Speakers and Topics

Berthold V. Koletzko, MD, PhD, Dr. h.c

• Long Term Effects of Early Nutrition on Brain Development and Function.
• Formula for Young Children: What is the Role?

Virgilio P. Carnielli, MD, PhD

• Medical Advances in the NICU.
• Lipid Metabolism in Neonates and Infants.

   
Magnus Domellöf, MD, PhD

• Early Nutrition and the Impact on Long-term Outcomes.
• Iron Intake and Human Milk Fat Globule Membranes in Neuro Development Magnus Domellöf.

Glenn R. Gibson, PhD

• Maintaining a Healthy Microbiome - Keys to Having Gut Bacteria Play Well Together in the Sandbox.
• Prebiotics and Gut Health: Friends in Low Places.

Hania Szajewska, MD

• Management of Common GI Concerns in the First Year of Life.
• The Role of Oligosaccharides on the Immune System and Long-term Outcomes.

Presentation Abstracts

Formula for Young Children – Berthold V. Koletzko, MD, PhD, Dr. h.c  

In 1987 the Codex Alimentarius of the World Health Organisation (WHO) and the Food and Agriculture Organisation (FAO) of the United Nations adopted a standard for follow-up formula (FUF), defining FUF as a food intended as a liquid part of the diet for infants and young children up to the age of 3 years.¹ FUF for infants from the time of introducing complementary feeding onwards have been widely used as a substitute for breast milk in many populations, and in some countries the large majority of infants receive FUF during the second half of the first year of life.^2,3 In addition, FUF for children aged 1-3 years have been marketed in many countries for more than 2 decades and are presented as superior alternatives to cows’ milk. Such products have been marketed under the names “lait de croissance” and “growing-up milk” that suggest specific effects on growth, which, however, have not been demonstrated by adequate scientific evidence. Therefore the term “growing-up milk” is not supported from a paediatric perspective. Also, the terms “toddler milk” and “milk for young children” may be too restrictive because it appears possible to produce such products not only from the milk of cows and other animals but also based on other sources, for example, soy bean protein. Formulas for young children are widely used and are reported to have achieved global sales amounting to US$15 billion in 2013.

Formula for Young Children are not a necessity for feeding young children because it is possible to generally meet the nutrient needs of young children with an adequately composed, well-balanced diet.^4-6 However, much lower than desirable nutrient intakes are common in toddlers even in Europe and other affluent countries, in particular with respect to omega-3 fatty acids, vitamin D, folate, iron, and iodine, while far higher than desired intakes are found for protein and saturated fats.^5,7 Young children in developing countries and in disadvantaged groups around the world in all countries are at an even higher risk of developing nutrient deficiencies, resulting from inadequate amounts and poor quality of complementary feeding and family foods. WHO recommends that for children not achieving adequate nutrient intakes from eating normal foods, the use of fortified foods and nutrient supplements including formula products should be considered to satisfy nutritional requirements.⁸

Adequately composed Formula for Young Children may help to improve nutrient supply and status in young children. An observational study in French children aged 1-2 years found that compared to those consuming Formula for Young Children, children consuming at least 250 mL/d of cows’ milk had a significantly higher protein supply and often an insufficient supply, compared to reference intakes, of linoleic acid (51%), alpha-linolenic acid (84%), iron (59%), vitamin C (49%), and vitamin D (100%).⁹ In a randomized, double-blind controlled trial in 92 German preschool children, Formula for Young Children with 2.85 µg vitamin D/100 mL significantly improved serum 25-hydroxyvitamin D concentrations particularly during winter months, compared with feeding cows’ milk.¹⁰
The Committee on Nutrition of the German Society of Paediatrics recommended that Formula for Young Children, if used, should retain the positive properties of milk such as high contents of calcium and B vitamins.4 Recommended energy and nutrient contents⁴ per 100 mL are 45-55 kcal, ≤2.0 g protein, 1.5-2.5 g fat, ≤5 g carbohydrates (lactose is desirable while other mono- and disaccharides should be ≤20% of total carbohydrates), calcium ≈120 mg, iodine ≈25 µg, 30-100 µg retinol equivalent (RE) vitamin A, ≈180 µg vitamin B2, and contents of iron and vitamin D as found in FUF for infants.³ It was emphasized that aromas, sweeteners, and a sweet taste should be avoided as much as possible, and the feeding of such products from a cup rather than a bottle should be encouraged.

