Nutrition Publication

NNIW66 - Drivers of Innovation in Pediatric Nutrition

Editor(s): B. Koletzko, S. Koletzko, F. Ruemmele. 66

This Workshop aimed to address and to identify forces that potentially drive innovation in pediatric nutrition, a vision which surpasses research, clinical and academic thinking.

Related Articles

Innovations in Infant Milk Feeding: From the Past to the Future

Author(s): B. Koletzko

Innovation is important for life science and economy, but the value of innovation for public health depends on its impact on promoting health. Breastfeeding is not innovative but evolved slowly over 250–300 million years, yet its total benefits are not surpassed by more innovative ways of infant feeding. Until the 19th century, infants fed inadequate breast milk substitutes suffered from high mortality. In 1865 a major improvement was von Liebig’s ‘soup for infants’, the first breast milk substitute based on chemical human milk analysis, soon followed by commercial applications.Other early innovations include whey protein-dominant formula, addition of specific carbohydrates to promote bifidobacteria (‘prebiotic’) and of live bacteria (‘probiotic’), predecessors of apparently recent innovations. Opportunities for innovations exist since many outcomes in formula-fed infants do not match those in breastfed populations.Of concern, expected economic benefits through innovations may override scientific arguments. Business and marketing desires must be counterbalanced by independent pediatric and scientific evaluation. Developing innovations with relevant outcome effects is complex, costly and cannot be expected to occur every few years.Cooperation between academic investigators, small and medium enterprises with high innovative potential, and large industries promotes progress and should be facilitated, e.g. by public research funding.

Novel Insights into Human Lactation as a Driver of Infant Formula Development

Author(s): B. Lönnerdal

Progress in research on human lactation and breast milk has advanced our knowledge about the significance of breast milk for the recipient infant and the effects of various components on long-term outcomes. Recent findings have expanded our knowledge in this area. Several growth factors and cytokines are present in breast milk and their capacity to persist in the infant gut and exert their activities is likely to affect maturation of immune function, possibly affecting the development of oral tolerance. A proper balance of polyunsaturated fatty acids (n-3/n-6 ratio) may also be of significance for allergy prevention in children, emphasizing the need for the mother to achieve a balance of these fatty acids in her diet. The recent findings that specific strains of bacteria are present in breast milk and act as probiotics in the early colonization of the infant gut and that human milk oligosaccharides are specific substrates for these probiotic strains may not only affect the defense against pathogens, but also affect energy utilization and development of obesity. Previously neglected milk fat globule membranes contain several components involved in protection against infection and may be an additional arm in the multifaceted shield that breastfed infants have developed against bacterial and viral antagonists. All these findings have implications for development of improved infant formulae.

The Clinical Challenge of Preventing and Treating Malnutrition

Author(s): P.A. Cooper

Malnutrition remains a major problem in children in large parts of the developing world. About 150 million young children in the developing world are either wasted or stunted, and it has been estimated that over half of childhood deaths are attributable to the potentiating effects of malnutrition. Thus, tackling both mild-moderate and severe malnutrition effectively is essential if the millennium development goals are to be achieved. Intervention strategies to promote exclusive breastfeeding for about 6 months in the absence of maternal HIV infection will result in significant improvements in nutrition, and are key to prevention strategies for malnutrition. Careful evaluation and effective counseling of HIV-positive mothers regarding feeding choices is essential. Evidence from a number of randomized controlled trials shows that ready to use foods have an important role to play in the prevention and treatment of both outpatient and inpatient malnutrition. Such foods were initially produced commercially, but it has been shown, particularly in Malawi, that such foods can be locally produced at low cost. In some parts of the world, HIV is a major underlying cause of malnutrition in children and is associated with high mortality rates in those with severe malnutrition. Strategies for the prevention and treatment of children with HIV need to be escalated.

Progress of Enteral Feeding Practice over Time: Moving from Energy Supply to Patient- and Disease-Adapted Formulations

Author(s): S. Koletzko

Enteral nutrition comprises the delivery of a liquid formula beyond the esophagus via a feeding tube in a patient with insufficient oral intake, as well as the provision of specialized nutritional formula irrespective of the route of delivery. Pediatric formulae have been designed for different age groups, and for children with certain diseases; examples are special formulations for regurgitating infants, metabolic diseases, cow’s milk or multiple food allergies, intestinal, pancreatic, renal, and hepatic insufficiency. Exclusive enteral nutrition is a therapeutic concept to induce remission in children and adolescents with active Crohn’s disease. A new area of nutritional research in pediatrics is potential immunonutrition in critically ill children. Formulae are enriched with single components or a combination of key substrates that might play a crucial role during intermediary metabolism in sepsis, inflammation, tissue healing, and growth. For pharmaconutrition, single components are investigated in a scientific stepwise procedure in order to identify effective disease-dedicated nutrition therapy. Any new formula needs to be evaluated, if possible in comparison to a normal diet or the reference formulation to demonstrate its safety and efficacy (equal or superior to standard formula).

