Clinical trial NCT05119166: International Milk Composition (IMiC) Consortium
Official title: International Milk Composition (IMiC) Consortium
Study type: OBSERVATIONAL
Overall status: ACTIVE_NOT_RECRUITING
Conditions: Infant Growth
Maternal Health
Infant Nutrition
Lead sponsor: University of Manitoba
Sponsor class: OTHER
Collaborators: name: Bill and Melinda Gates Foundation
name: Stanford University
name: The University of Western Australia
name: University of Idaho
name: Ludwig-Maximilians - University of Munich
name: Johns Hopkins University
name: Cedars-Sinai Medical Center
name: Sapient Bioanalytics
name: University of California, Davis
name: University of California, San Diego
name: University of Virginia
name: Aga Khan University
name: University Ghent
name: University of California, Berkeley
name: University Health Network, Toronto
name: USDA Beltsville Human Nutrition Research Center
name: Antigen Discovery Inc
name: USDA, Western Human Nutrition Research Center
First posted: 2021-11-15
Enrollment: 1000
Sex: ALL
Minimum age (years): 15
Standard ages: CHILD
ADULT
OLDER_ADULT
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: CHILD Study: observational study of healthy term infants from Canada, Multi-ethnic (\~70% Caucasian; 30% others: Asian, First Nations, Black, other) ELICIT Study: factorial RCT study design, cohorts from Haydom, Tanzania, predominantly of Black and East African descent VITAL Study: 3-arm RCT study design, cohorts from Karachi, Pakistan, predominantly of Asian descent MISAMEIII Study: 2x2 cross-over RCT study design, cohorts from Hounde District, Burkina Faso, predominantly of Black and West African descent

Brief summary: The IMiC Consortium will analyze milk from 1000 mother-infant dyads across 4 diverse settings (Tanzania, Pakistan, Burkina Faso and Canada). Samples will be stored centrally at the Manitoba Interdisciplinary Lactation Centre (MILC) biorepository and distributed to multiple laboratories for analysis of macronutrients, micronutrients, oligosaccharides, growth factors, immunoglobulins, cytokines, metabolites and microbes. Data will be harmonized and stored in a central database, and diverse statistical methods will be applied for data integration and analysis.

Detailed description: Human Milk Composition: Milk is a highly complex biofluid that has evolved over millions of years to nourish infants and protect them from infection while their immune system matures. In addition to delivering complete nutrition (i.e. macronutrients and micronutrients), milk provides bioactive components that further support infant growth, development and health. These include immunoglobulins, antibodies, hormones, growth factors, prebiotic oligosaccharides, and probiotic bacteria. Milk composition is specifically adapted to each mammalian species depending on the growth requirements of their young offspring. For example, the average energy content of human milk is around 70 kcal/100g, compared to 38 kcal/100g in donkey milk and 171 kcal/100g in mouse milk. Mice produce just 2 milk oligosaccharides, while humans produce over 150. Even among humans, milk composition is highly variable - for example, energy content can range from 57-83 kcal/100g and oligosaccharide concentrations range from 5-25 g/L.

Surprisingly little is known about the determinants and consequences of this variation. The investigators will study the following milk components in the IMiC Consortium to understand variability between individual women and across different geographic settings, and their associations with infant growth. In addition, to guide these analyses, a review of human milk components and infant growth will be undertaken by the IMiC members during Year 1 of the Project.

Priority Components (to be analyzed in all samples):

Macronutrients include carbohydrates (primarily lactose), proteins and lipids. Lipids provide about 50% of the energy content in human milk. The vast majority (98%) of milk lipids are triacylglycerides, with the remainder consisting of diacylglycerides, monoacylglycerides, free fatty acids, phospholipids and cholesterol. The fatty acid profile of human milk varies in relation to maternal diet and genetics, particularly in the long-chain polyunsaturated fatty acids (LCPUFAs), such as arachidonic and docosahexaenoic acids, which contribute to immune function and neurodevelopment.

Micronutrient quality and concentrations can be compromised by maternal malnutrition. Micronutrients in milk include minerals (e.g. Zinc, Calcium, Phosphorus, Magnesium, Iodine, Selenium) and vitamins (A, B1, B2, B6, B12, C, D, E; folate, choline).

Immunoglobulins (Ig) are transferred in human milk, including IgA, IgM and IgG. Infants are born with immature adaptive immunity, and rely on these maternal antibodies for defense against pathogens. Soluble IgA (sIgA) is the predominant antibody of human milk; sIgA-antigen complexes are taken up by intestinal dendritic cells, allowing for antigen recognition.

Cytokines are multifunctional peptides can cross the intestinal barrier, where they influence immune activity. Milk-borne cytokines include anti-inflammatory transforming growth factor (TGF)-b, interleukins (IL)-10 and IL-7, and proinflammatory tumor necrosis factor (TNF)-a, IL-6, IL-8, and interferon (IFN)-g.

Lactoferrin is an iron binding glycoprotein with antimicrobial activity against many bacteria, viruses, and fungi. Osteopontin is an extensively phosphorylated acidic glycoprotein that is present at high concentrations in human milk. It affects immune functions, intestinal development, and brain development.

Growth factors and hormones in human milk have wide-ranging effects on the infant intestinal tract, vasculature, nervous system, and endocrine system. Some act locally on the neonatal intestine and many are absorbed into systemic circulation through the 'leaky' infant gut. Epidermal growth factor (EGF) is critical to the maturation and healing of the intestinal mucosa. Insulin-like growth factor (IGF) promotes tissue growth. The metabolic hormones leptin, insulin, adiponectin and ghrelin regulate energy conservation, appetite and infant BMI.