In conclusion, adequately composed Formula for Young Children can improve children’s nutrient supply and status, particularly in the case of suboptimal dietary habits, with particular benefits for the supply of omega-3 fatty acids, iron, iodine, vitamin D, protein, and saturated fats. Potential disadvantages include an often very sweet taste and high sugar content and a strong aromatisation, which may disturb desirable taste imprinting, and an often 3- to 4-fold higher price compared with cows’ milk.

Author’s address: Prof. Dr. Dr.h.c. Berthold Koletzko, Dr. von Hauner Children’s Hospital, Ludwig-Maximians-University of Munich Medical Center, Lindwurmstr. 4, D-80337 München, Germany.
office.koletzko@med.lmu.de

References

1. Codex-Alimentarius-Commission. Codex Standard for Follow-Up Formula. Codex Stan 156-1987. Rome, Italy: Codex Alimentarius Commission; 1987:1-9.
2. Proposal to review the Codex standard for follow-up formula (Codex Stan 156-1987). Presented at: 34th session of the Codex Committee on Nutrition and Foods for Special Dietary Uses; December 3-7, 2012; Bad Soden am Taunus, Germany.
3. Koletzko B, Bhutta ZA, Cai W, et al. Compositional requirements of follow-up formula for use in infancy: recommendations of an international expert group coordinated by the Early Nutrition Academy. Ann Nutr Metab. 2013;62(1):44-54.
4. Ernährungskommission-der-Deutschen-Gesellschaft-für-Kinder-und-Jugendmedizin-(DGKJ)-[Commitee-on-Nutrition -G-S-f-P-a-A-M, Böhles HJ, Fusch C, Genzel-Boroviczény O, Jochum F, Kauth T, et al. Zusammensetzung und Gebrauch von Milchgetränken für Kleinkinder [Composition and use of milk drinks for young children]. Monatsschr Kinderheilkd. 2011;159:981-984.
5. EFSA Panel on Dietetic Products, Nutrition and Allergies (NDA). Scientific opinion on nutrient requirements and dietary intakes of infants and young children in the European Union. EFSA J. 2013;11(10):3408.
6. Ghisolfi J, Bocquet A, Bresson JL, et al. [Processed baby foods for infants and young children: a dietary advance? A position paper by the Committee on Nutrition of the French Society of Paediatrics]. Arch Pediatr. 2013;20(5):523-532.
7. Hilbig A, Drossard C, Kersting M, Alexy U. Nutrient adequacy and associated factors in a nationwide sample of German toddlers. J Pediatr Gastroenterol Nutr. 2015 Jan 21 [Epub ahead of print].
8. World Health Organization, eds. Essential Nutrient Actions. Improving Maternal, Newborn, Infant and Young Child Health and Nutrition. Geneva: WHO; 2013.
9. Ghisolfi J, Fantino M, Turck D, de Courcy GP, Vidailhet M. Nutrient intakes of children aged 1-2 years as a function of milk consumption, cows’ milk or growing-up milk. Public Health Nutr. 2013;16(3):524-534.
10. Hower J, Knoll A, Ritzenthaler KL, Steiner C, Berwind R. Vitamin D fortification of growing up milk prevents decrease of serum 25-hydroxyvitamin D concentrations during winter: a clinical intervention study in Germany. Eur J Pediatr. 2013;172(12):1597-1605.
     

Long-Term Effects of Early Nutrition on Brain Development and Function – Berthold V. Koletzko, MD, PhD, Dr. h.c  

The human brain grows and develops very rapidly during the last part of pregnancy and the first 2 years after birth. At birth, the brain comprises as much as 13% of body weight. At the age of 2 years, brain weight has already reached ≈80% of its final adult weight, while body weight is still less than 20% of adult weight. Pre- and postnally, critical neural tissue differentiation occurs, including dendritic arborisation, synapse formation, and myelination. All these processes depend on the adequate provision of energy, protein, and other essential nutrients.^1-3