Molecular Mechanisms of Pediatric Nutrition

Author(s): F. Rümmele

Over the last years, major scientific advances allowed to decrypt the human genome with over 22,000 protein-coding genes. We do know some of these genes, but yet only few of their functions and even less of their control and regulation as well as the complex interplay between different genes and their products. Genotyping allows to analyze particular genes, but it cannot predict phenotypes. What can we expect from the recent scientific advances with regard to the needs of the developing child or adult and the intention to prevent disease and/or to improve life quality? We address two particular points in this review: the (direct/indirect) interaction of nutrition with genes of the host and the impact of genetic variations (polymorphisms) on requirements, tolerance or metabolism of nutrition. Over the last 5 years, major research efforts were made to address the potential interaction of nutrition and genes, now named nutrigenomics (interaction of nutrition and genes) and nutrigenetics (impact of gene variants on nutrition and/or their metabolism). We give in this review examples of molecular approaches in the understanding of this bidirectional interaction between nutrition and genes, focusing also on epigenetic imprinting.

Epidemiological Research Drives a Paradigm Shift in Complementary Feeding - The Celiac Disease Story and Lessons Learnt

Author(s): K. Nordyke, C. Olsson, O. Hernell, A. Ivarsson

Breast milk is the initial natural food for infants, but already during the second half year complementary feeding is essential. Epidemiological research, first on celiac disease and later on atopic diseases, has driven a paradigm shift with respect to most favorable age to introduce complementary feeding. Simplified, this implies a shift from later to earlier introduction, which is now taken into account in recommendations on infant feeding. Complementary feeding, including all foods, should not be initiated for any infant before 4 months of age, and not later than around 6 months, including infants with elevated disease risk (e.g. for celiac disease or atopic diseases). Motivating reasons could be that ongoing breastfeeding provides an ‘immunological umbrella’ and/ or a different age interval gives a ‘window of opportunity’ for developing oral tolerance towards gluten and other food antigens. This will for some infants be in conflict with recent WHO recommendations on exclusive breastfeeding for 6 months. Epidemiology has evolved over time and could, if increasingly used, contribute even more to innovations in pediatric nutrition and other phenomena related to population health.

Technological Progress as a Driver of Innovation in Infant Foods

Author(s): M.G. Ferruzzi, A.P. Neilson

Advances in nutrition and food sciences are interrelated components of the innovative framework for infant formula and foods. While nutrition science continues to define the composition and functionality of human milk as a reference, food ingredient, formulation and processing technologies facilitate the design and delivery of nutritional and functional concepts to infant products. Expanding knowledge of both nutritive and non-nutritive components of human milk and their functionality guides selection and development of novel ingredient, formulation and processing methods to generate enhanced infant products targeting benefits including healthy growth, development as well as protection of health through the life cycle. In this chapter, identification and application of select novel ingredients/technologies will be discussed in the context of how these technological advancements have stimulated innovation in infant foods. Special focus will be given to advancements in protein technologies, as well as bioactive long-chain polyunsaturated fatty acids, prebiotics, probiotics that have allowed infant formula composition, and more critically functionality, to more closely align with that of human milk.

Health Economic Perspectives on Pediatric Malnutrition: Determinants of Innovative Progress

Author(s): J. Spieldenner

Despite some improvements in recent years, extreme poverty and malnutrition remain a critical concern for developing countries. Malnutrition, and more specifically pediatric malnutrition, is a reality affecting millions of children, particularly in South Asia and Africa. It causes increased mortality and morbidity, decreased physical and intellectual development, poor productivity and a number of negative economic outcomes. Health economics data clearly demonstrate that interventions are effective and efficient, but more data are needed to measure that efficiency. Initiatives to address microdeficiencies have focused on vitamin A, iodine, zinc, iron and folate. Iodine is often used as a best practice example. Two main institutions lead the efforts to address malnutrition throughout the world: the UN with its UN Millennium Development Goal project, and the Copenhagen Consensus. We consider micronutrient deficiencies, particularly in iodine, corresponding interventions, their effects and health economic data. We discuss how developing public/private partnership could boost the effectiveness of interventions by combining the competencies of both sides: credibility, national and international buy-in, experience of public institutions, commercial competencies, high penetration rate, and product knowledge of private industry.

