The Value of an Ecological Approach to Improve the Precision of Nutritional Assessment: Addressing Contributors and Implications of the "Multiple Burdens of Malnutrition".

Globally, children are exposed to multiple health risks associated with diet and nutrition. Rather than simply being a condition of having too much or too little food, malnutrition is more a syndrome comprising multiple burdens of coexisting and reciprocal malnutrition, infection, or other conditions. Importantly, children with such syndromes (e.g., stunting and anemia, which are neither specific nor necessarily sensitive to nutritional status) are more likely to also have irreversible functional outcomes such as poor growth, impaired immune function, or cognitive delays. The global health community has identified nutrition-related targets (e.g., Sustainable Development Goals (SDGs) and World Health Organization (WHO) Global Nutrition Targets) that, for multiple reasons, are difficult to address. Moreover, as the complexity of the global health context increases with persistent pandemics of infectious diseases and the rising prevalence of noncommunicable diseases, there is a growing appreciation that conditions selected as nutrition/health targets indeed represent syndromes for which nutritional status serves as both an input and outcome. In recognition of the impact of these combined challenges and the role of the multiple manifestations of malnutrition, we suggest an approach to nutritional assessment that is intended to improve the precision of context-specific, equitable approaches to health promotion, disease prevention, and treatment.

Exploring the Anemia Ecology: A New Approach to an Old Problem.

Our ability to identify anemia and all its permutations demands an approach that integrates the key elements of a complex "ecology," which intertwines biology and mechanistic aspects of nutrients with both the health status and underlying factors-physical, economic, social, behavioral, demographic, and environmental. The complexity of anemia demands an ecologic approach that appreciates systems biology, translates sensitive and specific assessment methodologies and interventions, and ultimately improves clinical and public health outcomes. This series of technical papers on anemia by the U.S. Agency for International Development (USAID) Advancing Nutrition Anemia Task Force (ATF) is a first step in translating our ecologic approach to anemia with a view toward balancing research with its translation to effective programs, interventions, and policy. This introductory overview describes the components of our ecologic approach-linking the biology of anemia with its assessment and using the learning from that confluence to devise context-specific interventions. This introductory review briefly discusses the topics that underlie the biology and primary etiologies of anemia and presents a framework for public health assessment of anemia, leading to appropriate public health interventions. The other 3 manuscripts in the supplement provide the details of the arguments laid out in the introduction.

Approaches to Address the Anemia Challenge.

Anemia is a multifactorial condition; approaches to address it must recognize that the causal factors represent an ecology consisting of internal (biology, genetics, and health) and external (social/behavioral/demographic and physical) environments. In this paper, we present an approach for selecting interventions, followed by a description of key issues related to the multiple available interventions for prevention and reduction of anemia. We address interventions for anemia using the following 2 main categories: 1) those that address nutrients alone, and, 2) those that address nonnutritional causes of anemia. The emphasis will be on interventions of public health relevance, but we also consider the clinical context. We also focus on interventions at different stages of the life course, with a particular focus on women of reproductive age and preschool-age children, and present evidence on various factors to consider when selecting an intervention-inflammation, genetic mutations, nutrient delivery, bioavailability, and safety. Each section on an intervention domain concludes with a brief discussion of key research areas.

The Reciprocal Relationship between Climate and Environmental Changes and Food Systems and Its Impact on Food/Nutrition Security and Health.

Changes in our climate and physical environments are having profound effects on all aspects of human existence, and the ability to develop sustainable and resilient food systems is critical not just to the environment but to all aspects of human health. The Pediatric Growth and Nutrition Branch (PGNB) of the Eunice Kennedy Shriver National Institute of Child Health and Human Development of the US National Institutes of Health has adopted a new paradigm to undergird the study of nutrition that recognizes the complex and reciprocal nature of the relationships between nutrition and health outcomes. This conceptual framework, termed the "nutritional ecology," views humans as complex biological systems interacting with both their internal and external environments. Herein, we focus on: (i) the reciprocal relationship between climate and environmental changes and food systems and their impact on food/nutrition security and health; and (ii) how PGNB is utilizing the "nutritional ecology" framework to support science addressing the interactions among health, nutrition, food systems, climate, and the environment.

An Ecological Approach for Advancing the Understanding of Nutrition and Health.

This Viewpoint discusses 2 new programs of the Eunice Kennedy Shriver National Institute of Child Health and Human Development's Pediatric Growth and Nutrition Branch that apply an ecological approach to understanding nutrition and public health.