The energy requirement of the brain is very high: the brain alone consumes as much as 60% of the total energy supply during the first year of life. The major portion of energy is provided by glucose, with a glucose uptake of up to 150 g/day in the preschool age or ≈55%-60% of resting energy expenditure in neonates and ≈66% in toddlers.⁴ Malnutrition during the period of rapid brain growth in infancy and the second year of life was shown to have marked adverse effects on brain structure and function, with lasting deficits in cognitive performance. For example, Walker et al showed that chronic malnutrition with stunting during the first 2 years of life in Jamaican children reduced adult intelligence by as much as 1 SD, which is equivalent to 15 IQ points.⁵ A meta-analysis of studies on infants in industrialized countries showed that even only moderate growth faltering reduced later IQ by 4.2 points.⁶ Therefore, early malnutrition must be effectively treated and prevented to protect children from lasting deficits, and society from a significant loss of productivity and wealth creation. This is of particular importance in very-low-birth-weight infants (VLBWI) in whom observational and controlled intervention studies have documented very marked benefits of higher energy and protein intakes, and of enhanced growth rate, on functional and structural brain development up to adolescence.⁷

Breast-feeding has been associated with a small but consistent advantage for later IQ development, with a benefit of about 2 IQ points in a meta-analysis of studies in term infants that adjusted for major confounding factors, and a greater benefit in VLBWI.^7,8 However, there has been controversy over whether this benefit is caused by the nutrient supply with breast milk, such as the content of n-3 docosahexaenoic acid (DHA) and other long-chain polyunsaturated fatty acids (LC-PUFA), or by residual confounding linked to better socioeconomic status, education, and health-consciousness in families that chose breast-feeding. Recent gene–nutrient interaction studies demonstrated that breast-feeding providing LC-PUFA increases IQ at school age by more than 4 IQ points compared with children whose ability to synthesize LC-PUFA endogenously is lower due to their genotype.^9,10 These studies provide strong support for a causal effect of breast-feeding and of postnatal LC-PUFA supply on better later IQ development.

For more than 2 decades, the addition of usually about 0.2%-0.3% (of fatty acids) DHA along with at least as much n-6 arachidonic acid (ARA) to infant formulae has been used in an attempt to partly mimic the nutrient supply and functional effects achieved with breast-feeding. Recently, the European Food Safety Authority suggested that infant formula used from birth in term infants should contain 0.4%-1% DHA and no ARA, which is a novel approach that has not been systematically tested for its effects, suitability, and safety.¹¹ The provision of high amounts of n-3 LC-PUFA without a concomitant supply of ARA has been associated with adverse effects on growth in premature infants.¹² Concerns regarding the effects of a high supply of DHA without increasing ARA intakes to infants are raised by the findings of a randomized controlled trial assigning term infants to formula providing either no LC-PUFA, or different levels of DHA intakes of 0.32%, 0.64%, and 0.96% at the same ARA level of 0.64%.¹³ While positive effects in tests on word production, a card sorting task, and an intelligence test were observed with the 2 lower DHA doses, performance of children assigned to the highest DHA dose of 0.96% but with a reduced ratio of dietary ARA to DHA was attenuated. Thus, it is considered premature to accept the use of formula for infants from birth with the addition of 20-50 mg/100 kcal DHA to infant formula without added ARA in the absence of accountable data on the suitability and safety from a thorough clinical evaluation of this novel approach.¹¹ Based on a systematic literature review, a minimal supply of about 100 mg DHA/d and 140 mg ARA/d to infants during the first half year of life, and continued DHA supply thereafter has been recommended.¹⁴

Iron deficiency not only induces anaemia and potentially reduced oxygen supply to tissues, but also alters neuro-metabolism in the hippocampus and striatum as well as the formation of myelin proteins and compaction.¹⁵ Iron deficiency in infancy predicts poor school achievements in adolescence, disturbed motor and affective outcomes, and reduced cognitive performance in adulthood. Iodine deficiency during pregnancy and the first years of life has marked adverse effects on brain development induced by low thyroxine production. Iodine deficiency is considered the most common preventable cause of early childhood mental deficiency by the World Health Organisation. Even mild iodine deficiency has marked adverse effects. Therefore, iodine supplements (eg, 100-150 μg/d) are usually recommended to all pregnant and lactating women in populations at risk for suboptimal iodine supply.¹⁶ There are also indications for an important role of early B vitamin supply on brain development. Vitamin B12 deficiency in infants of vegan mothers was shown to induce severe brain atrophy, mental retardation, and convulsions, with a high risk of persistent brain damage. Perinatal folic acid supply has been demonstrated to provide marked risk reduction for the occurrence of neural tube defects and thus to protect neural development.¹⁷ Moreover, a recent analysis on >80,000 Norwegian children found that a good maternal folic acid supply during early pregnancy reduced the later risk for childhood autistic disorders by about 40%.¹⁸
 

