“Mothers and infants form a biological and social unit; they also share problems of malnutrition and ill-health” [WHO, Infant and Young Child Nutrition: Global Strategy on infant and young child feeding. 2012]
From an evolutionary, nutritional and economic standpoint, human milk is the ideal food for the human infant for the first months of life. Exclusive breastfeeding for the first 6 months followed by breastfeeding supplemented with appropriate complementary foods for 1 year or longer continues to be the recommendation of the American Academy of Pediatrics (AAP) [1], Centers for Disease Control and Prevention (CDC) [2] and the World Health Organization [3]. In the US these recommendations are currently met by only 13 % of mothers leading to multiple initiatives by these agencies to improve the rates of breastfeeding initiation, duration and exclusivity. An important strategy is advocacy for “baby friendly hospitals” [3] to improve breastfeeding practices in US hospitals and communities. However, it is possible that a focus on specific populations for which feeding human milk makes a critical difference would have the most impact.
Milk is a complex fluid that exerts effects far beyond its nutritional value. Yet even its composition is not well-defined. A full appreciation of the range of nutritive and non-nutritive components of milk and their secretion could be translated into actionable policies that could impact the initiation, duration and exclusivity of breastfeeding as well as contribute to the intelligent design of human milk substitutes.
Topic I |
Human Milk Components and their Function
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Topic II |
Effects of milk on behavioral and cognitive development
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Topic III |
Maternal factors affecting milk volume and composition.
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Topic IV |
Breastfeeding and the at-risk neonate
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Topic V |
Training the future lactation biologist
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Topic VI |
Imperatives for advancing the field
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a. |
What is the composition of human milk?
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Research Target: A complete analysis of the structure and concentration of human milk components as well as factors influencing their variability between women and throughout lactation.
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New analytical tools that provide more quantitative and sensitive methods have become available over the last decade [15–17] and are revolutionizing our understanding of the diversity of molecules in milk. These tools can now be used to provide a catalogue of the structure of all proteins, oligosaccharides, glycoconjugates, metabolites, lipids and polynucleotides (RNA, DNA) in the various fractions of milk.
b. |
What are the detailed mechanisms by which milk components promote neonatal development? (Contributors: Donovan, Contractor, Goldman, Meier, Forman)
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Research Target: A detailed knowledge of the functional mechanisms by which milk components acting both individually and together, promote intestinal maturation, protect against infection and inflammation, and stimulate immune development in the infant.
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1) |
Regulation of the development of the infant’s immune system and inflammatory responses,
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2) |
The optimal duration of breastfeeding
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3) |
The role of milk in the future programming of diseases mediated by infections, immunologic events or inflammation.
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c. |
What is the role of human milk in establishing the infant microbiome? (Contributors: Frank, Janoff)
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1) |
How do the microbes that colonize the developing gut program immune development?
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2) |
Do perturbations of the GI microbiome resulting from mode of feeding, delivery, or antibiotic exposure have long term health consequences?
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3) |
Can a dysfunctional neonatal microbiome be bioremediated by dietary interventions?
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d. |
How do environmental agents and pharmaceuticals in milk affect infant development? (Contributors: Badger, Meier)
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Research Target: Compile a complete database of commonly used therapeutic drugs that includes their rate of secretion into milk as well as effects on infant health and development.
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e. |
What is the role of dairy products in infant nutrition? (Contributors: Williamson, German, Hovey)
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1) |
To what extent can the functions of human milk components be mimicked by the corresponding molecules in milk from other species?
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2) |
Can specific components of human milk be replaced by non-homologous components?
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3) |
Can molecules synthesized in yeast, fungi or plants, or recombinant molecules, be used to supplement formula with positive outcomes?
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Research Target: Determine the effect of specific and interacting components of milk on brain development and the behavioral phenotype.