Economic Perspectives on Pediatric Obesity: Impact on Health Care Expenditures and Cost-Effectiveness of Preventive Interventions

Author(s): J. John

This chapter surveys two segments of the economic literature on pediatric obesity: first, research regarding the impact of childhood obesity on health care expenditure, and second, research evaluating the cost-effectiveness of programs to prevent pediatric obesity. Evidence in support of the hypothesis that obese children and adolescents have higher health care costs than their otherwise similar healthy-weight peers has been found for female adolescents. Studies trying to calculate the complete lifetime health care costs attributable to childhood obesity are missing. Only a small number of studies assessing the cost-effectiveness of preventive obesity interventions among children have been published until now. The results call for the inclusion of nutrition behavior as an intervention target. There is some evidence that childhood obesity prevention might be successful in combining health gains with cost savings. However, it is not possible to rank the interventions according to their cost-effectiveness or to assess the generalizability of their results. Cost-effectiveness increasingly will be a major consideration in public reimbursement decisions. Therefore, evaluation research has to pay more attention to the economic aspects of new health technologies.Without providing good value for money, those technologies probably will not turn from inventions to innovations in health care. Moreover, future research should address various methodological and conceptual challenges and limitations which economic evaluations of preventive interventions into childhood obesity are faced with.

Sustainable Clinical Research, Health Economic Aspects and Marketing: Drivers of Product Innovation

Author(s): F. Haschke, P. Klassen-Wigger

Marketing-driven innovation in the field of pediatric nutrition, in particular in the infant formula segment is not sustainable. New benefits of products must be scientifically proven and safety and efficacy of new formulae established in clinical trials. The scientific innovation process of three infant formulae is described. Improvement in protein quality allowed to reduce the protein concentration in whey-based infant formula.Weight gain and BMI of infants fed those formulae corresponds to breastfed infants and is lower than in infants fed traditional formulae with higher protein concentration. A meta-analysis indicates associations between rapid weight gain in infancy and obesity later in life. If infants cannot be exclusively breastfed until 4–6 months of age, feeding low-protein formulae may contribute to positive long-term health outcome with potentially important health economic effects. A partially hydrolyzed whey based formula for prevention of allergic symptoms in children with hereditary risk for allergic diseases was developed more than 25 years ago. The most recent meta-analysis which included 15 randomized clinical trials indicates that the risk of all allergic diseases and atopic dermatitis/eczema is significantly reduced in infants at risk when the partially hydrolyzed formula is fed. The partially hydrolyzed formula had the same protective effect as casein-based high-degree extensively hydrolyzed formula. Because of substantial price differences between the two formulae, feeding the partially hydrolyzed whey formula is cost saving. Hypoallergenic claims can be made in many countries, and international nutrition committees have positively commented the preventive effect of those formulae.Acidified formulae have been widely used during the last decade in replacement feeding programs for infants whose mothers are HIV positive. The formula was innovated by improving whey protein quality and lowering protein concentration. The bacteriostatic properties of the new formula were proven in in vitro tests. Meta-analysis indicated that feeding the formula to immunocompromised infants resulted in growth similar to breastfeeding. The bacteriostatic effects of the acidified formula need to be communicated to health care professionals, but also the risks if replacement feeding is not acceptable, feasible, affordable, sustainable, and safe for mother and infant.

Evaluation of Dietetic Product Innovations: The Relative Role of Preclinical and Clinical Studies

Author(s): M. Makrides, R.A. Gibson

A variety of systems are used to establish efficacy of food ingredients. Immortal human cell lines have the advantage of rapid throughput and often have the ability to point to mechanisms of action. Transgenic and natural variants of animals (usually rats and mice) have proven to be extremely useful in elucidating effects in vivo, although extrapolation of results to humans has risks. Animal models are also useful in establishing safety and toxic levels of ingredients. Human trials have the most relevance to society. Types of evidence for efficacy rise from improved status level in subjects as a result of eating food (long-chain polyunsaturated fatty acid, levels in erythrocytes), change in surrogate markers as a result of eating food (plasma cholesterol or glutathione peroxidase activity), change in a physiological outcome (such as visual evoked potential acuity or heart rate variability) through to the highest level of evidence, a change in a clinical outcome (improved global development, reduction in infections) established in randomized controlled trials. Ultimately, there is a need for tests of pragmatic interventions that can easily be incorporated into usual dietary practices of the culture in which it is tested.

Regulatory Environment and Claims – Limits and Opportunities

Author(s): A. Martin

During the past decade, the use of claims became more and more important in many countries in relation to the increased awareness of consumer about the link between foods and health, offering to industry a valuable opportunity to differentiate and valorize their products and to promote innovation. However, more and more stringent regulations are developed, all based on the general principles adopted by the Codex Alimentarius Commission. In addition to the different regulatory processes and administrative requirements according to the country, the high level (and cost) of scientific substantiation of claims, the constraints introduced by nutrient profiles and the poor knowledge of the impact on consumer depending on the cultural contexts may limit these opportunities or, at least complicate their use. All these issues are briefly analyzed, highlighting some striking convergences and differences between countries.