The "Breastmilk Ecology: Genesis of Infant Nutrition (BEGIN)" Project - executive summary.

The public health community has come to appreciate that a deeper understanding of the biology of human milk is essential to address ongoing and emerging questions about infant feeding practices. The critical pieces of that understanding are that 1) human milk is a complex biological system, a matrix of many interacting parts that is more than the sum of those parts, and 2) human milk production needs to be studied as an ecology that consists of inputs from the lactating parent, their breastfed baby, and their respective environments. The "Breastmilk Ecology: Genesis of Infant Nutrition (BEGIN)" Project was designed to examine this ecology as well as its functional implications for both the parent and infant and to explore ways in which this emerging knowledge can be expanded via a targeted research agenda and translated to support the community's efforts to ensure safe, efficacious, and context-specific infant feeding practices in the United States and globally. The five working groups of the BEGIN Project addressed the following themes: 1) parental inputs to human milk production and composition; 2) the components of human milk and the interactions of those components within this complex biological system; 3) infant inputs to the matrix, emphasizing the bidirectional relationships associated with the breastfeeding dyad; 4) the application of existing and new technologies and methodologies to study human milk as a complex biological system; and 5) approaches to translation and implementation of new knowledge to support safe and efficacious infant feeding practices.

Parental factors that impact the ecology of human mammary development, milk secretion, and milk composition-a report from "Breastmilk Ecology: Genesis of Infant Nutrition (BEGIN)" Working Group 1.

The goal of Working Group 1 in the Breastmilk Ecology: Genesis of Infant Nutrition (BEGIN) Project was to outline factors influencing biological processes governing human milk secretion and to evaluate our current knowledge of these processes. Many factors regulate mammary gland development in utero, during puberty, in pregnancy, through secretory activation, and at weaning. These factors include breast anatomy, breast vasculature, diet, and the lactating parent's hormonal milieu including estrogen, progesterone, placental lactogen, cortisol, prolactin, and growth hormone. We examine the effects of time of day and postpartum interval on milk secretion, along with the role and mechanisms of lactating parent-infant interactions on milk secretion and bonding, with particular attention to the actions of oxytocin on the mammary gland and the pleasure systems in the brain. We then consider the potential effects of clinical conditions including infection, pre-eclampsia, preterm birth, cardiovascular health, inflammatory states, mastitis, and particularly, gestational diabetes and obesity. Although we know a great deal about the transporter systems by which zinc and calcium pass from the blood stream into milk, the interactions and cellular localization of transporters that carry substrates such as glucose, amino acids, copper, and the many other trace metals present in human milk across plasma and intracellular membranes require more research. We pose the question of how cultured mammary alveolar cells and animal models can help answer lingering questions about the mechanisms and regulation of human milk secretion. We raise questions about the role of the lactating parent and the infant microbiome and the immune system during breast development, secretion of immune molecules into milk, and protection of the breast from pathogens. Finally, we consider the effect of medications, recreational and illicit drugs, pesticides, and endocrine-disrupting chemicals on milk secretion and composition, emphasizing that this area needs much more research attention.

Ecologies, synergies, and biological systems shaping human milk composition-a report from "Breastmilk Ecology: Genesis of Infant Nutrition (BEGIN)" Working Group 2.

Human milk is universally recognized as the preferred food for infants during the first 6 mo of life because it provides not only essential and conditionally essential nutrients in necessary amounts but also other biologically active components that are instrumental in protecting, communicating important information to support, and promoting optimal development and growth in infants. Despite decades of research, however, the multifaceted impacts of human milk consumption on infant health are far from understood on a biological or physiological basis. Reasons for this lack of comprehensive knowledge of human milk functions are numerous, including the fact that milk components tend to be studied in isolation, although there is reason to believe that they interact. In addition, milk composition can vary greatly within an individual as well as within and among populations. The objective of this working group within the Breastmilk Ecology: Genesis of Infant Nutrition (BEGIN) Project was to provide an overview of human milk composition, factors impacting its variation, and how its components may function to coordinately nourish, protect, and communicate complex information to the recipient infant. Moreover, we discuss the ways whereby milk components might interact such that the benefits of an intact milk matrix are greater than the sum of its parts. We then apply several examples to illustrate how milk is better thought of as a biological system rather than a more simplistic "mixture" of independent components to synergistically support optimal infant health.