Human milk oligosaccharides (HMOs) are the third most abundant component of human milk. Over 100 different HMOs have been identified. These structurally diverse carbohydrates are not digested by the infant, but are metabolized by the infant's gut bacteria, providing a selective substrate to help shape the developing microbiome. In addition, HMOs serve as soluble decoy receptors and prevent pathogen attachment to infant mucosal surfaces, lowering the risk for viral and bacterial infections. HMOs may also modulate epithelial and immune cell responses and provide the infant with sialic acid, an important nutrient for brain development. In the CHILD cohort the investigators have observed that, beyond genetic secretor status, HMO composition is associated with ethnicity, lactation stage, parity, geographic location, season of collection, and breastfeeding exclusivity.

Omics approaches will be applied to broadly assess the complete spectrum of peptides, proteins, lipids, and metabolites in human milk. Targeted metabolomics analyses to be conducted using the Biocrates platform (\~500 metabolites), untargeted metabolomic analyses to be conducted by Sapient Bioanalytics via mass spectrometry.

Microbes are present in human milk. Culture-dependent and independent (sequencing-based) studies have confirmed the presence of bacteria and fungi in milk from healthy mothers. In the CHILD cohort, the investigators have found that milk microbiota composition differs by infant sex, method of feeding, maternal BMI, and maternal atopy. It is estimated that breastfed infants receive 10\^4-10\^6 bacteria per day, providing a source of live microbes to seed the infant gut, oral cavity and airways. Studies demonstrating strain similarities between maternal gut, milk, and infant gut support this hypothesis, and find that Bifidobacterium spp. constitute the majority of shared taxa between maternal milk and infant stool. Given the central role of the gut microbiome in infant growth, metabolism and protection from infectious disease, including in low to middle income (LMIC) settings, it is critical to understand the origins of these fundamentally important gut microbes early in life.

A secondary objective of IMiC will be to support data integration across sites to answer important questions related to 1) the impact of maternal health and nutrition interventions on breast milk composition, and 2) its relation to infant health, growth and development. Each site will own its own data and will also be independently addressing these same questions by site, as originally intended in their own grants/studies.

Eligibility criteria: Inclusion Criteria:

* CHILD Study: Full term healthy infant; singleton pregnancy; English literary
* ELICIT Study: Adult mothers, child \<14 days, lives within 25km of Haydom
* VITAL Study: Lactating, biological mothers
* MISAMEIII Study: Confirmed (pregnancy test/ultrasound) pregnant women 15-40 years old, informed consent, self, parents or husband (for minors; assent).

Exclusion Criteria:

* CHILD Study: IVF; congenital abnormality; preterm delivery
* ELICIT Study: Multiple gestation, birth defects/neonatal illness, weight \<1.5g, no intention to breastfeed, will move from area within 18 months
* VITAL Study: Use of any ointments or topical solutions immediately prior to sampling, non-consent
* MISAMEIII Study: Peanut allergy, gestational age \<20weeks, women who will not deliver babies in or live in study area by delivery date.

Primary outcomes:
measure: Create an international consortium of 4 birth cohorts in Tanzania, Pakistan, Burkina Faso and Canada (Field Site Partners), human milk scientists (Laboratory Partners), and data scientists and biostatisticians (Data Science Partners).
timeFrame: This outcome is anticipated to reach completion in December 2021.
measure: Create a centralized biorepository of human milk samples from the Field Site Partners, housed at the Manitoba Interdisciplinary Lactation Centre (MILC) at the University of Manitoba in Winnipeg, Manitoba, Canada.
timeFrame: This outcome is anticipated to reach completion in April 2022.
measure: Create a standardized protocol for the comprehensive analysis of human milk composition using state-of-the-art methods in expert laboratories
timeFrame: This outcome is anticipated to reach completion in December 2021.
measure: Create a harmonized dataset of human milk composition and relevant maternal, infant and environmental data from 1000 dyads
timeFrame: This outcome is anticipated to reach completion in October 2023.
measure: Create an integrated analysis of this dataset
timeFrame: This outcome is anticipated to reach completion in October 2023.
Secondary outcomes:
measure: A secondary objective of IMiC will be to support data integration across sites to answer important questions.
timeFrame: This outcome is anticipated to reach completion in October 2023.
Other outcomes:
Locations:
city: Winnipeg
country: Canada
facility: Manitoba Interdisciplinary Lactation Centre (MILC)
state: Manitoba
Study officials:
affiliation: University of Manitoba, CHILD Cohort Study
name: Meghan B Azad
role: PRINCIPAL_INVESTIGATOR
affiliation: Haydom Lutheran Hospital, ELICIT Trial
name: Estomih Mduma
role: STUDY_DIRECTOR
affiliation: Aga Khan University Pakistan, VITAL Trial
name: Fyezah Jehan
role: PRINCIPAL_INVESTIGATOR
affiliation: Institut de Recherche en Science de la Santa, MISAMEIII Trial
name: Laeticia Celine Toe
role: STUDY_DIRECTOR
affiliation: SickKids, CHILD Study
name: PJ Subbarao
role: STUDY_DIRECTOR
affiliation: Aga Khan University Pakistan, VITAL Trial
name: Yasir Shafiq
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Virginia, VITAL Trial
name: Mark D DeBoer
role: PRINCIPAL_INVESTIGATOR
affiliation: Ghent University, MISAMEIII Trial
name: Patrick Kolsteren
role: PRINCIPAL_INVESTIGATOR
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