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a. |
What are the components of milk that affect cognitive development and how do they work? (Contributors: Hinde, Donovan)
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Human milk has relatively high concentrations of molecules that foster brain development including choline, sialic acid and long-chain polyunsaturated fatty acids (LC-PUFA) [59]. Prenatal exposure to choline and its long-term effects on hippocampal development, learning, memory and emotional behavior have been studied extensively in animal models [60], although relevant data for humans are lacking. More recently, attention has been focused on sialic acid (SA) given that accretion of SA-containing gangliosides in brain increases nearly 3-fold from week 10 of gestation through 5 years of age [61]. Likewise, an important role for LC-PUFA in brain maturation has long been suspected; these lipids, particularly docosahexaenoic acid (DHA) and arachidonic acid (AA), are present in human milk at much higher concentrations than in bovine milk and can be altered by diets containing large amounts of fish oil [59]. Although infant formula is often supplemented with LC-PUFA [62], any long term effects of these components on cognitive development have been difficult to document in term infants [63].
1) |
Gene-diet interactions exist that may affect both milk composition and infant development.
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2) |
Any effects of genetic polymorphisms on infant outcomes may be masked when only mean values are compared across populations. The ends of the bell-shaped curve may give important information about the contribution of specific gene-diet combinations.
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b. |
What elements of breastfeeding affect behavioral phenotype? (Contributors: Hinde, Friedman)
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Behavioral phenotype is defined as the observable “behavioral characteristics of an individual resulting from the interaction of its genotype with the environment, often manifested in a suite of co-varying behaviors” [67]. Feeding mother’s-own milk reflects a complex physiological and behavioral negotiation between the mother and the infant that begins during pregnancy [68] when the mammary gland develops functionally and is potentially sensitive to fetal signals [69]. A number of components in milk subsequently impart specific effects on development. For example, relaxin in sow’s milk in the early post-partum period programs uterine development [70] giving rise to what Bagnell termed the “lactocrine hypothesis”. Behavioral interactions between mothers and their infants during lactation can influence milk removal and thereby alter milk synthesis [69]. But are there lactocrine influences on the infant’s behavioral trajectory?
Studies in the rhesus macaque strongly suggest that that the answer to this question is “Yes”. Specifically, the cortisol content of the mother’s milk was significantly related to infant’s behavioral phenotype [71]. Further, Hinde and Capitanio [71] demonstrated that milk energy density and yield predict behavioral outcomes for both male and female infants. Importantly, the observed temperament and behavioral outcomes reflected available milk energy from months earlier, not at the time of assessment, suggesting that early nutrition organizes, or programs, infant behavior during critical windows of development. In another setting a maternal diet high in fat (HFD) perturbed the central serotonergic system of offspring in monkeys leading female offspring from HFD-fed mothers to exhibit increased anxiety in response to threatening novel objects. These findings have important clinical implications as they demonstrate that a maternal HFD during gestation and lactation, independent of obesity, may increase the risk of developing behavioral disorders, such as anxiety, in the offspring [72].
c. |
Methods for studying the effects of milk on cognitive and behavioral development (Contributors: Badger, Donovan, Hinde, Friedman,)
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Research Target: Understand the effects of mother’s own milk and its components on the trajectory of infant cognitive and behavioral development.
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a. |
How do hormones and metabolism coordinately program the mammary gland for lactation? (Nommsen-Rivers, Neville, Hinde)
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A number of irreversible switches govern mammary gland development: The first is the increase in circulating estrogen at puberty that switches on ductal growth. The hormones of pregnancy, progesterone and prolactin, switch on alveolar development. At mid-pregnancy another switch (secretory differentiation, previously called lactogenesis I) leads to a decrease in proliferation and brings about differentiation of mammary epithelial cells such that they can produce milk during the subsequent lactation. At parturition a fall in progesterone switches on milk secretion (secretory activation, previously called lactogenesis II). Cessation of milk removal at weaning brings about the last switch that induces glandular involution. We have little understanding of the mechanisms by which epigenetic modifications in signaling pathways and gene expression might activate and regulate these switches [87].
The roles of estrogen, progesterone, EGF and related ligands, and prolactin, the receptors for these ligands, and their downstream signaling molecules appear to be well understood [80]. However, modern investigations of regulatory mechanisms in vivo during late pregnancy, at parturition and during lactation, mostly in mice, have been hampered by the problem that the loss of specific growth factors or signaling systems results in an early block of mammary gland development with a total loss of secretory activation and lactation. Further, we do not understand the relevance and application of these mechanistic data derived largely from studies in mice.