Infant factors that impact the ecology of human milk secretion and composition-a report from "Breastmilk Ecology: Genesis of Infant Nutrition (BEGIN)" Working Group 3.

Infants drive many lactation processes and contribute to the changing composition of human milk through multiple mechanisms. This review addresses the major topics of milk removal; chemosensory ecology for the parent-infant dyad; the infant's inputs into the composition of the human milk microbiome; and the impact of disruptions in gestation on the ecology of fetal and infant phenotypes, milk composition, and lactation. Milk removal, which is essential for adequate infant intake and continued milk synthesis through multiple hormonal and autocrine/paracrine mechanisms, should be effective, efficient, and comfortable for both the lactating parent and the infant. All 3 components should be included in the evaluation of milk removal. Breastmilk "bridges" flavor experiences in utero with postweaning foods, and the flavors become familiar and preferred. Infants can detect flavor changes in human milk resulting from parental lifestyle choices, including recreational drug use, and early experiences with the sensory properties of these recreational drugs impact subsequent behavioral responses. Interactions between the infant's own developing microbiome, that of the milk, and the multiple environmental factors that are drivers-both modifiable and nonmodifiable-in the microbial ecology of human milk are explored. Disruptions in gestation, especially preterm birth and fetal growth restriction or excess, impact the milk composition and lactation processes such as the timing of secretory activation, adequacy of milk volume and milk removal, and duration of lactation. Research gaps are identified in each of these areas. To assure a sustained and robust breastfeeding ecology, these myriad infant inputs must be systematically considered.

An equitable, community-engaged translational framework for science in human lactation and infant feeding-a report from "Breastmilk Ecology: Genesis of Infant Nutrition (BEGIN)" Working Group 5.

Human milk is the ideal source of nutrition for most infants, but significant gaps remain in our understanding of human milk biology. As part of addressing these gaps, the Breastmilk Ecology: Genesis of Infant Nutrition (BEGIN) Project Working Groups 1-4 interrogated the state of knowledge regarding the infant-human milk-lactating parent triad. However, to optimize the impact of newly generated knowledge across all stages of human milk research, the need remained for a translational research framework specific to the field. Thus, with inspiration from the simplified environmental sciences framework of Kaufman and Curl, Working Group 5 of the BEGIN Project developed a translational framework for science in human lactation and infant feeding, which includes 5 nonlinear, interconnected translational stages, T1: Discovery; T2: Human health implications; T3: Clinical and public health implications; T4: Implementation; and T5: Impact. The framework is accompanied by 6 overarching principles: 1) Research spans the translational continuum in a nonlinear, nonhierarchical manner; 2) Projects engage interdisciplinary teams in continuous collaboration and cross talk; 3) Priorities and study designs incorporate a diverse range of contextual factors; 4) Research teams include community stakeholders from the outset through purposeful, ethical, and equitable engagement; 5) Research designs and conceptual models incorporate respectful care for the birthing parent and address implications for the lactating parent; 6) Research implications for real-world settings account for contextual factors surrounding the feeding of human milk, including exclusivity and mode of feeding. To demonstrate application of the presented translational research framework and its overarching principles, 6 case studies are included, each illustrating research gaps across all stages of the framework. Applying a translational framework approach to addressing gaps in the science of human milk feeding is an important step toward the aligned goals of optimizing infant feeding across diverse contexts as well as optimizing health for all.

Evidence for human milk as a biological system and recommendations for study design-a report from "Breastmilk Ecology: Genesis of Infant Nutrition (BEGIN)" Working Group 4.

Human milk contains all of the essential nutrients required by the infant within a complex matrix that enhances the bioavailability of many of those nutrients. In addition, human milk is a source of bioactive components, living cells and microbes that facilitate the transition to life outside the womb. Our ability to fully appreciate the importance of this matrix relies on the recognition of short- and long-term health benefits and, as highlighted in previous sections of this supplement, its ecology (i.e., interactions among the lactating parent and breastfed infant as well as within the context of the human milk matrix itself). Designing and interpreting studies to address this complexity depends on the availability of new tools and technologies that account for such complexity. Past efforts have often compared human milk to infant formula, which has provided some insight into the bioactivity of human milk, as a whole, or of individual milk components supplemented with formula. However, this experimental approach cannot capture the contributions of the individual components to the human milk ecology, the interaction between these components within the human milk matrix, or the significance of the matrix itself to enhance human milk bioactivity on outcomes of interest. This paper presents approaches to explore human milk as a biological system and the functional implications of that system and its components. Specifically, we discuss study design and data collection considerations and how emerging analytical technologies, bioinformatics, and systems biology approaches could be applied to advance our understanding of this critical aspect of human biology.

