment of human milk nutrient composition. Approximately 500 women and their infants recruited, 250 dyads completing study
intervention type: Other
intervention name: Assessment of human milk nutrient composition
description: Observational study to measure nutrients in human milk during lactation and their relationship to maternal and infant nutritional status.
arm group label: Bangladesh
arm group label: Brazil
arm group label: Denmark
arm group label: The Gambia
Breast milk, blood, saliva, urine and feces
study pop: 
sampling method: Non-Probability Sample
criteria: 
gender: Female
gender based: Yes
gender description: Pregnant and lactating women
minimum age: 18 Years
maximum age: 40 Years
healthy volunteers: Accepts Healthy Volunteers
last name: Lindsay H Allen, PhD
role: Principal Investigator
affiliation: USDA/WHNRC
last name: Lindsay H Allen, PhD
phone: 530 752 5268
email: lindsay.allen@ars.usda.gov
last name: Setareh Shahab-Ferdows, PhD
phone: 530 752 9540
email: setti.shahab-ferdows@ARS.USDA.GOV
facility: 
status: Recruiting
contact: 
investigator: 
facility: 
status: Recruiting
contact: 
contact backup: 
facility: 
status: Recruiting
contact: 
contact backup: 
facility: 
status: Recruiting
contact: 
contact backup: 
country: Bangladesh
country: Brazil
country: Denmark
country: Gambia
responsible party type: Sponsor
sharing ipd: No
ipd description: Individual participants data will only be available as de-identified data.