Conclusions

Early development and long-term function of the brain are critically dependent on adequate nutrient supply during pregnancy and early childhood. Optimal nutrition during these critical stages of life must be supported, including

1. promotion, protection, and support of breast-feeding
2. an adequate supply of energy, macronutrients, and micronutrients to pregnant and breast-feeding women and their children, including
   a. iodine supplements (100-150 μg/d) to pregnant and breast-feeding women in populations at risk for suboptimal iodine intake,
   b. late cord clamping to improve neonatal iron stores,
   c. foods with bioavailable micronutrients such as iron, zinc, iodine, folic acid, and vitamin B12 to women, infants, and young children,
   d. >200 mg DHA/d to pregnant and breast-feeding women achieved by at least 2 weekly meals of ocean fish, or from supplements,
   e. a minimal supply of about 100 mg DHA/d and 140 mg ARA/d to infants during the first half year of life, and continued DHA supply thereafter.
    

Acknowledgements

Financially supported in part by the by the European Union’s Seventh Framework Programme (FP7/2007-2013), project NUTRIMENTHE under grant agreement FP7-212652 and project EarlyNutrition under grant agreement n°289346, and the European Research Council grant n° 322605. This abstract does not necessarily reflect the views of the Commission and in no way anticipates the future policy in this area.

Author’s address: Prof. Dr. Dr.h.c. Berthold Koletzko, Dr. von Hauner Children’s Hospital, Ludwig-Maximians-University of Munich Medical Center, Lindwurmstr. 4, D-80337 München, Germany.
office.koletzko@med.lmu.de
 

References

1. Berti C, Biesalski HK, Gartner R, et al. Micronutrients in pregnancy: current knowledge and unresolved questions. Clin Nutr. 2011;30(6):689-701.
2. Hermoso M, Vollhardt C, Bergmann K, Koletzko B. Critical micronutrients in pregnancy, lactation, and infancy: considerations on vitamin D, folic acid, and iron, and priorities for future research. Ann Nutr Metab. 2011;59(1):5-9.
3. Koletzko B, Bhatia J, Bhutta Z, et al, eds. Pediatric Nutrition in Practice. 2nd rev ed. Basel, Switzerland: Karger; 2015.
4. Kuzawa CW, Chugani HT, Grossman LI, et al. Metabolic costs and evolutionary implications of human brain development. Proc Natl Acad Sci U S A. 2014;111(36):13010-13015.
5. Walker SP, Chang SM, Powell CA, Simonoff E, Grantham-McGregor SM. Early childhood stunting is associated with poor psychological functioning in late adolescence and effects are reduced by psychosocial stimulation. J Nutr. 2007;137(11):2464-2469.
6. Corbett SS, Drewett RF. To what extent is failure to thrive in infancy associated with poorer cognitive development? A review and meta-analysis. J Child Psychol Psychiatry. 2004;45(3):641-654.
7. Koletzko B, Poindexter B, Uauy R, eds. Nutritional Care of Preterm Infants. Basel, Switzerland: Karger; 2014.
8. Horta BL, Victora CG. Long-term effects of breastfeeding. A systematic review. Geneva, Switzerland: World Health Organization; 2013.
9. Glaser C, Lattka E, Rzehak P, Steer C, Koletzko B. Genetic variation in polyunsaturated fatty acid metabolism and its potential relevance for human development and health. Matern Child Nutr. 2011;7(suppl 2):27-40.
10. Steer CD, Lattka E, Koletzko B, Golding J, Hibbeln JR. Maternal fatty acids in pregnancy, FADS polymorphisms, and child intelligence quotient at 8 y of age. Am J Clin Nutr. 2013;98(6):1575-1582. 
11. Koletzko B, Carlson SE, van Goudoever JB. Should infant formula provide both omega-3 DHA and omega-6 arachidonic acid? Ann Nutr Metab. 2015;66(2-3):137-138.
12. Carlson SE, Cooke RJ, Werkman SH, Tolley EA. First year growth of preterm infants fed standard compared to marine oil n-3 supplemented formula. Lipids. 1992;27(11):901-907.
13. Colombo J, Carlson SE, Cheatham CL, et al. Long-term effects of LCPUFA supplementation on childhood cognitive outcomes. Am J Clin Nutr. 2013;98(2):403-412.
14. Koletzko B, Boey CCM, Campoy C, et al. Current information and Asian perspectives on long-chain polyunsaturated fatty acids in pregnancy, lactation and infancy. Systematic review and practice recommendations from an Early Nutrition Academy workshop. Ann Nutr Metab. 2014;65(1):i49-i80.
15. Hermoso M, Vucic V, Vollhardt C, et al. The effect of iron on cognitive development and function in infants, children and adolescents: a systematic review. Ann Nutr Metab. 2011;59(2-4):154-165.
16. Koletzko B, Bauer CP, Bung P, et al. German national consensus recommendations on nutrition and lifestyle in pregnancy by the ‘Healthy Start - Young Family Network’. Ann Nutr Metab. 2013;63(4):311-322.
17. De-Regil LM, Fernandez-Gaxiola AC, Dowswell T, Pena-Rosas JP. Effects and safety of periconceptional folate supplementation for preventing birth defects. Cochrane Database Syst Rev. 2010;(10):CD007950.
18. Suren P, Roth C, Bresnahan M, et al. Association between maternal use of folic acid supplements and risk of autism spectrum disorders in children. JAMA. 2013;309(6):570-577.