Perspective: Nutritional Status as a Biological Variable (NABV): Integrating Nutrition Science into Basic and Clinical Research and Care.

The field of nutrition has evolved from one focused primarily on discovery of the identities, metabolic functions, and requirements for essential nutrients to one focused on the application of that knowledge to the development and implementation of dietary recommendations to promote health and prevent disease. This evolution has produced a deeper appreciation of not only the roles of nutrients, but also factors affecting their functions in increasingly complex global health contexts. The intersection of nutrition with an increasingly more complex global health context necessitates a view of nutritional status as a biological variable (NABV), the study of which includes an appreciation that nutritional status is: 1) not limited to dietary exposure; 2) intimately and inextricably involved in all aspects of human health promotion, disease prevention, and treatment; and 3) both an input and an outcome of health and disease. This expanded view of nutrition will inform future research by facilitating considerations of the contexts and variability associated with the many interacting factors affecting and affected by nutritional status. It will also demand new tools to study multifactorial relations to the end of increasing precision and the development of evidence-based, safe, and effective standards of health care, dietary interventions, and public health programs.

The need to study human milk as a biological system.

Critical advancement is needed in the study of human milk as a biological system that intersects and interacts with myriad internal (maternal biology) and external (diet, environment, infections) factors and its plethora of influences on the developing infant. Human-milk composition and its resulting biological function is more than the sum of its parts. Our failure to fully understand this biology in a large part contributes to why the duration of exclusive breastfeeding remains an unsettled science (if not policy). Our current understanding of human-milk composition and its individual components and their functions fails to fully recognize the importance of the chronobiology and systems biology of human milk in the context of milk synthesis, optimal timing and duration of feeding, and period of lactation. The overly simplistic, but common, approach to analyzing single, mostly nutritive components of human milk is insufficient to understand the contribution of either individual components or the matrix within which they exist to both maternal and child health. There is a need for a shift in the conceptual approach to studying human milk to improve strategies and interventions to support better lactation, breastfeeding, and the full range of infant feeding practices, particularly for women and infants living in undernourished and infectious environments. Recent technological advances have led to a rising movement towards advancing the science of human-milk biology. Herein, we describe the rationale and critical need for unveiling the multifunctionality of the various nutritional, nonnutritional, immune, and biological signaling pathways of the components in human milk that drive system development and maturation, growth, and development in the very early postnatal period of life. We provide a vision and conceptual framework for a research strategy and agenda to change the field of human-milk biology with implications for global policy, innovation, and interventions.

Understanding the Intersection of Climate/Environmental Change, Health, Agriculture, and Improved Nutrition: A Case Study on Micronutrient Nutrition and Animal Source Foods.

With a growing global population, the demand for high-quality food to meet nutritional needs continues to increase. Our ability to meet those needs is challenged by a changing environment that includes constraints on land and water resources and growing concerns about the impact of human activity including agricultural practices on the changing climate. Adaptations that meet food/nutritional demands while avoiding unintended consequences including negatively affecting the environment are needed. This article covers a specific case study, the role of animal source foods (ASFs) in meeting micronutrient needs in a changing environment. The article covers our understanding of the role of ASFs in meeting micronutrient needs, evidence-based approaches to the development of nutrition guidance, the current issues associated with the relation between animal production practices and greenhouse gas emissions, and examples of how we might model the myriad sources of relevant data to better understand these complex interrelations.

SARS-CoV-2 and human milk: what is the evidence?

The novel coronavirus SARS-CoV-2 has emerged as one of the most compelling public health challenges of our time. To address the myriad issues generated by this pandemic, an interdisciplinary breadth of research, clinical, and public health communities have rapidly engaged to find answers and solutions. One area of active inquiry is understanding the mode(s) of SARS-CoV-2 transmission. While respiratory droplets are a known mechanism of transmission, other mechanisms are possible. Of particular importance to global health is the possibility of vertical transmission from infected mothers to infants through breastfeeding or consumption of human milk. However, there is limited published literature related to vertical transmission of any human coronavirus (including SARS-CoV-2) via human milk and/or breastfeeding. There is a single study providing some evidence of vertical transmission of human coronavirus 229E, a single study evaluating presence of SARS-CoV in human milk (it was negative), and no published data on MERS-CoV and human milk. There are 9 case studies of human milk tested for SARS-CoV-2; none detected the virus. Importantly, none of the published studies on coronaviruses and human milk report validation of their analytical methods for use in human milk. These reports are evaluated here, and their implications related to the possibility of vertical transmission of coronaviruses (in particular, SARS-CoV-2) during breastfeeding are discussed.