The Role of Consumers

Author(s): M.M. Raats

It is particularly important that in areas of strategic public health significance, e.g. infant feeding, the processes used to extract robust scientific findings are timely, rigorous and transparent. Low rates of breastfeeding, poor weaning practices and variability within and between countries have been reported by many authors and resulted in a call for more consistency of recommendations across regions. The adoption of consumer behaviors in line with recommendations is of course not guaranteed. The consumers in this instance are both the infant and their mother or other carers. As infants completely depend on their carers to make food choices for them, it is important that they understand nutrition, and the importance of food choices for health of the baby and in future life. Parents obtain information from a variety of sources, the quality of which may vary, and is not necessarily evidence-based. Although carers decide what is offered or withheld, the infant may contribute to this decision by expressing dissatisfaction or refusing food. At the heart of all feeding choices lies this interplay between carer and child, influenced by the environment at household, community and societal level.

Bioethics and Innovation in Pediatric Nutrition Research

Author(s): N.W. Solomons

Advances in technology and understanding of fundamental human biology allow for an increasingly innovative research agenda in pediatric nutrition. All human research is governed by the norms of bioethics, which are in turn based on four primary principles: free will in participation, freedom from harm, opportunity to benefit, and non-discrimination in access. Legally, if not essentially, juveniles do not have free will to affirm their participation as research subjects. They have an absolute right, in nontherapeutic research, however, to decline. Pivotal in the discussion in nontherapeutic research in healthy children is the tolerance for risky procedures. Complicated situations include: multi-national protocols, choice of developing country sites, the inclusion of placebo treatment arms, analysis of genetic biomarkers, and research for commercial enterprises. The overly stringent interpretation of bioethical principles, as adapted to children, would stifle innovation in research. A relaxed bioethical attitude in pursuit of advancing science, by contrast, could violate essential human rights and expose a population worthy of special protection to undue risk and harm. By following the course of utility, seeking the steepest benefit-to-risk ratios, weighted toward safety and child welfare, the divergent nature of the considerations should be brought into convergence for the sake of continuing innovation.

The Role of Pediatricians as Innovators in Pediatric Nutrition

Author(s): F.R. Greer

Innovation is about making changes. When it comes to health care, innovations, though they may be something ‘new’, may not be beneficial if not demonstrated to be an improvement over what is current practice. Innovations in pediatric nutrition sometimes fall into this category. The establishment of safe water and milk supplies at the end of the 19th and beginning of the 20th centuries is viewed as one of the greatest advances in preventative medicine and truly was an ‘innovation’, with its dramatic impact on infant mortality. Other innovations in pediatric nutrition included the development of the caloric method of infant feeding which led to the large-scale adoption of a single infant formula. This required cooperation with industry and ultimately led to the development of life-saving specialty formulas for various disease states including inborn errors of metabolism. Over the last 50 years there have been further modifications of term infant formula that have included taurine, carnitine, nucleotides, whey proteins, PUFAs including decosahexenoic acid (DHA) and arachidonic acid, probiotics, and prebiotics. Many of these additions are of questionable benefit and are questioned as true innovations. Though the addition of novel nutrients to infant formula has been an area of great interest, more basic research (including randomized controlled trial) is needed to determine many pediatric nutrient requirements including the lower and upper limits of nutrients added to infant formula. Such research could be facilitated by institutions such as the US National Institute of Child Health whose establishment in 1962 was a significant ‘innovation’ as it led to advances in pediatric nutritional research. Much more research is needed to determine basic pediatric nutritional requirements and pediatricians should strive for such true innovations.

Promoting Innovation in Pediatric Nutrition

Author(s): D.M. Bier

Truly impactful innovation can only be recognized in retrospect. Moreover, almost by definition, developing algorithmic paths on roadmaps for innovation are likely to be unsuccessful because innovators do not generally follow established routes.Nonetheless, environments can be established within Departments of Pediatrics that promote innovating thinking. The environmental factors necessary to do so include: (1) demand that academic Pediatrics Departments function in an aggressively scholarly mode; (2) capture the most fundamental science in postnatal developmental biology; (3) focus education and training on the boundaries of our knowledge, rather than the almost exclusive attention to what we think we already know; (4) devote mentoring, time and resources to only the most compelling unanswered questions in the pediatric sciences, including nutrition; (5) accept only systematic, evidencebased answers to clinical questions; (6) if systematic, evidence-based data are not available, design the proper studies to get them; (7) prize questioning the answers to further move beyond the knowledge limit; (8) support the principle that experiments in children will be required to convincingly answer clinical questions important to children, and (9) establish the multicenter resources in pediatric scientist training, clinical study design and implementation, and laboratory and instrument technologies required to answer today’s questions with tomorrow’s methods.

Conclusions on Innovation in Pediatric Nutrition

Author(s): B. Koletzko