Virgilio P. Carnielli, MD, PhD  

Lipids serve as the primary source of energy for the young infant. Calories derived from fat represent about 50% of the caloric intake in infancy as opposed to much lower percentages in adulthood. Much of the fat content is provided in short-, medium-, and long-chain fatty acids contained in breast milk and infant formulas. In this presentation the characteristics of fatty acids and triglycerides consumed in infancy will be discussed and several studies will be reviewed that examine the correlation between the intake of specific fatty acids and various developmental outcomes. Significant attention will be dedicated to a discussion of specific fatty acids and triglycerides, including docosahexaenoic acid (DHA) and various triacylglycerols. The importance of palmitate and its proper positioning within triacylglycerols will also be discussed. Newly designed formulas and their attempts to maximize the composition and presentation of various fatty acids will also be explained. The presentation will stress the importance of a variety of fatty acids in the diet of the developing infant.
 

Magnus Domellöf, MD, PhD  

The human brain undergoes explosive growth during early life, reaching 85% of its adult size by year 3. As such, deficiency of key substrates necessary for the development of the central nervous system can have a detrimental effect on development. In this presentation, Prof. Domellöf will focus on several interventions that help to assure the provision of important building blocks for brain development. Specifically, this lecture will concentrate on the role played by iron supplementation, delayed cord clamping, and key proteins contained within the human milk fat globular membrane. The literature studying the effects of these interventions on childhood development will be reviewed and groups of children at increased risk will be identified. The participant should gain an increased understanding of the role played by each of these treatments on the healthy development of the infant and young child.
 

Glenn R. Gibson, PhD  

The gut is the most metabolically active organ in the human body. The gastrointestinal tract is a complex environment that is home to a wide variety of bacteria that coexist in a symbiotic relationship. In this presentation, the components of the colonic ecosystem will be described and their intertwined relationships will be highlighted. The importance of bacterial diversity will be emphasized while describing the influence of the microbiome not only on digestion but also on disorder.
The presentation will also focus on prebiotics—what they are, how they are produced, and their role in overall health of infants, children, and adults. Examples of individual prebiotics will be presented, with a review of their unique characteristics, advantages, and disadvantages. Finally, a look toward producing “designer” prebiotics and the role that prebiotics may play in the future will be discussed.
 

Hania Szajewska, MD  

Human breast milk contains unique components that promote the healthy growth and development of the young infant. This presentation will explore one of these components in detail and describe how our improved understanding has been applied to the design of modern infant formulas. Discussion will be devoted to human milk oligosaccharides (HMOs): what they are, how prevalent they are in human milk, and the mechanisms by which they protect the young infant. Prof. Szajewska will then explain how our understanding of HMOs lead to the inclusion of various prebiotics in infant formulas and will review existing evidence that shows the additional health outcomes associated with their addition. The effects of prebiotics on outcomes such as the frequency of a variety of common pediatric infections, the prevention of allergy, and the prevention of atopic dermatitis will be discussed. The participant should have an augmented understanding of the importance of oligosaccharides in human health.