SARS-CoV-2 and human milk: What is the evidence?

The novel coronavirus SARS-CoV-2 has emerged as one of the most compelling and concerning public health challenges of our time. To address the myriad issues generated by this pandemic, an interdisciplinary breadth of research, clinical and public health communities has rapidly engaged to collectively find answers and solutions. One area of active inquiry is understanding the mode(s) of SARS-CoV-2 transmission. Although respiratory droplets are a known mechanism of transmission, other mechanisms are likely. Of particular importance to global health is the possibility of vertical transmission from infected mothers to infants through breastfeeding or consumption of human milk. However, there is limited published literature related to vertical transmission of any human coronaviruses (including SARS-CoV-2) via human milk and/or breastfeeding. Results of the literature search reported here (finalized on 17 April 2020) revealed a single study providing some evidence of vertical transmission of human coronavirus 229E; a single study evaluating presence of SARS-CoV in human milk (it was negative); and no published data on MERS-CoV and human milk. We identified 13 studies reporting human milk tested for SARS-CoV-2; one study (a non-peer-reviewed preprint) detected the virus in one milk sample, and another study detected SARS-CoV-2 specific IgG in milk. Importantly, none of the studies on coronaviruses and human milk report validation of their collection and analytical methods for use in human milk. These reports are evaluated here, and their implications related to the possibility of vertical transmission of coronaviruses (in particular, SARS-CoV-2) during breastfeeding are discussed.

Exploring the Nutritional Ecology of Stunting: New Approaches to an Old Problem.

Despite a declining prevalence, stunting remains an elusive target for the global health community. The perception is that stunting represents chronic undernutrition (i.e., due to inadequate nutrient intake associated with food insecurity, low-quality diet, and suboptimal infant feeding practices in the first two years of life). However, other causes include maternal-fetal interactions leading to intrauterine growth retardation, poor maternal nutrition during pregnancy and lactation, and maternal and pediatric infections. Moreover, physical, economic, demographic, and social environments are major contributors to both food insecurity and conditions that limit linear growth. Overall, factors representing both the internal and external "nutritional ecologies" need to be considered in efforts to reduce stunting rates. Nutritional assessment requires better understanding of the mechanism and role of nutrition in growth, clear expectations about the sensitivity and specificity of the tools used, and inclusion of bio-indicators reflecting the extent and nature of the functional effect of poor nutrition and environmental factors contributing to human physical growth. We provide a perspective on current knowledge about: (i) the biology and contribution of nutrition to stunting/poor growth; (ii) our current nutritional assessment toolkit; (iii) the implications of current assessment approaches for clinical care and public interventions; and (iv) future directions for addressing these challenges in a changing global health environment.

Perspective: Integration to Implementation (I-to-I) and the Micronutrient Forum-Addressing the Safety and Effectiveness of Vitamin A Supplementation.

An ongoing challenge to our ability to address the role of food and nutrition in health promotion and disease prevention is how to design and implement context-specific interventions and guidance that are safe, efficacious, and avoid unintended consequences. The integration to effective implementation (I-to-I) concept is intended to address the complexities of the global health context through engagement of the continuum of stakeholders involved in the generation, translation, and implementation of evidence to public health guidance/programs. The I-to-I approach was developed under the auspices of the Micronutrient Forum and has been previously applied to the question of safety and effectiveness of interventions to prevent and treat nutritional iron deficiency. The present article applies the I-to-I approach to questions regarding the safety and utility of large-dose vitamin A supplementation programs, and presents the authors' perspective on key aspects of the topic, including coverage of the basic and applied biology of vitamin A nutrition and assessment, clinical implications, and an overview of the extant data with regard to both the justification for and utility of available intervention strategies. The article includes some practical considerations based on specific country experiences regarding the challenges of implementing vitamin A-related programs. This is followed by an overview of some challenges associated with engagement of the enabling communities that play a critical role in the implementation of these types of public health interventions. The article concludes with suggestions for potential approaches to move this important agenda forward.