While we know how prolactin affects the synthesis of many milk components [88], the signaling pathways and downstream targets for insulin, glucocorticoids and progesterone are less well understood. These hormones are active either in late pregnancy or in lactation, when systemic metabolic factors may also influence their activity. Similarly while the effects of estrogen on ductal development are reasonably well understood, many environmental agents have estrogenic activity, meaning it is important to understand precisely how estrogens modify mammary gland development and lactational competency. We summarize the roles of insulin, glucocorticoids and progesterone here and discuss estrogens in the context of their environmental presence.
b. |
What are the genetic and epigenetic elements that affect heritability of mammary gland development and lactation-related traits? (Contributors: Hadsell, Rijnkels)
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Research Target: Identify the genetic and epigenetic basis for heritable maternal traits related to lactation success.
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c. |
What are the mechanisms by which maternal nutrition, disease, and metabolic status affect milk composition and volume? (Contributors: Anderson, Friedman, MacLean, McManaman, Van Houten)
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Research Target: Carefully controlled studies in humans and relevant animal models to dissect the effects of nutrition, maternal adiposity, and metabolic disease on lactation performance.
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d. |
What breastfeeding practices prevent inadequate lactation performance? (Contributors: Morrow, Nommsen-Rivers, Meier, Bunik)
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Research Target: A fundamental understanding of the biological and psychosocial causes of inadequate lactation performance including delayed onset of lactation and consistent low milk production. Also the effect of low milk production during weaning on the composition of milk.
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e. |
How do environmental agents and pharmaceuticals affect milk volume and composition? (Contributors: Badger, Hovey, Horseman)
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Research Target: Determine the effects and long-term implications of drugs, hormones or phytochemicals (especially dietary factors) on lactation.
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a. |
What is the role of human milk in the nutrition of the preterm infant? (Contributors: Meier, Neu).
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Many organ systems are immature in preterm infants, particularly those who are born very low birth weight (VLBW; <1,500 g birth weight) and extremely low birth weight (ELBW; <1,000 g birth weight). These infants have substantially diminished stores of micro- and macronutrients that are ordinarily deposited during the last trimester in utero. These stores are rapidly depleted after birth due to the co-existence of morbidities that compound the difficult problems already associated with the nutrition of these very small infants. Immediately after birth, ELBW and VLBW infants receive parenteral nutrition with small volumes of enteral nutrition that are introduced and advanced as tolerated by the infant. However, even if full enteral nutrition is achieved, human milk does not meet the micro- and macronutrient requirements of these infants because of their high nutrient demands and the limited milk volumes they can safely ingest. Thus, commercial fortifiers and other exogenous supplements must be added to human milk to provide additional nutrients for ELBW and VLBW infants.
The fact that adequate early nutrition in the smallest preterm infants is subsequently linked to better neurodevelopmental outcomes, highlights the importance of preventing, recognizing and correcting nutrient deficits soon after birth. However, evidence-based strategies for doing so are limited. Feeding human milk to these infants does reduce the risk of serious and costly neonatal intensive care unit (NICU)-acquired morbidities such as NEC and late onset sepsis. Human milk also promotes intestinal [12], cognitive [141] and immune [142] development. An important mechanistic element may be the development of an appropriate intestinal microbiome [143]. There may also be critical periods during the NICU hospitalization when human milk is most important--delineating these periods remains a priority for research [144] as does the practical matter of collecting, storing, handling and feeding human milk.
As emphasized in section I, while a clear understanding of how milk components exert their effects is crucial, it is also imperative to understand the within- and between- mother variation in these components, and to determine the mechanisms underlying this variation. Potential influences include duration of gestation as well as genetic and dietary factors. Defining the temporal changes in human milk composition is critical for the design of regimens for feeding human milk to the premature infant in the NICU where expressed milk is seldom fed in any particular order [145]. While certain types of studies (for example, defining the microbiota) can be done using preterm infants as an experimental model, for many studies an animal model is required. Here a role for the neonatal pig is assuming greater importance [31, 146].
Because it is often difficult to obtain sufficient quantities of human milk from mothers of preterm infants, we also need to understand how to optimize milk synthesis and removal in these mothers, most of whom are breast pump-dependent for weeks or months. Mothers of preterm infants have documented risk factors for delayed onset of lactation and low milk volume, but the mechanisms underlying these problems as well as their diagnosis and management are poorly understood. Because preterm infants benefit from even small enteral feedings as soon as they are able to tolerate them, donor human milk is frequently recommended. However, many questions remain about the use of donor human milk including which infants should receive it, for how long, and where a source of suitable donors can be created [147].
b. |
What is the role of breastfeeding in preventing obesity in susceptible populations? (Contributors: Dabelea, Crume, MacLean, Friedman)
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Infants with intrauterine growth retardation as well as those born to obese mothers, to mothers with gestational diabetes, and to those who are malnourished are more susceptible to developing the metabolic syndrome later in life, including type II diabetes and heart disease [148, 149]. The extensive literature on fetal programming for metabolic disease will not be reviewed here. The important consideration is the role of breastfeeding in abrogating undesirable fetal programming.
c. |
What is the role of human milk in preventing growth stunting? (Contributors: Hambidge, Krebs)
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d. |
A community approach to lactation studies in at-risk human populations. (Contributor: Seewaldt)
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1) |
Support for high-quality free breast cancer screening at community clinics
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2) |
Partnership with breast and cervical cancer control programs
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3) |
Free or low cost follow-up and treatment services
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4) |
Community navigators
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5) |
Mentorship of minority scholars.
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Educational Target: New programs and resources to repopulate the diminishing pool of lactation biologists and promote communication between the diverse disciplines required to understand milk, its secretion and its effects on the neonate.
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a. |
Compelling reasons to pursue training in lactation biology.
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b. |
Skills required of the next generation of investigators.
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c. |
Training the next generation of investigators.
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Principle 1: |
There is an urgent need to define the precise function of the various components of human and other milks as well as their interactions.
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Principle 2: |
The role of breastfeeding in infant nutritional status must be studied in light of the changing dynamic between mother and child from preconception through pregnancy and into postnatal life.
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Principle 3: |
Priority should be given to studying the impact of breastfeeding in high-risk populations.
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Topic |
Models/Priority Targets |
Goals |
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1 |
Milk Biochemistry |
Humans, dairy species |
Describe the structure of all human milk components as well as their variability within- and among women; determine composition of bovine milk as basis for substitutes. |
2 |
Functional Properties of Milk Bioactives |
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Intestinal Development |
Humans, pig, tissue culture |
Determine the bioactive components of milk and the mechanisms of their effects on GI development, microbiome and GALT as well as their anti-infectious activities |
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Immune Tolerance |
Human |
Identify critical windows for development of immune tolerance or inflammatory reactivity to allergens as mediated by early life nutrition |
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Cognitive Development |
Human, monkey, rodent, pig |
Investigate cognitive and behavioral development as a function of milk constituents. |
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Stunting/Impaired Growth |
Undernourished infants |
Examine role of human milk, combined with maternal and infant interventions, for counteracting growth stunting in developing countries and elsewhere |
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3 |
Lactation |
Human, rodent, monkey, livestock, tissue culture models |
Determine molecular and cellular mechanisms by which genetic, physiologic, environmental, behavioral, and societal factors affect mammary development, milk production and composition with emphasis on endocrine agents and metabolic factors. |
4 |
Very low birth weight infants (VLBW) |
Pre-term, neonatal infants, pig |
Identify the components of human milk responsible for reducing the risk of morbidities in preterm infants, the mechanisms by which they act, and the efficacy of common practices for collecting, storing, handling and feeding human milk for this population |
5 |
Maternal Obesity |
Human, pig, rodent |
Understand the mechanism by which obesity affects mammary gland development, milk secretion and milk composition; determine how breastfeeding affects obesity programming in offspring. |
6 |
Breastfeeding Practices |
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Initiation |
Humans, particularly at-risk populations |
Utilize quantitative methods to assess effects of obstacles to breastfeeding on initiation of lactation and duration of breastfeeding in low income women and women with co-existing health problems. Determine the impact of exclusive breastfeeding beyond 12 weeks on mother and infant |
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Duration |
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Exclusivity |
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7 |
Valuation |
Humans |
Assess economic impacts via direct and indirect costs |
8 |
Scientific Interactions/Training |
Courses, meetings |
Support ongoing forums for discussion among students, researchers, and faculty; NIH training and conference grants; increase interactions between researchers in the human lactation and dairy fields. |